[{"CaseStudyId":"1855","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Each year, in England alone, approximately 152,000 people suffer a\u000d\u000a      stroke. In the UK, 1 in 5\u000d\u000a      strokes are fatal. The annual costs of stroke in the UK are estimated to\u000d\u000a      be between £3.7 billion and\u000d\u000a      £8 billion and the majority of this cost is rehabilitation and supporting\u000d\u000a      activities of daily living (e.g.\u000d\u000a      bathing, dressing and feeding) after stroke.\u000d\u000a    When stroke occurs, initial management is critical for the outcome of the\u000d\u000a      disease. Hypertension is\u000d\u000a      associated with poor short-term and long-term outcomes (see for example\u000d\u000a      Annals Neurol 1998\u000d\u000a      24:258-263 or J Internal Med 2001 249:467-473). Hypertension is\u000d\u000a      common after acute stroke, and\u000d\u000a      is also a major risk factor for stroke. However, best practice for\u000d\u000a      management of blood pressure in\u000d\u000a      acute stroke has been uncertain because of a scarcity of data from which\u000d\u000a      to draw evidence. This is\u000d\u000a      a serious concern. The research described in this case study has been used\u000d\u000a      to inform international\u000d\u000a      guidelines on the management of hypertension following stroke, promoting\u000d\u000a      better patient care with\u000d\u000a      the goal of improving outcomes from stroke.\u000d\u000a    The American Heart Association used the research outcomes from the CHHIPS\u000d\u000a      and COSSACS\u000d\u000a      studies to inform the 2013 `Guidelines for the Early Management of\u000d\u000a        Patients With Acute\u000d\u000a        Ischemic Stroke: A Guideline for Healthcare Professionals'.\u000d\u000a      (corroborating source A)\u000d\u000a    Both the CHHIPS study (their reference 411) and the COSSACS study (their\u000d\u000a      ref 433) are cited in\u000d\u000a      the text as supporting evidence for the following recommendations in the\u000d\u000a      guidelines which\u000d\u000a      acknowledge the important contribution these trials have made to this\u000d\u000a      controversial field.\u000d\u000a    Recommendation 2 (p892) states:\u000d\u000a    \"Patients who have elevated blood pressure and are otherwise eligible\u000d\u000a        for treatment with\u000d\u000a        intravenous rtPA should have their blood pressure carefully lowered\u000d\u000a        (Table 9) so that their\u000d\u000a        systolic blood pressure is <185 mm Hg and their diastolic blood\u000d\u000a        pressure is <110 mm Hg\u000d\u000a        (Class I; Level of Evidence B) before fibrinolytic therapy is initiated.\u000d\u000a        If medications are given\u000d\u000a        to lower blood pressure, the clinician should be sure that the blood\u000d\u000a        pressure is stabilized at\u000d\u000a        the lower level before beginning treatment with intravenous rtPA and\u000d\u000a        maintained below\u000d\u000a        180\/105 mm Hg for at least the first 24 hours after intravenous rtPA\u000d\u000a        treatment.\"\u000d\u000a    Specific reference to the COSSACS study is made in recommendation 10\u000d\u000a      (p893) which states:\u000d\u000a    \"Evidence from one clinical trial indicates that initiation of\u000d\u000a        antihypertensive therapy within 24\u000d\u000a        hours of stroke is relatively safe. Restarting antihypertensive\u000d\u000a        medications is reasonable\u000d\u000a        after the first 24 hours for patients who have pre-existing hypertension\u000d\u000a        and are\u000d\u000a        neurologically stable unless a specific contraindication to restarting\u000d\u000a        treatment is known\u000d\u000a        (Class IIa; Level of Evidence B).\"\u000d\u000a    The 2013 `Guidelines for the management of arterial hypertension'\u000d\u000a      from the European Society\u000d\u000a      of Hypertension and of the European Society of Cardiology (corroborating\u000d\u000a      source B) state that\u000d\u000a      blood pressure management during the acute phase of stroke is a matter of\u000d\u000a      continuing concern,\u000d\u000a      and that this is a difficult area. The CHHIPS study is used as evidence of\u000d\u000a      a beneficial impact of\u000d\u000a      administering lisinopril in patients with acute stroke and a systolic\u000d\u000a      blood pressure>160 mmHg.\u000d\u000a    The 2012 Royal College of Physicians `National Clinical Guidelines for\u000d\u000a        Stroke' (corroborating\u000d\u000a      source C) advise that parenteral drugs for control of blood pressure\u000d\u000a      should at present only be used\u000d\u000a      as part of a clinical trial (apart from certain conditions relating to\u000d\u000a      patients with very high blood\u000d\u000a      pressure or in preparation for thrombolysis) and highlight the need for\u000d\u000a      further research in blood\u000d\u000a      pressure management in acute stroke, with reference to the CHHIPS study.\u000d\u000a    As an additional approach to ensuring impact from the research, Potter\u000d\u000a      has contributed to the\u000d\u000a      preparation of clinical guidelines. For example, the 2008 guidelines from\u000d\u000a      the Royal College of\u000d\u000a      Physicians National Collaborating Centre for Chronic Conditions `Stroke:\u000d\u000a        national clinical\u000d\u000a        guideline for diagnosis and initial management of acute stroke and\u000d\u000a        transient ischaemic\u000d\u000a        attack (TIA)'.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Two multicentre clinical trials conducted by Professor Potter have\u000d\u000a      contributed to revised\u000d\u000a      international guidelines for the management of hypertension following\u000d\u000a      acute stroke, the single\u000d\u000a      largest cause of adult disability worldwide. Before these trials, there\u000d\u000a      was little evidence on the\u000d\u000a      effects of using antihypertensive drugs immediately after stroke and there\u000d\u000a      was concern that use of\u000d\u000a      these drugs could extend the stroke. The trials found no serious adverse\u000d\u000a      effects of using\u000d\u000a      antihypertensive drugs immediately after stroke whilst mortality after 3\u000d\u000a      months was halved. The\u000d\u000a      American Heart Association, the European Societies of Hypertension and of\u000d\u000a      Cardiology, and the\u000d\u000a      Royal College of Physicians all reference these trials in support of their\u000d\u000a      recent Guidelines, thereby\u000d\u000a      promoting better patient care and improved outcomes.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of East Anglia\u000d\u000a    ","Institutions":[{"AlternativeName":"East Anglia (University of)","InstitutionName":"University of East Anglia","PeerGroup":"B","Region":"East","UKPRN":10007789}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    (UEA authors in bold)\u000d\u000a    \u000a1. Potter JF, Mistri A, Brodie F, Chernova J, Wilson E,\u000d\u000a      Jagger C, James M, Ford G, Robinson T\u000d\u000a      Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS)\u000d\u000a      - a randomised\u000d\u000a      controlled trial\u000d\u000a      Health Technology Assessment 2009 13:article no.9\u000d\u000a      doi: 10.3310\/hta13090\u000d\u000a    \u000a\u000a2. Potter JF, Robinson TG, Ford GA, Mistri A, James M, Chernova\u000d\u000a      J, Jagger C\u000d\u000a      Controlling hypertension and hypotension immediately post-stroke (CHHIPS):\u000d\u000a      a randomised,\u000d\u000a      placebo-controlled, double-blind pilot trial\u000d\u000a      Lancet Neurology 2009 8:48-56\u000d\u000a      doi: 10.1016\/S1474-4422(08)70263-1\u000d\u000a    \u000a\u000a3. Wilson EC, Ford GA, Robinson T, Mistri A, Jagger C, Potter\u000d\u000a        JF\u000d\u000a      Controlling hypertension immediately post stroke: a cost utility analysis\u000d\u000a      of a pilot randomised\u000d\u000a      controlled trial.\u000d\u000a      Cost effectiveness and resource allocation 2010 8:article\u000d\u000a      no.3\u000d\u000a      doi: 10.1186\/1478-7547-8-3\u000d\u000a    \u000a\u000a4. Robinson TG, Potter JF, Ford G, Bulpitt C, Chernova J, Jagger\u000d\u000a      C, James M, Knight J, Markus\u000d\u000a      H, Mistri AK, Poulter NR\u000d\u000a      Effects of antihypertensive treatment after acute stroke in the Continue\u000d\u000a      Or Stop post-Stroke\u000d\u000a      Antihypertensives Collaborative Study (COSSACS): a prospective,\u000d\u000a      randomised, open, blinded-\u000d\u000a      endpoint trial.\u000d\u000a      Lancet Neurology 2010 9:767-75\u000d\u000a      doi: 10.1016\/S1474-4422(10)70163-0\u000d\u000a    \u000aGrant support:\u000d\u000a    COSSACS: This study was funded with grants from The Health\u000d\u000a      Foundation 2003-2009 (£310,000)\u000d\u000a      and The Stroke Association. Professor Potter developed the trial, sought\u000d\u000a      and obtained funding,\u000d\u000a      reviewed the analysis and revised the manuscript.\u000d\u000a    CHHIPS: The trial was funded with a grant from the UK National\u000d\u000a      Health Service Research and\u000d\u000a      Development Health Technology Assessment Programme 2004-2008 (£1.1M).\u000d\u000a      Professor Potter\u000d\u000a      was the principal investigator, developed the trial, sought and obtained\u000d\u000a      funding and was\u000d\u000a      responsible for the overall running, analysis and writing-up.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    A. Guidelines for the Early Management of Patients With Acute\u000d\u000a        Ischemic Stroke : A\u000d\u000a        Guideline for Healthcare Professionals\u000d\u000a      The American Heart Association\/American Stroke Association\u000d\u000a      Stroke 2013 44:870-947\u000d\u000a        doi: 10.1161\/STR.0b013e318284056a\u000d\u000a        References to UEA research: pp.890 & p.891 (their reference 411) and\u000d\u000a        p.890 (their reference\u000d\u000a        433)\u000d\u000a        B. Guidelines for the management of arterial hypertension\u000d\u000a        The European Society of Hypertension and The European Society of\u000d\u000a        Cardiology\u000d\u000a        Eur Heart J 2013 34:2159-2219\u000d\u000a        doi: 10.1093\/eurheartj\/eht151\u000d\u000a        Reference to the CHHIPS study is made on p42\u000d\u000a      C. National clinical guideline for stroke\u000d\u000a        Royal College of Physicians: Intercollegiate Stroke Working Party\u000d\u000a        London, 2012\u000d\u000a        www.rcplondon.ac.uk\/sites\/default\/files\/national-clinical-guidelines-for-stroke-fourth-edition.pdf Reference to UEA research: p54 - the CHHIPs study is cited as a\u000d\u000a        source reference for\u000d\u000a        recommendations I and J\u000d\u000a      ","Title":"\u000d\u000a    Influencing guidelines on management of hypertension following acute\u000d\u000a        stroke\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Blood pressure abnormalities are common after acute stroke, and both\u000d\u000a      hypertension and marked\u000d\u000a      hypotension (high and low blood pressure) are associated with poor\u000d\u000a      outcome. Stroke patients often\u000d\u000a      have pre-existing hypertension (which is the most important risk factor\u000d\u000a      for stroke, contributing to\u000d\u000a      more than 50% of all strokes) which may or may not have been treated\u000d\u000a      before the stroke. In these\u000d\u000a      cases, there has been uncertainty as to whether usual antihypertensive\u000d\u000a      treatments should be\u000d\u000a      continued in the period immediately following the stroke. When stroke\u000d\u000a      occurs, initial management\u000d\u000a      is critical for the outcome of the disease as hypertension is associated\u000d\u000a      with poor short-term and\u000d\u000a      long-term outcomes. However, best practice for management of blood\u000d\u000a      pressure in acute stroke has\u000d\u000a      been uncertain because of a scarcity of data from which to draw evidence.\u000d\u000a      Before our studies there\u000d\u000a      was concern that continuing antihypertensive therapy would lower blood\u000d\u000a      pressure and extend the\u000d\u000a      stroke. Our studies have shown that antihypertensive therapy is not\u000d\u000a      deleterious. Indeed the\u000d\u000a      contrary is true as lowering blood pressure halves the 3-month mortality.\u000d\u000a    Our research has involved two large, UK, multi-centre trials to\u000d\u000a      investigate management of blood\u000d\u000a      pressure following acute stroke:\u000d\u000a    The CHHIPS (Controlling Hypertension and Hypotension Immediately\u000d\u000a        Post-Stroke) trial assessed the feasibility, safety and effects of two antihypertensive\u000d\u000a      drugs (labetalol and lisinopril) to\u000d\u000a      lower blood pressure. CHHIPS was a randomised,\u000d\u000a      placebo-controlled, double-blind trial. Patients\u000d\u000a      were recruited at six centres in the UK from January 2005 to December\u000d\u000a      2007. Stroke patients\u000d\u000a      (symptom onset within 36hr and systolic blood pressure above 160mmHg) were\u000d\u000a      randomly\u000d\u000a      assigned to receive either treatment or a matched placebo. In 179\u000d\u000a      patients, the primary outcome -\u000d\u000a      death or dependency at 2 weeks - showed no difference between the active\u000d\u000a      treatment and placebo\u000d\u000a      groups. In addition, no neurological deterioration or serious adverse\u000d\u000a      effects were found with active\u000d\u000a      treatment, despite a significantly greater fall in systolic blood pressure\u000d\u000a      within the first 24hr,\u000d\u000a      compared to the placebo group. A striking result was that the 3-month\u000d\u000a      mortality was halved in\u000d\u000a      patients taking antihypertensives compared to the placebo group.\u000d\u000a      The conclusion was that labetalol and lisinopril are effective\u000d\u000a      antihypertensive drugs for acute stroke\u000d\u000a      that do not increase serious adverse effects (research references 1 &\u000d\u000a      2). A cost utility study\u000d\u000a      performed at UEA by Dr Wilson and colleagues from the Health Economics\u000d\u000a      unit at the Norwich\u000d\u000a      Medical School and Professor Potter demonstrated that antihypertensive\u000d\u000a      therapy in hypertensive\u000d\u000a      patients immediately post stoke is both effective and cost-effective\u000d\u000a      compared to placebo at 3\u000d\u000a      months after the stroke (research reference 3).\u000d\u000a    The COSSACS (Continue Or Stop post-Stroke Antihypertensives\u000d\u000a        Collaborative Study) trial assessed efficacy and safety of continuing or stopping pre-existing\u000d\u000a      treatment with antihypertensive\u000d\u000a      drugs in patients who had recently had a stroke. COSSACS was a\u000d\u000a      single-blind randomised\u000d\u000a      controlled trial. Patients were recruited at 49 UK NIHR Stroke Research\u000d\u000a      Network centres from\u000d\u000a      January 2003 to March 2009. 763 stroke patients (symptom onset within\u000d\u000a      48hr), who were currently\u000d\u000a      taking antihypertensive drugs were randomly assigned to continue or stop\u000d\u000a      the pre-existing\u000d\u000a      treatment for a 2-week period. Clinicians, blinded to the group to which\u000d\u000a      each patient belonged,\u000d\u000a      assessed outcomes after two weeks and six weeks. No substantial\u000d\u000a      differences were observed\u000d\u000a      between the two groups in adverse events, 6-month mortality or major\u000d\u000a      cardiovascular events. In\u000d\u000a      addition, lower blood pressure levels in those who continued\u000d\u000a      antihypertensive treatment were not\u000d\u000a      associated with an increase in adverse effects. As hypertension is the\u000d\u000a      major treatable risk factor for\u000d\u000a      future stroke, continuation of antihypertensive in the immediate stroke\u000d\u000a      period is safe and likely to\u000d\u000a      improve long-term outcomes.\u000d\u000a    The conclusion was that there is no obvious harm associated with\u000d\u000a      continuing pre-existing\u000d\u000a      antihypertensive drugs for a 2-week period following acute stroke\u000d\u000a      (research reference 4).\u000d\u000a    UEA researchers:\u000d\u000a    John Potter: Professor Potter was the principal investigator,\u000d\u000a      developed the trials, sought and\u000d\u000a      obtained funding and was responsible for the overall running, analysis and\u000d\u000a      writing of all\u000d\u000a      manuscripts. The studies were initiated at the University of Leicester and\u000d\u000a      continued at UEA since\u000d\u000a      2006. Since joining UEA, Professor Potter maintained a lead involvement in\u000d\u000a      the studies. Significant\u000d\u000a      patient recruitment and data collection continued, and analyses and\u000d\u000a      dissemination was undertaken\u000d\u000a      while at UEA.\u000d\u000a    Edward Wilson: Lecturer in Health Economics at UEA 2003-2013.\u000d\u000a    "},{"CaseStudyId":"1856","Continent":[],"Country":[],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Our new Tandem MS technology for simultaneous measurement of both 25OHD2\u000d\u000a      and 25OHD3 has had both clinical and economic impacts.\u000d\u000a    Impact on Patient Care: For the wider population the common\u000d\u000a      Vitamin D supplements provide Vitamin D2 whereas the common\u000d\u000a      (immunoassay) techniques for measuring Vitamin D levels are unable to\u000d\u000a      recognise this form, frequently resulting in significant underestimation\u000d\u000a      of total Vitamin D levels. The ability to detect both 25OHD2\u000d\u000a      and 25OHD3 simultaneously therefore has two major patient\u000d\u000a      benefits: the avoidance of over-supplementation — with the associated risk\u000d\u000a      of toxicity; and the unnecessary investigation of possible causes of\u000d\u000a      non-parathyroid related hypercalcaemia.\u000d\u000a    The 2013 National Osteoporosis Society guidelines `Vitamin D and Bone\u000d\u000a        Health. A Practical Clinical Guideline For Patient Management'\u000d\u000a      recommend that 25OHD should be measured by a method able to clearly\u000d\u000a      distinguish 25OHD2 and D3. Authorities involved in\u000d\u000a      Vitamin D research now recognise the problems arising from the lack of\u000d\u000a      specificity inherent in immunoassays and therefore recommend the use of\u000d\u000a      Tandem MS technology. (corroborating source A)\u000d\u000a    Impact on National Quality Assessment Methodologies: The\u000d\u000a      importance of the Tandem MS measurement technology has been recognised by\u000d\u000a      laboratories accredited to analyse samples for Vitamin D resulting in\u000d\u000a      significant expansion of use of this technology in NHS laboratories and\u000d\u000a      research establishments. This is clearly apparent from the regular reports\u000d\u000a      of the Vitamin D External Quality Assessment Scheme (DEQAS). The DEQAS\u000d\u000a      reports over a 10 year period highlight the increasing use of Tandem MS\u000d\u000a      technology by participants. For example, there were no users of Tandem MS\u000d\u000a      technology in 2004 and, following our development of the new assay, Tandem\u000d\u000a      MS usage rose to 12.8% of users in 2013. (corroborating source B)\u000d\u000a    Impact on Army Recruits via MOD Training Programmes: Based\u000d\u000a      on the underpinning research reported in references 1, 2 and 3 in section\u000d\u000a      3, Fraser wrote confidential reports for the MOD which led to three\u000d\u000a      collaborative programmes of work between the Army Recruitment and Training\u000d\u000a      Directorate and UEA. As a result, the MOD recognised that a high\u000d\u000a      percentage of recruits have significant Vitamin D deficiency and that\u000d\u000a      female recruits have a particular problem leading to high bone turnover\u000d\u000a      and predisposition to injury, especially post-partum.\u000d\u000a    This has resulted in:\u000d\u000a    \u000d\u000a      a review of the nutritional recommendations for all recruits in\u000d\u000a        training\u000d\u000a      a revised medical policy to protect postpartum service personnel in a\u000d\u000a        medically downgraded capacity for 12 months postpartum\u000d\u000a      an alteration in the training programme for female recruits — who are\u000d\u000a        now trained separately to male recruits.\u000d\u000a    \u000d\u000a    (corroborating source C)\u000d\u000a    These changes were based on the following findings from the collaborative\u000d\u000a      work:\u000d\u000a    a) Vitamin D and bone health: We have confirmed an association\u000d\u000a      between Vitamin D deficiency and impaired bone health in female Army\u000d\u000a      recruits, and a high incidence of Vitamin D deficiency in both men and\u000d\u000a      women entering \/ exiting training.\u000d\u000a    b) Pregnancy and postpartum: The postpartum period is recognised\u000d\u000a      to be a vulnerable time for female military personnel on return to\u000d\u000a      physically demanding roles with an increased risk of musculoskeletal\u000d\u000a      injury. Our work has shown increased bone turnover in a representative\u000d\u000a      population of women over a 6-month period.\u000d\u000a    c) Gender differences in bone density and morphology: It is\u000d\u000a      generally known that women are more likely to sustain a stress fracture\u000d\u000a      injury during training than men. Our collaborative work has shown that\u000d\u000a      this is due to differences in bone morphology between male and female\u000d\u000a      recruits. These findings have also provided evidence for individual\u000d\u000a      consideration of female-to-male transgender cases.\u000d\u000a    Impact on the NHS Economy: The Tandem MS technology has had\u000d\u000a      significant economic impact on the NHS. For example, the Norfolk and\u000d\u000a      Norwich University Hospital is an early adopter of this new assay where it\u000d\u000a      is now the routine method for measurement of 25OHD. The cost per sample\u000d\u000a      for a Tandem MS analysis is currently £12.50 compared to the cost of\u000d\u000a      analysis by immunoassay (the previous method of choice) which is £18.50.\u000d\u000a      The NNUH `hub' currently requests analysis of 3800 samples per annum\u000d\u000a      resulting in a cost saving of £125,000 in this region alone.\u000d\u000a      (corroborating source D)\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Use of our new Tandem Mass Spectrometry (MS) technology for measuring 25\u000d\u000a      Hydroxy Vitamin D (25OHD) has had both major clinical and economic impacts\u000d\u000a      on:\u000d\u000a    \u000d\u000a      patient care via the National Osteoporosis Society Guideline (April\u000d\u000a        2013) `Vitamin D and Bone Health — A Practical Clinical Guideline for\u000d\u000a          Patient Management'\u000d\u000a      accredited laboratory assay methodologies where reports from the\u000d\u000a        Vitamin D External Quality Assessment Scheme show increasing use of\u000d\u000a        Tandem MS in recognition of the need to accurately measure both 25OHD2\u000d\u000a        and D3\u000a\u000d\u000a      army recruits through the amended Ministry of Defence training policy\u000d\u000a        which now incorporates an approach to injury\/stress fracture prevention\u000d\u000a        and improvements in Vitamin D status\u000d\u000a      the NHS through uptake of the Tandem MS 25OHD assay.\u000d\u000a    \u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of East Anglia\u000d\u000a    ","Institutions":[{"AlternativeName":"East Anglia (University of)","InstitutionName":"University of East Anglia","PeerGroup":"B","Region":"East","UKPRN":10007789}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    (UEA authors in bold)\u000d\u000a    \u000a1) Fraser WD, Milan AM\u000d\u000a      Vitamin D assays: past and present debates, difficulties, and developments\u000d\u000a      Calcif Tissue Int. 2013 92:118-27\u000d\u000a      doi: 10.1007\/s00223-012-9693-3\u000d\u000a    \u000aSignificance: Quoted in the National Osteoporosis Society\u000d\u000a      Practical Guideline on Vitamin D for UK physicians. The basis for the\u000d\u000a      analytical recommendations in the guideline.\u000d\u000a    \u000a2) Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH\u000d\u000a      Association of maternal Vitamin D status during pregnancy with\u000d\u000a      bone-mineral content in offspring: a prospective cohort study\u000d\u000a      Lancet 2013 381:2176-83\u000d\u000a      doi: 10.1016\/S0140-6736(12)62203-X\u000d\u000a    \u000aSignificance: Editorial Comment on Vitamin D supplementation of\u000d\u000a      pregnant women in the UK.\u000d\u000a    \u000a3) MacDonald HM, Wood AD, Tang JC, Fraser WD\u000d\u000a      Comparison of Vitamin D2 and Vitamin D3\u000d\u000a      supplementation in increasing serum 25-hydroxyvitamin D status: a\u000d\u000a      systematic review and meta-analysis\u000d\u000a      American Journal of Clinical Nutrition 2012 96:1152-3\u000d\u000a      (author reply 1153-4)\u000d\u000a      doi: 10.3945\/ajcn.112.046110\u000d\u000a    \u000aSignificance: Discussion of the importance of using Vitamin D3\u000d\u000a      supplementation in preference to Vitamin D2 in deficient\u000d\u000a      patients.\u000d\u000a    Key grants supporting this research:\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          MRC Avon Longitudinal Study of Parents and Children\u000d\u000a            (ALSPAC) (2008-12)\u000d\u000a            Lawlor DA, Davey Smith G, Evans DMF,\u000d\u000a              Fraser WD, Guthrie\u000d\u000a            P, Hypponen ET\u000d\u000a          £1,280,874\u000d\u000a        \u000d\u000a        \u000d\u000a          MRC (2008-13)\u000d\u000a            Fraser WD, Selby P, Langston\u000d\u000a            A, Ralston S\u000d\u000a          £663,429\u000d\u000a        \u000d\u000a        \u000d\u000a          Arthritis Research UK (2009-14)\u000d\u000a            Ralston S, Langston A, Campbell M, Fraser\u000a              WD\u000a\u000d\u000a          £483,127\u000d\u000a        \u000d\u000a        \u000d\u000a          Arthritis Research UK (2010-13)\u000d\u000a            Hauser B, Riches P, Fraser WD,\u000d\u000a            Ralston S\u000d\u000a          £211,899\u000d\u000a        \u000d\u000a        \u000d\u000a          MRC Population and Systems Medicine Board (2011-14)\u000d\u000a            Parekh D, Dancer RC, Lax S, Cooper MS, Martineau AR, Fraser\u000a              WD, Tucker O, Alderson D, Perkins GD, Gao-Smith F, Thickett\u000d\u000a            DR\u000d\u000a          £489,444\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    A. Vitamin D and Bone Health. A Practical Clinical Guideline For\u000d\u000a        Patient Management (2013) National Osteoporosis Society http:\/\/www.nos.org.uk\/document.doc?id=1352\u000d\u000a    The guideline is endorsed by the Bone Research Society, British\u000d\u000a      Geriatrics Society, British Orthopaedic Association, International\u000d\u000a      Osteoporosis Foundation, Primary Care Rheumatology Society, Royal College\u000d\u000a      of Nursing, Royal Pharmaceutical Society, Society for Endocrinology,\u000d\u000a      British Dietetic Association, UK Clinical Pharmacy Association and the\u000d\u000a      Paget's Association.\u000d\u000a    Specific references to UEA work are on pages 9, 10, 22, 24.\u000d\u000a    The guideline states (page 11):\u000d\u000a      Notwithstanding the various technical aspects of measuring Vitamin D,\u000d\u000a        there are a few simple considerations that need to be applied from a\u000d\u000a        clinical perspective:\u000d\u000a    \u000d\u000a      \u000d\u000a        Measurement of serum 25OHD is the best way of estimating Vitamin D\u000d\u000a          status.\u000d\u000a      \u000d\u000a      The assay used should have the ability to recognise all forms of\u000d\u000a          25OHD (D2 or D3) equally. In practice, this means that it should use\u000d\u000a          either HPLC or, more likely, tandem MS. None of the immunoassays offer\u000d\u000a          the ability to recognise all forms of 25OHD.\u000d\u000a    \u000d\u000a    (copy held on file at UEA)\u000d\u000a    B. Vitamin D External Quality Assessment Service (DEQAS)\u000d\u000a      comparison data between 2004 and 2013:\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Date\u000d\u000a          Sample\u000d\u000a          N\u000d\u000a          LC-MS\u000d\u000a          LC-MS\u000a              percentag\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2004\u000d\u000a          251\u000d\u000a          97\u000d\u000a          0\u000d\u000a          0.00%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2005\u000d\u000a          271\u000d\u000a          141\u000d\u000a          2\u000d\u000a          1.42%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2006\u000d\u000a          291\u000d\u000a          161\u000d\u000a          9\u000d\u000a          5.59%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2007\u000d\u000a          311\u000d\u000a          229\u000d\u000a          20\u000d\u000a          8.73%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2008\u000d\u000a          331\u000d\u000a          339\u000d\u000a          35\u000d\u000a          10.32%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2009\u000d\u000a          351\u000d\u000a          565\u000d\u000a          53\u000d\u000a          9.38%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2010\u000d\u000a          371\u000d\u000a          774\u000d\u000a          86\u000d\u000a          11.11%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2011\u000d\u000a          391\u000d\u000a          986\u000d\u000a          104\u000d\u000a          10.55%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2012\u000d\u000a          411\u000d\u000a          1116\u000d\u000a          133\u000d\u000a          11.92%\u000d\u000a        \u000d\u000a        \u000d\u000a          Apr-2013\u000d\u000a          431\u000d\u000a          1102\u000d\u000a          141\u000d\u000a          12.79%\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    (data held on file at UEA)\u000d\u000a    C. Letter on behalf of the Ministry of Defence \/ Army Recruitment and\u000d\u000a        Training Directorate, which details the recommendations on army\u000d\u000a      training and dietary intake of Vitamin D for all new recruits.\u000d\u000a    (held on file at UEA)\u000d\u000a    D. NHS Vitamin D analysis sample figures: data provided by the\u000d\u000a      Norfolk and Norwich University Hospital and held on file at UEA.\u000d\u000a    ","Title":"\u000d\u000a    Accurate measurement of Vitamin D to develop guidelines for health\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Before our development of Tandem Mass Spectrometry, Vitamin D was\u000d\u000a      measured by a variety of immunoassays with poor standardisation that could\u000d\u000a      result in over or under estimation of Vitamin D levels leading to\u000d\u000a      erroneous diagnosis and incorrect treatment. This case study stems from a\u000d\u000a      body of research into the measurement of 25OHD2 and D3\u000d\u000a      using a High Performance Liquid Chromatography (HPLC) tandem Mass\u000d\u000a      Spectrometry (MS) methodology developed by Fraser and Dutton. This work\u000d\u000a      commenced in Liverpool leading to an early method for Tandem MS analysis\u000d\u000a      (see for example: Dutton, J and Fraser, WD The Technical and\u000d\u000a        Clinical benefits from Measuring 25 OH Vitamin D by LC-MS\/MS. Mass\u000d\u000a        Matters 2010 62:13-15) and continued with significant\u000d\u000a      scientific and technical developments to sample preparation and assay\u000d\u000a      technology following Fraser's move from Liverpool to UEA in April 2011.\u000d\u000a    The current technology allows measurement of both serum 25OHD2\u000d\u000a      and D3 with precision, accuracy and sensitivity, with\u000d\u000a      sufficient throughput to enable large-scale studies to be performed with\u000d\u000a      confidence. The major clinical advantage of the method is the ability to\u000d\u000a      estimate accurately both 25OHD2 and D3. All\u000d\u000a      immunoassays have poor Ab cross reactivity with D2 resulting in\u000d\u000a      underestimation of 25OHD2 and, depending on 250HD3\u000d\u000a      standardisation, total 250HD status. The specific detection of 25OHD2\u000d\u000a      also allows the detection of toxicity (hypercalcaemia) due to excessive\u000d\u000a      levels of 25OHD2 and hence the avoidance of unnecessary and\u000d\u000a      expensive patient investigation for malignancy as a cause of\u000d\u000a      hypercalcaemia.\u000d\u000a    The introduction at UEA of high-throughput extraction technology combined\u000d\u000a      with the excellent sensitivity of Tandem MS has allowed large numbers of\u000d\u000a      samples to be measured for several studies. This work has been underpinned\u000d\u000a      by grant income of £3.5M since 2005. The data obtained are unique as the\u000d\u000a      biochemical techniques developed allow measurement of Vitamin D\u000d\u000a      metabolites with a sensitivity, precision and accuracy not available to\u000d\u000a      the majority of researchers. This new technique has now superseded\u000d\u000a      immunoassays in many instances and has been used in a number of clinical\u000d\u000a      trials overturning the previously held consensus on Vitamin D therapy (1).\u000d\u000a    The studies performed at UEA to date, and where 25OHD2 has\u000d\u000a      significant association with, or effect on, disease, are extensive and\u000d\u000a      include prostate cancer, cardiovascular disease, respiratory disease\u000d\u000a      (COPD), diabetes, depression, dermatological conditions, problems of\u000d\u000a      pregnancy including eclampsia, non-clinical psychotic experiences,\u000d\u000a      behavioural problems, academic performance, cortical bone development and\u000d\u000a      increased stress fracture incidence. A notable recent clinical result\u000d\u000a      arising from the research at UEA is that there is no association between\u000d\u000a      maternal Vitamin D status in pregnancy and offspring bone-mineral content\u000d\u000a      in late childhood (2).\u000d\u000a    During 2011-2013, research at UEA established that 25OHD2\u000d\u000a      supplementation at currently recommended doses is not effective in\u000d\u000a      changing several clinical outcomes. This is having major scientific,\u000d\u000a      social and economic effects, resulting in new approaches to investigation\u000d\u000a      of Vitamin D effects and altering data interpretation. This research has\u000d\u000a      been quoted extensively and incorporated into several meta-analyses of the\u000d\u000a      role of 25OHD2 in disease, and in attempts to define the\u000d\u000a      optimal therapeutic thresholds for circulating 25OHD2 (3).\u000d\u000a    Associations of low circulating 25OHD2 with poorer outcomes in\u000d\u000a      disease has led to the funding of many important prospective randomised\u000d\u000a      studies investigating Vitamin D supplementation in treatment and\u000d\u000a      prevention of disease.\u000d\u000a    UEA researchers:\u000d\u000a    William Fraser: UEA Professor of Medicine since April 2011 and\u000d\u000a      Principal Investigator of the UEA research team.\u000d\u000a    Jonathan Tang: UEA Bio-analytical Facility Manager since April\u000d\u000a      2011.\u000d\u000a    There has been close collaboration in the clinical studies with\u000d\u000a      investigators from Bristol and Aberdeen.\u000d\u000a    "},{"CaseStudyId":"2582","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000d\u000a    \u000d\u000a      \u000aImpact on patients: An increasing number of\u000d\u000a        patients are waiting for a kidney transplant, and\u000d\u000a        those with HLA antibodies are waiting disproportionately longer and have\u000d\u000a        more health problems.\u000d\u000a        Our research on AIT has enabled the transplantation of more than 100 of\u000d\u000a        these immunologically\u000d\u000a        (most patients have multiple HLA antibodies) and physiologically complex\u000d\u000a        (patients may have\u000d\u000a        cardiovascular insufficiency and rigidity) cases since 2008 in Coventry\u000d\u000a        alone. Their complexity is\u000d\u000a        illustrated by an average time of renal failure of 14 years before we\u000d\u000a        transplanted them; 71% had\u000d\u000a        prior transplants, and 35% first developed renal failure as children.\u000d\u000a        The majority of these would\u000d\u000a        probably not have received a transplant without the use of the new tools\u000d\u000a        and techniques resulting\u000d\u000a        from our research7, c, d, e. Shared knowledge from our\u000d\u000a        research has resulted in the transplantation of\u000d\u000a        over 350 other similarly complex patients across the UK since 2008c,d,\u000d\u000a          and f. The Associate Medical\u000d\u000a        Director for Organ Donation at NHSBT has stated in supporting evidence,\u000d\u000a        `The impact of their\u000d\u000a        research has allowed greater access to transplantation for this group of\u000d\u000a        patients who have hitherto\u000d\u000a        been disadvantaged and the lessons learnt have been extrapolated into\u000d\u000a        other areas of solid organ\u000d\u000a        transplantation so leading to better outcomes in terms of quality and\u000d\u000a        length of life...'c.\u000d\u000a      \u000aImpact on the community: A long wait for transplantation\u000d\u000a        is not only a burden for the patient,\u000d\u000a        but also impacts on relationships, family and work, resulting in\u000d\u000a        emotional, social and financial\u000d\u000a        sufferingg. The benefits of successful transplantation of our\u000d\u000a        patients are illustrated by media\u000d\u000a        features (over 20 TV, radio, and national media features, see source f\u000d\u000a        for example).\u000d\u000a      \u000aImpact on health care professionals: The value of the\u000d\u000a        research for the day-to-day clinical\u000d\u000a        practice of the NHS is shown by the significant changes in clinical\u000d\u000a        protocol, which we1-4, and\u000d\u000a        others, have made since the 2003 protocol. This includes marked\u000d\u000a        reductions in the intensity of\u000d\u000a        immunosuppression in patients who do not develop rejection and this may\u000d\u000a        account for the UHCW\u000d\u000a        mortality rate being half that reported from the USA7, h. The\u000d\u000a        research work, with the involvement of\u000d\u000a        Higgins as chair of the guideline panel and Briggs, has led to the\u000d\u000a        publication of national clinical\u000d\u000a        guidelines for AIT by the British Transplantation Societyi.\u000d\u000a        These are the first such guidelines in the\u000d\u000a        world and are important for the provision of standardised, high-quality\u000d\u000a        care. UK Commissioners\u000d\u000a        expect transplant units to follow these guidelinesc. As a\u000d\u000a        result of our clinical research, UoW,\u000d\u000a        NHSBT together with UHCW, have helped other transplantation units\u000d\u000a        implement our AIT transplant\u000d\u000a        protocol and business model for obtaining funding through the NHS,\u000d\u000a        including DFPP and\u000d\u000a        cryofiltrationi. Specialist NHS Renal Centres that have\u000d\u000a        benefited directly from our research in this\u000d\u000a        way include Guy's, St Georges, Oxford, Cambridge, Cardiff, Bristol,\u000d\u000a        Leeds, Manchester, Dublin\u000d\u000a        and Portsmouthd. Two international clinical workshops in AIT\u000d\u000a        at Warwick for the dissemination of\u000d\u000a        knowledge to the patient benefit in 2008 (80 participants) and 2012\u000d\u000a        (100 participants) j, together\u000d\u000a        with presentations at international meetingsh, and citations\u000d\u000a        in the top clinical journali further\u000d\u000a        illustrate the international impact of our work. Our research has been\u000d\u000a        instrumental in the generation\u000d\u000a        of a national Registry for AIT in 2008 as a research and audit tool.\u000d\u000a        This Registry was proposed and\u000d\u000a        initiated by Higgins, who presented the data nationally and\u000d\u000a        internationally. Other units such as\u000d\u000a        Bristol and Cambridge have used Registry data provided by Higgins when\u000d\u000a        assessing and\u000d\u000a        developing their clinical programmes.\u000d\u000a      \u000aImpact on NHS: The financial impact of our programme\u000d\u000a        locally has been highlighted by the\u000d\u000a        Chief Executive of the University Hospital Coventry, who stated `the\u000d\u000a        UHCW has received over £6\u000d\u000a        million income for these transplants, and savings to the NHS from these\u000d\u000a        transplants exceeds £5\u000d\u000a        million over and above the extra costs of the programme' e.\u000d\u000a        In addition, this cost benefit goes up by\u000d\u000a        around £1 million a year as grafts continue to function and patients do\u000d\u000a        not need dialysisk. The\u000d\u000a        impact is also reflected in the support from the National Director for\u000d\u000a        Kidney Care at the UK\u000d\u000a        Department of Health who stated that, `This research has enabled not\u000d\u000a        only the transplant unit at\u000d\u000a        UHCW to be extremely productive, but has facilitated the development of\u000d\u000a        Antibody Incompatible\u000d\u000a        Transplantation nationally. The unit led the first NHS commissioned\u000d\u000a        service for these transplants;\u000d\u000a        national guidelines produced by the British Transplantation Society, and\u000d\u000a        proposed the National\u000d\u000a        Registry of cases that is run by NHS Blood and Transplant 'd.\u000d\u000a      \u000aCommercial impact and new innovation: The hardware for\u000d\u000a        these techniques is provided\u000d\u000a        through L.IN.C. Medical Systems Ltd, whose Managing Director has stated\u000d\u000a        that `...DFPP has\u000d\u000a        become established as the treatment of choice for such patients in many\u000d\u000a        transplant centres.\u000d\u000a        [Professor Higgins] was also the first physician to perform\u000d\u000a        cryofiltration DFPP outside of North\u000d\u000a        America and Japan... L.IN.C. Medical Systems is an independent UK\u000d\u000a        company and is now one of\u000d\u000a        the key suppliers of extra-corporeal therapies providing innovative\u000d\u000a        technologies that bring cost\u000d\u000a        effective solutions to the NHS...'a. Despite the advantages\u000d\u000a        of DFPP and cryofiltration over other\u000d\u000a        therapies, they remain non-selective. In a formal collaboration with\u000d\u000a        Pure Transplant Solutions and\u000d\u000a        Pure Protein LLC, Oklahoma City, we have successfully tested a\u000d\u000a        pre-clinical device to selectively\u000d\u000a        remove antibodies against HLA on the donor kidney. The Director of Pure\u000d\u000a        Protein has stated in\u000d\u000a        supporting evidence, `This is a well-developed collaboration between our\u000d\u000a        biotechnology\u000d\u000a        company... and the University of Warwick and University Hospital\u000d\u000a        Coventry... with their academic\u000d\u000a        and clinical credentials in AIT. Much progress has been made and ...\u000d\u000a        discussions with investors\u000d\u000a        have started to take this device into clinical patient testing' b.\u000d\u000a        Additionally, we are collaborating on\u000d\u000a        the development of a novel assay to measure HLA antibody potency, with a\u000d\u000a        first use preproduction\u000d\u000a        product and data presented at the 2013 American Society of\u000d\u000a        Histocompatibility meeting.\u000d\u000a    \u000d\u000a    ","ImpactSummary":"\u000d\u000a    Kidney disease affects about 10% of the population and 10% of\u000d\u000a      these patients develop established kidney failure (ERF). Transplantation\u000d\u000a      is a better treatment for\u000d\u000a      ERF than dialysis but is limited by acute and chronic graft rejection.\u000d\u000a      Treatment of rejection\u000d\u000a      mediated by the recipient's T-lymphocytes is now remarkably successful,\u000d\u000a      but antibody-mediated\u000d\u000a      rejection (AMR) remains challenging. A principal cause of AMR is recipient\u000d\u000a      antibodies targeting\u000d\u000a      human leukocyte antigen (HLA, also known a tissue type) on the transplant\u000d\u000a      organ. The presence of\u000d\u000a      such antibodies previously vetoed transplantation but in the last ten\u000d\u000a      years it has become\u000d\u000a      increasingly feasible to transplant across HLA antibody barriers. Research\u000d\u000a      at the University of\u000d\u000a      Warwick (UoW) by Dr Daniel Zehnder and Professor Robert Higgins has\u000d\u000a      facilitated and\u000d\u000a      accelerated this process. Their research includes the first detailed\u000d\u000a      monitoring of antibody levels\u000d\u000a      after transplantation, showing how these affect graft function, and the\u000d\u000a      development of new\u000d\u000a      techniques to remove antibodies from patients. This resulted in over 100\u000d\u000a      HLA-mismatched renal\u000d\u000a      transplants taking place in Coventry giving a net saving to the NHS of\u000d\u000a      over £5M. Their research\u000d\u000a      and its clinical translation encouraged the performing of another 350 such\u000d\u000a      transplants across the\u000d\u000a      UK and initiation of the National Case Registry.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Warwick\u000d\u000a    ","Institutions":[{"AlternativeName":"Warwick (University of)","InstitutionName":"University of Warwick","PeerGroup":"A","Region":"West Midlands","UKPRN":10007163}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2964574","Name":"Dublin"},{"GeoNamesId":"2964574","Name":"Dublin City"},{"GeoNamesId":"4544349","Name":"Oklahoma City"}],"References":"\u000d\u000a    \u000a1. Higgins R, et al. Double filtration plasmapheresis in\u000d\u000a      antibody-incompatible kidney\u000d\u000a      transplantation. Ther Apher Dial. 2010; 14:392-9. DOI:\u000d\u000a      10.1111:j.1744-9987.2010.00821.x.\u000d\u000a    \u000a\u000a2. Sinha D, et al. Cryofiltration in the treatment of\u000d\u000a      cryoglobulinemia and HLA antibody-incompatible\u000d\u000a      transplantation. Ther Apher Dial. 2012; 16:91-6. DOI:\u000d\u000a      10.1111:j.1744-9987.2011.01004.x.\u000d\u000a    \u000a\u000a3. Higgins R, et al. Rises and falls in donor-specific and\u000d\u000a      third-party HLA antibody levels after\u000d\u000a      antibody incompatible transplantation. Transplantation. 2009;\u000d\u000a      87:882-8. DOI:\u000d\u000a      10.1097:TP.0b013e31819a6788.\u000d\u000a    \u000a\u000a4. Higgins R, et al. Blood levels of donor-specific human\u000d\u000a      leukocyte antigen antibodies after renal\u000d\u000a      transplantation: resolution of rejection in the presence of circulating\u000d\u000a      donor-specific antibody.\u000d\u000a      Transplantation. 2007; 84:876-84. DOI:\u000d\u000a      10.1097\/01.tp.0000284729.39137.6e.\u000d\u000a    \u000a\u000a5. Higgins R, et al. The histological development of acute\u000d\u000a      antibody-mediated rejection in HLA\u000d\u000a      antibody-incompatible renal transplantation. Nephrol Dial Transplant.\u000d\u000a      2010; 25:1306-12. doi\/\u000d\u000a      10.1093:ndt:gfp610.\u000d\u000a    \u000a\u000a6. N.D. Evans, et al. Structural identifiability of surface\u000d\u000a      binding reactions involving heterogeneous\u000d\u000a      analyte: Application to surface plasmon resonance experiment. Automatica.\u000d\u000a      2013; 49:48-57.\u000d\u000a      DOI: 10.1016\/j.automatica.2012.09.015.\u000d\u000a    \u000a\u000a7. Higgins R, et al. Human leukocyte antigen\u000d\u000a      antibody-incompatible renal transplantation: excellent\u000d\u000a      medium-term outcomes with negative cytotoxic crossmatch. Transplantation.\u000d\u000a      2011; 92:900-6.\u000d\u000a      DOI: 10.1097:TP.0b013e31822dc38d.\u000d\u000a    \u000aAssociated Research Grants\u000d\u000a    • Daniel Zehnder (PI), Associate Professor, WMS. Improvement in\u000d\u000a      left ventricular geometry and\u000d\u000a      cardiovascular functional capacity after restitution of the failing kidney\u000d\u000a      through transplantation: a\u000d\u000a      prospective non-randomised concurrent control study. British Heart\u000d\u000a      Foundation, 05\/2011 - 04\/2014.\u000d\u000a      £220,713 (PG\/11\/66\/28982).\u000d\u000a    • Daniel Zehnder (PI) (Research Fellowship WMS David Lowe).\u000d\u000a      Characterisation of\u000d\u000a      immunological risk in antibody incompatible transplantation. NIHR,\u000d\u000a      Doctoral Research\u000d\u000a      Fellowship, 10\/2010 - 09\/2013. £284,270 (DRF-2010-03-045).\u000d\u000a    • Daniel Zehnder (PI) (Clinical Research Fellowship for Sunil\u000d\u000a      Daga), WMS. Clinical\u000d\u000a      characterisation and mathemathical modelling of donor kidney directed\u000d\u000a      antibody specificity and\u000d\u000a      affinity to determine risk of graft rejection. NIHR CRN WM South, Clinical\u000d\u000a      Mentorship Program,\u000d\u000a      09\/2011 - 08\/2013. £105,000\u000d\u000a    • Daniel Zehnder (PI), WMS. Characterisation of serum HLA\u000d\u000a      antibody in patients undergoing an\u000d\u000a      antibody incompatible renal transplant. NIHR CRN WM South, Clinical\u000d\u000a      Research Nurse support,\u000d\u000a      04\/2009 - 03\/2010. £80,000\u000d\u000a    • Robert Higgins (PI), Professor, WMS (Clinical Research\u000d\u000a      Fellowship WMS Rizwan Hamer).\u000d\u000a      Donor specific antibodies and complement in HLA-antibody incompatible\u000d\u000a      renal transplantation.\u000d\u000a      University Hospital Coventry and Warwickshire NHS Trust, 04\/2006 -\u000d\u000a      03\/2009. £200,000\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    a. Statement: Managing Director, LINC Medical Systems LTD,\u000d\u000a      Leicestershire, UK — Linc Medical.\u000d\u000a      (Identifier 1).\u000d\u000a    b. Statement: Director, Pure Protein, LLC; Oklahoma City. US\u000d\u000a      PureProtein. (Identifier 2).\u000d\u000a    c. Statement: Associate Medical Director, Organ Donation &\u000d\u000a      Transplantation Directorate, NHS\u000d\u000a      Blood & Transplant, Bristol, UK — NHSBT. (Identifier 3).\u000d\u000a    d. Statement: (Until 1 April 2013) National Director for Renal\u000d\u000a      Care, Department of Health,\u000d\u000a      Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford,\u000d\u000a      UK (Identifier 4).\u000d\u000a    e. Statement: Chief Executive Officer, University Hospital\u000d\u000a      Coventry & Warwickshire NHS Trust,\u000d\u000a      Coventry, UK — UHCW. (Identifier 5).\u000d\u000a    f. National and International impact: XXIII international Transplant\u000d\u000a      Society 17 August 2010,\u000d\u000a      Vancouver, Canada. Presentation: UK Registry of Antibody Incompatible\u000d\u000a      Kidney\u000d\u000a      Transplantation 2001-2010 (http:\/\/tinyurl.com\/o5z5fp8)\u000d\u000a    g. Patient testimonial: accessed 24 September 2013 (http:\/\/tinyurl.com\/qbg6spk)\u000d\u000a    h. International impact: Montgomery RA et al, Desensitization in\u000d\u000a      HLA-Incompatible Kidney\u000d\u000a      Recipients and Survival. N Engl J Med 2011; 365:318-326 DOI:\u000d\u000a        10.1056\/NEJMoa1012376.\u000d\u000a    i. Guidelines: British Transplant Society, National Guidelines for\u000d\u000a      Antibody Incompatible\u000d\u000a      Transplantation: http:\/\/tinyurl.com\/pc4hmtn\u000d\u000a    \u000d\u000a    j. Teaching and training: 2nd International Meeting on Antibody\u000d\u000a      Incompatible Transplantation.\u000d\u000a      http:\/\/tinyurl.com\/ney96d2 \u000d\u000a    k. Cost effectiveness of renal transplantation: http:\/\/www.organdonation.nhs.uk\/newsroom\/fact_\u000d\u000a        sheets\/cost_effectiveness_oftransplantation.asp).\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Successful Clinical Translation and Optimisation of\u000d\u000a        Antibody-Incompatible\u000d\u000a        Renal Transplantation\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"},{"GeoNamesId":"2653941","Name":"Cambridge"},{"GeoNamesId":"2652221","Name":"Coventry"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    When kidney transplantation first took place in the 1950's,\u000d\u000a      T-cell-mediated\u000d\u000a      rejection was the key barrier to success. The drugs available to treat\u000d\u000a      this have improved\u000d\u000a      enormously. However, it was recognised in the 1960's that severe rejection\u000d\u000a      could also be mediated\u000d\u000a      by the recipient's antibodies against Human Leukocyte Antigen (HLA, also\u000d\u000a      known as `tissue type';\u000d\u000a      the name given to the Major Histocompatibility Complex in humans)\u000d\u000a      expressed by the donor organ.\u000d\u000a      Although transplantation across HLA antibody barriers has become feasible\u000d\u000a      in the 21st century, the\u000d\u000a      success rate for recipients with higher levels of antibodies continues to\u000d\u000a      be poor, with an early\u000d\u000a      mortality of up to 15% at two years and graft survival about 50% at five\u000d\u000a      years.\u000d\u000a    The clinical programme at University Hospital Coventry and Warwickshire\u000d\u000a      NHS Trust (UHCW) was\u000d\u000a      started in 2003-4 by Higgins, Briggs and Zehnder, and was designed to be\u000d\u000a      research intensive. The\u000d\u000a      researchers have accumulated the world's largest bank of research\u000d\u000a      specimens from AIT patients.\u000d\u000a      The initial treatment protocol was based on practice at King's College\u000d\u000a      London and the Johns\u000d\u000a      Hopkins University, USA. Over the last 10 years their research led to\u000d\u000a      significant changes in the\u000d\u000a      clinical protocol1-4. This includes intensive therapy targeted\u000d\u000a      at high-risk patients to enable\u000d\u000a      transplantation, and marked reductions in the intensity of\u000d\u000a      immunosuppression in patients without\u000d\u000a      rejection so that mortality is reduced.\u000d\u000a      The research is a collaboration between Dr Daniel Zehnder, Associate\u000d\u000a      Professor 2004-present and\u000d\u000a      Dr Dan Mitchell, Associate Professor 2005-present at Warwick Medical\u000d\u000a      School (WMS): Professor\u000d\u000a      Robert Higgins, Consultant Nephrologist 1995-present at University\u000d\u000a      Hospital Coventry and\u000d\u000a      Warwickshire NHS Trust (UHCW), also WMS Honorary Professor 2004-present):\u000d\u000a      and Professor\u000d\u000a      David Briggs at NHS Blood and Transplant (NHSBT), Honorary Professor,\u000d\u000a      University of\u000d\u000a      Birmingham) 1-7.\u000d\u000a    \u000d\u000a      \u000aAntibody removal pre-transplant: High volume double filtration\u000d\u000a            plasmapheresis (DFPP):\u000d\u000a        Standard treatment for the removal of HLA antibody was traditionally\u000d\u000a        plasma exchange, where all\u000d\u000a        plasma components are removed and then replaced with plasma and albumin\u000d\u000a        free of HLA\u000d\u000a        antibodies. Adverse effects limit the amount of antibody that can be\u000d\u000a        removed. DFPP was\u000d\u000a        developed clinically in this context by Higgins, Zehnder and Briggs\u000d\u000a        between 2004 and 20091,a. In\u000d\u000a        this technique, plasma is filtered a second time rather than being\u000d\u000a        discarded. The pore size of the\u000d\u000a        second filter traps plasma proteins above a certain molecular weight,\u000d\u000a        including antibodies. Plasma\u000d\u000a        that passes through the second filter is returned to the patient. DFPP\u000d\u000a        removes fewer non-\u000d\u000a        immunological plasma proteins than plasma exchange and is better\u000d\u000a        tolerated by the patient's\u000d\u000a        cardiovascular system.\u000d\u000a      \u000aCryofiltration DFPP: Between 2008 and 2010,\u000d\u000a        Higgins, Zehnder and Briggs performed the\u000d\u000a        world's only plasma cryofiltration for the removal of HLA antibody in\u000d\u000a        individuals with cardiovascular\u000d\u000a        frailty. Recipient's plasma is filtered and then chilled to 0oC\u000d\u000a        for six minutes, resulting in the\u000d\u000a        antibodies clumping together and enabling their removal by filtration.\u000d\u000a        This method reduces\u000d\u000a        intravascular fluid shifts and minimises the risk of hypotension. It was\u000d\u000a        possible to use cryofiltration\u000d\u000a        safely and effectively in patients who experienced life threatening\u000d\u000a        hypotension with DFPP2, a.\u000d\u000a      \u000aHLA protein containing columns (HLA columns):\u000d\u000a        Since 2008 Zehnder, Mitchell, Higgins and\u000d\u000a        Briggs have collaborated with Pure Transplant Solutions, an American\u000d\u000a        company that produces\u000d\u000a        a wide range of high quality HLA proteinsb. A device that\u000d\u000a        immobilises HLA proteins in a column\u000d\u000a        has been developed. Three prototype devices have been tested successful\u000d\u000a        in UoW\u000d\u000a        laboratories, proving efficient removal of HLA antibodies from patient\u000d\u000a        plasma. The next step will\u000d\u000a        be first patient use with this patent protected device. This will be a\u000d\u000a        major advance over all other\u000d\u000a        techniques, which are non-selective and have limited ability to remove\u000d\u000a        large amounts of HLA\u000d\u000a        antibody.\u000d\u000a      \u000aReal time clinical HLA antibody monitoring: Briggs,\u000d\u000a        Higgins and Zehnder, together with\u000d\u000a        others, have between 2003 and 2012 refined the clinical application of\u000d\u000a        transplant recipient antibody\u000d\u000a        quantification and monitoring with HLA protein-coated microbeads using\u000d\u000a        fluorescence labelled anti-human\u000d\u000a        IgG antibody on the liquid array (Luminex) platform. This method allows\u000d\u000a        more sensitive and\u000d\u000a        specific measurement of HLA antibody levels than possible previously.\u000d\u000a        Daily pre-transplant\u000d\u000a        antibody monitoring enabled the team to deliver optimal doses of DFPP\u000d\u000a        before transplantation.\u000d\u000a        Post-transplant antibody monitoring has shown that the relationship\u000d\u000a        between antibody levels and\u000d\u000a        occurrence of rejection is complex3, but we have improved\u000d\u000a        markedly the prediction of the clinical\u000d\u000a        risk of AMR3, 4. This has allowed more effective targeting of\u000d\u000a        treatment before and during AMR, and\u000d\u000a        also holding off treatment when it is not necessary.\u000d\u000a      \u000aHistological characterisation of AMR: The understanding\u000d\u000a        of the histological changes that take\u000d\u000a        place during acute AMR has been changed by our research5. It\u000d\u000a        has been shown that the\u000d\u000a        internationally accepted definition of AMR was wrong, placing too much\u000d\u000a        reliance on staining for a\u000d\u000a        blood component called complement C4d in tissues, and that C4d could be\u000d\u000a        produced locally in\u000d\u000a        renal tissues, rather than being deposited from the blood.\u000d\u000a      \u000aSurface plasmon resonance (SPR) assessment of HLA antibody\u000d\u000a            affinity to patient HLA\u000d\u000a            protein: Recent results have shown that AMR is not\u000d\u000a        associated simply with the blood level of\u000d\u000a        antibody. Since 2009, Mitchell, Zehnder and Higgins have used SPR to\u000d\u000a        characterise the affinity of\u000d\u000a        recipient HLA antibodies. SPR is a real-time, label-free, sensitive and\u000d\u000a        high throughput method to\u000d\u000a        quantify binding of HLA antibodies to HLA proteins. Together with the\u000d\u000a        UoW Department of\u000d\u000a        Engineering (Dr Neil Evans, Associate Professor; Dr Mike Chappel,\u000d\u000a        Associate Professor), using\u000d\u000a        their skills in mathematical modelling6, they have developed\u000d\u000a        numerical quantification of this\u000d\u000a        biological process. The results have changed our perception of antibody\u000d\u000a        binding from a purely\u000d\u000a        concentration effect to a potency paradigm where multiple factors affect\u000d\u000a        antibody binding to tissues\u000d\u000a        and the clinical outcomes.\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"2613","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000aChanges in the industry\u000d\u000aThornalley presented his findings regarding protein damage with first-generation PD fluids and\u000d\u000aimproved clinical outcomes with low-GDP PD fluids at several international meetings, including the\u000d\u000a5th EuroPD conference in 2002, the American Society Nephrology Annual Renal Week meetings in\u000d\u000a1999, 2002, and 2005, and the 12th Congress of the International Society for Peritoneal Dialysis in\u000d\u000a2008. These meetings are attended by representatives from the major global manufacturers of\u000d\u000adialysis fluids, including Baxter Healthcare, Gambro AB (part of Baxter Healthcare from 2013) and\u000d\u000aFrenesius. With funding from Baxter Healthcare, Cancer Research UK, Dynamis Therapeutics Inc.,\u000d\u000aFresenius Medical Care AG, Gambro AB, GlaxoSmithKline, TransGenic Inc., Woerwag Pharma,\u000d\u000aand Chroma Therapeutics, Thornalley organized a colloquium on GDP researcha (entitled\u000d\u000a\"Enzymatic defence against glycation in health, disease and therapeutics\"), which was presented\u000d\u000aat the 679th Meeting of the Biochemical Society held in Colchester in 2003. Approximately 100\u000d\u000aclinicians, industry researchers and academics attended the colloquium. From 2002 onwards, in\u000d\u000alight of the data presented by Thornalley, major manufacturers of PD fluids, including Baxter\u000d\u000aHealthcare, Gambro AB, and Fresenius Medical Care AG, developed second-generation and third-\u000d\u000ageneration PD fluids and conducted clinical trials to assess clinical outcomes such as residual\u000d\u000arenal function, risk of peritonitis, and fluid infusion pain. Second-generation PD fluids with reduced\u000d\u000aGDP content were produced using two-compartment dialysis fluid bags, which separate glucose\u000d\u000afrom buffer salts during heat sterilization. Third-generation PD fluids, with even lower GDP counts,\u000d\u000awere then produced from osmolyte that is resistant to GDP formation, such as icodextrin. All of the\u000d\u000amajor companies that manufacture PD fluids, including Baxter Healthcare, Gambro AB, and\u000d\u000aFresenius Medical Care AG, have developed and marketed low-GDP solutions, and Gambro AB\u000d\u000anow produce only low-GDP PD fluids. The most recently developed PD fluids are designed to be\u000d\u000aresistant to GDP formation during transport to sites of use and storage.\u000d\u000aClinical benefits\u000d\u000aClinical evidence of the benefits of low-GDP PD fluids has emerged since 2008b,c, including data to\u000d\u000ashow improved preservation of residual renal function and decreased peritonitis, fluid infusion pain,\u000d\u000aand vascular inflammation. The British Renal Society now recommends that all patients\u000d\u000aexperiencing infusion pain, and preferably all other patients (provided there is no cost penalty),\u000d\u000ashould be given low-GDP PD solutions. The European Pediatric Dialysis Working Groupd\u000d\u000arecommends low-GDP fluid use in all paediatric patients receiving PD. Current usage of low-PD\u000d\u000afluids in Europe is 60% of patients receiving PD dialysis, although all patients receiving dialysis\u000d\u000awould probably benefit from the use of low-GDP PD fluids. The use of PD therapy for patients with\u000d\u000arenal failure is likely to increase at the rate of 5-6% per annum as diseases linked to renal failure\u000d\u000abecome more prevalent and access to dialysis improves, highlighting the continued importance of\u000d\u000aPD fluid development. An additional benefit to patients is that PD treatment with low-GDP PD fluids\u000d\u000aallows PD to continue for longer, reducing the need for haemodialysis.\u000d\u000aEconomic benefits\u000d\u000aThe total global market for PD therapy is around US$2.7 billion per year, for the dialysis of\u000d\u000aapproximately 240,000 patients. The use of low-GDP PD fluids has been shown to reduce\u000d\u000atreatment costs and increase efficacy.\u000d\u000aOther benefits\u000d\u000aIn addition to their impact on PD fluid composition, Thornalley's findings led the food industry to\u000d\u000adevelop glyoxalase-1-inducer-based foods for healthy ageing (Technology Strategy Board project\u000d\u000awith Unilever; funding £1.1 million). Selected dietary bioactive compounds at dietary exposure\u000d\u000alevels induce glyoxalase 1 through Nrf2 transcriptional signalling (Xue, M., Rabbani, N., Momiji, H.,\u000d\u000aImbasi, P., Anwar, M. M., Kitteringham, N. R., Park, B. K., Souma, T., Moriguchi, T., Yamamoto, M.\u000d\u000aand Thornalley, P. J. 2012 Transcriptional control of glyoxalase 1 by Nrf2 provides a stress\u000d\u000aresponsive defence against dicarbonyl glycation. Biochem. J. 443, 213-222). [This is not to be\u000d\u000aconfused with certain other dietary bioactive compounds at markedly higher exposures\/doses than\u000d\u000adietary, which have been reported to inhibit glyoxalase 1 in some cell model systems in vitro].\u000d\u000aOther research from Thornalley identified glyoxalase amplification in multidrug resistant (MDR)\u000d\u000atumours and sensitivity of such tumours to glyoxalase 1 inhibitors. This led pharmaceutical\u000d\u000acompanies such as AstraZeneca to develop glyoxalase 1 inhibitors for the treatment of multidrug-\u000d\u000aresistant tumours.e\u000d\u000a","ImpactSummary":"\u000d\u000aResearch led by Professor Paul J Thornalley since 1993, (University of Warwick, 2007-present),\u000d\u000arevealed the formation of harmful reactive dicarbonyl compounds (also known as glucose\u000d\u000adegradation products, GDPs) within the glucose osmolyte of first-generation peritoneal dialysis\u000d\u000a(PD) fluids. Clinical studies confirmed the increased damage to proteins in patients on PD therapy.\u000d\u000aIn response to these findings, major manufacturers of PD fluids changed their manufacturing\u000d\u000aprocesses to minimise GDP content by separating glucose and buffer components within two-compartment\u000d\u000abags for heat sterilisation, and by using osmolyte that is resistant to thermal\u000d\u000adegradation. PD fluids with low GDP content have been associated with improved clinical\u000d\u000aoutcomes for patients receiving dialysis, including maintained residual renal function, decreased\u000d\u000aperitonitis, and decreased fluid infusion pain. They have been widely implemented in clinical use\u000d\u000asince 2010. Globally, approximately 240,000 patients receive PD therapy.\u000d\u000a","ImpactType":"Health","Institution":"\u000d\u000aUniversity of Warwick\u000d\u000a","Institutions":[{"AlternativeName":"Warwick (University of)","InstitutionName":"University of Warwick","PeerGroup":"A","Region":"West Midlands","UKPRN":10007163}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a\u000a1. Rabbani, N. and Thornalley, P. J. (2011). Glyoxalase in diabetes, obesity and related\u000d\u000adisorders. Seminars in Cell & Developmental Biology. 22, 309-317;\u000d\u000ahttp:\/\/dx.doi.org\/10.1016\/j.semcdb.2011.02.015\u000d\u000a\u000a\u000a2. Rabbani, N., Godfrey, L., Xue, M., Shaheen, F., Geoffrion, M., Milne, R. and Thornalley, P. J.\u000d\u000a(2011). Glycation of LDL by methylglyoxal increases arterial atherogenicity a possible\u000d\u000acontributor to increased risk of cardiovascular disease in diabetes. Diabetes. 60, 1973-1980;\u000d\u000ahttp:\/\/dx.doi.org\/10.2337\/db11-0085 [UoA1 REF2 Submission].\u000d\u000a\u000a\u000a3. Thornalley, P. J. and Rabbani, N. (2009). Highlights and Hotspots of Protein Glycation in End-Stage\u000d\u000aRenal Disease. Seminars in Dialysis. 22, 400-404; http:\/\/dx.doi.org\/10.1111\/j.1525-139X.2009.00589.x\u000d\u000a\u000a\u000a4. Thornalley, P.J. et al. Imidazopurinones are markers of physiological genomic damage linked\u000d\u000ato DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids\u000d\u000aRes. 38, 5432-5442 (2010); doi: 10.1093\/nar\/gkq306\u000d\u000a\u000a\u000a5. Rabbani, N. and Thornalley, P.J. Quantitation of markers of protein damage by glycation,\u000d\u000aoxidation and nitration in peritoneal dialysis. Peritoneal Dialysis Internat. 29, Suppl. 2, S51-S56\u000d\u000a(2009).\u000d\u000a\u000a\u000a6. Rabbani, N. et al. Protein glycation, oxidation and nitration free adduct accumulation after\u000d\u000abilateral nephrectomy and ureteral ligation. Kidney Internat. 72, 1113-1121 (2007);\u000d\u000ahttp:\/\/dx.doi.org\/10.1038\/sj.ki.5002513\u000d\u000a\u000a\u000a7. Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, et al. Methylglyoxal\u000d\u000amodification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic\u000d\u000aneuropathy. Nature Med 18, 926-933 (2012); http:\/\/dx.doi.org\/10.1038\/nm.2750\u000d\u000a\u000aRelated Research Grant Funding\u000d\u000a• Awarding body: Wellcome Trust. Title of project: Structural and functional epitope mapping of\u000d\u000aproteins involved in mechanisms of disease (equipment grant with co-applicants G. Stanway\u000d\u000aand N Fernandez). Amount awarded: £220,760. Dates: 01\/10\/05-30\/09\/08.\u000d\u000a• Awarding body: Wellcome Trust. Title of project: Enzymatic defence against dicarbonyl\u000d\u000aglycation in diabetes, obesity, renal failure and ageing. Amount awarded: award in-kind (two\u000d\u000amutant mouse lines). Dates: 01\/10\/07-30\/09\/10.\u000d\u000a• Awarding body: British Council [RC125]. Title of project: Functional genomic models of\u000d\u000aglyoxalase 1 in diabetic nephropathy, renal failure and ageing. Amount awarded: £34,591.\u000d\u000aDates: 01\/09\/08-31\/05\/11.\u000d\u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a\u000d\u000a\u000aSupporting Statement: from Chair of the European Uremic Toxin Network (EUTox) - a\u000d\u000aworkgroup of the European Society of Artificial Organs (ESAO), the European Renal\u000d\u000aAssociation (ERA), and the Renal Dialysis and Transplantation Association (EDTA).\u000d\u000a(Identifier 1). Specifically acknowledges Thornalley's research contribution in this area, and\u000d\u000ahigh level of achievement and impact in terms of advances in provision of improved care for\u000d\u000apatients with renal failure.\u000d\u000a\u000aSupporting Statement: from the Medical Director of Baxter Healthcare, Deerfield, USA.\u000d\u000a(Identifier 2). Corroborates the clinical relevance of Thornalley's research, the formation of\u000d\u000awhich has been subsequently widely explored and clinical practice has changed as a result.\u000d\u000aAlso specifically confirms that Thornalley's research helped lead to the development,\u000d\u000aregistration and clinical use of the low-GDP fluid, PhysionealTM, across Europe, the Middle\u000d\u000aEast, Russia, Canada, Australia, New Zealand and Korea, and that global use of this fluid\u000d\u000acontinues to increase.\u000d\u000a\u000d\u000aCorroborating Sources\u000d\u000aa) Enzymatic defence against glycation in health, disease and therapeutics\u000d\u000a(http:\/\/212.250.180.38\/bst\/031\/1341\/0311341.pdf)\u000d\u000ab) Jorres A. Novel Peritoneal Dialysis Solutions — What Are the Clinical Implications? Blood\u000d\u000aPurif 33, 153-159 (2012). DOI: 10.1159\/000342712\u000d\u000ac) Cho, Y., Johnson, D. W., Badve, S., Craig, J. C., Strippoli, G. F. K. and Wiggins, K. J.\u000d\u000a(2013) Impact of icodextrin on clinical outcomes in peritoneal dialysis: a systematic review\u000d\u000aof randomized controlled trials. Nephrology Dialysis Transplantation. 28, 1899-1907;\u000d\u000a10.1093\/ndt\/gft050\u000d\u000ad) Schmitt, C. P. et al. Solutions for peritoneal dialysis in children: recommendations by the\u000d\u000aEuropean Pediatric Dialysis Working Group. Pediatr. Nephrol. 26, 1137-1147 (2011). DOI:\u000d\u000a10.1007\/s00467-011-1863-4\u000d\u000ae) Person who can be contacted: (Acting) Director of Structure & Biophysics, AstraZeneca,\u000d\u000aAlderley Park, Cheshire, UK. (Identifier 3).\u000d\u000a\u000d\u000a","Title":"\u000d\u000aImproving the Biocompatibility of Peritoneal Dialysis Fluids\u000d\u000a","UKLocation":[{"GeoNamesId":"2652618","Name":"Colchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aBefore the development of technologies to measure GDPs, it was unclear whether GDPs were\u000d\u000aformed during the thermal sterilisation of glucose-containing PD dialysis fluids. Thornalley\u000d\u000a(Professor of Systems Biology at the University of Warwick from January 2007-present) was\u000d\u000athe first person to develop validated analytical technology to assay levels of the GDP methylglyoxal\u000d\u000aand other GDPs and apply it to PD fluids. He demonstrated that methylglyoxal is a reactive\u000d\u000adicarbonyl metabolite that damages proteins and DNA in physiological systems, resulting in\u000d\u000aageing, vascular disease, glucose intolerance, and inflammation. These effects are suppressed by\u000d\u000amethylglyoxal metabolism by glyoxalase 1.1 In vitro methylglyoxal was found to modify vascular\u000d\u000atype IV collagen leading to endothelial detachment and cell death, a marker of vascular\u000d\u000ainflammation and risk predictor of fatal cardiovascular disease in end stage renal disease (Dobler\u000d\u000aet al., 2006). Studies in vitro and in a pre-clinical model found methylglyoxal modification of low\u000d\u000adensity lipoprotein (LDL) converted it to atherogenic small, dense LDL, with increased binding to\u000d\u000aarterial proteoglycan and arterial deposition in vivo.2 Thornalley showed that GDPs are formed in\u000d\u000aPD fluids upon the degradation of glucose osmolyte during heat sterilization, causing protein\u000d\u000adamage (measured by levels of proteolysis products) in patients with renal failure receiving therapy\u000d\u000awith a first-generation (high-GDP) PD fluid.3 In PD patients the flux of modification of proteins by\u000d\u000afirst generation PD fluids was increased approximately 10-fold (Agalou et al., 2005). Examples of\u000d\u000aproteins modified are vascular type IV collagen and LDL (indicated above) which, through\u000d\u000aendothelial cell detachment and atherogenic transformation, increased risk of thrombosis and\u000d\u000aatherosclerosis leading to high risk (20-fold increased risk) of heart disease, a common cause of\u000d\u000apremature death in dialysis patients.\u000d\u000aGDPs form adducts with proteins and DNA in a process that produces advanced glycation\u000d\u000aendproducts (AGEs). 1-4 MG-H1 is the most abundant AGEs linked to protein dysfunction. It is,\u000d\u000atherefore, one of the most important AGEs in human tissues and body fluids. In one study,\u000d\u000aexcreted flux and plasma concentrations of MG-H1 increased 10-fold and 18-fold, respectively.4\u000d\u000aReduced GDP exposure has been shown to decrease endothelial cell detachment, decrease\u000d\u000aatherogenic transformation of low-density lipoproteins and atherosclerosis, and decrease DNA\u000d\u000adamage and mutagenesis by GDPs, highlighting the clinical benefits of low-GDP PD fluids.\u000d\u000aIn 2003, with funding from the Wellcome Trust, Thornalley developed state-of-the-art analytical\u000d\u000atechnology (stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry) to\u000d\u000ameasure protein damage caused by GDPs5. Over this period, Thornalley received funding from\u000d\u000aBaxter Healthcare to research the damaging effects of GDPs and ways to avoid these effects.\u000d\u000aThornalley has also filed a patent (WO 2005\/051968 A1) for an amino acid derivative additive that\u000d\u000afurther improve the safety profile of dialysis fluids by catalyzing the degradation of GDPs. Amino-\u000d\u000aacid-containing GDP fluids where then developed by major manufacturers of PD fluid.\u000d\u000aMore recent research at the University of Warwick confirmed the profound accumulation of AGEs\u000d\u000ain experimental renal failure6 and established analytical technologies developed by Thornalley and\u000d\u000aco-worker Dr Naila Rabbani (Associate Professor of Experimental Systems Biology,\u000d\u000aUniversity of Warwick, January 2007-present) as state-of-the-art for measuring GDPs and their\u000d\u000aphysiological effects.5 Health benefits of low-GDP peritoneal dialysis fluids were supported by\u000d\u000aleading expert opinion and systematic review of randomised controlled clinical trials — see also\u000d\u000aSection 5, notesa,b,d,e,f. Thornalley and co-workers also showed that the GDP methylglyoxal\u000d\u000aproduced peripheral neuropathy7, which is common in renal failure patients (80% prevalence). Low\u000d\u000aGDP-fluids may also alleviate this symptom, reducing fluid infusion pain.\u000d\u000a"},{"CaseStudyId":"2703","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3895114","Name":"Chile"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"3190538","Name":"Slovenia"},{"GeoNamesId":"3865483","Name":"Argentina"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The demonstration by Warwick researchers that reduced dietary salt intake\u000d\u000a      lowers BP in a dose- dependent manner (1) and in different geographic\u000d\u000a      settings (3-4) across individuals with various baseline levels of BP (1)\u000d\u000a      gave impetus to national and global health policy developments. Crucially,\u000d\u000a      the prospective association of reduced salt intake with a lower risk of\u000d\u000a      fatal and non-fatal CVD events underpinned the development of national\u000d\u000a      salt reduction programmes in the UK (2008 - 2012) (a) and internationally\u000d\u000a      (2010-2013) (b-e).\u000d\u000a    National and international recommendations on dietary salt intake.\u000d\u000a      Dietary salt intake is high in almost all populations, and its reduction\u000d\u000a      would lead to a reduction in strokes and heart attacks (2). Through the\u000d\u000a      WHO Collaborating Centre at Warwick and Cappuccio's participation in\u000d\u000a      various committees (Population Reduction in Salt Intake, WHO, Geneva\u000d\u000a        [2006]; European Salt Initiative, WHO, Copenhagen [2006]; European\u000d\u000a      Salt Action Network [2007; founding member and lead of a subgroup], Public\u000a        Health Program Development Group for NICE Guidance on Prevention of\u000d\u000a      Cardiovascular Disease [2008-2010] and Expert Testimony; Cardiovascular\u000a        Disease Prevention through Dietary Salt Reduction, PAHO\/WHO,\u000d\u000a      Washington DC [2009-2012; subgroup lead]; and Advisory Group on Nutrition,\u000d\u000a      WHO Geneva [2012-2016]), we have influenced the adoption of policies\u000d\u000a      leading to reduced salt intake and have written protocols, guidelines and\u000d\u000a      recommendations on how to encourage lower salt intakes (a; b; d; g; j-l).\u000d\u000a    Policies to control salt intake are now recommended by the WHO and most\u000d\u000a      governments, and have been endorsed at the United Nations High Level\u000d\u000a      Meeting on the Prevention of Non- Communicable Disease (2011). In 2007,\u000d\u000a      WHO re-stated recommendations of salt targets of 5g per day. Since then,\u000d\u000a      it has developed policies in every continent for the implementation of\u000d\u000a      population salt reduction programmes under the WHO Action Plan on Obesity,\u000d\u000a      Diet and Physical Activityb. The WHO 65th World\u000d\u000a      Health Assembly (2012) decided that population dietary salt should be\u000d\u000a      reduced and should be a priority alongside tobacco control for the\u000d\u000a      reduction of non-communicable disease worldwide. Examples of early\u000d\u000a      adopters of these policies are Slovenia (monitoring and surveillance\u000d\u000a      2008-13), Argentina, Costa Rica and Chile (monitoring tools 2010-13) and\u000d\u000a      South Africa (regulation 2012) (b; d; e).\u000d\u000a    Increased public awareness. In addition to scientific\u000d\u000a      dissemination through publications, reviews, editorials and international\u000d\u000a      meeting presentations on the findings of underpinning research, Warwick\u000d\u000a      researchers have contributed to the three-pronged approach of salt\u000d\u000a      reduction programmes: consumer awareness, food reformulation, monitoring\u000d\u000a      and surveillance (Sutherland J et al. Br J Nutr 2013;110:552-8 -\u000d\u000a      Brinsden HC et al. BMJ Open 2013;3:e002936). Since 2008, the WHO\u000d\u000a      Collaborating Centre at Warwick has held the mandate to work within a\u000d\u000a      global platform to increase research output and operational support to WHO\u000d\u000a      offices (Geneva [Global], Copenhagen [Europe], Washington [PanAmerican],\u000d\u000a      and Cairo [Eastern Mediterranean), and to lead and support monitoring and\u000d\u000a      surveillance in individual countries. We have participated and contributed\u000d\u000a      directly through the WHO Global Platform to all aspects of the\u000d\u000a      three-pronged approach (b; d; e). We have engaged in additional\u000d\u000a      dissemination activities through our website (www2.warwick.ac.uk\/go\/cappuccio\/research_impact)\u000d\u000a      and partnership with non-governmental organizations, such as Consensus\u000d\u000a      Action on Salt and Health (CASH) (h) and the UK Health Forum (i).\u000d\u000a    Impact on public health and economy. Public health benefits\u000d\u000a      have been achieved through an increased public awareness about the\u000d\u000a      importance of lowering individual salt intake; through industry engagement\u000d\u000a      for the re-formulation of food with lowered salt content; and in the\u000d\u000a      monitoring of salt intake nationally through repeated surveys (Millett C et\u000a        al. PLoS ONE 2012; 7(1): e29836 - Shankar B et al. Health\u000d\u000a      Econ 2013; 22:243-50). Crucially, in England and Wales the salt reduction\u000d\u000a      programme has led to reduced salt intake from 9.5g per day in 2001 to 8.1g\u000d\u000a      per day in 2010, a reduction of 1.4 g per day (or 15%). This reduction is\u000d\u000a      estimated to have averted 20,000 CVD events in the UK, of which 8,500\u000d\u000a      would have been fatal (f) with ~131,000 Quality-Adjusted Life\u000d\u000a      Years (QALY) gained. A gain in QALY indicates an extension of life free\u000d\u000a      from illness. Our contribution is clearly listed in a salt reduction\u000d\u000a      timeline published by CASH (h).\u000d\u000a    In addition to substantial health gains for the population, reduction of\u000d\u000a      daily salt intake by 3g per day would lead to economic gains, an annual\u000d\u000a      equivalent savings of at least £40M a year in the UKf.\u000d\u000a      Globally, a 15% reduction of salt intake over 10 years could avert 6.5M\u000d\u000a      deaths from CVD at a cost ranging between $0.04 and $0.32 per person (g).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Many research groups around the world have produced evidence that\u000d\u000a      cardiovascular disease (CVD) can be prevented by dietary salt reduction.\u000d\u000a      The specific contribution of the University of Warwick consists of primary\u000d\u000a      research carried out between 2005 and 2013 by Professor Francesco\u000d\u000a      Cappuccio, who has demonstrated that lower salt intake can lead to a\u000d\u000a      reduction in strokes and total cardiovascular events. These results have\u000d\u000a      informed public health awareness and policy- making both nationally and\u000d\u000a      globally. The research contributed directly to the development of a\u000d\u000a      national policy for salt reduction by the UK National Institute for Health\u000d\u000a      and Care Excellence (NICE) in 2010 by indicating the likely health gains\u000d\u000a      of a population strategy. The research also influenced global policies set\u000d\u000a      out by the World Health Organization (WHO) in 2007, 2010 and 2012.\u000d\u000a      Population-wide reductions in dietary salt are now the second priority\u000d\u000a      after tobacco control set by the United Nations in 2011 for the prevention\u000d\u000a      of non-communicable disease worldwide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Warwick\u000d\u000a    ","Institutions":[{"AlternativeName":"Warwick (University of)","InstitutionName":"University of Warwick","PeerGroup":"A","Region":"West Midlands","UKPRN":10007163}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2660646","Name":"Genève"},{"GeoNamesId":"360630","Name":"Cairo"},{"GeoNamesId":"2618425","Name":"Copenhagen"}],"References":"\u000d\u000a    \u000a1. Aburto NJ et al. Effect of lower sodium intake on health\u000d\u000a      outcomes: systematic review and meta-analysis. BMJ 2013; 346:\u000d\u000a      f1326. doi: 10.1136\/bmj.f1326.[REF2 UoA1 submission]\u000d\u000a    \u000a\u000a2. Strazzullo P et al. Salt intake, stroke and cardiovascular\u000d\u000a      disease: meta-analysis of prospective studies. BMJ 2009; 339:b4567.\u000d\u000a      doi: 10.1136\/bmj.b4567 Cited in NICE PHG 25, 2010; Ministry of\u000d\u000a      Health Canada 2010]. [REF2 UoA1 submission].\u000d\u000a    \u000a\u000a3. Cappuccio FP et al. A community programme to reduce salt\u000d\u000a      intake and blood pressure in Ghana (IRSCTN 88789643). BMC Public\u000d\u000a        Health 2006; 6: 13. doi: 10.1186\/1471-2458-6- 13. [Cited in\u000d\u000a      WHO 2007a]\u000d\u000a    \u000a\u000a4. Ribič CH et al. Salt intake of the Slovene population assessed\u000d\u000a      by 24-hour urinary sodium excretion. Public Health Nutrition 2010;\u000d\u000a      13(11): 1803-9. doi: 10.1017\/S136898001000025X.\u000d\u000a    \u000a\u000a5. Ji C et al. Spatial variation of salt intake in Britain and\u000d\u000a      association with socio-economic status. BMJ Open 2013; 3:e002246.\u000d\u000a      doi:10.1136\/bmjopen-2012-002246\u000d\u000a    \u000a\u000a6. Cappuccio FP et al. Policy options to reduce population salt\u000d\u000a      intake. BMJ 2011;343:402-5. doi: 10.1136\/bmj.d4995\u000d\u000a    \u000aRelated peer-reviewed funding\u000d\u000a    •European Commission — Seventh Framework Programme (Hypergenes - EC\u000d\u000a      201550): €11.0M (£10.0M). Awarded to FP Cappuccio and other 18 European\u000d\u000a      partners (Warwick £393,172) (2008-2011).\u000d\u000a    •The Bupa Foundation (MR-12-002). Spatial variation in salt intake in\u000d\u000a      Britain and effect of socio-economic status: £56,215. Awarded to FP\u000d\u000a      Cappuccio (2012-2013).\u000d\u000a    Awards\u000d\u000a    • World Health Organization Collaborating Centre for Nutrition\u000d\u000a      (Centre Ref. No.: UNK-219) - Head: FP Cappuccio (2008-present).\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"11","Subject":"Nutrition and Dietetics"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    a. NHS National Institute for Health and Clinical Excellence. Prevention\u000a        of cardiovascular disease at population level. NICE Public Health\u000d\u000a      Guidance 25, June 2010 (Cappuccio FP. Expert testimony on salt and\u000d\u000a      cardiovascular disease, February 2009, cited in Annex Report 3) - UK\u000d\u000a      public health recommendations to prevent cardiovascular disease through\u000d\u000a      population salt reduction programmes and target settings for dietary salt.\u000d\u000a    b. WHO. Reducing salt intake in populations: report of a WHO forum\u000d\u000a        and technical meeting. WHO Geneva 2007; pp.1-60 (ISBN\u000d\u000a      978-92-4-159537-7) - global recommendations to reduce population dietary\u000d\u000a      salt intake to prevent cardiovascular disease.\u000d\u000a    c. Ministry of Health of Canada. Sodium reduction strategy for Canada.\u000d\u000a      July 2010 (ISBN: 978-1-100-16232-4) - Canadian recommendations to prevent\u000d\u000a      cardiovascular disease through population salt reduction programmes and\u000d\u000a      target settings for dietary salt.\u000d\u000a    d. WHO. Strategies to monitor and evaluate population sodium consumption\u000d\u000a      and sources of sodium in the diet. WHO Geneva 2011 (ISBN\u000d\u000a      978-92-4-150169-9) - global recommendations for the monitoring and\u000d\u000a      evaluation of population salt intake.\u000d\u000a    e. World Health Organization. Guideline: Sodium intake for adults and\u000d\u000a      children. Geneva, World Health Organization (WHO), 2012, pp.1-56 [ISBN 978\u000d\u000a      92 4 150483 6] - global recommendations to reduce population dietary salt\u000d\u000a      intake to prevent cardiovascular disease.\u000d\u000a    f. Barton P et al. Effectiveness and cost effectiveness of\u000d\u000a      cardiovascular disease prevention in whole populations: modelling study.\u000d\u000a      BMJ 2011; 343:d4044 - a health economic evaluation of population salt\u000d\u000a      reduction based on NICE Public Health Guidance 25\u000d\u000a    g. Asaria P et al. Chronic disease prevention: health effects and\u000d\u000a      financial costs of strategies to reduce salt intake and control tobacco\u000d\u000a      use. Lancet 2007; 370:2044-53 - a health economic evaluation of population\u000d\u000a      salt reduction based on WHO data\u000d\u000a    h. Consensus Action on Salt and Health (www.actiononsalt.org.uk\/salthealth\/Recommendations%20on%20salt\/index.html)\u000d\u000a    i. UK Health Forum (www.ukhealthforum.org.uk\/who-we-are\/our-members\/individual-and-\u000a        associate-members\/)\u000d\u000a    j. WHO. Creating an enabling environment for population-based salt\u000d\u000a      reduction strategies. WHO Geneva 2010; pp. 1-42 (ISBN:\u000d\u000a      978-92-4-150077-7)(citing 2,ii) - global recommendations for the methods\u000d\u000a      to implement a salt reduction programme\u000d\u000a    k. PAHO\/WHO. Salt Smart Americas. A guide for Country-Level Action.\u000d\u000a      Washington (DC), USA, 2013; pp. 1-174 www.paho.org\/hq\/index.php?option=com_content&view=article&id=8677%3Atechnical-document-salt-smart-americas&catid=5387%3Ahsd02k-salt-reduction-media-center&Itemid=39984&lang=en\u000d\u000a      - summary of recommendations for the implementation of the three-pillar\u000d\u000a      approach including a section on Monitoring and Surveillance\u000d\u000a    l. Supporting Statement: Regional Advisor and Unit Chief,\u000d\u000a      Non-communicable Diseases and Disabilities, Pan American Health\u000d\u000a      Organization, World Health Organization (WHO) (Identifier 1). \u000d\u000a    ","Title":"\u000d\u000a    Prevention of Cardiovascular Disease by Dietary Salt Reduction\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Cardiovascular disease (CVD) is the most common cause of death and\u000d\u000a      disability in the world — responsible for over 10M deaths and at least as\u000d\u000a      many disabilities globally every year (Global Burden of Disease).\u000d\u000a      According to the WHO, high blood pressure (BP) is the first attributable\u000d\u000a      cause of CVD. Effective drug therapy is now available to lower BP in\u000d\u000a      people with hypertension. However, pharmacological interventions, although\u000d\u000a      cost-effective in comparison with available treatments for other\u000d\u000a      conditions, are still expensive and not always accessible in low and\u000d\u000a      middle-income countries. Importantly, BP lowering treatments are directed\u000d\u000a      exclusively towards people with a very high risk of hypertension, whereas\u000d\u000a      the majority of CVD occurs in people with BP in a lower range where drug\u000d\u000a      therapy is not recommended. Thus, a non-pharmacological approach to lower\u000d\u000a      BP in the general population would yield the maximum benefit in terms of\u000d\u000a      reduced risk of CVD. A reduction in dietary salt intake lowers BP and\u000d\u000a      reduces CV events, such as strokes and heart attacks. Although the effects\u000d\u000a      of reduced salt intake on BP have been known for decades, the development\u000d\u000a      and implementation of public health policies gained momentum after the\u000d\u000a      publication of new WHO recommendations in 2007, which were supported\u000d\u000a      substantially by new data from Warwick Medical School (WMS).\u000d\u000a    The research underpinning the development and implementation of dietary\u000d\u000a      salt reduction policies nationally and globally was carried out by\u000d\u000a      Professor Francesco Cappuccio (Cephalon Chair of Cardiovascular Medicine\u000d\u000a      & Epidemiology, 2005-present) and his research group (Dr Michelle\u000d\u000a      Miller, Reader in Biochemical Medicine 2006-present and Dr Chen Ji,\u000d\u000a      Research Fellow 2006- present). Since joining Warwick in 2005, Cappuccio\u000d\u000a      has focused on extending his early research that consisted of small\u000d\u000a      randomised control trials (RCTs) into a systematic review and meta-\u000d\u000a      analysis of prospective population studies on the effects of high salt\u000d\u000a      intake on BP (1). His work has produced evidence that salt intake is\u000d\u000a      associated with increased risk of CVD, in particular stroke (2).\u000a      A systematic review and meta-analysis of all published prospective\u000d\u000a      population data in >177,000 participants followed for 3.5 to 19 years\u000d\u000a      found a 23% increase in stroke incidence and a 17% increase in total\u000d\u000a      cardiovascular events amongst people with high salt intake (2). This\u000d\u000a      evidence has been highly cited and has influenced subsequent national and\u000d\u000a      international policy making (see sections 4-5). Cappuccio also carried out\u000d\u000a      the first community-based RCT of salt restriction in sub- Saharan Africa.\u000d\u000a      All fieldwork for this study was completed under his supervision at St\u000d\u000a      George's, University of London, but analyses leading to significant\u000d\u000a      contributions to policy were conducted after Cappuccio moved to Warwick in\u000d\u000a      2005 (3). Cappuccio studied over 1,000 men and women living in semi-urban\u000d\u000a      and rural Ashanti, Ghana, assessing them at baseline and after 6 months of\u000d\u000a      a health promotion intervention that aimed to increase awareness of the\u000d\u000a      need to limit salt consumption. The intervention was carried out by\u000d\u000a      trained community health workers and administered to all villagers.\u000d\u000a      One-hour meetings were held daily in the first week and weekly thereafter\u000d\u000a      in communal areas. Flip charts were used with visual images on one side\u000d\u000a      (shown to participants) and written text on the other (to prompt health\u000d\u000a      workers). Reduction in salt intake averaged ~0.6g per day with a reduction\u000d\u000a      of average systolic BP of ~0.4mmHg at 3 months and ~0.3mmHg at 6 months.\u000d\u000a      The study proved the feasibility of dietary salt reduction at the\u000d\u000a      population level in low-income countries and its efficacy in reducing\u000d\u000a      blood pressure (3). As a result of this influential work WMS was\u000d\u000a      designated as a WHO Collaboration Centre for Nutrition in 2008. As such,\u000d\u000a      we were responsible for supporting governments in setting up systems to\u000d\u000a      monitor salt intake. These efforts have been successful in Slovenia (4),\u000d\u000a      where ~1g reduction in population salt intake was achieved in 5 years\u000d\u000a      (2007-2012). Our work contributed to the development of policy options\u000d\u000a      that were underpinned by research carried out at WMS. We applied\u000d\u000a      principles of monitoring and surveillance to dietary salt intake in\u000d\u000a      Slovenia (4), described for the first time inequalities in dietary salt\u000d\u000a      intake related to socioeconomic status in Great Britain (5), and suggested\u000d\u000a      various policy options (6) which have been adopted by the WHO.\u000d\u000a    "},{"CaseStudyId":"2728","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1835841","Name":"South Korea"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The Cardiff-led programme has defined the standard of care for AHA\u000d\u000a      internationally. This is evidenced by the new national5.2 and\u000d\u000a      international5.3,5.4 treatment guidelines for AHA that have\u000d\u000a      been written (led by Collins in Cardiff with Angela Huth-Kuhne in\u000d\u000a      Germany), based on novel data generated by Cardiff-led research3.1-3.6,\u000d\u000a      that for the first time allow evidence-based treatment of AHA.\u000d\u000a    Our All-Wales3.1 and UK3.2 studies initiated this\u000d\u000a      process prior to the REF impact period, forming the basis of UK national\u000d\u000a      guidelines in 20065.1 (150 citations). Missing information in\u000d\u000a      the 2006 guidelines was:\u000d\u000a    \u000d\u000a      Data about the relative efficacy of available immunosuppressive\u000d\u000a        regimens to eradicate the factor VIII inhibitors in matched patients\u000d\u000a      Comparison of the efficacy of haemostatic treatments to treat bleeds\u000d\u000a        in matched patients.\u000d\u000a      Information about the high frequency of diagnostic delay.\u000d\u000a      Information about the incidence of thrombotic complications of\u000d\u000a        haemostatic agents\u000d\u000a    \u000d\u000a    Over the REF period, further data from the European study3.3-3.6\u000d\u000a      led to the UK guidelines being substantially changed and updated in 20135.2,\u000d\u000a      a process co-ordinated by The UK Haemophilia Centre Directors'\u000d\u000a      Organisation (UKHCDO) Inhibitor Working Party chaired by Collins of\u000d\u000a      Cardiff University. These guidelines have been endorsed by the British\u000d\u000a      Committee on Standards in Haematology, UKHCDO and British Society of\u000d\u000a      Haematology. Of the 18 specific management recommendations on AHA in the\u000d\u000a      2013 guideline5.2, 14 are underpinned by evidence produced by\u000d\u000a      the Cardiff-led research programme. The guidelines have been agreed and\u000d\u000a      adopted by the English Specialised Commissioning Group (The Haemophilia\u000d\u000a      Clinical Reference Group) which has directed that all 90 UK haemophilia\u000d\u000a      centres must follow UKHCDO guidelines.\u000d\u000a    The Cardiff-led research programme has also resulted in the production of\u000d\u000a      two international guidelines5.3,5.4 as collaborations between\u000d\u000a      Cardiff University and European, north American and Japanese colleagues.\u000d\u000a      These guidelines have been adopted worldwide and are the most cited papers\u000d\u000a      in the field since 2009 (90 citations); they have been cited by groups\u000d\u000a      from Europe, north and south America, India, Korea and Japan as accepted\u000d\u000a      standard practice.\u000d\u000a    Recommendations in clinical guidelines and treatment protocols based\u000d\u000a        on Cardiff-led research\u000d\u000a    RECOGNITION AND DIAGNOSIS\u000d\u000a    1. Novel finding: Significant diagnostic delay is common even after\u000d\u000a      abnormal clotting tests have been found (European study)3.3\u000d\u000a    New treatment recommendation: Laboratories should investigate\u000d\u000a      abnormal clotting tests for AHA even if the referring clinician had not\u000d\u000a      requested them and haematologists should directly inform clinicians of the\u000d\u000a      implications of results5.2-5.4\u000d\u000a    2. Novel finding: Delay in recognition of symptoms of AHA (European\u000d\u000a      study)3.3\u000d\u000a    Action: Typical presentations highlighted in management guidelines\u000d\u000a      aimed at general clinicians5.2- 5.4\u000d\u000a    3. Novel finding: Fatal bleeding may occur up to 6 months after\u000d\u000a      diagnosis if inhibitor is not eradicated (UK study)3.2\u000d\u000a    New treatment recommendation: refer to specialist centres to start\u000d\u000a      immunosuppression as soon as the diagnosis is made even if presentation\u000d\u000a      appears benign5.2-5.4\u000d\u000a    TREATMENT\u000d\u000a    4. Novel finding: Combined steroids and cyclophosphamide result in\u000d\u000a      a higher stable remission rate than steroids alone and rituximab confers\u000d\u000a      no additional benefit (European study)3.4\u000d\u000a    New treatment recommendation: Recommended first line\u000d\u000a      immunosuppression protocol changed between the 2006 and 2013 UK guidelines\u000d\u000a      and rituximab to be reserved for second line therapy.5.2\u000d\u000a    5. Novel finding: There is a high incidence of relapse after\u000d\u000a      immunosuppression has been stopped (UK and European studies)3.2,3.4\u000d\u000a    New treatment recommendation: Longer (at least one year) and more\u000d\u000a      intensive follow up is required in specialist clinics5.2-5.4\u000d\u000a    SAFETY\u000d\u000a    6. Novel finding: There is significant morbidity and mortality\u000d\u000a      associated with immunosuppressive regimens (UK and European studies)3.2,3.4\u000d\u000a    New treatment recommendation: Immunosuppressive protocols adapted\u000d\u000a      to take the age and co- morbidity of patients into account5.2-5.4\u000d\u000a    7. Novel finding: The two available inhibitor bypassing agents are\u000d\u000a      equally as effective for controlling bleeds but both are better than\u000d\u000a      factor VIII (European study)3.5\u000d\u000a    New treatment recommendation: Bypassing agents should be used as\u000d\u000a      first line therapy to treat bleeds.5.2-5.4\u000d\u000a    8. Novel finding: Iatrogenic bleeding is common following\u000d\u000a      venepuncture, blood pressure monitoring and invasive procedures. (UK\u000d\u000a      study)3.2\u000d\u000a    New treatment recommendation: Venepuncture and blood pressure\u000d\u000a      monitoring should be kept to a minimum and invasive procedures postponed\u000d\u000a      until factor VIII level has increased.5.2-5.4\u000d\u000a    9. Novel finding: There is a high incidence of arterial and venous\u000d\u000a      thrombotic side effects associated with treating AHA with bypassing agents\u000d\u000a      (European study)3.5\u000d\u000a    New treatment recommendation: Bypassing agents should only be used\u000d\u000a      on the advice of specialist haemophilia centres. Bypassing agents in AHA\u000d\u000a      should not be used in combination or in high dose regimens licensed for\u000d\u000a      congenital haemophilia5.2-5.4\u000d\u000a    10. Novel finding: 25-30% of bleeds resolved without haemostatic\u000d\u000a      treatment and these bleeds have characteristic features (UK and European\u000d\u000a      studies)3.2,3.3,3.5\u000d\u000a    New treatment recommendation: Withhold bypassing agents in certain\u000d\u000a      types of bleeds to limit the risk of thrombotic complications.5.2-5.4\u000d\u000a    Effect of research on measures of clinical outcomes\u000d\u000a    The treatment guidelines have been disseminated to patient groups,\u000d\u000a      clinicians specialising in haemostasis and general physicians around the\u000d\u000a      world. By ensuring they receive the most appropriate treatment and care,\u000d\u000a      the recommendations impact on all patients with AHA. The international\u000d\u000a      guideline published in 2009, aimed at specialist haematologists working in\u000d\u000a      tertiary referral centres, has been cited by groups from Europe, north and\u000d\u000a      south America, India, Korea and Japan as accepted standard practice.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    A Cardiff researcher has led an International 15 year programme resulting\u000d\u000a      in multiple novel findings which have led to changes in the recommended\u000d\u000a      diagnosis and treatment of acquired haemophilia A (AHA). The research has,\u000d\u000a      for the first time, allowed the comparison of immunosuppressive regimens\u000d\u000a      for inhibitor eradication and comparison of the efficacy of treatment\u000d\u000a      strategies to control bleeds. Studies led directly to the production of UK\u000d\u000a      and International guidelines on the management of AHA with 14 of the 18\u000d\u000a      specific recommendations in the UK guideline being underpinned by\u000d\u000a      Cardiff-led research.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Cardiff University\u000d\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1. Collins P, Macartney N, Davies R, Lees S, Giddings J and\u000d\u000a      Majer R. (2004) A population based, unselected, consecutive cohort of\u000d\u000a      patients with acquired haemophilia A. Br J Haematol 124:86-90.\u000d\u000a      DOI: 10.1046\/j.1365-2141.2003.04731.x\u000d\u000a    \u000a\u000a3.2. Collins P, Hirsch S, Baglin T, Dolan G, Hanley J, Makris M,\u000d\u000a      Keeling D, Liesner R, Brown S, Hay C. (2007) Acquired haemophilia A in the\u000d\u000a      UK: a two year national surveillance study by UK Haemophilia Centre\u000d\u000a      Doctors' Organisation. Blood 109:1870-1877.\u000d\u000a      DOI:10.1182\/blood-2006—06- 029850.\u000d\u000a    \u000a\u000a3.3. Knoebl P, Marco P, Baudo F, Collins PW, Huth-Kühne A, Nemes\u000d\u000a      L, Pellegrini F, Tengborn L, Lévesque H. (2012) Demographic and clinical\u000d\u000a      data in acquired hemophilia A: Results from the European Acquired\u000d\u000a      Haemophilia (EACH2) Registry. J Thromb Haemostas 10:622-631. DOI:\u000d\u000a      10.1111\/j.1538-7836.2012.04654.x\u000d\u000a    \u000a\u000a3.4. Collins P, Baudo F, Knoebl P, Lévesque H, Nemes H,\u000d\u000a      Pellegrini F, Marco P, Tengborn L, Huth-Kühne A, (2012) Immunosuppression\u000d\u000a      for acquired hemophilia A: Results from the European Acquired Haemophilia\u000d\u000a      Registry (EACH2). Blood 120:47-55.\u000d\u000a      DOI:10.1182\/blood-2012-02-409185\u000d\u000a    \u000a\u000a3.5. Baudo F, Collins P, Huth-Kuehne A, Lévesque H, Marco P,\u000d\u000a      Nemes L, Pellegrini F, Tengborn L, Knoebl P. (2012) Management of Bleeding\u000d\u000a      in Acquired Haemophilia A: Results from the European Acquired Haemophilia\u000d\u000a      (EACH2) Registry. Blood 120:39-46. DOI :10.1182\/blood-2012-\u000d\u000a      02-408930\u000d\u000a    \u000a\u000a3.6. Tengborn L, Baudo F, Huth-Kühne A, Knoebl P, Lévesque H, Marco P,\u000d\u000a      Pellegrini F, Nemes L, Collins P. (2012) Pregnancy-associated\u000d\u000a      acquired haemophilia A: Results from the European Acquired Haemophilia\u000d\u000a      (EACH2) Registry. British Journal of Obs and Gynae 119:1529-1537.\u000d\u000a      DOI: 10.1111\/j.1471-0528.2012.03469.x\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    5.1. Hay C, Brown S, Collins P, Keeling D, Liesner R. (2006) The\u000d\u000a      diagnosis and management of factor VIII and IX inhibitors: a guideline\u000d\u000a      from the United Kingdom Haemophilia Centre Doctors Organisation. Br J\u000d\u000a        Haematol. 133:591-605. DOI: 10.1111\/j.1365-2141.2006.06087.x (Shows\u000d\u000a      guidelines included prior to research)\u000d\u000a    5.2. Collins P, Chalmers E, Hart D, Jennings I, Liesner R,\u000d\u000a      Rangarajan S, Talks K, Williams M, Hay. (2013) Diagnosis and management of\u000d\u000a      acquired coagulation factor inhibitors: a guideline from UKHCDO. Brit\u000d\u000a        J Haematol. 162:758-73, 2013. DOI: 10.1111\/bjh.12463 ((Backs up\u000d\u000a      claim of creation of new guidelines)\u000d\u000a    5.3. Collins P, Baudo F, Huth-Kühne A, Ingerslev J, Kessler C,\u000d\u000a      Mingot Castellano M, Shima M, St-Louis J, Lévesque H. (2010) Consensus\u000d\u000a      recommendations for the diagnosis and treatment of acquired hemophilia A.\u000d\u000a      BMC Research Notes 3:161 doi:10.1186\/1756-0500-3-161 (Backs up\u000d\u000a      claim of new treatment recommendation)\u000d\u000a    5.4. Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM,\u000d\u000a      Levesque H, Castellano ME, Shima M, St-Louis J. (2009) International\u000d\u000a      recommendations on the diagnosis and treatment of patients with acquired\u000d\u000a      haemophilia A. Haematologica 94:566-575. doi:\u000d\u000a      10.3324\/haematol.2008.001743 (Backs up claim of inclusion in international\u000d\u000a      guidelines and new treatment recommendations)\u000d\u000a    Suggested expert external referees who will confirm that 2013 UK\u000d\u000a        treatment guidelines were based on data derived from Cardiff University\u000d\u000a        research are:\u000d\u000a    \u000d\u000a      Chair of UK Haemophilia Centre Doctors' Organisation\u000d\u000a      Chair of the Haemostasis and Thrombosis Taskforce of the British\u000d\u000a        Committee for Standards in Haematology\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Cardiff-led research underpins new UK and International clinical\u000d\u000a        treatment guidelines for the management of acquired haemophilia A\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    AHA is an autoimmune disease caused by antibodies to clotting factor\u000d\u000a      VIII. It mainly affects older people with an incidence of\u000d\u000a      1.5\/million\/year. It may be precipitated by underlying autoimmune disease,\u000d\u000a      malignancy or pregnancy. AHA is associated with severe bleeding and 30-40%\u000d\u000a      one year mortality.\u000d\u000a    Before the Cardiff-led research programme, the description of AHA was\u000d\u000a      limited to single centre cohorts and collections of referral centre\u000d\u000a      experiences, reflecting only the more severely affected patients. This\u000d\u000a      information was not applicable to most patients. Studies had short\u000d\u000a      follow-up and long-term outcomes were unknown. There was only one\u000d\u000a      controlled study in the field and this was underpowered and uninformative.\u000d\u000a      Management guidelines therefore relied on expert opinion rather than\u000d\u000a      evidence.\u000d\u000a    To define standards of care for AHA based on evidence, the Cardiff team,\u000d\u000a      led by by Dr John Giddings (Lecturer and Senior Lecture, Cardiff\u000d\u000a      University, 1972 -2007) and Peter Collins (Cardiff and Vale, NHS\u000d\u000a      consultant until he became Cardiff University Senior Lecturer 2001-2010,\u000d\u000a      Reader in Haematology 2010-2013 and since promoted to Clinical Professor),\u000d\u000a      initiated a programme of studies in 1996, which evolved into UK and\u000d\u000a      Europe-wide collaborations.\u000d\u000a    The All Wales AHA cohort\u000d\u000a    An All-Wales study was designed to establish the incidence and long term\u000d\u000a      outcome of AHA in a well defined, unbiased cohort of patients between 1996\u000d\u000a      and 20023.1. This established the platform for Cardiff\u000d\u000a      University to design and lead a prospective UK-wide surveillance study.\u000d\u000a    UK AHA surveillance study\u000d\u000a    The UK study was initiated and led by Collins in Cardiff and documented\u000d\u000a      the first complete description of AHA and its treatment in an unbiased\u000d\u000a      cohort of patients. The unique and outstanding strength of the UK study is\u000d\u000a      that all UK Hospitals reported on all patients presenting with AHA over a\u000d\u000a      two-year period (2001-2003), generating a national cohort free from\u000d\u000a      recruitment or reporting bias. The study established the incidence,\u000d\u000a      predisposing conditions, age distribution and long-term outcomes of\u000d\u000a      patients with AHA and is recognised as the definitive publication in the\u000d\u000a      field3.2.\u000d\u000a    The European Acquired Haemophilia Registry (EACH2)\u000d\u000a    In rare diseases prospective randomised trials are challenging and so\u000d\u000a      Cardiff established a European collaboration (co-chaired by Collins)\u000d\u000a      designed to investigate the optimal treatment of AHA. Involving 93 centres\u000d\u000a      from 13 countries, this study recruited between 2003 and 2009 and included\u000d\u000a      about 14% of European patients during that time. Propensity score matching\u000d\u000a      allowed comparison of treatment outcomes.\u000d\u000a    World-first findings of this three stage research program were:\u000d\u000a    \u000d\u000a      The age-related incidence of AHA and the incidence in pregnancy3.1,3.2,3.6\u000a\u000d\u000a      The disease characteristics and underlying conditions in unselected\u000d\u000a        populations and the effect of these on long-term outcomes3.1,3.2,3.3\u000a\u000d\u000a      Evidence for significant diagnostic delay and lack of awareness of the\u000d\u000a        implications of abnormal coagulation results amongst clinicians that\u000d\u000a        puts patients at unnecessary risk of severe bleeding3.3\u000a\u000d\u000a      That fatal bleeding may occur up to 6 months after presentation even\u000d\u000a        if the initial presentation appears benign3.2\u000a\u000d\u000a      The remission rate and survival associated with different\u000d\u000a        immunosuppressive therapies in matched cohorts of patients. The\u000d\u000a        combination of steroids and cyclophosphamide was shown to be associated\u000d\u000a        with an improved remission rate compared to steroids alone. Regimens\u000d\u000a        using rituximab conferred no additional benefit, contrary to previously\u000d\u000a        held opinion and practice3.4\u000a\u000d\u000a      Significant morbidity and mortality associated with immunosuppressive\u000d\u000a        regimens3.2,3.4\u000a\u000d\u000a      The high incidence of relapse (10-20%) after stopping\u000d\u000a        immunosuppression3.2,3.4\u000a\u000d\u000a      The two inhibitor bypassing agents, licensed to treat bleeding in AHA,\u000d\u000a        are equally effective for controlling bleeding and both are better than\u000d\u000a        factor VIII3.5\u000a\u000d\u000a      There is a high incidence of serious thrombotic side effects\u000d\u000a        associated with the use of bypassing agents in patients with AHA3.5\u000a\u000d\u000a      Between 25 and 30% of bleeds resolved without haemostatic treatment\u000d\u000a        and a description of the characteristics of these self-limiting bleeds3.2,3.4\u000a\u000d\u000a\u000d\u000a        These findings were used to produce the first evidence-based treatment\u000d\u000a        guidelines in the field.5.2-5.4\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"2729","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2264397","Name":"Portugal"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"}],"Funders":["Wellcome Trust","Biotechnology and Biological Sciences Research Council"],"ImpactDetails":"\u000a    The impact from research conducted at the UoW and Neurosolutions can be\u000a      classified as:\u000a    \u000a      Patents, intellectual property (IP) and research publications by\u000a        Neurosolutions staff with academic and industrial partners, which have\u000a        ultimately led to Neurosolutions generating annual revenues averaging\u000a        £1.4M per annum.\u000a      Development of two novel compounds for treating pain. The first\u000a        compound NSL-043 for treating neuropathic pain was developed in\u000a        partnership with Sosei (Japan). The second, NSL-101 for treating dental\u000a        pain, was developed in partnership with Ampika (Cambridge).\u000a      The creation of new biotechnology companies by providing\u000a        \"proof-of-concept\" data to support financing\/fund-raising of these new\u000a        companies (e.g. Cambridge Biotechnology, Numedicus, Cerebrasol).\u000a      Facilitation of novel strategies and therapies for neurological\u000a        disorders through research contracts with industrial clients, earning\u000a        around £7.5M in revenue from the biotechnology and pharmaceutical\u000a        industry since 2001.\u000a    \u000a    In addition, D. Spanswick was nominated by industry for the BBSRC\u000a      Entrepreneur of the Year Award in 2011. Further details of each impact are\u000a      provided below.\u000a    By combining the biomedical research skills of Spanswick (neural networks\u000a      in isolated mammalian central neural preparations), Lee and Rush\u000a      (single-cell, molecular biology and electrophysiology) and Zhao and Jeggo\u000a      (in vivo electrophysiology in whole organisms and behaviour) to\u000a      address the site, mode and mechanism of action of novel compounds,\u000a      Neurosolutions was founded as a commercial enterprise at the interface\u000a      between academia and industry. Its aim was to provide services to the\u000a      pharmaceutical and biotechnology industries, to facilitate the development\u000a      of novel drugs for neurological disorders; and to commercialise academic\u000a      research.\u000a    Intellectual Property: Research conducted at Neurosolutions led to\u000a      the creation of intellectual property and two patents were granted (see\u000a      Section 3). Neurosolutions undertook all preclinical development of\u000a      compounds before taking public investment from Australia (£1.5M approx)\u000a      and floating on the ASX in 2005 to support clinical development of NSL-043\u000a      for neuropathic pain (successfully completed 2 Phase I studies in\u000a      2008-2009 and may possibly enter Phase II trials with a local partner in\u000a      China) and NSL-101 (which completed Phase II trials in 2009-2010 and is\u000a      currently under formulation as a topical cream treatment).\u000a    Contract Research: Neurosolutions is a profit-making contract\u000a      research organisation (a). With a growing reputation and increased demand\u000a      for services from North America (see below for details), Neurosolutions\u000a      expanded its operations with the creation of Cerebrasol (in Montreal) as a\u000a      sister company in 2010 (b, c). Fifteen full-time staff are currently based\u000a      in the UK and Montreal. Neurosolutions has provided expert translational\u000a      neuroscience services to over 100 industrial clients worldwide since its\u000a      foundation. Clients include major pharmaceutical companies - Merck (US),\u000a      Eli-Lilly (US and UK); GSK, Pfizer, Organon, Schering-Plough (both now\u000a      Merck); Johnson & Johnson; Astra Zeneca (Canada and Sweden); Merz,\u000a      Evotech (Germany); Bial (Portugal); Sepracor and Sunovion (US); Lundbeck\u000a      (Sweden); Upsher-Smith (US); Takeda (UK, US, Japan); UCB - and small to\u000a      medium-sized companies - Neurotherapeutics, Envoy Therapeutics, Elan (US),\u000a      Senexis, Xention, (UK); Pangenetics (Netherlands), Syngene (Australia).\u000a      Owing to the confidential nature of much of the work undertaken with these\u000a      companies we are unable to outline all aspects of the research in which\u000a      Neurosolutions has added value\/impact to companies. However, some examples\u000a      are given below.\u000a    Commercial Impact: Promoting Development of new Biotechnology\u000a        Companies: Neurosolutions has supported the development of 5 new\u000a      biotechnology companies. For example, proof-of-concept studies on leptin\u000a      mimetics for obesity and compounds for pain were undertaken for Cambridge\u000a      Biotechnology, which was founded in 2001. Cambridge Biotechnology\u000a      subsequently raised £10M from venture capitalists (Merlin Biosciences) and\u000a      was subsequently acquired by Boivitrum (2005), Proximagen (2009) and\u000a      Upsher-Smith in 2012 for £356.8M (d). Similarly, Neurosolutions provided\u000a      proof-of-concept data enabling the development of Numedicus.\u000a      Neurosolutions undertook extensive preclinical proof-of-concept data on\u000a      anti-Nerve Growth Factor antibodies and their utility for pain for the\u000a      Dutch\/UK company Pangenetics, which was subsequently acquired by Abbott\u000a      for US$170M in November 2009 (e).\u000a    Scientific impact: design of novel strategies and identification of\u000a        targets and mechanisms of action for therapeutic interventions.\u000a      Neurosolutions has provided consultancy and research services to\u000a      Neurotherapeutics (NTP; US), facilitating development of a research plan\u000a      to identify the mechanism of action of a novel NTP compound and providing\u000a      a preclinical data pack to support clinical development (f). A novel\u000a      mechanism of action of a series of GSK anticonvulsant compounds\u000a      (Carabersat, Tonabersat) was identified by Spanswick, initially\u000a      academically and subsequently by Neurosolutions. One of these compounds\u000a      (Tonabersat) was acquired by Proximagen with Upsher-Smith (US), and is\u000a      undergoing further mechanism of action work with Neurosolutions\u000a      (2012-2013). Tonabersat has already been subject to clinical trials for\u000a      migraine and is currently being re-profiled for epilepsy (g). Such has\u000a      been the success of the translational neuroscience research approach\u000a      adopted by us that Neurosolutions has extended the research capability to\u000a      psychiatry and neurodegeneration with a focus on cognitive deficits in\u000a      Parkinson's disease. In-house technologies have already been used\u000a      successfully to support development of novel compounds\/treatment\u000a      strategies for Alzheimer's disease with models of memory loss (Senexis,\u000a      Merz, Elan), with one of the Senexis compounds recently (2012) acquired by\u000a      BTG for clinical development (h).\u000a    Future Impact: Neurosolutions and Cerebrasol in partnership with\u000a      TransPharmation and Monash University are extending operations into\u000a      Australia (2013). This major collaborative project will form a new\u000a      Australian company (Pacific Discovery Services) as part of a consortium\u000a      focused on translational research and development of novel strategies and\u000a      treatments for neurological disorders. The initial focus is pain and\u000a      obesity, but will expand into other conditions as the company evolves.\u000a    ","ImpactSummary":"\u000a    Based on electrophysiological research conducted at the University of\u000a      Warwick from 2000, Neurosolutions was founded as a spin-out company in\u000a      2001. As well as developing its own novel compounds, Neurosolutions\u000a      provides specialised translational biomedical research services to the\u000a      biotechnology and pharmaceutical industries to facilitate preclinical drug\u000a      development of novel strategies to treat neurological disorders. In 2005,\u000a      Neurosolutions floated on the Australian Stock Exchange (ASX) as\u000a      Neurodiscovery to support the clinical development in-house of two\u000a      compounds (both are patent-protected): NSL-043 for neuropathic pain (which\u000a      completed 2 phase I studies in 2008-2009) and NSL-101 for dental pain\u000a      (which completed phase II trials in 2009-2010). In 2010, Neurosolutions\u000a      expanded its operations to Montreal, Canada. Neurosolutions is a profit-\u000a      making contract research organisation with 15 full-time staff based in the\u000a      UK and in Montreal, has annual revenues averaging £1.4M per annum and has\u000a      earned around £7.5M in contracts from the biotechnology and pharmaceutical\u000a      industries since its launch.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Warwick\u000a    ","Institutions":[{"AlternativeName":"Warwick (University of)","InstitutionName":"University of Warwick","PeerGroup":"A","Region":"West Midlands","UKPRN":10007163}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6077243","Name":"Montréal"}],"References":"\u000a    \u000a1. van den Top, M. et al. Orexigen-sensitive NPY\/AgRP pacemaker\u000a      neurons in the hypothalamic arcuate nucleus. Nature Neurosci.\u000a      2004; 7(5): 493-494. doi:10.1038\/nn1226\u000a    \u000a\u000a2. van den Top, M. et al. Pharmacological and molecular\u000a      characterization of ATP-sensitive K+ conductances in CART and\u000a      NPY\/AgRP expressing neurons of the hypothalamic arcuate nucleus. Neuroscience\u000a      2007; 144 (3): 815-824. doi:10.1016\/j.neuroscience.2006.09.0.\u000a    \u000a\u000a3. van den Top, M. et al. Orexins induce increased excitability\u000a      and synchronisation of rat sympathetic preganglionic neurones. J.\u000a        Physiol. 2003; 549: 809-821. doi:10.1113\/jphysiol.2002.033290.\u000a    \u000a\u000a4. Hudmon A, Choi JS, Tyrrell L, Black JA, Rush AM, Waxman SG, Dib-Hajj\u000a      SD. Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated\u000a      protein kinase increases current density in dorsal root ganglion neurons.\u000a      J Neurosci. 2008; 28(12): 3190-201. doi: 10.1523\/JNEUROSCI.4403-07.2008.\u000a    \u000a\u000a5. Zhao, F. Y. et al. GW406381, a novel COX-2 inhibitor,\u000a      attenuates spontaneous ectopic discharge in sural nerves of rats following\u000a      chronic constriction injury. Pain 2007; 128(1-2): 78-87. doi:10.1016\/j.pain.2006.08.032\u000a    \u000a\u000a6. Scopes, D. I. et al. A03b2 oligomer toxicity inhibitor\u000a      protects memory in models of synaptic toxicity. Br. J. Pharmacol.\u000a      2012; 167(2): 383-392. doi:10.1111\/j.1476-5381.2012.01973.x\u000a    \u000a \u000a    Peer-reviewed and industrial grants\u000a    A. Epilepsy Research Foundation. Modulation of gap-junction function in in\u000a        vitro models of epilepsy. £99,810. Oct 1998-Sep 2002. PIs: D.\u000a        Spanswick & S. Davies.\u000a    B. GlaxoSmithKline. Modulation of electrical synapses by novel\u000a      anticonvulsants. £50,000. Sep 2001-Aug 2002. PI: D. Spanswick.\u000a    C. Pfizer. Electrophysiological and pharmacological characterisation of\u000a      spinal dorsal horn neurones. £81,000. Mar 2001-Sep 2003. PI: D.\u000a        Spanswick.\u000a    D. Biotechnology & Biological Sciences Research Council (BBSRC).\u000a      Characterization of lamina I neurons in the adult spinal cord in vitro,\u000a      £179,867 (2001-2004). PI: K. Lee.\u000a    E. BBSRC. Integration of neurohormonal signalling mechanisms regulating\u000a      energy balance in the arcuate nucleus in vitro. £258,124. Apr\u000a      2002-Mar 2005. PI: D.Spanswick.\u000a    F. BBSRC. Molecular and physiological properties of electrical synapses\u000a      in mammalian central neurones. £217,256. Oct 2002-Sept 2005. Applicants:\u000a        K. Lee & D. Spanswick.\u000a    G. The Wellcome Trust (073934\/Z\/03\/Z): Modulation of neuronal activity\u000a      patterning by electrotonic coupling in the amygdala. £172,256. Mar\u000a      2004-Feb 2007. PI: D. Collins.\u000a    H. BBSRC (BB\/C001125\/1). Integration of signalling mechanisms in\u000a      neuropeptide Y\/Agouti related protein (NPY\/AgRP) pacemaker neurones in the\u000a      arcuate nucleus of the hypothalamus. £310,996. PI: D. Spanswick.\u000a    I. BBSRC\/Department of Trade Industry (DTI)-supported Knowledge Transfer\u000a      Partnership (KTP). Design, development and implementation of isolated\u000a      tissue and behavioural models of learning\/memory disorders. Awarded in\u000a      2008 for 2.5 years. £156,523. Applicants: D. Spanswick, E. O'Hare (Queens\u000a      University Belfast, N. Ireland) & Neurosolutions. PI: D Spanswick.\u000a    J. Technology Strategy Board (TSB)\/Neurosolutions-sponsored Knowledge\u000a      Transfer Partnership. The development, validation and commercialisation of\u000a      a new package of models to investigate stress\/anxiety and depressive\u000a      behaviours. Awarded in 2012 for 2 years. £128K. Applicants: D.\u000a        Spanswick, Dawn Collins (UoW) & Neurosolutions.\u000a    Patents:\u000a    • NZ564170, Thiazolopyrimidines for Use in Therapy (2005).\u000a    • WO2010010394, Local Pharmaceutical Compositions (2008).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    a. See http:\/\/www.neurodiscoveryltd.com\/default.htm\u000a    b. See http:\/\/www.cerebrasol.com\/contact.html\u000a    c. Supporting statement from CEO, Neurosolutions Ltd. and Cerebrasol.\u000a      (Identifier 1)\u000a    d. Supporting statement from Former Founder, MD and Chief Scientific\u000a      Officer, Cambridge Biotechnology (former Head of Discovery at Biovitrium\u000a      AB and Consultant to Proximagen): Provides a summary of the contributions\u000a      of Neurosolutions to Cambridge Biotechnology Ltd, Biovitrium AB,\u000a      Proximagen Group and Upsher Smith Laboratories. (Identifier 2).\u000a    e. See\u000a      http:\/\/www.news-medical.net\/news\/20091113\/Abbott-to-acquire-the-global-rights-to-PanGenetics-new-therapeutic-for-treatment-of-chronic-pain.aspx;\u000a      Neurosolutions reports NSLR- 103 and NSLR-110 illustrating some of the\u000a      work done, and supporting statement from former Vice President Preclinical\u000a      Development, Pangenetics (currently Chief Scientific Officer of SweetSpot\u000a      Therapeutics Ltd.): Confirms the value of the work undertaken by\u000a      Neurosolutions to Pangenetics. (Identifier 3).\u000a    f. See Neurosolutions reports NSLR-190, NSLR-199, NSLR-200, NSLR-201,\u000a      NSLR-203, NSLR- 206, NSLR-207, NSLR-208a, NSLR-208b, NSLR-209 (Restricted\u000a      access - available on request only), highlighting the mechanism of action\u000a      and preclinical proof-of-concept data delivered for NTP and research\u000a      strategy developed for this client.\u000a    g. Supporting statement from Head of Discovery, Proximagen (Upsher Smith\u000a      Laboratories): Provides a summary of contributions of Neurosolutions to\u000a      the development of Tonabersat and Carabersat by Proximagen and Upsher\u000a      Smith Laboratories. (Identifier 4).\u000a    h. Supporting statement from Director and Former CEO, Senexis Limited:\u000a      Confirms Senexis has benefitted considerably from Neurosolutions research\u000a      and that Neurosolutions' biomedical research has added value to Senexis'\u000a      drug discovery programmes. (Identifier 5). \u000a    ","Title":"\u000a    Neurosolutions: a commercial partnership between academia and industry\u000a        to develop novel drugs for neurological disorders\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The science underpinning Neurosolutions was based on four key areas of\u000a      research conducted at Warwick from 2000 to the present day by: Professor\u000a      David Spanswick (Professor of Molecular Neurosciences, Warwick Medical\u000a      School; 2000-present) and Professor Kevin Lee (Senior Lecturer, Department\u000a      of Biological Sciences, University of Warwick 2001-2004; Honorary\u000a      Professor Warwick Medical School; 2005-present; Currently CSO Rare disease\u000a      research at Pfizer; 2010-present); Dr Fei-Yue Zhao, visiting academic,\u000a      University of Warwick 2001-present); Dr Ross Jeggo (Senior Research\u000a      Fellow, Warwick Medical School; 2007-2008, and a visiting academic, School\u000a      of Life Sciences; 2003-present); Dr Tony Rush (Senior Research Fellow,\u000a      Warwick Medical School; 2007-2008) and visiting academic, School of Life\u000a      Sciences (2006-2009). This research is centred upon the following key\u000a      areas:\u000a    \u000a      Central neural control of bodyweight and obesity. Research on central\u000a        control of energy balance at Warwick revealed hypothalamic orexigenic\u000a        NPY\/AgRP neurones to be a key site of action of these hormones1, E,\u000a          H and described a broad role for ATP-sensitive potassium\u000a        channels in energy-sensing neurones in the arcuate nucleus, including\u000a        NPY\/AgRP and anorexigenic POMC\/CART neurones.2 This work\u000a        extended previous research conducted in Aberdeen showing leptin inhibits\u000a        hypothalamic neurones by activation of ATP-sensitive potassium channels\u000a        (Nature 1997; 390 (6659): 521-525 (587 citations)) and that\u000a        insulin has a similar action via a phosphoinositide 3-kinase\u000a        (PI3-kinase)- dependent mechanism (Nature Neurosci. 2000; 3(8):\u000a        757-758 (459 citations).\u000a      Our expertise in spinal cord slice electrophysiology and ability to\u000a        probe the functional operation of neural circuits in normal and diseased\u000a        states. Our group is one of few in the world to use dual whole-cell\u000a        patch clamp recording techniques in isolated mammalian brain and spinal\u000a        slice preparations to record electrical activity transmitted directly\u000a        between coupled nerve cells.3, A, B, F, G It was this\u000a        relatively rare technology and the ability to record from spinal cord\u000a        tissue in vitro using dual recording techniques that led to academic\u000a        collaborations with GlaxoSmithKline (GSK; see B), to identify the\u000a        mechanism of action of a family of novel anticonvulsants with utility\u000a        for pain, and Pfizer on novel targets for treating neuropathic pain. B,\u000a          C Lee was a pioneer in the use of electrophysiological recording\u000a        techniques combined with single-cell molecular biology techniques to\u000a        identify gene expression profiles in single identified neurones in\u000a        normal and diseased states. This technology is exploited in all aspects\u000a        of the research at UoW. 1, 2, 3; D-H Rush's research also\u000a        focussed on electrophysiological recording techniques to probe\u000a        properties of ion channels at the single-cell level. This improved\u000a        understanding of the action of novel agents targeting ion channels, in\u000a        particular those channels involved in transmitting pain signals in\u000a        peripheral nerves.4\u000a\u000a      Zhao's research focussed on pain, in particular novel peripheral and\u000a        spinal targets for treating pain. Electrophysiological recording and\u000a        behavioural research techniques were used to explore mechanisms\u000a        underlying pain and the site, mode and mechanism of action and\u000a        therapeutic potential of novel analgesics.5 Similar research\u000a        techniques were employed by Jeggo focussed on Alzheimer's Disease and\u000a        neurodegeneration.6\u000a\u000a    \u000a    This multidisciplinary academic expertise spanning the single-cell,\u000a      molecular and genetic (Lee, Rush), spinal cord and brain signalling in\u000a      neural circuits in isolated slice preparations (Spanswick, Lee) and whole\u000a      animal electrophysiology and behaviour (Zhao, Jeggo), provided a suite of\u000a      preclinical platform technologies designed to accelerate and facilitate\u000a      translation of basic neuroscience to clinical trials. To interface and\u000a      promote interaction with the pharmaceutical industry and provide the\u000a      vehicle to commercialise our research, we founded the Warwick spin-out,\u000a      Neurosolutions. We focused initially on pain and obesity and subsequently\u000a      through Knowledge Transfer partnerships (DTC, TSB and BBSRC-supported; I,\u000a        J) we expanded into other neurological indications including\u000a      Alzheimer's disease and psychiatric disorders.\u000a    "},{"CaseStudyId":"2933","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2661886","Name":"Sweden"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Generation of Income\u000d\u000a      In 1998 the DLQI was established as the leading dermatology measure,\u000d\u000a      planning long-term income generation. We allow its use without charge\u000d\u000a      except for studies funded by for-profit companies.\u000d\u000a      IMPACT: 83 pharmaceutical companies\/divisions have used the DLQI.\u000d\u000a      The total income generated for Cardiff University from the DLQI has been\u000d\u000a      £881,236 (equivalent to 176,000 patients); the total income from Aug 2008\u000d\u000a      - June 2013 was £617,778.\u000d\u000a    Establishment of guidelines\u000d\u000a      The breakthrough in making the DLQI useful to clinicians was our 2005\u000d\u000a      simple score interpretation method, the Banding Descriptor concept 3.3,\u000d\u000a      and the psoriasis severity \"Rule of Tens\" 3.4.\u000d\u000a      IMPACT: Development of NICE (2006-9) and SIGN (2010) guidelines for\u000d\u000a      the Biologics infliximab, adalimumab and ustekinumab in psoriasis 5.1,\u000a        5.2 and (NICE) (2009) for treatment of severe hand dermatitis 5.1.\u000d\u000a      Adoption within guidelines by national organisations and national\u000d\u000a      registries in 11 countries, e.g. Sweden 5.3 (8 since 2008).\u000d\u000a      Chren commented 5.4 on our Banding Descriptor paper 3.3\u000d\u000a      and another: \"These papers are important for several reasons. First, both\u000d\u000a      studies examine instruments that were developed and refined by Andrew\u000d\u000a      Finlay and his colleagues in Cardiff, highlighting the seminal and\u000d\u000a      sustained effects of their work on improving the measurement of complex\u000d\u000a      constructs in dermatology.\"\u000d\u000a    Reach\u000d\u000a      We have supervised 91 validated translations of the DLQI (51 since 2008),\u000d\u000a      reviewing back translations to ensure accuracy. The DLQI section of the\u000d\u000a      Dermatology Department website (www.dermatology.org.uk),\u000a      has since 1999 been an essential part of our strategy to make the DLQI\u000d\u000a      easily accessible worldwide. This is constantly updated. All translations\u000d\u000a      are available and instructions for use are given. The website was accessed\u000d\u000a      for DLQI information by 22,703 visits from Nov 2011 - June 2013, bringing\u000d\u000a      web-users to the Cardiff University site. A Google search for DLQI records\u000d\u000a      183,000 results. The original article 3.1 has been cited 1,029\u000d\u000a      times.\u000d\u000a    IMPACT: The DLQI is used internationally and can therefore be used\u000d\u000a      effectively for multi-centre studies e.g. DLQI was used as an outcome\u000d\u000a      measure in Phase III studies of cyclosporine and of all biologics in\u000d\u000a      psoriasis 3.6.\u000d\u000a    IMPACT: In 2012 alone, publications described DLQI usage in 105\u000d\u000a      studies of 37 diseases in 25,785 patients in 29 countries (review of all\u000d\u000a      2012 publications identified by PubMed). The DLQI has been used in over\u000d\u000a      678 research studies (PubMed review). The DLQI has been of great benefit\u000d\u000a      to dermatology research teams worldwide. Pharmaceutical companies use the\u000d\u000a      measure widely in Phase II and Phase III studies 3.6, as\u000d\u000a      reported in >148 publications (PubMed review). The DLQI is the most\u000d\u000a      frequently used adult QoL measure in psoriasis and in atopic dermatitis 5.5.\u000d\u000a      We continue to make the DLQI more accessible and useful for clinicians.\u000d\u000a      With Janssen Pharmaceuticals, we have upgraded a free iPhone and iPad app\u000d\u000a      \"360 Psoriasis\" to include the DLQI and a graphic score readout with\u000d\u000a      meaning. When released in 2014, >6,000 current users will be able\u000d\u000a      download this.\u000d\u000a    IMPACT: The DLQI in standard software will be used daily by GPs to\u000d\u000a      support decisions such as referral to secondary care and by dermatologists\u000d\u000a      to assist decisions concerning systemic therapy.\u000d\u000a    Clinicians and healthcare providers benefit\u000d\u000a      The DLQI assists clinicians to understand their patients and justify their\u000d\u000a      clinical decisions.\u000d\u000a    IMPACT: Since 2008, all patients with severe psoriasis or with\u000d\u000a      severe hand eczema are assessed with the DLQI (as recommended by NICE) 5.1,\u000a        5.2 and this directly influences whether the patient has access to\u000d\u000a      biologics. The DLQI may be helpful to health care providers to identify\u000d\u000a      conditions that need additional clinical support, and DLQI data is used to\u000d\u000a      support clinicians' requests for additional funding for individual patient\u000d\u000a      therapy. For example people with the condition hidradenitis suppurativa\u000d\u000a      have high scores, reflecting major but unrecognised QoL problems.\u000d\u000a    Patient benefit\u000d\u000a      Patient support groups in several countries, such as the Finnish\u000d\u000a      Psoriasis Association and the UK Ichthyosis Support Group, give patients\u000d\u000a      access online to the DLQI, so they can use the questionnaire in\u000d\u000a      discussions with their doctor, leading to more appropriate clinical\u000d\u000a      decisions.\u000d\u000a    IMPACT: When used routinely, 13.8% of clinical decisions in\u000d\u000a      general clinics were influenced by knowing the DLQI score, usually in\u000d\u000a      patients with scores >10 and who were consequently treated more\u000d\u000a      aggressively 5.6.\u000d\u000a    All dermatologists in the UK and in 10 other countries are required to\u000d\u000a      use the DLQI routinely to support decisions relating to the use of\u000d\u000a      biologics in psoriasis. DLQI usage has resulted in a measureable shift to\u000d\u000a      patient-centred dermatology 5.7.\u000d\u000a    IMPACT: It has become normal for dermatologists to think of QoL\u000d\u000a      and to measure it to assist their decisions, fundamentally altering the\u000d\u000a      practice of dermatology to a more patient-orientated speciality. Since\u000d\u000a      2008, 100% of dermatology clinicians in Wales stated that QoL was an\u000d\u000a      influence on their clinical decisions. DLQI scores have become integral to\u000d\u000a      European S3-guidelines 5.8, in defining treatment goals in\u000d\u000a      psoriasis 5.9 and for pharmaco-economic analysis 5.1.\u000d\u000a      By highlighting the major impact of skin involvement in other conditions,\u000d\u000a      such as HIV\/AIDS 5.10, DLQI data may further influence\u000d\u000a      appropriate management.\u000d\u000a    Competitors and additional Cardiff measures\u000d\u000a    Other research teams have created similar questionnaires to compete with\u000d\u000a      the DLQI, but the DLQI is the most frequently used measure in research and\u000d\u000a      in clinical practice (PubMed review). We have demonstrated the DLQI's many\u000d\u000a      strengths in comparison 5.7. Other measures developed in\u000d\u000a      Cardiff by Finlay and colleagues from 1993 to present include the\u000d\u000a      Children's-DLQI, Dermatitis Family Impact (DFI) and Infant's Dermatitis\u000d\u000a      Quality of Life (IDQoL). These are the most frequently used QoL measures\u000d\u000a      in children 5.5. They are available on the Dermatology\u000d\u000a      Department website (www.dermatology.org.uk), increasing the exposure of\u000d\u000a      the DLQI.\u000d\u000a    Conclusions\u000d\u000a    The DLQI as described by the indicators outlined above claims economic\u000d\u000a      impact, impact on the practice of health-care professionals and on health\u000d\u000a      and welfare outcomes for patients.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The Dermatology Life Quality Index (DLQI) questionnaire is a clinical and\u000d\u000a      research tool, which has fundamentally shifted dermatology from being\u000d\u000a      doctor-centred to patient-centred. Previously, no standard method to\u000d\u000a      quantify the impact of skin disease on patients existed. The DLQI was\u000d\u000a      created by interviewing people with skin disease and made clinically\u000d\u000a      useful through development and validation of score bands. NICE\/SIGN\u000d\u000a      require UK dermatologists to use the DLQI when assessing severe psoriasis\u000d\u000a      and hand eczema. DLQI is used in national psoriasis guidelines in 14\u000d\u000a      countries, is available in 91 language translations, has been used in 678\u000d\u000a      clinical research studies and generated £881,236 in royalties to Cardiff\u000d\u000a      University.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Cardiff University\u000d\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) -\u000d\u000a      A simple practical measure for routine clinical use. Clinical\u000d\u000a        and Experimental Dermatology, 1994; 19: 210-216. PMID: 8033378 DOI:\u000d\u000a      10.1111\/j.1365-2230.1994.tb01167.x (supplied on request) (1,029 citations,\u000d\u000a      Web of Knowledge).\u000d\u000a    \u000a\u000a3.2. Kurwa HA, Finlay AY. Dermatology inpatient admission greatly\u000d\u000a      improves life quality. British Journal of Dermatology, 1995; 133:\u000d\u000a      575-578. PMID: 7577587 DOI: 10.1111\/j.1365- 2133.1995.tb02708.x (supplied\u000d\u000a      on request) (84 citations)\u000d\u000a    \u000a\u000a3.3. Hongbo Y, Thomas C L, Harrison M A, Salek M S, Finlay A\u000d\u000a        Y. Translating the science of quality of life into practice: what do\u000d\u000a      Dermatology Life Quality Index scores mean? Journal of Investigative\u000d\u000a        Dermatology 2005; 125: 659-664. PMID: 16185263 DOI: 10.1111\/j.0022-\u000d\u000a      202X.2005.23621.x (supplied on request) (133 citations)\u000d\u000a    \u000a\u000a3.4. Finlay A Y. Current severe psoriasis and the Rule of Tens. British\u000a        Journal of Dermatology 2005; 152: 861-867. PMID: 15888138 DOI:\u000d\u000a      10.1111\/j.1365-2133.2005.06502.x (supplied on request) (123 citations)\u000d\u000a    \u000a\u000a3.5. Smith C H, Anstey A V, Barker J N W N, Burden A D, Chalmers\u000d\u000a      R J G, Chandler D, Finlay A Y, Griffiths C E M, Jackson K, McHugh\u000d\u000a      N J, McKenna K E, Reynolds N J, Ormerod A D. British Association of\u000d\u000a        Dermatologists' guidelines for use of biologic interventions for\u000d\u000a        psoriasis 2009. British Journal of Dermatology 2009; 161:\u000d\u000a      987-1019. DOI: 10.1111\/j.1365- 2133.2009.09505.x (103 citations)\u000d\u000a    \u000a\u000a3.6. Basra M K A, Fenech R, Gatt R M , Salek M S,\u000d\u000a        Finlay A Y. The Dermatology Life Quality Index 1994-2007: A\u000d\u000a      comprehensive review of validation data and clinical results. British\u000d\u000a        Journal of Dermatology 2008; 159: 997-1035. DOI:\u000d\u000a      10.1111\/j.1365-2133.2008.08832.x (85 citations) (see Table 17, p 1020-1026\u000d\u000a      to back up the claim of usage of DLQI in Phase II and III studies)\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"14","Level2":"2","Subject":"Applied Economics"}],"Sources":"\u000d\u000a    5.1. Basra MK, Chowdhury MM, Smith EV, Freemantle N, Piguet V.\u000d\u000a      A review of the use of the dermatology life quality index as a criterion\u000d\u000a      in guidelines and health technology assessments in psoriasis and hand\u000d\u000a      eczema. Dermatol Clin 2012; 30: 237-44. DOI:\u000d\u000a      10.1016\/j.det.2011.11.002 (Backs up the claim of establishment of\u000d\u000a      guidelines)\u000d\u000a    5.2. NICE and SIGN guidelines: Psoriasis: Infliximab TA134 (2008),\u000d\u000a      pages 4,6,8-13,15-16, available at http:\/\/www.nice.org.uk\/nicemedia\/live\/11910\/38954\/38954.pdf\u000d\u000a      and SIGN Guideline 121: diagnosis and management of psoriasis and\u000d\u000a      psoriatic arthritis in adults. Paragraph 4.3.1, available at \u000d\u000a        http:\/\/www.sign.ac.uk\/guidelines\/fulltext\/121\/section4.html (Backs\u000d\u000a      up the claim of establishment of guidelines)\u000d\u000a    5.3. Norlin JM, Steen Carlsson K, Persson U, Schmitt-Egenolf M. Analysis\u000d\u000a      of three outcome measures in moderate to severe psoriasis: a\u000d\u000a      registry-based study of 2450 patients. Br J Dermatol 2012; 166:\u000d\u000a      797-802. DOI: 10.1111\/j.1365-2133.2011.10778.x (Backs up the claim of\u000d\u000a      adoption within guidelines by national organisations and national\u000d\u000a      registries)\u000d\u000a    5.4. Chren M. Measurement of vital signs for skin diseases. J Invest\u000d\u000a        Dermatol 2005; 125 (4): viii-ix, available at http:\/\/www.nature.com\/jid\/journal\/v125\/n4\/full\/5603538a.html\u000d\u000a      (Backs up the involvement of Professor Finlay and colleagues in Cardiff in\u000d\u000a      improving the measurement of complex constructs in dermatology)\u000d\u000a    5.5. Rehal B, Armstrong AW. Health outcome measures in atopic dermatitis:\u000d\u000a      a systematic review of trends in disease severity and quality-of-life\u000d\u000a      instruments. PLoS One 2011; 6(4): e17520. DOI:\u000d\u000a      10.1371\/journal.pone.0017520 (Backs up the impact of patient benefit)\u000d\u000a    5.6. Salek S, Roberts A, Finlay AY. The practical reality of\u000d\u000a      using a patient-reported outcome measure in a routine dermatology clinic.\u000d\u000a      Dermatology 2007; 215: 315-9. PMID: 17911989 DOI: 10.1159\/000107625\u000d\u000a      (DLQI influenced decision taking in 37 (13.8%) consultations out of 268.\u000d\u000a      Backs up the impact of patient benefit)\u000d\u000a    5.7. Finlay AY, Basra MKA, Piguet V, Salek MS. The DLQI a\u000d\u000a      paradigm shift to patient-centered outcomes. J Invest Dermatol\u000d\u000a      2012; 132: 2464-5. DOI: 10.1038\/jid.2012.147 (Backs up the impact of\u000d\u000a      patient and clinician benefit)\u000d\u000a    5.8. Pathirana D, Ormerod AD, Saiag P et al. European S-3 guidelines on\u000d\u000a      the systemic treatment of psoriasis vulgaris. J Eur Acad\u000d\u000a        Dermatol Venereol 2009; 23 (Suppl 2): 1-70. DOI: 10.1111\/j.1468-\u000d\u000a      3083.2010.03671.x (Backs up the impact of patient benefit)\u000d\u000a    5.9. Mrowietz U, Kragballe K, Reich K et al. Definition of treatment\u000d\u000a      goals for moderate to severe psoriasis: a European consensus. Arch\u000d\u000a        Derm Res 2011; 303; 1-10. DOI: 10.1007\/s00403-010- 1080-1 (Backs up\u000d\u000a      the impact of patient benefit from having defined patient-orientated\u000d\u000a      treatment goals)\u000d\u000a    5.10. Shittu RO, Odeigah LO, Mahmoud AO, Sani MA, Bolarinwa OA.\u000d\u000a      Dermatology Quality of Life impairments among newly diagnosed\u000d\u000a      HIV\/AIDS-infected patients in the University of Ilorin Teaching Hospital\u000d\u000a      (UiTH), Ilorin, Nigeria. J Int Assoc Provid AIDS Care 2013 Jun 14\u000d\u000a      (epub ahead of print) (Backs up the impact of patient and clinician\u000d\u000a      benefit) \u000d\u000a    ","Title":"\u000d\u000a    The Dermatology Life Quality Index: the leading patient-orientated\u000d\u000a        dermatology outcome measure used worldwide.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2653822","Name":"Cardiff"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Patients' attitudes to their skin disease vary widely and the degree of\u000d\u000a      disability experienced is a key influence on clinical decision-making. It\u000d\u000a      was clear that a dermatology-specific measure was needed that could be\u000d\u000a      used for assessment of all dermatology diseases. In 1994, PhD student Dr\u000d\u000a      Gul Karim Khan supervised by Dr Andrew Finlay (Sen Lect 92-99, Prof 99-09,\u000d\u000a      post retirement in '09 taken on again as Professor of Dermatology with\u000d\u000a      fixed term contract until 2015) and co- supervisor Dr Sam Salek (Lect\u000d\u000a      85-96, Sen Lect 96-04, Reader 04-06, Prof 06-present, School of Pharmacy)\u000d\u000a      asked 130 patients in Cardiff with a range of skin diseases how their\u000d\u000a      disease had affected their life, and distilled the answers to create 10\u000d\u000a      questions, scored from 0-30. We designed the DLQI to be simple for use in\u000d\u000a      a busy clinic; questions fitting on one sheet with very simple scoring 3.1.\u000d\u000a      We established copyright (Library of Congress, Washington) and carried out\u000d\u000a      initial validation.\u000d\u000a    We demonstrated in Cardiff the utility of the DLQI in assessing\u000d\u000a      in-patient therapy 3.2, Behcet's disease, general practice and\u000d\u000a      hair loss studies (carried out by Finlay with dermatology registrars Dr\u000d\u000a      Habib Kurwa and Dr Diane Williamson, dermatologist Dr Sharon Blackford,\u000d\u000a      and general practitioner Dr Dilys Harlow in 1996-2001, all NHS employees).\u000d\u000a      This work demonstrated the practical value of the measure and worldwide\u000d\u000a      use of the DLQI rapidly developed.\u000d\u000a    Scores from quality of life (QoL) measures used to be published without\u000d\u000a      description of their meaning. Our study of 1,993 patients with skin\u000d\u000a      disease determined validated descriptive score bandings, allowing the DLQI\u000d\u000a      to be useful in informing clinical decisions (carried out in 2002-2004 by\u000d\u000a      research fellow Dr Yan Hongbo and dermatology registrar Dr Charles Thomas\u000d\u000a      (NHS employees), supervised by Salek and Finlay, published in 2005) 3.3.\u000d\u000a      The DLQI could then be used to enhance appropriateness of clinical\u000d\u000a      decisions, to audit dermatology services, to assess new drugs and to\u000d\u000a      inform resource allocation.\u000d\u000a    We sought to make the DLQI useful in daily practice. By proposing in 2005\u000d\u000a      the Rule of Tens3.4 as a clinical definition of severe current\u000d\u000a      psoriasis, Finlay enabled dermatologists to learn to interpret DLQI\u000d\u000a      scores, and to recognise that a score over 10 means major impact on life\u000d\u000a      quality 3.3. This Rule also embedded for the first time a QoL\u000d\u000a      measure into skin disease severity definition. This concept influenced the\u000d\u000a      development of national guidelines for the use of Biologics in psoriasis\u000d\u000a      in 2005 and 20093.5 in the UK and abroad.\u000d\u000a    The very widespread use of the DLQI resulted in many validation studies\u000d\u000a      being published worldwide. We undertook a detailed review identifying all\u000d\u000a      aspects of validation to assist DLQI users. Two School of Pharmacy\u000d\u000a      students supervised by Dr M Basra (Research Fellow 04-12), Salek and\u000d\u000a      Finlay carried out this work in 2007, published in 20083.6.\u000d\u000a    A further essential aspect to interpretation of scores is the magnitude\u000d\u000a      of the Minimal Clinically Important Difference (MCID) for DLQI scores. A\u000d\u000a      Cardiff study in 2002 provisionally established the value and we have\u000d\u000a      submitted for publication new data demonstrating the MCID. Basra with\u000d\u000a      Salek and Finlay carried out this work in 2009-2012.\u000d\u000a    "},{"CaseStudyId":"2999","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Medical practice for locally advanced prostate cancer has changed. Prior\u000d\u000a      to the underpinning\u000d\u000a      research, hormone therapy alone was considered adequate treatment.\u000d\u000a      Following the present\u000d\u000a      study, hormone therapy alone is no longer considered sufficient treatment\u000d\u000a      for such patients, and,\u000d\u000a      according to the guidelines, 100% of patients suitable for radiotherapy\u000d\u000a      must be offered it. In\u000d\u000a      Western countries, cancer treatment policies in major treatment centres\u000d\u000a      are governed by\u000d\u000a      guidelines, and therefore, while there are no data to measure the number\u000d\u000a      of men receiving this\u000d\u000a      treatment in comparison to earlier years, the changes to recognised\u000d\u000a      guidelines can be measured.\u000d\u000a      After the first UK presentation of the interim analysis, at the UK\u000d\u000a      National Cancer Research Institute\u000d\u000a      conference in 2010, Professor Sir Richard Peto (Professor of Medical\u000d\u000a      Statistics and Epidemiology,\u000d\u000a      University of Oxford ) stated publicly that he expected to see the\u000d\u000a      population mortality rates from\u000d\u000a      prostate cancer to fall following the implementation of this study. Our\u000d\u000a      estimates are that\u000d\u000a      implementation of these study results will prevent up to around 1,000\u000d\u000a      deaths per year from\u000d\u000a      prostate cancer in the UK, around 5,000 deaths per year in the USA, and of\u000d\u000a      the order of 50,000\u000d\u000a      deaths per year worldwide.\u000d\u000a    Following the first presentation of the interim analysis in 2010, by\u000d\u000a      Professor P Warde in the US and\u000d\u000a      by Professor M Mason in the UK, there was intense, worldwide media\u000d\u000a      interest. This was renewed\u000d\u000a      when the formal publication of the interim analysis was released in 2011;\u000d\u000a      a typical example being\u000d\u000a      the statement from the UK Prostate Cancer Charity, reported in the Daily\u000d\u000a      Telegraph, that\u000d\u000a      radiotherapy should be made a standard treatment for this condition5.1.\u000d\u000a      This view is further\u000d\u000a      endorsed by opinion leaders worldwide, for example, Professor W Shipley,\u000d\u000a      Harvard University and\u000d\u000a      Massachussets General Hospital, Boston, who states, quoting the present\u000d\u000a      study, that \"...the\u000d\u000a      combined use of [(RT) and (HT)] for patients with locally advanced\u000d\u000a      prostate cancer should be the\u000d\u000a      recognized standard of care throughout the world\"5.2,.\u000d\u000a    This change is reflected in the addition to published cancer treatment\u000d\u000a      guidelines. In the UK, the\u000d\u000a      National Institute of Clinical Excellence (NICE) guidelines on prostate\u000d\u000a      cancer5.3, 5.4 (update currently\u000d\u000a      in draft — October 2013) will quote this trial as evidence for mandating\u000d\u000a      the use of RT in these\u000d\u000a      patients. Similarly, in the US, the NCCN guidelines5.5, which\u000d\u000a      are regarded as the cornerstone of\u000d\u000a      approved forms of cancer treatment in the country, quote the Intergroup\u000d\u000a      publication and\u000d\u000a      recommend RT plus HT as a standard. In the US, like NICE guidance in the\u000d\u000a      UK, healthcare\u000d\u000a      providers are obliged to follow the recommended treatment pathways as\u000d\u000a      published by the National\u000d\u000a      Comprehensive Cancer Network (NCCN), and this is reflected in insurance\u000d\u000a      re-imbursement. The\u000d\u000a      European Association of Urology (EAU) guidelines5.6 also quote\u000d\u000a      the publication, but their status is\u000d\u000a      not mandatory at the present time. The trial will be quoted in the 2013\u000d\u000a      update of the EAU\u000d\u000a      guidelines, currently in preparation5.7. In relation to the\u000d\u000a      Lancet publication, Professor Patrick Walsh,\u000d\u000a      Johns Hopkins', Baltimore, USA, states \"The message is loud and clear. All\u000d\u000a      patients with locally\u000d\u000a      advanced prostate cancer (T3 or T4), organ confined disease with a PSA\u000d\u000a      concentration of more\u000d\u000a      than 40 ng\/ml, or PSA greater than 20 in the presence of Gleason score 8\u000d\u000a      or higher should receive\u000d\u000a      radiation in addition to androgen deprivation therapy\"5.8. The\u000d\u000a      survey of clinicians in the UK and in\u000d\u000a      Canada conducted by the Medical Research Council, and by the National\u000d\u000a      Cancer Institute of\u000d\u000a      Canada has been referred to earlier. Among the findings were that 91% of\u000d\u000a      clinicians in Canada,\u000d\u000a      and 88% in the UK regarded the evidence on hormone therapy plus\u000d\u000a      radiotherapy to be sufficiently\u000d\u000a      strong for this to be the standard of care5.9.\u000d\u000a    In summary, and as discussed above, this study has triggered a change in\u000d\u000a      medical practice, whose\u000d\u000a      reach is international, covering at least the UK, Europe, and North\u000d\u000a      America with recommendations\u000d\u000a      extending to Asia5.2.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Locally advanced prostate cancer (where a tumour has extended outside the\u000d\u000a      prostate gland to\u000d\u000a      surrounding tissues) will affect around 20,000 men per year in the US, and\u000d\u000a      4,000 men per year in\u000d\u000a      the UK. Prior to the underpinning research, there was no consensus on the\u000d\u000a      standard of care, with\u000d\u000a      hormone therapy often being given alone. The International randomised\u000d\u000a      clinical trial, led by Cardiff\u000d\u000a      researchers showed that treating locally advanced disease with a\u000d\u000a      combination of radiotherapy and\u000d\u000a      hormone therapy halved the risks of dying of prostate cancer.\u000d\u000a      Consequently, it is now a standard of\u000d\u000a      care, enshrined in European and North American guidelines, that all such\u000d\u000a      patients who are fit\u000d\u000a      enough to receive it, should now be offered combined modality radiotherapy\u000d\u000a      plus hormone therapy.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Cardiff University\u000d\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4347778","Name":"Baltimore"},{"GeoNamesId":"4930956","Name":"Boston"}],"References":"\u000d\u000a    \u000a3.1 Mason MD, Brewster S, Moffat LE, Kirkbride P, Cowan RA,\u000d\u000a      Malone P, Sydes M, and\u000d\u000a      Parmar MKB. Randomized trials in early prostate cancer. II Hormone therapy\u000d\u000a      and\u000d\u000a      radiotherapy for locally advanced disease: a question is still unanswered.\u000d\u000a      Clin Oncol (2000)\u000d\u000a      12:215-216 DOI:10.1053\/clon.2000.9156\u000d\u000a    \u000a\u000a3.2 Warde P, Mason M, (JOINT FIRST AUTHORS), Ding K, Kirkbride P,\u000d\u000a      Brundage M, Cowan\u000d\u000a      R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A,\u000d\u000a      Parmar\u000d\u000a      MKB, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes M &\u000d\u000a      Parulekar W. Combined\u000d\u000a      androgen deprivation therapy and radiation therapy for locally advanced\u000d\u000a      prostate cancer: a\u000d\u000a      randomised, phase 3 trial. Lancet (2011) 378 (9809):2104-2111 DOI:\u000d\u000a      10.1016\/S0140-\u000d\u000a      6736(11)61095-7\u000d\u000a    \u000a\u000a3.3 Mason MD, Parulekar W, Sydes MR, Parmar M, Anderson J, Barber\u000d\u000a      J, Brundage MD,\u000d\u000a      Cowan R, Gospodarowicz MK, Hayter C, Hetherington J, Hiltz AC, Kirkbride\u000d\u000a      P, Kpostashuk\u000d\u000a      E, Sanders K, Sathya J, Swanson GP, Chen B, Warde PR. Final analysis of\u000d\u000a      intergroup\u000d\u000a      randomized phase III study of androgen deprivation therapy (ADT) plus\u000d\u000a      radiation therapy\u000d\u000a      (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK,\u000d\u000a      INT: T94-\u000d\u000a      0110).J Clin Oncol 30, 2012 (suppl; abstr 4509) (Copy available on\u000d\u000a      request from HEI)\u000d\u000a    \u000aThe resources at the Clinical trials Units to run this trial were\u000d\u000a      supported by:\u000d\u000a    NCI-US Grant CA077202, awarded to the US South West Oncology Group 1993.\u000d\u000a    CCSRI Grants #14469 and # 015469, awarded to National Cancer Institute,\u000d\u000a      1993.\u000d\u000a    UK Medical Research Council Grant G9805643, awarded to MRC Clinical\u000d\u000a      Trials Unit (Named\u000d\u000a      grantholder Prof M Parmar; co-applicant M Mason).\u000d\u000a    UK National Cancer Research Network, provided infrastructure for follow\u000d\u000a      up.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    5.1 http:\/\/www.telegraph.co.uk\/health\/healthnews\/8865230\/Radiotherapy-helps-halve-prostate-\u000d\u000a        cancer-deaths-Lancet.html (An example to corroborate the media\u000d\u000a      interest, saved as .pdf on\u000d\u000a      2nd July 2013 and available on request from HEI)\u000d\u000a    5.2 Gray, P & Shipley, WU. The importance of combined radiation and\u000d\u000a      endocrine therapy in\u000d\u000a      locally advanced prostate cancer. Asian J Androl., 2011\u000d\u000a      14:245-246. DOI:\u000d\u000a      10.1038\/aja.2011.177 (Quotes the present study shows that the combined use\u000d\u000a      of RT and\u000d\u000a      HT for patients with locally advanced prostate cancer should be the\u000d\u000a      recognized standard of\u000d\u000a      care throughout the world)\u000d\u000a    5.3 National Institute for Clinical Excellence. Guidelines for the\u000d\u000a      management of prostate\u000d\u000a      cancer. (. http:\/\/guidance.nice.org.uk\/CG58\u000d\u000a        shows updated guidance in preparation and\u000d\u000a      due for publication in January 2014)\u000d\u000a    5.4 Director, NICE National Collaborating Centre for Cancer (will confirm\u000d\u000a      that the 2014 National\u000d\u000a      Institute of Clinical Excellence (NICE) guidelines on prostate cancer\u000d\u000a      quote publication 3.2,\u000d\u000a      and recommend treatment based on these findings).\u000d\u000a    5.5 NCCN Guidelines on prostate cancer.\u000d\u000a      http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/prostate.pdf\u000d\u000a      (use username\u000d\u000a      morgande@cardiff.ac.uk and password REF2014 to access. Quotes the\u000d\u000a      intergroup\u000d\u000a      publication and recommends RT and HT as a standard in the US. Also saved\u000d\u000a      as .pdf on 22\u000d\u000a      July 2013 and available on request from HEI)\u000d\u000a    5.6 EAU Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and\u000d\u000a      Treatment of\u000d\u000a      Clinically Localised Disease. Eur. Urol. 2011 59:61-71 DOI:\u000d\u000a      10.1016\/j.eururo.2010.10.039\u000d\u000a      (Backs up the claim that the study published as 3.2 is quoted in these\u000d\u000a      guidelines. Is\u000d\u000a      available on request from HEI)\u000d\u000a    5.7 Chairman of EAU Prostate Cancer Guidelines Committee, Department of\u000d\u000a      Urology, St\u000d\u000a      Etienne University Hospital, Paris (can corroborate that the trial will be\u000d\u000a      quoted in the 2013\u000d\u000a      update of the EAU guidelines, currently in preparation).\u000d\u000a    5.8 Published commentary written by Professor Walsh giving his opinion on\u000d\u000a      paper 3.2. Author:\u000d\u000a      Walsh P.C. Title: \"Re: Combined androgen deprivation therapy and radiation\u000d\u000a      therapy for\u000d\u000a      locally advanced prostate cancer: A randomised, phase 3 trial\". Journal\u000d\u000a        of Urology, Volume\u000d\u000a      188, Issue 3, September 2012, Page 810 DOI: 10.1016\/j.juro.2012.05.065\u000d\u000a      (Backs up the\u000d\u000a      quote from Professor Walsh regarding specific patient treatment and\u000d\u000a      available from HEI on\u000d\u000a      request)\u000d\u000a    5.9 Policy & Research Impact Co-ordinator, Medical Research Council\u000d\u000a      Clinical Trials Unit (can\u000d\u000a      provide full details and data for the survey of clinicians in the UK and\u000d\u000a      Canada conducted by\u000d\u000a      the Medical research Council and the National Cancer Institute of Canada)\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    A New Standard of Care for Locally Advanced Prostate Cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Prior to this underpinning research, the UK Medical Research Council\u000d\u000a      conducted a randomised\u000d\u000a      trial in patients with localised and locally advanced prostate cancer,\u000d\u000a      comparing hormone therapy\u000d\u000a      alone, radiotherapy alone, and hormone therapy plus radiotherapy. The\u000d\u000a      trial failed to accrue\u000d\u000a      sufficient patients to show any differences in outcomes, and the result\u000d\u000a      was uncertainty about the\u000d\u000a      role of radiotherapy in such patients. Surveys conducted by the Medical\u000d\u000a      Research Council in the\u000d\u000a      UK and the National Cancer Institute of Canada (NCIC) in Canada, indicated\u000d\u000a      that almost half of\u000d\u000a      clinicians would treat patients with locally advanced disease with hormone\u000d\u000a      therapy alone. On the\u000d\u000a      other hand, previous randomised trials had also indicated that, if such a\u000d\u000a      patient was to be treated\u000d\u000a      with radiotherapy, overall survival was improved if hormone therapy was\u000d\u000a      added. This added to the\u000d\u000a      confusion, since these latter trials could not differentiate between\u000d\u000a      benefits due to hormone therapy\u000d\u000a      per se, or to the combination of hormone therapy plus radiotherapy.\u000d\u000a    This was the background to the Intergroup Study (MRC PR07\/NCIC PR3),\u000d\u000a      which was designed to\u000d\u000a      test the efficacy of radiotherapy in patients being treated with hormone\u000d\u000a      therapy and led for the\u000d\u000a      Medical Research Council by Professor Malcolm Mason in Cardiff (Head of\u000d\u000a      Department, Section of\u000d\u000a      Oncology and Palliative Medicine since 1997). Patients with locally\u000d\u000a      advanced disease were\u000d\u000a      randomised to lifelong hormone therapy alone, or to the same plus\u000d\u000a      radiotherapy to the prostate\u000d\u000a      and pelvis3.1. The trial recruited patients from 1995-2005,\u000d\u000a      with 1205 patients recruited, the majority\u000d\u000a      of them by the Medical Research Council group. There were two pre-planned\u000d\u000a      interim analyses,\u000d\u000a      and after the second of these in August 2009, the independent Data\u000d\u000a      Monitoring and Safety\u000d\u000a      Committee recommended disclosure of the results. The results showed that\u000d\u000a      radiotherapy reduced\u000d\u000a      the chances of dying from any cause by 23%, and reduced the chances of\u000d\u000a      dying from prostate\u000d\u000a      cancer by 46%3.2.\u000d\u000a    The final analysis was presented at the American Society for Clinical\u000d\u000a      Oncology in June 20123.3.\u000d\u000a      This confirmed, and strengthened the beneficial effects of radiotherapy,\u000d\u000a      with a 30% reduction in the\u000d\u000a      chances of death from any cause, and a 54% reduction in the chances of\u000d\u000a      dying of prostate cancer.\u000d\u000a      The toxicity and adverse effects of radiotherapy were reported to be\u000d\u000a      modest, and acceptable, and\u000d\u000a      there was no demonstrable long-term adverse impact of radiotherapy on\u000d\u000a      quality of life.\u000d\u000a    The results of this trial are comparable with two other studies: a\u000d\u000a      Scandinavian Prostate Cancer\u000d\u000a      Group (published in 2009), and a French randomised trial (published in\u000d\u000a      2012) of similar design.\u000d\u000a      The French study is smaller (and therefore less powerful) than the present\u000d\u000a      study, and in addition\u000d\u000a      has insufficient length of follow up data to be able to measure the effect\u000d\u000a      of radiotherapy on survival.\u000d\u000a      The Scandinavian study was limited by its use of non-standard hormone\u000d\u000a      therapy (flutamide, which\u000d\u000a      is never used in the UK or USA in this context, and may be inferior to the\u000d\u000a      hormone therapy used in\u000d\u000a      the present study), and its patient population was comprised of men with a\u000d\u000a      better prognosis than in\u000d\u000a      the present study. A survey of UK and Canadian clinicians conducted by the\u000d\u000a      Medical Research\u000d\u000a      Council (see below) has shown that 97% of respondents were aware of the\u000d\u000a      PR07 trial, compared\u000d\u000a      with 79% being aware of the Scandinavian trial. For these reasons, the\u000d\u000a      present study is considered\u000d\u000a      the most influential.\u000d\u000a    The distinct roles of Prof Mason (Cardiff University) in this trial are:\u000d\u000a    \u000d\u000a      Chief Investigator for the UK MRC group.\u000d\u000a      Led the UK input into the design and modification of the study.\u000d\u000a      Oversight of the trial conduct for the UK patients (the majority of\u000d\u000a        the patients in this study),\u000d\u000a        and overseas patients recruited through the MRC (Russia, South Africa).\u000d\u000a      Led the UK input into the analysis and publication of the interim\u000d\u000a        analysis.\u000d\u000a      Gave the first presentation of the results of the final analysis.\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"3416","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The health impacts of our research have been improvements in genetic\u000d\u000a      counselling, genetic testing and bowel cancer prevention in familial\u000d\u000a      colorectal cancer. These impacts have been international, bringing\u000d\u000a      benefits to patients and families affected by or at risk of familial\u000d\u000a      colorectal cancer. Bowel cancer screening services have benefited through\u000d\u000a      more efficient targeting of colonoscopic screening to patients at very\u000d\u000a      high risk. The commercial impact has been through increased economic\u000d\u000a      activity in genetic diagnostic services internationally. In addition\u000d\u000a      Cardiff University has benefited through associated licence and royalty\u000d\u000a      income.\u000d\u000a    By showing for the first time that predisposition to colorectal cancer\u000d\u000a      could be transmitted as a recessive trait (MUTYH-associated polyposis,\u000d\u000a      MAP) our findings impacted directly upon genetic counselling for familial\u000d\u000a      colorectal cancer and the investigation and treatment of affected patients\u000d\u000a      and their families. By identifying the causative MUTYH mutations for this\u000d\u000a      recessive disorder and methods for their detection our research resulted\u000d\u000a      in diagnostic and predictive genetic tests for MAP. These tests have\u000d\u000a      enabled both definitive diagnosis for patients affected by MAP and bowel\u000d\u000a      cancer prevention for members of their families. Specifically,\u000d\u000a      asymptomatic family members who test positive for MAP have an\u000d\u000a      approximately 80% lifetime risk of colorectal cancer (Lubbe et al. J Clin\u000d\u000a      Oncol 2009 vol. 27 no. 24 3975-3980) but this risk can now be averted by\u000d\u000a      prophylactic polypectomy and\/or colectomy. By contrast, family members\u000d\u000a      who, upon gene testing are at low risk can be reassured. Since 2008 over\u000d\u000a      1500 individuals have had diagnostic or predictive tests of MUTYH gene\u000d\u000a      status in the NHS to guide clinical and genetic management5.1.\u000d\u000a    Across Europe the tests have been adopted progressively throughout the\u000d\u000a      assessment period and they are now provided by at least 84 state and\u000d\u000a      private sector diagnostic laboratories that are listed at Orphanet5.2.\u000d\u000a      MUTYH gene testing is also carried out by at least three centres in\u000d\u000a      Australasia.5.3\u000d\u000a    In North America, we protected our intellectual property on\u000d\u000a      MAP-associated MUTYH mutations and methods for their detection\u000d\u000a      through US patents 7,393,940 and 7,405,283 that were granted on 01.07.2008\u000d\u000a      and 29.07.2008 respectively. With assistance from the Wales Gene Park at\u000d\u000a      Cardiff University we licenced this intellectual property to Myriad\u000d\u000a      Genetics Inc. Between 2008 and 2011 Myriad undertook over 11,000 MUTYH\u000d\u000a      tests in North America, generating a gross income of $1,381,427 for MUTYH\u000d\u000a      testing alone and a further $3,485,574 through the Colaris AP test of the\u000d\u000a      MUTYH and APC genes together5.4. Cardiff University has\u000d\u000a      received £331,947 in royalties and licence fees.\u000d\u000a    The changes in clinical genetic, bowel screening and treatment practice\u000d\u000a      consequent on our research have been incorporated into guidelines for the\u000d\u000a      investigation and management of familial colorectal cancer published by\u000d\u000a      specialist societies and expert groups in the UK (2010)5.5,\u000d\u000a      Europe (2008)5.6, North America (2008)5.7 and\u000d\u000a      Australasia (2011)5.8.\u000d\u000a    The work contributed to the award of a Queen's Anniversary Prize to\u000d\u000a      Cardiff University in February 2008.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Identification of MUTYH by researchers at Cardiff University as\u000d\u000a      the first gene causing autosomal recessive colorectal cancer led to\u000d\u000a      international adoption of MUTYH genetic testing in the management\u000d\u000a      of familial colorectal cancer and thereby to global improvement in genetic\u000d\u000a      counselling and colorectal cancer prevention. Since 2008 MUTYH\u000d\u000a      gene testing has been introduced progressively and is now provided by at\u000d\u000a      least 84 European state and commercial diagnostic laboratories.\u000d\u000a      Commercialisation of testing in North America via a licence to Myriad\u000d\u000a      Genetics Inc. generated income of approximately $5M between 2008 and 2011\u000d\u000a      and licence fees and royalties to date of £331,947. Thus we claim impacts\u000d\u000a      in health and commercial benefit, the financial beneficiaries being Myriad\u000d\u000a      Genetics and Cardiff University.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    Cardiff University\u000d\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Al-Tassan N, Chmiel NH, Maynard J, Fleming N,\u000d\u000a      Livingston AL, Williams GT, Hodges AK, Davies\u000d\u000a        DR, David SS, Sampson JR, Cheadle JP.\u000d\u000a      Inherited variants of MYH associated with somatic G:C>T:A mutations in\u000d\u000a      colorectal tumors. Nat Genet. 2002;30:227-232. PMID: 11818965 DOI:\u000d\u000a      10.1038\/ng828\u000d\u000a    \u000a\u000a3.2 Jones S, Emmerson P, Maynard J, Best JM,\u000d\u000a      Jordan S, Williams GT, Sampson JR, Cheadle JP.\u000d\u000a      Biallelic germline mutations in MYH predispose to multiple colorectal\u000d\u000a      adenoma and somatic G:C-->T:A mutations. Hum Mol Genet 2002 Nov\u000d\u000a      1;11(23):2961-7. PMID: 12393807 DOI: 10.1093\/hmg\/11.23.2961\u000d\u000a    \u000a\u000a3.3 Sampson JR, Dolwani S, Jones S, Eccles D,\u000d\u000a      Ellis A, Evans DG, Frayling I, Jordan S, Maher ER, Mak T, Maynard\u000a        J, Pigatto F, Shaw J, Cheadle JP. Autosomal recessive\u000d\u000a      colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet.\u000d\u000a      2003 Jul 5;362(9377):39- 41. PMID: 12853198 DOI:\u000d\u000a      10.1016\/S0140-6736(03)13805-6\u000d\u000a    \u000a\u000a3.4 Jones N, Vogt S, Nielsen M, Christian D, Wark PA, Eccles D,\u000d\u000a      Edwards E, Evans DG, Maher ER, Vasen HF, Hes FJ, Aretz S, Sampson JR.\u000d\u000a      Increased colorectal cancer incidence in obligate carriers of heterozygous\u000d\u000a      mutations in MUTYH. Gastroenterology. 2009 Aug;137(2):489-94.\u000d\u000a      PMID: 19394335 DOI: 10.1053\/j.gastro.2009.04.047\u000d\u000a    \u000a\u000a3.5 US patents 7393940 granted on 01.07.08 and 7405283 granted on\u000d\u000a      29.07.2008 (Screening methods and sequences relating thereto, mutations of\u000d\u000a      MYH). Inventors Sampson JR and Cheadle JP (saved as .pdfs\u000d\u000a      on 22 July 2013 and available on request from HEI)\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    Corroboration of Uptake of MUTYH Genetic Testing by Diagnostic\u000d\u000a        Laboratories\u000d\u000a    5.1 Clinical Molecular Genetics Society Audit 2012. Data provided\u000d\u000a      by Dr Gail Norbury, Commissioning and Governance Director of Genetics\u000d\u000a      Laboratories, Guy's and St Thomas' NHS Foundation Trust.\u000d\u000a    5.2 Scientific Co-ordinator, Orphanet UK\u000d\u000a    5.3 Laboratories Performing Gene Tests in Australia and New Zealand:\u000d\u000a        http:\/\/genetictesting.rcpa.edu.au\/component\/gene\/genetest\/MUTYH\u000d\u000a      (saved as .pdf on 9th July 2013 and available on request from\u000d\u000a      HEI)\u000d\u000a    Corroboration of Evidence for Commercialization in North America\u000d\u000a    5.4 CEO Myriad Genetics, Inc.\u000d\u000a    Guidelines for management of familial colorectal cancer that recommend\u000d\u000a        MUTYH gene testing:\u000d\u000a    5.5 UK: Guidelines for colorectal cancer screening and surveillance in\u000d\u000a      moderate and high risk groups, British Society of Gastroenterology. GUT\u000d\u000a      2010;59:666 - 690. DOI:10.1136\/gut.2009.179804 (also available on request\u000d\u000a      from HEI)\u000d\u000a    5.6 Europe: Guidelines for the clinical management of familial\u000d\u000a      adenomatous polyposis (FAP). Gut. May 2008; 57: 704 - 713. PMID:\u000d\u000a      18194984, DOI:10.1136\/gut.2007.136127 (also available on request from HEI)\u000d\u000a    5.7 North America: American College of Gastroenterology Guidelines for\u000d\u000a      Colorectal Cancer Screening 2008 Am J Gastroenterol 2009; 104:\u000d\u000a      739-750; DOI:10.1038\/ajg.2009.104;\u000d\u000a    5.8 Australia: Early detection screening and surveillance for\u000d\u000a        colorectal cancer. Gastroenterological Society of Australia and the\u000d\u000a      Digestive Health Foundation (4th Edition, reprinted 2013, pages\u000d\u000a      10 and 11)\u000d\u000a      http:\/\/www.gesa.org.au\/files\/editor_upload\/File\/Professional\/Bowel%20Cancer.pdf\u000d\u000a      (also available on request from HEI) \u000d\u000a    ","Title":"\u000d\u000a    Identification of MUTYH, the first recessive\u000d\u000a        colorectal cancer gene, improves management of familial bowel cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Research at Cardiff University identified the role of inherited mutations\u000d\u000a      of MUTYH in the previously unrecognised disorder autosomal\u000d\u000a      recessive predisposition to colorectal adenoma and carcinoma3.1,3.2.\u000d\u000a      Prior to this, only autosomal dominant transmission of colorectal adenoma\u000d\u000a      and carcinoma predisposition had been recognised. The research was\u000d\u000a      undertaken by Julian Sampson (Clinical Professor), Jeremy Cheadle (then\u000d\u000a      Non-Clinical Senior Lecturer, now Professor) and their research team at\u000d\u000a      Cardiff University's Institute of Medical Genetics during the period\u000d\u000a      1999-2002. It involved the identification of patients with atypical\u000d\u000a      polyposis colorectal cancer and combined analysis of germline and somatic\u000d\u000a      mutations in these patients and their tumours. The researchers thereby\u000d\u000a      identified and characterised MUTYH deficiency as the first inherited\u000d\u000a      disorder of DNA base excision repair and as a novel mechanism of\u000d\u000a      colorectal tumorgenesis. From 2001 Sampson led further clinical genetic\u000d\u000a      research that provided fuller characterisation of the clinical and genetic\u000d\u000a      aspects of the inherited disorder associated with MUTYH mutations3.3,3.4,\u000d\u000a      now termed MUTYH- Associated Polyposis or MAP. This involved collaboration\u000d\u000a      with regional clinical genetics centres from across the UK and Europe to\u000d\u000a      identify further affected families whose genotypes and phenotypes were\u000d\u000a      investigated in detail. The disease-associated MUTYH mutations and\u000d\u000a      methods for their detection were the subject of US patents 7393940 and\u000d\u000a      7405283 granted to Sampson, Cheadle and their team members from Cardiff\u000d\u000a      University who were the sole inventors3.5.\u000d\u000a    "},{"CaseStudyId":"3417","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"298795","Name":"Turkey"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"1269750","Name":"India"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Cardiff's demonstration of the effectiveness of SLNB has helped establish\u000a      the technique as the global standard of care. As a result, beneficiaries\u000a      include:\u000a    \u000a      Breast cancer patients enjoying improved quality of life\u000a      Healthcare providers making time and cost savings on surgery\u000a      Surgical practitioners, who have been quickly and safely trained in a\u000a        new technique\u000a    \u000a    Impact on surgical training\u000a    As a result of the conclusive results of the ALMANAC trial, Mansel,\u000a      designed, secured funding for, and led a collaboration between Cardiff\u000a      University and the Royal College of Surgeons5.6 to set up and\u000a      participate in a national training programme called \"NEW START\" (funded by\u000a      the Department of Health). NEW START was directly informed by the ALMANAC\u000a      findings, both on the effectiveness of the dual technique and the\u000a      surgeons' `learning curve'. The programme, designed to introduce the\u000a      benefits of the research rapidly to the UK population, was introduced in\u000a      2004 and closed to new enrolments in December 2008. On completion, more\u000a      than 200 breast surgeons, operating on over 6,500 patients in 103 centres,\u000a      had been trained. The programme held centrally audited data on the\u000a      surgeons, and issued certificates of completion of training when they met\u000a      a pre-defined standard of performance. The programme results published in\u000a      2013 showed that surgeons, who had never done the procedure before, were\u000a      subsequently skilled to carry out this technique, with a less than 10%\u000a      risk of missing cancer in lymph nodes 3.7.\u000a    The programme involved close collaboration with the Administration of\u000a      Radioactive Substances Advisory Committee (ARSAC) which licences the use\u000a      of all medical isotopes5.7. This helped to exercise control\u000a      over unregulated and untrained enthusiasts who wished to perform the\u000a      procedure without suitable training. NEW START also ran training workshops\u000a      internationally (China\/India\/Brazil\/Turkey), funded by the International\u000a      Union Against Cancer (UICC), to spread the benefits in the international\u000a      population.\u000a    Impact on clinical guidelines\u000a    Following the conclusive results of the ALMANAC and other trials,\u000a      sentinel node biopsy has become the standard of care for breast cancer\u000a      surgery patients. It was adopted as the preferred method of axillary\u000a      staging and the recommended procedure for suitable patients in national\u000a      clinical guidelines in the USA (2010)5.5 and the UK (2009)5.3,\u000a      and in the surgical guidelines of the Association of Breast Surgeons\u000a      (2009)5.4. The ALMANAC trial is cited in all three guidelines\u000a      as having demonstrated the benefits to patients. Further NICE guidance,\u000a      drafted and undergoing consultation as of July 2013 and published the\u000a      following month, recommended the intra-operative node assessment trialled\u000a      by Mansel and cites NEW START and the ALMANAC findings on the\u000a      effectiveness of SLNB.\u000a    Impact on patients\u000a    Annual audits of breast screening in the UK show that no patients were\u000a      reported to have SLNB in 1997\/8 (the year that the MRC ALMANAC trial\u000a      started). By 2009\/10 the audit showed that 67% of 13,226 patients with\u000a      invasive cancer were undergoing SLNB. The latest figures, for 2011\/12,\u000a      show that of the 14,449 patients with invasive cancer undergoing axillary\u000a      surgery, 84% had sentinel node biopsy5.1.\u000a    The ALMANAC trial and other studies demonstrated the significant\u000a      improvement in quality of life that sentinel node biopsy has for the\u000a      50-75% of women with early breast cancer where no lymph node invasion has\u000a      occurred. The adoption of this method as the preferred axillary staging\u000a      technique for breast surgeons means that most patients now avoid the major\u000a      morbidity associated with having all the lymph nodes removed. These women\u000a      experience lower levels of pain, decreased arm and shoulder stiffness, and\u000a      a decreased risk of lymphoedema compared to those who received axillary\u000a      node clearance. A recent decision model analysis of SLNB's effectiveness\u000a      against axillary node dissection concluded that SLNB was more effective\u000a      with an average of 8 quality of life years gained per 1000 patients over a\u000a      20 year period.5.8\u000a    The research to refine methods for testing the molecular pathology of the\u000a      removed sentinel node within the operating theatre3.6 using\u000a      PCR quantification of two breast markers, also benefits patients. The\u000a      speed of the new test means that full axillary node clearance is possible,\u000a      when necessary, immediately following the biopsy. Patients avoid\u000a      undergoing a second surgical procedure and hospitalisation. They also\u000a      avoid the anxiety patients may experience of awaiting biopsy results (and\u000a      possible additional surgery).\u000a    The impact of sentinel node biopsy was summarised in a 2011 Clinical\u000a      Breast Cancer paper by staff at the University Hospital of North\u000a      Staffordshire, who had undergone New Start training. : They found the\u000a      technique allowed conservation in 80% of the patients with negative\u000a      sentinel lymph nodes and stated: \"Overall, sentinel node biopsy has\u000a      revolutionized the management of the axilla for the majority of patients\".\u000a      5.2\u000a    Impact on professional practice\u000a    The section of the 2009\/10 breast screening audit dealing with SLNB\u000a      (section 7.2) confirms the vital influence of the NEW START programme in\u000a      driving the adoption of the new technique among surgeons. It states: \"The\u000a      overall use of SLNB has increased by 9% since 2008\/09 as the roll out of\u000a      the NEW START Programme has continued.\" The same section of the 2011\/12\u000a      audit restates that the recommended technique should be the combined\u000a      isotope\/ blue dye technique, which is that advocated by ALMANAC and\u000a      specified in the NEW START programme.\u000a    In its 2009 guidelines, the Association of Breast Surgeons recommends\u000a      that practitioners take part in \"NEW START or equivalent training\u000a      programmes.\"5.4 The NICE Guidelines state that SLNB should only\u000a      be performed by teams \"validated in the use of the technique, as\u000a      identified in the NEW START training programme.\"5.3\u000a    The close collaboration with ARSAC allowed the safe introduction of the\u000a      isotope\/dye technique in nearly all hospitals across the UK over the\u000a      2007-2010 period as shown by the national breast screening data5.1 The\u000a      figures for 2011-12 show the dual isotope\/dye technique was used in 79% of\u000a      SLNB procedures.\u000a    The NEW START educational workshops held abroad speeded up the\u000a      introduction of sentinel node biopsy in many parts of the world where no\u000a      facilities existed for training. As a result, a cohort of highly trained\u000a      surgeons can now train the next generation around the globe in the\u000a      technique For example, In 2009, Mansel conducted a workshop for 50\u000a      consulting surgeons and surgical trainees in the principles of SLNB at\u000a      Kolkata, India. In 2011, he signed an agreement to establish a\u000a      standardised approach to SLNB at Chongqing, the most advanced cancer\u000a      hospital in western China.\u000a    Impact on healthcare costs\u000a    The recent decision model analysis of SLNB compared with axillary node\u000a      dissection5.8 noted that SLNB was less costly over 20 years\u000a      with $883 saved per patient. Cardiff's role in the development of\u000a      intra-operative sentinel node pathology testing has also helped reduce\u000a      healthcare costs. A recent paper from Spain shows that the testing makes a\u000a      per patient saving of 439 Euros compared to conventional post-operative\u000a      histology (Guillen-Paredes MP et al Cir esp 2011;89:456-62 available as\u000a      .pdf from HEI). The 2013 NICE guidelines conclude the techniques would\u000a      represent \"a cost-effective use of NHS resources\".\u000a    ","ImpactSummary":"\u000a    Research at Cardiff University is underpinning the abandonment of the\u000a      100-year-old surgical practice of removing all axillary lymph nodes in\u000a      cases of breast cancer. Such surgery frequently caused arm lymphoedema,\u000a      loss of arm mobility and lymphatic system damage. Cardiff led the seminal\u000a      ALMANAC trial which showed that full node clearance was unnecessary if a\u000a      biopsy of the first draining `sentinel' node was cancer-free. Cardiff then\u000a      spearheaded the impact on practice through a training and awareness\u000a      programme for surgeons, primarily in the UK, but also in China, India,\u000a      Brazil and Turkey. By 2010 these efforts had established the Sentinel\u000a      Lymph Node Biopsy (SLNB) procedure as standard in the UK, while the study\u000a      was also cited in USA guidelines. The main beneficiaries of the impact are\u000a      the 50-75% of breast cancer patients who now enjoy lower levels of pain,\u000a      shoulder disability and arm lymphoedema. Healthcare providers also benefit\u000a      financially from a reduced need for extensive surgery.\u000a    ","ImpactType":"Health","Institution":"\u000a    Cardiff University\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1275004","Name":"Kolkata"},{"GeoNamesId":"1814905","Name":"Chongqing Shi"}],"References":"\u000a    \u000a3.1 Goyal A, Douglas-Jones A, Newcombe R G, Mansel R E, on behalf\u000a      of the ALMANAC Trialists Group. Predictors of non-sentinel lymph node\u000a      metastasis in breast cancer patients. European Journal of Cancer\u000a      2004, 40: 1731-1737 DOI: 10.1016\/j.ejca.2004.04.006. ISSN: 0959-8049.\u000a    \u000a\u000a3.2 Mansel RE, Goyal A, Newcombe RG; ALMANAC Trialists Group.\u000a      Internal mammary node drainage and its role in sentinel lymph node biopsy:\u000a      the initial ALMANAC experience. Clin Breast Cancer. 2004\u000a      Oct;5(4):279-84; discussion 285-6. DOI 10.3816\/CBC.2004.n.031(available on\u000a      request from HEI)\u000a    \u000a\u000a3.3 Goyal A, Newcombe RG, Mansel RE on behalf of the ALMANAC\u000a      Trialists Group. Role of routine preoperative lymphoscintigraphy in\u000a      sentinel node biopsy for breast cancer. European Journal of Cancer\u000a      2005 41: 283-243. DOI:10.1016\/j.ejca.2004.05.008\u000a    \u000a\u000a3.4 Goyal A, Newcombe RG, Mansel RE; Axillary Lymphatic Mapping\u000a      Against Nodal Axillary Clearance (ALMANAC) Trialists Group. Clinical\u000a      relevance of multiple sentinel nodes in patients with breast cancer. Br\u000a        J Surg. 2005 Apr;92(4):438-42. DOI: 10.1002\/bjs.4906\u000a    \u000a\u000a3.5 Mansel RE, Fallowfield L, Kissin M et al. Randomised\u000a      multicenter trial of sentinel node biopsy versus standard axillary\u000a      treatment in operable breast cancer. The ALMANAC trial. JNCI 2006\u000a      , 98: 599-609 DOI: 10.1093\/jnci\/djj158\u000a    \u000a\u000a3.6 Mansel RE, Goyal A, Douglas-Jones A et al. Detection of\u000a      breast cancer metastasis in sentinel lymph nodes using intra-operative\u000a      real time GeneSearch BLN assay in the operating room: results of the\u000a      Cardiff study. Breast Cancer Res Treat. 2009 Jun;115(3):595-600\u000a      DOI:10.1007\/s10549-008-0155-6\u000a    \u000a\u000a3.7 Mansel RE, MacNeill F, Horgan K, Goyal A, Britten A, Townson\u000a        J, Clarke D, Newcombe RG and Keshtgar M.Results of a\u000a      national training programme in sentinel lymph node biopsy for breast\u000a      cancer. British Jnl Surgery, 2013,100:654-661 DOI:\u000a      10.1002\/bjs.9058\u000a    \u000aThe Validation phase of the ALMANAC study was supported by a grant from\u000a      the UK Medical Research Council. MRC grant No G9720984 Grant ID 53983. The\u000a      ALMANAC multicentre trial of sentinel node biopsy (Jan 1999 to Nov 2000),\u000a      total value £570K, PI Mansel\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    5.1 Annual audits of screen detected breast cancers are at \u000a      http:\/\/www.cancerscreening.nhs.uk\/breastscreen\/publications.\u000a      The 09\/10 audit confirms the influence of NEW START on surgical training,\u000a      the 11\/12 audit gives latest available figures for the increase in\u000a      patients having sentinel node biopsy.\u000a    5.2 Apostolopoulos A., Basit A., Kirby RM., Adjogatse JK., Lambert G,\u000a      Chan KY, Hancock A, Hackney L, Wall M. Conservation of the Axilla: an\u000a      audit of sentinel lymph node biopsy after a NEW START. Clinical Breast\u000a        Cancer 2011; 11:264-7. DOI: 10.1016\/j.clbc.2011.04.007 Corroborates\u000a      the revolutionary effect of sentinel node biopsy on patient management.\u000a    5.3 The 2009 guidelines for breast cancer published by NICE recommend\u000a      sentinel node biopsy as the preferred method of axillary staging, and also\u000a      endorse the NEW START training programme (http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG80NICEGuideline.pdf\u000a        )\u000a    5.4 SLNB is included in the surgical guidelines produced by the\u000a      Association of Breast Surgeons at BASO in 2009, which also endorses NEW\u000a      START DOI:10.1016\/j.ejso.2009.01.008\u000a      (http:\/\/www.cancerscreening.nhs.uk\/breastscreen\/publications\/ABS-BASO-guidelines.pdf\u000a      )\u000a    5.5 US NCCN Guidelines. The benefits to patients shown by the ALAMANAC\u000a      study are quoted in the 2010 edition. (username morgande@cardiff.ac.uk\u000a      password REF2014) http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/breast.pdf\u000a    5.6 Testimony from Royal College of Surgeons breast tutor corroborate the\u000a      collaboration between Cardiff University and the Royal College of Surgeons\u000a      in delivering NEW START the resulting improvement in professional practice\u000a    5.7 Testimony from Chair, Administration of Radioactive Substances\u000a      Advisory Committee (ARSAC) confirms the research was central to setting up\u000a      NEW START, leading to safe implementation of the isotope\/dye procedure\u000a    5.8 Verry et al. Effectiveness and cost-effectiveness of sentinel lymph\u000a      node biopsy compared with axillary node dissection in patients with\u000a      early-stage breast cancer: a decision model analysis. Br J Cancer.\u000a      2012 March 13: 106(6): 1045-1052. DOI:10.1038\/bjc.2012.62 Corroborates the\u000a      quality of life and healthcare costs benefits of SLNB.\u000a    (All web pages, testimonies and documents saved as pdfs and available on\u000a      request from the HEI.) \u000a    ","Title":"\u000a    Cardiff research yields evidence for benefits of sentinel node biopsy and\u000a      spearheads training in the technique as a standard of care in breast\u000a      cancer surgery\u000a    ","UKLocation":[{"GeoNamesId":"2653822","Name":"Cardiff"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Demonstrating the benefits of sentinel node biopsy\u000a    Each year, breast cancer affects more than 1.38 million women worldwide,\u000a      more than 37,000 of them in the UK. For more than a century, surgeons\u000a      advocated radical surgery to remove all the axillary lymph nodes that\u000a      drained the cancer-affected breast, as a way to diagnose and treat lymph\u000a      node involvement. Until recently 90% of patients worldwide underwent this\u000a      extensive surgery risking arm lymphoedema and damage to the lymphatic\u000a      system. The sentinel lymph node biopsy (SLNB) procedure, which removes\u000a      only one or two of the closest nodes to the cancer, was first explored in\u000a      the USA in the 1990s. Some breast surgeons used it to help identify\u000a      `sentinel' lymph nodes in the axilla, these being the first lymph nodes to\u000a      which breast cancer cells may have spread from a primary site. Critically,\u000a      the procedure had not undergone any formal evaluation or been compared to\u000a      the previous `gold standard' of axillary node clearance. By the late\u000a      1990's practice in some US academic comprehensive cancer centres was\u000a      changing in favour of the technique, although the question of whether SLNB\u000a      accurately defined node status remained unanswered [source:JNCI J Natl\u000a      Cancer Inst (2008)100(7):449-450]. Accordingly the value and potential\u000a      impact of the SLNB technique remained speculative.\u000a    In 1999 Robert Mansel (Professor of Surgery, Cardiff University;\u000a      1992-present) initiated and led the UK randomised trial of the SLNB\u000a      technique. Preparatory work, funded by a peer-assessed MRC grant, involved\u000a      initial training of the new technique to surgeons who had not practised it\u000a      in order to standardise the surgical technique. This preparation also\u000a      incorporated research studies to assess the `learning curve' for surgeons\u000a      becoming competent in the technique. 3.1,3.2,3.3\u000a    On the basis of this work, Cardiff launched the MRC multicentre UK\u000a      ALMANAC (Axillary Lymph node Mapping Against Normal Axillary Clearance)\u000a      randomised clinical trial to compare sentinel node biopsy with standard\u000a      axillary surgery. The trial (supported by grants from R&D Wales and\u000a      Amersham Health), was, at the time of its report, the largest randomised\u000a      trial of the preferred dual technique of using radioactive isotope and\u000a      blue dye in combination as markers. The trial comprised 1031 patients from\u000a      14 UK surgical centres, with Mansel as the Principal Investigator,\u000a      Newcombe as the statistician (Cardiff University 1992-present), and\u000a      Cardiff as the co-ordination centre. Patient quality of life assessments\u000a      for the trial were provided by Sussex University (Prof Lesley\u000a      Fallowfield).\u000a    Initially, Cardiff research evaluated the factors that could determine\u000a      the likelihood of additional positive nodes in the axilla in the presence\u000a      of sentinel node metastasis. Overall, in patients with a positive SLN, the\u000a      difference in the number of positive and negative sentinel lymph nodes\u000a      removed and size of the metastasis in the sentinel lymph node, all\u000a      predicted the frequency of additional positive nodes3.1 .\u000a      Research also established: the frequency of internal mammary drainage in\u000a      patients undergoing sentinel lymph node lymphoscintigraphy3.2;\u000a      the value of preoperative lymphoscintiscans in sentinel node visualisation3.3;\u000a      and the relevance of multiple sentinel nodes3.4. The final\u000a      analysis of the ALMANAC study3.5 showed that SLNB was a safe\u000a      and effective alternative to routine axillary dissection for nodal staging\u000a      in early-stage breast cancer. Compared with standard axillary treatment,\u000a      SLNB was associated with reduced arm morbidity and better quality of life\u000a      with no increase in anxiety. The collective research also established that\u000a      the majority of women with breast cancer could benefit from this\u000a      intervention, particularly those with small cancers detected by the NHS\u000a      Breast Screening Programme, 75% of whom have a negative axilla.\u000a    Technique refinement - validating intra-operative assessment\u000a    Continued clinical research was undertaken by Goyal (Lecturer, Cardiff\u000a      University; 2004-8), Douglas-Jones (Senior Lecturer, Cardiff University;\u000a      1995-2011) and Mansel - establishing the first clinical trial of an\u000a      intra-operative method of assessing cancer invasion of the sentinel node,\u000a      using PCR quantification of 2 breast markers3.6. The research\u000a      demonstrated that the presence of cancer in the sentinel node could be\u000a      ascertained at the time of surgery, enabling surgeons to immediately treat\u000a      the axilla in patients with a sentinel node invaded by cancer, rather than\u000a      having patients return for a second surgical procedure. The research was\u000a      published in Breast Cancer Research and Treatment and was the first\u000a      publication on this methodology in the UK and the first to suggest the\u000a      practicality of intra-operative assessment3.6. The quality of\u000a      the research and its potential benefit to patient care was recognised by a\u000a      Medical Futures Innovation Award from the Dept of Health in 2007.\u000a    "},{"CaseStudyId":"3418","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"1835841","Name":"South Korea"},{"GeoNamesId":"1562822","Name":"Vietnam"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"1605651","Name":"Thailand"},{"GeoNamesId":"3144096","Name":"Norway"},{"GeoNamesId":"102358","Name":"Saudi Arabia"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"1168579","Name":"Pakistan"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Health Policy Changes: In November 2009, Walsh and Toleman were\u000a      part of a UK-wide Department of Health (DoH) call alerting all UK\u000a      hospitals and departments (through the Public Health England Reference\u000a      Laboratory) to this new type of antibiotic resistance.5.1 Their\u000a      NDM-1 studies were used to invoke mandatory screening be conducted for all\u000a      patients arriving from overseas hospitals - these proposals were fully\u000a      adopted by the UK DoH. 5.1 The ECDC called for greater\u000a      surveillance and enhanced European-wide infection control measures to\u000a      contain the threat of NDM-1 - see Table 2 of reference 5.2. In South\u000a      Africa, the National Institute for Communicable Diseases issued a\u000a      nationwide alert calling for increased infection control measures due to\u000a      NDM-1. 5.3 In Canada (through governmental agency\u000a      focusing on practice and policy interventions for Canadian populations),\u000a      alerts and altered policies have been implemented. 5.4 \u000a    In August 2010 as a direct response to the first publication, the\u000a      Ministry of Health and Family Welfare together with the National Centre\u000a      for Disease Control in India constituted a National Task Force for the\u000a      containment of Antimicrobial resistance. In March 2011, this task force\u000a      produced India's first ever national antibiotic policy document entitled \"National\u000a        Policy for Containment of Antimicrobial Resistance in India\" (http:\/\/nicd.nic.in\/ab_policy.pdf).\u000a      In August 2012, all major Indian clinical, academic and research bodies\u000a      met in Chennai to discuss for the first time implementing 1. Antibiotic\u000a      stewardship. 2. Infection control and 3. National Surveillance. This\u000a      document, entitled \"The Chennai Declaration - A Roadmap to tackle the\u000a        Challenge of Antimicrobial Resistance\", is a direct response to\u000a      studies in India, led by Walsh and Toleman that have persuaded the Indian\u000a      government to acknowledge the very serious antibiotic resistance issues.5.5\u000a      Walsh is advising the authors of the Chennai declaration and the Pakistani\u000a      health authorities on antibiotic stewardship and infection control issues.\u000a    IMPACT: Prevention of the spread of NDM-1 bacteria throughout UK\u000a      hospital wards as witnessed by the recent example published in the Lancet\u000a      and International policy changes e.g. India.5.1-5.5\u000a    Public Behaviour Changes: These studies encouraged the Indian\u000a      government to take antibiotic resistance more seriously. The work was the\u000a      catalyst for the Indian government to organise emergency meetings\u000a      resulting in the publication of the first Indian Government policies on\u000a      tackling antibiotic resistance. The subsequent Chennai agreement has time\u000a      lined a road map for implementation of antibiotic stewardship and\u000a      infection control programs in response to Walsh's description of the\u000a      issues of multi-drug resistance in India - these are currently being\u000a      implemented across all of India so their impact is yet to be assessed.5.5\u000a      A secondary behaviour change has resulted from the work because it\u000a      highlights the threat posed by the growing industry of medical tourism and\u000a      international cosmetic surgery; this has caused clashes with Indian\u000a      private hospitals undertaking cosmetic surgery.\u000a    IMPACT: As a direct result of the research, stricter control of\u000a      antibiotic stewardship and national infection control programs are being\u000a      implemented in India. The research highlighted some of the medical issues,\u000a      i.e. post-surgical infections, associated with medical tourism.\u000a    Public Awareness of a Health Risk: Immediately following\u000a      publication of the seminal paper in Lancet Infectious Diseases,\u000a      NDM-1 was the fourth biggest story world-wide, the lead story on the BBC 6\u000a      o'clock news 5.6 and broadcasted by ABC, CNN,\u000a      Al-Jazeera, China-TV, India Today, SKY, ITV, Channel 4 and Channel 5. On\u000a      11th August, 2010 the NDM-1 story was covered on the front\u000a      pages of the Telegraph, Independent, Guardian, Mail, Times, Financial\u000a      Times, Sun and Mirror.5.6-5.8 Interviews with the\u000a      Telegraph, Times, Guardian and Independent provided informed editorials in\u000a      the weekend editions5.6-5.8 On the web, the NDM-1\u000a      feature registered 4.7 million internet hits in 2 days (11th-12th\u000a        August). Moreover, the follow-up study published in April 2011 was\u000a      covered widely in India and internationally including by the BBC - this\u000a      was the first study linking the emergence of \"superbugs\" to the lack of\u000a      sanitation in developing countries. This study was covered at the time by\u000a      a Channel 4 documentary and more recently by BBC Horizon and ABC public\u000a      awareness programs.5.9, 5.10\u000a    IMPACT: This global coverage changed the public's perception of\u000a      \"superbugs\" and demonstrated that resistance can be readily spread from\u000a      one bacterium to another - a clear demarcation from MRSA and \"C.\u000a        difficile\". This perception resulted in international alerts by the\u000a      Communicable Disease Centre (CDC) (USA), European CDC (ECDC) World Health\u000a      Organisation (WHO) etc. and resulted in global behavioural and policy\u000a      changes.\u000a    The Control of Diseases has Changed. The follow up study\u000a      describing the discovery of NDM-1 in the Indian tap-water and environment\u000a      has directly led to the Indian government issuing chlorine tablets to\u000a      sanitise tap water for New Delhi residents unable to afford bottled water.3.6\u000a      This practice continues, although control studies have not been undertaken\u000a      in India to assess the impact of the intervention.\u000a    IMPACT: Introduction of potable water treatment in New Delhi.\u000a    Impact on National and International Organisations: The impact of\u000a      NDM-1 has been detailed by many international health organisations\u000a      including: Individual national governments (China, Korea, France, USA and\u000a      UK) 5.1-5.5, the European Society of Clinical Microbiology and\u000a      Infectious Diseases, (CDC) (USA), WHO, European Parliament, and World\u000a      Health Assembly.  As a result of this international interest,\u000a      Walsh has been invited to give over 46 international talks (including\u000a      Australia, Norway, China, USA, Canada, Saudi Arabia, Thailand, Vietnam,\u000a      Japan, Pakistan and India) and Toleman has given talks in Italy,\u000a      Switzerland, Austria, USA, Saudi Arabia, and the UK. Walsh has addressed\u000a      the European parliament with the director of the WHO, Margaret Chan (http:\/\/www.who.int\/dg\/speeches\/2012\/amr_20120314\/en\/\u000a        available on request from HEI) on NDM-1; Toleman has addressed NATO\u000a      surgeons at the NATO headquarters in Brussels. Walsh has recently been\u000a      asked by the WHO and the Chinese CDC to act as a consultant on\u000a      international antibiotic resistance surveillance and was asked to become a\u000a      member on the World Health Associated infections forum (http:\/\/www.hai-forum.com\/ webcast). Walsh has also been asked by the UK government\u000a      \"GoScience\" to write a positioning paper predicting resistance rates in\u000a      2030 and its impact on human health. .\u000a    IMPACT: Mission statements and general alerts on the impact of\u000a      NDM-1 issued by the above organisations including national screening\u000a      programs.\u000a    Outcomes for Patients have Improved: The research on NDM-1 has\u000a      altered treatment of individuals presenting with NDM-1 positive\u000a      infections. The work documenting NDM-1 resistance profiles and prevention\u000a      measures for spread is known throughout the UK.5.1 A\u000a      recent case was of a traveller from India who required emergency admission\u000a      in at Southmead Hospital, Bristol. Treatment as above prevented further\u000a      spread of NDM-1 pathogens.3.6\u000a    IMPACT: Production of guidelines, in collaboration with the HPA,\u000a      for patient treatment and management. Less harm to patients, limited\u000a      spread of \"superbugs\" in UK hospitals and reduced costs.3.6\u000a    ","ImpactSummary":"\u000a    Cardiff Researchers in 2009 discovered the new antibiotic resistance\u000a      determinant NDM-1 and in 2010\/11 characterised its rapid worldwide spread\u000a      through Gram-negative bacteria (e.g. Escherichia coli and Vibrio\u000a        cholerae). NDM-1 redefined how antibiotic resistance can\u000a      spread locally and internationally and create new extensively-drug\u000a      resistance (XDR) that severely limits therapeutic options. This discovery\u000a      has resulted in: 1) new policies for the admission of overseas patients to\u000a      hospitals in the UK, France, USA, Australia and China, 2) linkage between\u000a      MDR transmission and poor sewerage treatment, 3) potable water treatment\u000a      in Southern Asia 4) positioning papers for the World Health Assembly and\u000a      5) policy-changes by the World Health Organisation.\u000a    ","ImpactType":"Political","Institution":"\u000a    Cardiff University\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2800867","Name":"Bruxelles-Capitale"},{"GeoNamesId":"1264527","Name":"Chennai"},{"GeoNamesId":"1261481","Name":"New Dehli"},{"GeoNamesId":"1261481","Name":"New Delhi"}],"References":"\u000a    \u000a3.1 Yong, Y., Toleman, M.A., Weeks, J., Giske, C., Walsh, T.R.\u000a      (2009) Characterisation of a new metallo-β-lactamase gene, blaNDM-1,\u000a      and a novel erythromycin esterase gene carried on a unique genetic\u000a      structure in Klebsiella pneumoniae sequence Type 14 from India. Antimicrob.\u000a        Agents and Chemother. 53, 5046-54. DOI: 10.1128\/AAC.00774-09 (cited\u000a      approx. 100 times).\u000a    \u000a\u000a3.2 Kumarasamy, K.K., Toleman, M.A., Walsh, T.R., I\u000a      (2010). Emergence of a new antibiotic resistance mechanism in India,\u000a      Pakistan, and the UK: a molecular, biological, and epidemiological study.\u000a      Lancet Infect Dis. 10, 597-602. DOI: 10.1016\/S1473- 3099(10)70143-2\u000a      (cited >600 times).\u000a    \u000a\u000a3.3 Hammerum, A.M., Toleman, M.A., Hansen, F., Kristensen, B.,\u000a      Lester, C.H., Walsh, T.R., Fuursted, K. (2010). Global spread of\u000a      New Delhi metallo-03b2-lactamase1.Lancet Infect Dis. 10, 829-30.\u000a      DOI: 10.1016\/S1473-3099(10)70276-0\u000a    \u000a\u000a3.4 Toleman, M. A., Spencer, J., Jones, L., Walsh, T.R.\u000a      (2012). blaNDM-1 is a chimera likely\u000a      constructed in Acinetobacter baumannii. Antimicrob Agents\u000a        Chemother. 56, 2773-6. DOI: 10.1128\/AAC.06297-11\u000a    \u000a\u000a3.5 Walsh, T.R., Weeks, J., Livermore, D.M., Toleman, M.A.\u000a      (2011). Dissemination of NDM-1 positive bacteria in the New Delhi\u000a      environment and its implications for human health: an environmental point\u000a      prevalence study. Lancet Infect Dis. 11, 355-62. DOI:\u000a      10.1016\/S1473- 3099(11)70059-7 (cited >130 times)\u000a    \u000a\u000a3.6 Darley, E., Jones, L., Daniels, V., Wootton, M., MacGowan, A.P., Walsh,\u000a        T.R. (2012). NDM-1 polymicrobial infections including Vibrio\u000a        cholerae. Lancet. 380 (9850), 1358. DOI:\u000a      10.1016\/S0140-6736(12)60911-8\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    5.1 UK: \u000a        http:\/\/www.hpa.org.uk\/webc\/HPAwebFile\/HPAweb_C\/1248854045473 (Backs\u000a      up claim of involvement in UK health policy changes and available on\u000a      request from HEI)\u000a    5.2 Europe-wide:\u000a        http:\/\/www.eurosurveillance.org\/ViewArticle.aspx?Articleid=19716\u000a      (Backs up claim of involvement in EU health policy changes and available\u000a      on request from HEI)\u000a    5.3 South Africa: National Institute for Communicable Diseases\u000a      http:\/\/www.nhls.ac.za\/?page=alerts&id=5&rid=110\u000a      (Backs up claim of South African health policy changes and available on\u000a      request from HEI)\u000a    5.4 Canada: http:\/\/www.nccid.ca\/the-w-5-of-ndm-1\u000a      (Backs up claim of involvement in Canadian health policy changes and\u000a      available on request from HEI).\u000a    5.5 Ghafur, A., et al. \"The Chennai Declaration.\" Indian J\u000a        Cancer 2012. 49; DOI:10.4103\/0019-509X.104065 (backs up claims of\u000a      Health Policy Changes, Public behaviour changes and public awareness of\u000a      health risks).\u000a    5.6 BBC news. http:\/\/www.bbc.co.uk\/news\/health-10930031)\u000a      (backs up claims of raising public awareness of a health risk)\u000a    5.7 Telegraph (http:\/\/www.guardian.co.uk\/science\/2010\/aug\/11\/antibiotics-efficiency-drug-\u000a        resistant-bacteria) (backs up claims of raising public awareness of\u000a      a health risk)\u000a    5.8 Guardian (http:\/\/www.dailymail.co.uk\/health\/article-1302358\/NDM-1-Were-blame-\u000a        indestructible-Indian-superbug.html) (backs up claims of raising\u000a      public awareness of a health risk)\u000a    5.9 BBC horizon (www.bbc.co.uk\/programmes\/b01ms5c6\u000a      television clips) (backs up claims of raising public awareness of a health\u000a      risk)\u000a    5.10 ABC 7.30 documentary. (http:\/\/www.abc.net.au\/7.30\/content\/2013\/s3810324.htm)\u000a      (backs up claims of raising public awareness of a health risk)\u000a    ","Title":"\u000a    Identification of a novel drug resistance determinant resulting in\u000a        global change of attitude and policy\u000a    ","UKLocation":[{"GeoNamesId":"2653822","Name":"Cardiff"},{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The problem of antibiotic resistance is listed as the WHO's key concern\u000a      for the 21stC - the increasing resistance to the most potent\u000a      drugs and the lack of new antibiotics being developed is heralding in an\u000a      era of untreatable infections. These sentiments have been recently echoed\u000a      by CMO, Prof. Sally Davies. Bacterial enzymes that break down antibiotics\u000a      such as penicillin are termed f062-lactamases and a sub-group, termed\u000a      carbapenemases break down the latest and most clinically useful group of\u000a      these antibiotics, carbapenems. The most potent of these enzymes are\u000a      metallo-f062-lactamases (MBL) as there are no clinical inhibitors for\u000a      these enzymes. In 2008, Timothy Walsh (Head of Microbiology Research, in\u000a      post since 2006) and Mark Toleman (Research Fellow, in Cardiff since 2007\u000a      and now Senior Lecturer) discovered and characterised a novel MBL, called\u000a      New Delhi Metallo-03b2-lactamase (NDM-1)3.1 The\u000a      hospitalised patient, a native Indian but Swedish resident, had just\u000a      returned to Stockholm from New Delhi. Collaborative studies in India\u000a      (Chennai and Haryana) initiated and funded by joint Welcome grant awarded\u000a      to Walsh and Toleman indicated that the NDM-1 gene was present in approx.\u000a      8% of clinical bacterial isolates f in the South and 13% in the north of\u000a      India. 3.2 NDM-1 is unique in structure, genetic\u000a      context, clinical epidemiology, and has spread globally more rapidly than\u000a      any other type of antibiotic resistance. 3.3, 3.4 In\u000a      September 2010 Walsh collaborated with Channel 4 journalists who were\u000a      making a documentary on the use of antibiotics in India and obtained water\u000a      and out-flow seepage samples. This work showed that the Indian environment\u000a      was significantly contaminated with NDM-1 positive bacteria. 3.5\u000a      The work on NDM-1 marked a seminal change in our global understanding of\u000a      antibiotic resistance. The key findings of the work were:\u000a    \u000a       NDM-1 was clearly widespread in the Southern Asian community as well\u000a        as hospitals making this very different from other types of antibiotic\u000a        resistance. 3.2,3.5\u000a\u000a       Genetic context, structure and the aetiology of the NDM-1 gene is\u000a        unique. 3.5\u000a\u000a       The success of NDM-1 spreading through diverse bacterial species has\u000a        been unparalleled in antibiotic resistance and related to their highly\u000a        promiscuous plasmids. 3.5 \u000a\u000a       Transfer of these plasmids transforms sensitive bacterial strains\u000a        into extreme drug resistant types only being sensitive to colistin and\u000a        tigecycline. 3.2,3.5\u000a\u000a       Global travel and in particular overseas surgery were a high-risk\u000a        factor in presenting with NDM-1. 3.2,3.6\u000a\u000a    \u000a    All work initially carried out on NDM-1, and 90% of the molecular\u000a      characterisation in the clinical epidemiology study was performed at\u000a      Cardiff University. Walsh and Toleman were the first to report NDM-1 in\u000a      key human pathogens such as Shigella spp. and Vibrio cholerae\u000a      (1, 2). These findings have influenced infection control policies in UK\u000a      hospitals for the isolation of NDM-1 positive pathogens as recently\u000a      reported in the Lancet. 3.6 They are currently co-ordinating\u000a      the biggest clinical trial to date in Southern Asia (Karachi) (funded by\u000a      Walsh's charitable foundation called SAARRP) to assess the\u000a      clinical significance of NDM-1 positive bacteria. Preliminary data from\u000a      this trial shows that 31% of patients admitted to public hospitals and 32%\u000a      on discharge carry NDM-1 bacteria as gut flora. Toleman's work in\u000a      Bangladesh has also found NDM in 60% of environmental water samples These\u000a      data when extrapolated to the whole of Southern Asia would suggest that\u000a      nearly 1 billion people could be carrying NDM-1 positive bacteria.\u000a    "},{"CaseStudyId":"3419","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Research Councils UK","Biotechnology and Biological Sciences Research Council","Engineering and Physical Sciences Research Council","Medical Research Council","Royal Society"],"ImpactDetails":"\u000d\u000a    Commercial Impact Of New Business Creation With Established Viability:\u000d\u000a    Background: The invention of DRAQ5™ led to the creation in\u000d\u000a      2001 of BioStatus Ltd (by Smith, Patterson and CEO Stefan Ogrodzinski; http:\/\/www.biostatus.com\/aboutus.asp)\u000d\u000a      to co-develop the dye technology, gain world-wide patent protection and\u000d\u000a      develop a route for sustainable commercial impact. A significant outcome\u000d\u000a      was the creation of a new market for far-red molecular probes (primary and\u000d\u000a      commercially-sensitive corroboration information from BioStatus Ltd CEO;\u000d\u000a      Factual Statement)5.1,5.2. Between 2002 and 2008, BioStatus Ltd\u000d\u000a      engaged academic opinion leaders and commercial organisations with a focus\u000d\u000a      on flow cytometry - winning two New Technologies Initiative Awards\u000d\u000a      in 2005 and funding research at 4 UK universities (Cardiff, Swansea,\u000d\u000a      Nottingham and Bradford). By 2009 BioStatus Ltd had secured granted DRAQ\u000d\u000a      patents5.3. Biostatus Ltd remains privately owned and in 2009\u000d\u000a      moved its direct sales and product development operations into its own\u000d\u000a      2,500 sq ft office & laboratory facility in Shepshed, Leicestershire5.1.\u000d\u000a    New product commercialized with revenue generation: In the\u000d\u000a      impact period, DRAQ5™ alone has an accumulated earnings of $3.2m, >95%\u000d\u000a      arising from export income, returning royalties of >$180K5.1,5.2\u000d\u000a      with a conservative estimate of ~5 million sample assays performed\u000d\u000a      to-date.\u000d\u000a    New linked start-ups funded by revenue from the core dye technology:\u000d\u000a      In 2008 Biostatus Ltd created Biosuspensions Ltd (www.biosuspensions.com\u000d\u000a      Register No.06780280) to progress its new drug and probe delivery\u000d\u000a      technology and in 2009 created the award-winning Oncotherics Ltd (www.oncotherics.com;\u000d\u000a      Register No.06940617) to progress a new anticancer drug based on its\u000d\u000a      accumulated company expertise in molecular probe chemistry.\u000d\u000a    Global reach of the innovation: To extend commercial global\u000d\u000a      reach, from 2008 BioStatus established a widening network of key\u000d\u000a      distributors including: ThermoFisher (2009-), e-Bio (now Affymetrix;\u000d\u000a      2009-) and AbCam (2010-). By 2013, the reach of the technology to its\u000d\u000a      research constituency was evidenced by its incorporation into research\u000d\u000a      practice world-wide in over 500 academic centres (source: client\u000d\u000a      management database Biostatus Ltd)5.1,5.2. By March 2013 the\u000d\u000a      widening significance and intensity of the influence of DRAQ5™ was\u000d\u000a      evidenced by its application featuring in 158 peer-reviewed articles (101\u000d\u000a      post-2008; source: SCOPUS) and a wider referencing of the use of DRAQ5™ as\u000d\u000a      a standard reagent in 3,060 text articles (2,340 post-2008; source: Google\u000d\u000a      Scholar). More recently, by October 2013 SCOPUS reported 925 Journal\u000d\u000a      references for DRAQ5™ and 338 patent applications exploiting DRAQ\u000d\u000a      technology published world-wide.\u000d\u000a    Recognition of impact: Successful translation of research\u000d\u000a      through to product impact was recognised by the award of the 2012\u000d\u000a        Royal Society of Chemistry Teamwork in Innovation Award to Smith,\u000d\u000a      Patterson, Errington and Biostatus Ltd, \"For worldwide exploitation and\u000d\u000a      impact of novel fluorescent molecular probes and cell detection\u000d\u000a      technologies in drug discovery, clinical diagnostics & the life\u000d\u000a      sciences\"  5.4.\u000d\u000a    Job creation: BioStatus Ltd is an ISO 9001 company,\u000d\u000a      currently employs 8 people and supports employment indirectly though\u000d\u000a      contracted activities for legal, synthesis and business support services5.1,5.2.\u000d\u000a    Impact On Business And New Medicines Discovery Sector Through Adoption\u000d\u000a        Of A New Technology:\u000d\u000a    Early partnerships with antibody suppliers (Cell Signalling Technologies\u000d\u000a      Inc, USA;www.cellsignal.com), major instrument developers (Amnis\u000d\u000a      Corporation; now EMD Millipore) and high-throughput assay developers\u000d\u000a      (Norak Biosciences, USA) led to validation for multi-colour microscopy and\u000d\u000a      imaging cytometry with product adoption by March 20085.1,5.2.\u000d\u000a    DRAQ5™ (product overview video: http:\/\/www.biostatus.com\/SearchResults.asp?Cat=1889)\u000d\u000a      is now used extensively on discovery imaging platforms with beneficiaries\u000d\u000a      being: GlaxoSmithKline, the world's leading pharmaceutical company (GSK\u000d\u000a      ranks #1, in the 2012 Access to Medicine Index), other major drug\u000d\u000a      companies (Roche, Bayer Schering & Takeda\/Nycomed) and contract\u000d\u000a      high-throughput screening organisations (eg Odyssey Thera) involved in new\u000d\u000a      medicine development for pharmaceutical clients. Here the commercial\u000d\u000a      impact has been a simplification of cell identification routines in\u000d\u000a      imaging-based screens, cost-reduction\/well, verified compatibility with\u000d\u000a      multiple green fluorescent protein reporter-based assays3.6 and\u000d\u000a      reduced attrition of naturally fluorescent drug candidates in screens5.1.\u000d\u000a    Impact On Health Through Delivering Improvements To The Analysis Of\u000d\u000a        Cells\u000d\u000a    New reagents for clinical diagnostics: DRAQ technology has\u000d\u000a      had the impact of delivering improvements to the accuracy of diagnostic\u000d\u000a      assays in a wide range of flow cytometry applications while providing\u000d\u000a      previously unattainable information or cost-savings in work flows. An\u000d\u000a      early trial in 2004 showed that DRAQ™ technology was readily adoptable by\u000d\u000a      regional flow cytometry clinical laboratory services employing cost-saving\u000d\u000a      and automated cytometers5.5. DRAQ5 is a validated reagent in\u000d\u000a      multiple applications, typical examples are: improved rare cell detection\u000d\u000a      in clinical diagnosis5.6, 5.7, more accurate myeloid to\u000d\u000a      erythroid precursors ratio determinations and a simplified workflow in\u000d\u000a      bone marrow analysis for haemato-oncology5.8, and improved\u000d\u000a      detection of nucleated erythroblasts5.9.\u000d\u000a    Evidence of widespread adoption in clinical assays: DRAQ5™\u000d\u000a      is featured directly in 29 independent medical publications (source:\u000d\u000a      SCOPUS search < DRAQ5>) providing evidence of the role of DRAQ5™ in\u000d\u000a      improving different clinical assays as a generic probe but for multiple\u000d\u000a      cell types - typical examples being: DRAQ5™ permitting the optimization of\u000d\u000a      multi-colour approaches for the clinical analysis of cancer cells, DRAQ5™\u000d\u000a      increasing the speed of assays by allowing single-step processing of\u000d\u000a      clinical samples such as bone marrow aspirates, DRAQ5™ simplifying assays\u000d\u000a      by allowing nucleated cells to be identified in blood and bone marrow\u000d\u000a      samples. Further DRAQ5™ introduces a new cell descriptor to enhance\u000d\u000a      accuracy of diagnosis in lymphoproliferative disorders and plasma cell\u000d\u000a      neoplasias. DRAQ5™ enables for the first time the simple extraction of\u000d\u000a      proliferation index of specific bone marrow cell compartments - an\u000d\u000a      important feature linked to patient outcomes. The core technology also\u000d\u000a      encompasses new derivatives. For example DRAQ7 detects cell viability and\u000d\u000a      is to be supplied in 2013 as a validated probe5.10 by Beckman\u000d\u000a      Coulter Inc - a leading in vitro diagnostics flow cytometry company. DRAQ7\u000d\u000a      is being evaluated further for an improved version of the ISHAGE protocol\u000d\u000a      for Paroxysmal Nocturnal Hemoglobinuria diagnostics and for the\u000d\u000a      standardization of flow cytometry for myelodysplastic syndromes.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Cardiff University research in 1997-2008 resulted in the development of a\u000d\u000a      family of novel far-red fluorescent dyes that stain the DNA of cells. The\u000d\u000a      leading live cell dye DRAQ5™ is now utilised in a wide range of laboratory\u000d\u000a      assays, transforming practice in clinical, commercial and research\u000d\u000a      sectors. Smith co-founded the multi-award-winning start-up company\u000d\u000a      Biostatus Ltd in 2001 to undertake product development. Commercial impact\u000d\u000a      post-2008 has been the generation of over $3.2 million in sales revenue\u000d\u000a      enabling job creation, direct funding of UK academic research positions\u000d\u000a      and creation of new technology start-up companies. Used in over 3,500\u000d\u000a      research, pharmaceutical and clinical organisations, DRAQ™ technology has\u000d\u000a      global reach.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    Cardiff University\u000d\u000a    ","Institutions":[{"AlternativeName":"Cardiff University","InstitutionName":"Cardiff University","PeerGroup":"A","Region":"Wales","UKPRN":10007814}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Smith PJ, Desnoyers, R., Blunt, N., et al Flow\u000d\u000a      cytometric analysis and confocal imaging of anticancer\u000d\u000a      alkylaminoanthraquinones and their N-oxides in intact human cells using\u000d\u000a      647-nm krypton laser excitation. Cytometry 1997;27:43-53 DOI:\u000d\u000a      10.1002\/(SIci)1097- 0320(19970101)27:1<43::AID-CYTO6>3.0.CO:2M\u000d\u000a    \u000a\u000a3.2 Smith PJ, Wiltshire, M., Davies, S., et al. A novel\u000d\u000a      cell permeant and far red-fluorescing DNA probe, DRAQ5, for blood cell\u000d\u000a      discrimination by flow cytometry. J Immunol Methods 1999;229:131-9\u000d\u000a      DOI: 10.1016\/S0022-1759(99)00116-7\u000d\u000a    \u000a\u000a3.3 Smith PJ, Blunt, N., Wiltshire M., et al\u000d\u000a      Characteristics of a novel deep red\/infrared fluorescent cell-permeant DNA\u000d\u000a      probe, DRAQ5, in intact human cells analyzed by flow cytometry, confocal\u000d\u000a      and multiphoton microscopy. Cytometry 2000;40:280-91 DOI:\u000d\u000a      10.1002\/1097- 0320(20000801)40:4<280::AID-CYTO4>3.0.CO:2-7\u000d\u000a    \u000a\u000a3.4 Njoh KL, Patterson LH, Zloh M, Wiltshire M, Fisher J, Chappell S,\u000d\u000a      Ameer-Beg S, Bai Y, Matthews D, Errington RJ, Smith PJ. Spectral\u000d\u000a      analysis of the DNA targeting bisalkylaminoanthraquinone DRAQ5 in intact\u000d\u000a      living cells. Cytometry A 2006;69:805-14 DOI: 10.1002\/cyto.a.20308\u000d\u000a    \u000a\u000a3.5 Errington RJ, Ameer-beg SM, Vojnovic B et al.\u000d\u000a      Advanced microscopy solutions for monitoring the kinetics and dynamics of\u000d\u000a      drug-DNA targeting in living cells. Adv Drug Deliv Rev\u000d\u000a      2005;57:153-67 DOI: 10.1016\/j.addr.2004.05.005\u000d\u000a    \u000a\u000a3.6 Smith PJ, Marquez, N., Wiltshire, M., et al. Mitotic bypass\u000d\u000a      via an occult cell cycle phase following DNA topoisomerase II inhibition\u000d\u000a      in p53 functional human tumor cells. Cell Cycle 2007;6:2071-81\u000d\u000a      DOI: 10.4161\/cc.6.16.4585\u000d\u000a    \u000aLinked research funding 1996-2008\u000d\u000a    • 1996-1999. MRC Project Grant G9526470. Development and\u000d\u000a      evaluation of novel flow cytometric assays for anticancer drug induced\u000d\u000a      cell cycle arrest. £220,000. PJ Smith (PI).\u000d\u000a    • 1997-2000. MRC\/HEFCW Joint Research Equipment Initiative. Two\u000d\u000a      photon confocal imaging. AK Campbell (PI) & PJ Smith £535,428.\u000d\u000a    • 2000-2003. Association for International Cancer Research:\u000d\u000a      Research (AICR) Grant ref: 00- 292. Title. High resolution timelapse\u000d\u000a      multiphoton imaging of anticancer drugs in living tumour cells: linking\u000d\u000a      single cell pharmacokinetics, tumour cell responses and treatment design\u000d\u000a      through bioinformatics. PJ Smith (PI) & RJ Errington & T Hoy. £115,771.\u000d\u000a    • 2000-2003. Amersham Biosciences PLC\/Kinetic Imaging Ltd:\u000d\u000a      Research Grant. Cell-based assay development. PJ Smith (PI) & RJ\u000d\u000a      Errington. £123,000.\u000d\u000a    • 2003-2005. BBSRC Research Grant SBRI19666. Far-red fluorescent\u000d\u000a      dyes and novel delivery\/detection systems for high throughput screening\u000d\u000a      (HTS) and cell-based biotechnology. PJ Smith (PI). £182,000.\u000d\u000a    • 2003-2006. BBSRC Grant 75\/E19292. The biology of drug\u000d\u000a      targeting: Predictive mathematical modelling of drug impact in complex and\u000d\u000a      dynamic cell populations. PJ Smith (PI) & RJ Errington. £177,392.\u000d\u000a      (A grade evaluation).\u000d\u000a    • 2003-2007. Research Councils' UK Basic Technology Research\u000d\u000a      Programme Grant GR\/S23483: Optical biochips. PJ Smith (PI), P Blood, SM\u000d\u000a      Ameer-Beg, PM Smowton, H Summers, B Vojnovic, RJ Errington, D Westwood, J\u000d\u000a      Burt, DM Taylor , £2,271,606.\u000d\u000a    • 2005-2008. Biostatus Ltd\/Cardiff University EPSRC CASE Award\u000d\u000a      RAUU001. Genomic and cell-based evolution of molecular oncotherapeutics.\u000d\u000a      PJ Smith (PI) & RJ Errington, £48,257.\u000d\u000a    • 2007. EPSRC HS-LSI feasibility grant EP\/E013104\/1: Stroboscopic\u000d\u000a      excitation fluorescence lifetime imaging. RJ Errington (PI). £103,000.\u000d\u000a    • 2007-2008. BBSRC Research Equipment Initiative Grant\u000d\u000a      BB\/E012574\/1. Time-based high- content screening. RJ Errington (PI) and PJ\u000d\u000a      Smith. £ 242,000.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"3","Level2":"2","Subject":"Inorganic Chemistry"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    5.1 Factual Statement: CEO Biostatus Ltd (Provides corroboration\u000d\u000a      of company activities)\u000d\u000a    5.2 Contact Person: CEO BioStatus Limited (Source corroboration\u000d\u000a      of financial and client information)\u000d\u000a    5.3 Combined pdf document of US patents: 6,468,753 2002;\u000d\u000a      7,060,427 2006; 7,605,280 2009: Smith PJ, Patterson LH; BioStatus Limited,\u000d\u000a      assignee; title: Anthraquinone and its derivatives (backs up claims of\u000d\u000a      commercial impact). <http:\/\/patft.uspto.gov\/netacgi\/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=0&f=S&l=50&TERM1=Anthraquinone+and+its+derivatives&FIELD1=TI&co1=AND&TERM2=Biostatus&FIELD2=ASNM&d=PTXT>\u000d\u000a    5.4 Scientific Organisation website:\u000d\u000a      http:\/\/www.rsc.org\/ScienceAndTechnology\/Awards\/TeamworkinInnovation\/2012-Winner.asp\u000d\u000a      (backs up claims of recognition of impact)\u000d\u000a    5.5 Research document: Luider J, Cyfra M, Johnson P & Auer I.\u000d\u000a      Lab Hematol. 2004;10(2):102-8 (backs up claims of new reagents for\u000d\u000a      clinical diagnosis).\u000d\u000a    5.6 Research document: Kraan, J., et al. Journal of Thrombosis\u000d\u000a      and Haemostasis 10.5 (2012): 931-939 (backs up claims of new reagents for\u000d\u000a      clinical diagnosis).\u000d\u000a    5.7 Research document: Swerts, K., et al. Clinica chimica acta\u000d\u000a      379.1 (2007): 154-157 (backs up claims of new reagents for clinical\u000d\u000a      diagnosis).\u000d\u000a    5.8 Research document: Allan, R.W., et al. Am J Clin Path 129.5\u000d\u000a      (2008): 706-713 (backs up claims of new reagents for clinical diagnosis)\u000d\u000a    5.9 Research document: A van de Geijn, G-J, et al. Cytometry Part\u000d\u000a      A79.9 (2011): 694-706 (backs up claims of new reagents for clinical\u000d\u000a      diagnosis)\u000d\u000a    5.10 Research document: Akagi, J et al. Cytometry A (2013) 83(2):\u000d\u000a      227-34 (backs up claims of adoption for clinical assays). \u000d\u000a    ","Title":"\u000d\u000a    Discovery and exploitation of fluorescent dyes in healthcare, drug\u000d\u000a        discovery and life sciences\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654993","Name":"Bradford"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Research on an unmet need: The study of cells and tissues\u000d\u000a      frequently utilizes fluorescent reagents, in particular dyes that can\u000d\u000a      stain nuclear DNA. Live cell DNA-specific dyes are especially valuable\u000d\u000a      since they can indicate cell cycle stage while at the same time preserving\u000d\u000a      cell function. Combining a live cell dye with other fluorescent tags\u000d\u000a      enhances `multi-colour' analyses on a range of cell imaging and cytometry\u000d\u000a      instruments. Such analyses encompass a wide range of clinical and\u000d\u000a      biomedical laboratory assays in research, diagnostic testing and\u000d\u000a      high-throughput screens. Before 2001, the choice of live cell dyes was\u000d\u000a      highly restricted and required an expensive UV laser for detection or\u000d\u000a      visualisation. Cardiff research focused on this unmet need.\u000d\u000a    Research at Cardiff University led by Paul Smith (Professor of Cancer\u000d\u000a      Biology; 1995-2013) had discovered the complex intracellular far-red\u000d\u000a      fluorescence patterns of drug-like anthraquinone molecules3.1.\u000d\u000a      In 1997 Smith initiated the underpinning research, funded by the MRC and\u000d\u000a      the Joint Research Equipment Initiative, to explore new molecular probes\u000d\u000a      for use in the life sciences. Paul Smith developed a new class of\u000d\u000a      anthraquinone-based DNA binding dyes that could penetrate into the nucleus\u000d\u000a      of living cells, undergo excitation by low cost red-emitting (633 nm)\u000d\u000a      lasers and fluoresce in the `far red' region of the spectrum. This\u000d\u000a      distinguished them from commonly used visible range fluorescent, making\u000d\u000a      them valuable in a wide range of biomedical applications.\u000d\u000a    Generating and screening candidate dyes: The research\u000d\u000a      involved the design of dye molecules with rapid penetration and high\u000d\u000a      binding affinity but with low quantum yield to decrease the `noise' from\u000d\u000a      unbound molecules. In collaboration with Laurence Patterson (Professor;\u000d\u000a      School of Pharmacy, De Montfort University), Paul Smith selected various\u000d\u000a      anthraquinone structures that were synthesised by Patterson and\u000d\u000a      transferred to Cardiff University for all subsequent research. During\u000d\u000a      1997-2000 Paul Smith utilized cell based imaging and flow cytometry, early\u000d\u000a      on discovering an optimal dye DRAQ5™ capable of entering living cells\u000d\u000a      (from microbes to human tissues) within seconds3.2,3.3. A\u000d\u000a      further breakthrough was the discovery that DRAQ5™ could also be excited\u000d\u000a      by conventional blue (488 nm) lasers making it compatible with all flow\u000d\u000a      cytometry platforms3.2 - a feature not shared by any other\u000d\u000a      vital DNA dye.\u000d\u000a    Applications, funding & intellectual property:\u000d\u000a      From 2000-2008, basic research at Cardiff University by Paul Smith and\u000d\u000a      Rachel Errington (Research Fellow, 1998-2003; Lecturer & Senior\u000d\u000a      Lecturer 2003-2011; Reader 2011; Professor 2013-present) created multiple\u000d\u000a      applications for this new class of dye molecules in the life sciences\u000d\u000a      including: lab-on-a-chip applications3.4 funded by Research\u000d\u000a      Councils UK, Optical Biochips Basic Technology Programme (2003-2007), high\u000d\u000a      resolution timelapse multiphoton imaging3.5 funded by the\u000d\u000a      Association for International Cancer Research (2000-2003), monitoring\u000d\u000a      drug-DNA targeting and high-content-screening assays funded by the BBSRC\u000d\u000a      (2003-2006 & 2007-2008). Industrial research partnerships between the\u000d\u000a      Cardiff team, Amersham Biosciences PLC & Kinetic Imaging Ltd\u000d\u000a      (2000-2003) established DRAQ5 dye compatibility in cell-based assays using\u000d\u000a      green fluorescent proteins3.6. Cardiff-Biostatus Ltd\u000d\u000a      partnerships [BBSRC Small Business Research Initiative grant (2003-2005)\u000d\u000a      & CASE\/EPSRC Studentship (2005-8)] led to the further development of\u000d\u000a      anthraquinone-based dye molecules (including CyTrak™Orange, ApoTrak™ and\u000d\u000a      DRAQ7™) for commercialisation by BioStatus Ltd. The underlying and linked\u000d\u000a      research has generated over £4m of research income. The core technology is\u000d\u000a      protected by US-granted patents (see below) citing Cardiff University's\u000d\u000a      published research.\u000d\u000a    "},{"CaseStudyId":"3673","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000a    Wright's research on screening for fetal anomalies and health conditions\u000a      during pregnancy has improved international healthcare provision. In 2004\u000a      Wright was commissioned by UK (NHS) Fetal Anomaly Screening Programme to\u000a      develop-implement a quality assurance tool for DS screening in the UK,\u000a      based on his NT and combined test research. As a result Wright formed, and\u000a      currently leads, DQASS. DQASS provides support for screening laboratories\u000a      and sonographers in all UK NHS hospitals, which are now required to submit\u000a      screening information and data to the Service according to its national\u000a      schedule. The analysis of this data focuses on identifying NT measurements\u000a      that are greater than expected (red flags - implying unacceptable bias in\u000a      sonographer performance), prompting the implementation of an action plan\u000a      aimed at improving sonographer performance: as recommended by FASP\/DQASS,\u000a      practitioners are required to complete 25 supervised NT measurements in\u000a      addition to three accurate paired NT and CRL measurements against the set\u000a      UK standards. Upon successful completion of these tasks, the sonographer\u000a      is permitted to return to independent practice.\u000a    Through DQASS, Wright's research has contributed to the improvement in\u000a      the efficacy of fetal anomaly screening in the UK NHS by enhancing the\u000a      quality of laboratory and sonographer practice, which has in turn\u000a      contributed towards a reduction in the number of women proceeding to\u000a      invasive testing where there is risk of fetal loss. Working with Wright,\u000a      the FASP established eight regional ultrasound coordinators tasked with\u000a      coordinating the recommended quality improvements and some 200 screening\u000a      support sonographers at hospitals throughout the UK to disseminate\u000a      information (specifically red flags) provided by DQASS. A series of\u000a      regional workshops were also held between 2006 and 2010 on standardising\u000a      and modernising practice, engaging over 2,000 sonographers and healthcare\u000a      workers in obstetrics and gynaecology, representing 30 NHS laboratories.\u000a    As a result, UK DS screening performance has significantly improved. In\u000a      2003, 36,968 invasive tests for suspected fetal anomaly were carried out\u000a      in the UK, whereas in 2009 only 13,595 were performed. This represents a\u000a      reduction of 63% in the previous over-investigation of chromosomal\u000a      abnormality, translating to 233 miscarriages avoided (based on a 1:100\u000a      invasive-test-linked miscarriage rate) (source: ACC, 2013). As stated in a\u000a      joint letter from Annette McHugh, Programme Manager for FASP, and Val\u000a      Armstrong, Deputy QA Lead (National), \"Both the improvement in the\u000a      performance of the [Down's Syndrome screening] test and the development of\u000a      new strategies has been supported by the work undertaken by [Wright],\u000a      contributing to the decreasing requirement for women to undergo\u000a      unnecessary invasive testing.\u000a    Wrights work with DQASS has also influenced screening programmes in other\u000a      countries. In Ontario, Canada, for example, it has been recognised that\u000a      accurate NT measurement is fundamental in DS screening, as the Director of\u000a      its national quality assurance agency, BORN, states: \"I am submitting a\u000a      letter of thanks to Prof. Dave Wright and the DQASS team for their support\u000a      in our efforts to implement a quality assurance programme for NT\u000a      ultrasound in Ontario, he has provided technical and statistical support,\u000a      advice and credibility [to the Ontario QA programme]... the partnership\u000a      with Wright and DQASS has been invaluable in this project... we can only\u000a      hope to achieve the same results Wright has enabled across the UK\".\u000a    Wright's research has also improved screening in private sector\u000a      healthcare worldwide: the FMF is a global charity aiming to improve the\u000a      health of pregnant women through research and training to support\u000a      professional groups and certified obstetricians. Historically, the FMF\u000a      supplied these groups with NT risk algorithms for a range of anomalies\u000a      using the Delta method, based on a singular distribution of NT\u000a      measurements. Recognising Wright's more accurate use of NT in trisomy risk\u000a      calculations, the FMF replaced Delta with the mixture model in 2008. Since\u000a      its introduction to the FMF, the mixture model has been commercially\u000a      applied by major equipment\/software companies operating in Europe and\u000a      Asia: GE Healthcare uses the model in its nine ultrasound machines, which\u000a      have been distributed to healthcare providers across the world while\u000a      Astraia Obstetrics use the model in its first trimester anomaly risk\u000a      calculator. Thermo Fisher Scientific Inc., one of the largest scientific\u000a      instruments companies in the world, use the mixture model on screening for\u000a      preeclampsia and state \"the work of Dave Wright has had a major impact on\u000a      the methodology and quality improvements of screening for fetal anomalies\u000a      and preeclampsia. The mixture model for NT is used throughout the world by\u000a      our customers\". They also state that \"the research of Dave Wright has been\u000a      instrumental in the introduction of our assay for PIGF (Placental Growth\u000a      Factor) in screening for preeclampsia using the competing risk model\".\u000a      Thermo Fisher has recently (2013) bought an asset purchase agreement\u000a      including a patent license for the exclusive rights of PIGF to diagnose\u000a      preeclampsia.\u000a    ","ImpactSummary":"\u000a    Research on risk assessment and screening led by Wright at Plymouth\u000a      University and including clinical participants from the Centre for Fetal\u000a      Medicine at King's College Hospital and Tübingen University, has improved\u000a      fetal and maternal healthcare. This research and work supporting the Fetal\u000a      Anomaly Screening Program (FASP) has contributed to reductions in the\u000a      number of unnecessary invasive diagnosis procedures in the UK, and has\u000a      improved screening performance through the implementation of the\u000a      NHS-endorsed Down's syndrome screening Quality Assurance Support Service\u000a      (DQASS). The research has also contributed to the risk algorithms of the\u000a      Fetal Medicine Foundation (FMF) which are used by the NHS and national and\u000a      international companies that provide technologies for the clinical\u000a      management of pregnancies by identifying high-risk groups for chromosomal\u000a      abnormalities and preeclampsia.\u000a    ","ImpactType":"Health","Institution":"\u000a    Plymouth University\u000a    ","Institutions":[{"AlternativeName":"Plymouth (University of)","InstitutionName":"Plymouth University","PeerGroup":"C","Region":"South West","UKPRN":10007801}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1.Nix, B., Wright*, D., Baker,* A. (2007) The impact of bias in MoM\u000a        values on patient risk and screening performance for Down syndrome.\u000a        Prenat Diagn; 27: 840-845. Prenatal Diagnosis communicates\u000a      peer-reviewed research in prenatal and pre-implantation diagnosis. The\u000a      journal ranks 22nd of 78 in the ISI Journal Citation Reports Ranking\u000a      (Obstetrics and Gyneacology, 2011), while its impact factor is 2.106.\u000a    \u000a\u000a2. Kagan, K.O., Wright*, D., Etchegaray, A., Zhou, Y., Nicolaides, K.H.\u000a      (2009) Effect of deviation of nuchal translucency measurements on the\u000a      performance of screening for trisomy 21. Ultrasound Obstet Gynecol; 33:\u000a      657-664. Ultrasound in Obstetrics & Gynecology is an\u000a      international, peer-reviewed journal including original papers, case\u000a      reports, reviews, opinion articles, and letters. The journal ranks 11th of\u000a      78 in the ISI Journal Citation Reports Ranking (Obstetrics and\u000a      Gynaecology, 2011), while its impact factor is 3.007.\u000a    \u000a\u000a3. Kagan, K.O, Hoopmann, N., Baker,* A., Huebner, M., Abele, H., Wright*,\u000a      D. (2012) Impact of bias in crown-rump length measurement at\u000a        first-trimester screening for trisomy 21. Ultrasound Obstet Gynecol; 40:\u000a        135-9. Ultrasound in Obstetrics & Gynecology is an\u000a      international, peer-reviewed journal including original papers, case\u000a      reports, reviews, opinion articles, and letters. The journal ranks 11th of\u000a      78 in the ISI Journal Citation Reports Ranking (Obstetrics and\u000a      Gynaecology, 2011), while its impact factor is 3.007.\u000a    \u000a\u000a4. Wright*, D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH. (2008) A\u000a      mixture model of nuchal translucency thickness in screening for\u000a      chromosomal defects. Ultrasound Obstet Gynecol. 31(4):376-83. Ultrasound\u000a        in Obstetrics & Gynecology is an international, peer-reviewed\u000a      journal including original papers, case reports, reviews, opinion\u000a      articles, and letters. The journal ranks 11th of 78 in the ISI Journal\u000a      Citation Reports Ranking (Obstetrics and Gynaecology, 2011), while its\u000a      impact factor is 3.007.\u000a    \u000a\u000a5. Kagan KO, Etchegaray A, Zhou Y, Wright,* D, Nicolaides KH. (2010)\u000a      Prospective validation of first-trimester combined screening for trisomy\u000a      21. Ultrasound Obstet Gynecol. 34(1):14-8. Ultrasound in\u000a        Obstetrics & Gynecology is an international, peer-reviewed\u000a      journal including original papers, case reports, reviews, opinion\u000a      articles, and letters. The journal ranks 11th of 78 in the ISI Journal\u000a      Citation Reports Ranking (Obstetrics and Gynaecology, 2011), while its\u000a      impact factor is 3.007.\u000a    \u000a\u000a6. Akolekar\u000a        R, Syngelaki A, Poon L, Wright,* D, Nicolaides KH. (2013) Competing\u000a      risks model in early screening for preeclampsia by biophysical and\u000a      biochemical markers. Fetal\u000a          Diagn Ther. 33(1):8-15. Fetal Diagnosis and Therapy\u000a      presents original, peer reviewed, papers covering both basic research and\u000a      clinical investigations into all aspects of fetal diagnosis leading to\u000a      therapy, including relevant technical advances and procedures. The journal\u000a      ranks 61st of 78 in the ISI Journal Citation Reports Ranking (Obstetrics\u000a      and Gynaecology, 2011), while its impact factor is Impact factor: 1.05.\u000a    \u000a*Current Plymouth University staff. Other institutional affiliations at\u000a      time of publication as follows:\u000a      Kings College Hospital: Akoleka, Ethchegarary, Gazzoni, Kagan, Nicolaides,\u000a      Poon, Syngelaki, Zhou, Molina (also Tübingen University).\u000a      Tübingen University: Abele, Hoopmann, Huebner.\u000a      Cardiff University: Nix.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    DQASS:\u000a    Joint written statement from Programme Manager and Deputy QA Lead\u000a      (National), UK National Screening Committee, Fetal Anomaly Screening\u000a      Programme, 344-354 Gray's Inn Road, London WC1X 8BP, tel +44 (0)207\u000a      1642100\u000a    List of DQASS resources on the NHS website explain the role of DQASS and\u000a      how the NHS works with Plymouth University: http:\/\/fetalanomaly.screening.nhs.uk\/qualityassurance\u000a    Written statement from Director, BORN, Ontario, 401 Smyth Road |Ottawa,\u000a      ON, K1H 8L1. A statement confirming the impact the research of Wright has\u000a      had on the introduction of quality assurance programme for NT ultrasound\u000a      in Ontario screening programme.\u000a    FMF and private sector healthcare providers:\u000a    Written statement from Director R+D, ThermoFisher Scientific. A statement\u000a      highlighting the major impact Wright's research has had on screening for\u000a      fetal anomalies and preeclampsia and that it is used by ThemoFisher\u000a      Scientific throughout the world. \u000a    ","Title":"\u000a    Improving screening during pregnancy\u000a    ","UKLocation":[{"GeoNamesId":"2640194","Name":"Plymouth"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Statistical research conducted by Wright (Professor of Applied Statistics\u000a      at Plymouth University, 2006-present) with Amy Baker (Senior Research\u000a      Fellow) and in association with clinical researchers established more\u000a      realistic models for risk assessment of fetal anomalies and of\u000a      preeclampsia. It also considered the way measurement errors of various\u000a      components in risk assessment impacted on performance risk assessment and\u000a      screening. This research raised the importance of quality assurance in\u000a      laboratory and ultrasound measurements.\u000a    The body of research began in 2005 with an investigation into\u000a      non-invasive screening for Trisomy 21 (T21), a form of Down's syndrome\u000a      (DS), demonstrating that false positive rates are influenced by the extent\u000a      to which factors such as smoking status are taken into account in the\u000a      calculation of risk pre-diagnosis (1). Building on this earlier research,\u000a      Wright et al. worked on understanding the effect of ubiquitously used\u000a      Nuchal Translucency (NT) median values in relation to the performance of\u000a      screening for T21. The research found that high quality screening is\u000a      dependent on accurate measurement of NT for which there was wide regional\u000a      variation (2), while further work in 2012 on the under\/over estimation of\u000a      Crown Rump Length in first trimester combined screening concluded that\u000a      individual sonographer variability must be taken into account when\u000a      calculating patient specific risk of chromosomal fetal abnormality (3).\u000a    Alongside this work, Wright introduced a mixture model for the\u000a      distribution of NT in chromosomally normal and abnormal pregnancies. The\u000a      model uniquely accounted for the fact that a minority subgroup of\u000a      chromosomally abnormal pregnancies can present in the same way as the\u000a      majority of chromosomally normal pregnancies. The mixture model was found\u000a      to be compatible with clinical findings of the pathophysiology of\u000a      increased NT in both chromosomally normal and abnormal fetuses, providing\u000a      a more realistic method of assessing the risk of fetal abnormalities\u000a      relative to other non-invasive screening models (4). Wright et al.\u000a      validated the model in 2009, demonstrating that the new risk algorithm for\u000a      T21 could achieve a 90% detection rate (for a 3% false-positive rate) when\u000a      NT is used in combination with maternal age and the biochemical markers\u000a      PAPP-A and free 03b2-hCG (5). This combination of markers is now\u000a      widely used as standard practice.\u000a    More recently Wright developed a competing risk survival model (3) that\u000a      estimated the time of delivery (birth) in cases of maternal preeclampsia\u000a      (PE). The work reflected some of the underlying principles and assumptions\u000a      about existing risk models as demonstrated in his NT research. Based on a\u000a      study of 1,426 PE pregnancies and 57,458 normal pregnancies, Wright\u000a      combined maternal characteristics with data collected at 11-13 weeks\u000a      gestation, namely uterine artery pulsatility index and mean arterial\u000a      pressure. The research showed that treating the time of delivery with PE\u000a      as a `continuous variable', statistically dependent on characteristics\u000a      such as maternal weight, ethnic origin and medical history, provided a\u000a      more efficient and effective way of assessing risks during early\u000a      pregnancy. Using the gestation at the time of delivery with PE meant that\u000a      the model could capture the severity of the condition on a continuum\u000a      rather than arbitrarily grouping into early and late PE (which were\u000a      formerly considered separate conditions with separate outcomes). This\u000a      model for effective first-trimester screening for PE has recently been\u000a      extended to include biochemical markers (6) and is undergoing validation\u000a      for adoption.\u000a    "},{"CaseStudyId":"3674","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2510769","Name":"Spain"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Hobart's work on scales has impacted internationally on MS trial based\u000a      research. As a result of the MS walking scale (MSWS-12) research,\u000a      developed by Hobart, a new diagnostic technology has been developed. This\u000a      has subsequently been translated throughout the world and has undergone\u000a      adaptation and validation. The scales have been translated into over 60\u000a      different languages including French, Dutch, Russian and Spanish and\u000a      evaluated for cross country validation. The MSWS-12 questionnaire has been\u000a      used around 9,200+ times and the longer MSIS-29 questionnaire has been\u000a      used around 30,000+ times (http:www.\/\/clinictrials.gov).\u000a    Since 2007, Plymouth University's trading company, UoPEL has received\u000a      £437,000 of license income for sales of measurement scales developed by\u000a      Hobart and targeted specifically at patients with Multiple Sclerosis (MS)\u000a      and Parkinson's disease. The University has received £135,000 of this in\u000a      the current financial year (2012\/13) and is projecting a total income this\u000a      year of c£200k (a further £65,000). This income is based on a range of 6\u000a      Scales developed by Hobart, derived via licenses established with Plymouth\u000a      University, University College London and the Plymouth Hospitals NHS\u000a      Trust. Commercial organisations such as Biogen Idec, TEVA Pharma,\u000a      Novartis, Ipsen and Merck continue to demand the use of the Scales in the\u000a      development and trialling of treatments for MS.\u000a    The scales have been used widely in MS clinical trials. For example, the\u000a      scale was used in two phase 3 clinical trials with the resulting data\u000a      demonstrating that the treatment effect was clinically significant for\u000a      people with MS leading to Fampridine being granted a conditional licence\u000a      by the European Medicines Agency (EMA) for MS. Fampridine is licensed to\u000a      improve walking ability for patients with MS. Hobart was asked to provide\u000a      evidence (2009) from this research that the treatment effect was\u000a      clinically significant at both the US and European regulatory deliberates\u000a      (FDA, EMA 2009).\u000a    This body of research has also recently influenced the decisions of the\u000a      United States Food and Drug Administration (FDA) in introducing new\u000a      regulatory guidelines and stimulated debate about the appropriateness of a\u000a      wide range of existing clinical outcome measures for a range of\u000a      conditions. These guidelines (2013) advise pharmaceutical companies\u000a      conducting trials on the outcome measures and approaches that FDA will\u000a      give credence to in terms of deciding on the labelling of drugs.\u000a    As stated by Laurie Burke, Associate Director for Study Endpoints and\u000a      Labeling, Office of New Drugs, Center for Drug Evaluation and Research,\u000a      Food and Drug Administration, \"Jeremy Hobart and Stefan Cano have had a\u000a      substantial impact at FDA. They have helped to make a complex science that\u000a      is fundamental to our work, accessible to us, and advance our\u000a      understanding and abilities to a higher level. This has enabled us to\u000a      appraise better the work we review such that our evaluations are as\u000a      accurate as we can make them, and our advice to industry is maximized. ...\u000a      They have also helped us to develop and ground our thinking in terms of\u000a      producing guidance to industry in the production of clinical outcomes\u000a      assessment instruments (patient, clinician, and observer-reported outcome\u000a      measurement instruments) for use in clinical trials. These documents are\u000a      very influential because they provide industry with roadmaps, guiding the\u000a      efficient modification and scientific upgrading of existing instruments,\u000a      and guiding development of the next generation of clinical outcomes\u000a      assessment instruments to assess interventions for patients.\"\u000a    The cannabinoids studies led by Zajicek have had clear impact on health\u000a      and welfare through the provision of clinical trial evidence. The results\u000a      have contributed to an overall understanding of clinical cannabinoid use,\u000a      and contributed to the weight of evidence for symptomatic and potential\u000a      neuroprotective action. A drug company is in the process of applying for\u000a      licensing of the cannabis extract used in CAMS and MUSEC studies, and\u000a      looking for larger pharmaceutical partners. Two patents have been granted\u000a      on the basis of this work.\u000a    The clinical trials have been the largest and longest studies of clinical\u000a      cannabinoid exposure, and the original CAMS study now has over 450\u000a      citations (~1 per week). These studies have received considerable media\u000a      coverage including the BBC, ITV News, New York Daily News, Nature,\u000a      Guardian. This is beyond the normal coverage for clinical trials, and the\u000a      results have been presented at major international MS meetings (most\u000a      recently in 2012 at 28th Congress of European Committee for\u000a      Treatment and Research in MS, ECTRIMS, in Lyon, France: http:\/\/ectrims2012.eventresult.com\/),\u000a      as well as national and local patient meetings. They have been summarised\u000a      on the MS Society website and are used as providing evidence on the search\u000a      for therapy in the disease's secondary progressive stage, when patients\u000a      have few treatment options. The results have demonstrated clearly the\u000a      difficulties of both conducting long-term clinical trials and\u000a      neurodegenerative disorders, but also the problems of side-effects often\u000a      leading to non-compliance. In addition these studies have provided more\u000a      data on the long term risks with cannabinoids which has global importance\u000a      for drug legislators.\u000a    ","ImpactSummary":"\u000a    This case study summarises a body of research on Multiple Sclerosis (MS)\u000a      developed at Plymouth University under the leadership of Professor Zajicek\u000a      and Professor Hobart. Hobart's work on linical outcome measurements has\u000a      directly influenced clinical research, trials and drug licensing,\u000a      especially in MS and Alzheimer's disease. The MS scales developed by\u000a      Hobart have been endorsed by the United States FDA and are in demand by\u000a      commercial organisations in the development and trialling of treatments\u000a      for MS and have led to the licensing of new drugs. Zajicek has led the\u000a      topical field in evaluating the potential benefits and risks of cannabis\u000a      for treating MS, contributing to the evidence base behind the medical use\u000a      of cannabinoids in general, and pioneering its global potential use to\u000a      slow neurodegeneration.\u000a    ","ImpactType":"Health","Institution":"\u000a    Plymouth University\u000a    ","Institutions":[{"AlternativeName":"Plymouth (University of)","InstitutionName":"Plymouth University","PeerGroup":"C","Region":"South West","UKPRN":10007801}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2163355","Name":"Hobart"},{"GeoNamesId":"2996944","Name":"Lyon"}],"References":"\u000a    \u000a1. Zajicek* J., Fox* P., Sanders* H., Wright* D., Vickery* J., Nunn A.,\u000a      Thompson A., UK MS Research Group. Cannabinoids for treatment of\u000a      spasticity and other symptoms related to multiple sclerosis (CAMS study):\u000a      multicentre randomised placebo-controlled trial. Lancet.\u000a      2003 Nov 8;362(9395):1517-26. PMID: 14615106. ISI:000186464500007. 1. All\u000a      authors contributed to study design and protocol development. Vickery was\u000a      trial coordinator, Wright was involved in statistical analysis, Zajicek,\u000a      Vickery, Sanders, and Wright wrote the paper, with revisions and\u000a      contributions from Fox and others.\u000a    \u000aThe Lancet has an impact factor of 38·28. The journal is\u000a      currently ranked second out of 153 journals in the general medicine\u000a      category.\u000a    \u000a2. John Zajicek*, Susan Ball*, David Wright*, Jane Vickery*, Andrew Nunn,\u000a      David Miller, Mayam Gomez Cano*, David McManus, Sharukh Mallik, Jeremy\u000a      Hobart*, on behalf of the CUPID investigator group. Effect of dronabinol\u000a      on progression in progressive multiple sclerosis (CUPID): a randomised,\u000a      placebo-controlled trial. Lancet Neurology 2013 Jul 13 [Epub ahead\u000a      of print] Zajicek contributed to the study concept and design and\u000a      participated in study conduct, patient enrolment, and interpretation of\u000a      data, Wright contributed to the study design, planned and supervised the\u000a      statistical analysis, and participated in the interpretation of data, Ball\u000a      and Cano did the statistical analysis and contributed to the\u000a      interpretation of data, Hobart contributed to the study design, conduct,\u000a      patient enrolment, data analysis and interpretation, Vickery coordinated\u000a      the study.\u000a    \u000aLancet Neurology has an impact factor of 23.92 and ranks highest\u000a      among the world's leading clinical neurology journals.\u000a    \u000a3. John Zajicek*, Jeremy C Hobart*, Anita Slade*, David Barnes,\u000a      Paul G Mattison, on behalf of the MUSEC Research Group. MUltiple Sclerosis\u000a      and Extract of Cannabis: results of the MUSEC trial J Neurol Neurosurg\u000a        Psychiatry 2012;83:11 1125-1132. Zajicek was\u000a      the chief investigator, and led the design, conduct and interpretation of\u000a      the study, Hobart and Slade conducted several analyses and reviewed the\u000a      paper in preparation. \u000a    \u000aThis international peer-reviewed journal for health professionals and\u000a      researchers publishes the most ground-breaking and cutting-edge research\u000a      in neurological sciences and has an impact factor of 4.7.\u000a    \u000a4. Hobart*, JC.; Riazi, A.; Lamping, DL.; et al (2003) Measuring the\u000a      impact of MS on walking ability: the 12-item MS walking scale (MSWS-12), Neurology,\u000a      Vol 60, pp 31-36, Lippincott, Williams and Wilkins, USA\u000a    \u000aThe leading clinical neurology journal worldwide, Neurology is directed\u000a      to physicians concerned with diseases and conditions of the nervous\u000a      system. Impact factor 8.31\u000a    \u000a5. Hobart* J, Cano* S. Improving the evaluation of therapeutic\u000a      interventions in multiple sclerosis: the role of new psychometric methods.\u000a      Health Technology Assessment, 13(12):1-200. ).\u000a    \u000aPeer-reviewed journal published by NIHR. Impact factor 6.91.\u000a    \u000a6. Hobart* J, Cano* S, Baron* R, Thompson A, Schwid S, Zajicek* J,\u000a      Andrich D. Achieving valid patient-reported outcomes measurement: A lesson\u000a      from fatigue in multiple sclerosis. MS Journal Online publication\u000a      ahead of print Apr 10, 2013.\u000a    \u000aInternational, peer-reviewed journal that leads within its specialism.\u000a      Impact factor 4.472.\u000a    *Current and former Plymouth University staff. Other institutional\u000a      affiliations at time of publication as follows:\u000a      University College Hospital: Mallik, McManus, Miller, Riazi, Thompson.\u000a      Oxfords University: Fitzpatrick\u000a      London School of Hygiene: Lampling\u000a      University of Western Australia: Andrich\u000a      Rochester university, NY: Schwid\u000a      MRC: Nunn,\u000a      NHS Trusts: Barnes, Mattison\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    Statement from United States Food and Drug Administration on the impact\u000a      of Hobart's work.\u000a    Fampridine FDA advisory committee meeting where Hobart presents his case,\u000a      using his scale data, that the effect of the drug on walking is clinically\u000a      meaningful for people with MS. http:\/\/www.fda.gov\/AdvisoryCommittees\/CommitteesMeetingMaterials\/Drugs\/PeripheralandCentral\u000a        NervousSystemDrugsAdvisoryCommittee\/ucm126190.htm\u000a    Commercial Information can be provided on a confidential basis from\u000a      Plymouth University's Trading Arm stating overall income, demand and\u000a      translations.\u000a    Report of Good Measurement Principles Task Force at the FDA\u000a      http:\/\/www.ispor.org\/TaskForces\/Good-Measurement-Practices-Clinician-Reported-Outcomes.asp\u000a    Review and Qualification Clinical Outcomes Assessment open workshop\u000a      organised by FDA, 19 October 2011 with presentation from Hobart\u000a      http:\/\/www.fda.gov\/Drugs\/NewsEvents\/ucm276110.htm\u000a    Summary of Cannabinoids research carried out by Zajicek on the Multiple\u000a      Sclerosis Society website:\u000a      http:\/\/www.ms-uk.org\/index.cfm\/cannabisresearch\u000a      Cannabis fails to slow progress in Multiple Sclerosis\u000a    Example of international media coverage and debate of the cannabinoids\u000a      research:\u000a      http:\/\/www.nydailynews.com\/life-style\/health\/cannabis-eases-multiple-sclerosis-ms-stiffness-study-article-1.1179450\u000a    \u000a    ","Title":"\u000a    Multiple Sclerosis: developing treatment and improving outcomes\u000a    ","UKLocation":[{"GeoNamesId":"2640194","Name":"Plymouth"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    This case study presents a body of clinical research into potential new\u000a      treatments, and clinical outcome measures, for MS with the aim of\u000a      developing new treatments, not only for modifying the disease course but\u000a      also in slowing progression. MS is the commonest cause of neurological\u000a      disability and death among young adults, with over 100,000 people affected\u000a      in the UK. Although there are an increasing number of treatments for the\u000a      inflammatory phase of relapsing-remitting MS, there are no treatments that\u000a      alter the course of progressive MS.\u000a    Clinical outcome measures are used to systematically track treatment and\u000a      they are the central dependent variable on which decisions about people's\u000a      treatments and the spending of public funds are made. Gait impairment is a\u000a      key issue in MS and is reported as a main complaint by 85% of patients.\u000a      Hobart initially undertook research on how to measure the impact of MS on\u000a      walking ability while at University College London (3). By interviewing\u000a      patients and clinicians, he developed a set of 12 statements on how MS\u000a      affected walking ability. He continued to develop and modify this scale\u000a      while at Plymouth University and produced Version Two, which is based on\u000a      new and independent rating scale methods. This was developed as part of\u000a      the wider programme of MS research at Plymouth.\u000a    Following a series of publications focussing on empirical examinations of\u000a      the most widely used clinical outcome measures, in 2007 Hobart re-asserted\u000a      in Lancet Neurology that many instruments used in state-of-the-art\u000a      clinical trials were not fit for purpose. The implications of this issue\u000a      was and remains significant; clinical trials are undermined, results are\u000a      not confident reflections of treatment effects, and patients may be\u000a      missing out on the opportunity to receive successful treatments.\u000a    In response to increasing calls from healthcare researchers and\u000a      practitioners for an accessible account of the new psychometric methods,\u000a      the National Institute for Health Research Health Technology Assessment\u000a      (NIHR HTA) funded Hobart in 2009 to study the advantages of applying\u000a      advanced level measurement science to clinical outcomes measurement (4).\u000a      This has enabled this newer version of the scale to be made.\u000a    Although there has been considerable anecdotal evidence on the benefits\u000a      of cannabinoids in symptomatic treatment of MS, there has been a paucity\u000a      of clinical trial evidence. Professor Zajicek (1995-to present) was the\u000a      Chief Investigator for an MRC-funded (£1.5m) Cannabinoids in MS (CAMS)\u000a      study (1). This 15-week on treatment, 33 centre, 667 patient, randomised\u000a      placebo-controlled trial provided evidence for symptomatic benefit of\u000a      pain, spasticity and muscle spasms. Based on the findings from CAMS,\u000a      Zajicek investigated the potential disease modifying benefits in the\u000a      Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) trial\u000a      (2). Supported by funding from MRC, NIHR, MS Society and MS Trust (£3.5m)\u000a      the CUPID trial randomised 493 patients with progressive MS to either oral\u000a      tetrahydrocannabinol (THC) or a placebo treatment. Whilst the main results\u000a      did not demonstrate overall efficacy, there was a suggestion of effect in\u000a      people with lower levels of disability. A further study, MUltiple\u000a      Sclerosis and Extract of Cannabis (MUSEC) was set up to investigate oral\u000a      cannabis extract and used an 11 point scale as a more patient orientated\u000a      measure of efficacy. Cannabis extract was confirmed as a viable treatment\u000a      option, and an effective form of pain relief, for those experiencing\u000a      muscle problems associated with MS. These studies and scale represent the\u000a      largest integrated trials of their kind globally.\u000a    "},{"CaseStudyId":"3788","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"357994","Name":"Egypt"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"2921044","Name":"Germany"}],"Funders":["Engineering and Physical Sciences Research Council"],"ImpactDetails":"\u000a    This project developed a new tamponade agent to enhance the clinical\u000a      outcome after treatment of retinal detachments. Standard tamponade agents\u000a      are based on silicone oils which can emulsify in the eye and cause adverse\u000a      side effects. The underpinning research provided proof of principle that a\u000a      silicone oil with an increased extensional viscosity had an increased\u000a      resistance to emulsification. This was achieved by the addition of a low\u000a      percentage of a very high molecular weight polymer of the same chemistry\u000a      to the silicone oil. Following on from this the UoL established that the\u000a      extensional viscosity property of the blend also made the material easier\u000a      to inject in comparison with an equivalent silicone oil with the same\u000a      shear viscosity but without the high molecular weight additive.\u000a    An additional benefit of this approach is that since there has been no\u000a      chemically different material added to the clinical grade silicone oil the\u000a      regulatory requirements were easier. In 2007 a collaboration was\u000a      established with Fluoron GmbH, a silicone oil tamponade manufacturer, to\u000a      develop the proof of principle prototype into a clinical grade product.\u000a      Fluoron GmbH licensed the technology from the University and have since\u000a      contributed a minimum payment of £10k pa and paid all patent costs.\u000a    Fluoron GmbH launched the product named Siluron® 2000 in 2008 (EC\u000a      certification: CE 575554) [4,6]. It accounted for 32% of its sales by\u000a      units in the period 2008-13 with 34,208 sales by 30th September\u000a      2013 [11]. A second product named Siluron® Xtra based on this technology\u000a      was launched for sale in July 2013 (EC certification: CE 575554). This\u000a      product has 10% of the high molecular weight additive further increasing\u000a      the resistance to emulsification while maintaining the ease of injection\u000a      within the range of current clinical products. Fluoron GmbH have brought\u000a      this second product to market in response to requests from vitreoretinal\u000a      surgeons [5] and it has sold 1,145 units part way through its first year\u000a      of introduction [11]. These products have enabled Fluoron to gain new\u000a      customers and reduce complaint rates by 40% [11].\u000a    The ultimate beneficiaries will be patients. Current tamponade agents are\u000a      either made from 1000mPas silicone oil that is known to emulsify in the\u000a      eye and cause adverse effects for the patient or 5000mPas silicone oil\u000a      that is very viscous and difficult to inject. All silicone oils are\u000a      currently removed after 3-6 months because of the risk of emulsification\u000a      leading to complications. The new Siluron® 2000 has a shear viscosity of\u000a      2000mPas making it easier to inject than 5000mPas oil but because of the\u000a      increased emulsification resistance will be less likely to cause adverse\u000a      effects to the patient [9,10]. Another major advantage of Siluron® 2000 is\u000a      that its extensional viscosity makes it easier to inject than an\u000a      equivalent oil meaning that smaller gauge instruments can be used to\u000a      inject and remove it from the eye causing a significant reduction in\u000a      trauma to the patient's eye due to the surgery. This also fits very well\u000a      with the general move, within vitreoretinal surgery, to the use of smaller\u000a      gauge instruments. Siluron® Xtra has a shear viscosity of 5000mPas and can\u000a      therefore be injected and removed using existing surgical equipment but\u000a      has been requested by clinicians owing to its enhanced resistance to\u000a      emulsification and thus improved clinical outcome for patients.\u000a    The market for silicone oil tamponades is not large but is valuable\u000a      because the patients requiring this treatment would go blind if not\u000a      treated. The incidence of retinal detachment is reported as 1 per 10,000\u000a      of population pa and of these 15-20% are treated with silicone oil\u000a      tamponades. Some vitreoretinal surgeons will not use oils because of the\u000a      oil related complications and therefore the availability of an oil with\u000a      increased emulsification resistance is expected to increase this treatment\u000a      option. This is the first product specifically designed to address this\u000a      problem. Fluoron GmbH has sold over 25,000 units of Siluron® 2000. In 2012\u000a      the units were sold across 37 different countries with the largest numbers\u000a      going to Germany and Egypt and substantial numbers going to Singapore,\u000a      Italy, Belgium and Switzerland. They have recently (August 2013) received\u000a      a licence to sell Siluron® 2000 and Xtra in China and believe this to be a\u000a      substantial market, expecting to sell over 1000 units in the first year.\u000a      An audit of its use in St Paul's Eye Unit at Royal Liverpool University\u000a      Hospital on 20 patients reported \"Clinically it proved easy to inject and\u000a      remove in a small-gauge setup. Anatomical success rates were comparable to\u000a      our experience with standard 5000cst silicone oil, so was its safety\u000a      profile.\" [7].\u000a    ","ImpactSummary":"\u000a    The University of Liverpool (UoL) has developed novel tamponade agents\u000a      used to treat retinal detachments. They are modified silicone oils that\u000a      have an increased extensional viscosity. This makes it easier to inject\u000a      into the eye by the vitreoretinal surgeons and, experimentally, they have\u000a      an increased emulsification resistance. This technology has been licenced\u000a      to Fluoron GmbH who manufacture these products under the name Siluron®\u000a      2000 and Siluron® Xtra. Siluron® 2000 has been on the market worldwide\u000a      since 2008 and used to treat patients providing an impact to health by\u000a      enhancing the clinical outcome for retinal detachment patients. Siluron®\u000a      Xtra was launched in July 2013.\u000a    ","ImpactType":"Technological","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"}],"References":"\u000a    Key Outputs\u000a    \u000a1. Williams RL, Day M, Garvey MJ, English R, Wong\u000a        D. Increasing the extensional viscosity of silicone oil reduces the\u000a      tendency for emulsification. Retina 30(2):300-304, 2010 DOI:\u000a      10.1097\/IAE.0b013e3181babe0c. Citations: 9 Impact Factor: 2.825\u000a    \u000a\u000a2. Williams RL, Day M, Garvey MJ, Morphis G,\u000a      Irigoyen C, Wong D and Stappler T. Injectability of\u000a      silicone oil-based tamponade agents. B. J. Ophthalmol. 95: 273-276, 2011\u000a      DOI: 10.1136\/bjo.2010.192344 Citations: 3 Impact Factor: 2.725\u000a    \u000a\u000a3. Garvey MJ, Williams RL and Day M. Composition for\u000a      treatment of a detached retina and method of production thereof WO\u000a      06\/413269 May 2006\u000a    \u000a\u000a4. Day M, Blanchard RL, English R, Dobbie T, Williams R, Garvey\u000a        M and Wong D, Shear and Extensional Rheometry of PDMS Tamponade\u000a      Agents Used in Vitroretinal Surgery, AIP Conference Proceedings 1027, 1411\u000a      (2008); doi: 10.1063\/1.2964592\u000a    \u000aOriginal grants\u000a    2005-2006. EPSRC. Identification of colloid science routes to\u000a      improve the clinical performance of tamponade agents, £65,717, PI RL\u000a        Williams, CoIs MJ Garvey, M Day\u000a    2007-2008. Fluoron GmbH. Producing novel tamponade agents,\u000a      £58,629 PI RL Williams\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    \u000a      Fluoron GmbH website description of Siluron® 2000 and Siluron® Xtra\u000a        http:\/\/www.geuder.de\/media\/raw\/RZ_Brochure_Siluron_GB_25072013.pdf\u000a        demonstrating commercial promotion of the products\u000a      Fluoron GmbH website user report on Siluron family of products\u000a        http:\/\/www.geuder.de\/media\/raw\/User_Report_Siluron_Xtra_by_Stappler_2013_E.pdf\u000a        providing a clinical testimonial of the product\u000a      EC-Certificate for Siluron® 2000 and Siluron® Xtra http:\/\/www.fluoron.de\/index.php?myID=56&sprache=en\u000a        demonstrating compliance with EU regulations\u000a      \u000aTheodor Stappler, Lazaros Konstantinidis and David Wong\u000a\u0009    Siluron 2000 Novel- Generation Silicone Oil: Proof of Concept and\u000a        One Year Clinical Results Invest Ophthalmol Vis Sci 2012;53:\u000a        E-Abstract 5792 providing evidence of clinical acceptability. This is an\u000a        audited clinical study that used the new oil and evaluated clinical\u000a        outcomes.\u000a      Caramoy A. Schröder S. Fauser S. and Kirchhof B. (2010) In vitro\u000a        emulsification assessment of new silicone oils. Br. J. Ophthalmol.\u000a        94(4):509-512 DOI: 10.1136\/bjo.2009.170852 demonstrating\u000a        emulsification resistance in comparison with other tamponade agents\u000a        evaluated by a different research group\u000a      Caramoy A. Hagedorn N. Fauser S. Kugler W. Gro03b2 T and Kirchhof B.\u000a        (2011) Development of emulsification-resistant silicone oils: Can we go\u000a        beyond 200mPas silicone oil. Invest. Ophthalmol. Vis. Sci.\u000a        52(8):5432-5436 DOI: 10.1167\/iovs.11-7250 Further demonstration\u000a        of emulsification resistance by a different group\u000a      Yau Kei Chan, Chiu-On Ng, Paul Knox, Michael Garvey, Rachel\u000a          Williams, and David Wong (2011) Emulsification of silicone\u000a        oil and eye movements Invest. Ophthalmol. Vis. Sci. 52:9721-9727 DOI:\u000a        10.1167\/iovs.11-8586 demonstrating emulsification resistance using a\u000a        different model designed by scientists at the University of Hong Kong to\u000a        mimic clinical eye movement and its influence on oil emulsification.\u000a      Letter: Geuder (Fluoron) dated 30th October 2013 and\u000a        accompanying sales data.\u000a    \u000a    ","Title":"\u000a    Development of Novel Tamponade Agents has Improved the Treatment of\u000a      Retinal Detachment\u000a    ","UKLocation":[{"GeoNamesId":"2644210","Name":"Liverpool"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Retinal detachment is an important cause of blindness in the western\u000a      world. It is the final common pathway for many disease processes including\u000a      diabetic retinopathy and age-related macular degeneration. Treatment\u000a      involves the removal of the vitreous from the eye and its replacement with\u000a      silicone oil to cause closure of the retinal tear. The emulsification of\u000a      silicone oil-based tamponade agents, which are used in the treatment of\u000a      complex retinal detachments, is a significant clinical problem. This\u000a      causes problems of clouding of vision and adverse biological responses\u000a      including inflammatory reactions and blocking of the fluid outflow from\u000a      the eye potentially leading to glaucoma. Currently, high shear viscosity\u000a      oils are used to counter emulsification but the higher the shear viscosity\u000a      the more difficult the oils are to inject and remove from the eye.\u000a    This project took a multidisciplinary approach involving Prof Rachel\u000a      Williams (then a senior lecturer in Department of Clinical Engineering,\u000a      UoL) and Dr Michael Garvey (then a Senior Research Fellow in the\u000a      Department of Physics, UoL) in collaboration with Prof David Wong,\u000a      Consultant Vitreoretinal surgeon, University of Hong Kong and Honorary\u000a      Professor (UoL), and Mr Theodor Stappler, Honorary Lecturer (Clinical,\u000a      Royal Liverpool University Hospital) who provided strong clinical input. A\u000a      highly qualified surfactant chemist (Dr Michael Day: Postdoctoral research\u000a      associate, UoL) studied the mechanisms involved in the formation of the\u000a      emulsions in the eye. The research showed that the process of\u000a      emulsification in the eye results from the oscillation of the\u000a      silicone\/water interface under a shear force which leads to the pulling\u000a      out of filaments of the oil into the aqueous phase which snap resulting in\u000a      the formation of satellite silicone droplets which will persist in the\u000a      aqueous phase. The addition of very high molecular weight polymers to the\u000a      oil increases the extensional viscosity and prevents filament snapping and\u000a      satellite droplet formation. The increase in extensional viscosity was\u000a      achieved by adding a range of high molecular weight additives of varying\u000a      molecular weight at different concentrations to clinical grade silicone\u000a      oil. The underpinning research was funded by EPSRC (EP\/C546679-1) in\u000a      2005-2006 under the post- doctoral mobility scheme to allow Dr Day to use\u000a      his expertise to address a cross-disciplinary problem.\u000a    The project demonstrated that modification of standard clinical grade\u000a      silicone oil tamponade agent (Siluron® 1000, Fluoron GmbH) with a low\u000a      percentage of a very high molecular weight (423k) polymer of the same\u000a      chemistry increased the extensional viscosity of the oil and reduced its\u000a      emulsification [1,4]. Furthermore these silicone oil blend have a lower\u000a      shear viscosity than Siluron® 5000 (Fluoron GmbH), the current high\u000a      viscosity clinical grade silicone oil, and thus are advantageous in terms\u000a      of ease of injection into and removal from the eye [2]. A patent [3] has\u000a      been filed to protect these findings (WO 06\/413269) in the EU, US and\u000a      Canada and has been granted in Australia, China, Hong Kong and Japan\u000a      (15\/02\/2013). Further funding was received from Fluoron GmbH (£58,629,\u000a      2007) to develop a product.\u000a    "},{"CaseStudyId":"3789","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Royal Society"],"ImpactDetails":"\u000d\u000aBuilding on the work of the Winstanley group prior to this impact period, when the research led to\u000d\u000awider recognition that transmissible strains of P. aeruginosa, and the LES in particular, are\u000d\u000aimportant in the context of CF, the group has achieved the following impacts:\u000d\u000a\u000d\u000aThe multiplex PCR test for transmissible strains (combining Winstanley group designed PCR\u000d\u000atests for the LES and Midlands1 strains with a published PCR assay for the Manchester\u000d\u000astrain) has been used routinely in the NHS diagnostic laboratories serving both Adult\u000d\u000a(Liverpool Heart & Chest Hospital) and Children's (Alder Hey Hospital) CF Units from 2008.\u000d\u000aThis therefore represents a new clinical product.\u000d\u000aThe clinical uptake of the multiplex PCR test has extended from local NHS to national\u000d\u000alevel, as HPA Colindale used it as its main assay to test P.aeruginosa isolates from CF\u000d\u000aUnits across the UK for the majority of the period Jan 2008 to July 2013. The PCR tests\u000d\u000adeveloped in Liverpool have helped in the recognition of the presence of the LES in other\u000d\u000aCF centres. HPA Colindale receives thousands of P. aeruginosa isolates each year from CF\u000d\u000aUnits across the UK for strain typing. Although they have more recently switched to wider\u000d\u000ause of an alternative typing method (VNTR), the PCR assays are still used occasionally by\u000d\u000aPublic Health England, Colindale [10]. The LES remains the most common clone of P.\u000d\u000aaeruginosa associated with CF infections in the UK (Martin et al. 2013 J Med Microbiol on-\u000d\u000aline ahead of print).\u000d\u000aThe use of the multiplex PCR test has allowed clinicians to make informed decisions about\u000d\u000apatients with transmissible strains of P. aeruginosa with respect to segregation of patients,\u000d\u000abecause patients are cohorted for treatment depending on their microbiological status (ie.\u000d\u000aLES-positive or LES-negative). This has had an impact on the health of CF patients\u000d\u000abecause the use of this test has contributed to the fact that new cases of LES infections are\u000d\u000aextremely rare in Liverpool. The main beneficiaries are CF patients who are not yet infected\u000d\u000awith P. aeruginosa. Prior to the use of PCR tests to identify patients infected with\u000d\u000atransmissible strains, there was no patient segregation. The consequence of this can be\u000d\u000aseen from the fact that prior to its discovery and the development of a simple test, the LES\u000d\u000awas already present in 80% of P. aeruginosa-infected patients in the Liverpool paediatric\u000d\u000aunit (Cheng et al 1996 Lancet 348:639-642, Panagea et al. 2004 Molecular Diagnosis\u000d\u000a7:195-200). Most of these patients have now moved on to the adult unit. Because of\u000d\u000aeffective segregation measures, there are now only small numbers of LES-infected patients\u000d\u000aat the Liverpool paediatric unit, and there have been no new cases for several years. Cases\u000d\u000ain the paediatric CF Unit in Liverpool have decreased from 47 LES-positive patients in 2003\u000d\u000ato 8 LES-positive patients in 2009. In the adult unit there was a reduction in the proportion\u000d\u000aof patients with LES (2003 to 2009) from 71% to 53% [12,13]. Since 2009, there have been\u000d\u000ano new cases of LES-infected patients in the Adult CF Unit other than patients new to the\u000d\u000aunit (ie. transferred from the paediatric centre or new to the region). There is a clear clinical\u000d\u000abenefit to restricting the spread of the LES, which is associated with increased patient\u000d\u000amorbidity (Al-Aloul et al. 2004 Thorax 59:334-336). This increased morbidity has been\u000d\u000ashown to be true also for patients in North America infected with the LES (Aaron et al. 2010\u000d\u000aJAMA 304:2145-2153). It is important to note that the impact of segregation based on\u000d\u000agenotyping is ongoing. Patients, including new patients and first-time P. aeruginosa infected\u000d\u000apatients, are regularly monitored using the PCR tests, enabling LES-positive patients to be\u000d\u000atreated apart from non-LES, and minimising the threat of further spread of the strain. It is\u000d\u000alikely that there has also been impact at other CF centres. Public Health England has\u000d\u000aconfirmed that \"Professor Winstanley's research has played an important role in the\u000d\u000asignificant extensions of lifespan and quality of life improvements experienced by CF\u000d\u000apatients in England in the last few years\" [10].\u000d\u000aIn addition, the research highlights the existence of transmissible strains of P. aeruginosa\u000d\u000a(thought unlikely before Liverpool's initial LES report in 1996) has impacted on\u000d\u000aresearchers worldwide and contributed to the discovery of other transmissible strains\u000d\u000a(Fothergill, Walshaw & Winstanley 2012 Eur Resp J 40:227-238), leading to changes in\u000d\u000aclinical procedures aimed at control of cross infection.\u000d\u000aThe use of our PCR assay is recommended in guidelines published by the UK Cystic\u000d\u000aFibrosis Trust Microbiology Laboratory Standards Group designed to underpin the\u000d\u000adevelopment of National Standard Operating procedures for the processing of respiratory\u000d\u000asamples submitted from people with Cystic Fibrosis [8]. This was circulated to all diagnostic\u000d\u000alaboratories in the UK serving CF units. Hence, the assay has impacted on policy change.\u000d\u000a\u000d\u000a","ImpactSummary":"\u000d\u000aChronic lung infections due to Pseudomonas aeruginosa are the major cause of morbidity and\u000d\u000amortality associated with cystic fibrosis. Some strains of P. aeruginosa transmit between patients\u000d\u000a(epidemic strains). The Winstanley group, at the University of Liverpool (UoL) since 1999, in\u000d\u000acollaboration with clinicians in Liverpool, has developed diagnostic PCR assays for identification of\u000d\u000athe most widely reported UK epidemic strains of P. aeruginosa. The NHS clinicians use these\u000d\u000atests to make informed decisions about patient segregation leading to markedly reduced incidence\u000d\u000aof LES infections. Researchers internationally have adopted the UoL research results and strategy\u000d\u000ato tackle other transmissible strains and modify clinical procedures.\u000d\u000a","ImpactType":"Health","Institution":"\u000d\u000aUNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000aThe impacts stem from a whole series of research papers published in peer-reviewed journals\u000d\u000aidentifying, characterising and developing \/ refining diagnostic tests for epidemic strains, especially\u000d\u000athe LES. Some relevant publications are listed below.\u000d\u000a\u000a1. Mowat E, Paterson S, Fothergill JL, Wright EA, Ledson MJ, Walshaw MJ, Brockhurst\u000d\u000aMA and Winstanley C (2011). Pseudomonas aeruginosa population diversity and turnover\u000d\u000ain cystic fibrosis chronic infections. American Journal of Respiratory and Critical Care\u000d\u000aMedicine 183:1674-1679. Citations: 39 Impact Factor: 11.041\u000d\u000a\u000a\u000a2. Winstanley C, Langille MGI, Fothergill JL, Kukavica-Ibrulj I, Paradis-Bleau C,\u000d\u000aSanschagrin F, Thompson NR, Winsor GL, Quail MA, Lennard N, Bignell A, Clarke L,\u000d\u000aSeeger K, Saunders D, Harris D, Parkhill J, Hancock REW, Brinkman FSL and Levesque\u000d\u000aRC (2009). Newly introduced genomic prophage islands are critical determinants of in vivo\u000d\u000acompetitiveness in the Liverpool Epidemic Strain of Pseudomonas aeruginosa. Genome\u000d\u000aResearch 19:12-23. Citations: 85 Impact Factor: 14.397\u000d\u000a\u000a\u000a3. Fothergill JL, Upton A, Pitt TL, Hart CA and Winstanley C (2008). Diagnostic multiplex\u000d\u000aPCR assay for the identification of the Liverpool, Midlands 1 and Manchester epidemic\u000d\u000astrains of Pseudomonas aeruginosa. Journal of Cystic Fibrosis 7:258-261. Citations: 16\u000d\u000aImpact Factor: 2.873\u000d\u000a\u000a\u000a4. Salunkhe P, Smart CH, Morgan JAW, Panagea S, Walshaw MJ, Hart CA, Geffers R,\u000d\u000aTümmler B and Winstanley C (2005). A cystic fibrosis epidemic strain of Pseudomonas\u000d\u000aaeruginosa displays enhanced virulence and antimicrobial resistance. Journal of\u000d\u000aBacteriology 187:4908-4920. Citations: 94 Impact Factor: 3.177\u000d\u000a\u000a\u000a5. Al-Aloul M, Crawley J, Winstanley C, Hart CA, Ledson MJ and Walshaw MJ (2004).\u000d\u000aIncreased morbidity associated with colonization by an epidemic Pseudomonas aeruginosa\u000d\u000astrain in cystic fibrosis patients. Thorax 59:334-336. Citations: 80 Impact Factor: 8.376\u000d\u000a\u000a\u000a6. Parsons YN, Panagea S, Smart CHM, Walshaw MJ, Hart CA and Winstanley C (2002)\u000d\u000aUse of subtractive hybridization to identify a diagnostic probe for a cystic fibrosis epidemic\u000d\u000astrain of Pseudomonas aeruginosa. Journal of Clinical Microbiology 40: 4607-4611.\u000d\u000aCitations: 34 Impact Factor: 4.068\u000d\u000a\u000a\u000a7. Fothergill JL, White J, Foweraker JE, Walshaw MJ, Ledson MJ, Mahenthiralingam, E. and\u000d\u000aWinstanley C (2010). Impact of Pseudomonas aeruginosa genomic instability on the\u000d\u000aapplication of typing methods in chronic cystic fibrosis infections. Journal of Clinical\u000d\u000aMicrobiology 48:2053-2059. Citations: 13 Impact Factor: 4.068\u000d\u000a\u000aGrant awards relating to this work\u000d\u000a2013-2016. Cystic Fibrosis Trust. Clinical Exploitation of Genomics Data Produced by the\u000d\u000aPseudomonas International Consortium, £99,743, PI C Winstanley\u000d\u000a2013-2016. Cystic Fibrosis Canada. Clinical Exploitation of Genomics Data Produced by\u000d\u000athe Pseudomonas International Consortium, C$316,000 (£204,000) CoI C Winstanley\u000d\u000a2011-2014. Wellcome Trust. Genetic diversification and within-host evolution of chronic\u000d\u000aPseudomonas aeruginosa infections in cystic fibrosis patients, £249,795, S Paterson, C\u000d\u000aWinstanley and M Brockhurst\u000d\u000a2009-2012. Wellcome Trust. Understanding the role of temperate bacteriophages in the\u000d\u000aecology and evolution of Pseudomonas aeruginosa in the cystic fibrosis lung environment,\u000d\u000a£223,208 C Winstanley and M Brockhurst\u000d\u000a2008-2011. Dr. Hadwen Trust. Response of populations of P. aeruginosa to antimicrobial\u000d\u000achallenge during chronic infections in CF, £134,954, C Winstanley\u000d\u000a2008-2012. NIHR. Virulent epidemic strains of Pseudomonas aeruginosa in cystic fibrosis,\u000d\u000aNIHR, £153,762 (approx.) C Winstanley (A component of the Biomedical Research Centre\u000d\u000ain Microbial Diseases c.£20 million total grant)\u000d\u000a2005-2008. CF Trust\/Big Lottery Fund. Genetic factors contributing to the success of CF\u000d\u000a\"superbugs\" in the UK, £93,867, C Winstanley and CA Hart\u000d\u000a2002-2005. Cystic Fibrosis Trust. Use of subtractive hybridisation to identify novel\u000d\u000agenomic regions of an epidemic strain of Pseudomonas aeruginosa, £62,705, C\u000d\u000aWinstanley and CA Hart\u000d\u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000aEach source listed below provides evidence for the corresponding numbered claim made in section\u000d\u000a4 (details of the impact).\u000d\u000a\u000d\u000a\"Laboratory Standards for Processing Microbiological Samples from People with Cystic\u000d\u000aFibrosis\" (2010)\u000d\u000ahttps:\/\/www.cysticfibrosis.org.uk\/media\/82034\/CD_Laboratory_Standards_Sep_10.pdf. Section\u000d\u000a4.3.1 gives details of a multiplex-PCR test developed in Liverpool for three epidemic\u000d\u000astrains (LES, Midlands1 and Manchester), quoting two UoL studies [3,7] (Fothergill et al.\u000d\u000a2008; Fothergill et al. 2010).\u000d\u000aContact: Alder Hey Children's Hospital, CF paediatric unit, can confirm that the PCR tests\u000d\u000ahave been used routinely to screen CF patients in Liverpool and corroborate the clinical\u000d\u000aimpact in terms of reduced incidence of LES infection.\u000d\u000aLetter: Public Health England, Colindale.\u000d\u000aContact: Papworth, can confirm that the PCR targets devised by us for the LES (PS21 and\u000d\u000aLES-F9) are used in PCR assays.\u000d\u000aThe publication Ashish et al. 2013 Journal of the Royal Society of Medicine 4:1 includes\u000d\u000adata supporting the clinical impact in terms of reduced incidence of LES infection in\u000d\u000aLiverpool.\u000d\u000aMorris D, Fallon L, Heaf L, Burrows EF, Wallace H, McNamara PS, Winstanley C, Southern\u000d\u000aKW. (2009) A reducing prevalence of the Liverpool Epidemic Strain of Pseudomonas\u000d\u000aaeruginosa in children attending the index paediatric clinic. Ped Pulmonol vol 32 pp 325\u000d\u000a\u000d\u000a\u000d\u000a","Title":"\u000d\u000aDiagnostic Tests for Cystic Fibrosis Epidemic Strains\u000d\u000a","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aCystic Fibrosis (CF) affects over 9000 people in the UK alone, and CF patients require lifelong\u000d\u000ahealthcare. An estimated £110m pa is spent on treating UK CF patients. Chronic lung infections\u000d\u000adue to Pseudomonas aeruginosa are the major cause of morbidity and mortality associated with\u000d\u000aCF. It is very important that CF patients are kept free from infection with P. aeruginosa for as long\u000d\u000aas possible because (i) once a chronic infection is established, it is never eradicated and (ii) the\u000d\u000aearlier the infection, the worse the patient prognosis. The UoL has played the main role in\u000d\u000arecognising the important contribution in CF of a limited number of epidemic (transmissible) strains\u000d\u000aof P. aeruginosa, in particular the Liverpool Epidemic Strain (LES), which is the most prevalent in\u000d\u000athe UK, and has also been reported in North America. Patients infected with the LES suffer greater\u000d\u000amorbidity than patients infected with other strains.\u000d\u000aResearch at the UoL (2002-2013) carried out by the Winstanley group (specialising in microbiology\u000d\u000aand infection) has included the design, development and publication of PCR assays to identify the\u000d\u000aLES and Midlands1 epidemic strains, and a multiplex PCR assay for the identification of the three\u000d\u000amost widely reported UK epidemic strains of P. aeruginosa (LES, Midlands1 and Manchester\u000d\u000astrain). The work involved collaboration with clinical colleagues, particularly Dr Martin Walshaw\u000d\u000a(Head of the Adult CF Unit, Liverpool and Honorary status in UoL). The clinical collaboration\u000d\u000aensured the supply of relevant clinical samples and strains to enable testing of the assays, and\u000d\u000afacilitated the introduction into diagnostic laboratories, initially in Liverpool. The Winstanley group\u000d\u000apublished a PCR assay for the LES in 2002 and further improvements to the assay in 2006, along\u000d\u000awith a PCR assay for another prominent epidemic strain (Midlands1). A multiplex PCR assays for\u000d\u000athree epidemic strains was published in 2008. Other publications by the Winstanley group were\u000d\u000aused to demonstrate the utility of the assays and generate the basic science used to design and\u000d\u000aimprove the assays.\u000d\u000aThe assays were designed by using various genetic \/ genomic techniques to identify regions of the\u000d\u000agenomes of P. aeruginosa epidemic strains that could be targeted for the design of specific PCR\u000d\u000aassays (ie. regions present only in these strains).\u000d\u000aSince being introduced into the routine analysis of strains from CF patients in Liverpool, these tests\u000d\u000ahave been used to guide clinicians with respect to decisions regarding segregation of patients.\u000d\u000aCraig Winstanley is Professor of Bacteriology in the UoL and has worked at the University\u000d\u000acontinuously since 1999. There were various PhD students and postdoctoral researchers (under\u000d\u000athe supervision of Winstanley) involved in the work, as well as clinical collaborators (particularly Dr\u000d\u000aMartin Walshaw Head of the Adult CF Unit in Liverpool and honorary UoL academic), who were\u000d\u000aresponsible for providing samples and clinical input. Dr Jo Fothergill (Research Fellow) also\u000d\u000aplayed a prominent role in the work (since 2005). Along with Winstanley, she was responsible for\u000d\u000adeveloping the multiplex PCR assay.\u000d\u000a"},{"CaseStudyId":"3790","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    The Liverpool studies of bronchodilator responsiveness in COPD have\u000d\u000a      changed the respiratory community's view of the optimal management of\u000d\u000a      COPD. Before our studies, guidance from the American and European\u000d\u000a      Respiratory Societies and the Global initiative for COPD recommended that\u000d\u000a      bronchodilator testing should be a routine part of diagnostic evaluation\u000d\u000a      in COPD [8,9]. The publication of the data by Calverley et al led to a\u000d\u000a      change in the approach adopted in the first NICE guidelines in 2005 and\u000d\u000a      then in the revised GOLD guidance in 2007 [10]. These issues have recently\u000d\u000a      been reviewed by Albert et al in Lancet Respiratory Medicine. The\u000d\u000a      preliminary presentation of data by Albert et al in 2010 led the\u000d\u000a      Department of Health to revise their quality outcome points allocation by\u000d\u000a      removing routine reversibility testing from the points allocated to GPs\u000d\u000a      assessing COPD patients [11], Instead points were awarded for undertaking\u000d\u000a      better quality spirometry and recording symptom intensity which we have\u000d\u000a      shown to be better markers of disease severity. In this regard the Chief\u000d\u000a      scientist in the Department of Health said `The work of Professor\u000d\u000a      Calverley and his colleagues in Liverpool has had a direct effect on the\u000d\u000a      recommendations for assessment of the COPD patient' [12].\u000d\u000a    The paper by Davis et al on oral corticosteroids in exacerbations [3] has\u000d\u000a      been cited 344 times as of November 2013 and has been quoted in many COPD\u000d\u000a      guidelines documents [8-10] and in the NICE evidence review about the\u000d\u000a      management of COPD exacerbations [7]. Subsequent work from Canada\u000d\u000a      published in the NEJM confirmed Liverpool's findings and showed that\u000d\u000a      corticosteroid treatment reduced re-admission rates. Recent data from\u000d\u000a      clinical trials indicate that upwards of 80% of exacerbations are now\u000d\u000a      managed using oral corticosteroids, a considerable change when the\u000d\u000a      previous practice, where antibiotics were the first line of treatment.\u000d\u000a      After the UoL RCT of hospital-at home-care, multiple NHS Trusts have set\u000d\u000a      up outreach teams based on the model the UoL developed and this has now\u000d\u000a      been taken up across the UK from 2008 onwards. Dr Davies has spoken\u000d\u000a      extensively nationally and internationally on this topic and members of\u000d\u000a      the UoL team have helped developed the British Thoracic Society Guidelines\u000d\u000a      on Hospital at Home Care [13] which accelerated the adoption of research\u000d\u000a      into wider practice. A Spanish trial reported that these protocols reduced\u000d\u000a      COPD treatment costs by 62%, reduced hospitalisation from 4.2 to 1.7 days\u000d\u000a      and increased patient satisfaction [18].\u000d\u000a    Professor Calverley has given invited lectures to all the UK medical\u000d\u000a      Royal Colleges, all the international respiratory societies (ATS, ERS,\u000d\u000a      APSR, ELAT) and in many other countries on the subject of inhaled\u000d\u000a      corticosteroids and long acting inhaled bronchodilators and related\u000d\u000a      topics. The TORCH study provided the pivotal evidence which led the FDA to\u000d\u000a      license the combination of an inhaled corticosteroid and a bronchodilator\u000d\u000a      in the prevention of COPD exacerbations, the first time the Agency had\u000d\u000a      accepted exacerbation prevention as an indication for COPD treatment [8].\u000d\u000a      The data the Liverpool group generated played an important role in the\u000d\u000a      evidence-based evaluation of drug therapy in COPD conducted by NICE and\u000d\u000a      now published as revised guidance [7]. Similar recommendations were made\u000d\u000a      by the international GOLD guidelines [9,10] The new drug roflumilast,\u000d\u000a      which the UoL investigated in several large clinical trials, has been\u000d\u000a      reviewed by both the European Medicines Agency and the Federal Drugs\u000d\u000a      Administration and in each case our data, together with expert witness\u000d\u000a      input from Prof Calverley, played an important role in the licensing of\u000d\u000a      this therapy as well as identifying areas for future research [16]. This\u000d\u000a      led the sponsor's Medical Director to say, `(Prof Calverley's) advice\u000d\u000a        has significantly helped our company to bring Roflumilast to the market\u000d\u000a        and provide the severe ill COPD patients an additional treatment\u000d\u000a        option...' - global sales were £19m in 2012, >200% increase over\u000d\u000a      2011 [17].\u000d\u000a    The large clinical studies have involved a range of collaborators in\u000d\u000a      other UK centres and across Europe and North America. This has led to\u000d\u000a      on-going collaborations such as the NIHR HTA grant held with Prof Wedzicha\u000d\u000a      at UCL and the jointly managed EU FP7 grant recently awarded to UoL and\u000d\u000a      colleagues in the Politecnico di Milano to study the early identification\u000d\u000a      of exacerbations in COPD patients with co-morbidity monitored at home.\u000d\u000a      Professor Calverley has been able to translate the findings into practical\u000d\u000a      effect, having served from 2000-2011 on the GOLD Executive Committee and\u000d\u000a      as Chair of both the Science and Dissemination Committees. He helped\u000d\u000a      develop the joint ATS\/ERS COPD guidelines and the UK NICE Guidelines. He\u000d\u000a      chaired the Department of Health External Reference Group which produced\u000d\u000a      the Clinical Strategy for COPD Care published in 2011 [15] and presently\u000d\u000a      chairs the NIHR Respiratory Speciality Group charged with delivering high\u000d\u000a      quality clinical trials of the type the Calverley group has conducted for\u000d\u000a      the last decade.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    COPD affects up to 3.5 million people in the UK and costs the NHS £700m\u000d\u000a      pa. Over the last 15 years, research by Professor Calverley and colleagues\u000d\u000a      at the University of Liverpool (UoL) has impacted significantly on the\u000d\u000a      care of COPD patients. Specifically, this group showed that routine\u000d\u000a      testing of COPD patients for the presence of bronchodilator reversibility\u000d\u000a      was unreliable and did not predict clinical outcomes. This changed\u000d\u000a      international guideline recommendations in 2007 and the Quality Outcomes\u000d\u000a      Framework payments to GPs in 2009. They showed that oral corticosteroids\u000d\u000a      accelerated recovery from exacerbations and that anti-inflammatory drugs,\u000d\u000a      whether inhaled corticosteroids or PDEIV inhibitors, reduced exacerbations\u000d\u000a      by 25% with a subsequent fall in the number and length of\u000d\u000a      hospitalisations. This led to changed NICE guidance for corticosteroids in\u000d\u000a      2010 and drug registration with EMA and FDA for the PDEIV inhibitor\u000d\u000a      treatment in 2011. Treatment in UK and Western Europe has changed as a\u000d\u000a      result of this research.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW.\u000d\u000a      Bronchodilator reversibility testing in chronic obstructive pulmonary\u000d\u000a      disease. Thorax 2003 August;58(8):659-64. Citations: 244 Impact Factor:\u000d\u000a      8.376\u000d\u000a    \u000a\u000a2. Albert P, Agusti A, Edwards L, Tal-Singer R, Yates J, Bakke P\u000d\u000a      et al. Bronchodilator responsiveness as a phenotypic characteristic of\u000d\u000a      established chronic obstructive pulmonary disease. Thorax 2012 August;\u000d\u000a      67(8):701-8. Citations: 11 Impact Factor: 8.376\u000d\u000a    \u000a\u000a3. Davies L, Angus RM, Calverley PMA. Oral corticosteroids in\u000d\u000a      patients admitted to hospital with exacerbations of chronic obstructive\u000d\u000a      pulmonary disease: A prospective randomised controlled trial. Lancet\u000d\u000a      1999;354 (9177):456-60. Citations: 344 Impact Factor: 39.060\u000d\u000a    \u000a\u000a4. Davies L, Wilkinson M, Bonner S, Calverley PMA, Angus\u000d\u000a      RM. \"Hospital at home\" versus hospital care in patients with exacerbations\u000d\u000a      of chronic obstructive pulmonary disease: prospective randomised\u000d\u000a      controlled trial. BMJ 2000 November 18;321 (7271):1265-8. Citations: 115\u000d\u000a      Impact Factor: 17.215\u000d\u000a    \u000a\u000a5. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,\u000d\u000a      Jones PW et al. Salmeterol and fluticasone propionate and survival in\u000d\u000a      chronic obstructive pulmonary disease. N Engl J Med 2007 February 22;356\u000d\u000a      (8):775-89. Citations: 1428 Impact Factor: 51.658\u000d\u000a    \u000a\u000a6. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM,\u000d\u000a      Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary\u000d\u000a      disease: two randomised clinical trials. Lancet 2009 August 29;374\u000d\u000a      (9691):685-94. Citations: 281 Impact Factor: 39.060\u000d\u000a    \u000aKey Grants\u000d\u000a    2000-2003. GlaxoSmithKline. Genetic basis of COPD, PMA\u000d\u000a        Calverley, £350k\u000d\u000a    2003-2007 GlaxoSmithKline: Towards a Revolution in COPD Health, PMA\u000d\u000a        Calverley. £200k\u000d\u000a    2006-2008. British Lung Foundation. Chest wall movement and tidal\u000d\u000a      flow limitation in COPD, PMA Calverley, £105k\u000d\u000a    2008-2011. GlaxoSmithKline. Evaluation of Clinical variables to\u000d\u000a      Identify Prospective Surrogate Endpoints (ECLIPSE), PMA Calverley,\u000d\u000a      £440k\u000d\u000a    2011-2014. MRC\/ABPI COPD consortium, Phenotyping COPD in the UK,\u000d\u000a      PMA Calverley (co-applicant), £6.3m\u000d\u000a    2010-2015. NIHR Programme Grant. Innovative use of antibiotics in\u000d\u000a      the prevention of COPD exacerbations, PMA Calverley (jointly with\u000d\u000a      JA Wedzicha), £2.0m\u000d\u000a    2012-2015. FP7 Innovation for Health. Clinical trials for elderly\u000d\u000a      patients with multiple diseases, PMA Calverley (jointly with R\u000d\u000a      Dellaca, Politecnico di Milano University) €2.2m\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section 4 (details of the impact). Specifically sources 8-12\u000d\u000a      relate to the work on reversibility testing cited above, source 13 to the\u000d\u000a      hospital at home management programme and sources 7, 10, 14, 16, 17 and 18\u000d\u000a      to the studies of anti-inflammatory therapy.\u000d\u000a        \u000d\u000a\u0009O'Reilly J, Jones MM, Parnham J, Lovibond K, Rudolf M. Management of\u000d\u000a      stable chronic obstructive pulmonary disease in primary and secondary\u000d\u000a      care: summary of updated NICE guidance. BMJ 2010 June 25;340:c3134. doi:\u000d\u000a      10.1136\/bmj.c3134.:c3134.\u000d\u000a    Chronic obstructive pulmonary disease. National clinical guideline on\u000d\u000a      management of chronic obstructive pulmonary disease in adults in primary\u000d\u000a      and secondary care. Thorax 2004 February;59 Suppl 1:1-232.\u000d\u000a    Celli BR, MacNee W. Standards for the diagnosis and treatment of\u000d\u000a      patients with COPD: a summary of the ATS\/ERS position paper. Eur Respir J\u000d\u000a      2004 June;23(6):932-46.\u000d\u000a    Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P\u000d\u000a      et al. Global strategy for the diagnosis, management, and prevention of\u000d\u000a      chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir\u000d\u000a      Crit Care Med 2007 September 15;176(6):532-55.\u000d\u000a    The percentage of all patients with COPD diagnosed after 1st April\u000d\u000a      2009 in whom the diagnosis has been confirmed by post bronchodilator\u000d\u000a      spirometry https:\/\/mqi.ic.nhs.uk\/IndicatorDefaultView.aspx?ref=1.09.03.01\u000a\u000d\u000a    Letter from Department of Health - provided\u000d\u000a    Intermediate care--Hospital-at-Home in chronic obstructive pulmonary\u000d\u000a      disease: British Thoracic Society guideline. Thorax 2007\u000d\u000a      March;62(3):200-10.\u000d\u000a    GSK's Advair Diskus approved for COPD exacerbations by US FDA\u000d\u000a      05\/05\/2008.\u000d\u000a      http:\/\/www.thepharmaletter.com\/article\/gsk-s-advair-diskus-approved-for-copd-\u000a        exacerbations-by-us-fda\u000a\u000d\u000a    An Outcomes Strategy for Chronic Obstructive Pulmonary Disease (COPD)\u000d\u000a      and Asthma Department of Health\/Medical Directorate\/Respiratory Team July\u000d\u000a      2011\u000d\u000a      https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/216139\/dh_1\u000a        28428.pdf.\u000d\u000a    Committee for medicinal products for human use (CHMP) European\u000d\u000a      Medicines Agency summary of opinion Daliresp-Roflumilast.\u000d\u000a      EMA\/CHMP\/825394\/2010\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Summary_of_opinion_-\u000a        Initial_authorisation\/human\/002398\/WC500099959.pdf\u000a\u000d\u000a    E-mail from Takeda Phamaceuticals (N.B. Takeda Pharmaceuticals annual\u000d\u000a      reports states 2012 roflumilast sales were ¥3b (£19m) and ¥1.3b in 2011).\u000d\u000a    Hernandez C et al. Home Hospitlaization of exacerbated\u000d\u000a      chronic obstructive pulmonary disease patients. Eur Respir J 2003; 21:\u000d\u000a      58-67. DOI 10.1183\/09031936.03.00015603.\u000d\u000a\u0009\u000d\u000a    ","Title":"\u000d\u000a    The Evidence-Based Diagnosis and Treatment of Chronic Obstructive\u000d\u000a      Pulmonary Disease (COPD)\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Historically, clinicians have used the short-term change in forced\u000d\u000a      expiratory volume in 1 second (FEV1) after inhaled\u000d\u000a      bronchodilators to define COPD patients more responsive to treatment. This\u000d\u000a      led treatment guidelines to recommend routine testing of all COPD patients\u000d\u000a      to detect those who `reversed' with treatment. The UoL Respiratory Group\u000d\u000a      led by Professor Calverley undertook systematic investigation of\u000d\u000a      reversibility testing and showed that it was influenced by baseline lung\u000d\u000a      function, the number of drugs used to test for a response and the criteria\u000d\u000a      adopted to define responder status [1].\u000d\u000a    In 2012 Paul Albert (Academic Fellow 2009-), analysing data from the\u000d\u000a      large international prospective ECLIPSE cohort which Prof Calverley\u000d\u000a      designed and direct, showed that the absolute change in lung function was\u000d\u000a      normal in moderate\/severe COPD and decreased rather than increased in very\u000d\u000a      severe disease. They showed that physiological variation in airway calibre\u000d\u000a      explained the between-test variation in reversibility response but did not\u000d\u000a      predict clinical outcomes. COPD is characterised by persistent pulmonary\u000d\u000a      inflammation that worsens during acute exacerbations which commonly lead\u000d\u000a      to hospitalisation [2].\u000d\u000a    Work within The UoL Respiratory Group led by Dr Lisa Davies (Lecturer\u000d\u000a      1998\/2002) tested whether anti-inflammatory treatment with oral\u000d\u000a      corticosteroids could influence recovery from an exacerbation event. She\u000d\u000a      conducted a technically demanding blinded randomised control trial of oral\u000d\u000a      corticosteroids and showed that FEV1 improved more rapidly and\u000d\u000a      hospital stay was shorter with the active treatment [3]. The Liverpool\u000d\u000a      data showed that these benefits could be achieved at lower doses than used\u000d\u000a      in a similar trial, subsequently reported in the USA. Given that the\u000d\u000a      duration of acute episodes could be shortened with treatment, it was\u000d\u000a      reasonable to consider whether more patients could be managed successfully\u000d\u000a      outside of hospital. In a further randomized controlled trial Davies and\u000d\u000a      colleagues demonstrated that hospital-at-home nurse-led teams could safely\u000d\u000a      manage patients in the community who would have previously been\u000d\u000a      hospitalised without increasing their risk of readmission [4].\u000d\u000a    Determining whether regular anti-inflammatory treatment has a favourable\u000d\u000a      risk\/benefit profile in COPD involved much larger and long randomized\u000d\u000a      multi-centre clinical trials. In the last decade, Professor Calverley has\u000d\u000a      developed and led a series of international studies examining the effects\u000d\u000a      of anti-inflammatory treatment of relevant outcomes like exacerbations,\u000d\u000a      frequency, hospitalization, health status and mortality in COPD patients.\u000d\u000a      The initial studies published in the Lancet in 2003 showed that inhaled\u000d\u000a      steroids were effective alone and in combination with long-acting beta\u000d\u000a      agonists findings confirmed in the 3 year multi-national TORCH study [5].\u000d\u000a      Calverley designed, analysed and reported this three year study involving\u000d\u000a      144 centres in 40 countries. It provided evidence that inhaled therapy\u000d\u000a      decreased the rate of decline in FEV1 during the study. The\u000d\u000a      TORCH trial and other subsequent studies involving Professor Calverley,\u000d\u000a      showed for the first time that pneumonia occurred more often with inhaled\u000d\u000a      corticosteroid treatment. Using an alternative approach of inhibiting of\u000d\u000a      PDE4 pathways to reduce inflammation Calverley et al demonstrated that\u000d\u000a      oral roflumilast treatment improved lung function and in patients with a\u000d\u000a      history of exacerbations and chronic bronchitis decreased exacerbation\u000d\u000a      frequency independently of background treatment [6].\u000d\u000a    "},{"CaseStudyId":"3859","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"927384","Name":"Malawi"},{"GeoNamesId":"3175395","Name":"Italy"}],"Funders":["Wellcome Trust","Engineering and Physical Sciences Research Council","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Those benefiting from the UoL TDM research in the period 2008-2013 are 1)\u000d\u000a      patients and patient\u000d\u000a      groups through optimisation of appropriate treatment doses and therefore\u000d\u000a      better disease\u000d\u000a      prognosis; 2) healthcare providers who are more effectively using their\u000d\u000a      resources; 3) the economy\u000d\u000a      through continued high levels of ritonavir sales and; 4) commerce through\u000d\u000a      the performance of a\u000d\u000a      spin-out company.\u000d\u000a    Impact on health policy and patient welfare\u000d\u000a    Although TDM was incorporated into guidelines of many European countries\u000d\u000a      (including the UK)\u000d\u000a      before the current REF evaluation period, TDM was introduced into US\u000d\u000a      national (DHHS) guidelines\u000d\u000a      in 2008. In the UK, around 4,000 TDM tests are requested from >100 NHS\u000d\u000a      Trusts each year. TDM\u000d\u000a      is recommended in selected, often difficult to treat patients, including\u000d\u000a      children, pregnancy, liver\u000d\u000a      impairment, suspected non-adherence and clinical failure.\u000d\u000a    Examples of guidelines developed since 2008 which recommend use of TDM\u000d\u000a      are British HIV\u000d\u000a      Association Guidelines for HIV treatment in Adults (2012), Pregnancy\u000d\u000a      (2012), TB co-infection\u000d\u000a      (2011), European Pediatric Treatment (PENTA) guidelines (2009) , European\u000d\u000a      AIDS Clinical\u000d\u000a      Society Treatment Guidelines (2012; translated into 13 languages) [8-12].\u000d\u000a      The UoL's role in\u000d\u000a      influencing both the policy, and its subsequent implementation includes\u000d\u000a      (i) developing the requisite\u000d\u000a      evidence base through studies describing variability, linking that\u000d\u000a      variability to failure, (ii) being one\u000d\u000a      of the earliest to undertake an RCT to examine the utility of TDM, (iii)\u000d\u000a      developing the infrastructure\u000d\u000a      to deliver a national (and international) TDM service which was\u000d\u000a      comprehensive in number of drugs\u000d\u000a      analysed, quality assured (GCLP) and timely, (iv) developing the training\u000d\u000a      and education required\u000d\u000a      to undertake TDM (talks, written\/web resources including webcasts), (v)\u000d\u000a      tools to interpret TDM\u000d\u000a      such as mathematical models, particularly when optimal sampling is\u000d\u000a      difficult e.g. evening dosing,\u000d\u000a      children and (vi) advocacy.\u000d\u000a    TDM interpretation algorithms were developed in Liverpool from 2008 -\u000d\u000a      2010, and adopted across\u000d\u000a      the UK, as well as by the HIV TDM reference laboratory in Torino, Italy\u000d\u000a      (currently undertakes 3,500\u000d\u000a      TDMs\/ year). Since 2008, the UoL has developed new TDM assays, including\u000d\u000a      for darunavir,\u000d\u000a      raltegravir, etravirine, rilpivirine and maraviroc - these now account for\u000d\u000a      over a third of TDM\u000d\u000a      requests.\u000d\u000a    The uptake of TDM across the UK, and widespread adoption into a broad\u000d\u000a      range of BHIVA\u000d\u000a      guidelines attests to the utility of TDM in complex patients and clinical\u000d\u000a      scenarios such as extremes\u000d\u000a      of age and body weight, pregnancy, drug interactions, drug toxicity, poor\u000d\u000a      treatment response or\u000d\u000a      adherence, renal or liver impairment, acute opportunistic infection, solid\u000d\u000a      organ transplantation or\u000d\u000a      malignancy.\u000d\u000a    Modelling outputs since 2008 have informed health policy, changed\u000d\u000a      clinical practice and drug\u000d\u000a      labelling, e.g. challenging systematic and widespread underdosing of young\u000d\u000a      children and\u000d\u000a      optimising the use of TB and HIV drugs in late pregnancy. Examples\u000d\u000a      include:\u000d\u000a    \u000d\u000a      WHO guidelines revising rifampicin\/isoniazid pediatric dosing (2010)\u000d\u000a        cited 3 PKPDia\u000d\u000a        studies.\u000d\u000a      Malawian Ministry of Health dosing guidelines revised to include\u000d\u000a        pediatric formulations,\u000d\u000a        informed by UoL PK data\u000d\u000a      Modelling and simulation of oral dihydroartemisinin-piperaquine in\u000d\u000a        malaria argued for\u000d\u000a        revised dosing for children, now under review by WHO and Medicines for\u000d\u000a        Malaria Venture.\u000d\u000a      Modelling and simulation of intramuscular artesunate in severe malaria\u000d\u000a        argued for revised\u000d\u000a        dosing in children, now under review by the manufacturer.\u000d\u000a      International (including WHO) guidelines on dosing of lopinavir and\u000d\u000a        efavirenz have been\u000d\u000a        informed by PKPDia studies.\u000d\u000a    \u000d\u000a    Impact on economy\u000d\u000a    Use of ritonavir as a `booster' has expanded globally as a consequence of\u000d\u000a      the UoL's initial\u000d\u000a      description, and is now the standard of care globally. Since 2008,\u000d\u000a      co-formulation of\u000d\u000a      lopinavir\/ritonavir has been licensed for children, and generic\u000d\u000a      formulations (manufactured in India\u000d\u000a      and Brazil) are a backbone of second line regimens utilised in low\/middle\u000d\u000a      income countries (eg\u000d\u000a      approximately 9% of treated patients across sub-Saharan Africa are on\u000d\u000a      boosted protease\u000d\u000a      inhibitors). New formulations of darunavir (the most commonly prescribed\u000d\u000a      protease inhibitor in the\u000d\u000a      UK) requiring ritonavir boosting were introduced for children (2012) and\u000d\u000a      adults (2013).\u000d\u000a    Impact on Health & Wealth\u000d\u000a    Following initial spin-out of TDM from the University in 2005 to Delphic\u000d\u000a      Diagnostics, the company\u000d\u000a      grew as a direct result, adding a further 4 full time positions between\u000d\u000a      2008-2009. TDM was\u000d\u000a      acquired by Lab21 in Dec 2009, and a new laboratory service introduced in\u000d\u000a      2010 (with continuing\u000d\u000a      input from the University of Liverpool). In addition, a second laboratory\u000d\u000a      at St George's Hospital,\u000d\u000a      London established TDM for HIV from 2008 onwards. An international quality\u000d\u000a      control programme\u000d\u000a      reported that by the end of 2009, 56 laboratories across the world were\u000d\u000a      offering TDM [16].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The University of Liverpool (UoL) was the first to identify the potential\u000d\u000a      role for Therapeutic Drug\u000d\u000a      Monitoring (TDM) for HIV drugs (1994) and was at the forefront of\u000d\u000a      describing use of ritonavir as a\u000d\u000a      pharmacoenhancer to boost drug concentrations (1997); now the standard of\u000d\u000a      care globally for HIV\u000d\u000a      protease inhibitors. The work has steered TDM's incorporation into\u000d\u000a      treatment guidelines in the UK\u000d\u000a      and Europe. In 2008 TDM was adopted by US guidelines. Since then, we have\u000d\u000a      developed TDM\u000d\u000a      interpretation through use of population modelling, with uptake from UK\u000d\u000a      and European providers;\u000d\u000a      4,000 patients in the UK benefit each year from safe and effective dosing\u000d\u000a      as a result. This work is\u000d\u000a      led by Professors DJ Back and SH Khoo, with additional contributions from\u000d\u000a      Prof A Owen (2008\u000d\u000a      onwards) and Dr M Siccardi (2012 onwards).\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3165524","Name":"Turin"},{"GeoNamesId":"3165524","Name":"Torino"}],"References":"\u000d\u000a    \u000a1. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P,\u000d\u000a      Soriano V, Albalater M,\u000d\u000a      Hopper-Borge E, Bonora S, Di Perri G, Back DJ, Khoo S, Pirmohamed\u000d\u000a        M, Owen A.\u000d\u000a      Genetic variants of ABCC10, a novel tenofovir transporter, are associated\u000d\u000a      with kidney\u000d\u000a      tubular dysfunction. J Infect Dis. 2011 Jul;204(1):145-53\u000d\u000a      Citations: 20 Impact Factor:\u000d\u000a      5.848\u000d\u000a    \u000a\u000a2. Rodríguez-Nóvoa S, Labarga P, Soriano V, Egan D, Albalater M,\u000d\u000a      Morello J, Cuenca L,\u000d\u000a      González-Pardo G, Khoo S, Back D, Owen A.\u000d\u000a      Predictors of Kidney Tubular Dysfunction in\u000d\u000a      HIV-Infected Patients Treated with Tenofovir: A Pharmacogenetic Study. Clin\u000d\u000a        Infect Dis.\u000d\u000a      2009;48:e108-116 Citations: 87 Impact Factor: 9.374\u000d\u000a    \u000a\u000a3. Else LJ, Jackson A, Puls R, Hill A, Fahey P, Lin E, Amara\u000d\u000a        A, Siccardi M, Watson V, Tjia\u000d\u000a        J, Emery S, Khoo S, Back DJ, Boffito M.\u000d\u000a      Pharmacokinetics of lamivudine, and lamivudine-triphosphate\u000d\u000a      after administration of 300 mg and 150 mg once-daily to healthy\u000d\u000a      volunteers.\u000d\u000a      The ENCORE 2 Study. Antimicrob Agents Chemother. 2011 Dec 19.\u000d\u000a      PMID: 22183172\u000d\u000a      Citations: 5 Impact Factor: 4.565\u000d\u000a    \u000a\u000a4. Pollock L, Else L, Poerksen G, Molyneux E, Moons P, Walker S,\u000d\u000a      Fraser W, Back D, Khoo\u000d\u000a        S. Pharmacokinetics of nevirapine in HIV-infected children with and\u000d\u000a      without malnutrition\u000d\u000a      receiving divided adult fixed-dose combination tablets. J Antimicrob\u000d\u000a        Chemother. 2009\u000d\u000a      Dec;64(6):1251-9. Citations: 14 Impact Factor: 5.338\u000d\u000a    \u000a\u000a5. Stöhr W, Back D, Dunn D, Sabin C, Winston A, Gilson R, Pillay\u000d\u000a      D, Hill T, Ainsworth J,\u000d\u000a      Pozniak A, Leen C, Bansi L, Fisher M, Orkin C, Anderson J, Johnson M, P, Gibbons\u000d\u000a        S,\u000d\u000a      Khoo S. Factors Influencing Efavirenz and Nevirapine Plasma\u000d\u000a      Concentration: Effect of\u000d\u000a      Ethnicity, Weight, and Co-Medication. Antivir Ther 2008;13:675-85\u000d\u000a      Citations: 47 Impact\u000d\u000a      Factor: 3.073\u000d\u000a    \u000a\u000a6. Boffito M, Jackson A, Amara A, Back D, Khoo S, Higgs\u000d\u000a      C, Seymour N, Gazzard B, Moyle\u000d\u000a      G. Pharmacokinetics of darunavir\/ritonavir and atazanavir-ritonavir once\u000d\u000a      daily over 72 hours\u000d\u000a      following drug cessation. Antimicrob Agents Chemother.\u000d\u000a      Sep;55(9):4218-23. Epub 2011\u000d\u000a      Jun 27. PMID:21709075 Citations: 4 Impact Factor: 4.565\u000d\u000a    \u000a\u000a7. Khoo SH, Lloyd J, Dalton M, Bonington A, Hart E, Gibbons S,\u000d\u000a      Flegg P, Sweeney J,\u000d\u000a      Wilkins EGL, Back DJ. Pharmacological Optimization of PIs and\u000d\u000a      NNRTIs (POPIN)- a\u000d\u000a      randomised controlled trial of therapeutic drug monitoring and adherence\u000d\u000a      support. J Acquir\u000d\u000a        Immune Defic Syndr 2006;41(4):461-7. Citations: 43 Impact Factor:\u000d\u000a      4.653\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section\u000d\u000a      4 (details of the impact).\u000d\u000a    The following guidelines demonstrate the adoption of TDM into the\u000d\u000a      standard treatments for HIV.\u000d\u000a    \u000d\u000a      British HIV Association guidelines for the treatment of HIV-infected\u000d\u000a        adults with antiretroviral\u000d\u000a        therapy (2012). Gazzard B, on behalf of the BHIVA Writing Committee. HIV\u000d\u000a          Med, 9: 563-\u000d\u000a        608.\u000d\u000a      BHIVA treatment guidelines for TB\/HIV infection. Pozniak AL, Miller\u000d\u000a        RF, Lipman MCI,\u000d\u000a        Freedman AR, Ormerod LP, Johnson MA, Collins S, Lucas SB, on behalf of\u000d\u000a        the BHIVA\u000d\u000a        guidelines writing committee. (2005). HIV Med, 6 (suppl 2):\u000d\u000a        62-83.\u000d\u000a      BHIVA Guidelines on treatment of HIV in Pregnancy (www.bhiva.org)\u000d\u000a      Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected\u000d\u000a        Adults and Adolescents\u000d\u000a        (January 29, 2008) Developed by the DHHS Panel on Antiretroviral\u000d\u000a        Guidelines for Adults\u000d\u000a        and Adolescents - A Working Group of the Office of AIDS Research\u000d\u000a        Advisory Council\u000d\u000a      European AIDS Clincial Society Guidelines for treatment of HIV\u000d\u000a        infected adults in Europe.\u000d\u000a        (http:\/\/www.eacsociety.org\/Portals\/0\/Guidelines_Online_131014.pdf)\u000d\u000a    \u000d\u000a    The following papers in the scientific literature demonstrate the\u000d\u000a      widespread use of TDM across the\u000d\u000a      developed world, and establishment of laboratory infrastructure to deliver\u000d\u000a      this diagnostic.\u000d\u000a    \u000d\u000a      van Luin M, Kuks PF, Burger DM. Use of therapeutic drug monitoring in\u000d\u000a        HIV disease. Curr\u000d\u000a        Opin HIV AIDS. 2008 May;3(3):266-71.\u000d\u000a      Higgins N, Tseng A, Sheehan NL, la Porte CJ. Antiretroviral\u000d\u000a        therapeutic drug monitoring in\u000d\u000a        Canada: current status and recommendations for clinical practice. Can J\u000d\u000a        Hosp Pharm.\u000d\u000a        2009 Nov;62(6):500-9.\u000d\u000a      La Porte CJL, Back DJ, Blaschke T, Boucher CAB, Fletcher CV,\u000d\u000a        Flexner C, et al. Updated\u000d\u000a        guidelines to perform therapeutic drug monitoring for antiretroviral\u000d\u000a        agents. Rev Antiviral\u000d\u000a        Ther. 2006;3:4-14\u000d\u000a      Burger et al, The International Interlaboratory Quality Control\u000d\u000a        Program for Measurement of\u000d\u000a        Antiretroviral Drugs in Plasma: a global proficiency testing program.\u000d\u000a        Ther Drug Monit\u000d\u000a        2011;33(2):239-43.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Therapeutic Drug Monitoring for HIV drugs\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In 1994 the UoL started measuring HIV drug concentrations, and in 1999,\u000d\u000a      acquired mass\u000d\u000a      spectrometry (supported by MRC funding) allowing high throughput assays\u000d\u000a      and highly sensitive\u000d\u000a      measurement of drugs in plasma, cells and compartments. This capability\u000d\u000a      supported basic\u000d\u000a      science, clinical and epidemiological studies through an expanded\u000d\u000a      repertoire of drug analysis (to\u000d\u000a      cover all licensed HIV drugs), to measure drug concentrations in putative\u000d\u000a      sanctuaries such as the\u000d\u000a      genital tract, tissue, CNS, across the placenta, breast milk and inside\u000d\u000a      cells. Examples of these\u000d\u000a      studies included two UK Dept of Health grants to study TDM (including one\u000d\u000a      of only a few\u000d\u000a      randomised controlled trials in 2006), and a Gates funded study into use\u000d\u000a      of HIV drugs to prevent\u000d\u000a      infection in exposed individuals (2012).\u000d\u000a    The UoL established a TDM service in 1999, and by 2005 this had grown to\u000d\u000a      become a national\u000d\u000a      reference laboratory undertaking 4,500 tests\/year across >100 NHS\u000d\u000a      Trusts, with a revenue of\u000d\u000a      >£400,000. CPA accreditation was successfully acquired for the TDM\u000d\u000a      programme in 2003, and\u000d\u000a      GCLP accreditation since 2010. By this time the UoL was also undertaking\u000d\u000a      TDM for the Republic of\u000d\u000a      Ireland, Scandinavia, Israel and Singapore. In 2005 the TDM service was\u000d\u000a      spun into Delphic\u000d\u000a      Diagnostics Ltd, and in 2009 this service was acquired by Lab21. The UoL\u000d\u000a      has a supporting\u000d\u000a      programme of research around TDM, including development of new assays and\u000d\u000a      semi-automated\u000d\u000a      reporting algorithms, use of population pharmacokinetic modelling for\u000d\u000a      predicting exposure and\u000d\u000a      integration of drug levels with resistance data. In addition to developing\u000d\u000a      the analytical techniques,\u000d\u000a      the UoL developed algorithms, rules and models which allow the\u000d\u000a      interpretation of that drug\u000d\u000a      concentration, depending on the clinical context, and time of sampling.\u000d\u000a      The UoL was one of the\u000d\u000a      earliest to conduct an RCT of TDM vs standard of care (the POPIN Study)\u000d\u000a      [7].\u000d\u000a    A key area for TDM has been optimising Protease Inhibitor (PI)\u000d\u000a      concentrations. The UoL published\u000d\u000a      the first report of the use of ritonavir as a pharmacoenhancer or booster\u000d\u000a      of other PIs in HIV+\u000d\u000a      patients [Merry et al, AIDS 1997]. This became, and remains the standard\u000d\u000a      of care for PI therapy,\u000d\u000a      yet variability in drug concentrations achieved remained a challenge and\u000d\u000a      was a key factor in use of\u000d\u000a      TDM in selected patients. The research has shown how to optimally manage\u000d\u000a      the use of ritonavir,\u000d\u000a      alone or with other PIs, thereby benefiting patient health and increasing\u000d\u000a      the cost-effectiveness of\u000d\u000a      treatment.\u000d\u000a    The UoL's research and its impact are integrally linked: MRC and Dept of\u000d\u000a      Health\/NIHR funding\u000d\u000a      established bioanalytical capability so that early clinical studies could\u000d\u000a      be undertaken leading to the\u000d\u000a      implementation of TDM into UK Treatment Guidelines since 2003.\u000d\u000a      Approximately £5.8m of\u000d\u000a      research funding from Wellcome, MRC, EPSRC, NIHR, Gates and industry\u000d\u000a      grants to the University\u000d\u000a      of Liverpool have been supported by this capability. Conversely, large\u000d\u000a      datasets (>20,000\u000d\u000a      measurements) within the UoL's TDM Registry have supported its research\u000d\u000a      through validation of\u000d\u000a      population pharmacokinetic (and pharmacogenetic) models, and enabled the\u000d\u000a      successful award\u000d\u000a      and completion of a Wellcome Programme in PK-PD modelling (PKPDia; PI:\u000d\u000a      Khoo).\u000d\u000a    "},{"CaseStudyId":"3860","Continent":[{"GeoNamesId":"6255146","Name":"Africa"}],"Country":[{"GeoNamesId":"927384","Name":"Malawi"}],"Funders":["Wellcome Trust","Royal Society"],"ImpactDetails":"\u000a    Very few research programmes take a clinical sign from obscurity to the\u000a      standard textbook description of a disease. This is exactly what research\u000a      by the Department of Eye and Vision Science has done with malarial\u000a      retinopathy, and it is all the more remarkable because malaria is a common\u000a      and frequently fatal disease.\u000a    There are approximately 10 million episodes of cerebral malaria in Africa\u000a      a year and examination for malarial retinopathy has the potential to\u000a      improve the care of all of these cases. It is plausible that half these\u000a      cases, since 2008, have some sort of funduscopy as a consequence of this\u000a      UoL research, improving the assessment of prognosis in 5 million and\u000a      uncovering misdiagnosis in 1.25million. Patients benefit from improved\u000a      diagnosis and better directed treatment. This research has \"revealed the\u000a      importance of the ocular funduscopic examination in distinguishing \"true\"\u000a      cerebral malaria from \"faux\" cerebral malaria\" [15].\u000a    Malarial retinopathy is now included in the description of malaria in\u000a      standard medical textbooks which is a key indicator of the impact of this\u000a      research. Since 2008, retinal photographs taken by Beare and colleagues\u000a      such as that presented here) appear in four standard text books -\u000a      Harrison's Principles of Internal Medicine [7], Davidson's Principles and\u000a      Practice of Medicine [8], Lecture Notes: Tropical Medicine [9] and\u000a      Manson's Tropical Diseases[10], as well as multiple reviews on severe\u000a      malaria and its pathogenesis. These are major reference works used by\u000a      clinician's worldwide to guide clinical practice. Malarial retinopathy\u000a      (with the UoL figure) and the importance of funduscopy is now included in\u000a      the 2013 WHO guidelines on severe malaria [11], particularly used by\u000a      clinicians and policy makers in malaria-endemic countries to determine\u000a      best practice, and also regional guidelines eg South-East Asian Regional\u000a      Guidelines for the Management of Severe Malaria in Large Hospitals 2006\u000a      [12].\u000a\u0009  \u000a\u0009  Note the characteristic patchy retinal whitening around the fovea (~3\u000a      disc diameters to the right of the optic disc) and also some white-centred\u000a      haemorrhages.\u000a\u0009  \u000a    The reasons that the authors of these authoritative texts have included\u000a      malarial retinopathy in the description of malaria for the first time are\u000a      the quality of the UOL research and the importance of its findings. This\u000a      includes the startling retinal photographs and results of retinal\u000a      angiography which demonstrated graphically the information on CM\u000a      pathogenesis that can be gleaned from the retina. The high quality colour\u000a      images allowed the features of malarial retinopathy to be demonstrated to\u000a      non-ophthalmologists, and to teach them to recognise malarial retinopathy\u000a      for themselves. The research has been disseminated by peer-review\u000a      publication and conference presentation to key opinion leaders initially\u000a      before wider dissemination in textbooks and guidelines. Publications 1 and\u000a      2 were featured by the American Academy of Ophthalmology in its EyeNet\u000a      magazine and on its Homepage respectively, as well as reported by medical\u000a      media and Voice of America radio.\u000a    The discovery that malarial retinopathy alone can reliably distinguish\u000a      malarial coma from co-infection in a comatose child was of particular\u000a      importance, and has literally redefined the disease of cerebral malaria.\u000a      Now malarial retinopathy is required to be present in order to diagnose CM\u000a      with specificity. This is established practice in Malawi and has been\u000a      taken up by other research units in endemic areas; as well as clinical\u000a      practice in endemic and non-endemic areas to the benefit of critically-ill\u000a      children in coma. This is now confirmed in a popular website, www.malariasite.com\u000a      [13].\u000a    The Department of Eye and Vision Science has worked with its\u000a      collaborators who have set up the Paediatric Research Ward in Malawi and\u000a      have provided for patients with severe malaria and other comas from 1990\u000a      to present. Since 2008 this has cared for more than 1,500 patients who\u000a      have had funduscopy. The malarial retinopathy programme is led by the\u000a      Department of Eye and Vision Science, whilst collaborators provide\u000a      expertise in malaria.\u000a    Improved specificity in the diagnosis of CM by using malarial retinopathy\u000a      has reduced spurious results in other CM research which previously\u000a      included misdiagnosed patients. It has allowed parallel research\u000a      programmes to use patients without retinopathy as controls or comparators,\u000a      and to focus on retinopathy-positive CM. Eliminating misdiagnosed patients\u000a      from studies of severe malaria improves their power to demonstrate the\u000a      benefit of the investigation or treatment they are studying. As a result\u000a      of UoL research on malarial retinopathy more studies on severe malaria can\u000a      be conducted with fewer patients with quicker results. \"Without the \"eye\u000a      findings\", our clinical case definition would be far less precise, and the\u000a      work would have proceeded at a much slower rate.\" [15]\u000a    This case study of malarial retinopathy demonstrates impacts on health\u000a      and welfare, by advancing care of children in coma; public policy and\u000a      services through WHO guidelines on severe malaria; practitioners and\u000a      services through improving medical texts and knowledge [14-17]. A clinical\u000a      diagnostic paradigm has been changed with new criteria adopted into\u000a      clinical practice. The treatment of a major global health issue has been\u000a      improved with the reduction of potential harm. New research findings have\u000a      been applied into clinical practice and an improvement in international\u000a      quality of life and welfare has occurred.\u000a    ","ImpactSummary":"\u000a    Since 1997 University of Liverpool (UoL) investigators have led global\u000a      research into malarial retinopathy, the fundus features associated with\u000a      severe malaria. The work has propelled this phenomenon from little-known\u000a      curiosity to an essential component in the diagnosis of cerebral malaria\u000a      (CM) and has altered understanding of how CM causes coma and kills. It has\u000a      changed medical practice of those diagnosing one of the commonest fatal\u000a      diseases in tropical countries. Malarial retinopathy is now considered an\u000a      essential clinical feature of CM aiding the appropriate management of coma\u000a      in infants. This change in practice has expanded from African research\u000a      settings to clinical practice required by WHO guidelines and disseminated\u000a      in major clinical textbooks from 2008.\u000a    ","ImpactType":"Health","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Beare NAV, Taylor TE, Harding SP, Lewallen S, Molyneux\u000a        ME. Malarial retinopathy: a newly established diagnostic sign in\u000a      severe malaria. Am J Trop Med Hyg. 2006;75(5):790- 797. http:\/\/www.ajtmh.org\/content\/75\/5\/790.long\u000a      Citations: 103 Impact factor: 2.59\u000a    \u000a\u000a2. Beare\u000a          NA, Southern C, Chalira C, Taylor TE, Molyneux ME, Harding\u000a          SP. Prognostic significance and course of retinopathy in\u000a      children with severe malaria. Arch Ophthalmol. 2004;122:1141-1147.doi:10.1001\/archopht.122.8.1141\u000a      Citations: 51 Impact factor: 3.71\u000a    \u000a\u000a3. Beare NAV, Harding SP, Taylor TE, Lewallen S, Molyneux\u000a        M. Perfusion abnormalities in children with cerebral malaria and\u000a      malarial retinopathy. J Inf Dis. 2009;199:263-271. doi:10.1086\/595735\u000a      Citations: 49 Impact factor: 5.848\u000a    \u000a\u000a4. White VA, Lewallen S, Beare NAV, Molyneux ME, Taylor\u000a      TE. Retinal Pathology of Pediatric Cerebral Malaria in Malawi. 2009. PLoS\u000a      ONE 4(1): e4317. doi:10.1371\/journal.pone.0004317 Citations: 38 Impact\u000a      factor: 3.730\u000a    \u000a\u000a5. Lewallen S, Beare NAV, Bronzan R, Molyneux M, Taylor\u000a      T. Using malarial retinopathy to classify children with clinically defined\u000a      cerebral malaria. Trans Roy Soc Trop Med Hyg. 2008;102(11): 1089-1094 doi:10.1016\/j.trstmh.2008.06.014\u000a      Citations: Impact factor: 2.16\u000a    \u000a\u000a6. Maude RJ, Dondorp AM, Sayeed AA, Day NPJ, White NJ, Beare NAV.\u000a      The Eye in Cerebral Malaria: What Can it Teach Us? Trans Roy Soc Trop Med\u000a      Hyg. 2009; 103(7):661-664. doi:10.1016\/j.trstmh.2008.11.003\u000a      Citations: 14 Impact factor: 2.16 .\u000a    \u000aKey grants\u000a    2005 - 2008. The Wellcome Trust (Ref 075125\/Z\/04\/Z). The eye in\u000a      life-threatening malaria: a clinical and clinicopathological study,\u000a      £93,239, ME Molyneux, NAV Beare, SP Harding.\u000a    2011 - 2014. Wellcome Trust programme grant. Retinal\u000a      microvasculature in cerebral malaria, £600k, SP Harding, RS\u000a      Heyderman, AG Craig, PS Hiscott, ME Molyneux, TE Taylor, S\u000a      Kampondeni, NAV Beare, P Knox, Y Zheng.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    \u000a      Harrison's Principles of Internal Medicine. 17th Ed 2008,\u000a        figure 203; 18th Ed 2012 figure 210. ISBN-13: 978-0071748896\u000a      Davidson's Principles and Practice of Medicine. 21st Ed\u000a        2010, figure 13.31. ISBN-13: 978-0702030857\u000a      Lecture Notes: Tropical Medicine. 6th Ed 2009, figure 9.2.\u000a        ISBN-13: 978-1405180481\u000a      Manson's Tropical Diseases 23rd Ed 2013. ISBN-13:\u000a        978-1416044703\u000a      Management of severe malaria: a practical handbook, WHO, 3rd\u000a        Edition (2013), pages 15, 43 and figure 3. ISBN: 978 92 4 154852 6\u000a        http:\/\/www.who.int\/entity\/malaria\/publications\/atoz\/9789241548526\/en\/index.html\u000a\u000a      South-East Asian Regional Guidelines for the Management of Severe\u000a        Malaria in Large Hospitals 2006. \"Ocular Manifestations\" page 16.\u000a      http:\/\/www.malariasite.com\/malaria\/Complications3.htm\u000a      \u000aChildhood acute\u000a          non-traumatic coma: aetiology and challenges in management in\u000a          resource-poor countries of Africa and Asia. Gwer S, Chacha C,\u000a        Newton CR, Idro R. Paediatr Int Child Health. 2013;33(3):129-38. doi:\u000a        10.1179\/2046905513Y.0000000068.\u000a\u0009\u0009\u000a      Referees\u000a      The following individuals are leading experts on malaria, and can\u000a        corroborate the impact of malarial retinopathy on clinical practice and\u000a        research.\u000a\u0009\u0009\u000a      Letter: University Distinguished Professor in the College of\u000a        Osteopathic Medicine at Michigan State University and Director of the\u000a        Blantyre Malaria Project, Malawi.\u000a      Professor of Tropical Medicine, Nuffield Department of Medicine,\u000a        Director of the Wellcome-KEMRI-Oxford Collaborative Research Programme\u000a      Locum consultant, Heart of England NHS Trust; Research Fellow,\u000a        University of Oxford.\u000a    \u000a    ","Title":"\u000a    Malarial Retinopathy has Redefined the Diagnosis of Cerebral Malaria and\u000a      Improved the Management of Coma in African Children\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Malaria kills an estimated 655,000 people a year, 86% of whom are\u000a      children under five in Africa. Most die of CM, a complication\u000a      characterised by sudden and profound coma, convulsions and death in\u000a      10-20%. It is not understood how malaria causes coma and death, but\u000a      adherence of infected red cells to the microvascular lining\u000a      (sequestration) is thought to be critical [4]. However, malaria is a\u000a      common infection and a child may present in coma due to another cause and\u000a      be misdiagnosed with CM because of a coincidental malaria infection. This\u000a      is surprisingly common occurring in 25-50% of cases.\u000a    The key problems that this research addresses are\u000a    \u000a      Can malarial retinopathy detection improve the diagnosis of severe\u000a        malaria?\u000a      Can malarial retinopathy improve understanding of disease processes in\u000a        severe malaria which in turn improve care and treatment?\u000a    \u000a    The research to address these questions was conducted by UOL researchers\u000a      starting in 1997 at the Malawi field site and Liverpool in collaboration\u000a      with the Liverpool School of Tropical Medicine (LSTM),\u000a      Malawi-Liverpool-Wellcome Clinical Research Unit (MLW), Malawi College of\u000a      Medicine and Blantyre Malaria Project (BMP), Michigan State University,\u000a      but the ophthalmic input is almost entirely from UOL. No other research\u000a      group has had significant output to address these questions, so the impact\u000a      claimed is wholly from UoL research. The principal investigator for this\u000a      research is Beare (1999-present, now Hon Snr Lecturer) with Harding\u000a      (2003-present, Professor of Clinical Ophthalmology) and Molyneux (Prof\u000a      until 2009, now Emeritus Prof).\u000a    The research has shown that the detection of malarial retinopathy is the\u000a      only reliable diagnostic sign or test for CM [1]. About 25% of Malawian\u000a      children who appeared to die of CM had another cause of death at autopsy,\u000a      whilst co-infected with malaria. The presence of malarial retinopathy was\u000a      the only clinical or laboratory feature which was able to distinguish\u000a      malarial coma from other causes. Molyneux initiated, co-directed and\u000a      funded this ten year autopsy study, and Beare's analysis, supervised by\u000a      Harding, established the specificity (100%) and sensitivity (95%) of\u000a      malarial retinopathy.\u000a    Studies led by Beare and supervised by Harding and Molyneux, conducted in\u000a      collaboration with LSTM, MLW and BMP found that (i) the severity malarial\u000a      of retinopathy predicts risk of death better than any other clinical or\u000a      laboratory variable in CM [2] and (ii) that patients fulfilling the\u000a      traditional case definition of CM without malarial retinopathy have lower\u000a      mortality, shorter coma, and are more likely to have a pre-existing\u000a      predisposition to epilepsy [2,5]. These insights allow greater prognostic,\u000a      as well as diagnostic, accuracy enabling clinicians to focus resources.\u000a    In 2006 Beare et al commenced a study of retinal perfusion in CM\u000a      using a fundus camera with capacity for retinal angiography. The retina is\u000a      central nervous tissue with a similar embryology and structure to the\u000a      brain, and with comparable malaria parasite sequestration. The study found\u000a      that there are retinal perfusion abnormalities in the majority of patients\u000a      with CM [3]. The commonest are multiple zones of ischaemia from\u000a      microvascular occlusion. There is also breakdown of the blood-retina\u000a      barrier in association with ischaemia; and in a much more profound way\u000a      prior to death. This study demonstrated CNS perfusion abnormalities in\u000a        vivo in CM for the first time, and altered theories of CM\u000a      pathogenesis as it is likely that these abnormalities are also mirrored in\u000a      the brain [6]. Understanding of CM pathogenesis has turned towards\u000a      ischaemia and blood-tissue breakdown; and away from the previous\u000a      hypothesis of the effect of a cytokine and neurotransmitter `storm'. Now\u000a      substantiated by MRI studies in children with CM, the next generation of\u000a      clinical trials are assessing supportive therapies in cerebral malaria, in\u000a      particular therapies to reduce intra-cranial pressure and hypoxic injury.\u000a    "},{"CaseStudyId":"3862","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2629691","Name":"Iceland"},{"GeoNamesId":"783754","Name":"Albania"},{"GeoNamesId":"798549","Name":"Romania"},{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"3077311","Name":"Czech Republic"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"390903","Name":"Greece"},{"GeoNamesId":"798544","Name":"Poland"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2264397","Name":"Portugal"}],"Funders":[],"ImpactDetails":"\u000a    The UoL research has directly led to national screening programmes for DR\u000a      in the UK and\u000a      overseas which are being increasingly implemented since 2008. The National\u000a      Screening\u000a      Committee (Chair J Muir Gray [20]) commissioned reviews and an economic\u000a      analysis between\u000a      1999 and 2001 which references the UoL work and supported the introduction\u000a      of screening [10-\u000a      12].The UoL team was heavily involved in the design of the national\u000a      screening programme which\u000a      launched in 2006.\u000a    After initial pilot work the English programme started roll-out in 2006\u000a      gradually expanding over\u000a      subsequent years to cover the target population nearing full capacity\u000a      after 2008. Most recent\u000a      figures from the English Diabetic Eye Screening Programme (DESP) give\u000a      estimates for 2012-13\u000a      that 1.9 million people with diabetes have been screened [17].\u000a    Significant impact for these people includes the detection of 100,800\u000a      (7.6%) cases of sight\u000a      threatening maculopathy and 22,800 (1.2%) of sight threatening retinopathy\u000a      with referral for\u000a      management in the hospital eye service. Also in 2012-13 an estimated\u000a      14,000 (0.74%) people\u000a      were referred for urgent laser therapy for proliferative retinopathy and\u000a      between 21,250 and 42,500\u000a      for treatment of clinically significant macular oedema. This would not\u000a      have occurred if the DESP\u000a      had not been established; as a result these patients received timely and\u000a      appropriate treatment.\u000a      The Clinical Director of the Diabetic Eye Screening Programme (England)\u000a      confirms that, \"The\u000a        introduction of screening has had a significant impact reducing the risk\u000a        of visual loss for large\u000a        numbers of people\" and \"The Liverpool evidence contributed\u000a        significantly to the case for the\u000a        establishment of a National Risk Reduction Programme.\" [17]\u000a    Scotland's DR Screening Programme launched in 2007 and gradually expanded\u000a      post 2008 to a\u000a      current annual rate of 240,388; approx. 7,000 of these are referred for\u000a      assessment\/treatment\u000a      [13,14]. The Director of Scottish Grading Programme said \"At all\u000a        stages, from the initial SIGN\u000a        guidelines, the Health Technology Board for Scotland's Health Technology\u000a        Assessment, to the\u000a        Scottish Government's Diabetic Retinopathy Screening Services in\u000a        Scotland implementation\u000a        report, evidence from the University of Liverpool has played a pivotal\u000a        role in shaping Scotland's\u000a        Retinal Screening Programme.\" and \"The Liverpool Diabetic Eye Study,\u000a        using mobile fundus\u000a        cameras, played a pivotal role in making the case for retinal screening\u000a        in Scotland and throughout\u000a        the United Kingdom.\"[18]\u000a    The English DESP has provided training and employment for retinal\u000a      screeners who have been\u000a      employed specifically to support the DESP. 1,600 technicians have\u000a      completed the National Level\u000a      3 Retinal Screener qualification (DM Broadbent developed course and\u000a      certificate); 831 were\u000a      actively studying [17].\u000a    Since 2005, UoL research has been used by policy makers from Europe and\u000a      around the world to\u000a      set screening models and implement DR services including screening.\u000a      Dissemination has been\u000a      through published research and the initiative, \"Screening for Diabetic\u000a      Retinopathy in Europe\"\u000a      (www.drscreening.eu) with\u000a      international conferences in 2008 [15] and 2011 [16] including\u000a      WHO,\u000a      European Commission and International Diabetes Foundation engagement. The\u000a      Liverpool team\u000a      (Harding, Broadbent) established this initiative in 2005 producing The\u000a      Liverpool Declaration which\u000a      set targets on screening for DR in Europe and shared experience of\u000a      implementation of evidence\u000a      based service changes. Nationally identified policy makers from over 20\u000a      countries in Europe have\u000a      joined the initiative. This has proven to be highly influential as the\u000a      second and subsequent\u000a      meetings have shown that countries have adopted the screening approaches.\u000a      National\u000a      representatives have requested continuation of the initiative.\u000a    An example of this is from Sweden where Liverpool's pivotal work extended\u000a      screen intervals to\u000a      three years in 2010 for people with no DR reducing the cost of screening\u000a      and the burden of\u000a      attendance for an estimated 356,000 people. A past Director of the Swedish\u000a      Diabetic Retinopathy\u000a      Screening Programme said, \"In 2009, thanks to the Liverpool work, we\u000a        found it both safe and cost\u000a        effective to revise our national guidelines and since then extension of\u000a        retinal examination intervals\u000a        from two to three years in type 2 diabetic subjects without retinopathy\u000a        are recommended since\u000a        2010. The recommendation was based on previous estimates of the low risk\u000a        for progression from\u000a        no to sight-threatening retinopathy in this particular group in\u000a        Liverpool (Younis et al. Lancet 2003).\"\u000a      [19]. For England, this output has triggered debate on the safety of\u000a      introducing extended screen\u000a      intervals across the much larger and diverse target population of 3\u000a      million people leading to the\u000a      aforementioned two NIHR grants.\u000a    Other examples of the effect of the \"Screening for Diabetic Retinopathy\u000a      in Europe\" initiative\u000a      reported in 2011 [11] include10% decrease in the incidence of blindness\u000a      due to DR in the Czech\u000a      Republic; a significant improvement in vision loss in Iceland; Denmark,\u000a      The Netherlands and Spain\u000a      introduced national screening programmes; Poland and Romania have patchy\u000a      screening which is\u000a      slowly widening; Greece and Portugal have introduced local screening\u000a      programmes; Italy saw a\u000a      big improvement in the quality of DR diagnosis and treatment; Albania has\u000a      used the initiative to\u000a      improve access to lasers. In 2012 Eire introduced a national screening\u000a      programme [21].\u000a      UoL work [3-6,8] has been widely referred to in the 2012 RCOphth\u000a      Guidelines on Diabetic\u000a      Retinopathy in statements on disease definitions,[8] epidemiology [4,5,6]\u000a      and screening [8].\u000a      Accessed at http:\/\/www.rcophth.ac.uk\/page.asp?section=451§ionTitle=Clinical+Guidelines.\u000a    This case study demonstrates major impacts on health and welfare, public\u000a      policy and services,\u000a      practitioners and services and international development. The\u000a      beneficiaries have been the\u000a      diabetic patients in the UK and elsewhere who have seen a reduction in the\u000a      rates of visual\u000a      impairment and laser therapy since the introduction of screening. Without\u000a      the Liverpool work on\u000a      cost-effectiveness and methodology the introduction of systematic\u000a      screening would not have been\u000a      possible or would have been delayed, nor would the St. Vincent declaration\u000a      have been revised and\u000a      implemented internationally. Outcomes for patients and the public health\u000a      have improved, a new\u000a      clinical intervention and technology has been developed and adopted with\u000a      improved disease\u000a      prevention and detection, and new guidelines have been developed. The NHS\u000a      has adopted new\u000a      technology and new jobs have been created. The cost effectiveness and\u000a      access to a public\u000a      service have been improved and international agencies and policy have been\u000a      influenced.\u000a    ","ImpactSummary":"\u000a    The University of Liverpool (UoL) has provided pivotal evidence for the\u000a      introduction and\u000a      development of national screening programmes for diabetic retinopathy\u000a      (DR). Technician based\u000a      screening, which has been introduced since 2008, is now covering over 1.9\u000a      million UK people at\u000a      risk and employing over 1,000 technicians across 96 programmes. Sweden and\u000a      Scotland have\u000a      introduced 2 and 3 year screening for patients with no DR based on UoL\u000a      work on extended screen\u000a      intervals. The UoL led the revision of the St. Vincent Declaration, the\u000a      principal policy statement of\u000a      the WHO on the management of diabetes, and has continued to develop pan\u000a      European policy and\u000a      influence national policies in several European countries (including\u000a      Italy, Germany, Spain).\u000a    ","ImpactType":"Health","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Harding SP, Broadbent DM, Neoh C, White MC, Vora J.\u000a      Sensitivity and specificity of\u000a      photography and direct ophthalmoscopy in screening for sight threatening\u000a      eye disease - The\u000a      Liverpool Diabetic Eye Study. Br Med J 1995;311:1131-1135. Citations: 158\u000a      Impact factor:\u000a      17.215 This publication has continued to be regularly cited (average 7.28\u000a      per year in last 18\u000a      years)\u000a    \u000a\u000a2. Broadbent DM, Scott JA, Vora JP, Harding SP.\u000a      Prevalence of diabetic eye disease in an inner\u000a      city population: the Liverpool Diabetic Eye Study. Eye 1999;13:160-165.\u000a      Citations: 37 Impact\u000a      factor: 1.818\u000a    \u000a\u000a3. James M, Turner DA, Broadbent DM, Vora J, Harding SP.\u000a      Cost-effectiveness analysis of\u000a      screening for sight threatening diabetic eye disease. Br Med J\u000a      2000;320:1627-31 DOI:\u000a      10.1136\/bmj. 320.7250.1627. Citations: 82 Impact factor: 17.215\u000a    \u000a\u000a4. Younis N, Broadbent DM, Harding SP, Vora JP.\u000a      Prevalence of Diabetic Eye Disease in\u000a      Patients Entering a Systematic Primary Care Based Eye Screening Programme.\u000a      Diabetic Med\u000a      2002, 19: 1014-21. DOI: 10.1046\/j.1464-5491.2002.00854.x. Citations: 27\u000a      Impact factor: 3.241\u000a    \u000a\u000a5. Younis N, Broadbent DM, Vora JP, Harding SP.\u000a      Incidence of sight threatening retinopathy in\u000a      type 2 diabetes in a systematic screening programme. Lancet\u000a      2003;361:195-200. Citations: 111\u000a      Impact factor: 39.060 This publication has been cited consistently since\u000a      publication in 2003 and\u000a      utilised by national and international research groups in design of\u000a      clinical studies and setting of\u000a      guidance.\u000a    \u000a\u000a6. Younis N, Broadbent DM, Harding SP, Vora JP.\u000a      Incidence of sight-threatening retinopathy in\u000a      Type 1 diabetes in a systematic screening programme. Diabetic Medicine\u000a      2003 20: 758-65.\u000a      DOI: 10.1046\/j.1464-5491.2003.01035.x Citations: 43 Impact factor: 3.421\u000a    \u000aInterpretation of the research and setting of the agenda in screening for\u000a      DR was covered in the\u000a      following policy setting articles and editorials:\u000a    \u000a7. Owens DR, Gibbins RL, Kohner E, Grimshaw GM, Greenwood R, Harding\u000a        SP. Screening for\u000a      diabetic retinopathy. Editorial. Diab Med 2000;17:493-494. DOI:\u000a      10.1046\/j.1464-\u000a      5491.2000.00333.x\u000a    \u000a\u000a8. Harding SP, Greenwood RM, Aldington A, Gibson JM, Owens DR,\u000a      Taylor R, Kohner E,\u000a      Scanlon P, Leese GR. Grading and disease management in national screening\u000a      for diabetic\u000a      retinopathy in England and Wales. Diabet Med 2003; 20:965-971 DOI:\u000a      10.1111\/j.1464-\u000a      5491.2003.01077.x This publication sets out the national screening\u000a      committee grading\u000a      classification that has been adopted worldwide.\u000a    \u000a\u000a9. Harding SP, Talbot JF, Garvican L. The impact of national\u000a      diabetic retinopathy screening on\u000a      ophthalmology: the need for urgent planning. Eye 2005;19:1009-1011.\u000a    \u000aThe quality and importance of this work has been recognised by the award\u000a      of a NIHR Programme\u000a      Development Grant (end of grant report available) and a full Programme\u000a      Grant for Applied\u000a      Research, with the UoL the leading partner in a programme of research to\u000a      measure safety and\u000a      acceptability of extended screen intervals in England based on\u000a      individualised risk.\u000a    \u000a      2010-2011. NIHR Programme Development Grant. Acceptability and\u000a        effectiveness of risk\u000a        based intervals in screening for diabetic retinopathy - towards a\u000a        personalised approach, £99k,\u000a        Harding SP, Gabbay M, Grey P, James M, Stratton I, Broadbent\u000a          DM, Fisher A, Vora JP,\u000a        Roberts J, Byrne P, Garcia-Finana M. (RP-DG-0709-10138).\u000a      2013-2018. NIHR Programme Development Grant. Introducing\u000a        personalised risk based\u000a        intervals in screening for diabetic retinopathy: development,\u000a        implementation and assessment of\u000a        safety, cost-effectiveness and patient experience, Harding SP, Broadbent\u000a          DM, Gabbay M,\u000a        Grey P, James M, Stratton I, Fisher AC, Vora JP, Roberts J, Byrne\u000a          P, Garcia-Finana M, Breen\u000a          R, Williamson P. (RP-DG-1210-12016). £1,961,766\u000a    \u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section\u000a      4 (details of the impact).\u000a    \u000a    \u000a      Garvican, L., et al. Preservation of sight in diabetes: developing a\u000a        national risk reduction\u000a        programme.\" Diabet Med 2000;17:627-634\u000a      Gillow JT and Gray JA. The National Screening Committee review of\u000a        diabetic retinopathy\u000a        screening. Eye 2001;15:1-2\u000a      James MA, Little R. Diabetic retinopathy. Report to the National\u000a        Screening Committee. Centre\u000a        for Health Planning. Keele University. April 2001\u000a      Facey K, et al. Health Technology Assessment Report 1. Organisation of\u000a        services for diabetic\u000a        retinopathy screening. http:\/\/www.ndrs.scot.nhs.uk\/Links\/Docs\/hta1.pdf\u000a\u000a      Diabetic Retinopathy Screening Services in Scotland: Recommendations\u000a        for Implementation\u000a        http:\/\/www.ndrs.scot.nhs.uk\/Links\/Docs\/Recommendations\u000a        %20for%20Implementing%20DRS.pdf\u000a\u000a    \u000a    International Conferences\u000a    \u000a    \u000a      Amsterdam 2008 http:\/\/www.drscreening2005.org.uk\/amsterdam_2008.html\u000a\u000a      Gdansk 2011 http:\/\/www.drscreening2005.org.uk\/gdansk_2011.html\u000a        including links to national\u000a        guidelines on screening for diabetic retinopathy have been linked to the\u000a        initiative and are\u000a        available for Czech Republic, Finland, Hungary, Italy, Norway, Scotland,\u000a        Spain, and Sweden.\u000a    \u000a    Clinical Health Service Leaders who can corroborate the impact of this\u000a      case study:\u000a    \u000a    \u000a      Letter: National Diabetic Eye Screening Programme (England)\u000a      Letter: Scottish Diabetic Retinopathy Screening Programme\u000a      Letter: Department of Ophthalmology, Skåne University Hospital\u000a      Contact: National Screening Committee.\u000a      Contact: Diabetic Retinopathy Screening Programme, Ireland.\u000a    \u000a    ","Title":"\u000a    The Liverpool Diabetic Eye Study has set the Standard for Screening for\u000a      Sight-Threatening\u000a      Diabetic Retinopathy in the UK and Europe.\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Liverpool Diabetic Eye Study is a collaboration at the UoL between\u000a      Eye and Vision Science\u000a      (Harding, Broadbent) and Obesity and Endocrinology (Vora) dating back to\u000a      1992.\u000a      Diabetic retinopathy (DR) is the commonest cause of blindness in the\u000a      developed world in working\u000a      age people. The WHO estimates that the prevalence of diabetes mellitus\u000a      will rise from a current\u000a      estimate of 170 million to 366 million worldwide by 2030. At any one time\u000a      40% will have DR.\u000a      Treatment for DR is only effective in the early stages before visual\u000a      impairment occurs.\u000a    Between 1993 and 1995 a model of screening for DR was studied in UoL\u000a      comprising technician\u000a      based, ambulatory, community based, 3 field retinal photography conducted\u000a      through dilated pupils\u000a      and graded using a standardised classification developed for the\u000a      programme. Sensitivity and\u000a      specificity for the detection of sight threatening DR (STDR) were shown to\u000a      be superior to the then\u000a      standard of direct ophthalmoscopy [1]. Between 1996 and 1999 the\u000a      prevalence of DR categorised\u000a      by these developed grades was estimated [2].\u000a    Between 1999 and 2004 work expanded to address key evidence gaps in order\u000a      to develop the\u000a      argument for establishment of a national DR screening programme. A cost\u000a      effectiveness study\u000a      was performed with colleagues from Liverpool John Moores University (James\u000a      M, Turner DA)\u000a      which demonstrated good cost effectiveness of the Liverpool model when\u000a      compared to\u000a      opportunistic screening [3]. Incidence and prevalence estimates were\u000a      repeated and rates of\u000a      progression used to estimate the appropriate time interval between\u000a      screening episodes depending\u000a      on levels of risk (duration of diabetes, retinopathy, glycaemic control)\u000a      [4-6]. Results were obtained\u000a      from 20,570 screening events in people with type 2 diabetes. For a 95%\u000a      probability of remaining\u000a      free of STDR, mean screening intervals by baseline status were: no\u000a      retinopathy 5.4 years (95% CI\u000a      4.7-6.3), background 1.0 years (0.7-1.3), and mild pre-proliferative 0.3\u000a      years (0.2-0.5). Similar\u000a      results were obtained for type 1 diabetes. We recommended that a 3 year\u000a      screening interval could\u000a      be safely adopted for patients with no retinopathy.\u000a    Since 2008 the UoL DR screening research team led by Harding has expanded\u000a      to include\u000a      academics with research expertise in primary care (Gabbay), biostatistics\u000a      (van der Hoek),\u000a      sociology (Byrne) and computer science (Fisher), referenced in Section 3,\u000a      and has continued to\u000a      influence the national and international research agenda.\u000a    Between 1999 and 2003 SP Harding and JP Vora were Honorary Senior\u000a      Lecturers and DM\u000a      Broadbent, Honorary Clinical Lecturer. As of 2010 SP Harding is Chair in\u000a      Clinical Ophthalmology\u000a      and Head, Department of Eye and Vision Science (DEVS), Institute of Ageing\u000a      and Chronic\u000a      Disease. JP Vora is Honorary Professor of Diabetes and Endocrinology and\u000a      DM Broadbent is\u000a      Honorary Senior Lecturer, DEVS. All of the research was conducted in the\u000a      UoL.\u000a    "},{"CaseStudyId":"3863","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    800 people develop CML each year in the UK and there are currently over\u000d\u000a      6,000 patients with the disease. The estimated cost to the NHS is £290m pa\u000d\u000a      and rising.\u000d\u000a    Due to his work on imatinib resistance and on nilotinib and dasatinib,\u000d\u000a      Prof Clark became one of two experts co-opted by the National Institute of\u000d\u000a      Clinical Excellence (NICE) to appraise these drugs, on behalf of the Royal\u000d\u000a      College of Pathologists and the British Society for Haematology. Based on\u000d\u000a      the data of nilotinib superiority over imatinib in ENESTnd, on which Clark\u000d\u000a      was the UK Chief Investigator, and also the parallel study of dasatinib,\u000d\u000a      NICE considered the use of second line nilotinib and dasatinib in a\u000d\u000a      multitechnology appraisal from 2009-2011, resulting in approval for\u000d\u000a      nilotinib but not dasatinib in January 2012 [9]. NICE similarly involved\u000d\u000a      Prof Clark in a second Technology Appraisal in 2012 that recommended that\u000d\u000a      nilotinib should also be approved for first line treatment of\u000d\u000a      chronic phase CML [10]. Clark and the UoL's studies over the past few\u000d\u000a      years have been key to this shift of the standard of care for newly\u000d\u000a      diagnosed CML patients from imatinib to nilotinib. A similar change from\u000d\u000a      imatinib to nilotinib is also happening in most other Western countries,\u000d\u000a      where their current clinical trials offer only nilotinib (with or without\u000d\u000a      other treatments) to newly diagnosed CML patients. Nilotinib (trade name Tasigna\u000d\u000a      ) is licensed as first line therapy for newly diagnosed CML patients\u000d\u000a      throughout the EU, Switzerland, Japan and the US, and as a second line\u000d\u000a      treatment in over 100 countries for patients resistant or intolerant to\u000d\u000a      existing treatments [11].\u000d\u000a    The change to nilotinib as the treatment of choice [12] is underlined by\u000d\u000a      the £21.9m industry funded SPIRIT 3 trial that will soon be underway in\u000d\u000a      the UK (as of November 2013, applications for ethical and MHRA approval\u000d\u000a      are currently under consideration but see next paragraph). This randomised\u000d\u000a      phase III trial intends to recruit 1,000 newly diagnosed chronic phase CML\u000d\u000a      patients. It will examine whether nilotinib remains a superior treatment\u000d\u000a      to imatinib if patients who have inadequate early molecular responses are\u000d\u000a      offered an early switch of treatment. The trial will also examine whether\u000d\u000a      treatment de- escalation and then cessation can be achieved in patients\u000d\u000a      with excellent and sustained treatment responses for some years, in case\u000d\u000a      these patients are functionally cured [13]. This de-escalation and\u000d\u000a      stopping strategy is being piloted in a phase II trial called DESTINY, led\u000d\u000a      from Liverpool and for which Clark is the Chief Investigator (supported by\u000d\u000a      Leukaemia & Lymphoma Research) which is opening in November 2013.\u000d\u000a    However, during 2013 several reports have emerged on a small apparent\u000d\u000a      excess of cardiovascular events on nilotinib than imatinib. It is not\u000d\u000a      possible to be certain on this as ENESTnd and smaller studies were not\u000d\u000a      designed to test this. In addition, on October 8th 2013, the US\u000d\u000a      Food & Drugs Administration unexpectedly announced an investigation\u000d\u000a      into cardiovascular events in patients receiving ponatinib, a 3rd\u000d\u000a      generation TKI that is part of the `early switch' strategy in the UK\u000d\u000a      SPIRIT3 trial. Interest in nilotinib (and ponatinib) has therefore evolved\u000d\u000a      to determining whether cardiovascular events are a genuine and clinically\u000d\u000a      relevant unwanted effect, and also on the underlying mechanism.\u000d\u000a    Finally, the UoL group's scientific observations have also had clinical\u000d\u000a      impact, partly in relation to the switch from imatinib to nilotinib. The\u000d\u000a      UoL's demonstration of HLA-associated expression of BCR-ABL fusion\u000d\u000a      peptides [6] led directly to several studies of peptide vaccination in CML\u000d\u000a      and other leukaemias [14]. There is also much interest in biomarkers in\u000d\u000a      CML, to predict a poor clinical outcome (transformation to acute\u000d\u000a      leukaemia), and the UoL's identification of CIP2A [7] has evolved into a\u000d\u000a      more thorough study of this protein in many other cancers (exemplified by\u000d\u000a      30 further reports on CIP2A in the 2 years since publication). The most\u000d\u000a      recent data in Liverpool indicate that while CML patients with high CIP2A\u000d\u000a      expression have a high probability of disease progression to blast crisis\u000d\u000a      if treated with imatinib, this is not true if receiving nilotinib, and\u000d\u000a      that this may be due to differential effects of the two drugs on various\u000d\u000a      ancillary proteins involved in CIP2A regulation (data presented at the\u000d\u000a      European School of Haematology 2013 and manuscript submitted to a high\u000d\u000a      impact journal in November 2013 [15]). These laboratory observations\u000d\u000a      support the case that high CIP2A expressing patients should preferentially\u000d\u000a      receive nilotinib from original diagnosis.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Since 2000, the tyrosine kinase inhibitor (TKI) imatinib has transformed\u000d\u000a      CML from a fatal disease for half of patients within 5 years, to a chronic\u000d\u000a      disease whereby ~ 90% of patients lead normal lives for at least 9 years.\u000d\u000a      This remarkable transformation has spawned a second phase of clinical and\u000d\u000a      translational research aiming to cure CML. The University of Liverpool\u000d\u000a      (UoL) CML research group headed by Prof Richard Clark has been integral in\u000d\u000a      both phases, particularly in the development of the second generation TKI\u000d\u000a      nilotinib. Important contributions have also shed light on CML biology and\u000d\u000a      the possible mechanism of acute leukaemic transformation (blast crisis).\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Thomas J, Wang L, Clark RE, Pirmohamed M.\u000d\u000a      Active transport of imatinib into and out of cells: Implications for drug\u000d\u000a      resistance. Blood 2004; 104: 3739-3745. Citations: 362 Impact Factor:\u000d\u000a      9.060\u000d\u000a    \u000a\u000a2. Wang L, Giannoudis A, Lane S, Williamson P,\u000d\u000a        Pirmohamed M, Clark RE. Expression of the uptake drug\u000d\u000a      transporter hOCT1 is an important clinical determinant of the response to\u000d\u000a      imatinib in chronic myeloid leukemia. Clinical Pharmacology &\u000d\u000a      Therapeutics 2008; 83: 258-264. Citations: 135 Impact Factor: 6.846\u000d\u000a    \u000a\u000a3. Giannoudis A, Davies A, Lucas CM, Harris RJ,\u000d\u000a        Pirmohamed M, Clark RE. Effective dasatinib uptake may occur\u000d\u000a      without human Organic Cation Transporter 1 (hOCT1): implications for the\u000d\u000a      treatment of imatinib resistant chronic myeloid leukaemia. Blood 2008,\u000d\u000a      112: 3348-3354. Citations: 65 Impact Factor: 9.060\u000d\u000a    \u000a\u000a4. Davies A, Jordanides NE, Giannoudis A, Lucas CM,\u000d\u000a      Hatziieremia S, Harris, RJ, Jørgensen HG, Holyoake TL, Clark\u000d\u000a        RE, Mountford JC. Nilotinib concentration and efficacy in CD34+ CML\u000d\u000a      cells are not mediated by active uptake or efflux by major drug\u000d\u000a      transporters. Leukemia 2009; 23: 1999-2006. Citations: 54 Impact Factor:\u000d\u000a      10.164\u000d\u000a    \u000a\u000a5. Saglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C,\u000d\u000a      Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N,\u000d\u000a      Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM. ENESTnd: A\u000d\u000a      randomized comparison of nilotinib and imatinib for newly diagnosed\u000d\u000a      chronic myeloid leukemia. New England Journal of Medicine 2010; 362:\u000d\u000a      2251-2259. Citations: 444 Impact Factor: 51.658\u000d\u000a    \u000a\u000a6. Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, MacIntyre\u000d\u000a        AR, Rojas J, Bourdon A, Bonner PLR, Wang L, Christmas SE,\u000d\u000a      Travers P, Creaser CS, Rees RC, Madrigal JA. Direct evidence that\u000d\u000a      leukaemic cells present HLA-associated immunogenic peptides derived from\u000d\u000a      the BCR-ABL b3a2 fusion protein. Blood 2001, 98: 2887-2893. Plenary paper,\u000d\u000a      with editorial in Blood 2001, 98: 2885. Citations: 179 Impact Factor:\u000d\u000a      9.060\u000d\u000a    \u000a\u000a7. Lucas CM, Harris RJ, Giannoudis A, Clark RE.\u000d\u000a      Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid\u000d\u000a      leukaemia is a critical determinant of disease progression. Blood 2011;\u000d\u000a      117: 6660-6668. Citations: 18 Impact Factor: 9.060\u000d\u000a    \u000a\u000a8. Schmidt T, Loges S, Maes C, Jonckx B, Masouleh BK, Kleppe M, de\u000d\u000a      Keersmaecker K, Tjwa1 M, Schenk T, Bee K, DeWolf-Peeters C, Clark RE,\u000d\u000a      Vandenberghe P, Brümmendorf TH, Holyoake T, Hochhaus A, Cools J, Carmeliet\u000d\u000a      G, Carmeliet P. Loss or Inhibition of Stromal-Derived PlGF Prolongs\u000d\u000a      Survival of Mice with Imatinib-Resistant Bcr-Abl1+ Leukemia. Cancer Cell\u000d\u000a      2011; 19: 740-753. Citations: 26 Impact Factor: 24.755\u000d\u000a    \u000aKey research grants of over £150,000 since 2000. Liverpool\u000d\u000a        grantholders are in bold:\u000d\u000a    2001 - 2006. Kay Kendall Research Fund. The Identification of\u000d\u000a      Immunodominant Peptide Epitopes from bcr\/abl and abl\/bcr, and their use in\u000d\u000a      monitoring immune responses in CML patients and in Clinical Translational\u000d\u000a      Trials for Immunotherapy of CML'. £325k, Dodi AI, Travers PJ, Rees RC,\u000d\u000a      Creaser CS, Bonner P, Falkenburg F, Clark RE and Madrigal JA.\u000d\u000a    2003 - 2009. Leukaemia Research Fund. `A phase I\/II feasibility\u000d\u000a      study of peptide vaccination in chronic myeloid leukaemia', &\u000d\u000a      `extension to normal subjects, £551,688, Clark RE\u000d\u000a    2004 - 2007. Leukaemia Research Fund. Do transporter proteins\u000d\u000a      contribute to clinical resistance to imatinib in chronic myeloid\u000d\u000a      leukaemia? A combined study in Liverpool and Glasgow, correlating\u000d\u000a      transporter expression and function with imatinib uptake and efflux,\u000d\u000a      £300,056, Clark RE, Mountford J, Pirmohamed M and Holyoake\u000d\u000a      TL\u000d\u000a    2005 - 2008. Novartis (invited application). Mechanisms of\u000d\u000a      imatinib resistance in chronic myeloid leukaemia: A laboratory and\u000d\u000a      clinical study of uptake and efflux transporters, $465,100 (£252,998), Clark\u000d\u000a        RE\u000d\u000a    2008 - 2011. Kay Kendall Leukaemia Fund (2008): £276,959 over 3\u000d\u000a      years for `The role of transporter proteins in the efficacy of imatinib\u000d\u000a      and newer tyrosine kinase inhibitors in chronic myeloid leukaemia,\u000d\u000a      £276,959, PI Clark RE (PI) and Pirmohamed M\u000d\u000a    2008 - 2011. Leukaemia Research Fund. Development of a\u000d\u000a      pharmacokinetic- pharmacodynamic model for imatinib to allow\u000d\u000a      individualisation of therapy for chronic myeloid leukaemia, £167,510 , Clark\u000d\u000a        RE (PI), Pirmohamed M, Davies A and Lane S\u000d\u000a    2009 - 2012. Medical Research Council. A randomised phase 2 trial\u000d\u000a      of imatinib versus imatinib with hydroxychloroquine for patients with CML\u000d\u000a      in major cytogenetic response with residual disease by quantitative PCR,\u000d\u000a      £580,811, Holyoake TL, Marin D, Clark RE.\u000d\u000a    2010. Genzyme Inc (now Sanofi-Aventis) (2010). PHANTASTIC, a\u000d\u000a      clinical trial of plerixafor for stem cell harvesting, £202,431 (plus ~£1m\u000d\u000a      of free drug), Clark RE\u000d\u000a    2010 - 2013. Leukaemia & Lymphoma Research. The AML Pick a\u000d\u000a      Winner Programme, £276,046, Burnett AK, Hills R, Clark RE, Russell\u000d\u000a      N, Thomas I, Milligan D\u000d\u000a    2012. Ariad Pharmaceuticals. SPIRIT3: a randomised trial in newly\u000d\u000a      diagnosed chronic myeloid leukaemia, £21.9m (of which £2,317,126 to UoL),\u000d\u000a      O'Brien SG, Apperley JF and Clark RE\u000d\u000a    2013 - 2016. Leukaemia & Lymphoma Research (formerly\u000d\u000a      Leukaemia Research Fund). DESTINY: a trial of de-escalation and stopping\u000d\u000a      treatment in CML patients with excellent responses to tyrosine kinase\u000d\u000a      inhibitor therapy, £160,530, Clark RE (lead), O'Brien SG, Copland\u000d\u000a      M, Foroni L, Cox T and Haycox A.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section 4 (details of the impact). \u000d\u000a    \u000d\u000a      National Institute for Health and Clinical Excellence. Dasatinib,\u000d\u000a        high-dose imatinib and nilotinib for the treatment of imatinib-resistant\u000d\u000a        chronic myeloid leukaemia (CML) (part review of NICE technology\u000d\u000a        appraisal guidance 70), and dasatinib and nilotinib for people with CML\u000d\u000a        for whom treatment with imatinib has failed because of intolerance.\u000d\u000a        January 2012. http:\/\/publications.nice.org.uk\/dasatinib-high-dose-imatinib-and-nilotinib-for-the-treatment-of-imatinib-resistant-chronic-myeloid-ta241)\u000d\u000a      National Institute for Health and Clinical Excellence. Leukaemia\u000d\u000a        (chronic myeloid, first line) - dasatinib, nilotinib and standard-dose\u000d\u000a        imatinib (TA251). April 2012. http:\/\/guidance.nice.org.uk\/TA251\u000a\u000d\u000a      Novartis Annual Report 2012. p155-6. http:\/\/www.novartis.co.uk\/cs\/groups\/public\/@nph_uk_corp\/documents\/document\/n_prod_477856.pdf\u000a\u000d\u000a      ARIAD and the U.K. National Cancer Research Institute to Collaborate\u000d\u000a        on SPIRIT 3 Clinical Study. Business Wire 2013. http:\/\/www.businesswire.com\/news\/home\/20130107005605\/en\/ARIAD-U.K.-National-Cancer-Research-Institute-Collaborate\u000a\u000d\u000a      The trial specific SPIRIT 3 website is not fully functional as of\u000d\u000a        November 2013. The following public website has some details: http:\/\/public.ukcrn.org.uk\/search\/StudyDetail.aspx?StudyID=15142\u000a\u000d\u000a      \u000aRojas JM, Knight K, Wang L, Clark RE. Clinical Evaluation of\u000d\u000a        BCR-ABL Peptide Immunisation in Chronic Myeloid Leukaemia: results of\u000d\u000a        the EPIC study. Leukemia 2007; 21: 2287-2295. This paper was\u000d\u000a          selected by Biomed Central for inclusion in their Faculty of 1000.\u000a\u000d\u000a      \u000aLucas CM, McDonald E, Holcroft AK, Giannoudis A, Harris RJ, Clark\u000d\u000a          RE. Second generation tyrosine kinase inhibitors prevent high\u000d\u000a        CIP2A patients progressing to BC by targeting the CIP2A\/C-MYC\/E2F1\u000d\u000a        pathway. Submitted to Lancet Oncology November 2013.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Changing Clinical practice from Imatinib to Nilotinib in Chronic Myeloid\u000d\u000a      Leukaemia (CML)\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    CML is a malignant disease of the haemopoietic stem cell, characterised\u000d\u000a      by expansion of myeloid cell production. It can progress to acute\u000d\u000a      leukaemia (blast crisis) which is usually fatal within 6 months. CML is\u000d\u000a      driven by the fusion oncoprotein BCR-ABL, formed by the t(9;22)\u000d\u000a      Philadelphia translocation. The BCR-ABL gene product is a constitutively\u000d\u000a      active version of ABL, a tyrosine kinase. In the late 1990s, the tyrosine\u000d\u000a      kinase inhibitor (TKI) imatinib was introduced. This inhibits BCR-ABL to\u000d\u000a      which CML cells are `addicted'. Using sensitive PCR based molecular\u000d\u000a      testing for BCR-ABL, imatinib has been shown to produce far deeper\u000d\u000a      remissions than alpha interferon (IFN), and patients with such `major\u000d\u000a      molecular responses' (MMR) have an extremely low risk of blast crisis\u000d\u000a      after at least 9 years of follow up. Imatinib has therefore become the\u000d\u000a      standard of care in CML since endorsement by the National Institute of\u000d\u000a      Clinical Excellence (NICE) in 2003. However, 40% of patients become\u000d\u000a      resistant to or intolerant of imatinib. Resistance mechanisms include the\u000d\u000a      evolution of subclones with BCR-ABL kinase domain mutations that interfere\u000d\u000a      with imatinib binding, or the development of new genomic lesions that are\u000d\u000a      unaffected by imatinib.\u000d\u000a    Prof Clark's group at the UoL showed that imatinib is actively\u000d\u000a      transported into leukaemia cells by the transporter hOCT1 [1]. This was\u000d\u000a      the first time that an INFLUX (as opposed to an efflux) transporter has\u000d\u000a      ever been identified as of clinical relevance in any cancer. The group\u000d\u000a      went on to show that this is a powerful clinical predictor of patients\u000d\u000a      failing imatinib [2], subsequently confirmed by several other groups. Low\u000d\u000a      hOCT1 expression\/activity is therefore an additional and common mechanism\u000d\u000a      of imatinib resistance, discovered by the Clark group.\u000d\u000a    In 2006, the second generation TKIs dasatinib and nilotinib were shown by\u000d\u000a      others in phase II studies to achieve leukaemia clearance from the marrow\u000d\u000a      and MMR in the majority of patients who fail imatinib. Research at the UoL\u000d\u000a      showed that both drugs are transported into cells independently of hOCT1\u000d\u000a      [3,4]. This led to phase III trials of nilotinib vs. imatinib (ENESTnd, in\u000d\u000a      which Clark was the UK Chief Investigator) and of dasatinib vs. imatinib\u000d\u000a      (the ongoing NCRI SPIRIT2 trial, for which Clark chairs the management\u000d\u000a      group). ENESTnd has demonstrated that nilotinib has higher MMR rates and\u000d\u000a      lower acute leukaemia progression rates than imatinib [5] that are\u000d\u000a      maintained at 5 years [data to be presented at ASH 2013].\u000d\u000a    Clark's CML group has also made important contributions to CML biology\u000d\u000a      including the demonstration of HLA-associated expression of BCR-ABL fusion\u000d\u000a      peptides [6], and the identification of cancerous inhibitor of PP2A\u000d\u000a      (CIP2A) [7] and the loss of placental derived growth factor as biomarkers\u000d\u000a      of disease progression [8].\u000d\u000a    "},{"CaseStudyId":"3864","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Economic and Social Research Council","Medical Research Council"],"ImpactDetails":"\u000a    Research at the University of Liverpool has collectively improved\u000a      understanding of the genetic basis of drug-induced hypersensitivity and\u000a      provided \"proof of principle\" for the clinical use of genetic testing\u000a      before prescribing drug therapy. UoL research has contributed to changes\u000a        in the prescribing information for two widely used drugs,\u000a      carbamazepine and abacavir. The prescribing information has been revised\u000a      to include information on the genetic predisposing factors to\u000a      hypersensitivity reactions caused by these two drugs; clinical\u000a        guidelines have also been changed for abacavir to reflect the need\u000a      for genotyping prior to drug administration. The research has impacted on\u000a      the clinical care and lives of patients with chronic diseases such as\u000a      epilepsy, bipolar disorder, neuropathic pain and AIDS. Therapy has been\u000a      optimised by individualising drug prescription to a patient based on key\u000a      characteristics such as genetic factors. This reduces the risk of severe\u000a      and potentially fatal ADRs.\u000a    Abacavir hypersensitivity\u000a    The study showed that it would be cost-effective to undertake\u000a      pre-treatment screening for HLA- B*57:01 to predict susceptibility\u000a      to abacavir hypersensitivity [2]. This has led to the following impacts.\u000a    \u000a      Clinical guidelines from societies, e.g. the British HIV Association,\u000a        were changed in 2008 to recommend testing for HLA-B*57:01 before\u000a        the use of abacavir [7]. This is now well established in NHS practice.\u000a      The drug labels (i.e. prescribing information) were changed in the US,\u000a        EU and Australia after 2008 to recommend the use of HLA-B*57:01\u000a        genotyping prior to the use of abacavir [8-10].\u000a      The evidence from the UoL study was used by the NHS to implement the\u000a        use of the HLA-B*57:01 testing in HIV clinics from 2006. This has led to\u000a        a marked reduction of the incidence of abacavir hypersensitivity (from\u000a        7.8% to 2% [11]). It is now rare to see any cases of abacavir\u000a        hypersensitivity in clinical practice to the benefit of patients — this\u000a        has been demonstrated in a publication from the Chelsea and Westminster\u000a        HIV clinic which showed that the incidence of hypersensitivity had gone\u000a        down from 7.8% to 2% [11]\u000a      The number of HLA-B*57:01 genetic tests undertaken in the NHS rose\u000a        sharply after 2006, and at the same time the use of abacavir also\u000a        increased (see figure), and continues to the present day.\u000a\u0009\u0009Most of the HLA-B*57:01 testing was provided by Delphic\u000a      Diagnostics, a University of Liverpool spin-out company (co-founders were\u000a      Prof Khoo and Back, Dept of Pharmacology, UoL). Delphic was bought out by\u000a      Lab21 in 2009. Total number of tests in 2007-08 and 2008-09 were 3,493\u000a      (revenue £186,850) and 1,908 (£100,630) respectively.\u000a    \u000a\u000aFigure: The increase in HLA testing and at the same time, the rise in the use of abacavir (kivexa)\u000a\u000a    The importance of this work is confirmed by a case study by The Academy\u000a      of Medical Sciences in 2012 [12]. Pre-prescription genotyping for HLA-B*57:01\u000a      is now used in most countries and has also been shown to improve clinical\u000a      outcomes (i.e. reduce hypersensitivity) in Australia and France, and has\u000a      been shown to be cost-effective in several countries including the US and\u000a      Germany.\u000a    Carbamazepine hypersensitivity\u000a    UoL research showed susceptibility to carbamazepine hypersensitivity\u000a      reactions in Caucasian patients was localised to the MHC, but that the\u000a      risk factor in Caucasians was distinct to that demonstrated in Chinese\u000a      patients [3]. Thus, in Caucasians, HLA-B*1502, is not a risk\u000a      factor for SJS\/TEN and for hypersensitivity syndrome, two distinct\u000a      phenotypes associated with carbamazepine treatment. This publication was\u000a      utilised by the FDA, who in December 2007, recommended that patients of\u000a      Asian ancestry, but not Caucasians, should be tested for HLA-B*1502\u000a      prior to the start of carbamazepine therapy [13]. The drug label was also\u000a      changed in the EU in 2008, again recommending the use of testing in Asian\u000a      patients, but not in Caucasians [14].\u000a    The continuing work of UoL in this area has recently identified HLA-A*31:01\u000a      as a genetic risk factor for carbamazepine-induced hypersensitivity\u000a      reactions in Caucasians [5]. The prescribing information for carbamazepine\u000a      has been changed in Japan, in the EU and in the US since 2011 making\u000a      prescribers aware of the association between this allele and carbamazepine\u000a      hypersensitivity in Caucasians [15].\u000a    In 2010, the UoL became the global co-ordinating centre for the\u000a      International Consortium on Drug Hypersensitivity (ITCH), sponsored by the\u000a      International Serious Adverse Events Consortium (iSAEC) (http:\/\/www.saeconsortium.org\/).\u000a      We have now recruited 1500 patients with hypersensitivity reactions from\u000a      12 international centres, and 50 UK centres.\u000a    In 2013, we were awarded an i4i grant from the NIHR in collaboration with\u000a      MC Diagnostics to develop a HLA-testing biomarker panel which can\u000a      simultaneously test for multiple HLA alleles at a low cost (<£20) with\u000a      turnaround time of <48h.\u000a    ","ImpactSummary":"\u000a    The University of Liverpool (UoL) research has had health impact on\u000a      immune-mediated drug hypersensitivity reactions, which can be severe and\u000a      life-threatening. It has shown that predisposition to hypersensitivity\u000a      reactions caused by abacavir, nevirapine, carbamazepine and flucloxacillin\u000a      is due to specific HLA genes on chromosome 6. This has led to changes in\u000a      the drug label and guidelines for abacavir, increased HLA-B*57:01\u000a      gene testing in the NHS through a University spin-out company, and a\u000a      reduction in the incidence of hypersensitivity from 7% to <1%. The more\u000a      recent demonstration of HLA-A*31:01 and predisposition to\u000a      carbamazepine hypersensitivity, has led to drug label changes for\u000a      carbamazepine.\u000a    ","ImpactType":"Technological","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Pirmohamed M, Lin K, Chadwick D, Park BK\u000a      (2001). TNF-α promoter region gene polymorphisms in\u000a      carbamazepine-hypersensitive patients. Neurology, 56, 890-896 (PMID:\u000a      11294926) Citations: 96 Impact Factor: 8.249\u000a    \u000a\u000a2. Hughes DA, Vilar FJ, Ward CC, Alfirevic A,\u000a      Park BK, Pirmohamed M. (2004). Cost- effectiveness analysis\u000a      of HLA B*5701 genotyping in preventing abacavir hypersensitivity.\u000a      Pharmacogenetics, 14, 335-342 (PMID: 15247625) Citations: 147 Impact\u000a      Factor: 3.608\u000a    \u000a\u000a3. Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW,\u000a        Park BK, Pirmohamed M. (2006). HLA-B locus in Caucasian\u000a      patients with carbamazepine hypersensitivity. Pharmacogenomics, 7, 813-818\u000a      (DOI: 10.2217\/14622416.7.6.813) Citations: 122 Impact Factor: 3.857\u000a    \u000a\u000a4. Yip VL, Marson AG, Jorgensen AL, Pirmohamed\u000a        M, Alfirevic A. (2012). HLA genotype and\u000a      carbamazepine-induced cutaneous adverse drug reactions: a systematic\u000a      review. Clin Pharmacol Ther, 92, 757-765 (DOI: 10.1038\/clpt.2012.189)\u000a      Citations: 5 Impact Factor: 6.846\u000a    \u000a\u000a5. McCormack M, Alfirevic A, Bourgeois S, Farrell JJ,\u000a      Kasperaviciute D, Carrington M, Sills GJ, Marson T, Jia X, De\u000a      Bakker PI, Chinthapalli K, Molokhia M, Johnson MR, O'connor GD, Chaila E,\u000a      Alhusaini S, Shianna KV, Radtke RA, Heinzen EL, Walley N, Pandolfo M,\u000a      Pichler W, Park BK, Depondt C, Sisodiya SM, Goldstein DB, Deloukas\u000a      P, Delanty N, Cavalleri GL, Pirmohamed M. (2011). HLA-A*3101 and\u000a      carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J\u000a      Med, 364, 1134-1143 (DOI: 10.1056\/NEJMoa1013297) Citations: 156 Impact\u000a      Factor: 51.658\u000a    \u000a\u000a6. Carr DF, Chaponda M, Jorgensen AL, Castro EC, Van Oosterhout\u000a      JJ, Khoo SH, Lalloo DG, Heyderman RS, Alfirevic A,\u000a      Pirmohamed M. (2013). Association of human leukocyte antigen\u000a      alleles and nevirapine hypersensitivity in a Malawian HIV-infected\u000a      population. Clin Infect Dis, 56, 1330-1339 (DOI: 10.1093\/cid\/cit021)\u000a      Citations: 0 Impact Factor: 9.374\u000a    \u000aKey research grants\u000a    2007-2013. The Department of Health. Department of Health Chair\u000a      in Pharmacogenetics, £3.3m (£33,000 supplement; 2009), PI M Pirmohamed,\u000a      CoI BK Park\u000a    2008-2013. Wolfson Foundation. Wolfson Centre for Personalised\u000a      Medicines, £2m, PI M Pirmohamed\u000a    2008-2013. MRC. MRC Centre for Drug Safety Sciences, £3.7m,\u000a      Director BK Park, Deputy Director M Pirmohamed\u000a    2006-2009. The Wellcome Trust. The Pharmacology of Nevirapine in\u000a      Malawian Patients: Implications for Dosing and Understanding of\u000a      Hypersensitivity Reactions, £438,229. (Clinical Training Fellowship for\u000a      Chaponda, Pirmohamed primary supervisor)\u000a    2010-2013. EU FP7 Initial Training Network. Priorities and\u000a      Standards in Pharmacogenomic Research: Opportunities for a Safer and More\u000a      Efficient Pharmacotherapy, €3.2m (£936,049 to Liverpool), PI M Pirmohamed\u000a    2010-2013. Serious Adverse Event Consortium. Development of the\u000a      International Consortium on Drug Hypersensitivity, £300k, PI M\u000a        Pirmohamed\u000a    2010-2016. MRC (and Industry partners including GSK, AZ, ICON). North\u000a        West England MRC Fellowships in Clinical Pharmacology and Therapeutics,\u000a      £3,012,100, Programme Leader M Pirmohamed\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    Abacavir\u000a    \u000a      BHIVA prescribing guidelines for antiretrovirals (2008)\u000a        http:\/\/www.liv.ac.uk\/hiv\/BHIVATreatmentGuidelines2008.pdf\u000a\u000a      FDA abacavir warning on abacavir hypersensitivity and HLA testing\u000a        (2008 onwards)\u000a        http:\/\/www.fda.gov\/Drugs\/DrugSafety\/PostmarketDrugSafetyInformationforPatientsandProviders\/ucm094302.htm\u000a\u000a      EMEA warning for products containing abacavir (2008 onwards) http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/000581\/human_med_000878.jsp&murl=menus\/medicines\/medicines.jsp&jsenabled=true\u000a\u000a      WHO Collaborating Centre for International Drug Monitoring, Uppsala\u000a        Sweden, newsletter (2008) http:\/\/www.who.int\/medicines\/publications\/newsletter\/2008news3.pdf\u000a\u000a      WATERS LJ, MANDALIA S, GAZZARD B, NELSON M. (2007). Prospective\u000a        HLA-B*5701 screening and abacavir hypersensitivity: a single centre\u000a        experience. AIDS. 21:2533-4 [academic article demonstrating how\u000a        screening for abacavir reduces the occurrence of abacavir\u000a        hypersensitivity. Although demonstrated in 2007, the impact of the\u000a        testing to prevent hypersensitivity continues to the present day].\u000a      Case study on abacavir hypersensitivity and HLA-B*57:01 testing\u000a        (including mention of Delphic) in the Academy of Medical Science report\u000a        on stratified medicine.\u000a        http:\/\/www.google.co.uk\/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=8&ved=0CFgQFjAH&url=http%3A%2F%2Fwww.acmedsci.ac.uk%2Fdownload.php%3Ffile%3D%2Fimages%2Fproject%2FCasestud.pdf&ei=Q-1NUs3UFeah0QW9oIGgAw&usg=AFQjCNHAl0ubLPdOdLJlfNGSfQQNLCwgzA&sig2=s0w_g6KKm-_hmyiTmeOiFw\u000a        (see case study 2)\u000a    \u000a    Carbamazepine\u000a    \u000a      FDA carbamazepine warning instructing prescribers to test for\u000a        HLA-B*15:02 in certain ethnic groups but not in Caucasians (December\u000a        2007) (citing [3]) http:\/\/www.fda.gov\/Drugs\/DrugSafety\/PostmarketDrugSafetyInformationforPatientsandProviders\/ucm124718.htm\u000a\u000a      MHRA carbamazepine warning article Drug Safety Update April 2008;\u000a          Vol 1, Issue 9: 5:\u000a        http:\/\/www.mhra.gov.uk\/Safetyinformation\/DrugSafetyUpdate\/CON084888\u000a\u000a      Summary of product characteristic (drug label) for carbamazepine with\u000a        the warnings about HLA-A*31:01 and risk of carbamazepine\u000a        hypersensitivity in Caucasians.\u000a        http:\/\/www.medicines.org.uk\/emc\/medicine\/24201\/SPC\/Tegretol+Prolonged+Release+200mg+and+400mg+Tablets+%28formerly+Tegretol+retard%29\/\u000a\u000a    \u000a    ","Title":"\u000a    HLA alleles as genetic predictors for drug-induced hypersensitivity\u000a      reactions\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The research described was all undertaken at the UoL after 1993 and led\u000a      by Professors Munir Pirmohamed and Kevin Park and Dr Ana Alfirevic (Snr\u000a      Lecturer).\u000a    Adverse drug reactions (ADRs) account for 6.5% of all hospital admissions\u000a      (Pirmohamed et al, BMJ. 2004; 329:15-9). Immune-mediated ADRs\u000a      (also called hypersensitivity reactions) are not predictable from the\u000a      pharmacology of the drug and can lead to fatalities. The reactions are\u000a      mediated by antigen-specific T cells interacting with HLA-restricted\u000a      antigen presenting cells, providing a functional rationale to the\u000a      potential role of the major histocompatibility complex (MHC), and the HLA\u000a      alleles contained therein, as markers of susceptibility. The research in\u000a      this area began in 2000, with our first publication in 2001 showing the\u000a      importance of genes within the MHC, including HLA alleles, in\u000a      carbamazepine-induced hypersensitivity [1].\u000a    Abacavir is an antiretroviral that can cause life threatening\u000a      hypersensitivity in 5-7% of patients, with rechallenge leading to severe\u000a      and fatal reactions. Work undertaken in Australia in 2002 showed that HLA-B*57:01\u000a      predisposed to abacavir hypersensitivity. UoL research undertaken between\u000a      2002 and 2004, which included the identification and recruitment of\u000a      abacavir hypersensitivity patients and controls [2], showed that not only\u000a      was HLA-B*57:01 associated with the reaction, but in addition, it\u000a      was the first study to demonstrate the cost effectiveness of pre-\u000a      treatment testing for HLA-B*57:01 in preventing hypersensitivity.\u000a    Carbamazepine, an anticonvulsant, can cause a wide range of\u000a      hypersensitivity reactions including dangerous or even fatal skin\u000a      reactions. In 2004, a Taiwanese group reported that all Han Chinese\u000a      patients who experienced carbamazepine-induced Stevens-Johnson syndrome\u000a      (SJS) were positive for HLA-B*15:02. UoL research showed that this\u000a      allele was not important in patients of European ancestry because of its\u000a      low prevalence [3], and it did not predispose to another type of\u000a      hypersensitivity reaction called DRESS (drug reaction with eosinophilia\u000a      and systemic symptoms). A recent UoL systematic review has shown that HLA-B*15:02\u000a      is important in Chinese, Thai, Malay and Indian populations, but not in\u000a      Caucasians or Japanese [4].\u000a    In March 2011, UoL research showed that HLA-A*31:01 is associated\u000a      with CBZ-hypersensitivity reactions in Caucasians [5]. HLA-A*31:01,\u000a      unlike HLA-B*15:02, is associated with all forms of\u000a      hypersensitivity reactions to CBZ (including maculopapular eruptions,\u000a      hypersensitivity syndrome and SJS). The same finding has also been\u000a      demonstrated in Japanese patients. The finding is particularly important\u000a      given the wider worldwide distribution of HLA-A*31:01\u000a      compared with HLA- B*15:02 which is found predominantly in South\u000a      East Asia.\u000a    The research has investigated other hypersensitivity reactions:\u000a      e.g. it has shown that HLA- B*57:01 is a predisposing factor for\u000a      flucloxacillin hepatitis (Daly et al; Nat Genet 2009;41:816-9) and HLA-C*04:01\u000a      is a predisposing factor nevirapine-induced SJS in Malawians [6].\u000a    "},{"CaseStudyId":"3896","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Although the majority of craniosynostosis cases are considered\u000d\u000a      non-syndromic (occurring as an\u000d\u000a      isolated incident), 15% of craniosynostosis cases are associated with\u000d\u000a      specific syndromes and\u000d\u000a      around 23% of all cases (syndromic or non-syndromic) now have a genetic\u000d\u000a      diagnosis, 38% of\u000d\u000a      which were identified by the Clinical Genetics Laboratory in Oxford. This\u000d\u000a      research has led to the\u000d\u000a      development of genetic tests for accurate diagnosis, improved clinical\u000d\u000a      management, and enhanced\u000d\u000a      quality of life for patients and their families worldwide.\u000d\u000a    Accurate Genetic Diagnosis\u000d\u000a      The Clinical Genetics Laboratory's determination of 14 genes relating to\u000d\u000a      craniofacial syndromes\u000d\u000a      has led to the development of the first genetic diagnostic tests for these\u000d\u000a      syndromes, now available\u000d\u000a      in multiple laboratories around the world. The GeneTests website,\u000d\u000a      hosted by the National Centre\u000d\u000a        for Biotechnology Information, USA, lists 34 laboratories in 15\u000d\u000a      different countries offering tests for\u000d\u000a      mutations in the FGFR2 gene alone6. In the UK eight\u000d\u000a      genes discovered by the Wilkie lab have now\u000d\u000a      been approved for genetic testing, including ERF and TCF12,\u000d\u000a      through the UK Genetic Testing\u000d\u000a        Network gene dossiers process7. These tests provide a\u000d\u000a      range of safe and accurate diagnostic\u000d\u000a      options including: pre-implantation genetic diagnosis, prenatal diagnosis,\u000d\u000a      and ultrasound scanning.\u000d\u000a      Data from the Clinical Molecular Genetics Society Audit, showed\u000d\u000a      there were 127 prenatal\u000d\u000a      diagnoses in the UK for craniosynostosis between 2010 and 20118.\u000d\u000a      The Oxford Medical Genetics\u000d\u000a      Laboratories tested 260 new patient samples (for craniosynostosis\u000d\u000a      syndromes) between 2010 and\u000d\u000a      2012 (174 from the United Kingdom and 86 abroad)9, representing\u000d\u000a      a small sample of the total\u000d\u000a      tests carried out worldwide each year.\u000d\u000a    Improved Clinical Management\u000d\u000a      The great significance of prenatal diagnosis for craniofacial syndromes on\u000d\u000a      a case-by-case basis is\u000d\u000a      shown in a 2007 study of five cases of suspected Apert syndrome, confirmed\u000d\u000a      prenatally by FGFR2\u000d\u000a      mutation analysis. While three of these pregnancies were terminated, it is\u000d\u000a      important to note that\u000d\u000a      two families chose to continue with pregnancy. In such cases, the accurate\u000d\u000a      prenatal diagnosis\u000d\u000a      allows swift clinical responses, such as early referral to specialists,\u000d\u000a      better communication with\u000d\u000a      families, a more precise long-term prognosis, and improved clinical\u000d\u000a      management10.\u000d\u000a    The effect of accurate genetic diagnosis for improved clinical outcomes\u000d\u000a      is exemplified in a further\u000d\u000a      study from the Clinical Genetics Laboratory, which was published in 2009.\u000d\u000a      This study shows that\u000d\u000a      patients with Saethre-Chotzen syndrome (related to the TWIST1\u000d\u000a      mutation) have a 42% recurrence\u000d\u000a      rate of intracranial hypertension following standard surgical\u000d\u000a      intervention. As a result, it is now\u000d\u000a      recommended that all patients with syndromic features should be tested for\u000d\u000a      TWIST1 mutations in\u000d\u000a      order to prevent the recurrence of intracranial hypertension following\u000d\u000a      surgery11. The following\u000d\u000a      supplementary commentary from senior plastic surgeon, Scott P. Bartlett,\u000d\u000a      M.D. Division of Plastic\u000d\u000a      Surgery, Children's Hospital of Philadelphia, reflects increasing\u000d\u000a      realisation among clinicians of the\u000d\u000a      importance of genetic screening as a management tool12: \"This\u000d\u000a        is an important article. I hope those\u000d\u000a        who deal with this area will read it closely and share it with members\u000d\u000a        of their craniofacial team who\u000d\u000a        do not have access to this publication.\" 12\u000d\u000a    Improved Quality of Life\u000d\u000a      Craniosynostosis is a common condition causing illness and uncertainty for\u000d\u000a      thousands of patients\u000d\u000a      and their families worldwide. Accurate genetic diagnosis offers definitive\u000d\u000a      explanations for these\u000d\u000a      often misdiagnosed, misunderstood, and mismanaged disorders.\u000d\u000a    The following testimonials represent a small percentage of the thousands\u000d\u000a      of individual lives\u000d\u000a      affected by this research:\u000d\u000a    Quote from the mother of a boy accurately diagnosed with a mutation in\u000d\u000a      ERF:\u000d\u000a      \"When Charlie was finally diagnosed it came as a relief that somebody\u000d\u000a        had listened to us and was\u000d\u000a        able to put a name to the problem. I always suspected that something was\u000d\u000a        wrong despite tests\u000d\u000a        coming back normal.\" 13\u000d\u000a    Email to Professor Wilkie from a young woman with a mutation in TCF12:\u000d\u000a      \"After letting things settle and sink in over the weekend, I would just\u000d\u000a        like to say a quick a huge\u000d\u000a        thank you for speaking with me on Friday, and completely putting my\u000d\u000a        prospective future of having\u000d\u000a        children in a completely different light. For this, I cannot thank you\u000d\u000a        enough.\"14\u000d\u000a    Email to Professor Wilkie from a family involved in the group's ERF\u000d\u000a      study:\u000d\u000a      \"I have finally read the reports and information on the Internet and\u000d\u000a        have been meaning to email\u000d\u000a        you just to thank you and your team for your hard work in helping find\u000d\u000a        answers for families like us.\u000d\u000a        Thank you to you and your team for giving us a name for (my sons)\u000d\u000a        problems... in some ways it\u000d\u000a        has definitely made a difference in how we feel about it all, a lot of\u000d\u000a        things with (my son) make\u000d\u000a        sense now and the problems he has had in the past and still experiencing\u000d\u000a        now...\" 15\u000d\u000a    ","ImpactSummary":"\u000d\u000a    As a result of research from Oxford's Professor Andrew Wilkie, accurate\u000d\u000a      genetic diagnostic tests\u000d\u000a      are now available for over 23% of all craniosynostosis cases nationally\u000d\u000a      and internationally, leading\u000d\u000a      to improved family planning and clinical management of this common\u000d\u000a      condition worldwide. The\u000d\u000a      premature fusion of cranial sutures, known as craniosynostosis, is a\u000d\u000a      common developmental\u000d\u000a      abnormality that occurs in 1 in 2,500 births. Over the past 20 years, the\u000d\u000a      University of Oxford's\u000d\u000a      Clinical Genetics Lab, led by Professor Wilkie in collaboration with the\u000d\u000a      Oxford Craniofacial Unit,\u000d\u000a      has identified more than half of the known genetic mutations that cause\u000d\u000a      craniosynostosis and other\u000d\u000a      malformations of the skull.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4560349","Name":"Philadelphia"}],"References":"\u000d\u000a    \u000a1. Wilkie, A. O. et al. Apert syndrome results from localized\u000d\u000a      mutations of FGFR2 and is\u000d\u000a      allelic with Crouzon syndrome. Nat. Genet. 9, 165-172\u000d\u000a      (1995).\u000d\u000a      Primary paper showing results from research into FGFR2 gene mutation\u000d\u000a          in\u000d\u000a          Apert Syndrome.\u000d\u000a    \u000a\u000a2. Robertson, S. P. et al. Localized mutations in the gene\u000d\u000a      encoding the cytoskeletal\u000d\u000a      protein filamin A cause diverse malformations in humans. Nat. Genet.\u000d\u000a      33, 487-491\u000d\u000a      (2003). Paper outlining gene mutations for otopalatodigital\u000d\u000a          syndromes.\u000d\u000a    \u000a\u000a3. Twigg, S. R. F. et al. Reduced dosage of ERF causes complex\u000d\u000a      craniosynostosis in\u000d\u000a      humans and mice and links ERK1\/2 signaling to regulation of osteogenesis.\u000d\u000a      Nat.\u000d\u000a        Genet. 45:308-313 (2013). doi: 10.1038\/ng.2539.\u000d\u000a      Paper showing mutations in the ERF gene in patients with\u000d\u000a          craniosynostosis.\u000d\u000a    \u000a\u000a4. Sharma, V. P. et al. Mutations in TCF12, encoding a basic\u000d\u000a      helix-loop-helix partner of\u000d\u000a      TWIST1, are a frequent cause of coronal craniosynostosis. Nat. Genet.\u000d\u000a      45:304-307\u000d\u000a      (2013). doi: 10.1038\/ng.2531.\u000d\u000a      Paper showing mutations in the TCF12 gene in patients with\u000d\u000a          craniosynostosis.\u000d\u000a    \u000a\u000a5. Wilkie, A. O. M. et al. Prevalence and complications of\u000d\u000a      single-gene and chromosomal\u000d\u000a      disorders in craniosynostosis. Pediatrics 126, e391-400\u000d\u000a      (2010). doi:\u000d\u000a      10.1542\/peds.2009-3491.\u000d\u000a      Paper outlining the burden of genetic abnormalities in\u000d\u000a          craniosynostosis.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust, the Medical Research\u000d\u000a      Council, BDF\/Newlife,\u000d\u000a      NIHR (Via the Oxford BRC Genomics theme and OUCAGS), the Royal College of\u000d\u000a      Surgeons\u000d\u000a      (London), EPA Cephalosporin Fund (Oxford), the NHS Department of Health\u000d\u000a      (QIDIS scheme), the\u000d\u000a      National Research Foundation-Ministry of Health in Singapore (who funded a\u000d\u000a      one-year of DPhil\u000d\u000a      post), and the British Association of Oral and Maxillofacial Surgeons.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    \u000d\u000a      NCBI, GeneTests, FGFR2-Related Craniosynostosis.[online] Seattle.\u000d\u000a        University of\u000d\u000a        Washington (2013) Available at:\u000d\u000a        http:\/\/www.ncbi.nlm.nih.gov\/sites\/GeneTests\/lab\/clinical_disease_id\/2760?db=genetests\u000d\u000a        [Accessed 4 April 2013] GeneTests website containing information\u000d\u000a            about all\u000d\u000a            genetic tests for craniofacial malformations currently available in\u000d\u000a            the US and\u000d\u000a            around the world.\u000a\u000d\u000a      NHS, UK Genetic Testing Network. (2012) [online] Available at:\u000d\u000a        http:\/\/www.ukgtn.nhs.uk\/gtn\/Home\u000d\u000a        [Accessed 4 April 2013] Gene Dossiers for all\u000d\u000a            approved genetic tests can be found on the UK Genetic Testing\u000d\u000a            Network\u000d\u000a            website.\u000a\u000d\u000a      Clinical Molecular Genetics Society Audit of Data 2010-11. [online]\u000d\u000a        London, CMGS,\u000d\u000a        (2012). Available at:\u000d\u000a        http:\/\/www.cmgs.org\/CMGS%20audit\/2011%20audit\/CMGSAudit10_11_FINAL.pdf\u000d\u000a        [Accessed 4 April 2013] CMGS audit published in 2012, showing\u000d\u000a            there were 127\u000d\u000a            prenatal diagnoses in the UK for craniosynostosis between 2010 and\u000d\u000a            2011.\u000a\u000d\u000a      Oxford University Hospitals NHS. Oxford Medical Genetics Laboratories\u000d\u000a        audit of\u000d\u000a        revenue from genetic testing of craniofacial and skeletal disorders, for\u000d\u000a        the period 1\u000d\u000a        March 2011 to 28 Feb 2012 (available on request). Audit from the\u000d\u000a            National\u000d\u000a            Specialised Commissioning Group outlining total revenue from Oxford\u000d\u000a            Medical\u000d\u000a            Genetics Laboratories genetic testing of craniofacial and skeletal\u000d\u000a            disorders from\u000d\u000a            1 March 2011 to 28 Feb 2012.\u000a\u000d\u000a      David, A. L. et al. Diagnosis of Apert syndrome in the\u000d\u000a        second-trimester using 2D and\u000d\u000a        3D ultrasound. Prenat. Diagn. 27, 629-632 (2007). Study\u000d\u000a            of five cases of suspected\u000d\u000a            Apert syndrome, confirmed prenatally by FGFR2 mutation analysis.\u000a\u000d\u000a      Woods, R. H. et al. Reoperation for intracranial hypertension\u000d\u000a        in TWIST1-confirmed\u000d\u000a        Saethre-Chotzen syndrome: a 15-year review. Plast. Reconstr. Surg.\u000d\u000a        123, 1801-1810\u000d\u000a        (2009). doi: 10.1097\/PRS.0b013e3181a3f391. A study showing that\u000d\u000a            patients with\u000d\u000a            Saethre-Chotzen syndrome have a 42% recurrence rate of intracranial\u000d\u000a            hypertension following standard surgical intervention, emphasising\u000d\u000a            the clinical\u000d\u000a            importance of genetic testing.\u000a\u000d\u000a      Bartlett, S. P. & Foo, R. Discussion. Reoperation for intracranial\u000d\u000a        hypertension in\u000d\u000a        TWIST1-confirmed Saethre-Chotzen syndrome: a 15-year review. Plast.\u000d\u000a          Reconstr.\u000d\u000a          Surg. 123, 1811-1812 (2009). doi:\u000d\u000a        10.1097\/PRS.0b013e3181a3f213. Supplementary\u000d\u000a            commentary for (Woods, R. H. et al 2009) supporting genetic\u000d\u000a            screening as a\u000d\u000a            clinical tool.\u000a\u000d\u000a      Nottinghamshire 10 year old diagnosed with super-rare condition. IRIS\u000d\u000a        Magazine:[online] March 2011 Available at:\u000d\u000a        http:\/\/www.askiris.org.uk\/uploads\/docs\/Iris_12pp_Mag_3_Mar_aw.pdf\u000d\u000a        [Accessed 4\u000d\u000a        April 2013] Article about the impact of correct genetic diagnosis\u000d\u000a            (mutation in ERF\u000d\u000a            gene) for a 10-year-old boy who had been previously misdiagnosed\u000d\u000a            with\u000d\u000a            Crouzon syndrome.\u000a\u000d\u000a      Patient diagnosed with a TCF12 mutation. Email statement addressed to\u000d\u000a        Professor\u000d\u000a        Andrew Wilkie received 25th March 2013 (available on request).\u000d\u000a        Email statement\u000d\u000a            from a patient who was diagnosed with a TCF12 gene mutation,\u000d\u000a            thanking\u000d\u000a            Professor Wilkie for genetic counseling.\u000a\u000d\u000a      Mother of a child with ERF craniosynostosis. Email statement addressed\u000d\u000a        to Professor\u000d\u000a        Andrew Wilkie, received 20th March 2013 (available on\u000d\u000a        request).\u000d\u000a        Email statement from the mother of a patient, which supports the\u000d\u000a            work of\u000d\u000a            Professor Wilkie's group.\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    DEFINING CRANIOFACIAL DISORDERS FOR IMPROVED\u000d\u000a        CLINICAL MANAGEMENT\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Craniosynostosis is the most common form of non-cleft craniofacial\u000d\u000a      malformation, affecting one in\u000d\u000a      2,500 children and around 52,000 births worldwide each year. While the\u000d\u000a      majority of\u000d\u000a      craniosynostosis cases occur as isolated incidents, around 15% of all\u000d\u000a      cases relate to over 150\u000d\u000a      different syndromes, many of which are the result of genetic mutations.\u000d\u000a    Since 1993, the University of Oxford's Clinical Genetics Laboratory, led\u000d\u000a      by Professor Andrew\u000d\u000a      Wilkie, has been collaborating closely with plastic surgeons at the Oxford\u000d\u000a      Craniofacial Unit to\u000d\u000a      research genetic mutations behind rare craniofacial malformations. Over\u000d\u000a      the past 20 years the\u000d\u000a      laboratory has identified the genetic causes of 14 craniofacial disorders,\u000d\u000a      including many of the\u000d\u000a      most common and important conditions, such as Apert syndrome (FGFR2\u000d\u000a      gene)1, Pfeiffer\u000d\u000a      syndrome (FGFR2 gene), the otopalatodigital syndromes (FLNA)2,\u000d\u000a      craniofrontonasal syndrome\u000d\u000a      (EFNB1) and recently two new syndromes caused by mutations in ERF3\u000d\u000a      and TCF124. Each of\u000d\u000a      these syndromes is a serious disorder, which commonly presents at birth\u000d\u000a      and affects the\u000d\u000a      development of multiple organ systems, with potential lifelong\u000d\u000a      consequences for health, and in\u000d\u000a      some cases, mental development. By identifying the genetic mutations\u000d\u000a      behind more than half of all\u000d\u000a      known syndromes, the Wilkie group have made the largest single\u000d\u000a      contribution to the genetics of\u000d\u000a      human craniofacial disorders in the world.\u000d\u000a    In 2010 the Clinical Genetics Laboratory made a major contribution to our\u000d\u000a      understanding of the\u000d\u000a      overall burden of genetic disorders in craniosynostosis. Through a\u000d\u000a      comprehensive genetic testing\u000d\u000a      programme conducted on 326 children with craniosynostosis a study\u000d\u000a      identified 84 children (and 64\u000d\u000a      of their relatives) with genetic alterations. This study was the first to\u000d\u000a      demonstrate the full potential\u000d\u000a      and accuracy of genetic testing among patients with craniofacial syndromes\u000d\u000a      in a large prospective\u000d\u000a      cohort5.\u000d\u000a    Recent studies from the Clinical Genetics Laboratory have highlighted the\u000d\u000a      importance of accurate\u000d\u000a      genetic diagnosis in improving the management of craniosynostosis. This\u000d\u000a      principle is exemplified in\u000d\u000a      the case of mutations in two genes, termed ERF3 and TCF124,\u000d\u000a      which each account for 1-2% of all\u000d\u000a      craniosynostosis cases. The Oxford laboratory's analysis of genetic data,\u000d\u000a      from more than 400\u000d\u000a      families collected over a 20-year period, has indicated that these new\u000d\u000a      disorders show markedly\u000d\u000a      different clinical features. Patients with ERF mutations often\u000d\u000a      present later in childhood but can\u000d\u000a      develop serious complications with raised intracranial pressure leading to\u000d\u000a      brain damage in\u000d\u000a      untreated cases3. In contrast, patients with mutations in the TCF12\u000d\u000a      gene present early in life and\u000d\u000a      require surgery within the first 6-18 months4. Importantly,\u000d\u000a      several of the parents tested in this\u000d\u000a      study, who showed no clinical signs of craniosynostosis, were found to\u000d\u000a      carry the TCF12 mutation;\u000d\u000a      indicating that accurate diagnosis and risk estimation for such families\u000d\u000a      is only possible through\u000d\u000a      genetic testing4. These contemporary studies3,4\u000d\u000a      demonstrate the importance of accurate genetic\u000d\u000a      testing in management, as well as in establishing prognosis.\u000d\u000a    "},{"CaseStudyId":"3897","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The production and use of the antibody ALK1 by the University of Oxford\u000d\u000a      has had a major impact on lymphoma diagnosis and provided invaluable\u000d\u000a      information on tumour development. ALK-positive ALCL is now also included\u000d\u000a      in the World Health Organization's (WHO) current classification of\u000d\u000a      haematological malignancies.\u000d\u000a    Accurate Diagnosis\u000d\u000a      The production and use of the antibody ALK1 by the University of Oxford\u000d\u000a      has had a major impact on lymphoma diagnosis, enabling the definitive\u000d\u000a      diagnosis of the tumour entity ALK-positive ALCL. ALCL was previously\u000d\u000a      regarded as an aggressive incurable disease and frequently misdiagnosed as\u000d\u000a      a carcinoma or other haematological malignancy, resulting in inappropriate\u000d\u000a      treatment. Not only has the antibody ALK1 revolutionised the accurate\u000d\u000a      diagnosis and understanding of ALK-positive ALCL, this tumour now\u000d\u000a      represents the best characterised T-cell lymphoma, with the exception of\u000d\u000a      cutaneous T-cell lymphoma, which has a far worse prognosis7,8,9.\u000d\u000a      Importantly, the sensitivity of the antibody has permitted the detection\u000d\u000a      of minimal residual disease. The latter is an important factor in cancers\u000d\u000a      since it can lead to a failure to detect disease and result in the patient\u000d\u000a      relapsing. A vital element of the value of an antibody for diagnostic use\u000d\u000a      is its inclusion in the NEQAS scheme. The United Kingdom National External\u000d\u000a      Quality Assessment Service (UK NEQAS) ensures the accuracy and reliability\u000d\u000a      of laboratory tests and is used by all diagnostic labs. ALK1 fulfills this\u000d\u000a      category. The following statement was received via email on the 19th\u000d\u000a      of September 2012, from Doctor Merdol Ibrahim, Manager of UK NEQAS-ICC.\u000d\u000a      This email, and the antibody usage table, has been kept on file: \"NEQAS\u000a        requested ALK for its lymphoma module about 1.5 years ago for the first\u000d\u000a        time. We distributed a composite control of a tonsil and anaplastic\u000d\u000a        large cell lymphoma for participants to stain. Participants also\u000d\u000a        submitted their methodologies and I have attached the antibody usage\u000d\u000a        table (second table on the right), which shows that 104\/179 (58%)\u000d\u000a        participants used the Dako CD246 clone. It is one of the most popular\u000d\u000a        antibodies and had a very good pass rate with respect to the expected\u000d\u000a        staining levels.\"10\u000d\u000a    Policy and Guidelines\u000d\u000a      The identification of ALK-positive ALCL (as opposed to ALK-negative ALCL)\u000d\u000a      has gained worldwide acceptance and is now included in the current\u000d\u000a      classification of haematological malignancies, first published by the\u000d\u000a      World Health Organization in 2008. ALK1 is considered to be the gold\u000d\u000a      standard antibody for the diagnosis of ALK-positive ALCL9.\u000d\u000a    Clinical outcomes\u000d\u000a      Approximately 870 children are diagnosed with non-Hodgkin's lymphoma every\u000d\u000a      year in the USA 11, equating to about 175 new cases of ALK+ALCL\u000d\u000a      annually. For adults, this figure rises to approximately 1,50012.\u000d\u000a      Before 1997 it was difficult to compare the survival rates of patients\u000d\u000a      with ALCL due to problems with the actual diagnosis of the disease. This\u000d\u000a      was compounded by a lack of common staging systems, relatively small\u000d\u000a      numbers of patients, and a variety of different treatment regimens being\u000d\u000a      used in the clinics. This meant that patients may have undergone\u000d\u000a      unnecessary surgery or invasive therapies as a result of misdiagnosis. The\u000d\u000a      availability of the ALK1 antibody in 1997 enabled the correct diagnosis of\u000d\u000a      ALK-positive ALCL, resulting in improvements in targeted therapy and\u000d\u000a      greater survival rates for patients with this lymphoma. For example, the\u000d\u000a      five year overall survival rates increased from 71% in 199913\u000d\u000a      to 89% in 200814. It is expected that additional improvements\u000d\u000a      in patient survival will continue from future clinical trials. The\u000d\u000a      widespread introduction of ALK-specific kinase inhibitors is a distinct\u000d\u000a      possibility.\u000d\u000a    Commercialisation\u000d\u000a      The ALK1 antibody is licensed commercially throughout the world by\u000d\u000a      DakoCytomation15 and is considered to be the international gold\u000d\u000a      standard for identifying this ALK-positive ALCL. The below graph shows the\u000d\u000a      upward trend in total units of ALK1 sold by Dako from 2010 to 201215.\u000d\u000a      When patent restrictions are removed in 2014 this upward trend is\u000d\u000a      predicted to continue.\u000d\u000a    \u000d\u000a      \u000d\u000a      \u000d\u000a    Total royalties received for ALK reached approximately £50,000 for the\u000d\u000a      period 1998-2005. Sales of the antibody have since increased due to\u000d\u000a      worldwide interest in ALK. The total amount of royalties received by the\u000d\u000a      University of Oxford for ALK from 2008 to 2009 reached £22,875, with\u000d\u000a      royalties now consistently exceeding £10,000 per annum16.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The production and use of monoclonal antibody, ALK1, by researchers in\u000d\u000a      Oxford has been pivotal in enabling the accurate diagnosis and treatment\u000d\u000a      of Anaplastic Large Cell Lymphoma (ALCL). This research also led to the\u000d\u000a      formal classification of ALK-positive ALCL tumours by the World Health\u000d\u000a      Organization in 2008. While ALCL accounts for 10-20% of\u000d\u000a      paediatric\/adolescent non-Hodgkin's lymphoma worldwide, its diagnosis had\u000d\u000a      been problematical due to the absence of suitable reagents. This was\u000d\u000a      remedied in 1997 when Oxford researchers created the first monoclonal\u000d\u000a      antibody, ALK1, recognising anaplastic lymphoma kinase (ALK), a molecule\u000d\u000a      that is associated with up to 90% of ALCL.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Pulford, K. et al. Detection of anaplastic lymphoma\u000d\u000a      kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in\u000d\u000a      normal and neoplastic cells with the monoclonal antibody ALK1. Blood\u000d\u000a      89, 1394-404 (1997). Describes the production and\u000d\u000a          characterization of the monoclonal antibody ALK1.\u000d\u000a    \u000a\u000a2. Stein, H. et al. CD30(+) anaplastic large cell lymphoma: a\u000d\u000a      review of its histopathologic, genetic, and clinical features. Blood\u000d\u000a      96, 3681-95 (2000). Collaborative review of the work leading\u000d\u000a          up to description of ALK-positive ALCL\u000d\u000a    \u000a\u000a3. Bischoff, D., Pulford, K., Mason, D.Y., & Morris, S.W. Role of the\u000d\u000a      nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated\u000d\u000a      NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol Cell\u000d\u000a      Biol. 17, 2312-2325 (1997). Reference to the importance of\u000d\u000a          the NPM-ALK fusion protein.\u000d\u000a    \u000a\u000a4. Ait-Tahar, K., et al. Correlation of the autoantibody response\u000d\u000a      to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive\u000d\u000a      anaplastic large cell lymphoma with tumor dissemination and relapse risk.\u000d\u000a      Blood 115, 3314-9 (2010). doi:\u000d\u000a      10.1182\/blood-2009-11-251892. ª From Oxford and *Joint last authors. Description\u000a          of the immunogenicity of ALK protein and the first description of the\u000d\u000a          immune response to ALK being of prognostic significance and also\u000d\u000a          having a potential role in tumour spread.\u000d\u000a    \u000a\u000a5. Lamant, L. et al. Expression of the ALK tyrosine kinase gene\u000d\u000a      in neuroblastoma. Am J Pathol 156, 1711-21 (2000). First\u000a          description of ALK being expressed in neuroblastoma.\u000d\u000a    \u000a\u000a6. National Cancer Institute (NCI). COG-ANHL0131 - Phase III Randomized\u000d\u000a      Study of Consolidation Chemotherapy Comprising Doxorubicin and Prednisone\u000d\u000a      in Combination With Vincristine Versus Vinblastine in Patients With\u000d\u000a      Advanced Anaplastic Large Cell Lymphoma. In ClinicalTrials.gov [Internet].\u000d\u000a      Bathesda (MD): National Library of Medicine (US). 2000-[cited 2013 Apr\u000d\u000a      04]. Available from: http:\/\/clinicaltrials.gov\/show\/NCT00059839\u000d\u000a      NLM Identifier: NCT00059839. Clinical trial on ALCL in which the\u000d\u000a          biological studies on the immune response to ALK involving the ALK1\u000d\u000a          antibody was studied.\u000d\u000a    \u000aThis research was funded by the Leukaemia and Lymphoma Research Fund,\u000d\u000a      Cancer Research UK, the Starmer-Smith Memorial Fund, Sam Foye Fund and the\u000d\u000a      Medical Research Fund of the University of Oxford.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    \u000d\u000a      Benharroch, D. et al. ALK-positive lymphoma: a single disease\u000d\u000a        with a broad spectrum of morphology. Blood 91, 2076-84\u000d\u000a        (1998). First paper in which the antibody ALK1 was used to\u000d\u000a            identify ALK-positive lymphomas as a distinct entity.\u000a\u000d\u000a      Delsol, G. et al. Anaplastic large cell lymphoma (ALCL),\u000d\u000a        ALK-positive. In: Swerdlow, S.H. et al, editors. WHO\u000d\u000a          Classification of Tumours of Haematopoietic and Lymphoid Tissues.\u000d\u000a        Lyon. IARC Press; 2008. Reference refers to the description of\u000d\u000a            ALK-positive ALCL in the current World Health Classification scheme\u000d\u000a            for Haematological malignancies.\u000a\u000d\u000a      Kinney, M.C. et al. Anaplastic large cell lymphoma:\u000d\u000a        twenty-five years of discovery. Arch Pathol Lab Med 135,19-43\u000a        (2011). doi: 10.1043\/2010-0507-RAR.1. This reference refers an\u000d\u000a            important update on ALK-positive ALCL.\u000a\u000d\u000a      NEQAS-ICC. UK Manager. Email statement explaining inclusion of ALK in\u000d\u000a        the NEQAS lymphoma module labs, received 19th September 2012 (available\u000d\u000a        on request). Statement confirming use of ALK by NEQAS-ICC.\u000a\u000d\u000a      Childhood Cancer Statistics. American Childhood Cancer\u000d\u000a          Organization at\u000d\u000a        http:\/\/www.acco.org\/Information\/AboutChildhoodCancer\/ChildhoodCancerStatistics.aspx\u000d\u000a        (Accessed 2013) Website for statistics on childhood cancer in the\u000d\u000a            USA.\u000a\u000d\u000a      Lymphoma Statistics at http:\/\/www.lymphomation.org\/statistics.htm#keyfacts\u000d\u000a        (Accessed 2013) Website for statistics on adult cancer in the\u000d\u000a            USA.\u000a\u000d\u000a      Falini, B. et al. ALK+lymphoma: clinico-pathological findings\u000d\u000a        and outcome. Blood 93, 2697-2706 (1999). Paper\u000d\u000a            showing increase in 5 year overall survival rates for ALK.\u000d\u000a      Lamant, L. et al. Prognostic impact of morphologic and\u000d\u000a        phenotypic features of childhood ALK-positive anaplastic large-cell\u000d\u000a        lymphoma: results of the ALCL99 study. J Clin Oncol. 29,\u000d\u000a        4669-4676 (2011). doi: 10.1200\/JCO.2011.36.5411. Reference\u000d\u000a            describing prognosis in ALK+ALCL where antibody ALK1 was used.\u000a\u000d\u000a      Monoclonal Mouse Anti-Human CD246, ALK Protein, Clone ALK1. Dako\u000d\u000a        at\u000d\u000a        http:\/\/www.dako.com\/uk\/ar38\/p118620\/prod_products.htm\u000d\u000a        (Accessed 2013) The antibody ALK1 has been commercialised by\u000d\u000a            DakoCytomation. \u000a\u000d\u000a      University of Oxford Finance Division. Royalties Officer. Email\u000d\u000a        stating royalties for licensed antibodies against ALK, received 30th\u000d\u000a        July 2012 (available on request). Details of the\u000d\u000a            commercialisation and upward sales trend of the ALK1 antibody from\u000d\u000a            DAKO and information on royalties received by the University of\u000d\u000a            Oxford.\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    ACCURATE DIAGNOSIS: IMPROVING SURVIVAL RATES FOR CHILDREN WITH CANCER\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2640729","Name":"Oxford"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Before 1997 Anaplastic large cell lymphoma (ALCL) posed a major\u000d\u000a      diagnostic problem to clinicians because of the lack of reagents able to\u000d\u000a      distinguish ALCL from other tumours. Patients were frequently misdiagnosed\u000d\u000a      with carcinoma, histiocytosis X or Hodgkin's disease, leading to\u000d\u000a      unnecessary and often invasive therapy, including surgery. In 1997 the\u000d\u000a      late Professor David Y. Mason (deceased Feb 2008), Dr Karen Pulford, and\u000d\u000a      the Leukaemia Research Fund Immunodiagnostics Unit (now Leukaemia and\u000d\u000a      Lymphoma Research Fund) produced the first monoclonal antibody, ALK1,\u000d\u000a      against the anaplastic lymphoma kinase (ALK) protein, which is the\u000d\u000a      principal cause of oncogenesis in ALCL1. Oncogenic\u000d\u000a      translocations create fusion proteins of ALK and partners capable of high\u000d\u000a      expression and dimerization, after which dimerisation leads to ALK\u000d\u000a      autophosphorylation and constitutive activation.\u000d\u000a    The ALK1 antibody made a precise diagnosis of ALK-positive ALCL possible\u000d\u000a      for the first time. The ALK1 antibody identified ALK-positive ALCL as a\u000d\u000a      molecular pathological entity (distinct from ALK-negative ALCL), showing\u000d\u000a      that this cancer accounts for 10-20% of childhood lymphomas and 3% of\u000d\u000a      adult non-Hodgkins lymphomas2. Due to improved survival rates\u000d\u000a      associated with ALK-positive ALCL, the ability to distinguish between\u000d\u000a      ALK-positive and negative forms of the disease represented a vitally\u000d\u000a      important step in achieving accurate diagnosis and appropriate treatment\u000d\u000a      for patients.\u000d\u000a    Researchers at the University of Oxford have gone on to use the antibody\u000d\u000a      ALK1 to identify additional ALK fusion proteins in ALCL and confirm the\u000d\u000a      role of the ALK proteins play a primary role in tumour development 3.\u000d\u000a      They have shown that ALK fusion proteins may be immunogenic and candidates\u000d\u000a      for immunotherapy4.\u000d\u000a    The antibody ALK1 has been used to show ALK protein expression in\u000d\u000a      neuroblastoma5, and ALK has also been identified in a number of\u000d\u000a      other solid tumours, such as lung cancer. Studies on the immune response\u000d\u000a      to ALK, using ALK1 antibody as an essential reagent (initiated by Oxford\u000d\u000a      and later performed as collaborative studies within international phase\u000d\u000a      III clinical trials6), are included in the clinical trial `ALCL\u000d\u000a      2012'. This phase III clinical study organised by the European Inter-group\u000d\u000a      for Childhood non-Hodgkin's Lymphoma (EICNHL) will identify high-risk\u000d\u000a      patients so that they can be directed to more effective therapies as soon\u000d\u000a      as possible.\u000d\u000a    "},{"CaseStudyId":"3898","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    Rheumatoid arthritis is a persistent inflammatory arthritis of synovial\u000a      joints that currently affects around 500,000 people in England and an\u000a      estimated 0.5-1% of the adult population worldwide. Rheumatoid arthritis\u000a      can lead to pain, deformity and loss of function, work disability,\u000a      economic losses and premature death. Prior to the development of anti-TNFα\u000a      therapies, a considerable proportion of patients treated with the\u000a      available disease-modifying antirheumatic drugs (DMARDs) were still\u000a      plagued by premature death rates, and had evidence of persistent disease\u000a      activity, with many patients remaining wheelchair bound due to ongoing\u000a      joint damage and disability.\u000a    The commercial introduction of anti-TNFα agents from 1999 has profoundly\u000a      changed the management of severe rheumatoid arthritis throughout the\u000a      developed world, with over 2 million patients having received this\u000a      treatment. Anti-TNFα therapy has had a profound impact on the quality of\u000a      life of patients with rheumatoid arthritis. It is capable of not only\u000a      controlling symptoms such as pain and stiffness, it can also protect\u000a      joints from the structural damage which leads to disability. This has also\u000a      prompted the successful use of anti-TNFα therapy in a number of other\u000a      immune-inflammatory diseases, such as juvenile rheumatoid arthritis,\u000a      ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative\u000a      colitis, and psoriasis. One study on the effects of anti-TNFα therapy in\u000a      patients with Crohn's disease showed that it significantly improved the\u000a      quality of life of patients, by increasing their ability to work and\u000a      participate in leisure activities, decreasing fatigue, depression, and\u000a      anger7. In addition, whilst TNF inhibition in established\u000a      disease does not result in cure, evidence is emerging that commencing\u000a      treatment during early disease can result in drug-free remission8.\u000a      The British Society of Rheumatology issued guidelines on the use of\u000a      anti-TNFα inhibitors in rheumatoid arthritis in 2001, and the National\u000a      Institute for Health and Clinical Excellence endorsed the therapy in 20029.\u000a      The combination of an anti-TNFα agent with methotrexate remains\u000a      unsurpassed in reducing the signs and symptoms of rheumatoid arthritis and\u000a      in improving joint destruction10. Current UK guidelines also\u000a      address the optimal use of biologics and disease modifying antirheumatic\u000a      drugs (including methotrexate) for the management of rheumatoid arthritis11,\u000a        12. The 2010 European League Against Rheumatism guidelines for the\u000a      management of rheumatoid arthritis recognise the importance of early\u000a      introduction of biologic TNFα inhibitors in patients failing to reach a\u000a      treatment target of remission or low disease activity on conventional,\u000a      non-biologic synthetic DMARDs13. Anti-TNFα therapy is the\u000a      recommended first line treatment, and if therapeutic response is not\u000a      achieved within 3-6 months, the guidelines recommend a trial of either a\u000a      second anti-TNF agent or a biologic of an alternative mechanism of action13.\u000a    The development of anti-TNFα inhibitors by the Kennedy Institute has had\u000a      a major impact on the pharmaceutical industry. Sales of the five licensed\u000a      anti-TNFα inhibitors (Key Patents: US App 08\/446,674 \/ 20030064070A1; US\u000a      App 20020136723A1; US App 20020010180A1) for all indications reached\u000a      US$24.4 billion in 201114, most of which was used for the\u000a      treatment of rheumatoid arthritis. Interest in the therapeutic use of\u000a      biologics has blossomed since their discovery, with monoclonal antibodies\u000a      making up around one-third of drugs in the sector, essentially all for\u000a      chronic disease. High unit production costs of monoclonal antibodies are\u000a      falling as their use grows. New products are now also being launched,\u000a      including generic versions of the top selling antibodies as they lose\u000a      patent protection, which should eventually benefit patients and society.\u000a      It is predicted that by 2014, three of the four top drugs sold worldwide\u000a      will be anti-TNFs15, while the top 5 will be biologics,\u000a      monoclonal antibodies and antibody like fusion proteins. This shows the\u000a      outstanding impact of this research on the field of therapeutics15.\u000a    ","ImpactSummary":"\u000a    Rheumatoid arthritis is a debilitating inflammatory condition, affecting\u000a      around 500,000 people in the UK and around 0.5-1% of the adult population\u000a      worldwide. Using novel techniques to study human synovium, Professor Sir\u000a      Marc Feldmann and Professor Sir Ravinder Maini from the Kennedy Institute\u000a      of Rheumatology identified a therapeutic target, TNFα, for treatment of\u000a      rheumatoid arthritis. Following successful clinical trials, showing the\u000a      safety and effectiveness of this new target, anti-TNFα antibodies have now\u000a      become the gold standard treatment for severe rheumatoid arthritis\u000a      worldwide. In addition to dramatically impacting patient care, anti-TNFα\u000a      antibodies represent the largest group of therapies against rheumatoid\u000a      arthritis on the market, with annual sales currently exceeding US$24.4\u000a      billion.\u000a    ","ImpactType":"Economic","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Bottazzo G.F., Hanafusa T., Pujol-Borrell R., Feldmann M. Role of\u000a      aberrant HLA-DR expression and antigen presentation in the induction of\u000a      endocrine autoimmunity. Lancet 322 (8359):1115-9 (1983). http:\/\/dx.doi.org\/10.1016\/S0140-6736(83)90629-3\u000a      First< conception of hypothesis that antigen presentation and its\u000a          regulation by cytokines< could be important in the pathogenesis of\u000a          autoimmunity.\u000a    \u000a\u000a2. Brennan F.M., Chantry D., Jackson A., Maini R.N., Feldmann M.\u000a      Inhibitory effect of TNFα antibodies on synovial cell interleukin-1\u000a      production in rheumatoid arthritis. Lancet 334(8657):244-247\u000a      (1989). http:\/\/dx.doi.org\/10.1016\/S0140-6736(89)90430-3,\u000a      First demonstration that TNFα was a therapeutic target, as blocking\u000a          TNF also blocked other proinflammatory cytokines, IL-1 in this case.\u000a    \u000a\u000a3. Maini R.N. et al.Therapeutic efficacy of multiple intravenous\u000a      infusions of anti-tumor necrosis factor a monoclonal antibody combined\u000a      with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis\u000a       Rheum 41:1552-63 (1998). doi:10.1002\/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W.\u000a\u0009   Paper reporting follow-up randomised controlled trial, which combined the use of\u000a          methotrexate with infliximab.\u000a    \u000a\u000a4. Maini R. et al. Infliximab (chimeric anti-tumour necrosis factor a\u000a      monoclonal antibody) versus placebo in rheumatoid arthritis patients\u000a      receiving concomitant methotrexate: a randomised phase III trial. ATTRACT\u000a      Study Group. Lancet 354(9194):1932-39 (1999).\u000a      doi:10.1016\/S0140-6736(99)05246-0. Reporting findings from\u000a          additional clinical studies, showing biologic TNFα inhibition plus\u000a          methotrexate inhibits structural joint damage.\u000a    \u000a\u000a5. Taylor P.C. et alReduction of chemokine levels and leukocyte traffic\u000a      to joints by tumor necrosis factor alpha blockade in patients with\u000a      rheumatoid arthritis. Arthritis Rheum 43:38-47 (2000).\u000a      doi:10.1002\/1529-0131(200001)43:1<38::AID-ANR6>3.0.CO;2-L. Paper\u000a      reporting that TNFα regulates inflammatory cell migration to joints via\u000a          modulation of chemokines, adhesion molecules, and joint vascularity.\u000a    \u000a\u000a6. Taylor P.C. et al. Comparison of ultrasonographic assessment of\u000a      synovitis and joint vascularity with radiographic evaluation in a\u000a      randomized, placebo-controlled study of infliximab therapy in early\u000a      rheumatoid arthritis. Arthritis Rheum 50:1107-16 (2004).\u000a      doi:10.1002\/art.20123. Paper reporting a follow-up study, which\u000a          demonstrated that TNFα regulates inflammatory cell migration to joints\u000a          via modulation of chemokines, adhesion molecules, and joint\u000a          vascularity.\u000a    \u000aThis research was initially funded by the Nuffield Foundation, the\u000a      Medical Research Council, and the Wellcome Trust. Over the years the major\u000a      funder for non-clinical has been Arthritis Research UK, and for clinical\u000a      Centocor, Inc.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    \u000a      Lichtenstein, G. R., Bala, M., Han, C., DeWoody, K. & Schaible, T.\u000a        Infliximab improves quality of life in patients with Crohn's disease. Inflamm\u000a          Bowel Dis 8, 237-243 (2002) DOI:\u000a        10.1097\/00054725-200207000-00001 Paper reporting the impacts of\u000a            anti-TNFα therapy on the quality of life of patients with Crohn's\u000a            disease.\u000a\u000a      van der Kooij, S.M. et al.Drug-free remission, functioning and\u000a        radiographic damage after 4 years of response-driven treatment in\u000a        patients with recent-onset rheumatoid arthritis. Ann Rheum Dis.\u000a        68:914-21 (2009). doi:10.1136\/ard.2008.092254 Paper\u000a            reporting evidence that TNF treatment during early disease can\u000a            result in drug-free remission.\u000a\u000a      National Institute for Health and Clinical Excellence. Rheumatoid\u000a        arthritis — etanercept and infliximab (NICE technology appraisal\u000a          guidance TA36) issued 2002.\u000a        http:\/\/guidance.nice.org.uk\/TA36\u000a        [Accessed 2013] Original guidance endorsing the use of TNFα\u000a            inhibitors in rheumatoid arthritis. This guidance has been\u000a            superseded by Reference 11.\u000a\u000a      Taylor, P.C., Feldmann, M. Anti-TNF biologic agents: still the therapy\u000a        of choice for rheumatoid arthritis. Nat Rev Rheumatol 5:578-82\u000a        (2009). doi:10.1038\/nrrheum.2009.181 Review reporting that the\u000a            combination of an anti-TNFα agent with methotrexate remains the\u000a            therapy of choice to reduce the signs and symptoms of rheumatoid\u000a            arthritis.\u000a\u000a      National Institute for Health and Clinical Excellence. [Guidance on\u000a        TNF inhibitors in RA (TA130, TA186, TA195) issued 2007 and 2010] http:\/\/guidance.nice.org.uk\/TA\/WaveR\/61\u000a        Current NICE technology appraisal guidance outlining the optimal\u000a            use of biologics, and disease modifying antirheumatic drugs, for the\u000a            management of rheumatoid arthritis.\u000a\u000a      British Society for Rheumatology and British Health Professionals in\u000a        Rheumatology guideline for the management of rheumatoid arthritis (after\u000a        the first 2 years) (2009) http:\/\/www.rheumatology.org.uk\/includes\/documents\/cm_docs\/2009\/m\/management_of_rh\u000a          eumatoid_arthritis_first_2_years.pdf. Updated clinical\u000a            guidelines outlining the optimal use of biologics, and disease\u000a            modifying antirheumatic drugs, for the management of rheumatoid\u000a            arthritis.\u000a\u000a      Smolen J.S. et al. EULAR recommendations for the management of\u000a        rheumatoid arthritis with synthetic and biological disease-modifying\u000a        antirheumatic drugs. Ann Rheum Dis 69(6):964-975 (2010).\u000a        doi: 10.1136\/ard.2009.126532 Clinical guidelines for the\u000a            management of rheumatoid arthritis, which recognise the importance\u000a            of the early introduction of biologic TNFα inhibitors for patients\u000a            failing to reach a treatment target of remission with DMARD drugs.\u000a\u000a      R&D Pipeline News Apr 26 2012. Special Edn 1. Top 30 Biologics\u000a        2011.\u000a        \u000a          http:\/\/www.pipelinereview.com\/index.php\/2012042647751\/FREE-Reports\/TOP-30-\u000a          Biologics-2011.html. (2013). Review outlining sales figures\u000a            and commercial outcomes of the research.\u000a\u000a      Merck Research Laboratories. Slide from Senior Vice President, MRL\u000a        Franchise Head, Respiratory and Immunology. Email including data from\u000a        EvaluatePharma received 27th June 2012 (available on\u000a        request).\u000a\u0009\u0009\u000a\u0009\u0009\u000a        \u000a        \u000a    ","Title":"\u000a    REVOLUTIONISING THE TREATMENT OF RHEUMATOID ARTHRITIS\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Since the late 1980s disease-modifying antirheumatic drugs (a term used\u000a      to describe several medications, which reduce the rate of damage to bone\u000a      and cartilage) have been widely used to decrease disease activity and\u000a      prevent joint damage in patients with rheumatoid arthritis. However, many\u000a      of these drugs have been known to cause serious side effects, such as low\u000a      white blood cell counts and liver damage. After testing his hypothesis\u000a      that antigen presentation and cytokines were important in autoimmunity1\u000a      Professor Sir Marc Feldmann first identified tumour necrosis factor alpha\u000a      (TNFα) as a key therapeutic target for rheumatoid arthritis in 19832.\u000a      In 1992, Professor Feldmann, his colleague Professor Maini, and their team\u000a      embarked on a number of significant studies and clinical trials, using\u000a      monoclonal antibodies against TNFα. These trials showed that inhibition of\u000a      TNFα was safe and rapidly effective, and led to the development and\u000a      commercialisation of anti-TNFα as a treatment for rheumatoid arthritis,\u000a      first approved in 1998 in the US.\u000a    The first clinical study, performed at Charing Cross Hospital in 1993,\u000a      enrolled 20 patients who had previously shown resistance to all existing\u000a      treatments. After giving them an infusion of cA2, a monoclonal antibody to\u000a      TNFα, now termed \"Infliximab\", patients experienced a dramatic improvement\u000a      in their symptoms and signs. These results led to a randomised\u000a      placebo-controlled trial in collaboration with three other European\u000a      centres. The response rate with the highest dose of infliximab was 79% at\u000a      4 weeks in comparison to 8% with placebo. The success of repeated\u000a      treatments was then demonstrated in a smaller study, however, the duration\u000a      of response diminished, partly due to an immune response against the TNFα\u000a      antibody itself. Further studies using a mouse model of rheumatoid\u000a      arthritis indicated that the combination of an anti-TNF monoclonal\u000a      antibody with therapy targeting T cells might improve the effectiveness.\u000a      This finding led to the combined use of methotrexate (already established\u000a      in the treatment of rheumatoid arthritis) with infliximab, in the next\u000a      randomised controlled trial3. The demonstration of synergy with\u000a      this combination therapy, without increased toxicity, set the gold\u000a      standard for pharmacological management of rheumatoid arthritis.\u000a      Additional clinical studies led by the Kennedy Institute showed that\u000a      biologic TNFα inhibition plus methotrexate markedly inhibits the\u000a      structural joint damage previously thought to be an irreversible feature\u000a      of rheumatoid arthritis4. In addition, follow-up studies\u000a      demonstrated that TNFα regulates inflammatory cell migration to joints via\u000a      modulation of chemokines, adhesion molecules, and joint vascularity5,6.\u000a    The primary research underpinning the impact of anti-TNFα took place at\u000a      the Kennedy Research Institute between 1993 and 1998. While the Institute\u000a      was then based at Imperial College London between 2000 and 2011, the\u000a      Kennedy Research Institute remained a separate, freestanding division and\u000a      in August 2011 the Kennedy Institute was fully incorporated into the\u000a      University of Oxford. Professor Sir Marc Feldmann continues to lead\u000a      research into the role of cytokines in disease.\u000a    "},{"CaseStudyId":"3901","Continent":[{"GeoNamesId":"6255146","Name":"Africa"}],"Country":[{"GeoNamesId":"3355338","Name":"Namibia"},{"GeoNamesId":"192950","Name":"Kenya"},{"GeoNamesId":"51537","Name":"Somalia"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    By providing key data to the World Health Organization, national\u000a      governments, world leaders, and the general public, the University of\u000a      Oxford's MPHD has made a significant contribution to the global fight\u000a      against malaria. MPHD's research has led to:\u000a    The Malaria Atlas Project\u000a    The Malaria Atlas Project is an interactive and globally accessible\u000a      online mapping tool, which publishes MPHD's epidemiological, geographic\u000a      and demographic data. The Malaria Atlas Project receives an average of\u000a      70,000 hits from around 216 nations every year (including all malaria\u000a      endemic countries in the world). MPHD work in collaboration with national\u000a      governments in Africa to develop Malaria Atlas Project maps specific to\u000a      the needs of each nation. A recent Malaria Programme Review conducted in\u000a      Namibia relied on the Malaria Atlas Project's \"Malaria Risk in Namibia,\u000a      2009\" map7 to provide updated data on transmission risk in\u000a      Namibia8. Malaria Atlas Project maps4,5 have also\u000a      been used by African nations to seek funding for malaria aid and\u000a      interventions, including Kenya and Somalia's successful proposals to the\u000a      Global Fund in August 20109,10.\u000a    Changes in WHO Policy and Practice\u000a      The research on the distribution of impregnated nets carried out by MPHD\u000a      in Kenya3 led directly to changes in WHO policy. Following new\u000a      guidance released in 2007, the WHO now recommends that insecticidal nets\u000a      be distributed free, or highly subsidised, to all members of affected\u000a      communities11. In a press release distributed by the WHO, Arata\u000a      Kochi, head of the WHO's Global Malaria Programme made the following\u000a      statement regarding MPHD's research: \"This data from Kenya ends the\u000a        debate about how to deliver long-lasting insecticidal nets. No longer\u000a        should the safety and well-being of your family be based upon whether\u000a        you are rich or poor. When insecticide treated mosquito nets are easily\u000a        available for every person, young or old, malaria is reduced\"11.\u000a    This policy change, leading to the scaled-up delivery of insecticide\u000a      treated bed nets, has significantly reduced malaria-related child\u000a      mortality among African communities12. A study from the World\u000a      Health Organization, published in 2011, showed that the rapid increase in\u000a      the use of ITNs in Zanzibar led to a reduction in mortality of 75% within\u000a      5 years of scaled-up intervention12. This paper showed that\u000a      intensified malaria control (as recommended by MPHD) has, and will,\u000a      significantly contribute to the success of the WHO's Millennium\u000a        Development Goal 4 target, to reduce mortality in children under the\u000a      age of five by two-thirds between 1990 and 201512.\u000a    Improved Global Resource Allocation and Funding\u000a      By providing new estimates showing the global burden of malaria, research\u000a      undertaken by MPHD has been critical for funding and international\u000a      planning of resources required for malaria control. MPHD's epidemiological\u000a      studies and maps have been used by the UK Department for International\u000a      Development13, the World Bank14, and the\u000a      WHO Roll Back Malaria Partnership15. The following statement\u000a      from Alastair Robb, the UK Department for International Development's\u000a      Senior Health Adviser and Regional Malaria Adviser for Africa,\u000a      encapsulates the broad impact of MPHD's work on funding, national\u000a      planning, policy and risk reduction in Africa13: \"The work\u000a        of Snow and the Malaria Public Health and Epidemiology Group has been\u000a        very influential. It has had an impact on decisions of donors, national\u000a        programmes and other researchers. They have highlighted the importance\u000a        of knowing more about malaria epidemiology, so that national policies\u000a        are based on evidence. Their work is already being used to help target\u000a        money so that it will achieve maximal benefit. This is coming at an\u000a        important time in malaria control. DFID has been influenced by the\u000a        approach taken by Snow and his team. Recent conversations with WHO, RBM,\u000a        US PMI, Gates, CDC and Swiss Tropical Institute have all referenced the\u000a        work of Snow's team in helping them refine their thinking from a blue\u000a        print approach to malaria to a more nuanced approach\"13.\u000a    Resources provided by the WHO's Roll Back Malaria Partnership have also\u000a      been guided by MPHD's data. The following `Letter Of Recommendation' from\u000a      Dr Thomas Teuscher, Executive Director for the WHO Roll Back Malaria\u000a      Partnership, emphasises the importance of MPHD's research in this field15.\u000a      \"The KEMRI-University of Oxford-Wellcome Trust Collaborative Program\u000a        under your leadership has been one of the principal providers of\u000a        scientific evidence that operationally guides the malaria control\u000a        community. Your recent work has supported the targeting of international\u000a        aid in support of malaria control to regions where level of endemicity,\u000a        population at risk and domestic income produce maximum value for money.\u000a        Your continued work on the epidemiology of malaria provides partners\u000a        like RBM with essential guidance on global resource allocation for\u000a        malaria control\"15.\u000a    ","ImpactSummary":"\u000a    In spite of recent reductions in transmission, malaria continues to kill\u000a      over half a million people annually. To assist in fighting the global\u000a      burden of malaria, Kenya-based Oxford research team, the Malaria Public\u000a      Health Department (MPHD) has spent the past decade analysing malaria risk,\u000a      interventions, and control methods, to better define and target malaria.\u000a      This research has been used to inform local governments, the World Health\u000a      Organization (WHO), and international funding organisations about malaria\u000a      risk, interventions and control methods to better define and target\u000a      malaria.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1273874","Name":"Cochin"}],"References":"\u000a    \u000a1. Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I.\u000a      The global distribution of clinical episodes of P. falciparum\u000a      malaria. Nature 434, 214-217 (2005). Primary paper\u000a        outlining global burden of malaria.\u000a    \u000a\u000a2. Hay, S. I. et al. A world malaria map: P. falciparum\u000a      endemicity in 2007. PLoS Med. 6, e1000048 (2009). doi:\u000a      10.1371\/journal.pmed.1000048. Paper outlining transmission risk\u000a        of malaria worldwide.\u000a    \u000a\u000a3. Noor, A. M., Amin, A. A., Akhwale, W. S. & Snow, R. W. Increasing\u000a      coverage and decreasing inequity in insecticide-treated bed net use among\u000a      rural Kenyan children. PLoS Med. 4, e255 (2007). Paper\u000a          reporting the effect of free provision of ITNs in Kenya.\u000a    \u000a\u000a4. Noor, A. M. et al. Spatial prediction of P. falciparum\u000a      prevalence in Somalia. Malar. J. 7, 159 (2008). doi:\u000a      10.1186\/1475-2875-7-159. Study showing geographical and epidemiological\u000a          distribution of malaria in Somalia.\u000a    \u000a\u000a5. Noor, A. M. et al. The risks of malaria infection in Kenya in\u000a      2009. BMC Infect. Dis. 9, 180 (2009). doi:\u000a      10.1186\/1471-2334-9-180. Study showing geographical and epidemiological\u000a          distribution of malaria infection in Kenya.\u000a    \u000a\u000a6. Snow, R. W., Okiro, E. A., Gething, P. W., Atun, R. & Hay, S. I.\u000a      Equity and adequacy of international donor assistance for global malaria\u000a      control: an analysis of populations at risk and external funding\u000a      commitments. Lancet 376, 1409-1416 (2010). doi:\u000a      10.1016\/S0140- 6736(10)61340-2. Paper showing the need for donor\u000a          assistance in malaria affected areas.\u000a    \u000aThis research was funded by the Wellcome Trust.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    \u000a      Namibia - Malaria risk. Malaria Atlas Project at http:\/\/www.map.ox.ac.uk\/explore\/countries\/nam\/\u000a        (Accessed 2013). Malaria Atlas Project (MAP) website.\u000a\u000a      Republic of Namibia Ministry of Health and Social Services. Namibia\u000a        Malaria Program Performance Review. Draft report. National Vector-Borne\u000a        Diseases Control Program. Directorate of Special Programs Ministry of\u000a        Health and Social Services, July 2010 (available on request). Namibia\u000a            Malaria Program Performance Review including Malaria Atlas Project\u000a            map of Namibia from 2009.\u000a\u000a      The Global Fund. Proposal Form - Round 10 Single Country Applicant\u000a        Sections 1-2. Kenya, 20 August 2010 (available on request). Kenya\u000a            Global Fund Application including Malaria Atlas Project maps\u000a            and MPHEG data.\u000a\u000a      The Global Fund. Proposal Form - Round 10 Single Country Applicant\u000a        Sections 1-2. Somalia, 20 August 2010 (available on request). Somalia\u000a            Global Fund Application including Malaria Atlas Project maps\u000a            and MPHD data.\u000a\u000a      WHO releases new guidance on insecticide-treated mosquito nets. World\u000a          Health Organization at\u000a        http:\/\/www.who.int\/mediacentre\/news\/releases\/2007\/pr43\/en\/index.html\u000a        (Accessed 2013). Press release from the World Health Organisation\u000a            outlining changes to policy directly resulting from MPHD's\u000a            research in Kenya.\u000a\u000a      Aregawi, M. W. et al. Reductions in malaria and anaemia case\u000a        and death burden at hospitals following scale-up of malaria control in\u000a        Zanzibar, 1999-2008. Malar. J. 10, 46 (2011). doi:\u000a        10.1186\/1475-2875-10-46. WHO study reporting the reduction in\u000a            child mortality over a five year period in Zanzibar\u000a            hospitals due to scaled-up interventions.\u000a\u000a      Department for International Development. Senior Health Adviser,\u000a        Regional Malaria Adviser for Africa. Statement supporting MPHD work in\u000a        Africa (available on request). Email correspondence from\u000a            Alastair Robb outlining the Department for International Development's\u000a            support for the research carried out by MPHD.\u000a\u000a      World Development Report 2009: Reshaping Economic Geography.\u000a        Washington D.C.: The World Bank: 117. (2009)\u000a        \u000a          http:\/\/www.map.ox.ac.uk\/client_media\/publications\/Hay_et_al_2009a.pdf\u000a        (Accessed 2013). World Development Report from The World Bank,\u000a            using mapping data from the Malaria Atlas Project.\u000a\u000a      World Health Organization. Executive Director for the WHO Roll Back\u000a        Malaria Partnership. Letter of recommendation (available on request). A\u000a            letter of support from Thomas Teuscher, Roll Back Malaria\u000a            (WHO).\u000a\u000a    \u000a    ","Title":"\u000a    KNOWLEDGE IS POWER: INFORMING NATIONAL GOVERNMENTS IN THE GLOBAL FIGHT\u000a        AGAINST MALARIA\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Following the rapid decline of malaria transmission among African nations\u000a      at the turn of the century, it became clear that updated intelligence\u000a      based on sound epidemiological data would play a major role in the\u000a      continued success of the global fight against malaria. Responding to this\u000a      need, Kenya-based University of Oxford Professor Bob Snow established the\u000a      Malaria Public Health Department (MPHD) to undertake the following tasks:\u000a    Geographic analysis of the global burden of malaria\u000a      MPHD published its first pivotal paper in 2005, which showed there was an\u000a      estimated 515 million episodes of clinical P. falciparum malaria\u000a      worldwide in 2002 - higher than that reported by the World Health\u000a      Organization (WHO)1. It also showed Africa as the dominant\u000a      contributor to the global burden of malaria, while highlighting a hidden\u000a      burden in Asia1. In a subsequent paper, MPHD assessed the\u000a      global spatial distribution of P. falciparum malaria. It showed\u000a      that of the 1.38 billion people exposed to stable P. falciparum\u000a      malaria risk worldwide in 2007, 759 million (approximately 55%) lived in\u000a      conditions of very low endemicity with the potential for malaria to be\u000a      eliminated altogether. It also identified that a much more aggressive\u000a      control strategy was required for the 345 million people living in areas\u000a      of high risk2. The quality of the geographical data presented\u000a      in these papers led the University of Oxford to establish the Malaria\u000a      Atlas Project, a continuously updated open access online mapping resource,\u000a      which describes the distribution of malaria in every country around the\u000a      world.\u000a    Provision of evidence-based data on malaria intervention coverage\u000a      Between 2004 and 2006 MPHD undertook a cohort study of 3,700 children aged\u000a      0-4 years in four districts of Kenya (Bondo, Greater Kisii, Kwale, and\u000a      Makueni) to assess the uptake of insecticide treated nets (ITNs), funded\u000a      by the Wellcome Trust and the UK Government's Department for International\u000a      Development. Following the introduction of free ITNs, the prevalence of\u000a      usage rose from 7.1% to 67.3% demonstrating that rapid protection of\u000a      Africa's poorest rural children can be achieved through free mass ITN\u000a      distribution campaigns3.\u000a    Gauge malaria transmission risk among African nations Since the\u000a      establishment of the Malaria Atlas Project, MPHD have used maps to\u000a      visually represent their data in key studies on malaria risk among African\u000a      nations. Such national studies include their work on the spatial\u000a      prediction of P. falciparum prevalence and malaria risk in Somalia\u000a      and Kenya4, 5.\u000a    Guiding global resource allocations for malaria In an analysis of\u000a      the equity and adequacy of international donor assistance for global\u000a      malaria control, MPHD found that the US$4.9 billion spent on malaria\u000a      control worldwide in 2010 was 60% lower than it needed to be for\u000a      comprehensive control. They also found that while some of the countries\u000a      receiving overseas development assistance were able to fund malaria\u000a      control from domestic resources, other countries with the least\u000a      development assistance remained some of the poorest countries in Africa6.\u000a    "},{"CaseStudyId":"3904","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2300660","Name":"Ghana"},{"GeoNamesId":"149590","Name":"Tanzania"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2328926","Name":"Nigeria"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"226074","Name":"Uganda"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"1210997","Name":"Bangladesh"},{"GeoNamesId":"192950","Name":"Kenya"},{"GeoNamesId":"1327865","Name":"Myanmar"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    The existence of fake antimalarial medication has had a devastating\u000d\u000a      effect on malaria-related\u000d\u000a      deaths in highly affected areas. The continued use of counterfeit drugs\u000d\u000a      could lead to advancing\u000d\u000a      drug resistance and loss of efficacy for artemisinin combination\u000d\u000a      therapies, resulting in devastating\u000d\u000a      global outcomes6. Dr Newton's research into the counterfeit\u000d\u000a      drug trade initiated public awareness\u000d\u000a      into this damaging activity and has led to several criminal\u000d\u000a      investigations, arrests of drug traffickers,\u000d\u000a      and further investigation from the World Health Organization (WHO).\u000d\u000a    Response from the World Health Organization\u000d\u000a    In 2005 the WHO launched a rapid alert system, enabling information about\u000d\u000a      counterfeit drugs to be\u000d\u000a      rapidly reported to relevant authorities in participating countries. At\u000d\u000a      the time the alert was rolled out\u000d\u000a      the WHO estimated 10% of all drugs sold globally were counterfeits and\u000d\u000a      that the figure was as high\u000d\u000a      as 25% in developing countries7. The WHO is now investigating\u000d\u000a      the global expansion of this\u000d\u000a      system. In January 2011, the WHO released a report8 surveying\u000d\u000a      the quality of selected antimalarial\u000d\u000a      medicines circulating in six countries of sub-Saharan Africa, referencing\u000d\u000a      Dr Newton's 20011 paper\u000d\u000a      on Fake artesunate in southeast Asia as a primary source, as well\u000d\u000a      as the 2004 paper by Dondorp\u000d\u000a      and Newton2. The information obtained in this report outlined\u000d\u000a      the overall quality of antimalarial\u000d\u000a      medications being distributed in sub-Saharan Africa; this has contributed\u000d\u000a      to the development of\u000d\u000a      regulatory systems and enforcement, improvement in surveillance\u000d\u000a      technology, the introduction of\u000d\u000a      Minilabs, and increased cooperation between national drug regulatory\u000d\u000a      authorities8.\u000d\u000a    Advanced Screening Technology\u000d\u000a    In February 2011 the Global Pharma Health Fund announced they would be\u000d\u000a      establishing 20\u000d\u000a      Minilabs in Nigeria, which will enable efficient and effective\u000d\u000a      identification of counterfeit drugs and\u000d\u000a      low quality medication. They also reported that health organisations and\u000d\u000a      local governments will roll\u000d\u000a      out a total of 420 Minilabs throughout the 70 African, Asian and Latin\u000d\u000a      American regions9.\u000d\u000a    The University of Oxford's underpinning research has provided academic\u000d\u000a      justification for the\u000d\u000a      mPedigree Network (www.mpedigree.net),\u000d\u000a      a Ghana-based organisation empowering African\u000d\u000a      patients and consumers to protect themselves from pharmaceutical\u000d\u000a      counterfeiting. The Network,\u000d\u000a      which connects a number of African countries to a central registry where\u000d\u000a      pedigree information of\u000d\u000a      product brands are stored, allows all patients and consumers to verify the\u000d\u000a      safety and quality of their\u000d\u000a      medicines instantly by using their own (or a shared) mobile phone at no\u000d\u000a      cost, where a mobile\u000d\u000a      signal is available. This technology has since been rolled out for use in\u000d\u000a      Nigeria and Kenya and is\u000d\u000a      now being tested in Uganda, Tanzania, South Africa, India and Bangladesh.\u000d\u000a      Since the\u000d\u000a      establishment of mPedigree in 2007, 6.5 million packs of medication have\u000d\u000a      been tested in various\u000d\u000a      pilots10. \"The problem of counterfeit drugs in Africa came\u000d\u000a        to our attention in 2004. With the help of\u000d\u000a        the Ghana government, local activists, and academics we established a\u000d\u000a        network of people who\u000d\u000a        were committed to creating change. The underpinning research from Dr\u000d\u000a        Newton and his\u000d\u000a        collaborators, not only gave our cause academic credibility; it also\u000d\u000a        gave us a better understanding\u000d\u000a        of the reach and proximity of the problem.\" — mPedigree Network,\u000d\u000a      founder Bright Simons10.\u000d\u000a    Criminal Investigations\u000d\u000a    The University of Oxford's research and its collaboration with other\u000d\u000a      investigators, the WHO, and\u000d\u000a      INTERPOL, has led to the arrest of alleged traders of fake antimalarial\u000d\u000a      drugs in southern China\u000d\u000a      and Burma, and the seizure of a large quantity of drugs in 2006. The\u000d\u000a      suspects from China's\u000d\u000a      Yunnan Province were alleged to have traded 240,000 blister packs of\u000d\u000a      counterfeit artesunate in\u000d\u000a      2006, enough to treat almost a quarter of a million adults over the coming\u000d\u000a      years. Chinese\u000d\u000a      authorities were able to seize 24,000 of these packs before they were\u000d\u000a      distributed, potentially\u000d\u000a      saving the lives of thousands11. In February 2011 a similar\u000d\u000a      operation supported by INTERPOL took\u000d\u000a      place in Ghana, leading to the seizure of thousands of illegal and fake\u000d\u000a      antimalarial drugs and other\u000d\u000a      medications. Initiated by the International Medical Products\u000d\u000a      Anti-Counterfeiting Taskforce\u000d\u000a      (IMPACT) and supported by INTERPOL, Operation Harmattan led to the arrest\u000d\u000a      and prosecution of\u000d\u000a      over 30 counterfeit drug traffickers12.\u000d\u000a    Public Outreach and Media Engagement\u000d\u000a    This research has led to the Worldwide Antimalarial Resistance Network\u000d\u000a      (WWARN) Antimalarial\u000d\u000a      Quality Surveyor, an antimalarial mapping module enabling researchers,\u000d\u000a      government, and the\u000d\u000a      public to access studies on the type of medications on the market, the\u000d\u000a      source of these medications\u000d\u000a      and the quality of antimalarial medicines13. The work of Dr\u000d\u000a      Paul Newton and his collaborators has\u000d\u000a      been widely publicised around the world. As an expert in the field of\u000d\u000a      counterfeit medications, Dr\u000d\u000a      Newton has been quoted and referenced in a number of articles by several\u000d\u000a      world news providers,\u000d\u000a      including The Guardian, BBC News and the New York Times14,15.\u000d\u000a      As a result of this public\u000d\u000a      outreach, Oxford's research into counterfeit medications continues to\u000d\u000a      garner worldwide attention,\u000d\u000a      inspiring ongoing action from global leaders, criminal investigators and\u000d\u000a      international health\u000d\u000a      organisations.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    With over half a million malaria-related deaths every year, the existence\u000d\u000a      of counterfeit antimalarial\u000d\u000a      medication continues to have a devastating effect on malaria-related\u000d\u000a      mortality and morbidity on a\u000d\u000a      global scale. Primary investigations into this murderous trade, led by Dr\u000d\u000a      Paul Newton at the\u000d\u000a      University of Oxford's Centre for Tropical Medicine, have prompted\u000d\u000a      criminal investigations, drug\u000d\u000a      trafficking arrests, intervention from the World Health Organization, and\u000d\u000a      have also led to the\u000d\u000a      establishment of new screening facilities and mobile screening technology\u000d\u000a      in affected areas. This\u000d\u000a      research, and the interventions it has fuelled will save thousands of\u000d\u000a      lives.\u000d\u000a    ","ImpactType":"Societal","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1785694","Name":"Yunnan Sheng"},{"GeoNamesId":"5128638","Name":"New York"}],"References":"\u000d\u000a    \u000a1. Newton, P. et al. Fake artesunate in southeast Asia. Lancet\u000d\u000a      357, 1948-1950 (2001).\u000d\u000a      Primary Paper from Dr Newton investigating counterfeit drugs in\u000d\u000a          Southeast Asia.\u000d\u000a    \u000a\u000a2. Dondorp, A. M. et al. Fake antimalarials in Southeast Asia are\u000d\u000a      a major impediment to\u000d\u000a      malaria control: multinational cross-sectional survey on the prevalence of\u000d\u000a      fake antimalarials.\u000d\u000a      Trop. Med. Int. Health 9, 1241-1246 (2004). Subsequent\u000d\u000a          Paper from Oxford's Professor\u000d\u000a          Dondorp and Dr Newton investigating prevalence of counterfeit drugs in\u000d\u000a          Southeast\u000d\u000a          Asia.\u000d\u000a    \u000a\u000a3. Newton, P. N. et al. A collaborative epidemiological\u000d\u000a      investigation into the criminal fake\u000d\u000a      artesunate trade in South East Asia. PLoS Med. 5, e32\u000d\u000a      (2008). doi:\u000d\u000a      10.1371\/journal.pmed.0050032. Collaborative investigation into\u000d\u000a          counterfeit drug\u000d\u000a          trafficking in Southeast Asia.\u000d\u000a    \u000a\u000a4. Newton, P. N. et al. Poor quality vital antimalarials in\u000d\u000a      Africa — an urgent neglected public\u000d\u000a      health priority. Malar. J. 10, 352 (2011). doi:\u000d\u000a      10.1186\/1475-2875-10-352. Paper\u000d\u000a          investigating counterfeit antimalarial drug trade in Africa.\u000d\u000a    \u000a\u000a5. Nayyar, G. M. L., Breman, J. G., Newton, P. N. & Herrington, J.\u000d\u000a      Poor-quality\u000d\u000a      antimalarial drugs in southeast Asia and sub-Saharan Africa. Lancet\u000d\u000a        Infect Dis. 12, 488-496\u000d\u000a      (2012). doi: 10.1016\/S1473-3099(12)70064-6. Collaborative paper\u000d\u000a          reviewing poor-quality\u000d\u000a          antimalarial medication in Southeast Asia and sub-Saharan Africa.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000d\u000a      \u000d\u000a    Newton, P. N., Green, M. D. & Fernández, F. M. Impact of\u000d\u000a      poor-quality medicines in the\u000d\u000a      `developing' world. Trends Pharmacol. Sci. 31, 99-101\u000d\u000a      (2010). doi:\u000d\u000a      10.1016\/j.tips.2009.11.005. Review from Dr Paul Newton and\u000d\u000a          colleagues outlining the\u000d\u000a          global impact of fake antimalarial medication.\u000a\u000d\u000a    Parry, J. WHO combats counterfeit malaria drugs in Asia. BMJ 330,\u000d\u000a      1044 (2005). An\u000d\u000a          independent paper reviewing the World Health Organization's\u000d\u000a          interventions on fake\u000d\u000a          drug trafficking.\u000a\u000d\u000a    Survey of the quality of selected antimalarial medicines circulating in\u000d\u000a      six countries of sub-Saharan\u000d\u000a      Africa. January 2011. World Health Organization at\u000d\u000a      http:\/\/www.who.int\/medicines\/publications\/WHO_QAMSA_report.pdf\u000d\u000a      (Accessed 2013).\u000d\u000a      Report on the World Health Organization's survey into the quality of\u000d\u000a          antimalarial\u000d\u000a          medication in sub-Saharan Africa. This report refers to two of Dr\u000d\u000a          Newton's papers as\u000d\u000a          primary sources.\u000a\u000d\u000a    Latest news. GPHF Global Pharma Health Fund E.V. at\u000d\u000a      http:\/\/www.gphf.org\/web\/en\/news\/meldungen.htm\u000d\u000a      (Accessed 2013). News items from the\u000d\u000a          Global Pharma Health Fund website, listing information about the\u000d\u000a          establishment of\u000d\u000a          Minilabs in Ghana.\u000a\u000d\u000a    \u000amPedigree Network Website\u000d\u000a      http:\/\/mpedigree.net\/mpedigree\/index.php?option=com_content&view=article&id=46&Itemid\u000d\u000a        =53 (Accessed 2013). mPedigree Founder Statement (available on\u000d\u000a      request).\u000d\u000a      mPedigree Network information and statement from Mr Bright Simons.\u000a\u000d\u000a    Fake antimalarial drugs analysis highlights threat to global health. Wellcome\u000d\u000a        Trust at\u000d\u000a      http:\/\/www.wellcome.ac.uk\/News\/Media-office\/Press-releases\/2008\/WTX043187.htm\u000d\u000a      (Accessed 2013). Press Release from the Wellcome Trust, information\u000d\u000a          about criminal\u000d\u000a          investigation into counterfeit drug trafficking.\u000a\u000d\u000a    Ghana INTERPOL-supported operation leads to counterfeit medical products\u000d\u000a      seizures.\u000d\u000a      INTERPOL at http:\/\/www.interpol.int\/News-and-media\/News-media-releases\/2011\/N20110214\u000d\u000a      (Accessed 2013). Press Release from INTERPOL including\u000d\u000a          information about Operation Harmattan.\u000a\u000d\u000a    WWARN Antimalarial Quality Surveyor. Worldwide Antimalarial\u000d\u000a        Resistance Network\u000d\u000a        (WWARN) at http:\/\/www.wwarn.org\/resistance\/surveyors\/antimalarial-quality\u000d\u000a      (Accessed\u000d\u000a      2013). Worldwide Antimalarial Resistance Network (WWARN)\u000d\u000a          Antimalarial Quality\u000d\u000a          Surveyor and interactive map.\u000a\u000d\u000a    Fake and poor quality malaria drugs risk crisis in Africa, warn\u000d\u000a      scientists. The Guardian at\u000d\u000a      http:\/\/www.guardian.co.uk\/society\/2012\/jan\/16\/fake-poor-quality-malaria-drugs-africa\u000d\u000a      (Accessed 2013). Article from The Guardian featuring commentary\u000d\u000a          from Dr Paul\u000d\u000a          Newton.\u000a\u000d\u000a    Malaria: Fake and Substandard Drugs Grow as Threat to Fight Disease. The\u000d\u000a        New York\u000d\u000a        Times at http:\/\/www.nytimes.com\/2012\/05\/22\/health\/policy\/fake-and-substandard-drugs-grow-as-threat-to-fight-malaria.html?_r=2\u000d\u000a      (Accessed 2013). Article from The New York\u000d\u000a          Times based on Dr Newton's collaboration with the National Institute\u000d\u000a          of Health into\u000d\u000a          the poor quality of drugs in Asia and Africa. Article published May 21st\u000d\u000a      2012.\u000a\u000d\u000a\u0009  \u000d\u000a    ","Title":"\u000d\u000a    EXPOSING A MURDEROUS TRADE\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The introduction of highly effective artemisinin combination drug\u000d\u000a      therapies over the past decade\u000d\u000a      has significantly reduced malaria transmission across Africa, with a 25%\u000d\u000a      global reduction in\u000d\u000a      malaria mortality since 2000. In spite of this, the 2011 \"World Malaria\u000d\u000a      Report\" estimated there were\u000d\u000a      655,000 malaria-related deaths in 2010, with the majority of these\u000d\u000a      occurring among children in\u000d\u000a      Africa. One such reason for this continued death toll is the existence of\u000d\u000a      fake antimalarial drugs.\u000d\u000a    Concerned about the public health impact of counterfeit antimalarial\u000d\u000a      drugs, a team of researchers\u000d\u000a      at the University of Oxford's Centre for Tropical Medicine, based in\u000d\u000a      Bangkok, Thailand, set out to\u000d\u000a      investigate this damaging trade as far back as 1999.\u000d\u000a    In a primary study led by Dr Paul Newton at the University of Oxford's\u000d\u000a      Centre for Tropical\u000d\u000a      Medicine, researchers were the first to identify the characteristics and\u000d\u000a      to describe the epidemiology\u000d\u000a      of fake antimalarial drugs in Southeast Asia. After analysing 104 samples\u000d\u000a      of artesunate-based\u000d\u000a      medication from stores and pharmacies in Cambodia, Laos, Myanmar (Burma),\u000d\u000a      Thailand, and\u000d\u000a      Vietnam, they found that 38% of the drugs did not contain any detectable\u000d\u000a      artesunate. They also\u000d\u000a      noted that the cost and physical appearance of the fake packaging made the\u000d\u000a      counterfeits difficult to\u000d\u000a      distinguish from genuine drugs. This discovery shed light on the illicit\u000d\u000a      trade of counterfeit\u000d\u000a      antimalarials, prompting further investigation into the problem1,2.\u000d\u000a      In a collaborative study led by Dr\u000d\u000a      Newton and an international multidisciplinary group, supported by the\u000d\u000a      International Criminal Police\u000d\u000a      Organization (INTERPOL) and the Western Pacific World Health Organization\u000d\u000a      Regional Office,\u000d\u000a      Oxford researchers aimed to determine the source of counterfeit drugs in\u000d\u000a      Southeast Asia. The\u000d\u000a      research team confirmed that the 49.9% of drugs thought to be counterfeit\u000d\u000a      (on the basis of\u000d\u000a      packaging), contained no, or very small quantities of artesunate; they\u000d\u000a      also found 16 different types\u000d\u000a      of counterfeit packaging of escalating sophistication. In a chemical\u000d\u000a      analysis, Oxford researchers\u000d\u000a      also demonstrated that many of the fake drugs identified contained a\u000d\u000a      variety of banned\u000d\u000a      pharmaceuticals, such as safrole (a carcinogen), a raw material used in\u000d\u000a      the street drug\u000d\u000a      methylenedioxymethamphetamine, also known as \"ecstasy\". This suggested\u000d\u000a      that manufacturers of\u000d\u000a      narcotics were involved in making counterfeit antimalarials. In a novel\u000d\u000a      analysis of pollen within the\u000d\u000a      tablets, to obtain evidence pertaining to the flora around the\u000d\u000a      manufacturing site, as well as detailed\u000d\u000a      chemical analysis of a rare type of chalk in the counterfeits, research\u000d\u000a      data strongly suggested that\u000d\u000a      some of the counterfeit artesunate was manufactured in southern China.\u000d\u000a      This prompted a criminal\u000d\u000a      investigation through INTERPOL, by the Chinese government3 and\u000d\u000a      the (then) Burmese\u000d\u000a      Government, resulting in the interruption of the counterfeit artesunate\u000d\u000a      trade route.\u000d\u000a    Following increasing reports of poor quality antimalarials in Africa, the\u000d\u000a      University of Oxford\u000d\u000a      scientists led a team of researchers in collecting seven artemisinin\u000d\u000a      derivative monotherapies, ACT,\u000d\u000a      and halofantrine malarial medications of suspicious quality in eleven\u000d\u000a      African countries, between\u000d\u000a      2002 and 2010. This research confirmed that the production of harmful\u000d\u000a      antimalarial counterfeit\u000d\u000a      drugs had spread to Africa4.\u000d\u000a    The University of Oxford's most recent collaboration with the National\u000d\u000a      Institute of Health (United\u000d\u000a      States) indicated that one-third of antimalarial drugs tested from the\u000d\u000a      private sector in Southeast\u000d\u000a      Asia and sub-Saharan Africa are now fake, this particular paper has gained\u000d\u000a      worldwide media\u000d\u000a      attention5.\u000d\u000a    "},{"CaseStudyId":"3906","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    One of just two interferon-gamma release assays (IGRAs) recommended by\u000d\u000a      the Centers for Disease Control and Prevention6 the T-SPOT test\u000d\u000a      has had a significant impact on the accuracy of TB diagnosis worldwide\u000d\u000a      since its commercial release in 2004.\u000d\u000a    Accurate Diagnosis:\u000d\u000a    The ability to diagnose TB more rapidly, specifically and sensitively\u000d\u000a      than the alternative TST method is a major impact of the T-SPOT test1\u000d\u000a      7 8. The TST method of diagnosis involves injecting an extract\u000d\u000a      of TB into a patients skin, waiting two to three days2, then\u000d\u000a      examining the skin for lesions — with an inflamed lesion indicating\u000d\u000a      exposure to TB. Diagnosing TB with the T-SPOT test is faster, easier to\u000d\u000a      administer, and easier to read than the TST method7.\u000d\u000a    By taking a small blood sample from the patient, the T-SPOT test can give\u000d\u000a      a result in under 24 hours1. The T-SPOT test is also easy to\u000d\u000a      read and, because it measures cell numbers, it is highly quantitative. In\u000d\u000a      contrast, the TST test is frequently difficult to interpret, particularly\u000d\u000a      in patients where the swelling is difficult to read, such as children with\u000d\u000a      sensitive skin9 or patients with conditions like rheumatic\u000d\u000a      disease (which can cause skin swelling)10. Interpretation of\u000d\u000a      the TST test is a significant issue, particularly for doctors in developed\u000d\u000a      countries, who are less experienced in examining the skin lesions produced\u000d\u000a      by the TST method. By using proteins that are specific to TB infection,\u000d\u000a      rather than BCG, the T-SPOT test is more effective than the TST method in\u000d\u000a      distinguishing between patients infected with TB and those who have simply\u000d\u000a      been vaccinated 1,11. The T-SPOT test is also far more\u000d\u000a      accurate than the TST method in identifying individuals who have latent TB\u000d\u000a      infection5,12 .\u000d\u000a    Policy and Guidelines:\u000d\u000a    The commercial availability and superior diagnostic value of the T-SPOT\u000d\u000a      test has had an impact on global health policy and guidelines. Since its\u000d\u000a      commercial approval in 2004 the T-SPOT test has been included in TB\u000d\u000a      control guidelines in the USA (Centers for Disease Control and Prevention)\u000d\u000a      and Europe, with more than 20 countries now recommending the T-SPOT test\u000d\u000a      to diagnose and screen patients for TB infection6 13. In 2011\u000d\u000a      the UK National Institute for Health and Clinical\u000d\u000a    Excellence (NICE) updated their guidelines on control and prevention,\u000d\u000a      recommending interferon- gamma release assays, such as the T-SPOT test,\u000d\u000a      for use in a number of diagnostic situations14, including:\u000d\u000a    \u000d\u000a       In a TB outbreak, when large numbers of individuals need to be\u000d\u000a        screened;\u000d\u000a       For migrants between 16 and 34 years of age, coming from high\u000d\u000a        incidence countries;\u000d\u000a       Patients who suffer from immunodeficiency;\u000d\u000a       NHS employees who have had contact with patients in a high incidence\u000d\u000a        setting; and\u000d\u000a       For individuals who have been vaccinated against TB, and those who\u000d\u000a        have tested positive in a TST test.\u000d\u000a    \u000d\u000a    Commercialisation and Reach:\u000d\u000a    Manufactured by Oxford Immunotec Ltd, the T-SPOT.TB test was\u000d\u000a      commercially approved for sale in Europe in 2004. T-SPOT.TB sales\u000d\u000a      have substantially increased since their first year on the market, growing\u000d\u000a      from 2,000 tests sold in 2004 to 500,000 in 2011. While the cost of the\u000d\u000a      T-SPOT. TB test is £30, in comparison to the TST (which is sold\u000d\u000a      for around £2), the accuracy of the T-SPOT.TB test effectively\u000d\u000a      eliminates wasted resources in following up patients with false positive\u000d\u000a      TST results, avoiding greater costs related to the treatment of TB in\u000d\u000a      those who receive false negative TST results15. Tests have been\u000d\u000a      sold predominately to developed countries such as the USA, Germany, UK,\u000d\u000a      Switzerland and France, and have been requested by clinicians from a\u000d\u000a      variety of specialties including: pulmonology, occupational health, public\u000d\u000a      health and infectious disease15.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Developed in 2001, the University of Oxford's T-SPOT test is capable of\u000d\u000a      detecting both latent and active TB infection more rapidly and accurately\u000d\u000a      than the tuberculin skin test (TST). Since its commercial release in 2004,\u000d\u000a      T-SPOT has been adopted by public health agencies for TB control and\u000d\u000a      prevention in the US, UK and Europe. Tuberculosis (TB) is the second\u000d\u000a      leading cause of death from an infectious disease, killing an estimated\u000d\u000a      1.5 million people worldwide each year. One-third of the approximately 9\u000d\u000a      million people infected with TB each year are asymptomatic, yet many go on\u000d\u000a      to develop active TB if left untreated.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Lalvani, A. et al. Rapid detection of Mycobacterium\u000d\u000a      tuberculosis infection by enumeration of antigen-specific T cells. Am.\u000d\u000a        J. Respir. Crit. Care Med. 163, 824-828 (2001). Primary\u000a          paper reporting results from Oxford clinical trials for the T-SPOT.TB\u000d\u000a          test.\u000d\u000a    \u000a\u000a2. Centers for Disease Control and Prevention. Tuberculosis TB. Fact\u000d\u000a      Sheets — Tuberculin Skin Testing for TB. Page last reviewed June 20, 2011.\u000d\u000a      [Available from]\u000d\u000a      http:\/\/www.cdc.gov\/tb\/publications\/factsheets\/testing\/skintesting.htm\u000d\u000a      (accessed 26th March 2013). United States CDC Fact Sheet with\u000d\u000a          information about how to administer TB Skin Test.\u000d\u000a    \u000a\u000a3. Lalvani, A. et al. Enhanced contact tracing and spatial\u000d\u000a      tracking of Mycobacterium tuberculosis infection by enumeration of\u000d\u000a      antigen-specific T cells. Lancet 357, 2017-2021 (2001) http:\/\/dx.doi.org\/10.1016\/S0140-6736(00)05115-1.\u000d\u000a      Paper reporting primary results from Oxford study comparing the\u000d\u000a          efficacy of the T-SPOT assay in comparison to the Tuberculin Skin\u000d\u000a          Test.\u000d\u000a    \u000a\u000a4. Oxford Immunotec. T-SPOT®.TB test [[available\u000d\u000a      from]]\u000d\u000a        http:\/\/www.oxfordimmunotec.com\/T-SPOT_International (accessed 26\u000d\u000a      March 2013). Product Information about the T-SPOT.TB test can be\u000d\u000a          found on the Products and Services page of the Oxford Immunotec\u000d\u000a          website.\u000d\u000a    \u000a\u000a5. Chapman, A. L. N. et al. Rapid detection of active and latent\u000d\u000a      tuberculosis infection in HIV-positive individuals by enumeration of\u000d\u000a      Mycobacterium tuberculosis-specific T cells. AIDS 16,\u000d\u000a      2285-2293 (2002). Paper reporting Oxford study into the specificity\u000d\u000a          and sensitivity of the T-SPOT.TB Test when compared to the TST method.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust and the Medical Research\u000d\u000a      Council.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000d\u000a    \u000d\u000a       Centers for Disease Control and Prevention. Updated Guidelines for\u000d\u000a        Using Interferon Gamma Release Assays to Detect Mycobacterium\u000d\u000a        tuberculosis Infection --- United States, 2010. MMWR 5(RR-05),\u000d\u000a        1-25 (2010). [available from]\u000d\u000a        http:\/\/www.cdc.gov\/mmwr\/preview\/mmwrhtml\/rr5905a1.htm\u000d\u000a        (accessed 26 March 2013). United States Government updated CDC\u000d\u000a            guidelines recommending the use of T-SPOT.TB test in addition to the\u000d\u000a            QuantiFERON-TB Gold in tube test, to detect TB infection. \u000a\u000d\u000a       Thomas, M. M. et al. Rapid diagnosis of Mycobacterium\u000d\u000a        tuberculosis meningitis by enumeration of cerebrospinal fluid\u000d\u000a        antigen-specific T-cells. Int. J. Tuberc. Lung Dis. 12,\u000d\u000a        651-657 (2008). Paper outlining rapid diagnosis of TB using\u000d\u000a            ELISPOT (T-SPOT.TB) test.\u000a\u000d\u000a       Meier, T., Eulenbruch, H.-P., Wrighton-Smith, P., Enders, G. &\u000d\u000a        Regnath, T. Sensitivity of a new commercial enzyme-linked immunospot\u000d\u000a        assay (T SPOT-TB) for diagnosis of tuberculosis in clinical practice. Eur.\u000a          J. Clin. Microbiol. Infect. Dis. 24, 529-536 (2005) DOI\u000d\u000a        10.1007\/s10096-005-1377-8. Paper showing sensitivity of T-SPOT\u000d\u000a            test.\u000a\u000d\u000a       Liebeschuetz, S. et al. Diagnosis of tuberculosis in South\u000d\u000a        African children with a T-cell-based assay: a prospective cohort study.\u000d\u000a        Lancet 364, 2196-2203 (2004)\u000d\u000a        http:\/\/dx.doi.org\/10.1016\/S0140-6736(04)17592-2\u000d\u000a        Paper showing diagnostic sensitivity of the ELISPOT (T-SPOT.TB)\u000d\u000a            test to be higher than the TST and less affected by health factors\u000d\u000a            associated with childhood tuberculosis in developing countries.\u000d\u000a        \u000a\u000d\u000a       Xie, X. et al. A T-cell-based enzyme-linked immunospot assay\u000d\u000a        for tuberculosis screening in Chinese patients with rheumatic diseases\u000d\u000a        receiving infliximab therapy. Clin. Exp. Med. 11,\u000d\u000a        155-161 (2011) doi: 10.1007\/s10238-010-0123-4. Paper showing the\u000d\u000a            T-SPOT.TB test to be more specific than TST in detecting\u000d\u000a            tuberculosis during infliximab therapy in Chinese patients with\u000d\u000a            rheumatic diseases. \u000a\u000d\u000a       Sun, L. et al. Interferon gamma release assay in diagnosis of\u000d\u000a        pediatric tuberculosis: a meta-analysis. FEMS Immunol. Med.\u000d\u000a          Microbiol. 63, 165-173 (2011) doi:\u000d\u000a        10.1111\/j.1574-695X.2011.00838.x Paper showing the far greater\u000d\u000a            specificity of interferon-gamma release assays (eg.T-SPOT,\u000d\u000a            QuantiFERON-TB) in comparison to TST, particularly in children with\u000d\u000a            previous BCG vaccination.\u000a\u000d\u000a       Soysal, A. et al. Diagnosing latent tuberculosis infection in\u000d\u000a        haemodialysis patients: T-cell based assay (T-SPOT.TB) or tuberculin\u000d\u000a        skin test? Nephrol. Dial. Transplant. 27,\u000d\u000a        1645-1650(2012).doi:10.1093\/ndt\/gfr516 Paper showing the\u000d\u000a            T-SPOT.TB test's enhanced diagnosis of latent TB in patients with\u000d\u000a            haemodialysis.\u000a\u000d\u000a       Oxford Immunotec Guidelines. Many countries have developed\u000d\u000a          guidelines, which incorporate the use of interferon gamma release\u000d\u000a          assays (IGRA) such as T-SPOT.TB... [Available from] http:\/\/www.oxfordimmunotec.com\/Guidelines_International\u000d\u000a        (accessed 26 March 2013). List of worldwide guidelines\u000d\u000a            recommending the use of the interferon- gamma release assays\u000d\u000a            for the diagnosis of TB. \u000a\u000d\u000a       National Institute for Health and Clinical Excellence. Tuberculosis:\u000d\u000a        clinical diagnosis and management of tuberculosis, and measures for its\u000d\u000a        prevention and control (NICE clinical guideline 117). Developed by the\u000d\u000a        National Collaborating Centre for Chronic Conditions and the Centre for\u000d\u000a        Clinical Practice at NICE. Issued March 2011. [Available from]\u000d\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/13422\/53638\/53638.pdf\u000d\u000a        (accessed 26 March 2013) Updated NICE Guideline recommending the\u000d\u000a            use of the interferon-gamma release assays in a number of specific\u000d\u000a            diagnostic circumstances.\u000a\u000d\u000a       Oxford Immunitec Sales Statement. Chris Granger: Director\u000d\u000a        Global Professional Relations. Oxford Immunotec Ltd. 2012. Sales\u000d\u000a            Statement in email received from Chris Granger, Director Global\u000d\u000a            Professional Relations, Oxford Immunotec Ltd on 1st\u000d\u000a            February 2012. (available on request) \u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    IMPROVING THE DIAGNOSIS OF TUBERCULOSIS\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In 1993, the World Health Organization (WHO) declared tuberculosis to be a\u000d\u000a    global health emergency, estimating that around 35 million people would die\u000d\u000a    from TB between 2000 and 2020, if control measures were not significantly\u000d\u000a    improved. A notoriously difficult disease to diagnose, the tuberculin skin\u000d\u000a    test (TST) has been the standard method of detecting TB infection for over\u000d\u000a    100 years. One of the biggest problems with the TST method is its inability\u000d\u000a    to differentiate between TB infection and patients who have been vaccinated\u000d\u000a    against TB with the related strain, bacillus Calmette-Guérin (BCG). In\u000d\u000a    addition, the TST method cannot detect latent TB infection, greatly\u000d\u000a    affecting diagnostic yields.\u000d\u000a    In the mid 1990s, Professor Adrian Hill and his team at Oxford University\u000d\u000a      responded to the WHO's declaration of emergency, by applying a method they\u000d\u000a      had previously used in detecting malarial infection, to identify\u000d\u000a      TB-infected patients. By stimulating blood cells from malaria-exposed\u000d\u000a      patients, they had been able to identify key malaria proteins recognised\u000d\u000a      by the immune system. Applying the same method to patients suffering from\u000d\u000a      TB, this simple overnight ELISPOT (enzyme-linked immunospot assay) or\u000d\u000a      \"T-SPOT\" test involved mixing blood cells from test subjects with TB\u000d\u000a      proteins, allowing the number of TB protein-specific T cells to be\u000d\u000a      counted. After performing clinical trials over a 16 month period (October\u000d\u000a      1997 to January 1999) the Oxford University researchers found that their\u000d\u000a      T-SPOT test could not only rapidly diagnose TB-infected patients, but was\u000d\u000a      also far more specific and sensitive than TST1. Their findings\u000d\u000a      indicated that the T-SPOT assay detected 96% of TB infections, compared to\u000d\u000a      the TST method, which detected only 69%1. In clinical trials\u000d\u000a      performed on TB-vaccinated subjects, 85% of TST-tested patients respondent\u000d\u000a      positively to TB infection, while none of the patients tested positive by\u000d\u000a      the T-SPOT method1.\u000d\u000a    The research also showed that the T-SPOT method of diagnosing TB enabled\u000d\u000a      rapid (overnight) detection of the infection, in comparison to the TST,\u000d\u000a      which is read 48 to 72 hours2 after administration. The T-SPOT\u000d\u000a      test is also far more accurate in detecting TB in asymptomatic patients\u000d\u000a      who are at a high risk of active infection3. The T-SPOT assay\u000d\u000a      was licensed across Europe in July 2004 and received FDA premarket\u000d\u000a      approval in July 20084. The T-SPOT test has brought accurate\u000d\u000a      and effective TB testing to many new patient groups where the skin test\u000d\u000a      had previously given poor or unreliable results5.\u000d\u000a    "},{"CaseStudyId":"3907","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    The International Subarachnoid Aneurysm Trial (ISAT) was the first of its\u000d\u000a      kind to compare neurosurgical clipping and endovascular coiling for\u000d\u000a      patients suffering from subarachnoid haemorrhage. It showed endovascular\u000d\u000a      coiling to be the superior treatment for cerebral aneurysms, leading to\u000d\u000a      significant changes in clinical guidelines for the management of\u000d\u000a      aneurysmal subarachnoid haemorrhage, and major changes in practice around\u000d\u000a      the world.\u000d\u000a    Clinical Guidelines:\u000d\u000a      In 2012 the American Heart Association and American Stroke Association\u000d\u000a      issued guidelines for the management of aneurysmal subarachnoid\u000d\u000a      haemorrhage, recommending endovascular coiling for patients with ruptured\u000d\u000a      aneurysms6. The guidelines, which cite ISAT as their primary\u000d\u000a      source of data, support the use of coiling as the preferred treatment for\u000d\u000a      patients with aneurysmal subarachnoid haemorrhage, and also emphasise the\u000d\u000a      importance of follow-up imaging for patients who have received both\u000d\u000a      coiling and clipping treatments due to the small risk of re-bleeding,\u000d\u000a      which was demonstrated in the trial6. Current National\u000d\u000a      Institute for Health and Clinical Excellence (NICE) guidelines support the\u000d\u000a      use of coil embolisation of ruptured intracranial aneurysms due to the\u000d\u000a      safety and efficacy of the procedure in comparison to surgical clipping.\u000d\u000a      They also stated that due to the small risk of re-bleeding, patients\u000d\u000a      should receive long-term monitoring following both procedures7.\u000d\u000a      In addition, the NICE Interventional Procedures Consultation Document for\u000d\u000a      Embolisation of Intracranial Aneurysms states that the endovascular\u000d\u000a      coiling procedure is superior to surgical clipping in the short term8.\u000d\u000a      In 2009 the American Association of Neuroscience Nurses Clinical Practice\u000d\u000a      Guidelines for the Care of Patients with Aneurysmal Subarachnoid\u000d\u000a      Haemorrhage recommended endovascular coiling as the preferred method of\u000d\u000a      aneurysm treatment in cases where both surgical clipping and endovascular\u000d\u000a      coiling are potential options9.\u000d\u000a    Practice Patterns:\u000d\u000a      A 2003 Position Statement from the Executive Committee of the American\u000d\u000a      Society of Interventional and Therapeutic Neuroradiology and the American\u000d\u000a      Society of Neuroradiology concluded: \"the ISAT study was a\u000d\u000a        well-designed and well-executed, randomized, controlled trial on a large\u000d\u000a        number of patients. These data provide the highest level of evidence\u000d\u000a        supporting the use of detachable coils for patients with ruptured\u000d\u000a        cerebral aneurysms suitable for endovascular therapy\"10.\u000d\u000a      The 2009 Stroke Association haemorrhagic stroke factsheet recommends\u000d\u000a      coiling as the preferred treatment option for subarachnoid haemorrhage,\u000d\u000a      because 77% of patients make a good or full recovery, in comparison to 70%\u000d\u000a      following surgical clipping11. In the UK, endovascular coiling\u000d\u000a      is increasingly the treatment of choice12 and this is\u000d\u000a      associated with a beneficial effect on survival. The NHS now claims that\u000d\u000a      65% of people survive aneurysms in comparison to the 50% mortality rate\u000d\u000a      cited in Jan van Gijn's 2007 Lancet paper on subarachnoid haemorrhage2.\u000d\u000a      Such an improved outlook is partly down to better treatment, and party due\u000d\u000a      to more urgent admissions. Patients undergoing neurosurgery have to wait\u000d\u000a      for up to a week to be stabilised for treatment, whereas coiling can be\u000d\u000a      administered immediately.\u000d\u000a    In a 2011 review13 analysing the impact of ISAT on clinical\u000d\u000a      practice in the United States, it was concluded that as a result of the\u000d\u000a      trial there were significant pattern changes in the treatment of ruptured\u000d\u000a      aneurysms in the US, with far more patients undergoing the endovascular\u000d\u000a      coiling treatment for ruptured aneurysms than clipping. Changes in\u000d\u000a      clinical guidelines following the publication of ISAT also led to a 3%\u000d\u000a      decrease in mortality for those suffering from ruptured aneurysms13\u000d\u000a      in the period up to 2011. The report concluded: \"The results of the\u000d\u000a        ISAT have been associated with a prominent change in practice patterns\u000d\u000a        related to the treatment of ruptured aneurysms. The review also\u000d\u000a      claimed: \"The cost of hospitalization has increased and the mortality\u000d\u000a        has decreased, presumably due to a larger proportion of patients\u000d\u000a        receiving any treatment and endovascular (coil) treatment\"13.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The University of Oxford's International Subarachnoid Aneurysm Trial\u000d\u000a      (ISAT) changed clinical practice worldwide by showing that endovascular\u000d\u000a      coiling is a more effective and safer treatment than neurosurgery\u000d\u000a      following subarachnoid haemorrhage, with fewer complications and improved\u000d\u000a      quality of life. Subarachnoid haemorrhages account for 1 in 14 strokes and\u000d\u000a      are caused by bleeding in and around the brain; approximately 85% occur\u000d\u000a      when cerebral aneurysms rupture. ISAT was the first trial to compare\u000d\u000a      neurosurgery, or neuroradiological endovascular coiling in patients with\u000d\u000a      ruptured cerebral aneurysms causing acute subarachnoid haemorrhage.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Feigin, V. L. et al. Risk factors for subarachnoid hemorrhage:\u000d\u000a      an updated systematic review of epidemiological studies. Stroke 36,\u000d\u000a      2773-2780 (2005). Article providing an overview of the risk factors\u000d\u000a          for subarachnoid haemorrhage.\u000d\u000a    \u000a\u000a2. van Gijn, J., Kerr, R. S. & Rinkel, G. J. E. Subarachnoid\u000d\u000a      haemorrhage. Lancet 369, 306-318 (2007). Paper\u000d\u000a          providing information about subarachnoid haemorrhage.\u000d\u000a    \u000a\u000a3. Guglielmi, G., Viñuela, F., Sepetka, I. & Macellari, V.\u000d\u000a      Electrothrombosis of saccular aneurysms via endovascular approach. Part 1:\u000d\u000a      Electrochemical basis, technique, and experimental results. J.\u000d\u000a        Neurosurg. 75, 1-7 (1991). Part I: Primary paper from\u000d\u000a          Doctor Guido Guglielmi, University of California Los Angeles,\u000d\u000a          outlining the endovascular approach to treating aneurysms.\u000d\u000a    \u000a\u000a4. Guglielmi, G., Viñuela, F., Dion, J. & Duckwiler, G.\u000d\u000a      Electrothrombosis of saccular aneurysms via endovascular approach. Part 2:\u000d\u000a      Preliminary clinical experience. J. Neurosurg. 75, 8-14\u000d\u000a      (1991). Part II: Primary paper from Doctor Guido Guglielmi,\u000d\u000a          University of California Los Angeles, presenting data from clinical\u000d\u000a          trial for endovascular coiling.\u000d\u000a    \u000a\u000a5. Molyneux, A. et al. International Subarachnoid Aneurysm Trial\u000d\u000a      (ISAT) of neurosurgical clipping versus endovascular coiling in 2143\u000d\u000a      patients with ruptured intracranial aneurysms: a randomised trial. Lancet\u000d\u000a      360, 1267-1274 (2002). Primary paper from ISAT clinical\u000d\u000a          trial, which was managed by the University of Oxford's Diabetes Trials\u000d\u000a          Unit and Neurovascular Research Unit.\u000d\u000a    \u000aThe pilot phase of this study was supported by a grant from Oxford\u000d\u000a      Regional Health Authority Research and Development (1994-1997). The main\u000d\u000a      trial was supported by grants from: the Medical Research Council, UK; and\u000d\u000a      Programme Hospitalier de Recherche Clinique 1998 of the French Ministry of\u000d\u000a      Health (AOM 98150). It was sponsored by Assistance Publique, Hôpitaux de\u000d\u000a      Paris (AP-HP); the Canadian Institutes of Health Research; and the Stroke\u000d\u000a      Association of the UK for the Neuropsychological assessments.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"}],"Sources":"\u000d\u000a    \u000d\u000a      Connolly, E. S. et al. Guidelines for the Management of\u000d\u000a        Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare\u000d\u000a        Professionals From the American Heart Association\/American Stroke\u000d\u000a        Association. Stroke 43, 1711-37\u000d\u000a        (2012).doi:10.1161\/STR.0b013e3182587839. AHA and ASA guidelines\u000d\u000a            supporting the use of coiling as the preferred treatment for\u000d\u000a            subarachnoid hemorrhage, ISAT is cited as primary evidence.\u000a\u000d\u000a      Coil embolisation of ruptured intracranial aneurysms. Interventional\u000d\u000a        Procedure Guidance 106 (January 2005). National Institute for Health\u000d\u000a          and Care Excellence at\u000d\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/11036\/30674\/30674.pdf\u000d\u000a        (Accessed 2013). Guidelines supporting the use of coil\u000d\u000a            embolization of ruptured intracranial aneurysms in comparison to\u000d\u000a            surgical clipping.\u000a\u000d\u000a      Interventional procedures consultation document - embolisation of\u000d\u000a        intracranial aneurysms.  National Institute for Health and Care\u000d\u000a          Excellence at\u000d\u000a        http:\/\/www.nice.org.uk\/guidance\/index.jsp?action=article&o=30672\u000d\u000a        (Accessed 2013). NICE Interventional Procedures Consultation\u000d\u000a            Document stating the short term superiority of endovascular coiling\u000d\u000a            procedure in comparison to surgical clipping.\u000a\u000d\u000a      Care of the Patient with Aneurysmal Subarachnoid Hemorrhage: AANN\u000d\u000a        Clinical Practice Guideline Series. American Association of\u000d\u000a          Neuroscience Nurses at\u000d\u000a        http:\/\/www.aann.org\/pdf\/cpg\/aannaneurysmalsah.pdf\u000d\u000a        (Accessed 2013). AANN\u000d\u000a            Clinical Practice Guidelines for the care of patients with\u000d\u000a            aneurysmal subarachnoid hemorrhage, recommending coiling as the\u000d\u000a            preferred method of aneurysm treatment in comparison to surgical\u000d\u000a            clipping. ISAT cited as evidence.\u000a\u000d\u000a      Derdeyn, C.P. et al. The International Subarachnoid Aneurysm\u000d\u000a        Trial (ISAT): a position statement from the Executive Committee of the\u000d\u000a        American Society of Interventional and Therapeutic Neuroradiology and\u000d\u000a        the American Society of Neuroradiology. AJNR Am J Neuroradiol. 24,1404-8\u000a        (2003). Position statement on the ISAT study and the high level\u000d\u000a            of evidence it presents to support the use of detachable coils.\u000a\u000d\u000a      Haemorrhagic stroke - references used. The Stroke Association\u000d\u000a        at\u000d\u000a        http:\/\/www.stroke.org.uk\/referenced\/haemorrhagic-stroke\u000d\u000a        (Accessed 2013). Stroke Association UK's haemorrhagic stroke\u000d\u000a            factsheet, recommending coiling as the preferred treatment option\u000d\u000a            for subarachnoid hemorrhage.\u000a\u000d\u000a      Subarachnoid Haemorrhage. NHS Choices at\u000d\u000a        http:\/\/www.nhs.uk\/conditions\/Subarachnoid-haemorrhage\/Pages\/Introduction.aspx\u000d\u000a        (Accessed 2013). National Institute of Health UK, online fact\u000d\u000a            sheet for subarachnoid haemorrhage.\u000a\u000d\u000a      Qureshi, A. I. et al. Impact of International Subarachnoid\u000d\u000a        Aneurysm Trial results on treatment of ruptured intracranial aneurysms\u000d\u000a        in the United States. Clinical article. J. Neurosurg. 114,\u000d\u000a        834-841 (2011). Paper analysing the impact of the ISAT on\u000d\u000a            treatment patterns in the US. \u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    THE INTERNATIONAL SUBARACHNOID ANEURYSM TRIAL: CHANGING CLINICAL\u000d\u000a        PRACTICE\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    A subarachnoid haemorrhage occurs when a cerebral aneurysm (a bulge in a\u000d\u000a      weakened wall of a brain blood vessel) ruptures. This predominately occurs\u000d\u000a      in the subarachnoid space surrounding the brain and is responsible for up\u000d\u000a      to 7% of all strokes1, while 50% of haemorrhages are fatal2.\u000d\u000a      For a long time the standard treatment for cerebral aneurysms was\u000d\u000a      neurosurgical clipping, an invasive procedure requiring general\u000d\u000a      anaesthetic and craniotomy, where the surgeon removes a small piece of\u000d\u000a      bone from the skull and inserts a metal clip into the aneurysm to seal it.\u000d\u000a    In 1991, Dr Guido Guglielmi at the University of California Los Angeles3,4\u000d\u000a      developed a less invasive technique called endovascular coiling. This\u000d\u000a      technique uses detachable platinum coils, which are inserted into the\u000d\u000a      aneurysm using a microcatheter via an artery in the leg or groin. The\u000d\u000a      coils block blood flow to the aneurysm and stop the aneurysm from growing.\u000d\u000a      Over time the coils seal the aneurysm off from the main artery to prevent\u000d\u000a      rupture.\u000d\u000a      While this technique (which can be done under local anaesthetic) quickly\u000d\u000a      became a popular alternative to neurosurgical clipping, the relative\u000d\u000a      benefits of the two treatments remained uncertain.\u000d\u000a    In 1994 Professor Rury Holman of the University of Oxford's Diabetes\u000d\u000a      Trials Unit collaborated with Mr Richard Kerr and Dr Andrew Molyneux from\u000d\u000a      the University of Oxford's Neurovascular Research Unit, to design and\u000d\u000a      manage a clinical trial on behalf of the International Subarachnoid\u000d\u000a      Aneurysm Trial (ISAT) Collaborative Group. This compared the safety and\u000d\u000a      efficacy of the new endovascular coiling treatment with neurosurgical\u000d\u000a      clipping for subarachnoid aneurysms5.\u000d\u000a    This five-year randomised controlled trial enrolled 2,143 patients with\u000d\u000a      ruptured intracranial aneurysms from 42 neurosurgical centres in 12\u000d\u000a      countries throughout the UK and Europe, with 1,070 patients allocated to\u000d\u000a      neurosurgical clipping and 1,073 to endovascular coiling. Clinical\u000d\u000a      outcomes were assessed at two months and at one year after randomisation5.\u000d\u000a      The trial was stopped early in May 2002 when data showed that patients\u000d\u000a      receiving the neurosurgical clipping technique were at a significant\u000d\u000a      disadvantage to those who were randomised to the endovascular coiling\u000d\u000a      treatment5. The trial results, published in 2002, showed that\u000d\u000a      patients allocated to endovascular treatment were 23% less likely to be\u000d\u000a      dependent on carers, and 7% were less likely to have died than those\u000d\u000a      allocated to neurosurgical clipping5.\u000d\u000a    Results from this ISAT trial, which showed endovascular coiling to be the\u000d\u000a      superior treatment for cerebral aneurysms, have led to the adoption of\u000d\u000a      coiling as the preferred treatment worldwide for ruptured cerebral\u000d\u000a      aneurysms.\u000d\u000a    "},{"CaseStudyId":"3908","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Diffuse Large B cell Lymphoma (DLBCL) is the most common\u000a      non-Hodgkin's lymphoma. It accounts for approximately a third of\u000a      lymphomas, and is the seventh most common cancer, with an annual incidence\u000a      of 25,000 cases in the USA. Despite recent improvements in therapies,\u000a      fewer than 50% of patients survive for more than 5 years.\u000a    Gene expression profiling has identified two different types of DLBCL,\u000a      the germinal centre-subtype and the more aggressive activated B-cell\u000a      derived subtype, which is associated with markedly inferior survival rates7.\u000a      Accurate identification of these DLBCL subtypes in patients allows more\u000a      specific targeted therapy, and will ultimately improve a patient's chance\u000a      of survival.\u000a    Although gene expression profiling had linked FOXP1 expression to the\u000a      activated B-cell DLBCL subtype (associated with inferior survival rates)8,\u000a      this technique was not found suitable for routine clinical use. This paved\u000a      the way for the accurate detection of FOXP1 using simple and reproducible\u000a      immunostaining methods.\u000a    Research performed at Oxford showed a good correlation between results\u000a      obtained from gene expression profiling and the use of antibody JC12 in\u000a      immunocytochemical staining9, leading to this methodology being\u000a      used in clinics worldwide for routine diagnostic procedures.\u000a    Major steps in achieving worldwide use of JC12 in routine diagnostics\u000a      include the following series of trials:\u000a    \u000a      A collaboration initiated by Professor Banham demonstrating that\u000a        immunolabelling with the monoclonal antibody JC12, identified patients\u000a        with poor prognosis activated B-cell subtype of DLBCL, under the new\u000a        gold standard treatment, CHOP-R10.\u000a      Clinical collaborations between Professor Banham (Oxford) and the\u000a        French Groupe d'Etudes des Lymphomes de l'Adulte supported the clinical\u000a        relevance of FOXP1 expression in CHOP-R treated DLBCL, in two randomised\u000a        trials LNH98-5 and LNH01-5B11.\u000a      The international CORAL study identified FOXP1 as being of prognostic\u000a        relevance for predicting progression free disease in DLBCL12.\u000a      In 2012 the International DLBCL Rituximab-CHOP Consortium Program\u000a        Study recognised that FOXP1 expression was one of the three most\u000a        significant molecules for predicting outcome in DLBCL. Significantly,\u000a        they confirmed that the addition of a FOXP1 antibody to a panel of\u000a        antibodies used in routine immunostaining purposes constituted a highly\u000a        effective panel for defining clinically relevant DLBCL subtypes13.\u000a    \u000a    The anti-FOXP1 monoclonal antibody, JC12, has since been licensed for\u000a      research and in vitro diagnostic use worldwide14. The\u000a      JC12 antibody is routinely used to classify DLBCL and to identify patients\u000a      who require, and those who do not require, more intensive treatment\u000a      regimes.\u000a    The successful development and assessment of new DLBCL drugs by the\u000a      pharmaceutical industry continues to require the accurate classification\u000a      of tumour sub-types. As one example, the Oxford University researchers are\u000a      currently collaborating with the UK REMoDL-B Clinical Trial Management\u000a      Group15 to explore the use of FOXP1 and its isoforms as markers\u000a      of a potential response to the proteasome inhibitor Bortezomib in DLBCL.\u000a    ","ImpactSummary":"\u000a    Researchers from the University of Oxford identified the novel human\u000a      protein Forkhead box transcription factor 1 (FOXP1) and showed it to be an\u000a      important prognostic biomarker in cancer. Expression of FOXP1 can\u000a      distinguish those patients with diffuse large B-cell lymphoma (DLBCL) who\u000a      are at high risk of disease progression, making it possible for clinicians\u000a      to target more intensive therapy to this group. DLBCL accounts for one\u000a      third of lymphomas and is the seventh commonest form of cancer. The\u000a      anti-FOXP1 monoclonal antibody developed by Oxford University is now used\u000a      worldwide in clinical diagnostics.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Banham AH, et al. The FOXP1 winged helix transcription factor is a\u000a        novel candidate tumor suppressor gene on chromosome 3p. Cancer Res\u000a        61: 8820-9 (2001). Available at\u000a\u0009\u0009http:\/\/cancerres.aacrjournals.org\/content\/61\/24\/8820.full.pdf+html (accessed 2013)\u000a      This is the original paper describing the identification of FOXP1\u000a          and the use of the FOXP1-specific monoclonal antibody.\u000a    \u000a\u000a2. Banham AH, et al. Expression of the FOXP1 transcription factor is\u000a        strongly associated with inferior survival in patients with diffuse\u000a        large B-cell lymphoma. Clin Cancer Res 11: 1065-72 (2005).\u000a        Available at\u000a\u0009\u0009http:\/\/clincancerres.aacrjournals.org\/content\/11\/3\/1065.full.pdf+html(accessed 2013)\u000a      This paper presents the results of research originally presented in\u000a          the Abstract shown below with the same authors published in Blood\u000a          102A, Part 1, Meeting Abstract 346 thus providing evidence of a 2003\u000a          priority date.\u000a\u0009\u0009  \u000a\u000a\u0009\u0009  \u000a\u0009\u0009  \u000a    \u000a3. Choi WW, et al. A new immunostain algorithm classifies diffuse large\u000a      B-cell lymphoma into molecular subtypes with high accuracy. Clin\u000a        Cancer Res 15: 5494-502 (2009). doi: 10.1158\/1078-0432.CCR-09-0113\u000a        Available at http:\/\/clincancerres.aacrjournals.org\/content\/15\/17\/5494.long (accessed 2013)\u000a\u0009\u0009The analysis of FOXP1 protein expression was identified\u000a          by the National Institute of Health Lymphoma\/Leukemia Molecular\u000a          Profiling Project Group as being a vital component of a panel of\u000a          antibodies for classifying DLBCL and identifying high risk patients.\u000a    \u000a\u000a4. Fox SB, et al. Expression of the Forkhead transcription factor\u000a        FOXP1 is associated with estrogen receptor and improved survival in\u000a        primary human breast carcinomas. Clin Cancer Res 10: 3521-27\u000a        (2004). doi: 10.1158\/1078-0432.CCR-03-0461 Available at\u000a\u0009\u0009http:\/\/clincancerres.aacrjournals.org\/content\/10\/10\/3521.full.pdf+html (Accessed 2013)\u000a\u0009\u0009Paper supporting a role for FOXP1 as a\u000a          possible co-regulator of the estrogen receptor in breast cancer and\u000a          also providing evidence for a role in the regulation of additional\u000a          pathways involved in cancer development.\u000a    \u000a\u000a5. Bates GJ, et al. Expression of the forkhead transcription factor\u000a        FOXP1 is associated with that of oestrogen receptor in primary invasive\u000a        breast carcinomas. Breast Cancer Res Treat 111: 453-459\u000a        (2008). doi 10.1007\/s10549-007-9812-4\u000a\u0009\u0009Available at  http:\/\/link.springer.com\/content\/pdf\/10.1007%2Fs10549-007-9812-4 (Accessed 2013)\u000a      This paper reported that FOXP1 expression correlated significantly\u000a          with oestrogen receptorb as well as oestrogen receptora and survival\u000a          in primary invasive breast cancer. Importantly FOXP1 expression was\u000a          not oestrogen regulated.\u000a    \u000a\u000a6. Brown PJ, et al. Potentially oncogenic B-cell activation-induced\u000a        smaller isoforms of FOXP1 are highly expressed in the activated B\u000a        cell-like subtype of DLBCL. Blood 111: 2816-2824\u000a      (2008) doi: 10.1182\/blood-2007-09-115113\u000a      Available at\u000a      http:\/\/bloodjournal.hematologylibrary.org\/content\/111\/5\/2816.long (accessed 2013)\u000a      This paper provides the first description of the presence of smaller\u000a          isoforms of FOXP1 during normal B-cell activation and cell lines and\u000a          patient samples derived from activated B-cell DLBCL. It was suggested\u000a          that these smaller isoforms could represent a mechanism for increased\u000a          FOXP1 expression in this DLBCL subtype and that they might be\u000a          functionally distinct from the full length protein.\u000a    \u000aThis research was funded by the Leukaemia and Lymphoma Research Fund,\u000a      Cancer Research UK, the Breast Cancer Campaign, Isis University Innovation\u000a      Fund, the Starmer Smith Memorial Fund, the Association of International\u000a      Cancer Research, and Tenovus.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, et al. Distinct\u000a        types of diffuse large B-cell lymphoma identified by gene expression\u000a        profiling. Nature. 403: 503-511(2000).\u000a\u0009\u0009Available at http:\/\/www.nature.com\/nature\/journal\/v403\/n6769\/full\/403503a0.html (accessed 2013)\u000a\u0009\u0009The description of a gene expression\u000a            profiling study reporting two distinct forms of DLBCL, namely\u000a            germinal centre B-like DLBCL and activated B-like DLBCL. Germinal\u000a            centre B-like was associated with improved survival.\u000a\u000a      Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark\u000a        side of B-cell differentiation. Nat Rev Immunol. 2: 920-32\u000a        (2002). doi:10.1038\/nri953 Available at\u000a\u0009\u0009http:\/\/www.nature.com\/nri\/journal\/v2\/n12\/pdf\/nri953.pdf (accessed 2013)\u000a\u0009\u0009Gene expression profiling identifying the\u000a            FOXP1 transcript as being highly expressed in activated B-cell\u000a            subtype of DLBCL.\u000a\u000a      Ballabio E, et al. Comparison of Choi and Hans algorithmns by\u000a        immunohistochemistry and quantitative reverse transcriptase-PCR — Letter. Clin Cancer Res. 16: 3805-3806 (2010).\u000a\u0009\u0009Available at http:\/\/clincancerres.aacrjournals.org\/content\/16\/14\/3805.full.pdf+html (accessed 2013)\u000a\u0009\u0009A report describing the correlation between\u000a            gene expression profiling and immunohistochemistry for subtyping\u000a            patients.\u000a\u000a      Nyman H, Jerkeman M, Karjalainen-Linsdberg M-J, Banham AH, Leppa S.\u000a        Prognostic impact of activated B-cell focused classification in diffuse\u000a        large B-cell lymphoma patients treated with R-CHOP. Mod Path.\u000a        22: 1094-1101(2009). doi:10.1038\/modpathol.2009.73\u000a        Available at http:\/\/www.nature.com\/modpathol\/journal\/v22\/n8\/pdf\/modpathol200973a.pdf (accessed 2013).\u000a\u0009\u0009Paper reporting the identification of a\u000a            panel of antibodies that enable the identification of subtyes of\u000a            DLBCL using immunocytochemical staining techniques. Emphasis is\u000a            placed on the FOXP1 and MUM-1 proteins as markers of activated\u000a            B-cell derived DLBCL, with their expression linked to significant\u000a            inferior failure-free survival.\u000a\u000a      Copie-Bergman C, et al. Immunofluorescence in situ hybridisation index\u000a        predicts survival in patients with diffuse large B-cell lymphoma treated\u000a        with R-CHOP: a GELA study. J Clin Oncol. 27: 5573-79 (2009).\u000a        doi: 10.1200\/JCO.2009.22.7058\u000a        Available at http:\/\/jco.ascopubs.org\/content\/27\/33\/5573.full.pdf+html (accessed 2013).\u000a\u0009\u0009A report from two clinical trials\u000a            describing the importance of using immunohistochemical labelling for\u000a            FOXP1 combined with in situ hybridisation detecting the BCL2, BCL6\u000a            and c-MYC oncogenes to predict survival in elderly patients treated\u000a            with R-CHOP.\u000a      Thieblemont C, Briere J, Mounier N, et al The germinal\u000a        center\/activated B-cell subclassification has a prognostic impact for\u000a        response to salvage therapy in relapsed\/refractory diffuse large B-cell\u000a        Lymphoma: A Bio-CORAL study. J Clin Oncol. 29: 4079-4087 (2011).\u000a        doi: 10.1200\/JCO.2011.35.4423.\u000a        Available at http:\/\/jco.ascopubs.org\/content\/29\/31\/4079.full.pdf+html (accessed 2013)\u000a\u0009\u0009Paper linking FOXP1 protein expression with\u000a            inferior survival in patients with activated B-cell DLBCL.\u000a\u000a      Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, et al.\u000a        Comprehensive gene expression profiling and immunohistochemical studies\u000a        support application of immunophenotypic algorithm for molecular subtype\u000a        classification in diffuse large B-cell lymphoma: a report from the\u000a        International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia.\u000a        26: 2103-13 (2012). doi: 10.1038\/leu.2012.83. Available at\u000a        http:\/\/www.nature.com\/leu\/journal\/v26\/n9\/pdf\/leu201283a.pdf (accessed 2013).\u000a\u0009\u0009  A publication from the International DLBCL\u000a            Rituximab-CHOP Consortium Program Study in which FOXP1 was reported\u000a            to be one of the three significant molecules for predicting outcome\u000a            in DLBCL.\u000a\u000a      \u000ahttp:\/\/www.abdserotec.com\/product\/jc12-anti-foxp1-antibody-mca2485t.html (accessed 2013)\u000a\u0009  An example of a website from a company\u000a            commercialising the JC12 antibody.\u000a\u000a      Letter from Dr Andrew Davies, Honorary Consultant Medical Oncology,\u000a        Cancer Services Division, University of Southampton. Letter kept on\u000a        file, available on request. A letter from Dr Andrew Davies\u000a            (member of the lead centre in the study) to Professor Banham for the\u000a            REMoDL-B study.\u000a\u000a    \u000a    ","Title":"\u000a    FOXP1: ENABLING TARGETED CANCER THERAPY\u000a    ","UKLocation":[{"GeoNamesId":"2640729","Name":"Oxford"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In 1999 Professor Alison Banham's group at the University of Oxford\u000a      Leukaemia Research Fund Immunodiagnostics Unit identified the novel human\u000a      FOXP1 transcription factor, as well as a subfamily of related FOXP\u000a      transcription factors, and was the first to patent the use of FOXP1 as a\u000a      potential biomarker. FOXP1 is responsible for regulating gene expression\u000a      during normal development and adulthood; however, dysregulated FOXP1 can\u000a      lead to haematological malignancies, including diffuse large B-cell\u000a      lymphoma (DLBCL) and solid tumours. Increased expression of FOXP1 in DLBCL\u000a      with a post-germinal centre (or activated B-cell) phenotype was linked to\u000a      poor survival (patent: PCT\/GB00\/04590) and identified FOXP1 as a potential\u000a      tumour suppressor protein(1). The University of Oxford\u000a      researchers then developed JC12, the first anti-FOXP1 specific monoclonal\u000a      antibody. The development of the JC12 antibody was a major advance in this\u000a      field, making it possible for clinicians to measure the FOXP1 protein in\u000a      patients' cells, using relatively straightforward and direct\u000a      immunocytochemistry labelling techniques.\u000a    In 2003 an international collaborative study instigated by Professor\u000a      Banham showed that FOXP1 expression predicted DLBCL with a high-risk of\u000a      progression2. This was independent of the International\u000a      Prognostic Index (the conventional clinical scoring system used to predict\u000a      outcome)2. In 2009, a further collaboration with the highly\u000a      influential Lymphoma\/Leukemia Molecular Profiling Project, run by the US\u000a      National Institutes of Health, confirmed the importance of FOXP1 protein\u000a      expression in identifying the clinically relevant molecular subtypes of\u000a      DLBCL. Significantly, this study also showed high FOXP1 expression in\u000a      DLBCL patients with the more aggressive activated B-cell subtype disease3.\u000a    Researchers from the University of Oxford have also played a pivotal part\u000a      in highlighting the potential for FOXP1 as a biomarker in prostate and\u000a      breast cancer. Collaborations between Professor Banham and Professor\u000a      Adrian Harris at the Weatherall Institute of Molecular Medicine,\u000a      University of Oxford, using the JC12 antibody, showed the significant\u000a      correlation of FOXP1 expression with oestrogen receptors and survival4,5.\u000a      FOXP1 was found not to be oestrogen regulated5, suggesting that\u000a      FOXP1 and oestrogen receptors may share a common regulatory pathway.\u000a    In 2007, Oxford researchers were the first in the world to report smaller\u000a      isoforms of FOXP1 associated with a more aggressive activated B-cell\u000a      subtype of DLBCL6. The existence of these potentially oncogenic\u000a      smaller isoforms represents a possible answer to the contradictory\u000a      findings that FOXP1 represents a favourable prognostic marker in breast\u000a      and prostate carcinomas, while also representing an adverse risk factor in\u000a      B-cell lymphomas.\u000a    "},{"CaseStudyId":"3910","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The UKPDS Risk Engine and UKPDS Outcomes Model are currently being used\u000d\u000a      in a range of clinical, commercial and administrative settings -\u000d\u000a      evaluating long-term medical risks in patients, as well as economic and\u000d\u000a      clinical outcomes for patient populations worldwide.\u000d\u000a    The UKPDS Risk Engine\u000d\u000a      The UKPDS Risk Engine has become a significant tool in managing the risk\u000d\u000a      of cardiac complications in patients with diabetes, both in the UK and\u000d\u000a      internationally, and is recommended by the NHS6. The UKPDS Risk\u000d\u000a      Engine calculates the real risk of diabetes rather than the assessed risk.\u000d\u000a      Influencing national healthcare procedure, the UK National Institute for\u000d\u000a      Clinical Excellence (NICE) guidelines recommend the UKPDS Risk Engine for7:\u000d\u000a      annually estimating cardiovascular risk in patients not considered to be\u000d\u000a      at high cardiovascular risk; educational purposes, when discussing\u000d\u000a      cardiovascular complications and risk estimates with individual patients;\u000d\u000a      patients 40 years old and above with low cardiovascular risk from\u000d\u000a      non-hyperglycaemia-related factors7.\u000d\u000a    As described and referenced by Adler5, the Risk Engine has\u000d\u000a      also been used to: assess the cost-effectiveness of screening for\u000d\u000a      diabetes; evaluate the cost-effectiveness of treatments; assist health\u000d\u000a      planners to direct scarce resources to high-risk patients; help clinical\u000d\u000a      trialists to determine likely event rates and calculate more accurate\u000d\u000a      outcome trial sample sizes; and enable actuaries and epidemiologists to\u000d\u000a      forecast disease distribution.\u000d\u000a    The Risk Engine was the most successful model of its type at the\u000d\u000a      worldwide Mount Hood Challenge Meeting in 2004. Its equations have been\u000d\u000a      incorporated in many other leading models8. The UKPDS Risk\u000d\u000a      Engine was licenced by ISIS Innovation - the technology transfer arm of\u000d\u000a      The University of Oxford - in 2002. It is provided free of charge to\u000d\u000a      academic and clinical groups, but there is a charge for commercial\u000d\u000a      companies to use the model. Over 180,000 free copies have been downloaded\u000d\u000a      to date. In addition, approximately 14 commercial licences have been sold\u000d\u000a      by ISIS (10 to pharmaceutical companies, two to medical publishers, and\u000d\u000a      two to IT companies)9.\u000d\u000a    The UKPDS Outcomes Model\u000d\u000a      Intended to facilitate health economic evaluations of both individual\u000d\u000a      patient and entire populations, the UKPDS Outcomes Model can be used to:\u000d\u000a    \u000d\u000a      Evaluate likely rates and sequences of complications (e.g.\u000d\u000a        myocardial infarction, stroke, heart failure, renal failure, amputation)\u000d\u000a        over a patient's simulated lifetime;\u000d\u000a      Assist health service planning for populations with diabetes4.\u000d\u000a        For example, it can help healthcare systems decide how many future\u000d\u000a        coronary care or renal units they need to build, or estimate the overall\u000d\u000a        difference a new diabetes treatment might make in terms of quality of\u000d\u000a        life and costs;\u000d\u000a      Help ensure more accurate calculations for life insurance premiums by\u000d\u000a        specifically estimating the life expectancy of people with type 2\u000d\u000a        diabetes4;\u000d\u000a      Assist academic or clinical groups, or pharmaceutical companies, to\u000d\u000a        model or design clinical trials4; or\u000d\u000a      Assist healthcare providers to evaluate applications for new diabetes\u000d\u000a        drugs.\u000d\u000a    \u000d\u000a    The UKPDS Outcomes Model is now the preferred healthcare analysis tool\u000d\u000a      used by NICE10 to benchmark and evaluate applications for new\u000d\u000a      licensed diabetes drugs. The UKPDS Outcomes Model is capable of\u000d\u000a      facilitating large scale economic evaluations by estimating changes in\u000d\u000a      life expectancy and quality of life, when risk factors are altered3.\u000d\u000a      The Model has been used to assess economic impact of diabetic populations\u000d\u000a      in the United Kingdom, Australia and Canada. The UKPDS Outcomes Model was\u000d\u000a      touted the \"best diabetes economic model in existence,\" for the purposes\u000d\u000a      of the Ontario Diabetes Economic Model11. The Ontario Model was\u000d\u000a      created to provide policymakers with a tool for assessing the long-term\u000d\u000a      economic benefits of diabetes management, how to best allocate healthcare\u000d\u000a      resources, and to estimate the cost of treating diabetes in Ontario11.\u000d\u000a      The UKPDS Outcomes Model was also used in a cost-effectiveness study of\u000d\u000a      diabetes health services in Australia, improving health outcomes for\u000d\u000a      patients with type 2 diabetes12. The UKPDS Outcomes Model was\u000d\u000a      the subject of an invited Keynote speech at the 2012 Second Annual\u000d\u000a      PharmaCoEconomics Middle East Forum in Abu Dhabi, attended by\u000d\u000a      international and regional experts, regulators, and other key\u000d\u000a      stakeholders. It is now being used by the Health Authority of Abu Dhabi to\u000d\u000a      assess future diabetes health care requirements.\u000d\u000a    The UKPDS Outcomes Model was licenced by ISIS Innovation - the technology\u000d\u000a      transfer arm of The University of Oxford - in 2005. It is provided free of\u000d\u000a      charge to academic and clinical groups, but there is a charge for\u000d\u000a      commercial companies to use the model. Since 2005, ISIS Innovation has\u000d\u000a      provided over 170 licences worldwide in total for the UKPDS Outcomes\u000d\u000a      Model. Of these, around 140 are non-commercial and 28 are commercial\u000d\u000a      licences. The commercial licences sold by ISIS (three to healthcare\u000d\u000a      providers, three to insurance companies, 17 to pharmaceutical and biotech\u000d\u000a      companies, one to a university doing paid consultancy and four to\u000d\u000a      individuals undertaking paid consultancy) have generated contracts worth\u000d\u000a      over £450,000 in revenue for The University of Oxford9.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    We are facing a diabetes epidemic: the number of people affected\u000d\u000a      worldwide is estimated to rise from 366 million in 2011 to 552 million by\u000d\u000a      2030, representing a huge financial burden on society. Using data from the\u000d\u000a      United Kingdom Prospective Diabetes Study (UKPDS), the University of\u000d\u000a      Oxford's Diabetes Trials Unit developed two assessment tools - the UKPDS\u000d\u000a      Risk Engine (a diabetes-specific heart attack and stroke risk calculator)\u000d\u000a      and the UKPDS Outcomes Model (a lifetime simulator for people with\u000d\u000a      diabetes) to better understand and plan for diabetes risk and its outcomes\u000d\u000a      on both individuals and society as a whole. Patients, clinicians and\u000d\u000a      policymakers globally are now using these tools to assist in planning for\u000d\u000a      future health economic needs, and for predicting health risks for people\u000d\u000a      with diabetes.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"292968","Name":"Abu Dhabi"}],"References":"\u000d\u000a    \u000a1. Guzder, R. N., Gatling, W., Mullee, M. A., Mehta, R. L. & Byrne,\u000d\u000a      C. D. Prognostic value of the Framingham cardiovascular risk equation and\u000d\u000a      the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2\u000d\u000a      diabetes: results from a United Kingdom study. Diabet. Med. 22,\u000d\u000a      554-562 (2005). doi: 10.1111\/j.1464-5491.2005.01494.x Paper stating\u000d\u000a          the Framingham risk equation underestimates risk for coronary heart\u000d\u000a          disease in people with newly-diagnosed diabetes.\u000d\u000a    \u000a\u000a2. Stevens, R. J., Kothari, V., Adler, A. I., Stratton, I. M. United\u000d\u000a      Kingdom Prospective Diabetes Study (UKPDS) Group The UKPDS risk engine: a\u000d\u000a      model for the risk of coronary heart disease in Type II diabetes (UKPDS\u000d\u000a      56). Clin. Sci. 101, 671-679 (2001). Paper\u000d\u000a          describing the coronary heart disease risk calculation capability of\u000d\u000a          the UKPDS Risk Engine.\u000d\u000a    \u000a\u000a3. Kothari, V. et al. UKPDS 60: risk of stroke in type 2 diabetes\u000d\u000a      estimated by the UK Prospective Diabetes Study risk engine. Stroke\u000d\u000a      33, 1776-1781 (2002). doi: 10.1161\/01.STR.0000020091.07144.C7 Paper\u000a          describing the stroke risk calculation capability of the UKPDS Risk\u000d\u000a          Engine.\u000d\u000a    \u000a\u000a4. Clarke, P. M. et al. A model to estimate the lifetime health\u000d\u000a      outcomes of patients with type 2 diabetes: the United Kingdom Prospective\u000d\u000a      Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68). Diabetologia\u000d\u000a      47, 1747-1759 (2004). doi 10.1007\/s00125-004-1527-z Paper\u000d\u000a          describing the UKPDS Outcomes Model.\u000d\u000a    \u000a\u000a5. Adler A.I. Chapter 13, \"UKPDS - modelling of cardiovascular risk\u000d\u000a      assessment and lifetime simulation of outcomes\". From UKPDS: The First\u000d\u000a        30 Years, First Edition. Edited by Rury R Holman and Peter J\u000d\u000a      Watkins. Published 2008 by Blackwell Publishing Ltd (John Wiley &\u000d\u000a      Sons). Commentary describing the impact and use of the UKPDS\u000d\u000a          Outcomes Model.\u000d\u000a    \u000aFunding for this research was provided by a consortium of pharmaceutical\u000d\u000a      companies including: Novo-Nordisk, Bayer, Bristol-Myers Squibb, Hoechst,\u000d\u000a      Lilly, Lipha and Farmitalia Carlo Erba, GlaxoWellcome, SmithKline Beecham,\u000d\u000a      Pfizer, Zeneca, Pharmacia and Upjohn, and Roche.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      National Institute for Health and Care Excellence NHS Clinical\u000d\u000a        Knowledge Summaries - Clinical topic - CVD risk assessment and\u000d\u000a        management. CVD risk calculators. Available at: http:\/\/cks.nice.org.uk\/cvd-risk-assessment-and-management#!scenarioclarification\u000d\u000a        (accessed 2013). Cardiovascular risk assessment and management\u000d\u000a            advice from the NHS, recommending the use of the UKPDS Risk Engine\u000d\u000a            for people with type 2 diabetes.\u000a\u000d\u000a      National Institute for Health and Clinical Excellence (NICE) Type 2\u000d\u000a        diabetes:The management of type 2 diabetes, NICE Clinical Guideline 87\u000d\u000a        March 2009. Available at:\u000d\u000a          http:\/\/www.nice.org.uk\/nicemedia\/live\/12165\/44320\/44320.pdf. Clinical\u000a            guidelines outlining recommendations for management of type 2\u000d\u000a            diabetes in the NHS in England and Wales.\u000a\u000d\u000a      Mount Hood 4 Modeling Group. Computer modeling of diabetes and its\u000d\u000a        complications: a report on the Fourth Mount Hood Challenge Meeting. Diabetes\u000a          Care 30 (6): 1638-1646 (2007). doi:10.2337\/dc07-9919. Paper\u000d\u000a            reporting outcomes of the Mount Hood Challenge Meeting where the\u000d\u000a            UKPDS Risk Engine was shown to be the most successful model of its\u000d\u000a            type.\u000a\u000d\u000a      Sales statistics have come from Brendan Spillane, Senior Technology\u000d\u000a        Transfer Manager, ISIS Innovation Ltd. Oxford. Email from Brendan\u000d\u000a        Spillane confirming statistics kept on file. Statistics and\u000d\u000a            licence information from ISIS innovation.\u000a\u000d\u000a      National Institute for Health and Clinical Excellence (NICE) Type 2\u000d\u000a        diabetes: newer agents, NICE Short clinical guideline 87, May 2009.\u000d\u000a        Available at http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG87ShortGuideline.pdf\u000d\u000a        Clinical guidelines outlining recommendations for use of newer\u000d\u000a            agents in the management of type 2 diabetes in the NHS in England\u000d\u000a            and Wales.\u000a\u000d\u000a      O'Reilly, D et al. on behalf of Ontario Ministry of Health and\u000d\u000a        Long-term Care Development of an Ontario Diabetes Economic Model (ODEM)\u000d\u000a        and Application to a Multidisciplinary Primary Care Diabetes Management\u000d\u000a        Program. November 2006 Available at http:\/\/www.path-hta.ca\/Libraries\/Reports\/Development_of_an_Ontario_Diabetes_Economic_Model_O\u000d\u000aDEM_and_Application_to_a_Multidisciplinary_Primary_Care_Diabetes_Management_Program.sflb.ashx\u000d\u000a        (accessed 2013) Report recommending the use of the UKPDS Outcomes\u000d\u000a            model in Ontario.\u000a\u000d\u000a      McRae, I. S. et al. A cost effectiveness study of integrated\u000d\u000a        care in health services delivery: a diabetes program in Australia. BMC\u000a          Health Serv Res 8, 205 (2008). doi:\u000d\u000a        10.1186\/1472-6963-8-205 Paper describing how the UKPDS Outcomes\u000d\u000a            model was used in an Australian cost effectiveness study. \u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    PLANNING FOR A FUTURE WITH DIABETES: TOOLS TO ASSESS DIABETES RISK AND\u000d\u000a        OUTCOMES\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Predictive models are useful tools to help healthcare systems plan for\u000d\u000a      the future. Using data from the United Kingdom Prospective Diabetes Study\u000d\u000a      (UKPDS), the University of Oxford's Diabetes Trials Unit (DTU) developed\u000d\u000a      two key risk assessment models to evaluate the medical and economic\u000d\u000a      impacts of diabetes, in individual patients and on patient populations\u000d\u000a      globally.\u000d\u000a    UKPDS Risk Engine: helping doctors and patients assess heart and\u000d\u000a        stroke risk\u000d\u000a      Ensuring a patient's risk is estimated correctly is essential to inform\u000d\u000a      both patient and healthcare professionals with respect to treatment\u000d\u000a      decisions. It is also important to know that high-risk patients, who might\u000d\u000a      otherwise receive suboptimal care, are not overlooked. Prior to the UKPDS,\u000d\u000a      heart disease and stroke risks were calculated using Boston University's\u000d\u000a      Framingham Heart Study, but this underestimates heart disease and stroke\u000d\u000a      risks in patients with diabetes1. To estimate accurate risks\u000d\u000a      specifically for people with type 2 diabetes, the DTU used UKPDS data from\u000d\u000a      over 5,100 diabetic patients to develop the UKPDS Risk Engine. This\u000d\u000a      provides robust risk estimates and 95% confidence intervals for coronary\u000d\u000a      heart disease (nonfatal and fatal)2 and stroke (nonfatal and\u000d\u000a      fatal)3. It is available as a free, easy-to-use software\u000d\u000a      package fully compatible with computing platforms used in primary care,\u000d\u000a      and can be used to:\u000d\u000a    \u000d\u000a      Help determine likely event rates in clinical trials and calculate\u000d\u000a        more accurate outcome trial sample sizes;\u000d\u000a      Calculate single risk estimates for multiple risk factors;\u000d\u000a      Illustrate likely effects of therapeutic interventions;\u000d\u000a      Support the need for more intensive therapy; or Empower patients and\u000d\u000a        motivate therapy adherence.\u000d\u000a    \u000d\u000a    A new enhanced version of the UKPDS Risk Engine, to be released shortly,\u000d\u000a      incorporates the 10-year post-trial UKPDS follow-up data, and provides\u000d\u000a      risk estimates for individuals with established, as well as\u000d\u000a      newly-diagnosed type 2 diabetes. It will also provide risk estimates for\u000d\u000a      individuals with, as well as without, a prior history of cardiovascular\u000d\u000a      disease.\u000d\u000a    The UKPDS Outcomes Model: simulating the impact of health\u000d\u000a        interventions\u000d\u000a      The UKPDS Outcomes Model is a computer simulation model developed\u000d\u000a      specifically for people with type 2 diabetes4 by the DTU in\u000d\u000a      collaboration with Oxford University's Health Economics Research Centre,\u000d\u000a      using UKPDS data supplemented by cross-sectional surveys of non-inpatient\u000d\u000a      healthcare use and quality of life statistics4. As described by\u000d\u000a      Adler5, the model simulates the burden of complications for a\u000d\u000a      hypothetical population with diabetes by predicting the series of events\u000d\u000a      that unfold over time. The UKPDS Outcomes Model can determine life\u000d\u000a      expectancy, quality-adjusted life expectancy and cost-effectiveness, and\u000d\u000a      can also calculate event rates. It models four functions:\u000d\u000a    \u000d\u000a      Incidence and interdependence of complications;\u000d\u000a      Changes in risk factors over time;\u000d\u000a      Quality of life associated with each complication; and\u000d\u000a      Costs associated with complications and therapies.\u000d\u000a    \u000d\u000a    Because of this, the Model is particularly valuable to health economists\u000d\u000a      in facilitating evaluations of both individual patient and entire\u000d\u000a      populations.\u000d\u000a    "},{"CaseStudyId":"4862","Continent":[{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1605651","Name":"Thailand"},{"GeoNamesId":"2088628","Name":"Papua New Guinea"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    In 2007 there were an estimated 54.7 million pregnancies in areas with\u000a      stable P. falciparum malaria, and a further 70.5 million in areas\u000a      with low malaria transmission. With the increasing use of artemisinin\u000a      combination treatments for malaria, the survival rates of those in\u000a      affected areas have increased. As pregnant women are often excluded from\u000a      drug treatment trials, however, (particularly trials of newer\u000a      antimalarials) they have continued to receive ineffective treatment7.\u000a    The prospective research conduced by the SMRU has had a significant\u000a      impact on the health outcomes of pregnant women and infants in malaria\u000a      affected areas, with findings leading to major changes in world health\u000a      policy relating to malaria in pregnancy.\u000a    Policy\/Guidelines:\u000a    Results from SMRU's epidemiological and pharmacokinetic studies, which\u000a      provided evidence for the first time of the deleterious effect of malaria\u000a      on early fetal growth, have led to a significant paradigm shift in\u000a      clinical and world health policy. Although it was once considered\u000a      acceptable for pregnant women with asymptomatic malaria to remain\u000a      untreated, SMRU's research has shown that malaria must be prevented and\u000a      treated as early as possible during pregnancy. This has led to changes in\u000a      the World Health Organization malaria treatment guidelines in pregnancy8,\u000a      and the Green Top Guidelines on Prevention9 and Treatment10\u000a      of malaria in pregnancy.\u000a    SMRU recently provided much of the evidence for the Annual World Health\u000a      Organization Meeting on treatment and prevention of malaria in pregnancy\u000a      in the Asia Pacific Region in 201111. Now collaborating with\u000a      other investigators to promote treatment and pharmacokinetic studies in\u000a      pregnancy in Africa12 and Papua New Guinea13, SMRU\u000a      is also a partner in the Malaria in Pregnancy Consortium. The research\u000a      team has produced 96 articles, book chapters and abstracts on the topic of\u000a      maternal malaria.\u000a    Health:\u000a    Early detection and treatment of malaria in pregnancy has had clear\u000a      benefits to Karen woman and the local community on the border of Thailand.\u000a      This has been highlighted by the large reduction in malaria related\u000a      maternal mortality (from 1,000 deaths per 100,000 in 1985 to zero in 2005)14,\u000a      an increased birth weight in local infants (from 2.7 to 3 kg), and the low\u000a      prevalence of placental malaria related lesions. Due to SMRU's research,\u000a      early detection and treatment is increasingly being recognised as an\u000a      effective strategy to reduce the morbidity and mortality caused by malaria\u000a      in areas of low transmission. On the Thai-Myanmar border the beneficiary\u000a      population extends to the refugee and the migrant workers communities —\u000a      circa 300,000 people. The deleterious effects of malaria (P.falciparum\u000a      but also P.vivax) are also increasingly being recognised.\u000a    The change in pregnancy surveillance has also had a dramatic impact on\u000a      mortality rates related to non-malaria febrile illness, including adverse\u000a      fetal outcomes in those with rickettsial infection. This has also\u000a      significantly improved health outcomes for mothers and infants in the\u000a      border area15.\u000a    ","ImpactSummary":"\u000a    Research by the University of Oxford's Shoklo Malaria Research Unit\u000a      (SMRU), Mae Sot (Thailand), has had a significant impact on the health\u000a      outcomes of pregnant women and infants in malaria affected areas, with\u000a      findings leading to major changes in World Health Organization\u000a      recommendations for the prevention and treatment of malaria in pregnancy.\u000a      Its studies have established the optimum treatment regimes (using\u000a      artemisinin-based drugs) and have shown that early detection and treatment\u000a      of malaria, including asymptomatic infection, during pregnancy prevents\u000a      maternal mortality, morbidity, and improves the outcome of pregnancy.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Roll Back Malaria. Malaria in pregnancy [online]. Geneva: World Health\u000a      Organization, Available at: \u000a        http:\/\/www.rbm.who.int\/cmc_upload\/0\/000\/015\/369\/RBMInfosheet_4.htm\u000a      (Accessed 2012) \u000a    \u000aWorld Health Organisation's statistics on malaria during pregnancy.\u000a    \u000a2. McGready, R. et al. Adverse effects of falciparum and vivax\u000a      malaria and the safety of antimalarial treatment in early pregnancy: a\u000a      population-based study. Lancet Infect Dis 12\u000a      388-96(2012).doi:10.1016\/S1473-3099(11)70339-5\u000a    \u000aResearch from SMRU showing there is no significant effect on\u000a          miscarriage or congenital abnormality rates as a result of\u000a          antimalarial use.\u000a    \u000a3. Rijken, M. J. et al. Ultrasound evidence of early fetal growth\u000a      restriction after maternal malaria infection. PLoS One 7,\u000a      e31411 (2012). doi: 10.1371\/journal.pone.0031411.\u000a    \u000aStudy showing the fetal head diameter is reduced after a single\u000a          malarial infection.\u000a    \u000a4. McGready, R. & Nosten, F. The Thai-Burmese border: drug studies of\u000a      Plasmodium falciparum in pregnancy. Ann Trop Med Parasitol 93\u000a        Suppl 1, S19-23 (1999).\u000a    \u000aPaper reporting on the safety and efficacy of various antimalarials\u000a          in pregnancy.\u000a    \u000a5. McGready, R. et al. Artemisinin antimalarials in pregnancy: a\u000a      prospective treatment study of 539 episodes of multidrug-resistant\u000a      Plasmodium falciparum. Clin. Infect. Dis. 33, 2009-2016\u000a      (2001).\u000a    \u000aStudy showing ACTs are safe in pregnancy.\u000a    \u000a6. McGready, R. et al. A randomised controlled trial of\u000a      artemether-lumefantrine versus artesunate for uncomplicated plasmodium\u000a      falciparum treatment in pregnancy. PLoS Med. 5, e253\u000a      (2008). doi: 10.1371\/journal.pmed.0050253.\u000a    \u000aSMRUs final pharmacokinetic trial showing the standard six-doze\u000a          antimalarial treatment is safe in pregnant women with malaria.\u000a    This research was funded by the Wellcome Trust.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a\u0009\u000a    White, N. J., McGready, R. M. & Nosten, F. H. New medicines for\u000a      tropical diseases in pregnancy: catch-22. PLoS Med. 5,\u000a      e133 (2008). doi: 10.1371\/journal.pmed.0050133.\u000a    Paper reporting ineffective ACT treatment in pregnant women.\u000a    World Malaria Report [online]. Geneva: World Health Organization, 2009\u000a      Available at: http:\/\/whqlibdoc.who.int\/publications\/2009\/9789241563901_eng.pdf\u000a      (Accessed 2012)\u000a    WHO Malaria treatment guidelines for pregnant women.\u000a    Royal College of Obstetricians and Gynaecologists The prevention of\u000a      malaria in pregnancy [online]. (54A RG-tg, ed.):,2010 Available at: http:\/\/www.rcog.org.uk\/files\/rcog-\u000a        corp\/GTG54aPreventionMalariaPregnancy0410.pdf (Accessed 2012)\u000a    The RCOG Green-top Guidelines on the prevention of malaria in\u000a          pregnancy.\u000a    Royal College of Obstetricians and Gynaecologists.The diagnosis and\u000a      treatment of malaria in pregnancy [online]. (54B RG-tg, ed) 2010 :\u000a      Available at: http:\/\/www.rcog.org.uk\/files\/rcog-\u000a        corp\/GTG54bDiagnosisTreatmentMalariaPregnancy0810.pdf (Accessed\u000a      2012)\u000a    The RCOG Green-top Guidelines on the treatment of malaria in\u000a          pregnancy.\u000a    Rijken, M. J. et al. Malaria in pregnancy in the Asia-Pacific\u000a      region. Lancet Infect Dis 12, 75-88 (2012). doi:\u000a      10.1016\/S1473-3099(11)70315-2.\u000a    SMRUs report on the treatment and prevention of malaria in the\u000a          Asia-Pacific region, presented at the Annual WHO Meeting 2012.\u000a    Piola, P. et al. Efficacy and safety of\u000a      artemether-lumefantrine compared with quinine in pregnant women with\u000a      uncomplicated Plasmodium falciparum malaria: an open-label, randomised,\u000a      non-inferiority trial. Lancet Infect Dis 10, 762-769\u000a      (2010). doi: 10.1016\/S1473-3099(10)70202-4.\u000a    Collaboration study into the efficacy and safety of antimalarials\u000a          in pregnant women in Africa.\u000a    Poespoprodjo, J. R. et al. Adverse pregnancy outcomes in an\u000a      area where multidrug-resistant plasmodium vivax and Plasmodium falciparum\u000a      infections are endemic. Clin. Infect. Dis. 46, 1374-1381\u000a      (2008). doi: 10.1086\/586743.\u000a    Collaboration study into the efficacy and safety of antimalarials\u000a          in pregnant women in Papua New Guinea.\u000a    McGready, R, M. et al. Effect of early detection and\u000a      treatment on malaria related maternal mortality on the north-western\u000a      border of Thailand 1986-2010. PLoS One. 7, e40244 (2012).\u000a      doi: 10.1371\/journal.pone.0040244.\u000a    Report showing the large reduction in malaria related maternal\u000a          mortality on the north-western border of Thailand between 1985 to\u000a          2005.\u000a    McGready, R. et al. Arthropod borne disease: the leading\u000a      cause of fever in pregnancy on the Thai-Burmese border. PLoS Negl Trop\u000a        Dis 4, e888 (2010). doi: 10.1371\/journal.pntd.0000888.\u000a    Report showing improved outcomes from mothers and infants on the\u000a          Thai-Burmese border. \u000a\u0009\u0009  \u000a    ","Title":"\u000a    MALARIA TREATMENT IN PREGNANCY\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Contracting Malaria during pregnancy is estimated to cause as many as\u000a      10,000 maternal deaths and up to 8% of all infant deaths each year1.\u000a      Despite these statistics, malaria in pregnancy has been a relatively\u000a      neglected problem, with less than 5% of pregnant women having access to\u000a      effective interventions. This situation has been due to both the absence\u000a      of data measuring the impact of malaria during pregnancy, and the lack of\u000a      information regarding the safety of malarial drugs for both the mother and\u000a      fetus. To address these problems, Professor François Nosten and his\u000a      research team at the University of Oxford's Shoklo Malaria Research Unit\u000a      (SMRU) set out to study the epidemiology, prevention and treatment of\u000a      malaria during pregnancy, in an area of multidrug resistance in South East\u000a      Asia. Over 26 years SMRU has carried out the largest prospective cohort\u000a      study of malaria in pregnancy, with detailed assessment and follow up of\u000a      over 50,000 pregnancies between 1986 and 2012. It also undertook a number\u000a      of randomised controlled treatment trials (including pharmacokinetic\u000a      studies) on malaria in pregnancy.\u000a    Epidemiological Studies:\u000a    In the largest published series of epidemiological studies on malaria in\u000a      the first trimester (17,613 women), SMRU found that the risk of\u000a      miscarriage increases in women with malaria, whether symptomatic or not.\u000a      They also found that there was no significant effect on miscarriage or\u000a      congenital abnormality rates as a result of the antimalarial drugs they\u000a      used, and that P. vivax malaria, which is often considered a\u000a      benign infection, is also associated with fetal loss in the first\u000a      trimester2. To further understand the effects of malaria on the\u000a      fetus, SMRU also conducted detailed ultrasonography studies using 3D\u000a      imaging technology. The studies showed that the fetal head diameter is\u000a      reduced after a single (often asymptomatic) infection3, as well\u000a      as the placenta volume; this provided further evidence of the deleterious\u000a      effect of malaria (both falciparum and vivax) on early fetal growth.\u000a    Treatment Trials and Pharmacokinetic Studies:\u000a    Early detection of parasitaemia and prompt treatment with a safe and\u000a      effective therapy, are paramount to the reduction of maternal mortality\u000a      and the adverse effects of malaria in pregnancy. Due to the\u000a      ineffectiveness of generally recommended drugs (quinine,\u000a      sulfadoxine-pyrimethamine, and chloroquine) against multidrug resistant P.falciparum\u000a      parasites, SMRU set out to study the safety and efficacy of various\u000a      antimalarials in pregnancy4. Of all treatment tested, 7 days of\u000a      quinine\/clindamycin and 3 days of Malarone\/artesunate provided the best\u000a      outcome, with more than 90% efficiency. These trials also provided\u000a      evidence that the artemisinins were safe in pregnancy5. SMRUs\u000a      final pharmacokinetic trial, published in 2008, showed that the standard\u000a      six-dose (3 days) artemether-lumefantrine regimen was well tolerated and\u000a      safe in pregnant Karen women with uncomplicated falciparum malaria. This\u000a      trial also showed that the efficacy was lower than the 90% recommended by\u000a      the WHO because of low concentrations of lumefantrine6.\u000a    "},{"CaseStudyId":"4864","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d    The University of Oxford's research showing artemisinin and ACT to be the\u000d      superior treatment for malaria in both children and adults, led the World\u000d      Health Organization (WHO) to recommend ACT as the preferred antimalarial\u000d      in 20067. As a result, this research has led directly to the\u000d      successful cure of millions of malaria sufferers worldwide.\u000d    Since 2000 an increasing number of countries in which malaria is endemic\u000d      have adopted ACT in the treatment of malaria, with the number of ACT\u000d      treatment courses surging from 500,000 in 2001 to 31.3 million in 20058\u000d      - more than 80% of these orders were placed through the WHO8.\u000d      This number increased to 76 million in 2006 and reached 158 million people\u000d      in 20099. By the end of 2009, 11 African countries had provided\u000d      sufficient courses of ACT to cover more than 100% of malaria cases seen in\u000d      the public sector, while a further 8 African countries delivered enough\u000d      courses to treat between 50-100% of cases9.\u000d    In 2008, 78 countries reported a policy of treatment with ACT for malaria10.\u000d      In 2009, of the 108 countries in which malaria is endemic, 77 were using\u000d      ACT for the treatment of malaria and 52 were offering ACT free of charge\u000d      in the public sector for children under 5 years10. Due to the\u000d      availability of ACT along with other malarial control measures, such as\u000d      insecticide-treated nets and indoor-residual spraying, there has been a\u000d      50% reduction in confirmed malaria cases and malaria caused deaths in 13\u000d      African nations11.\u000d    WHO guidelines recommending the use of ACT7 along with other\u000d      control measures, such as insecticide-treated nets and indoor-residual\u000d      spraying, effectively saved the lives of 736,700 children in 34 African\u000d      countries between 2001 and 201012. A recent news release\u000d      circulated by the WHO on World Malaria Day 2012, showed that the number of\u000d      ACT courses distributed worldwide by government health departments had\u000d      \"increased exponentially\", from 11 million in 2005 to 181 million in 2010.\u000d      Along with long-lasting insecticidal nets, sprays, and better diagnostic\u000d      tests, this increased coverage has led to more than 1 million lives saved\u000d      over the past 10 years13.\u000d    ","ImpactSummary":"\u000d    The University of Oxford's Professor Nick White and his colleagues\u000d      successfully demonstrated the effectiveness of artemisinin (an ancient\u000d      Chinese remedy) in the treatment of malaria. They also pioneered\u000d      artemisinin-combination therapy (ACT), the most effective and fast-acting\u000d      malaria treatment in the world. Responsible for saving hundreds of\u000d      thousands of lives every year, ACT was recommended by the World Health\u000d      Organization (WHO) in 2006 as the primary method of malarial treatment\u000d      globally. Malaria kills more than half a million and affects over 225\u000d      million people every year.\u000d    ","ImpactType":"Health","Institution":"\u000d    The University of Oxford\u000d    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d    \u000a1. Antimalaria studies on Qinghaosu. Chin. Med. J. 92,\u000d      811-816 (1979).\u000d    \u000aPrimary paper from Chinese researchers showing that artemisinin\u000d          compounds are capable of treating malaria.\u000d    \u000a2. White, N. J. Artemisinin: current status. Trans. R. Soc. Trop.\u000d        Med. Hyg. 88 Suppl 1, S3-4 (1994).\u000d    \u000aFirst trial from Oxford researchers showing artemisinin compounds\u000d          to be the most rapidly acting of all antimalarial drugs.\u000d    \u000a3. Price, R. N. et al. Effects of artemisinin derivatives on\u000d      malaria transmissibility. Lancet 347, 1654-1658 (1996).\u000d    \u000aProspective study showing artemisinin derivatives reduce the\u000d          transmission potential of malaria.\u000d    \u000a4. Nosten, F., Hien, T. T. & White, N. J. Use of artemisinin\u000d      derivatives for the control of malaria. Med Trop (Mars) 58,\u000d      45-49 (1998).\u000d    \u000aTrial showing artemisinin-combination therapy (ACT) reduces the\u000d          risk of treatment failure, parasite resistance and side effects in\u000d          patients more effectively than monotherapy.\u000d    \u000a5. Dondorp, A. et al. Artesunate versus quinine for treatment of\u000d      severe falciparum malaria: a randomised trial. Lancet 366,\u000d      717-725 (2005).\u000d    \u000aA landmark paper showing that intravenously administered\u000d          artemisinin was a more potent, rapid, safer, simpler to administer and\u000d          more effective antimalarial treatment than quinine in adults.\u000d    \u000a6. Dondorp, A. M. et al. Artesunate versus quinine in the\u000d      treatment of severe falciparum malaria in African children (AQUAMAT): an\u000d      open-label, randomised trial. Lancet 376, 1647-1657\u000d      (2010). doi: 10.1016\/S0140-6736(10)61924-1.\u000d    \u000aTrial successfully showing artemisinin and ACT to be the superior\u000d          treatment for malaria in children.\u000d    This research was funded by the Wellcome Trust.\u000d    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000d    \u000d      Guidelines For The Treatment Of Malaria. World Health Organization\u000d        at\u000d        http:\/\/www.who.int\/malaria\/publications\/atoz\/9789241547925\/en\/index.html\u000d        (Accessed 2013).\u000d      WHO guidelines recommending the use of ACT as preferred\u000d            antimalarial. These guidelines directly reference a number of\u000d            Professor White's publications, including AQUAMAT, for\u000d            recommendations for ACT use in children.\u000d      Bosman, A. & Mendis, K. N. A major transition in malaria\u000d        treatment: the adoption and deployment of artemisinin-based combination\u000d        therapies. Am. J. Trop. Med. Hyg. 77, 193-197 (2007).\u000d      Paper reporting the increasing number of countries adopting ACTs\u000d            as the preferred treatment for malaria.\u000d      Global Health Observatory (GHO). World Health Organization at\u000d        http:\/\/www.who.int\/gho\/malaria\/control\/treatment_text\/en\/index.html\u000a\u000d      WHO report showing 100% coverage of sufficient courses of ACTs in\u000d            11 African countries.\u000d      World Malaria Report 2009. World Health Organization at\u000d        http:\/\/whqlibdoc.who.int\/publications\/2009\/9789241563901_eng.pdf\u000a          (Accessed 2013).\u000d      WHO malaria report, showing uptake of ACT treatment policy in 78\u000d            countries between 2008 and 2009.\u000d      World Malaria Report Summary 2010. World Health Organization\u000d        at\u000d        http:\/\/www.who.int\/malaria\/world_malaria_report_2010\/malaria2010_summary_keypoi\u000ants_en.pdf\u000a          (Accessed 2013).\u000d      WHO report showing a 50% reduction in confirmed malaria cases and\u000d            malaria caused deaths in 13 African nations in 2010.\u000d      Roll Back Malaria Progress & Impact Series: Saving Lives with\u000d        Malaria Control: Counting Down to the Millennium Development Goals. Roll\u000a          Back Malaria at\u000d        http:\/\/www.rbm.who.int\/ProgressImpactSeries\/report3.html\u000d        (Accessed 2013).\u000d      Report showing that the introduction of ACTs between 2001 and\u000d            2010, (along with other interventions) have effectively saved the\u000d            lives of 736,700 children in 34 African countries.\u000d      World Malaria Day 2012: Media Release and Report. World Health\u000d          Organization at\u000d        http:\/\/www.who.int\/mediacentre\/news\/releases\/2012\/malaria_20120424\/en\/index.html\u000a          (Accessed 2013).\u000d      WHO malaria day 2012 report showing the enormous increase in the\u000d            number of ACTs distributed worldwide between 2005-2010. This has\u000d            contributed to more than 1 million lives saved over the past 10\u000d            years.\u000d    \u000d    ","Title":"\u000d    INTRODUCING ARTEMISININ TO THE WORLD\u000d    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    Malaria is a deadly mosquito-borne infectious disease that has been\u000d      affecting humans for over 50,000 years. Until recently one of the most\u000d      widely used treatments for malaria was quinine, isolated from the bark of\u000d      cinchona trees. Quinine was first applied as an antimalarial in the 17th\u000d      century, but after years of use malaria parasites have developed a\u000d      resistance to quinine, as well as other antimalarial medications.\u000d    Artemisinin is a compound derived from the leaves of the annual wormwood\u000d      Artemisia annua. Chinese herbalists have used derivatives of annual\u000d      wormwood for thousands of years in the treatment of malaria and other\u000d      diseases, however, the artemisinin compound capable of treating malaria\u000d      was only officially discovered by Chinese researchers in 19721.\u000d    More than a decade after this initial discovery, the University of\u000d      Oxford's Professor Nick White and his Bangkok-based research team began\u000d      undertaking clinical trials to test the relative effectiveness of\u000d      artemisinin as an antimalarial treatment. In their first trial, they found\u000d      artemisinin compounds to be the most rapidly acting of all antimalarial\u000d      drugs2. The team then undertook a series of prospective studies\u000d      of 5,193 adults and children with acute malaria on the western border of\u000d      Thailand, between 1990 and 1995. After finding that artemisinin\u000d      derivatives reduce the transmission potential of malaria3, they\u000d      then trialed a combination treatment of mefloquine (a synthetic form of\u000d      quinine) and artemisinin. Combining artemisinin-based derivatives to\u000d      rapidly clear malaria parasites from the body, along with slower acting\u000d      partner drugs to destroy any surviving parasites, proved to be the most\u000d      effective way of treating malaria. Compared to monotherapy,\u000d      artemisinin-combination therapy (ACT) reduced the risk of treatment\u000d      failure, parasite resistance and side effects in patients4.\u000d    In a landmark paper published in 2005, the University of Oxford team\u000d      showed that in adults, intravenously administered artemisinin was a more\u000d      potent and rapid antimalarial treatment than quinine5. They\u000d      also found artemisinin to be safer, simpler to administer and more\u000d      effective, with mortality rates reduced by 34.7% in artemisinin recipients\u000d      compared to those treated with quinine5.\u000d    Since the majority of malarial mortality occurs in children under the age\u000d      of five, White and his team continued their research to prove the\u000d      effectiveness of artemisinin in the treatment of infants and children. In\u000d      a study of African children suffering from severe malaria, mortality\u000d      occurred in 297 of the 2,713 children treated with quinine, in comparison\u000d      to 230 deaths from the 2,712 children treated with artemisinin6,\u000d      a relative reduction in mortality of 22.5%. Post-treatment hypoglycaemia\u000d      was also less frequent in the artemisinin treatment group than in the\u000d      quinine group6.\u000d    As a result of this research, the University of Oxford successfully\u000d      showed artemisinin and ACT to be the superior treatment for malaria in\u000d      both children and adults6.\u000d    "},{"CaseStudyId":"4865","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"1605651","Name":"Thailand"},{"GeoNamesId":"1327865","Name":"Myanmar"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    Researchers from the University of Oxford's Mahidol-Oxford Research Unit,\u000a      Thailand (MORU), were the first to expose the full extent of artemisinin\u000a      resistance in western Cambodia, prompting urgent action from local\u000a      governments and the WHO7. The Unit's longitudinal study showing\u000a      the spread of resistance to the Thailand-Myanmar border confirmed the\u000a      ferociousness of the problem, prompting further action and funding from\u000a      health authorities and governments around the world for rapid research and\u000a      containment programmes. Following the publication of MORU's June 20093\u000a      paper on artemisinin resistance in western Cambodia the WHO released a Global\u000a        report on antimalarial drug efficacy and drug resistance: 2000-20108,\u000a      which cites MORU's 2009 study as key evidence to artemisinin resistance.\u000a      This research also provided evidence for the WHO's definition of\u000a      resistance, characterised by slow rates of parasite clearance8.\u000a    MORU's July 20094 paper also provided evidence to the WHO that\u000a      measures can be taken in the clinic to prevent the spread of resistance8.\u000a      The study was cited in the WHO's Global report on antimalarial drug\u000a        efficacy and drug resistance: 2000-20108, which\u000a      emphasised the need for correct prescribing, adherence to prescribed drug\u000a      regimens, and provision of effective treatment regimens, particularly\u000a      among hyperparasitaemic patients. In 2011 the WHO released its Global\u000a        plan for artemisinin resistance containment (GPARC)9 - a\u000a      worldwide \"call to action\" for the prevention of further resistance. The\u000a      GPARC report cites evidence from MORU4 studies and recommends\u000a      several courses of action, reflecting MORU's key strategies5\u000a      for the containment of malaria resistance, including9:\u000a    — Stopping the spread of resistant parasites, e.g. mass screening and\u000a      drug administration in target areas;\u000a    — Increasing monitoring and surveillance to evaluate the threat of\u000a      artemisinin resistance;\u000a    — Improving access to diagnostics and rational treatment with ACTs;\u000a    — Investing in artemisinin resistance-related research; and\u000a    — Motivating action and mobilising resources (from stakeholders at\u000a      global, regional, and national levels)9.\u000a    As a result of the University of Oxford's research and the subsequent\u000a      call to action from the WHO, a number of government organisations have\u000a      pledged assistance for further research into artemisinin resistance in\u000a      Southeast Asia. The UK Department for International Development has set up\u000a      the Artemisinin Resistant Malaria Program appointing MORU as the\u000a      lead research institute on the project. The aim of this collaborative\u000a      program is to rapidly identify and geographically contain artemisinin\u000a      resistance, in order to prevent its spread to other parts of Southeast\u000a      Asia and Africa10. As part of this program the Tracking\u000a        Resistance to Artemisinin Collaboration was launched in January\u000a      2011, to investigate the spread of parasite resistance to\u000a      artemisinin-based therapies in western Cambodia, and on the Thailand\u000a      Myanmar border11. MORU's 2012 study, which emphasised the\u000a      global threat of artemisinin resistance, has received worldwide media\u000a      attention from Reuters12 and TIME magazine13, to The\u000a      Times of India14, and the Deccan Herald (India)15.\u000a      Such widespread media attention has highlighted the problem of resistance,\u000a      encouraging charities and investors to support global containment\u000a      programs. This media attention has also improved social understanding of\u000a      the problem in high-risk areas, such as India.\u000a    Increased funding for research into artemisinin resistance has led to\u000a      ground-breaking outcomes in the genetic understanding of malaria\u000a      parasites. A recent discovery from Oxford University researchers,\u000a      published in April 2013, shows that malaria parasites in western Cambodia\u000a      are genetically different from the strains of parasites found in other\u000a      parts of the world, such as Africa. These findings will make it possible\u000a      for health care workers to track the resistant strains of malaria\u000a      parasites as they emerge, and to develop an appropriate response16.\u000a    ","ImpactSummary":"\u000a    Researchers at the Mahidol-Oxford Research Unit (MORU) in Thailand\u000a      performed the first comparative trials to unambiguously show artemisinin\u000a      resistance in Plasmodium falciparum parasites in western Cambodia,\u000a      as well as its emergence on the Thailand-Myanmar border. These studies\u000a      emphasised the importance of urgent containment, leading to rapid\u000a      responses from the World Health Organization (WHO) and international\u000a      governments for the tracking and containment of drug-resistant malaria.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Jambou, R. et al. Resistance of Plasmodium falciparum field\u000a      isolates to in-vitro artemether and point mutations of the SERCA-type\u000a      PfATPase6. Lancet 366, 1960-1963 (2005). http:\/\/dx.doi.org\/10.1016\/S0140-6736(05)67787-2.\u000a      First study to raise concerns about tolerance to artemisinin in\u000a          western Cambodia.\u000a    \u000a\u000a2. Noedl, H. et al. Evidence of artemisinin-resistant malaria in\u000a      western Cambodia. N. Engl. J. Med. 359, 2619-2620 (2008).\u000a      doi: 10.1056\/NEJMc0805011. Study reporting artemisinin resistance\u000a          in 3% of patients in the Battambang Province, western Cambodia.\u000a    \u000a\u000a3. Dondorp, A. M. et al. Artemisinin resistance in Plasmodium\u000a      falciparum malaria. N. Engl. J. Med. 361, 455-467 (2009).\u000a      doi: 10.1056\/NEJMoa0808859. Mahidol-Oxford's pivotal study showing\u000a          a 30% resistance rate to artesunate in Plasmodium falciparum parasites\u000a          in western Cambodia.\u000a    \u000a\u000a4. White, N. J. et al. Hyperparasitaemia and low dosing are an\u000a      important source of anti-malarial drug resistance. Malar. J. 8,\u000a      253 (2009). doi: 10.1186\/1475-2875-8-253. Mahidol-Oxford's study\u000a          showing that standard dosing of artemisinin can cause resistance in\u000a          patients with low drug levels and high parasite burdens, as well as\u000a          patients with hyperparasitaemia.\u000a    \u000a\u000a5. Dondorp, A. M. et al. Artemisinin resistance: current status\u000a      and scenarios for containment. Nat. Rev. Microbiol. 8,\u000a      272-280 (2010). doi: 10.1038\/nrmicro2331. A review from\u000a          Mahidol-Oxford summarising the extent of artemisinin resistance and\u000a          outlining key strategies to delay and contain its spread.\u000a    \u000a\u000a6. Phyo, A. P. et al. Emergence of artemisinin-resistant malaria\u000a      on the western border of Thailand: a longitudinal study. Lancet 379,\u000a      1960-1966 (2012). doi: 10.1111\/j.1365-2125.2011.04103.x. Mahidol-Oxford's\u000a          ten-year longitudinal study showing that artemisinin-resistant\u000a          Plasmodium falciparum parasites had emerged along the Thailand-Myanmar\u000a          border eight years prior to publication, and that rates of resistance\u000a          were rapidly increasing.\u000a    \u000aThis research was funded by the Wellcome Trust.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Samarasekera, U. Countries race to contain resistance to key\u000a        antimalarial. Lancet 374, 277-280 (2009). http:\/\/dx.doi.org\/10.1016\/S0140-6736(09)61349-0.\u000a        Review by Udani Samarasekera, senior editor of The Lancet,\u000a            regarding the emergence of artemisinin resistance. This review\u000a            outlines the timeline of the discovery of resistance, showing the\u000a            pivotal role of Mahidol-Oxford's research in identifying resistance,\u000a            and prompting action from local governments and the WHO.\u000a\u000a      World Health Organization. Global Report on Antimalarial Drug\u000a          Efficacy and Drug Resistance: 2000-2010. Geneva:WHO (2010).\u000a        [Accessed June 2013]\u000a        http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241500470_eng.pdf\u000a        WHO report released in 2010 following Mahidol-Oxford's\u000a            identification of artemisinin resistance. This report directly cites\u000a            Mahidol-Oxford's June 2009 study as key evidence for artemisinin\u000a            resistance, and its July 2009 study as evidence for the use of\u000a            combination therapy over monotherapy, for the prevention of\u000a            resistance.\u000a\u000a      World Health Oganisation. Global Plan For Artemisinin Resistance\u000a          Containment (GPARC). Geneva: WHO, (2011). [Accessed July 2013]\u000a        http:\/\/www.who.int\/malaria\/publications\/atoz\/artemisinin_resistance_containment_201\u000a          1.pdf WHO's Global plan for artemisinin resistance\u000a            containment, a worldwide \"call to action\" for the prevention of\u000a            further resistance, citing evidence from Mahidol-Oxford, and\u000a            recommending several courses of action, reflecting Mahidol-Oxford's\u000a            key strategies for the containment of malaria resistance.\u000a\u000a      Department for International Development - Research for Development\u000a        Project Record. Artemisinin Resistant Malaria Programme,\u000a        2010-2014.\u000a        [Accessed July 2013] http:\/\/r4d.dfid.gov.uk\/Project\/60881\/Default.aspx.\u000a        Mahidol-Oxford is the lead research institute working on the UK\u000a            Department for International Development's, Artemisinin Resistant\u000a            Malaria Program.\u000a\u000a      WorldWide Antimalarial Resistance Network (WWARN).Tracking\u000a        Resistance to Artemisinin Collaboration (TRAC) [Accessed July 2013]\u000a        http:\/\/www.wwarn.org\/partnerships\/projects\/trac.\u000a        Mahidol-Oxford is the leading partner institute for the Worldwide\u000a            Antimalarial Resistance Network's, Tracking Resistance to\u000a            Artemisinin Collaboration.\u000a\u000a      Lyn, T.E. Drug-resistant malaria spreads along Thai-Myanmar\u000a        border-study Reuters (U.S. Edition) [online] (6 April 2012)\u000a        [Accessed July 2013]\u000a        http:\/\/www.reuters.com\/article\/2012\/04\/05\/us-malaria-myanmar-drugresistance-idUSBRE8340ZI20120405.\u000a        News article about artemisinin resistance on Thai-Myanmar border.\u000a\u000a      Walshe, B. Drug-Resistant Malaria Is Spreading, and It Could Be a\u000a        Public Health Disaster. TIME [Online] (6 April 2012) [Accessed\u000a        July 2013]\u000a        http:\/\/healthland.time.com\/2012\/04\/06\/drug-resistant-malaria-is-spreading-and-it-could-be-a-public-health-disaster\/.\u000a        News article about artemisinin resistance on Thai-Myanmar border.\u000a\u000a      Sinha, K. Drug-resistant malaria spreading faster and wider. Times\u000a          of India [online] (6 April 2012) [Accessed July 2013] http:\/\/articles.timesofindia.indiatimes.com\/2012-04-06\/science\/31299610_1_drug-resistant-parasite-artemisinin-resistance-drug-resistant-malaria\u000a        News article about artemisinin resistance on Thai-Myanmar border.\u000a\u000a      Drug-resistant malaria may spread, India warned. Deccan Herald\u000a        [Online] (6 April 2012) [Accessed July 2013]\u000a        http:\/\/www.deccanherald.com\/content\/240094\/drug-resistant-malaria-may-spread.htmlNews\u000a            article about artemisinin resistance on Thai-Myanmar border.\u000a\u000a      Miotto, O. et al. Multiple populations of\u000a        artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet.\u000a        45(6):648-55 (2013). doi: 10.1038\/ng.2624. The most recent\u000a            discovery from Mahidol-Oxford shows that malaria parasites in\u000a            western Cambodia are genetically different from the strains of\u000a            parasites found in other parts of the world, such as Africa. This\u000a            will enable researchers to track resistant strains of malaria\u000a            parasites, allowing rapid detection of resistance as it emerges.\u000a\u000a    \u000a    ","Title":"\u000a    ALERTING THE WORLD TO ARTEMISININ RESISTANCE\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Plasmodium falciparum parasite is transmitted by the female\u000a      Anopheles mosquito and causes the most dangerous form of malaria in\u000a      humans. Due to vital research from the University of Oxford's\u000a      Mahidol-Oxford Research Unit (MORU) in Thailand, ACT was recommended by\u000a      the WHO as the first-line treatment for malaria in 2006, and has since\u000a      been used to treat both mild and severe Plasmodium falciparum\u000a      malaria worldwide. As a result, ACT, along with scaled up preventative\u000a      measures in malaria endemic areas, has been responsible for significant\u000a      reductions in malaria-related mortality of more than 25% globally over the\u000a      past decade. The continued success of artemisinin as the gold-standard\u000a      antimalarial has been a major public health priority for local\u000a      governments, the WHO, and MORU for the past two decades. But while MORU\u000a      researchers were collating data for a longitudinal study on the resistance\u000a      profile of artemisinin on the northwestern border of Thailand, concerns\u000a      regarding tolerance to artemisinin in western Cambodia began to emerge1.\u000a      These concerns were confirmed in a 2008 study2, which reported\u000a      artemisinin resistance in approximately 3% of patients in the Battambang\u000a      Province2.\u000a    Responding quickly, University of Oxford researchers at MORU performed\u000a      two randomised trials comparing the effectiveness of artemisinin-based\u000a      treatments for uncomplicated falciparum malaria in western Cambodia and\u000a      northwestern Thailand3. Published in June 2009, this study\u000a      showed reduced in vivo susceptibility to artesunate in Plasmodium\u000a        falciparum parasites in western Cambodia, resulting in a resistance\u000a      rate of approximately 30% - ten times higher than previous reports3.\u000a      One month later, in July 2009 the MORU published a study showing that\u000a      standard dosing of artemisinin can cause resistance in patients with low\u000a      drug levels and high parasite burdens, particularly among children and\u000a      pregnant women. This study also showed that patients with\u000a      hyperparasitaemia (a parasite blood count greater than 250,000 per µL),\u000a      who had received several treatments, were at a greater risk of\u000a      reoccurrence and resistance to artemisinin therapy. This research\u000a      emphasised the importance of ensuring that only artemisinin combinations\u000a      are used, rather than monotherapies. It also highlighted the importance of\u000a      tailoring treatment regimens to suit the pharmacokinetic needs of\u000a      patients, particularly children, pregnant women, and those suffering from\u000a      hyperparasitaemia4.\u000a    A 2010 review from MORU summarised the extent of artemisinin resistance\u000a      and outlined key strategies to delay and contain its spread, including5:\u000a      increased coverage with prompt and effective antimalarial treatment;\u000a      reduction of drug pressure, e.g. exploring alternative treatments; mass\u000a      ACT administration to targeted populations; increased surveillance,\u000a      investigation, and targeted control measures; further research into\u000a      identifying multiple first-line therapies; and further research into\u000a      alternative control methods, e.g. malaria vaccines5.\u000a    In 2012 MORU published its ten-year longitudinal study on the resistance\u000a      profile of artemisinin therapy on the northwestern border of Thailand,\u000a      between 2001 and 2010. This pivotal study not only showed that\u000a      artemisinin-resistant Plasmodium falciparum parasites had emerged\u000a      along the Thailand-Myanmar border, eight years prior to publication, it\u000a      also reported that rates of resistance were rapidly increasing6,\u000a      further emphasising the need for rapid containment.\u000a    "},{"CaseStudyId":"4866","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1733045","Name":"Malaysia"},{"GeoNamesId":"1562822","Name":"Vietnam"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    By identifying the best fluid replacement techniques for the management\u000d\u000a      of severe shock, OUCRU has significantly improved clinical understanding\u000d\u000a      and management of DSS globally. This research has improved international\u000d\u000a      guidelines and clinical practice guidance in endemic countries, and has\u000d\u000a      also directly influenced changes in the WHO's 2009 Dengue Guidelines\u000d\u000a        for Diagnosis, Treatment, Prevention and Control, and the WHO's 2012\u000d\u000a      Handbook for Clinical Management of Dengue. The impact on patients\u000d\u000a      has been faster, safer and more effective resuscitation. The guidelines\u000d\u000a      have simplified management for clinicians and helped to avoid unnecessary\u000d\u000a      interventions.\u000d\u000a    WHO 2009 Guidelines\u000d\u000a    WHO guidelines for the management of dengue were first formulated in 1975\u000d\u000a      and subsequently updated in 1986, 1994, and 1997. While these guidelines\u000d\u000a      recommended immediate treatment with crystalloid solutions for dengue\u000d\u000a      shock, and colloid treatment for persistent shock, a lack of evidence and\u000d\u000a      any significant updates since 1975 led to increasing concern that the\u000d\u000a      recommendations were outdated and ineffective. In particular, there was\u000d\u000a      debate among clinicians regarding the use of crystalloids versus colloids.\u000d\u000a    OUCRU ended this debate by performing the first three randomised blind\u000d\u000a      trials, investigating the effect of different crystalloid and colloid\u000d\u000a      fluid regimens on the outcome of DSS. This work provided key evidence for\u000d\u000a      the WHO's 2009 Dengue guidelines for the management of DSS.\u000d\u000a    The following recommendations were published in the 2009 WHO Dengue\u000d\u000a        Guidelines for Diagnosis, Treatment, Prevention and Control,\u000d\u000a      directly citing OUCRU's three fluid trials2,3,5 as key\u000d\u000a      evidence:\u000d\u000a    \"The action plan for treating patients with compensated shock is as\u000d\u000a        follows... Start intravenous fluid resuscitation with isotonic\u000d\u000a        crystalloid solutions at 5-10 ml\/kg\/hour over one hour.\" 7\u000d\u000a      \"Based on the three randomized controlled trials comparing the\u000d\u000a        different types of fluid resuscitation regime in dengue shock in\u000d\u000a        children, there is no clear advantage to the use of colloids over\u000d\u000a        crystalloids in terms of the overall outcome2,3,5.\u000d\u000a        However, colloids may be the preferred choice if the blood pressure has\u000d\u000a        to be restored urgently...\"7\u000d\u000a    \"Colloids have been shown to restore the cardiac index and reduce the\u000d\u000a        level of haematocrit faster than crystalloids in patients with\u000d\u000a        intractable shock.\" 7\u000d\u000a    Ministry of Health Malaysia 2010 Guidelines\u000d\u000a    The 2009 WHO updates led a number of local health ministries to revise\u000d\u000a      their own clinical practice guidelines. The Ministry of Health Malaysia\u000d\u000a      and Academy of Medicine Malaysia revised its Management of Dengue\u000d\u000a        Infection in Adults, Clinical Practice Guidelines in 2010, directly\u000d\u000a      citing the three key papers from OUCRU8.\u000d\u000a    \"To date, only three randomised controlled trials studying different\u000d\u000a        types of fluid regime in DSS in children aged from 5 to 15 years of age\u000d\u000a        are available2,3,5. Our recommendations are\u000d\u000a        extrapolated from these studies. These studies showed no clear advantage\u000d\u000a        of using any of the colloids over crystalloids in terms of the overall\u000d\u000a        outcome. However, colloids may be preferable as the fluid of choice in\u000d\u000a        patients with intractable shock in the initial resuscitation.\" 8\u000d\u000a    WHO Handbook for Clinical Management of Dengue 2012\u000d\u000a    The WHO released a revised Handbook for Clinical Management of Dengue\u000d\u000a      in 20129, emphasising the importance of early aggressive\u000d\u000a      resuscitation. OUCRU's three key papers on fluid replacement regimens were\u000d\u000a      cited directly in this handbook9.\u000d\u000a    \"All patients (infants, children and adults) with hypotensive shock\u000d\u000a      should be managed more vigorously...Colloids may be the preferred\u000d\u000a        choice if the BP has to be restored urgently, i.e. in those with pulse\u000d\u000a        pressure less than 10 mmHg. Colloids have been shown to restore the\u000d\u000a        cardiac index and reduce the level of haematocrit faster than\u000d\u000a        crystalloids in patients with intractable shock 2,3,5.\u000d\u000a      9\u000d\u000a    UpToDate Clinical Guidelines 2013\u000d\u000a    OUCRU Vietnam's three papers on fluid replacement regimens are also cited\u000d\u000a      in UpToDate, an evidence-based clinical decision support system,\u000d\u000a      which is authored by physicians to help clinicians make the right\u000d\u000a      decisions at the point of care. Last updated in 201310, the\u000d\u000a      following recommendations appear on the UpToDate page for the Prevention\u000a        and Treatment of Dengue Virus Infection.\u000d\u000a    \"There has been debate as to whether crystalloids or colloids should\u000d\u000a        be used for volume replacement in critically ill patients. Three\u000d\u000a        randomized, blinded trials have investigated the effect of different\u000d\u000a        fluid regimens on outcome2,3,5. The largest of these\u000d\u000a        studies was a double-blind randomized comparison of three fluids for\u000d\u000a        initial resuscitation of 512 Vietnamese children with dengue shock\u000d\u000a        syndrome5....This trial established that Ringer's lactate\u000d\u000a      was a safe, effective, and inexpensive alternative in initial\u000d\u000a      resuscitation of patients with moderate shock. In patients with severe\u000d\u000a      shock, dextran and starch colloid solutions performed similarly, although\u000d\u000a      dextran was associated with more hypersensitivity reactions.\"\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research in the Oxford University Clinical Research Unit (OUCRU) in\u000d\u000a      Vietnam have spent the past two decades defining effective management\u000d\u000a      strategies for dengue, which is the most significant mosquito-borne viral\u000d\u000a      disease in humans. Dengue affects an estimated 50 million people and kills\u000d\u000a      over 22,000 patients (mainly children) worldwide each year. OUCRU research\u000d\u000a      directly underpins the clinical practice guidelines worldwide for the\u000d\u000a      treatment of dengue shock syndrome (DSS), including the World Health\u000d\u000a      Organization's (WHO) 2009 Dengue Guidelines, leading to faster, more\u000d\u000a      effective and safer resuscitation of affected individuals.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. World Health Organisation, Dengue, Dengue Haemorrhagic Fever and\u000d\u000a      Dengue Shock Syndrome in the Context of the Integrated Management of\u000d\u000a      Childhood Illness, Discussion Papers on Child Health (2005). Available at\u000d\u000a      http:\/\/whqlibdoc.who.int\/hq\/2005\/WHO_FCH_CAH_05.13_eng.pdf\u000d\u000a      (Accessed 2013) WHO report showing fatality rates among children\u000d\u000a          with DSS were 2.5% in 2005.\u000d\u000a    \u000a\u000a2. Dung, N. M. et al. Fluid replacement in dengue shock syndrome:\u000d\u000a      a randomized, double-blind comparison of four intravenous-fluid regimens.\u000d\u000a      Clin. Infect. Dis. 29, 787-794 (1999). Trial\u000d\u000a          comparing the top four intravenous-fluid regimens for resuscitation\u000a          of children with DSS.\u000d\u000a    \u000a\u000a3. Ngo, N. T. et al. Acute management of dengue shock syndrome: a\u000d\u000a      randomized double-blind comparison of 4 intravenous fluid regimens in the\u000d\u000a      first hour. Clin. Infect. Dis. 32, 204-213 (2001) doi:\u000d\u000a      10.1086\/318479. Trial comparing the same four intravenous\u000d\u000a          fluid regimens in the initial resuscitation of a larger group of Vietnamese\u000a          children with DSS.\u000d\u000a    \u000a\u000a4. Wills, B. A. et al. Size and charge characteristics of the\u000d\u000a      protein leak in dengue shock syndrome. J. Infect. Dis. 190,\u000d\u000a      810-818 (2004). doi: 10.1086\/422754 Study focusing on\u000d\u000a          specific aspects of DSS pathogenesis, including investigations into\u000d\u000a          the characteristics of protein leaks in DSS.\u000d\u000a    \u000a\u000a5. Wills, B. A. et al. Comparison of three fluid solutions for\u000d\u000a      resuscitation in dengue shock syndrome. N. Engl. J. Med. 353,\u000d\u000a      877-889 (2005) doi: 10.1056\/NEJMoa044057. A third larger\u000d\u000a          scale resuscitation trial comparing the top three performing fluid\u000d\u000a        solutions for DSS.\u000d\u000a    \u000a\u000a6. Deen, J. L. et al. The WHO dengue classification and case\u000d\u000a      definitions: time for a reassessment. Lancet 368, 170-173\u000d\u000a      (2006). doi: 10.1016\/S0140-6736(06)69006-5. Paper calling for a\u000d\u000a          reassessment of the WHO's dengue classification and case definitions.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000d\u000a    \u000d\u000a      WHO Dengue Guidelines for Diagnosis, Treatment, Prevention and\u000d\u000a        Control. New Edition 2009. WHO Chapter 2. Page 50 (2009).\u000d\u000a        Available at http:\/\/whqlibdoc.who.int\/publications\/2009\/9789241547871_eng.pdf\u000d\u000a         (Accessed 2013). WHO Dengue management recommendations,\u000d\u000a            directly citing OUCRU's three fluid trials as key evidence\u000d\u000a            for management procedures.\u000a\u000d\u000a      Ministry of Health, Malaysia and Academy of Medicine, Malaysia. Management\u000a          of Dengue Infection in Adults. (2010) Available at http:\/\/www.moh.gov.my\/attachments\/5502\u000d\u000a        (Accessed 2013). Revised Management of Dengue Infection\u000d\u000a            in Adults, Clinical Practice Guidelines, directly citing the three\u000d\u000a            key papers from OUCRU.\u000a\u000d\u000a      World Health Organisation Handbook for Clinical Management of Dengue.\u000d\u000a        apps.who.int (2012). Available at http:\/\/apps.who.int\/iris\/bitstream\/10665\/76887\/1\/9789241504713_eng.pdf\u000d\u000a        (Accessed 2013) WHO revised Handbook for Clinical Management of\u000d\u000a            Dengue emphasising the importance of early aggressive\u000d\u000a            resuscitation. OUCRU's three key papers on fluid replacement\u000d\u000a            regimens are cited.\u000a\u000d\u000a      Rothman, A. L., Srikiatkhachorn, A. & Kalayanarooj, S. Prevention\u000d\u000a        and treatment of dengue virus infection (2013) In UpToDate Basow, DS\u000d\u000a        (Ed), UpToDate, Waltham, MA, 2013.(Accessed 2013) Website accessible to\u000d\u000a        subscribers only (available on request). http:\/\/www.uptodate.com\/contents\/prevention-and-treatment-of-dengue-virus-infection?\u000d\u000asource=search_result&search=dengue+virus+infection&selectedTitle=2%7E\u000d\u000a          43. OUCRU's three papers on fluid replacement regimens are\u000d\u000a            cited in UpToDate's guidelines on Dengue management.\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    CLINICAL MANAGEMENT OF DENGUE FEVER\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Dengue haemorrhagic fever and dengue shock syndrome (DSS) are major\u000d\u000a      causes of childhood morbidity and mortality. For many years, fluid\u000d\u000a      resuscitation has been the leading treatment for DSS, as it helps to\u000d\u000a      counteract plasma leakage from intravascular permeability, which leads to\u000d\u000a      shock. In spite of the relative success of fluid resuscitation, the WHO\u000d\u000a      reported in 2005 that fatality rates among children with DSS were still\u000d\u000a      2.5%1, equating to approximately 550 children per year. As\u000d\u000a      Aedes mosquitoes (found in tropical and subtropical regions) are\u000d\u000a      responsible for the spread of dengue, over 70% of cases arise in Southeast\u000d\u000a      Asia and the Western Pacific. In Vietnam alone there were 105,370 cases of\u000d\u000a      dengue and 87 dengue related deaths in 2009.\u000d\u000a    Without an effective vaccine or specific cure for dengue fever,\u000d\u000a      researchers at the OUCRU in Vietnam have spent the past two decades\u000d\u000a      investigating successful interventions for improved clinical management\u000d\u000a      and outcomes.\u000d\u000a    While WHO guidelines for the management of dengue were first published in\u000d\u000a      1975, by 1997 updates to these guidelines still identified the need for\u000d\u000a      evidence-based recommendations for the management of DSS. In particular,\u000d\u000a      concerns were raised regarding intravenous-fluid regimens for the\u000d\u000a      management of moderate and severe shock.\u000d\u000a    In 1999 OUCRU published the first randomised, double-blind trial,\u000d\u000a      comparing the top four intravenous-fluid regimens for resuscitation of\u000d\u000a      children with DSS2. The University of Oxford group found that\u000d\u000a      the two colloids used (dextran and gelatin) restored cardiac index, blood\u000d\u000a      pressure, and normalised blood cells more rapidly than the two\u000d\u000a      crystalloids (Ringer's lactate and \"normal\" saline). The trial also showed\u000d\u000a      that out of the four fluids used, dextran provided the most rapid\u000d\u000a      normalisation of blood cells and restoration of the cardiac index, without\u000d\u000a      adverse effects2.\u000d\u000a    A subsequent trial from OUCRU compared the same four intravenous fluid\u000d\u000a      regimens in the initial resuscitation of a larger group of Vietnamese\u000d\u000a      children with DSS3. While all children survived, and there was\u000d\u000a      no clear advantage to using any of the four fluids, researchers noted that\u000d\u000a      the group receiving Ringer's lactate (a crystalloid) took the longest to\u000d\u000a      recover. In an analysis of the pulse pressure of patients before and after\u000d\u000a      fluid regimens, the trial also showed significant benefits from colloids\u000d\u000a      among children presenting with lower pulse pressures3.\u000d\u000a    Following these initial studies OUCRU addressed further specific aspects\u000d\u000a      of DSS pathogenesis, including investigations into the characteristics of\u000d\u000a      protein leaks in DSS4. A third larger scale resuscitation trial\u000d\u000a      compared the top three performing fluid solutions for DSS5.\u000d\u000a      Results from this trial indicated that Ringer's lactate should be used for\u000d\u000a      aggressive initial resuscitation in children with moderately severe shock,\u000d\u000a      while both colloids work equally as well in patients with severe shock. A\u000d\u000a      superior side effect profile also supported the use of hydroxyethyl starch\u000d\u000a      as the preferred colloid over dextran5.\u000d\u000a    This research showed:\u000d\u000a    \u000d\u000a      The benefits of aggressive early fluid resuscitation using isotonic\u000d\u000a        crystalloid solution (Ringer's lactate) for children with moderately\u000d\u000a        severe shock;\u000d\u000a      Equal survival rates for colloid and crystalloid regimens in patients\u000d\u000a        with severe shock; and\u000d\u000a      The preferred use of colloids for rapid recovery in severe shock.\u000d\u000a    \u000d\u000a    Following the publication of OUCRU's third trial in 2005, researchers\u000d\u000a      from OUCRU Vietnam contributed to a pivotal paper, calling for a complete\u000d\u000a      reassessment of the WHO's dengue classification and case definitions, to\u000d\u000a      ensure better diagnosis and management of DHF and DSS6.\u000d\u000a    "},{"CaseStudyId":"4867","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"1643084","Name":"Indonesia"},{"GeoNamesId":"357994","Name":"Egypt"},{"GeoNamesId":"1562822","Name":"Vietnam"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    The rapid spread of avian and human H5N1 infection throughout Asia in\u000a      2004 occurred less than 12 months after the global SARS outbreak, which\u000a      almost reached pandemic proportions (8,273 cases worldwide, 9.6% fatality)\u000a      in 2003. Not surprisingly the unknown and significantly more deadly human\u000a      H5N1 virus, with a fatality rate of 60%, became a high priority concern to\u000a      the WHO. Fortunately, unlike SARS, first responders soon realised that\u000a      human cases of H5N1 were mostly contracted through direct contact with\u000a      birds, reducing the frightening possibility of human-to-human infection.\u000a      As a result, containment of H5N1 in humans has been relatively successful.\u000a      The WHO recently reported a total of 608 confirmed human cases of H5N1 and\u000a      359 deaths between 2003 and 2012.\u000a    As Vietnam faced the third largest number of all cases worldwide (after\u000a      Egypt and Indonesia) the University of Oxford's OUCRU researchers in\u000a      Vietnam were at the frontline of the global investigation into H5N1. As a\u000a      result, Oxford's research into the epidemiological and pathological\u000a      features of human H5N1 infection provided the WHO with key evidence for\u000a      rapid clinical guidelines for the management and investigation of H5N1\u000a      infection globally during the period from 2006-2013.\u000a    WHO rapid advice guidelines on pharmacological management of humans\u000a          infected with avian influenza A (H5N1) virus7\u000a    In early 2006, as mortality rates rose and infection spread throughout\u000a      the world, the WHO assembled an international panel of experts and\u000a      clinicians, including Professor Jeremy Farrar (Director of OUCRU Vietnam),\u000a      to assist in developing rapid advice for the pharmacological management of\u000a      patients with human H5N1 infection.\u000a    The early research from OUCRU1 provided the panel with key\u000a      data on the clinical features of H5N1 infection in humans, as well as\u000a      preliminary epidemiologic findings. Research from OUCRU Vietnam directly\u000a      led to the WHO's strong recommendations for the use of Oseltamivir\u000a      antiviral drugs in patients with, \"confirmed or strongly suspected H5N1\u000a      infection\"2,3.\u000a    The 2006 guidelines also included a clinical algorithm adapted from an\u000a      algorithm used at the Hospital for Tropical Diseases, in Ho Chi Minh City,\u000a      by OUCRU's Dr Tran Tinh Hien7. The WHO guidelines for the\u000a      management of H5N1 have remained in place since 2006 and have been the\u000a      major instrument for the treatment of cases in the period 2006-2013.\u000a    WHO guidelines for investigation of human cases of avian influenza\u000a          A(H5N1)8\u000a    The WHO's 2007 guidelines provide a framework for public health\u000a      authorities and researchers to investigate H5N1 infection in humans. Based\u000a      on research from OUCRU the guidelines recommend that clinicians\u000a      investigating patients with possible H5N1 infection should obtain\u000a      background information on the patients family and household, including all\u000a      people who have come into contact with the patient within two weeks of the\u000a      onset of symptoms. This information directly cites research from OUCRU,\u000a      which shows that H5N1 virus is mostly detected in respiratory specimens\u000a      within two weeks of symptomatic illness2-4. Studies from OUCRU\u000a      also underpin recommendations for the collection of specimens (for\u000a      laboratory testing) in patients with fever or respiratory symptoms,\u000a      followed by appropriate medical management, including antiviral therapy\u000a      (Oseltamivir)8. The WHO guidelines for the investigation of\u000a      H5N1 have been used continuously for the investigation of sporadic cases\u000a      since 2007 without modification.\u000a    WHO guidelines for pharmacological management of pandemic influenza\u000a          A(H1N1) 2009 and other influenza viruses. Part II - review of evidence9\u000a    OUCR's research on H5N1 has additionally had important impact on the\u000a      management of other forms of influenza since 2008. H1N1 influenza or\u000a      \"Swine Flu\" was first identified in April 2009, claiming the lives of over\u000a      294,500 people globally in just 12 months. After declaring H1N1 a pandemic\u000a      in June 2009, the WHO published recommendations for the Pharmacological\u000a      Management of Pandemic Influenza A (H1N1) in August 2009. In the\u000a      absence of any systematic reviews for the treatment of H1N1, the WHO used\u000a      OUCRU Vietnam's 2009 study of H5N1 to provide key evidence regarding\u000a      safety concerns for corticosteroid treatment in influenza A viruses6.\u000a      As a result of this research routine use of corticosteroids is no longer\u000a      recommended in patients suffering from influenza A viruses9.\u000a    Reduction in mortality\u000a    Cases of H5N1 infection have slowly been decreasing since the height of\u000a      the outbreak in 2006, when a reported 115 cases resulted in 79 deaths\u000a      worldwide10. In 2012 these numbers had reduced significantly,\u000a      down to just 30 cases and 19 related deaths worldwide. Although the\u000a      reduction in mortality is in line with the reduction of cases, a small\u000a      decrease can be seen in mortality rates from 68.6% in 2006 to 63.3% in\u000a      2012. In Vietnam these rates have fallen even further from 69% mortality\u000a      in 2006 to 50% in 201210. While there are many factors involved\u000a      in the reduction in human cases of H5N1, improved clinical management\u000a      (particularly in Vietnam) has been a key determinant of increased\u000a      survival.\u000a    ","ImpactSummary":"\u000a    The human influenza A (H5N1) infection emerged in China in 2003 and\u000a      quickly spread throughout Asia, killing more than half of those infected.\u000a      Researchers at the Oxford University Clinical Research Unit in Vietnam\u000a      (OUCRU) provided rapid information to the World Health Organization (WHO)\u000a      on the pathological and clinical features of H5N1 infection in humans, as\u000a      it emerged in Vietnam. The WHO used this front line information to inform\u000a      recommendations for the investigation, diagnosis, management, and\u000a      treatment of H5N1 globally, ultimately reducing mortality by up to 19%.\u000a    ","ImpactType":"Political","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1580578","Name":"Ho Chi Minh City"}],"References":"\u000a    \u000a1. Tran, T. H. et al. Avian influenza A (H5N1) in 10 patients in\u000a      Vietnam. N. Engl. J. Med. 350, 1179-1188 (2004).\u000a    \u000aEarly study reporting clinical features and preliminary\u000a          epidemiologic findings in 10 patients with confirmed cases of human\u000a          H5N1. Referred to as (Hien et al. 2004) in WHO guidelines.\u000a    \u000a2. de Jong, M. D. et al. Oseltamivir resistance during treatment\u000a      of influenza A (H5N1) infection. N. Engl. J. Med. 353,\u000a      2667-2672 (2005).\u000a    \u000aStudy showing that while Oseltamivir treatment is successful,\u000a          resistance may occur in a small percentage of patients, highlighting\u000a          the need for alternative or combination antiviral therapy.\u000a    \u000a3. Beigel, J. H. et al. Avian influenza A (H5N1) infection in\u000a      humans. N. Engl. J. Med. 353, 1374-1385 (2005).\u000a    \u000aReview from `The Writing Committee of the World Health Organization\u000a          Consultation on Human Influenza', providing essential information on\u000a          human H5N1.\u000a    \u000a4. de Jong, M. D. et al. Fatal outcome of human influenza A\u000a      (H5N1) is associated with high viral load and hypercytokinemia. Nat.\u000a        Med. 12, 1203-1207 (2006).\u000a    \u000aA study showing that high viral load and inflammatory responses are\u000a          key outcomes of H5N1 infection in humans, emphasising the importance\u000a          of early diagnosis and treatment.\u000a    \u000a5. Writing Committee of the Second World Health Organization Consultation\u000a      on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus\u000a      Abdel-Ghafar, A.N. et al. Update on avian influenza A (H5N1) virus\u000a      infection in humans. N. Engl. J. Med. 358, 261-273 (2008).\u000a      doi:10.1056\/NEJMra0707279\u000a    \u000aWHO Writing Committee Report citing (de Jong, M.D. et al. 2006) in\u000a          regards to the virulence of H5N1 infection in humans. de Jong was also\u000a          listed as an author on this report.\u000a    \u000a6. Liem, N. T. et al. Clinical features of human influenza A\u000a      (H5N1) infection in Vietnam: 2004-2006. Clin. Infect. Dis. 48,\u000a      1639-1646 (2009). doi:10.1086\/599031\u000a    \u000aStudy showing that treatment with corticosteroids is associated\u000a          with an increased risk in mortality.\u000a    This research was funded by the Wellcome Trust.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"99","Subject":"Other Medical and Health Sciences"}],"Sources":"\u000a    \u000a      \u000aWorld Health Organization WHO Rapid Advice Guidelines on\u000a        pharmacological management of humans infected with avian influenza A\u000a        (H5N1) virus [online]. Geneva: WHO Press. (2006). Available at:\u000a        http:\/\/whqlibdoc.who.int\/hq\/2006\/WHO_PSM_PAR_2006.6_eng.pdf [Accessed\u000a        2013]\u000a      WHO rapid advice guidelines for pharmacological management of\u000a            H5N1 citing several papers from OUCRU Vietnam.\u000a      \u000aWorld Health Organization WHO guidelines for investigation of\u000a        human cases of avian influenza A(H5N1) [online]. (2007).Available at:\u000a        http:\/\/www.who.int\/influenza\/resources\/documents\/WHO_CDS_EPR_GIP_2006_4r1.pdf\u000a[Accessed\u000a        2013]\u000a      WHO guidelines for investigation of H5N1 citing several papers\u000a            from OUCRU Vietnam.\u000a      \u000aWorld Health Organization WHO Guidelines for Pharmacological\u000a        Management of Pandemic Influenza A(H1N1) 2009 and other Influenza\u000a        Viruses [online]. (2010).Available at:\u000a        http:\/\/www.who.int\/csr\/resources\/publications\/swineflu\/h1n1_guidelines_pharmaceutical_mngt.pdf\u000a[Accessed\u000a        2013]\u000a      WHO guidelines for pharmacological management of H1N1, and other\u000a            influenza viruses, citing OUCRU Vietnam paper on H5N1 treatment.\u000a      \u000aWorld Health Organization Cumulative number of confirmed human\u000a        cases for avian influenza A(H5N1) reported to WHO, 2003-2012 [online].\u000a        (2012).Available at:\u000a        http:\/\/www.who.int\/influenza\/human_animal_interface\/EN_GIP_20120810CumulativeNumberH5N1cases.pdf\u000a[Accessed\u000a        2013]\u000a        WHO report on number of cases and deaths related to H5N1\u000a              between 2003 and 2012.\u000a      \u000a    \u000a    ","Title":"\u000a    ON THE FRONT LINE: DEFINING THE CLINICAL FEATURES OF H5N1 IN VIETNAM\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    H5N1, also known as \"bird flu\", is a type of influenza virus that causes\u000a      a highly infectious and deadly respiratory disease in birds. Initially\u000a      identified in a farmed goose in China in 1996, the first human case of\u000a      avian influenza was reported 12 months later, in Hong Kong. After a\u000a      five-year hiatus, H5N1 infection was again reported in birds and humans in\u000a      Hong Kong in February 2003, and quickly spread from China throughout Asia.\u000a      The first human case of H5N1 was reported in Vietnam in January 2004.\u000a    OUCRU researchers swiftly undertook studies on the initial 10 patients\u000a      admitted to hospitals in Ho Chi Minh City and Hanoi, to gain a better\u000a      understanding of this largely unknown and deadly virus. This research was\u000a      significant in classifying the clinical and pathological features of H5N1\u000a      infection in and in identifying the preliminary epidemiologic findings1.\u000a      The 2004 study showed that H5N1 infection resulted in fever, respiratory\u000a      symptoms, and lymphopenia, and confirmed the high risk of death. It also\u000a      confirmed that the virus was transmitted from infected poultry in all 10\u000a      cases1.\u000a    In a further study conducted in 2005 OUCRU researchers investigated the\u000a      use of antiviral treatment in the disease. They identified high-level\u000a      resistance to antiviral influenza treatment with Oseltamivir in two of\u000a      eight Vietnamese patients. While Oseltamivir treatment led to a rapid\u000a      decline in viral loads among six patients (all of whom survived), the two\u000a      resistant patients died of H5N1 infection, in spite of early treatment2.\u000a      This study identified the effectiveness of existing antiviral treatments\u000a      in some cases, whilst also highlighting the significant danger of\u000a      resistance in the event of viral spread.\u000a    As avian and human cases of H5N1 began to spread from Asia to Siberia in\u000a      2005 the WHO assembled a review panel of 13 clinicians and experts from\u000a      around the world to identify key features of H5N1 infection in humans. The\u000a        Writing Committee of the World Health Organization Consultation on Human\u000a        Influenza3, including four researchers from OUCRU,\u000a      provided a comprehensive review of essential information on H5N1\u000a      transmission, clinical severity, diagnosis, pathogenesis, and responses to\u000a      treatment. This review also exposed the urgent need for additional\u000a      clinical and epidemiological research3.\u000a    Accordingly, at the height of the outbreak in 2006, researchers from\u000a      OUCRU performed further immunological and viral studies to better\u000a      understand the virulence of H5N1 infection in humans. This study showed\u000a      that an adverse outcome during human H5N1 infection was determined by high\u000a      viral loads and inflammatory responses; it also emphasised the importance\u000a      of early diagnosis and treatment4. This study provided The\u000a        Writing Committee of the Second World Health Organization Consultation\u000a        on H5N1 Virus, with key information on the virulence of the\u000a      infection in humans5.\u000a    To better understand treatment options for human H5N1 infection, OUCRU\u000a      researchers conducted a retrospective study of H5N1 management in Vietnam\u000a      between 2004 and 2006. This study showed that while Oseltamivir treatment\u000a      is indeed beneficial to patients, treatment with corticosteroids is\u000a      associated with an increased risk in mortality6.\u000a    "},{"CaseStudyId":"4868","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    In the autumn of 2009 public health officials in the United Kingdom were\u000a      faced with an emerging influenza A H1N1 pandemic with the potential to\u000a      overwhelm the NHS. One of the most effective methods of controlling the\u000a      pandemic was likely to be immunisation of children (the `super-spreaders'\u000a      of influenza), however there was an almost complete absence of paediatric\u000a      data on the two vaccines available in the UK7.\u000a    The Oxford Vaccine Group's rapid provision of reactogenicity and\u000a      immunogenicity data on the two novel Influenza A H1N1 vaccines to the\u000a      Joint Committee for Immunisation and Vaccination (JCVI) and Department of\u000a      Health therefore had a profound impact on the immunisation policy for the\u000a      2009-2010 influenza A H1N1 pandemic. Specifically, data from an interim\u000a      analysis on the rates of systemic and local reactions to immunisation were\u000a      provided to the JCVI in mid-November, and gave reassurance that concerns\u000a      regarding theoretical risks of high rates of febrile convulsions with\u000a      these vaccines were unfounded8,9.\u000a    These data were a key element in this committee's subsequent\u000a      recommendation to the Department of Health that an influenza vaccine be\u000a      offered to all children less than 5 years of age10. By February\u000a      2010, 518,000 children had received an influenza A H1N1 vaccine, with\u000a      immunisation uptake rates in children varying from 23.6% in England to\u000a      44.6% in Scotland11. Almost all of these received the\u000a      split-virion vaccine, with the whole-virion vaccine being reserved for\u000a      those with an egg allergy.\u000a    Although it is not possible to precisely determine the effect of the\u000a      immunisation campaign on reducing childhood disease and community spread\u000a      of the influenza A H1N1 virus, a single dose of the split-virion vaccine\u000a      was found to be 77% (95% C.I. 11% to 94%) effective in preventing\u000a      influenza infection in children aged 0- 9 years12. While 70\u000a      children died as a result of influenza A H1N1 between June 2009 and March\u000a      2010 in England13, only two of these had been immunised,\u000a      however, as deaths occurred within 48 hours of immunisation these were not\u000a      considered vaccine failures. It is arguable that without the expedited\u000a      influenza A H1N1 study, immunisation rates in children would have been\u000a      considerably lower with a resultant increase in the paediatric disease\u000a      burden.\u000a    The study received extensive coverage in local and national media14,\u000a        15, 16, and its high media profile provided very public evidence\u000a      that determining the side-effect profile of the vaccines was an important\u000a      aspect of the Department of Health's pandemic influenza strategy. Data on\u000a      vaccine reactogenicity and immunogenicity was important not only in\u000a      informing the national immunisation strategy, but also in providing an\u000a      evidence base for clinicians in their discussions regarding immunisation\u000a      with parents. As a result of this research parents could be reassured that\u000a      rates of fever after a single dose of split-virus vaccine were low, and\u000a      that no unexpected reactions had been observed.\u000a    ","ImpactSummary":"\u000a    Clinical Trials undertaken by the Oxford Vaccine Group led to the\u000a      recommended immunisation of three million UK children during the 2009 H1N1\u000a      influenza pandemic. This research was also used to inform World Health\u000a      Organization (WHO) global policy. The 2009 H1N1 influenza pandemic, or\u000a      \"Swine Flu\", was first identified in April 2009 and declared a pandemic by\u000a      the WHO in June 2009. After acquiring two novel flu vaccines for the 2009\u000a      H1N1 influenza virus, the UK government approached the Oxford Vaccine\u000a      Group to provide paediatric data on the safety of each vaccine. Rapidly\u000a      recruiting 943 children to the study, the Group delivered essential data\u000a      to the Department of Health prior to the onset of the winter influenza\u000a      season. In August 2010, the WHO declared the H1N1 pandemic over.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Pollard AJ et, al. Expediting clinical trials in a pandemic. BMJ.\u000a      2009; 339: 1099 - 1100. doi:10.1136\/bmj.b4652 Letter\u000a          outlining the benefit of an expedited approval process in obtaining\u000a          rapid data in an influenza pandemic.\u000a    \u000a\u000a2. Waddington CS et, al. Safety and immunogenicity of AS03B adjuvanted\u000a      split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in\u000a      UK children aged 6 months-12 years: open label, randomised, parallel\u000a      group, multicentre study. BMJ 2010; 340:c2649.\u000a      doi:10.1136\/bmj:c2649 Manuscript reporting results of the head to\u000a          head pandemic influenza vaccine study. This article has been cited 67\u000a          times in the 2 years since publication (source Harzing's Publish or\u000a          Perish).\u000a    \u000a\u000a3. Waddington C et, al. Open-label, randomised, parallel-group,\u000a      multicentre study to evaluate the safety, tolerability and immunogenicity\u000a      of an AS03(B)\/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion\u000a      versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6\u000a      months to 12 years of age. Health Technol Assess. 2010;14:1-130.\u000a      doi:10.3310\/hta14460-01 Extended report on the head to head\u000a          pandemic influenza vaccine study included in themed H1N1 influenza and\u000a          Pandemic flu publication by NIHR HTA.\u000a    \u000a\u000a4. Andrews NJ et, al. Predictors of immune response and reactogenicity to\u000a      AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1\u000a      pandemic influenza vaccines. Vaccine. 2011; 29: 7913-9.\u000a      doi:10.1016\/jvaccine.2011.08.076 Additional analysis of predictors\u000a          of immunogenicity in the influenza vaccine study.\u000a    \u000a\u000a5. Walker WT et, al. H1N1 antibody persistence 1 year after immunization\u000a      with an adjuvanted or whole-virion pandemic vaccine and immunogenicity and\u000a      reactogenicity of subsequent seasonal influenza vaccine: a multicenter\u000a      follow-on study. Clin. Infect Dis. 2012 (Epub Jan 19 ahead of\u000a      print). doi:10.1093\/cid\/cir905. Manuscript reporting results of the\u000a          `follow-on' study.\u000a    \u000a\u000a6. de Whalley P et, al. A 1-year follow-on study from a randomized,\u000a      head-to-head, multicenter, open-label study of two pandemic influenza\u000a      vaccines in children Health Technology Assessment. 2011; 15:1\u000a      - 128. doi:10.3310\/hta15450 Extended report of results from the\u000a          `follow-on' study.\u000a    \u000aThis research was funded by the National Institute for Health Research.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    \u000a       Scientific Advisory Group for Emergencies (SAGE), Swine Flu. Minutes\u000a        of meeting held on 20th May 2009 [online]. Available at:\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/@dh\/@ab\/documents\/digitalasset\/dh_126077.pdf\u000a        [Accessed 20th June 2013]. Items 3 and 4 of these minutes relate\u000a            SAGE's assessment of the lack of data on the use of the pandemic\u000a          influenza vaccines in children, and the urgent need to obtain\u000a          reactogencity data on the novel vaccines as a research priority. NB\u000a          archived but still available by clicking on link to the UK Government\u000a          Web archive.\u000a\u000a       Joint Committee on Vaccination and Immunisation (JCVI). Minute of\u000a        meeting head on 8th October 2009 [online]. Available at:\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/@dh\/@ab\/documents\/digitalasset\/dh_108833.pdf\u000a        [Accessed 20th Junes 2013] Point 24 of these minutes\u000a            relates the ongoing attention paid to the paediatric\u000a            Influenza A H1N1 vaccine study by the JCVI.\u000a\u000a       JCVI updated advice on H1N1v vaccination. 8 December 2009 [online]\u000a        Available at\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/@dh\/@ab\/documents\/digitalasset\/dh_109839.pdf.\u000a        [Accessed 20th June 2013] This advice from the JCVI to the\u000a            Department of Health recommends use of a single dose spilt virus\u000a            vaccine (Pandemrix) for children. Evidence cited in support of this\u000a            includes `preliminary data on the reactogenicity of H1N1v vaccine\u000a            from a paediatric trial coordinated by the Health Protection\u000a            Agency'. This refers to the head to head study led by the Oxford\u000a            Vaccine Group - data on reactogenicity was collated and analysed by\u000a            the Health Protection Agency.\u000a\u000a       Department of Health Pandemic H1N1 (2009) influenza- letter from\u000a        Chief Medical Officer, Sir Liam Donaldson (27th January\u000a        2010). [online] Available at\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/documents\/digitalasset\/dh_111598.pdf\u000a        [Accessed 20th June 2013]This letter from the Chief Medical\u000a            Officer was distributed to all health professionals in the UK, and\u000a            outlines the ongoing influenza immunisation policy (including\u000a            routine immunisation of children aged 6 months to 5 years), as well\u000a            as referencing data on the comparative immunogenicity of the two\u000a            vaccines obtained, in part, from the OVG influenza vaccine study.\u000a\u000a       Health Protection Agency. Epidemiological report of pandemic (H1N1)\u000a        2009 in the UK. October 2010 [online]. Available at:\u000a        http:\/\/www.hpa.org.uk\/webc\/HPAwebFile\/HPAweb_C\/1284475321350\u000a        [Accessed 20thJune 2013]. Page 45 of this report outlines\u000a            immunisation uptake.\u000a\u000a       Andrews N, Wright, O, Yung CF, Miller E. Age -specific effectiveness\u000a        of an oil-in-water adjuvanted pandemic (H1N1) 2009 vaccine against\u000a        confirmed infection in high risk groups in England. J. Infect. Dis;\u000a        203:32 - 39 (2011). Doi:10:1093\/in fdis\/jiq014.This\u000a            manuscript provides an estimate of effectiveness of immunisation\u000a            against pandemic influenza A H1N1 in children.\u000a\u000a       Sachedina N, Donaldson LJ. Paediatric mortality related to pandemic\u000a        influenza A H1N1 infection in England: an observational population-based\u000a        study. The Lancet; 376: 1846 - 52 (2010).\u000a        doi:10.1016\/S0140-6736(10)61195-6 This manuscript, co-authored by\u000a            the then chief medical officer, reports the numbers of childhood\u000a            deaths from pandemic influenza.\u000a\u000a       BBC news `Babies will test swine flu jabs' [online]. 23rd\u000a        September 2009 Available at:\u000a        http:\/\/news.bbc.co.uk\/1\/hi\/england\/8271813.stm\u000a        [Accessed 20th June 2013] BBC media report announcing\u000a            the impending pandemic influenza vaccine study, evidence of the high\u000a            public profile of the study and providing public reassurance that\u000a            collecting data on the safety of these vaccines was a Department of\u000a            Health Priority.\u000a\u000a       BBC news `UK children receive swine flu jab' [online] 29th\u000a        September 2009 Available at\u000a        http:\/\/news.bbc.co.uk\/1\/hi\/uk\/8279826.stm\u000a        [Accessed 20th June 2013]. Further media report on the\u000a            pandemic influenza vaccine study, which followed the first weekend\u000a            of recruitment. This was accompanied by television interviews with\u000a            participating parents.\u000a\u000a       The Guardian `Children respond well to swine flu vaccines, trial\u000a        shows' 28th May 2010 [online] . Available at: http:\/\/www.guardian.co.uk\/world\/2010\/may\/28\/children-swine-flu-vaccine-trial\u000a        [Accessed 20th June 2013]. Print media report on the\u000a            final publication of study results.\u000a\u000a    \u000a    ","Title":"\u000a    PREVENTING THE SPREAD OF H1N1: IMMUNISATION TRIALS IN UK CHILDREN\u000a    ","UKLocation":[{"GeoNamesId":"2640729","Name":"Oxford"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The 2009 H1N1 influenza pandemic was a devastating world health crisis.\u000a      It claimed the lives of over 294,500 people globally between 2009 and\u000a      2010.\u000a    In autumn 2009, just months after H1N1 flu was declared a pandemic, two\u000a      novel influenza A H1N1 vaccines were supplied to the United Kingdom prior\u000a      to the winter influenza season. Both vaccines differed in crucial aspects\u000a      from the standard `seasonal' influenza vaccines used each season. One,\u000a      known as the `split-virion' vaccine (Pandemrix), was the first licensed\u000a      vaccine to contain a new adjuvant (AS03B), while the other (Celvapan) was\u000a      made from an inactivated version of the whole virus, rather than virus\u000a      sub-units. Both vaccines were designed to improve immunogenicity, but\u000a      potentially would increase the rates of adverse reactions. Due to the\u000a      urgent need for effective vaccines against the H1N1 virus, both Pandemrix\u000a      and Celvapan had been licensed for use without having ever been\u000a      administered to children — one of the highest risk groups and primary\u000a      transmitters of influenza infection. Accordingly, the UK Scientific\u000a      Advisory Group for Emergencies (UK-SAGE) identified an urgent need to\u000a      obtain paediatric data on the immunogenicity and reactogenicity and other\u000a      adverse effects of these vaccines before the expected influenza season in\u000a      December. This was judged a national priority.\u000a    In view of its extensive experience with paediatric vaccine studies the\u000a      University of Oxford's Oxford Vaccine Group was approached to lead an\u000a      urgent clinical trial to provide essential data on the safety and\u000a      efficiency of these vaccines in children. With protocol development,\u000a      ethical, NHS and regulatory approval all `fast-tracked', recruitment of\u000a      the first participant came in late September - just five weeks after\u000a      provisional funding approval was granted1.\u000a    Five weeks later 943 children aged between six months and 12 years were\u000a      recruited across five sites. Children received two doses of either the\u000a      split-virion or whole-virion vaccine, and blood tests were taken prior to\u000a      and three weeks after the immunisation course. Parents mailed diaries\u000a      recording immunisation reactions to study sites to allow rapid acquisition\u000a      of these data. Crucially, by mid-November the study team provided the\u000a      Department of Health with an interim analysis demonstrating that both\u000a      vaccines were well tolerated by most children. Immunisation with either\u000a      vaccine induced antibody levels above the correlates of protection in most\u000a      children, however the split-virion vaccine was the more immunogenic. In\u000a      children under 3 years of age antibody concentrations were over ten times\u000a      higher following immunisation with the split-virion vaccine than the\u000a      whole-virion vaccine2, 3. Surprisingly, children previously\u000a      immunised with seasonal influenza vaccines had a lower response to the\u000a      `swine-flu' vaccines than influenza vaccine-naïve participants4.\u000a    The following year the NIHR funded a `follow-on' study, demonstrating\u000a      that 98% of children receiving the split-virion vaccine maintained\u000a      Influenza A H1N1 antibodies above the threshold of protection one year\u000a      after immunisation, compared with only 51% of children receiving the\u000a      whole- virion vaccine5,6. This showed that the administration\u000a      of a seasonal influenza vaccine was safe and immunogenic and confirmed the\u000a      superiority of the Pandemrix vaccine.\u000a    "},{"CaseStudyId":"4869","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    University of Oxford research has led to the first non-invasive prenatal\u000a      genetic diagnostic tests. This non-invasive alternative to traditional\u000a      tests has significantly improved the quality of care offered to pregnant\u000a      women at a high risk of carrying a genetic mutation. This research has\u000a      also significantly reduced fetal risk, as traditional early diagnostic\u000a      tests, such as chorionic villus sampling, carry a risk of miscarriage of\u000a      around 1%.\u000a    Fetal Sex Determination\u000a      Prenatal fetal sex determination is recommended to women at high risk of\u000a      serious genetic disorders affecting a specific sex, such as congenital\u000a      adrenal hyperplasia, haemophilia or Duchenne muscular dystrophy. The\u000a      identification of cell-free fetal DNA in maternal circulation has allowed\u000a      the development of non-invasive prenatal diagnostic tests, which are\u000a      capable of determining fetal sex early and without risk. An independent\u000a      paper published in 2008, showed that early determination of fetal sex is\u000a      feasible and reliable using cell-free fetal DNA tests from just seven\u000a      weeks, and should be made available to all women at risk of X-linked\u000a      disorders as well as metabolic conditions7. The report also\u000a      stated that use of this technology could reduce the need for invasive\u000a      procedures by up to 50%7. A national audit assessing the\u000a      effectiveness and clinical utility of non-invasive prenatal genetic\u000a      diagnosis for fetal sex determination in the UK concluded that\u000a      non-invasive prenatal diagnosis through cell-free fetal DNA testing is\u000a      highly accurate in determining fetal sex when performed in NHS\u000a      laboratories8. In addition to fetal sex determination,\u000a      non-invasive cell-free fetal DNA tests are now available in the UK to test\u000a      the rhesus blood group in a fetus within 12 weeks of pregnancy without any\u000a      risk9, enabling fast effective prenatal care for mother and\u000a      child.\u000a    Diagnosis of Down Syndrome\u000a      The first non-invasive maternal blood test for Down syndrome, the\u000a      MaterniT21 assay, became available to physicians on request in 20 regions\u000a      within the United States in October 2011. The MaterniT21 assay, developed\u000a      by Sequenom Ltd, is capable of accurately testing maternal blood as early\u000a      as 10 weeks into gestation, and has been made available to pregnant women\u000a      at a high risk of carrying a fetus with Down syndrome. With an estimated\u000a      750,000 high-risk pregnancies in the United States each year, the test\u000a      offers a safer, more specific and sensitive alternative to invasive tests\u000a      such as amniocentesis and chorionic villus sampling. The accuracy of the\u000a      MaterniT21 assay was confirmed in a 2011 study, which showed the Down\u000a      syndrome detection rate for the MaterniT21 test was 98.6%10.\u000a      The MaterniT21 assay is not yet available for clinical use outside of the\u000a      US.\u000a    Clinical Practice Guidelines\u000a      In the March 2011 NHS UK Genetic Testing Network's \"best practice\u000a      guidelines for non-invasive prenatal diagnosis to determine fetal sex for\u000a      known carriers of congenital adrenal hyperplasia\", recommended the use of\u000a      cell-free fetal DNA testing as an alternative for prenatal sex\u000a      determination11.\u000a    The NHS UK Genetic Testing Network guidelines also report that there are\u000a      no cost implications for service providers, due to testing being\u000a      cost-neutral, and that the cell-free fetal DNA technique is a highly\u000a      sensitive and specific diagnostic test11.\u000a    In November 2011 the NHS released additional guidance for commissioners\u000a      and public health officials, supporting the use of cell-free fetal DNA for\u000a      fetal sex determination in serious genetic disorders12.\u000a    Commercialisation\u000a      The patent for \"non-invasive prenatal diagnosis using cell-free fetal\u000a        DNA\" was filed in the United Kingdom in March 1998, application\u000a      number: PCT\/GB98\/0069013. Yuk-Ming Dennis Lo and James Stephen\u000a      Wainscoat are listed as co-inventors, while Isis Innovation Limited is the\u000a      named patent holder. Under this patent family a US patent was filed in\u000a      July 2001, US Patent number 625854013, and since 2005 Sequenom\u000a      Inc. have held an exclusive licence to the invention.\u000a    The Sequenom Inc. 2010 Annual Report states that in October 2005 Sequenom\u000a      Inc. acquired exclusive rights in certain countries, including the United\u000a      States, United Kingdom and other countries in Europe and elsewhere, to\u000a      non-invasive prenatal diagnostic intellectual property from Isis\u000a      Innovation Ltd. After receiving upfront royalties totaling $0.8 million,\u000a      an amendment to the agreement in November 2009 led to a second one-time\u000a      royalty payment of $1,000,000. During the years 2010, 2009 and 2008, the\u000a      amount of royalties paid to ISIS in connection to product sales was $0.1\u000a      million annually14.\u000a    The total number of MaterniT21 PLUS tests run since the initial product\u000a      launch in 2011 increased from 20,000 in the first year, to 65,000 by mid\u000a      2012. Due to the rapid growth in adoption the Sequenom Inc. now predicts\u000a      they will bill 50,000 MaterniT21 PLUS tests in 201215.\u000a    ","ImpactSummary":"\u000a    University of Oxford researchers have developed the first safe, accurate\u000a      and non-invasive prenatal diagnostic tests. After confirming that\u000a      fragments of fetal DNA circulate in maternal blood, University of Oxford\u000a      scientists used the polymerase chain reaction technique to accurately\u000a      identify fetal DNA in maternal serum and plasma. This technique, known as\u000a      cell-free fetal DNA testing, has enabled the first non-invasive prenatal\u000a      genetic tests for the determination of fetal gender and the diagnosis of\u000a      genetic disorders. Patented in 2001 and commercially released in 2011,\u000a      cell-free fetal DNA testing is now recommended by the UK National Health\u000a      Service as a safe and accurate alternative to invasive prenatal tests.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Lo, Y. M. et al. Prenatal sex determination by DNA\u000a      amplification from maternal peripheral blood. Lancet 2,\u000a      1363-1365 (1989). Paper showing the potential for the use PCR\u000a          technique in the analysis of fetal DNA in the bloodstream.\u000a    \u000a\u000a2. Lo, Y. M., Fleming, K. A. & Wainscoat, J. S. Strategies for the\u000a      detection of autosomal fetal DNA sequence from maternal peripheral blood.\u000a      Ann. N. Y. Acad. Sci. 731, 204-213 (1994) doi:\u000a      10.1111\/j.1749-6632.1994.tb55772.x Paper showing that fetal cells\u000a          appear in maternal circulation as early as six weeks into pregnancy.\u000a    \u000a\u000a3. Lo, Y. M. et al. Two-way cell traffic between mother and\u000a      fetus: biologic and clinical implications. Blood 88,\u000a      4390-4395 (1996). Paper showing the use of PCR to detect male cells\u000a          in the peripheral blood of pregnant women bearing male fetuses.\u000a    \u000a\u000a4. Lo, Y. M. et al. Presence of fetal DNA in maternal plasma and\u000a      serum. Lancet 350, 9076, 485- 487 (1997)\u000a      doi.org\/10.1016\/S0140-6736(97)02174-0. A landmark paper describing\u000a          the presence of fetal DNA circulating in the plasma of pregnant women,\u000a          giving rise to the field of non-invasive prenatal diagnosis.\u000a    \u000a\u000a5. Lo, Y. M. et al. Quantitative analysis of fetal DNA in\u000a      maternal plasma and serum: implications for noninvasive prenatal\u000a      diagnosis. Am. J. Hum. Genet. 62, 768-775 (1998)\u000a      doi.org\/10.1086\/301800. A paper showing that fetal DNA can be\u000a          readily detected in maternal plasma or serum.\u000a    \u000a\u000a6. Lo, Y. M. et al. Prenatal diagnosis of fetal RhD status by\u000a      molecular analysis of maternal plasma. N. Engl. J. Med. 339,\u000a      1734-1738 (1998) doi: 10.1056\/NEJM199812103392402. A paper showing\u000a          that non-invasive fetal genotyping for Rhesus Disease can be performed\u000a          in the second trimester of pregnancy through maternal plasma.\u000a    \u000aThis research was funded in part by the Wellcome Trust.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    \u000a      Finning, K. M. & Chitty, L. S. Non-invasive fetal sex\u000a        determination: impact on clinical practice. Semin Fetal Neonatal Med13,\u000a        69-75 (2008) doi.org\/10.1016\/j.siny.2007.12.007. An independent\u000a            paper reporting that early determination of fetal sex is feasible\u000a            and reliable using cell-free fetal DNA tests from just seven weeks,\u000a            reducing the need for invasive procedures by up to 50%.\u000a\u000a      Hill, M. et al. Non-invasive prenatal determination of fetal\u000a        sex: translating research into clinical practice. Clin. Genet. 80,\u000a        68-75 (2011) doi: 10.1111\/j.1399-0004.2010.01533.x.. A national\u000a            (UK) audit reporting that cell-free fetal DNA testing is highly\u000a            accurate in determining fetal sex.\u000a\u000a      NHS Choices, Rhesus disease - Diagnosis (Accessed 2013) Available from\u000a        http:\/\/www.nhs.uk\/Conditions\/Rhesus-disease\/Pages\/Diagnosis.aspx\u000a        NHS Choices webpage showing that non-invasive cell-free fetal DNA\u000a            tests are now available in the UK to test the rhesus blood group in\u000a            a fetus within 12 weeks of pregnancy.\u000a\u000a      Palomaki, G. E. et al. DNA sequencing of maternal plasma to\u000a        detect Down syndrome: an international clinical validation study. Genet.\u000a          Med. 13, 913-920 (2011) doi: 10.1097\/GIM.0b013e3182368a0e.\u000a        A 2011 study confirming the Down syndrome detection rate for the\u000a            MaterniT21 test is 98.6%.\u000a\u000a      NHS UK Genetic Testing Network. Best practice guidelines for non\u000a        -invasive prenatal diagnosis to determine fetal sex for known carriers\u000a        of congenital adrenal hyperplasia ( CAH) (undated) (Accessed 2013)\u000a        <Available from http:\/\/www.ukgtn.nhs.uk\/gtn\/digitalAssets\/1\/1050_BPCAREPATWAYSNIPDCAHFINA\u000a          L.pdf> NHS UK Genetic Testing Network's \"best practice\u000a            guidelines\" recommending the use of cell-free fetal DNA testing as\u000a            an alternative source of fetal DNA for prenatal sex determination.\u000a\u000a      Burton, D. H., Farndon P., Westwood, J., Chitty, L. Cell-free fetal\u000a        DNA for fetal sex determination in serious genetic disorders (2011)\u000a        (Accessed 2013) . <Available from\u000a        http:\/\/www.rapid.nhs.uk\/wp-content\/uploads\/2011\/11\/Commisioning-\u000a          Guide.pdf> Additional guidance from the NHS for\u000a            commissioners and public health officials, supporting the use of\u000a            cell-free fetal DNA for fetal sex determination in serious genetic\u000a            disorders.\u000a\u000a      Lo, Y-MD, and Wainscoat, J.S.Inventors; 2001 Jul 10 Non-invasive\u000a        prenatal diagnosis, United States patent US6,258,540 (Accessed 2013) .\u000a        <Available from\u000a        http:\/\/www.google.com\/patents?id=0eUHAAAAEBAJ&printsec=abstract&zoom=4#v=o\u000a          nepage&q&f=false>Patent information for\u000a            non-invasive prenatal diagnosis using cell-free fetal DNA.\u000a\u000a      Sequenom Inc Financial Reports (Accessed 2013) <Available from\u000a        http:\/\/www.sequenom.com\/home\/investors\/financial-reports-ir>\u000a        Sequenom, Inc. 2010 Annual Financial Report.\u000a\u000a      Sequenom, Inc. Reports Financial Results For The Second Quarter Of\u000a        2012 And Increases Full-Year MaterniT21™ PLUS Test Volume Goal To 50,000\u000a        - Jul 26, 2012. sequenom.investorroom.com (2012) (Accessed 2013)\u000a        <Available from\u000a        http:\/\/sequenom.investorroom.com\/2012-07-26-Sequenom-Inc.-Reports-Financial-\u000aResults-For-The-Second-Quarter-Of-2012-And-Increases-Full-Year-MaterniT21-\u000a          PLUS-Test-Volume-Goal-To-50-000> Press release from\u000a            Sequenom, Inc. reporting financial results between 2011 and 2012.\u000a\u000a    \u000a    ","Title":"\u000a    SAFE, ACCURATE AND NON-INVASIVE PRENATAL DIAGNOSIS\u000a    ","UKLocation":[{"GeoNamesId":"2640729","Name":"Oxford"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Prenatal screening for genetic diseases in a fetus or embryo was first\u000a      introduced in the 1960s. Although traditional diagnostic techniques such\u000a      as amniocentesis and chorionic villus sampling continue to be used\u000a      clinically for prenatal diagnosis, these invasive tests have been known to\u000a      cause damage to the fetus and miscarriage in approximately 1% of cases.\u000a    Using a polymerase chain reaction (PCR) to analyse fetal DNA in the\u000a      maternal bloodstream, Professor James Wainscoat and Professor Dennis Lo,\u000a      at the University of Oxford's Nuffield Department of Clinical Laboratory\u000a      Sciences, saw great potential for this technique in prenatal diagnosis1.\u000a      In 1994 they reported the detection of fetal cells in maternal circulation\u000a      as early as six weeks into pregnancy2. The Oxford researchers\u000a      began researching the potential for prenatal diagnosis and in 1996 used\u000a      PCR to detect male cells in the peripheral blood of pregnant women bearing\u000a      male fetuses; however, this technique proved difficult to make reliable\u000a      enough for clinical use3.\u000a    The breakthrough came in 1997 when their seminal paper was published in\u000a      the Lancet describing the presence of fetal DNA circulating in the plasma\u000a      of pregnant women. Although the absolute amount of fetal DNA was small,\u000a      the relative concentration of fetal to maternal DNA circulating was much\u000a      higher than in the cellular part of blood4. This finding gave\u000a      rise to the field of non-invasive prenatal diagnosis.\u000a    The University of Oxford's Professor Wainscoat continued to collaborate\u000a      with Professor Lo following the latter's relocation to the Department of\u000a      Chemical Pathology at the Chinese University of Hong Kong. In 1998 they\u000a      showed that fetal DNA can be readily detected in maternal plasma or serum,\u000a      confirming that maternal blood samples may be a valuable source of fetal\u000a      DNA for non- invasive diagnosis5. In a subsequent paper\u000a      published that same year, they conclusively showed that rapid and reliable\u000a      non-invasive fetal genotyping for Rhesus Disease could be performed in the\u000a      second trimester of pregnancy using maternal plasma6.\u000a    "},{"CaseStudyId":"4870","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Research carried out by the University of Oxford's Clinical Genetics\u000d\u000a      Laboratory has directly\u000d\u000a      influenced changes in sperm donor guidelines in the UK and abroad. The\u000d\u000a      research has also\u000d\u000a      received significant media attention, contributing to improved social\u000d\u000a      awareness of paternal age\u000d\u000a      effect mutations, as well as public awareness of genetic diagnostic\u000d\u000a      testing.\u000d\u000a    Changes to Practice Guidelines\u000d\u000a      Oxford University's 1996 discovery of the paternal age effect on mutations\u000d\u000a      in Apert syndrome was\u000d\u000a      a major contributor to the 1999 decision of the British Andrology Society\u000d\u000a      to introduce an upper age\u000d\u000a      limit of 40 years for sperm donors7. The University of Oxford's\u000d\u000a      1996 paper3 was one of two studies\u000d\u000a      from the same year that were cited as primary evidence for imposing the\u000d\u000a      age limit to prevent the\u000d\u000a      transmission of somatic mutations (the other describing an association of\u000d\u000a      increase in parental age\u000d\u000a      with cases of dyskinetic cerebral palsy). In a review of sperm donor\u000d\u000a      guidance in 20048, the UK\u000d\u000a      Human Fertilisation and Embryology Authority confirmed the British\u000d\u000a      Andrology Society's\u000d\u000a      recommendations for an upper age limit, again citing the group's 1996\u000d\u000a      paper3.\u000d\u000a    This upper age limit for sperm donors was upheld in the British Andrology\u000d\u000a      Society's 2008\u000d\u000a      guidance9. The Practice Committee of the American Society for\u000d\u000a      Reproductive Medicine, and the\u000d\u000a      Practice Committee of the Society for Assisted Reproductive Technology\u000d\u000a      have since introduced an\u000d\u000a      upper age limit for sperm donors10.\u000d\u000a    Public Awareness of Paternal Age Effect\u000d\u000a      In October 2009, the Clinical Genetics Laboratory's description of\u000d\u000a      selective advantage due to\u000d\u000a      deleterious mutations in the testes5 received wide coverage in\u000d\u000a      national newspapers. Articles\u000d\u000a      featuring commentary from Professor Wilkie were published in The Times11,\u000d\u000a      The Telegraph12, and\u000d\u000a      the Daily Mail Online13. These articles and the associated\u000d\u000a      research have increased public\u000d\u000a      consciousness and understanding of the parental age effect. The impact\u000d\u000a      this research has had on\u000d\u000a      society is illustrated in a recent feature article on late fatherhood,\u000d\u000a      published in the Daily Mail14. The\u000d\u000a      article received over 70 comments from readers14.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research from the University of Oxford's Clinical Genetics Laboratory\u000d\u000a      initiated the introduction of\u000d\u000a      an upper age limit of 40 years for sperm donors in the UK and\u000d\u000a      internationally and led to increased\u000d\u000a      public awareness of the effect of paternal age in the transmission of\u000d\u000a      inherited disease. Oxford\u000d\u000a      researchers, led by Professor Andrew Wilkie, were the first to describe\u000d\u000a      the exclusively paternal\u000d\u000a      transmission of de novo mutations, in a rare craniofacial disorder\u000d\u000a      called Apert Syndrome; they also\u000d\u000a      showed that the accumulation of such mutations leads to a disproportionate\u000d\u000a      risk of disease\u000d\u000a      transmission with age. By showing that the frequency of mutations\u000d\u000a      increases with paternal age,\u000d\u000a      this research contributed to important changes in clinical practice\u000d\u000a      relating to sperm donation. This\u000d\u000a      has also had a significant cultural impact, as the research and its\u000d\u000a      clinical outcomes have\u000d\u000a      challenged public perceptions of paternal age.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Wilkie, A. O. et al. Apert syndrome results from localized\u000d\u000a      mutations of FGFR2 and is allelic\u000d\u000a      with Crouzon syndrome. Nat. Genet. 9, 165-172 (1995)\u000d\u000a      doi:10.1038\/ng0295-165. Primary\u000d\u000a          paper describing the FGFR2 gene mutation in Apert Syndrome.\u000d\u000a    \u000a\u000a2. Risch, N., Reich, E. W., Wishnick, M. M. & McCarthy, J. G.\u000d\u000a      Spontaneous mutation and\u000d\u000a      parental age in humans. Am. J. Hum. Genet. 41, 218-248\u000d\u000a      (1987). Inconclusive statistical\u000d\u000a          analysis study of parental age and the incidence of new mutations.\u000d\u000a    \u000a\u000a3. Moloney, D. M. et al. Exclusive paternal origin of new\u000d\u000a      mutations in Apert syndrome. Nat.\u000d\u000a        Genet. 13, 48-53 (1996) doi:10.1038\/ng0596-48. Study\u000d\u000a          showing that an increase in\u000d\u000a          paternal age is associated with an increased likelihood of inheriting\u000d\u000a          an FGFR2\u000d\u000a          mutation.\u000d\u000a    \u000a\u000a4. Goriely, A., McVean, G. A. T., Röjmyr, M., Ingemarsson, B. &\u000d\u000a      Wilkie, A. O. M. Evidence for\u000d\u000a      selective advantage of pathogenic FGFR2 mutations in the male germ line. Science\u000d\u000a      301,\u000d\u000a      643-646 (2003) doi: 10.1126\/science.1085710. The first paper to\u000d\u000a          describe the accurate\u000d\u000a          measurement of any individual mutation in human sperm.\u000d\u000a    \u000a\u000a5. Goriely, A. et al. Activating mutations in FGFR3 and HRAS\u000d\u000a      reveal a shared genetic origin for\u000d\u000a      congenital disorders and testicular tumors. Nat. Genet. 41,\u000d\u000a      1247-1252 (2009) doi:\u000d\u000a      10.1038\/ng.470. Paper outlining the implications for the\u000d\u000a          inheritance of\u000d\u000a          craniosynostosis syndromes and other disease-causing mutations in\u000d\u000a          sperm.\u000d\u000a    \u000a\u000a6. Giannoulatou E, McVean G, Taylor IB, McGowan SJ, Maher GJ, Iqbal Z,\u000d\u000a      Pfeifer SP, Turner\u000d\u000a      I, Burkitt-Wright EMM, Shorto J, Itani A, Turner K, Gregory L, Buck D,\u000d\u000a      Rajpert-De Meyts E,\u000d\u000a      Looijenga LHJ, Kerr B, Wilkie AOM* & Goriely A* (2013). Contributions\u000d\u000a      of intrinsic mutation\u000d\u000a      rate and selfish selection to levels of de novo HRAS mutations in the\u000d\u000a      paternal germline.\u000d\u000a      Proc Natl Acad Sci USA in press. Shows how selfish spermatogonial\u000d\u000a          selection\u000d\u000a          combines with mutation rate to cause the increased burden of mutations\u000d\u000a          in the sperm\u000d\u000a          of healthy older men.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust, with support from the\u000d\u000a      Government of Malaysia,\u000d\u000a      who funded a DPhil post.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    \u000d\u000a      British Andrology Society. British Andrology Society guidelines for\u000d\u000a        the screening of semen\u000d\u000a        donors for donor insemination (1999). Hum. Reprod. 14,\u000d\u000a        1823-1826 (1999) doi:\u000d\u000a        10.1093\/humrep\/14.7.1823. Guidelines recommending the upper age\u000d\u000a            limit of 40 years\u000d\u000a            for all sperm donors within the UK. Guidelines directly cite the\u000d\u000a            Moloney et al. (1996)\u000d\u000a            paper from Oxford as key evidence to support the upper age limit of\u000d\u000a            40 years.\u000d\u000a      Human Fertilisation & Embryology Authority: Seed Review: (SCAG\/ELC\u000d\u000a        (06\/04) 02 — ANNEX\u000d\u000a        A)(2004, June 17). (Accessed 2013), Available from\u000d\u000a        http:\/\/www.hfea.gov.uk\/docs\/ELC_Annex_A_Audit_June04.pdf.\u000d\u000a        The Human Fertilisation and Embryology Authority sperm donor\u000d\u000a            guidance review,\u000d\u000a            confirming recommendations for an upper age limit of 40 years for\u000d\u000a            sperm donors.\u000d\u000a            This audit directly cites Moloney, et al (1996) as key evidence.\u000a\u000d\u000a      Association of Biomedical Andrologists; Association of Clinical\u000d\u000a        Embryologists; British\u000d\u000a        Andrology Society; British Fertility Society; Royal College of\u000d\u000a        Obstetricians and\u000d\u000a        Gynaecologists UK guidelines for the medical and laboratory screening of\u000d\u000a        sperm, egg and\u000d\u000a        embryo donors (2008) Human Fertility,11:4,201 — 210\u000d\u000a        (2008) doi:\u000d\u000a        10.1080\/14647270802563816. Also available from\u000d\u000a        http:\/\/www.britishandrology.org.uk\/BAS\/Policy\/New%202008%20Donor%20Guidelines.pdf\u000d\u000a          (Accessed 2013) British Andrology Society guidelines\u000d\u000a            confirming the upper age limit\u000d\u000a            of 40 for all sperm donors within the UK.\u000a\u000d\u000a      Practice Committee of the American Society for Reproductive Medicine\u000d\u000a        and the Practice\u000d\u000a        Committee of the Society for Assisted Reproductive Technology.\u000d\u000a        Recommendations for\u000d\u000a        gamete and embryo donation: a committee opinion Fertil Steril.\u000d\u000a        Jan;99(1):47-62 (2013). doi:\u000d\u000a        10.1016\/j.fertnstert.2012.09.037. Also available from\u000d\u000a        http:\/\/www.asrm.org\/uploadedFiles\/ASRM_Content\/News_and_Publications\/Practice_Guidelines\/Guidelines_and_Minimum_Standards\/2008_Guidelines_for_gamete(1).pdf\u000d\u000a        (Accessed\u000d\u000a        2013) Guidelines from the Practice Committee of the American\u000d\u000a            Society for\u000d\u000a            Reproductive Medicine, and the Practice Committee of the Society for\u000d\u000a            Assisted\u000d\u000a            Reproductive Technology recommending an upper age limit of 40 for\u000d\u000a            all sperm\u000d\u000a            donors within the US.\u000a\u000d\u000a      Scientists discover link between older dads and genetic diseases — The\u000d\u000a          Times (October 26th\u000d\u000a        2009) (Accessed 2013). Available from\u000d\u000a        http:\/\/www.thetimes.co.uk\/tto\/science\/genetics\/article1844016.ece\u000d\u000a        Article reporting findings from Goriely et al (2009) paper\u000d\u000a            featuring commentary from\u000d\u000a            Professor Andrew Wilkie.\u000a\u000d\u000a      Older fathers linked to genetic disease due to testicular tumours — The\u000d\u000a          Telegraph (October\u000d\u000a          26th 2009) (Accessed 2013). Available\u000d\u000a        from\u000d\u000a        http:\/\/www.telegraph.co.uk\/health\/healthnews\/6435802\/Older-fathers-linked-to-genetic-\u000d\u000a          disease-due-to-testicular-tumours.html Article reporting\u000d\u000a            findings from Goriely et al\u000d\u000a            (2009) paper featuring commentary from Professor Andrew Wilkie.\u000a\u000d\u000a      Why older fathers are more likely to have children with genetic\u000d\u000a        disorders — Mail Online\u000d\u000a        (October 26th 2009) (Accessed 2013) Available from\u000d\u000a        http:\/\/www.dailymail.co.uk\/health\/article-1223025\/Why-older-fathers-likely-children-genetic-disorders.html\u000d\u000a          Article reporting findings from Goriely et al (2009) paper\u000d\u000a            featuring\u000d\u000a            commentary from Professor Andrew Wilkie.\u000a\u000d\u000a      We all know late-life motherhood poses risks for babies. But worrying\u000d\u000a        new research reveals\u000d\u000a        how having an older father can damage a child's health too. — Mail\u000d\u000a          Online (February 21st\u000d\u000a        2013) (Accessed 2013) Available from http:\/\/www.dailymail.co.uk\/femail\/article-\u000d\u000a          2282033\/We-know-late-life-motherhood-poses-risks-babies-But-worrying-new-research-\u000d\u000a          reveals-having-older-father-damage-childs-health.html Article\u000d\u000a            reviewing the risks of late\u000d\u000a            fatherhood, quoting Professor Wilkie and his work.\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    THE PATERNAL AGE EFFECT: HIS CLOCK IS TICKING\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Since 1993, the University of Oxford's Clinical Genetics Laboratory,\u000d\u000a      directed by Professor Andrew\u000d\u000a      Wilkie, has been collaborating closely with plastic surgeons at the Oxford\u000d\u000a      Craniofacial Unit to\u000d\u000a      research the genetic basis of rare craniofacial disorders. In 1995 this\u000d\u000a      group discovered that\u000d\u000a      mutations in the FGFR2 gene were responsible for Apert syndrome: a\u000d\u000a      rare craniofacial disorder1.\u000d\u000a      Since previous studies had revealed a positive correlation between\u000d\u000a      parental age and Apert\u000d\u000a      syndrome2, the group set out to investigate the origin of FGFR2\u000d\u000a      mutations.\u000d\u000a    In a pivotal study of 57 Apert syndrome families published in 19963,\u000d\u000a      the researchers revealed that\u000d\u000a      without exception the FGFR2 mutation was inherited from the\u000d\u000a      father. Furthermore, they found that\u000d\u000a      an increase in paternal age was associated with an increased likelihood of\u000d\u000a      inheriting an FGFR2\u000d\u000a      mutation3. Further work by the Clinical Genetics Laboratory\u000d\u000a      revealed that while FGFR2 mutations\u000d\u000a      can be detrimental to an embryo, they are advantageous to the cells that\u000d\u000a      generate sperm4. These\u000d\u000a      findings showed that sperm-generating cells with an FGFR2 mutation\u000d\u000a      could outcompete their non-mutant\u000d\u000a      counterparts in the testes, leading to an increased proportion of sperm\u000d\u000a      carrying the FGFR2\u000d\u000a      mutation4. This research established the general principle that\u000d\u000a      deleterious mutations can have\u000d\u000a      competitive advantage, and the group went on to show a similar paternal\u000d\u000a      age-effect mechanism for\u000d\u000a      mutations in other genes, responsible for testicular tumors and other\u000d\u000a      craniofacial disorders5. The\u000d\u000a      Oxford researchers have argued that these findings will have broad\u000d\u000a      implications for the origins of\u000d\u000a      many inherited genetic diseases4-5. They recently showed how\u000d\u000a      spermatogonial selection combines\u000d\u000a      with mutation rates to cause an increased burden of HRas mutations in the\u000d\u000a      sperm of healthy older\u000d\u000a      men6.\u000d\u000a    The research has shown, unambiguously, that paternal age is a risk factor\u000d\u000a      for the occurrence of\u000d\u000a      mutations, and has identified a mechanism by which this risk can be\u000d\u000a      amplified with age, causing\u000d\u000a      serious and unexpected disorders in offspring.\u000d\u000a    "},{"CaseStudyId":"6025","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"1605651","Name":"Thailand"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"3469034","Name":"Brazil"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Melioidosis is a threat to human health throughout South and East Asia,\u000d\u000a      Northern Australia, the Indian subcontinent and areas of South America.\u000d\u000a      Due to rising life expectancy and an increase in predisposing conditions\u000d\u000a      for melioidosis (such as diabetes mellitus), the annual incidence of human\u000d\u000a      melioidosis in the Ubon Ratchathani province of Thailand has substantially\u000d\u000a      increased from 4.4 per 100,000 people for the period 1987 to 1991, to 21\u000d\u000a      per 100,000 in 2012.\u000d\u000a    The number of people dying from melioidosis in northeast Thailand is now\u000d\u000a      comparable to deaths from tuberculosis, and exceeds those from malaria,\u000d\u000a      diarrhoeal illnesses and measles combined, diseases considered to be a\u000d\u000a      high priority by funding agencies and global health organisations.\u000d\u000a    In north-eastern Thailand, melioidosis accounts for 20% of all\u000d\u000a      community-acquired septicaemias, and causes death in 40% of conventionally\u000d\u000a      treated patients. B pseudomallei is an environmental saprophyte\u000d\u000a      found in wet soils. Melioidosis is characterised by formation of\u000d\u000a      abscesses, especially in the lungs, liver, spleen, skeletal muscle, and\u000d\u000a      prostate. In a third of paediatric cases in Southeast Asia, the disease\u000d\u000a      presents as a parotid abscess. In northern Australia, 4% of patients\u000d\u000a      present with brain stem encephalitis.\u000d\u000a    The work of The University of Oxford's MORU has primarily been to define\u000d\u000a      strategies to reduce mortality from melioidosis and to develop\u000d\u000a      evidence-based guidelines on the prevention of infection.\u000d\u000a    International Guidelines:\u000d\u000a    As a result of MORU's underpinning research into treatment regimes5,\u000d\u000a        7, the World Health Organization's Centers for Disease Control and\u000d\u000a      Prevention now recommend the use of ceftazidime or meropenem as an\u000d\u000a      intravenous therapy for melioidosis8.\u000d\u000a    The same recommendations can also be found on UpToDate®, an\u000d\u000a      evidence-based clinical decision support system authored by physicians to\u000d\u000a      help clinicians make the right decisions at the point of care. The\u000d\u000a      articles cite the MORU studies as the primary evidence in support of\u000d\u000a      treatment 9.\u000d\u000a    An important advance has come from MORU's research demonstrating the\u000d\u000a      superiority of carbapenem antibiotics for severe acute disease10.\u000d\u000a      UpToDate® have also included these observations, reporting on\u000d\u000a      treatment in the Northern Territory of Australia where melioidosis is\u000d\u000a      hyperendemic. According to UpToDate® all patients requiring\u000d\u000a      intensive care unit (ICU) admission in the Northern Territory are treated\u000d\u000a      with meropenem. Meropenem is used rather than imipenem because of fewer\u000d\u000a      neurologic side effects. Without access to appropriate antibiotics\u000d\u000a      (principally ceftazidime or meropenem), the septicaemic form of\u000d\u000a      melioidosis has a mortality rate that exceeds 90%.9\u000d\u000a    UpToDate® cites the 1999 and 2005 MORU trials as the primary\u000d\u000a      evidence for the recommended 3 month eradication therapy with TMP-SMX and\u000d\u000a      doxycycline.\u000d\u000a    Clinical Practice:\u000d\u000a    The Unit's research has also identified nutritional support as a major\u000d\u000a      determinant of the outcome of chronic melioidosis infection. This has led\u000d\u000a      to new strategies to support patient nutrition and has improved survival\u000d\u000a      rates.\u000d\u000a    Focus on high-risk individuals and rapid diagnosis is important in order\u000d\u000a      to start treatment at an early stage. The introduction of\u000d\u000a      immunofluorescent based assays to detect bacteria by microscopy of pus,\u000d\u000a      sputum, and urine has been useful in Thailand. The time to diagnosis has\u000d\u000a      been reduced to 30 minutes.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Sustained research by the University of Oxford's Mahidol Oxford Tropical\u000d\u000a      Medicine Research Unit in Thailand (MORU) has been the driving force\u000d\u000a      behind the current World Health Organization recommendations for the\u000d\u000a      management of acute and chronic infection in patients with melioidosis.\u000d\u000a      This research has motivated improvements in treatments and provided new\u000d\u000a      strategies to identify at-risk populations, enabling clinicians to make\u000d\u000a      early diagnoses. Melioidosis is a major cause of severe illness in parts\u000d\u000a      of Southeast Asia and there are increasing numbers of cases in India,\u000d\u000a      China, and Brazil.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2064513","Name":"Northern Territory"},{"GeoNamesId":"1906688","Name":"Changwat Ubon Ratchathani"}],"References":"\u000d\u000a    \u000a1. Suputtamongkol, Y. et al. The epidemiology of melioidosis in\u000d\u000a      Ubon Ratchatani, northeast Thailand. Int J Epidemiol 23,\u000d\u000a      1082-1090 (1994).\u000d\u000a    \u000aPrimary paper from MORU showing that an underlying disease (mainly\u000d\u000a          diabetes mellitus) and malnutrition, significantly increases a\u000d\u000a          person's likelihood of contracting a chronic melioidosis infection.\u000d\u000a    \u000a2. Wuthiekanun, V. et al. Rapid immunofluorescence microscopy for\u000d\u000a      diagnosis of melioidosis. Clin. Diagn. Lab. Immunol. 12, 555-556\u000d\u000a      (2005). doi: 10.1128\/CDLI.12.4.555-556.2005.\u000d\u000a    \u000aTwo rapid diagnostic tests for melioidosis, published by MORU,\u000d\u000a          based on direct immunofluorescence (IF) of bacteria, making it\u000d\u000a          possible to detect disease faster and at an earlier stage.\u000d\u000a    \u000a3. Smith, M. D., Wuthiekanun, V., Walsh, A. L. & White, N. J.\u000d\u000a      In-vitro activity of carbapenem antibiotics against beta-lactam\u000d\u000a      susceptible and resistant strains of Burkholderia pseudomallei. J.\u000d\u000a        Antimicrob. Chemother. 37, 611-615 (1996).\u000d\u000a    \u000aThis research from MORU shows that the carbapenem antibiotics\u000d\u000a          imipenem and meropenem perform better than ceftazidime.\u000d\u000a    \u000a4. Simpson, A. J. et al. Comparison of imipenem and ceftazidime\u000d\u000a      as therapy for severe melioidosis. Clin. Infect. Dis. 29, 381-387\u000d\u000a      (1999).\u000d\u000a    \u000aA randomized comparative trial showing that high dose imipenem is\u000d\u000a          equally as effective as ceftazidime for severe melioidosis, with fewer\u000d\u000a          treatment failures in those given imipenem.\u000d\u000a    \u000a5. Chierakul, W. et al. Two randomized controlled trials of\u000d\u000a      ceftazidime alone versus ceftazidime in combination with\u000d\u000a      trimethoprim-sulfamethoxazole for the treatment of severe melioidosis. Clin.\u000a        Infect. Dis. 41, 1105-1113 (2005). doi: 10.1086\/444456\u000d\u000a    \u000aA randomized controlled trial of 449 patients with severe\u000d\u000a          melioidosis in Thailand.\u000d\u000a    \u000a6. Chaowagul, W. et al. A comparison of chloramphenicol,\u000d\u000a      trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as\u000d\u000a      maintenance therapy for melioidosis. Clin. Infect. Dis. 29,\u000d\u000a      375-380 (1999).\u000d\u000a    \u000aA combination therapy trial showing that relapse cases were\u000d\u000a          significantly higher with doxycycline alone.\u000d\u000a    This research was funded by the Wellcome Trust.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a      Cheng, A. C. et al. Dosing regimens of cotrimoxazole\u000d\u000a        (trimethoprim-sulfamethoxazole) for melioidosis. Antimicrob. Agents\u000d\u000a          Chemother. 53, 4193-4199 (2009) doi: 10.1128\/AAC.01301-08.\u000d\u000a\u0009\u0009  \u000d\u000a      The World Health Organization's Centers for Disease Control and\u000d\u000a            Prevention now recommend the use of ceftazidime or meropenem as an\u000d\u000a            intreveous therapy for melioidosis. This recommendation was based on\u000d\u000a            MORU's findings.\u000d\u000a\u0009\u0009\u0009\u000d\u000a      Centers for Disease Control and Prevention (CDC) - Treatment -\u000d\u000a        Melioidosis (Accessed 2013) . cdc.gov at Available at http:\/\/www.cdc.gov\/melioidosis\/treatment\/index.html\u000a\u000d\u000a\u0009\u0009\u000d\u000a      The WHO's Centers for Disease Control and Prevention recommend\u000d\u000a            Trimethoprim-sulfamethoxazole or Doxycycline as an alternative oral\u000d\u000a            therapy for the treatment of melioidosis based on MORU's research.\u000d\u000a      \u000d\u000a\u0009  Currie, B and Anstey, N. Treatment and prognosis of melioidosis. In\u000d\u000a        UpToDate Basow, DS (Ed), UpToDate, Waltham, MA, 2013.(Accessed 2013).\u000d\u000a        Website accessible to subscribers only (available on request).\u000d\u000a        http:\/\/www.uptodate.com\/contents\/treatment-and-prognosis-of-melioidosis?source=search_result&search=melioidosis&selectedTitle=2%7E23\u000a\u000d\u000a\u0009\u0009\u000d\u000a      Recommendations for the introduction of TMP-SMX during initial\u000d\u000a            intensive therapy on UpToDate® directly cite MORU studies.\u000d\u000a\u000d\u000a\u0009\u0009\u0009Wuthiekanun, V. et al. Survey of antimicrobial resistance in\u000d\u000a        clinical Burkholderia pseudomallei isolates over two decades in\u000d\u000a        Northeast Thailand. Antimicrob. Agents Chemother. 55,\u000d\u000a        5388-5391 (2011) doi: 10.1128\/AAC.05517-11.\u000d\u000a\u0009\u0009\u000d\u000a      MORUs research demonstrating the utility of carbapenem\u000d\u000a            antibiotics for severe acute disease.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    MELIOIDOSIS: MANAGING ACUTE AND CHRONIC INFECTION\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The University of Oxford's Mahidol Oxford Tropical Medicine Research Unit\u000d\u000a      (MORU) is the world's leading authority on melioidosis and carries out\u000d\u000a      wide-ranging research into the aetiology, diagnosis and treatment of this\u000d\u000a      disease.\u000d\u000a    Building on its discovery of ceftazidime as the first effective treatment\u000d\u000a      for melioidosis in 1989, MORU's research has driven sustained improvement\u000d\u000a      in the management of melioidosis across Asia and South America over the\u000d\u000a      past 25 years.\u000d\u000a    The identification of at-risk groups:\u000d\u000a    By undertaking surveys in northern Thailand MORU has shown that most\u000d\u000a      adult patients have an underlying disease (mainly diabetes mellitus)\u000d\u000a      predisposing them to melioidosis infection. MORU also found that\u000d\u000a      malnutrition, due to poor dietary intake, significantly increases a\u000d\u000a      persons likelihood of contracting a chronic melioidosis infection1.\u000d\u000a    Rapid diagnosis:\u000d\u000a    In 2005 MORU published two rapid diagnostic tests for melioidosis, based\u000d\u000a      on direct immunofluorescence (IF) of the causative bacterium, Burkholderia\u000a        pseudomallei, making it possible to detect disease at an earlier\u000d\u000a      stage2. The sensitivities of both IF tests were 66%, and the\u000d\u000a      specificities were 99.5 and 99.4%, respectively. This showed that this new\u000d\u000a      test was not only faster; it was also far more specific and sensitive than\u000d\u000a      the former diagnostic test.\u000d\u000a    The treatment of acute infection:\u000d\u000a    In 1996, researchers from MORU showed that the carbapenem antibiotics\u000d\u000a      imipenem and meropenem have the lowest minimum inhibitory concentrations\u000d\u000a      (MIC) against B. pseudomallei and as such perform better than\u000d\u000a      ceftazidime3. In a randomized, comparative trial from Thailand\u000d\u000a      published in 1999, the Unit also showed that a high dose imipenem was\u000d\u000a      equally as effective as ceftazidime for severe melioidosis, with fewer\u000d\u000a      treatment failures in those given imipenem4.\u000d\u000a    MORU has tested several other conventional treatments for melioidosis in\u000d\u000a      clinical trials. In 2005 it asked whether the addition of\u000d\u000a      Trimethoprim\/Sulfamethoxazole (TMP-SMX), which has very good tissue\u000d\u000a      penetration, would provide further benefit in mortality reduction compared\u000d\u000a      with monotherapy with ceftazidime in acute disease. This question was\u000d\u000a      addressed in randomized controlled trials of 449 patients with severe\u000d\u000a      melioidosis in Thailand5. The in-hospital mortality rate was\u000d\u000a      not significantly different between the treatment groups (25.1 compared\u000d\u000a      with 26.6 percent with combination therapy, respectively) and showed no\u000d\u000a      long-term benefit. At a median of 71 weeks, there was no difference\u000d\u000a      between the two groups with regard to the combined end point of mortality\u000d\u000a      or culture-confirmed recurrent melioidosis (17.8 versus 18.3 percent) with\u000d\u000a      ceftazidime alone5. This study has since led to changes in\u000d\u000a      clinical practice, refining treatment and reducing the physical and\u000d\u000a      financial costs associated with TMP-SMX in the acute setting.\u000d\u000a    Eradication of persistent infection:\u000d\u000a    Eradication therapy is necessary to prevent reactivation or relapse after\u000d\u000a      an acute infection with melioidosis, and in 1999 MORU published the most\u000d\u000a      important trial of treatment for this stage of the disease. In this trial\u000d\u000a      it compared the efficacy of a combination of chloramphenicol (first four\u000d\u000a      weeks only), TMP-SMX, and doxycycline versus doxycycline alone in\u000d\u000a      eradicating chronic infection. It found that relapse cases were\u000d\u000a      significantly higher with doxycycline alone6. In 2005, a\u000d\u000a      randomized trial in Thailand found no benefit from adding chloramphenicol\u000d\u000a      to (TMP-SMX) plus doxycycline regimen. This body of work has led to a\u000d\u000a      simple and effective cure for chronic infection in many thousands of\u000d\u000a      individuals.\u000d\u000a    "},{"CaseStudyId":"6026","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    The World Health Organization (WHO) estimated there were 8.8 million new\u000d\u000a      cases of tuberculosis,\u000d\u000a      of all forms, in the world in 2010 and 1.45 million deaths. TB meningitis\u000d\u000a      represents 1% of cases but\u000d\u000a      is disproportionately important because it causes such high mortality and\u000d\u000a      severe disability. It\u000d\u000a      affects all groups but peaks in children aged 2-4 years and makes up 5-7%\u000d\u000a      of admissions to\u000d\u000a      specialist paediatric neurology units in some countries. It is also common\u000d\u000a      in untreated HIV infection\u000d\u000a      and the incidence of tuberculosis is increasing in some industrialised\u000d\u000a      countries, for example\u000d\u000a      doubling in London in the last 10 years5.\u000d\u000a    Primary research from OUCRU Vietnam showing that dexamethasone treatment,\u000d\u000a      given in\u000d\u000a      combination with existing antibiotic treatment significantly improves\u000d\u000a      survival rates in adults and\u000d\u000a      adolescents with TB meningitis, led the British Infection Society\u000d\u000a      and the WHO to introduce\u000d\u000a      adjuvant corticosteroid treatment as standard therapy for TB meningitis.\u000d\u000a    An independent Cochrane review published in 2008 emphasised the\u000d\u000a      importance of the OUCRU\u000d\u000a      trial in providing the first, adequately randomised trial of steroids in\u000d\u000a      TB meningitis with adequate\u000d\u000a      follow-up and blinded outcome assessment. The Cochrane meta analysis,\u000d\u000a      which combined all\u000d\u000a      data, concluded that dexamethasone indeed reduces mortality and disability\u000d\u000a      by 30%6.\u000d\u000a    In 2009 the British Infection Society guidelines for the diagnosis\u000d\u000a        and treatment of tuberculosis of\u000d\u000a        the central nervous system in adults and children, which was\u000d\u000a      authored by Dr Guy Thwaites (first\u000d\u000a      author of OUCRU Vietnam's pivotal 2004 longitudinal study) showed that\u000d\u000a      dexamethasone\u000d\u000a      (corticosteroid) therapy improves survival in patients with TB meningitis.\u000d\u000a      These guidelines cite the\u000d\u000a      key research from OUCRU Vietnam recommending: \"Adjunctive corticosteroids\u000d\u000a      (either\u000d\u000a      dexamethasone or prednisolone) should be given to all patients with TBM,\u000d\u000a      regardless of disease\u000d\u000a      severity\"7.\u000d\u000a    Chapter eight of the WHO's Treatment of Tuberculosis Guidelines —\u000d\u000a        Fourth Edition8, which was\u000d\u000a      last updated in 2010, cites OUCRU Vietnam's primary 2004 paper as key\u000d\u000a      evidence in its guidance\u000d\u000a      for the treatment of TB meningitis, stating: \"Unless drug resistance is\u000d\u000a      suspected, adjuvant\u000d\u000a      corticosteroid treatment is recommended for TB meningitis and\u000d\u000a      pericarditis\"8.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Researchers at the Oxford University Clinical Research Unit (OUCRU) in\u000d\u000a      Vietnam demonstrated\u000d\u000a      the effectiveness of dexamethasone (a corticosteroid) as an adjuvant\u000d\u000a      treatment for Tuberculous\u000d\u000a      Meningitis (TB meningitis). OUCRU's research persuaded the World Health\u000d\u000a      Organization (WHO) to\u000d\u000a      recommend corticosteroid therapy for the treatment of TB meningitis, and\u000d\u000a      this has been shown to\u000d\u000a      reduce the mortality and long-term disability caused by this devastating\u000d\u000a      disease by 30%.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Thwaites, G. E. & Tran, T. H. Tuberculous meningitis: many\u000d\u000a      questions, too few answers.\u000d\u000a      Lancet Neurol 4, 160-170 (2005)\u000d\u000a      doi.org\/10.1016\/S1474-4422(05)01013-6.\u000d\u000a    \u000aThis review indicates that while there have been many small scale\u000d\u000a          studies suggesting\u000d\u000a          the use of corticosteroid therapy (as an additional\u000d\u000a        treatment for TB meningitis), none\u000d\u000a          were adequate or large enough to encourage changes to clinical\u000d\u000a          management.\u000d\u000a    \u000a2. Thwaites, G. E. et al. Dexamethasone for the treatment of\u000d\u000a      tuberculous meningitis in\u000d\u000a      adolescents and adults. N. Engl. J. Med. 351, 1741-1751\u000d\u000a      (2004) doi:\u000d\u000a      10.1056\/NEJMoa040573.\u000d\u000a    \u000aThe first large scale trial of corticosteroid treatment in patients\u000d\u000a          with TB meningitis,\u000d\u000a          showing that adjunctive treatment with dexamethasone improves\u000d\u000a          survival.\u000d\u000a    \u000a3. Thwaites, G. E. et al. Serial MRI to determine the effect of\u000d\u000a      dexamethasone on the cerebral\u000d\u000a      pathology of tuberculous meningitis: an observational study. Lancet\u000d\u000a        Neurol 6, 230-236 (2007)\u000d\u000a      doi.org\/10.1016\/S1474-4422(07)70034-0.\u000d\u000a    \u000aIn a follow-up study showing the underlying mechanisms leading to\u000d\u000a          increased survival\u000d\u000a          rates resulting from dexamethasone therapy.\u000d\u000a    \u000a4. Török, M. E. et al. Dexamethasone and long-term outcome of\u000d\u000a      tuberculous meningitis in\u000d\u000a      Vietnamese adults and adolescents. PLoS One 6, e27821\u000d\u000a      (2011) doi:\u000d\u000a      10.1371\/journal.pone.0027821.\u000d\u000a    \u000aA study confirming that adjunctive dexamethasone treatment improves\u000d\u000a          survival in\u000d\u000a          patients with TB meningitis, until at least two years of follow-up.\u000d\u000a    This research was funded by the Wellcome Trust.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    \u000d\u000a      Thwaites, G.E., van Toorn, R. & Schoeman, J. Yuberculous\u000d\u000a        meningitis: more questions, still\u000d\u000a        to few answers. Lancet Neurol, (2013)\u000d\u000a        S1474-4422(13)70168-6. 10.1016\/S1474-4422(13)70168-6.\u000d\u000a     This general review highlights the scale of the problem caused by\u000d\u000a          tuberculous\u000d\u000a          meningitis worldwide and provides a context for improvements by\u000d\u000a          adjunctive therapy.\u000d\u000a      Prasad, K., & Singh, M. B. (2008). Corticosteroids for managing\u000d\u000a        tuberculous meningitis.\u000d\u000a        Cochrane database of systematic reviews (Online), (1), CD002244.\u000d\u000a        doi:10.1002\/14651858.CD002244.pub3\u000d\u000a      Cochrane review emphasising the importance of the OUCRU trial in\u000d\u000a            providing the first,\u000d\u000a            adequately randomized trial of steroids in TB meningitis with\u000d\u000a            adequate follow-up and\u000d\u000a            blinded outcome assessment.\u000d\u000a      Thwaites, G. et al. British Infection Society guidelines for\u000d\u000a        the diagnosis and treatment of\u000d\u000a        tuberculosis of the central nervous system in adults and children. J\u000d\u000a          Infect 59, 167-187 (2009)\u000d\u000a        doi: 10.1016\/j.jinf.2009.06.011.\u000d\u000a      British Infection Society guidelines recommending adjunctive\u000d\u000a            corticosteroid treatment\u000d\u000a            should be given to all patients with Tuberculous Meningitis. These\u000d\u000a            guidelines directly\u000d\u000a            cite key research from OUCRU Vietnam.\u000d\u000a      World Health Organization Treatment of Tuberculosis Guidelines.\u000d\u000a        (2010). Available at\u000d\u000a        http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241547833_eng.pdf\u000d\u000a        (Accessed 2013)\u000d\u000a      Chapter eight of the WHO's Treatment of Tuberculosis Guidelines —\u000d\u000a            Fourth Edition,\u000d\u000a            cites OUCRU Vietnam's primary 2004 paper as key evidence for the use\u000d\u000a            of adjuvant\u000d\u000a            corticosteroid in treating Tuberculous Meningitis.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    IMPROVED TREATMENT FOR TUBERCULOUS MENINGITIS\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    TB meningitis is a life-threatening infectious disease, which causes\u000d\u000a      inflammation of the meninges —\u000d\u000a      a protective membrane that surrounds the brain and spinal cord. It causes\u000d\u000a      up to 50% mortality or\u000d\u000a      severe long-term disability even in patients who are treated with\u000d\u000a      combination antibiotic therapy.\u000d\u000a    While a number of early studies suggested the use of corticosteroids1\u000d\u000a      might be an effective\u000d\u000a      adjuvant therapy, the small scale of these trials lacked evidence for\u000d\u000a      global change to clinical\u000d\u000a      practice and guidelines.\u000d\u000a    To address this problem, OUCRU Vietnam researchers undertook the first\u000d\u000a      large scale trial of\u000d\u000a      dexamethasone (a type of corticosteroid) in patients with TB meningitis.\u000d\u000a      Published in 2004, this\u000d\u000a      randomised, double-blind, placebo-controlled trial of 545 adults and\u000d\u000a      adolescents (over 14 years of\u000d\u000a      age) showed that adjunctive treatment with dexamethasone improves survival2.\u000d\u000a    In a follow-up study to determine the underlying mechanisms behind\u000d\u000a      increased survival rates\u000d\u000a      resulting from dexamethasone, OUCRU Vietnam researchers aimed to determine\u000d\u000a      the effect of\u000d\u000a      dexamethasone on the brains of adults with TB meningitis. This study\u000d\u000a      showed that dexamethasone\u000d\u000a      reduces increased fluid from around the brain and prevents tissue death,\u000d\u000a      leading to improved\u000d\u000a      survival3.\u000d\u000a    Increased survival rates were again confirmed in a collaborative study,\u000d\u000a      published in 2011, between\u000d\u000a      Oxford's Vietnam Unit, Imperial College, and Cambridge University. This\u000d\u000a      longitudinal study also\u000d\u000a      showed that adjunctive dexamethasone treatment improves survival in\u000d\u000a      patients with TB meningitis,\u000d\u000a      until at least two years of follow-up4.\u000d\u000a    "},{"CaseStudyId":"6028","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    The UKPDS publications are landmark studies in the treatment of type 2\u000a      diabetes. They have influenced diabetes treatment guidelines and standards\u000a      of care worldwide7,8, leading to earlier and more effective\u000a      therapy globally for people with diabetes.\u000a    Impacting clinical guidelines\u000a    References to UKPDS publications can be found in virtually all\u000a      evidence-based international guidelines9, including the UK\u000a      National Institute for Clinical Excellence Guidelines10,\u000a      International Diabetes Federation Global Guidelines8, British\u000a      Columbia Guidelines11, and the Australian National Health and\u000a      Medical Research Council Guidelines for Blood Glucose Control in Type 2\u000a      Diabetes12. Each of these guidelines reflect UKPDS findings by\u000a      recommending intensive glucose control and tight blood pressure control\u000a      following the diagnosis of type 2 diabetes, as well as the use of\u000a      metformin as the first-line treatment for type 2 diabetes. In addition,\u000a      the first joint consensus guidelines from the American Diabetes\u000a      Association and European Association for the Study of Diabetes explicitly\u000a      state that metformin should be the foundation therapy, along with diet, in\u000a      patients with type 2 diabetes13. These guidelines were also\u000a      based on evidence presented in the UKPDS. As a result, metformin is now\u000a      the most commonly prescribed therapy for diabetes worldwide14,15.\u000a    Educating the medical community and the public\u000a    The UKPDS trial quickly became a staple in many of the tens of thousands\u000a      of continuing medical education programmes on type 2 diabetes and its\u000a      management since 1998. The findings have been cited in educational\u000a      material aimed at healthcare professionals including nurses and\u000a      dieticians, and formed part of the information given to the public7.\u000a    Impact on patients\u000a    The complete impact of this study is impossible to quantify, however a\u000a      number of experts have given their opinion on the very large impact the\u000a      UKPDS trial has had on patients and the lives of those living with\u000a      diabetes. For example, writing in the recently published `Understanding\u000a      Medical Research, the Studies that Shaped Medicine', Philip Home comments\u000a      that the UKPDS trial affects the lives of over 200 million people every\u000a      day16. And in his paper in Diabetic Medicine Genuth\u000a      writes that the UKPDS has contributed to the slow overall global trend of\u000a      decreasing HbA1c levels -a measure of the average amount of\u000a      sugar in the blood - of treated diabetic patients7.\u000a    Given its influence on the development of guidelines, clinical education\u000a      and the thinking of healthcare professionals, Philip Home, this time\u000a      writing in Diabetic Medicine, concludes that \"by inference it must\u000a      be responsible for a significant part of the improvement in health\u000a      outcomes in people with type 2 diabetes in the last decade\"9.\u000a      It is likely that the impact of UKPDS is not yet fully realised. Data from\u000a      the uniquely valuable cohort of patients in this study are likely to yield\u000a      even more insights into diabetes, complications and benefits of treatment\u000a      in the years to come7.\u000a    ","ImpactSummary":"\u000a    The University of Oxford's United Kingdom Prospective Diabetes Study\u000a      (UKPDS) was a landmark 30-year clinical trial, reported in over 80\u000a      academic research papers between 1983 and 2008. It showed beyond doubt\u000a      that diabetic complications, previously thought to be inevitable\u000a      consequences of the condition, could be delayed or prevented by improved\u000a      treatment from the time of diagnosis. These findings have had a profound\u000a      influence on the management of type 2 diabetes, clinical guidelines, and\u000a      standards of care, and have reduced diabetes-related complications\u000a      worldwide, lowering the incidence of blindness, kidney failure,\u000a      amputation, heart attack and stroke.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. UK Prospective Diabetes Study (UKPDS) Group Intensive blood glucose\u000a      control with sulphonylureas or insulin compared with conventional\u000a      treatment and risk of complications in patients with type 2 diabetes\u000a      (UKPDS 33). The Lancet. 352:837-53; (1998) UKPDS\u000a          paper showing how intensive glucose control following the diagnosis of\u000a          type 2 diabetes improved long-term patient health.\u000a    \u000a\u000a2. UK Prospective Diabetes Study Group. Tight blood pressure control and\u000a      risk of macrovascular and microvascular complications in type 2 diabetes:\u000a      UKPDS 38. Brit Med J.;317:703-13.(1998) UKPDS paper\u000a          showing how tight blood pressure control following the diagnosis of\u000a          type 2 diabetes improved long-term patient health.\u000a    \u000a\u000a3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive\u000a      blood-glucose control with metformin on complications in overweight\u000a      patients with type 2 diabetes (UKPDS 34). The Lancet.352,\u000a      854-65(1998). UKPDS paper showing how metformin treatment reduced\u000a          cardiovascular disease outcomes.\u000a    \u000a\u000a4. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet,\u000a      sulfonylurea, metformin, or insulin in patients with type 2 diabetes\u000a      mellitus: progressive requirement for multiple therapies (UKPDS 49). UK\u000a      Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281,\u000a      2005-12(1999). UKPDS paper showing that type 2 diabetes is a\u000a          progressive condition requiring multiple therapies.\u000a    \u000a\u000a5. Clarke P et al Cost-effectiveness analysis of intensive blood glucose\u000a      control with metformin in overweight patients with type 2 diabetes. UKPDS\u000a      No. 51 Diabetologia. 44, 298-304(2001). Paper\u000a          showing that treating overweight patients with type 2 diabetes with\u000a          metformin was cost effective.\u000a    \u000a\u000a6. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil,\u000a      H. A. W. 10-year follow-up of intensive glucose control in type 2\u000a      diabetes. N. Engl. J. Med. 359, 1577-1589 (2008). doi:\u000a      10.1056\/NEJMoa0806470 Paper describing the legacy effect identified\u000a          by the 10-year UKPDS post trial follow-up study.\u000a    \u000aThe UKPDS received funding from the UK Medical Research Council, the\u000a      British Diabetic Association, the UK Department of Health, the National\u000a      Eye Institute and the National Institute of Diabetes and Digestive and\u000a      Kidney Disease (the US National Institutes of Health), the British Heart\u000a      Foundation, The Wellcome Trust, the Charles Wolfson Charitable Trust, the\u000a      Clothworkers' Foundation, the Health Promotion Research Trust, the Alan\u000a      and Babette Sainsbury Trust, the Oxford University Medical Research Fund\u000a      Committee.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    \u000a      Genuth, S. The UKPDS and its global impact. Diabet. Med. 25\u000a          Suppl 2, 57-62 (2008).\u000a        doi:10.1111\/j.1464-5491.2008.0204.x. Paper summarising global\u000a            impact of UKPDS.\u000a\u000a      International Diabetes Federation Clinical guidelines task force\u000a        Global Guideline for Type 2 Diabetes Chapter 9. Glucose control:oral\u000a        therapy [online] (2005). Available at:\u000a        http:\/\/www.idf.org\/webdata\/docs\/GGT2D%2009%20Oral%20therapy.pdf\u000a        [Accessed 2013] The International Diabetes Federation's\u000a            guidelines for treating diabetes with oral therapy.\u000a\u000a      Home, P. D. Impact of the UKPDS--an overview. Diabet. Med. 25\u000a          Suppl 2, 2-8 (2008). doi:10.1111\/j.1464-5491.2008.02501.x. Paper\u000a            summarising impact of the UKPDS trial.\u000a\u000a      National Institute for Health and Clinical Excellence (NICE)\u000a        Guidelines, UK. Type 2 diabetes: The management of type 2 diabetes.\u000a        [online] March 2009 Available at:\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/12165\/44320\/44320.pdf\u000a        [Accessed 21st June 2013] Clinical guidelines\u000a            outlining recommendations for management of type 2 diabetes in the\u000a            NHS in England and Wales.\u000a\u000a      British Columbia Ministry of Health Guidelines. Diabetes Care.\u000a        [online] September 2010. Available at:\u000a          http:\/\/www.bcguidelines.ca\/guideline_diabetes.html [Accessed 21st\u000a        June 2013] Clinical guidelines outlining recommendations for\u000a            diabetes care in British Columbia.\u000a\u000a      Australian Government National Health and Medical Research Council.\u000a        National Evidence Based Guideline for Blood Glucose Control in Type 2\u000a        Diabetes [online] July 2009.Available at:\u000a        http:\/\/www.nhmrc.gov.au\/_files_nhmrc\/publications\/attachments\/di19-diabetes-blood-glucose-control.pdf\u000a        [Accessed 21st June 2013] Clinical guidelines\u000a            outlining type 2 diabetes blood glucose control recommendations in\u000a            Australia.\u000a\u000a      Nathan DM, et al. Medical management of hyperglycaemia in type 2\u000a        diabetes mellitus: a consensus algorithm for the initiation and\u000a        adjustment of therapy: a consensus statement from the American Diabetes\u000a        Association and the European Association for the Study of Diabetes. Diabetologia.\u000a        52:17-30. 2009 doi: 10.1007\/s00125-008-1157-y First joint\u000a            consensus guidelines for glucose control in type 2 diabetes from the\u000a            American Diabetes Association and European Association for the Study\u000a            of Diabetes.\u000a\u000a      National Collaborating Centre for Chronic Conditions. Type 2 diabetes:\u000a        national clinical guideline for management in primary and secondary care\u000a        (update).[online] London: Royal College of Physicians, 2008. Available\u000a        at:\u000a        http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG66FullGuideline0509.pdf.\u000a        [Accessed 21st June 2013] UK clinical guideline for\u000a            type 2 diabetes management.\u000a\u000a      American Diabetes Association Standards of medical care in\u000a        diabetes--2009. Diabetes Care, 32 Suppl 1, S13-61.\u000a        (2009). doi:10.2337\/dc09-S013 References to the UKPDS can be\u000a            found in this article about the standards of medical care in\u000a            diabetes.\u000a\u000a      Home, P Diabetes Therapy and the Prevention of Vascular Damage In\u000a        Goodfellow, JA, ed. Understanding Medical Research: The Studies that\u000a          Shaped Medicine, 1st ed. Chichester.\u000a        Wiley-Blackwell.2012. pp.235-245. Commentary\u000a            summarising the vast effect of the UKPDS trial on the lives of\u000a            patients.\u000a\u000a    \u000a    ","Title":"\u000a    DEFINING TYPE 2 DIABETES IN THE UNITED KINGDOM\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In 2011 2.9 million people within the UK and 346 million people worldwide\u000a      were known to have diabetes. With these numbers increasing every year, the\u000a      World Health Organization has projected that deaths from diabetes will\u000a      double between 2005 and 2030. More than 90% of patients diagnosed with the\u000a      disease suffer from type 2 diabetes. Predominately the result of obesity\u000a      and physical inactivity, clinicians had long suspected an association\u000a      between the complications of type 2 diabetes and elevated blood glucose\u000a      levels, without quantifiable proof.\u000a    The UK Prospective Diabetes Study (UKPDS) was a 20-year prospective\u000a      randomised controlled clinical trial of 5,102 newly diagnosed type 2\u000a      diabetic patients from 23 clinical centres across the UK, which concluded\u000a      in 1997. The trial was designed to determine whether improved blood\u000a      glucose and improved blood pressure control in hypertensive patients could\u000a      prevent complications and reduce the incidence of mortality. Conceived and\u000a      initiated by the late Professor Robert Turner and Professor Rury Holman at\u000a      the University of Oxford's Diabetes Trials Unit, the UKPDS was the largest\u000a      clinical research study into diabetes ever conducted at the time of\u000a      publication.\u000a    Results of the trial showed that:\u000a    \u000a      intensive glucose control following the diagnosis of type 2 diabetes\u000a        improved patient health in the long-term1;\u000a      tight blood pressure control following the diagnosis of type 2\u000a        diabetes improved patient health in the long-term2 ;\u000a      treating patients with metformin reduced cardiovascular disease\u000a        outcomes, with a 36% relative risk reduction in mortality and a 39%\u000a        relative risk reduction in myocardial infarction3;\u000a      demonstrated for the first time that type 2 diabetes is a progressive\u000a        condition requiring multiple therapies over time4;\u000a      using metformin to treat overweight patients with type 2 diabetes was\u000a        cost effective5.\u000a    \u000a    But the findings of the Oxford-run UKPDS did not end in 1998. Following\u000a      completion of the trial all patients returned to their usual healthcare\u000a      providers but continued to be monitored for diabetic complications for an\u000a      additional ten years. The results of the UKPDS post-trial monitoring\u000a      study, published in 2008, showed that intensive glucose control beginning\u000a      as soon as type 2 diabetes was diagnosed, led to a `legacy effect' of\u000a      sustained and extended benefits in the longer term, with a 15% reduced\u000a      risk of heart attacks and 13% fewer deaths in patients6.\u000a    This post-trial monitoring study also showed that the benefits of earlier\u000a      improved blood glucose, as well as the earlier use of metformin, in\u000a      overweight patients continued to provide benefit for ten years after the\u000a      trial was completed6. With 83 primary papers published, and\u000a      well over 10,000 citations, the UKPDS has influenced clinical\u000a      understanding of diabetes and improved its management worldwide.\u000a    "},{"CaseStudyId":"6029","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The Oxford Scores have transformed the assessment of orthopaedic surgical\u000d\u000a      outcomes worldwide\u000d\u000a      and are being used in the United Kingdom and abroad to influence\u000d\u000a      department of health policy and\u000d\u000a      guidelines.\u000d\u000a    Clinical Use and Outcomes\u000d\u000a      In April 2009 the UK National Health Service (NHS) adopted the Oxford\u000d\u000a      Scores for use by the\u000d\u000a      Department of Health in all NHS Hospitals, to monitor hip and knee\u000d\u000a      replacement operations7. In\u000d\u000a      2012 the National Joint Registry for England and Wales incorporated the\u000d\u000a      use of the Oxford\u000d\u000a      Shoulder Score in their national guidance for data collection8.\u000d\u000a      A number of private providers also\u000d\u000a      use the Oxford Scores to monitor quality9. Long-term outcome\u000d\u000a      studies linking data from National\u000d\u000a      Joint Registries to the Oxford Scores have demonstrated that approximately\u000d\u000a      20% of patients are\u000d\u000a      dissatisfied with joint replacement surgery due to persistent pain. In\u000d\u000a      addition, around 10% have\u000d\u000a      some functional deficit. This is often in the absence of any technical\u000d\u000a      problems with the surgery or\u000d\u000a      the implant requiring revision surgery10.\u000d\u000a    In a cost-benefit study of the Oxford Knee Scores in 2009, clinicians\u000d\u000a      from the South West London\u000d\u000a      Elective Orthopedic Center, Surrey, UK reported that the Oxford Knee\u000d\u000a      Scores had a 98% response\u000d\u000a      rate from patients. The paper states: \"The OKS is a short, practical,\u000d\u000a        and easy to use patient-based\u000d\u000a        questionnaire with good validity and a high completion rate. In our\u000d\u000a        study, at 2 years, the response\u000d\u000a        rate for Oxford questionnaire was 98%. It eliminates inter-observer\u000d\u000a        error making it a reliable\u000d\u000a        questionnaire\" 11.\u000d\u000a    In a large-scale independent study from Lund University Hospital in\u000d\u000a      Sweden, the Oxford Scores\u000d\u000a      were ranked as the best disease\/site-specific PROM for assessing outcome\u000d\u000a      of arthroplasty12.\u000d\u000a    International Use\u000d\u000a      Licensed by Isis Innovation (a subsidiary of the University of Oxford,\u000d\u000a      which commercialises\u000d\u000a      intellectual property arising from academic research within the\u000d\u000a      University), the Oxford Scores have\u000d\u000a      been translated into 15 languages and are now available for use worldwide.\u000d\u000a      They are currently\u000d\u000a      available from Isis Innovation in: Polish, Finnish, Korean, Russian,\u000d\u000a      Spanish, Chinese, Danish,\u000d\u000a      French, Farsi, Japanese, Dutch, Portugese, Swedish, German and Turkish.\u000d\u000a      Internationally,\u000d\u000a      governments and departments of health have adopted the Oxford Scores to\u000d\u000a      monitor the outcome\u000d\u000a      and effectiveness of orthopaedic surgical procedures, particularly joint\u000d\u000a      replacements. The use of\u000d\u000a      the Oxford Scores in New Zealand and Scandinavia has allowed early\u000d\u000a      identification (at 6 months\u000d\u000a      post-surgery) of poorly performing implants, which subsequently require\u000d\u000a      revision after 5 years. The\u000d\u000a      early withdrawal of poorly performing implants significantly reduces the\u000d\u000a      number of joint\u000d\u000a      replacement failures and the attendant morbidity and cost13.\u000d\u000a    Clinical Guidance and Policy\u000d\u000a      The Oxford Hip and Knee Scores are routinely collected by the NHS,\u000d\u000a      following joint replacement\u000d\u000a      operations. These PROMs are co-ordinated by the Department of Health,\u000d\u000a      while a number of\u000d\u000a      organisations are involved in the collection, processing, analysis and\u000d\u000a      reporting of PROMs data,\u000d\u000a      including providers, primary care trust commissioners, the NHS information\u000d\u000a      centres and\u000d\u000a      contractors7. As a result of these routine collections, monthly\u000d\u000a      and annual reports are published to\u000d\u000a      inform patients, health care providers and commissioners on surgical\u000d\u000a      outcomes7. The NHS also\u000d\u000a      provides guidance on the use and interpretation of the Oxford Scores,\u000d\u000a      including guides and video\u000d\u000a      clips for patients and the public7. In addition, the Department\u000d\u000a      of Health and Health Care\u000d\u000a      Commissioners in the UK have adopted the Oxford Scores for use in\u000d\u000a      measuring surgical\u000d\u000a      outcomes14. More recently there have been moves by some health\u000d\u000a      commissioners to use the\u000d\u000a      Oxford Scores as a threshold for decision making regarding referral for\u000d\u000a      surgery. The University of\u000d\u000a      Oxford are working with health care planners and policy makers to\u000d\u000a      determine how appropriate the\u000d\u000a      use of the Oxford Scores will be as a decision aid for health\u000d\u000a      commissioners.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    In response to inadequately designed assessment systems for patients\u000d\u000a      recovering from\u000d\u000a      orthopaedic surgery, researchers from the University of Oxford developed a\u000d\u000a      series highly reliable\u000d\u000a      and sensitive patient recorded questionnaires, known as the Oxford Scores.\u000d\u000a      Providing a set of\u000d\u000a      standardised outcomes for appraisal and on-going monitoring of patients,\u000d\u000a      the Oxford Scores\u000d\u000a      enable the informed assessment of clinical outcomes. Used to predict and\u000d\u000a      detect early failure of\u000d\u000a      poorly performing surgical interventions, the Oxford Scores have been\u000d\u000a      adopted by health providers\u000d\u000a      and regulators worldwide, leading to policy and treatment guideline\u000d\u000a      changes and significant\u000d\u000a      improvements in the quality of life of patients.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Dawson, J., Fitzpatrick, R., Carr, A. & Murray, D. Questionnaire\u000d\u000a      on the perceptions of\u000d\u000a      patients about total hip replacement. J Bone Joint Surg Br 78,\u000d\u000a      185-190 (1996). Paper\u000d\u000a          reporting the first Oxford Score PROMs for hip replacements.\u000d\u000a    \u000a\u000a2. Dawson, J., Fitzpatrick, R. & Carr, A. Questionnaire on the\u000d\u000a      perceptions of patients about\u000d\u000a      shoulder surgery. J Bone Joint Surg Br 78, 593-600 (1996).\u000d\u000a      Paper reporting the first\u000d\u000a          Oxford Score PROMs for shoulder surgery.\u000d\u000a    \u000a\u000a3. Dawson, J., Fitzpatrick, R., Murray, D. & Carr, A. Questionnaire\u000d\u000a      on the perceptions of\u000d\u000a      patients about total knee replacement. J Bone Joint Surg Br 80,\u000d\u000a      63-69 (1998). Paper\u000d\u000a          reporting the first Oxford Score PROMs for total knee replacement.\u000d\u000a    \u000a\u000a4. Dawson, J., Fitzpatrick, R. & Carr, A. The assessment of shoulder\u000d\u000a      instability. The\u000d\u000a      development and validation of a questionnaire. J Bone Joint Surg Br\u000d\u000a      81, 420-426 (1999).\u000d\u000a      Paper reporting the first Oxford Score PROMs for shoulder\u000d\u000a          instability.\u000d\u000a    \u000a\u000a5. Dawson, J. et al. The development and validation of a\u000d\u000a      patient-reported questionnaire to\u000d\u000a      assess outcomes of elbow surgery. J Bone Joint Surg Br 90,\u000d\u000a      466-473 (2008) doi:\u000d\u000a      10.1302\/0301-620X.90B4.20290. Paper reporting the first Oxford\u000d\u000a          Score PROMs for\u000d\u000a          elbow surgery.\u000d\u000a    \u000a\u000a6. Browne, J et al. Patient Reported Outcome Measures (PROMs) in\u000d\u000a      Elective Surgery Report\u000d\u000a      to the Department of Health. Health Services Research Unit, London School\u000d\u000a      of\u000d\u000a      Hygiene & Tropical Medicine & Clinical Effectiveness Unit, Royal\u000d\u000a      College of Surgeons of\u000d\u000a      England. December 2007. Accessed 2013. Available from:\u000d\u000a      http:\/\/www.lshtm.ac.uk\/php\/hsrp\/research\/proms_report_12_dec_07.pdf\u000d\u000a      A detailed\u000d\u000a          comparative study, in which the Oxford Scores were ranked highest,\u000d\u000a          making them the\u000d\u000a          preferred assessment method for use in the UK and Nationally.\u000d\u000a    \u000aThis research was funded by the Department of Health, Oxford Regional\u000d\u000a      Health Authority, The\u000d\u000a      Norman Collisson Foundation, The Botnar Foundation, The Lord Nuffield\u000d\u000a      Orthopaedic Centre Trust\u000d\u000a      and The National Institute for Health Research (NIHR).\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    \u000d\u000a      NHS Choices. What are PROMs? (Accessed 2013) Available from\u000d\u000a        http:\/\/www.nhs.uk\/NHSEngland\/thenhs\/records\/proms\/Pages\/aboutproms.aspx\u000d\u000a        NHS\u000d\u000a            Choices page offering advice to patients and healthcare providers on\u000d\u000a            the use of\u000d\u000a            PROMs.\u000a\u000d\u000a      National Joint Registry. National Joint Registry, launch data\u000d\u000a        collection for shoulder and\u000d\u000a        elbow joint replacements 2012. (Accessed 2013) Available from\u000d\u000a        http:\/\/www.njrcentre.org.uk\/njrcentre\/tabid\/240\/Default.aspx\u000d\u000a        Press Release from the\u000d\u000a            National Joint Registry reporting the use of the Oxford Scores in\u000d\u000a            data collection for\u000d\u000a            shoulder and elbow joint replacements.\u000a\u000d\u000a      BUPA. Bupa calls for compulsory collection of PROMS in all private\u000d\u000a        hospitals 16th June\u000d\u000a        2008. (accessed 2013) Available from\u000d\u000a        http:\/\/www.bupa.co.uk\/about\/html\/pr\/160608_proms_collection.html\u000d\u000a          Report stating the\u000d\u000a            compulsory use of PROMs as an assessment tool for private health\u000d\u000a            provider Bupa.\u000a\u000d\u000a      Baker, P. N., van der Meulen, J. H., Lewsey, J., Gregg, P. J. The role\u000d\u000a        of pain and function in\u000d\u000a        determining patient satisfaction after total knee replacement. Data from\u000d\u000a        the National Joint\u000d\u000a        Registry for England and Wales. J Bone Joint Surg Br 89,\u000d\u000a        893-900 (2007). doi:\u000d\u000a        10.1302\/0301-620X.89B7.19091 Paper reporting use of the Oxford\u000d\u000a            Scores in determining\u000d\u000a            patient outcomes following total knee replacement.\u000a\u000d\u000a      Medalla, G. A., Moonot, P., Peel, T., Kalairajah, Y. & Field, R.\u000d\u000a        E. Cost-benefit comparison of\u000d\u000a        the Oxford Knee score and the American Knee Society score in measuring\u000d\u000a        outcome of total\u000d\u000a        knee arthroplasty. J Arthroplasty 24, 652-656 (2009).\u000d\u000a        doi: 10.1016\/j.arth.2008.03.020 Cost-benefit\u000d\u000a            study stating 98% response rate for the Oxford Knee Scores.\u000a\u000d\u000a      Dunbar, M. J., Robertsson, O., Ryd, L. & Lidgren, L. Appropriate\u000d\u000a        questionnaires for knee\u000d\u000a        arthroplasty. Results of a survey of 3600 patients from The Swedish Knee\u000d\u000a        Arthroplasty\u000d\u000a        Registry. J Bone Joint Surg Br 83, 339-344 (2001). doi:\u000d\u000a        10.1302\/0301-620X.83B3.11134\u000d\u000a        Study comparing results from several PROMs questionnaires,\u000d\u000a            including the Oxford\u000d\u000a            Scores.\u000a\u000d\u000a      Rothwell, A. G., Hooper, G. J., Hobbs, A. & Frampton, C. M. An\u000d\u000a        analysis of the Oxford hip\u000d\u000a        and knee scores and their relationship to early joint revision in the\u000d\u000a        New Zealand Joint\u000d\u000a        Registry. J Bone Joint Surg Br 92, 413-418 (2010) doi:\u000d\u000a        10.1302\/0301-620X.92B3.22913.\u000d\u000a        Paper reporting use of the Oxford Scores in the early revision of\u000d\u000a            hip and knee\u000d\u000a            replacements in New Zealand.\u000a\u000d\u000a      NHS Guidance on Patient Reported Outcome Measures (PROMs)\u000d\u000a        http:\/\/www.improvement.nhs.uk\/pee\/documents\/DH_081179[1]PROMS.PDF\u000d\u000a        (2009\/2010)\u000d\u000a        NHS Guidance on the collection of PROMs for the assessment of\u000d\u000a            surgical outcomes,\u000d\u000a            recommending the use of Oxford Hip and Knee Scores.\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    STANDARDISING PATIENT APPRAISAL: ASSESSING OUTCOMES\u000d\u000a        OF ORTHOPAEDIC SURGERY\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In the 1980s joint replacement surgery came into widespread use for\u000d\u000a      patients suffering from\u000d\u000a      osteoarthritis, or age-related degenerative joint disease. Due to the high\u000d\u000a      demands of an actively\u000d\u000a      aging population, rates of joint replacement surgery are now on the rise,\u000d\u000a      with over 125,000 hip and\u000d\u000a      knee replacements being performed annually in the UK, and over 1.2 million\u000d\u000a      in the USA. As such,\u000d\u000a      it is now even more important that joint replacement surgery improves the\u000d\u000a      quality of life of patients.\u000d\u000a      In the early 1990s it became clear that there were significant\u000d\u000a      methodological deficiencies with the\u000d\u000a      evaluation and reporting of orthopaedic surgical outcomes — particularly\u000d\u000a      for implants and joint\u000d\u000a      replacements. At the time, regular reviews of large numbers of patients\u000d\u000a      for assessment of the long-term\u000d\u000a      impact of surgical procedures (such as joint replacements) was rare, with\u000d\u000a      the majority of\u000d\u000a      patients receiving no monitoring. Clinical assessment in hospital was\u000d\u000a      neither feasible nor\u000d\u000a      affordable and introduced the potential for bias, due to inadequately\u000d\u000a      designed assessment\u000d\u000a      systems.\u000d\u000a    To combat this problem, between 1993 and 2008, Professor Andrew Carr,\u000d\u000a      Professor David Murray,\u000d\u000a      Professor Ray Fitzpatrick and Dr Jill Dawson of the University of Oxford's\u000d\u000a      Nuffield Department of\u000d\u000a      Orthopaedics, Rheumatology and Musculoskeletal Sciences and Department of\u000d\u000a      Public Health\u000d\u000a      designed a series of new scores for use following orthopaedic surgery,\u000d\u000a      based on the then novel\u000d\u000a      principle of patient reported outcomes (PROMs). Devising five 12 item\u000d\u000a      questionnaires specific to\u000d\u000a      patients recovering from total hip replacement1, shoulder\u000d\u000a      operations2, total knee replacement3,\u000d\u000a      shoulder instability4 and elbow surgery5, the group\u000d\u000a      showed that their PROM questionnaires were\u000d\u000a      capable of quickly, practically, reliably, and sensitively measuring\u000d\u000a      clinical outcomes and important\u000d\u000a      changes over time.\u000d\u000a    Designed through patient and clinician interviews, followed by refinement\u000d\u000a      and testing, the Oxford\u000d\u000a      Scores provide assessments of pain and function, as well as the social and\u000d\u000a      psychological status of\u000d\u000a      patients. The questionnaires are distributed to patients by post or\u000d\u000a      deployed by various electronic\u000d\u000a      platforms, making the follow-up of large study populations much more\u000d\u000a      feasible and cost-effective\u000d\u000a      than former clinical assessments, which require a return visit to\u000d\u000a      hospital. This format also\u000d\u000a      eliminates bias, as patients are able to complete the questionnaire\u000d\u000a      independent of a clinical team\u000d\u000a      or surgeon.\u000d\u000a    In addition to the successful measurement of clinical outcomes, this\u000d\u000a      research also demonstrates a\u000d\u000a      strong commitment to the involvement and engagement of patients in\u000d\u000a      research. During the design\u000d\u000a      of the Oxford Scores patients were involved from the very beginning of the\u000d\u000a      research process,\u000d\u000a      allowing the Oxford team to fully take into account real world health\u000d\u000a      problems, to increase\u000d\u000a      relevance, and to achieve the best possible assessment of outcome for\u000d\u000a      patients.\u000d\u000a    The Oxford Scores' superiority over former assessment methods was\u000d\u000a      confirmed in 2007, in a\u000d\u000a      report commissioned by the UK Department of Health, produced by the London\u000d\u000a      School of Hygiene\u000d\u000a      and Tropical Medicine, and The Royal College of Surgeons. The Oxford\u000d\u000a      Scores were ranked\u000d\u000a      highest of all methods in this detailed comparative study, making them the\u000d\u000a      preferred assessment\u000d\u000a      tool for use in the UK and internationally6.\u000d\u000a    "},{"CaseStudyId":"6030","Continent":[{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":[],"ImpactDetails":"\u000a    Since its introduction in 1998, around one million people worldwide have\u000a      been treated with the Phase 3 Oxford Knee. The minimally invasive and more\u000a      reliable Phase 3 Oxford Knee, has dramatically improved the quality of\u000a      life for these patients by effectively curing pain and disability with\u000a      little risk of complication, or need for revision surgery3,7,8.\u000a    Improved Health and Quality of Life\u000a    Patients requiring knee replacements usually suffer from severe pain in\u000a      the knee, particularly when active; they also experience poor function,\u000a      stiffness, deformity and disability. As a result, patients often find\u000a      everyday activities difficult. Following implantation of a Phase 3 Oxford\u000a      Knee these symptoms are significantly improved and often cured, allowing\u000a      patients to return to their normal lifestyles3,4. The elderly\u000a      can retain their independence, the young can return to work, and active\u000a      sportspeople — who often suffer most from knee injury and ineffective knee\u000a      replacements — can remain active.\u000a    Without the availability of the Phase 3 Oxford Knee most patients would\u000a      have previously received a TKR, which requires the whole knee to be\u000a      replaced rather than just the damaged compartment. As a result of less\u000a      invasive surgery, complications occur much less frequently with the Phase\u000a      3 Oxford Knee, and when they do occur they are far less severe1.\u000a      For example, the rate of infection and blood clots in Phase 3 Oxford Knee\u000a      implants is approximately half compared to the TKR. During the first three\u000a      months after knee replacement mortality rates (adjusted hazard ratio)\u000a      after UKR (such as the Oxford Knee) are around three times less than after\u000a      TKR. The recovery after the operation is also around three times faster\u000a      with UKR, therefore patients can return home earlier.\u000a    Following implantation of the Phase 3 Oxford Knee, the kinematics of the\u000a      knee is virtually normal, in comparison to very abnormal kinematics after\u000a      TKR. As a result, the Phase 3 Oxford Knee offers a better range of\u000a      movement and improved function, particularly with demanding activities1,7.\u000a      Furthermore, if problems arise following Oxford Knee surgery it is much\u000a      easier to convert the replacement to a TKR, than it is to revise a TKR.\u000a      With updates constantly being implemented, such as the introduction of the\u000a      cementless Oxford Knee these results are improving. Data from the New\u000a      Zealand, and England and Wales, National Registers show that the recent\u000a      introduction of the cementless Oxford Knee has halved the need for\u000a      revision9,10.\u000a    The research from the University of Oxford and other groups, showing the\u000a      advantages of the Phase 3 Oxford Knee over fixed bearing UKR and TKR, has\u000a      contributed to the wider use of the Oxford Knee7,11. Treatment\u000a      options for young active patients with arthritis have been limited in the\u000a      past because TKR does not tend to allow patients to be very active,\u000a      similarly to fixed bearing UKRs, they also have an increased failure rate.\u000a      In contrast, the Phase 3 Oxford Knee allows patients to achieve high\u000a      levels of activity, without significantly increasing the failure rate6.\u000a      The high failure rate of UKR has also prevented obese patients from\u000a      receiving a knee replacement, however, as shown by the Murray group,\u000a      obesity does not compromise the outcome or increase the failure rate of\u000a      the Phase 3 Oxford Knee6.\u000a    Commercial & Financial Outcome\u000a    As a result of its high performance, the Phase 3 Oxford Knee is now\u000a      dominating the UKR market. In 2011, the National Joint Registry for\u000a      England and Wales reported that the Oxford Knee was used in 70-80% of\u000a      cases between 2003 and 20109. Other National Joint Registers\u000a      such as that from New Zealand also show the high numbers of Oxford Knees\u000a      being implanted10.\u000a    As reported by The National Joint Registry in 2011, the enhanced speed of\u000a      recovery associated with the Phase 3 Oxford Knee has led to patients being\u000a      discharged (on average) two days earlier than those receiving TKR9.\u000a      An increasing number of clinical centres around the world are now treating\u000a      Phase 3 Oxford Knee patients as day cases, resulting in greater cost\u000a      savings for patients, the NHS, and health care providers9,12.\u000a    ","ImpactSummary":"\u000a    Research at University of Oxford led to the development of the Phase 3\u000a      Oxford Knee in 1998, a significantly improved and less invasive knee\u000a      replacement, allowing implantation through a small incision. Due to its\u000a      many advantages over other knee replacements, including faster recovery,\u000a      fewer complications and better function, the Phase 3 Oxford Knee is now\u000a      the most widely used partial knee replacement in the world. Approximately\u000a      1 million people have benefitted from this development.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Goodfellow J, O'Connor J, Dodd C, Murray D. Unicompartmental\u000a        Arthroplasty with the Oxford Knee. Oxford University Press, Oxford.\u000a      June 2006. A book describing the Oxford knee and focusing on\u000a          indications, techniques, results and complications. It summarises all\u000a          the research supporting the Oxford knee.\u000a    \u000a\u000a2. Kendrick B, et al. Polyethylene wear of mobile-bearing\u000a      unicompartmental knee replacement at 20 years. J Bone Joint Surg Br\u000a      93, 470-475, (2011) doi: 10.1302\/0301- 620X.93B4.25605. Oxford\u000a          Stereo-Xray study demonstrating that the wear of the Oxford knee is\u000a          very low.\u000a    \u000a\u000a3. Pandit H, Jenkins C, Gill H, Barker K, Dodd C, Murray D.Minimally\u000a      invasive Oxford phase 3 unicompartmental knee replacement: results of 1000\u000a      cases. J Bone Joint Surg Br 93, 198- 204 (2011) doi:\u000a      10.1302\/0301-620X.93B2.25767. Oxford study describing the outcome\u000a          of the first 1000 Phase 3 Oxford Knees, implanted using the minimally\u000a          invasive surgical approach.\u000a    \u000a\u000a4. Reilly, K. et al. Efficacy of an accelerated recovery protocol for\u000a      Oxford unicompartmental knee arthroplasty--a randomised controlled trial.\u000a      Knee 12, 351-7 (2005) doi.org\/10.1016\/j.knee.2005.01.002.Oxford\u000a          randomised study showing it is safe, effective and cost effective to\u000a          discharge patients early after the Oxford Knee.\u000a    \u000a\u000a5. Pandit, H. et al.Unnecessary contraindications for mobile-bearing\u000a      unicompartmental knee replacement. J Bone Joint Surg Br 93,\u000a      622-628 (2011). doi: 10.1302\/0301- 620X.93B5.26214. Oxford study\u000a          showing that the outcome of the Oxford UKR is not compromised by\u000a          weight, age, activity, the state of the patellofemoral joint, and\u000a          chondrocalcinosis, so these should not be contra-indications.\u000a    \u000a\u000a6. Liddle, A D et al. Cemented versus cementless fixation in Oxford\u000a      Unicompartmental Knee Arthroplasty at five years: a randomised controlled\u000a      trial. Bone Joint J 95-B. SUPP 1 67 (2013) Supplement available at\u000a        http:\/\/www.bjjprocs.boneandjoint.org.uk\/content\/95-\u000a        B\/SUPP_1\/67.abstract (Accessed 2013) Presented at British\u000a      Orthopaedic Association Annual meeting, Manchester, England 11-14\u000a      September 2012. Oxford randomised study showing improved results\u000a          and fixation with the cementless compared to the cemented Oxford Knee.\u000a    \u000aThis research was funded by Arthritis Research UK, Biomet, the British\u000a      Medical Association (Doris Hillier grant), the Nuffield Orthopaedic Centre\u000a      General Charity, and the Royal College of Surgeons of England.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Willis-Owen, C et al. Unicondylar knee arthroplasty in the UK National\u000a        Health Service: an analysis of candidacy, outcome and cost efficacy. Knee\u000a        16, 473-478 (2009) doi: 10.1016\/j.knee.2009.04.006. An\u000a            independent study showing that UKR have better outcomes and cost\u000a            saving (£1,761 per knee) compared with TKRs and should be considered\u000a            the primary treatment option for about 50% of patients needing knee\u000a            replacement.\u000a\u000a      Price, A & Svard, U A second decade lifetable survival analysis of\u000a        the Oxford unicompartmental knee arthroplasty. Clin. Orthop. Relat.\u000a          Res. 469, 174-179 (2011) doi: 10.1007\/s11999-010-1506-2. Study\u000a            showing that the survival of the Oxford Knee in an independent\u000a            centre is about 90% at 20 years.\u000a\u000a      National Joint Registry for England and Wales 8th Annual\u000a        Report (2011). Available at http:\/\/www.njrcentre.org.uk\/NjrCentre\/Portals\/0\/Documents\/NJR%208th%20Annual%20Repo\u000art%202011.pdf\u000a          (Accessed 2013). The National joint registry shows the high\u000a            numbers of OUKR being implanted. It also shows the lower death rate,\u000a            lower complication rate and lower in patient stay of UKR compared to\u000a            TKR.\u000a\u000a      The New Zealand Joint Registry Thirteen year report January 1999 to\u000a        December 2011 Available at http:\/\/www.cdhb.govt.nz\/njr\/reports\/A2D65CA3.pdf\u000a        (Accessed 2013). Report showing the increasing numbers of Oxford\u000a            UKR implants in New Zealand, and that the cementless Oxford has the\u000a            lowest revision rate of any commonly used UKR.\u000a\u000a      Sun, P & Jia, Y. Mobile bearing UKA compared to fixed bearing TKA:\u000a        A randomized prospective study The Knee 19 103-106\u000a        (2012) doi: 10.1016\/j.knee.2011.01.006. Randomised study that\u000a            concludes, \"After the learning curve UKR should be considered the\u000a            primary treatment option for unicompartmental knee arthritis\".\u000a      Munk, S et al Early recovery after fast-track Oxford unicompartmental\u000a        knee arthroplasty. 35 patients with minimal invasive surgery. Acta\u000a          Orthopaedica; 83 41-45. (2012) doi:\u000a        10.3109\/17453674.2012.657578. Paper describing day case Oxford Knee\u000a            replacement.\u000a\u000a    \u000a    ","Title":"\u000a    THE OXFORD KNEE: REVOLUTIONISING KNEE REPLACEMENTS\u000a    ","UKLocation":[{"GeoNamesId":"2640729","Name":"Oxford"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    For more than 35 years researchers at the University of Oxford have led a\u000a      programme of research focusing on the knee. Professor David Murray has\u000a      directed this programme for almost 20 years, leading research that has\u000a      significantly improved our understanding of how the knee works, why it\u000a      fails, and how it can best be treated. On the basis of this research, the\u000a      Oxford Knee and associated surgical techniques, instrumentation,\u000a      indications and teaching methods have been developed, assessed and\u000a      progressively improved over the past two decades1.\u000a    Osteoarthritis is the most common cause of joint dysfunction and often\u000a      leads to knee replacement. Two types of knee replacement can be used: a\u000a      total knee replacement (TKR), where the whole joint is replaced and the\u000a      ligaments removed; and a partial or unicompartmental knee replacement\u000a      (UKR), such as the Oxford Knee, where only the damaged surfaces on one\u000a      side (compartment) of the joint are replaced and the ligaments are\u000a      preserved. In the majority of cases, osteoarthritis primarily affects one\u000a      compartment of the knee, and in these cases the Oxford Knee can be used1.\u000a      As wear is a major problem with knee replacements, particularly in young\u000a      and active individuals, the original design for the Oxford Knee aimed to\u000a      minimise wear by using a mobile bearing, which reproduces the functions of\u000a      the normal meniscus1.\u000a    While a recent stereo-Xray study confirmed the success of this design in\u000a      minimising wear over 20 years2, the original Oxford Knee was\u000a      plagued by inconsistent surgical outcomes. In spite of performing well in\u000a      the hands of the designer surgeon (and a number of independent surgeons),\u000a      clinical results nationally and internationally were consistently\u000a      variable.\u000a    The Phase 3 Oxford Knee was introduced in 1998 to address this problem.\u000a      Designed to be simpler to implant and more reliable, the Phase 3 Oxford\u000a      Knee has improved implant design, instrumentation, surgical technique and\u000a      instruction, leading to positive clinical results3.\u000a      Traditionally the Oxford Knee and other UKR and TKR have been implanted\u000a      through the same surgical approach, which involves dividing the extensor\u000a      muscles of the knee and dislocating the kneecap. As the Phase 3 Oxford\u000a      Knee is implanted through a short incision, without damaging the muscles\u000a      or dislocating the kneecap it is a far less invasive surgery1.\u000a    Since introducing the Phase 3 Oxford Knee, the University of Oxford\u000a      researchers have undertaken several studies to show the advantages of the\u000a      new design. These studies have shown: improved overall function, less\u000a      complications, less severe complications, and significantly faster\u000a      recovery times (three times faster than a TKR and twice as fast as\u000a      traditional UKR) 1,4. An additional study showed that due to a\u000a      lack of wear, the Phase 3 Oxford Knee (which also uses mobile bearings)\u000a      can be used more frequently than any other UKR among young, active, or\u000a      obese patients1,5. Since the introduction of the Phase 3 Oxford\u000a      Knee, additional research and development has led to the introduction of\u000a      the cementless Oxford Knee, which is even simpler to implant and has much\u000a      better fixation than the cemented6.\u000a    "},{"CaseStudyId":"6031","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    By demonstrating the frequency, the severity, and the risk factors for\u000a      pseudotumours related to\u000a      MoM hip replacements (MoMHR), this research has led to dramatic changes in\u000a      clinical practice\u000a      and guidelines nationally and internationally. As a result, implantation\u000a      of MoM replacements has\u000a      now virtually ceased. For those already implanted, routine surveillance is\u000a      recommended and all\u000a      patients with problems, including mild complaints, are investigated in\u000a      detail. Early revision is\u000a      encouraged to prevent significant soft tissue damage. This has had a\u000a      significant impact on patient\u000a      health, clinical guidelines and the orthopaedic industry.\u000a    Health and Patient Care\u000a    The identification of pseudotumours and the severe problems that they can\u000a      cause after MoM hip\u000a      replacement has led to a dramatic reduction in the use of these implants.\u000a      Data from the National\u000a      Joint Registry for England and Wales has shown that the use of MoM\u000a      resurfacing halved between\u000a      2008 and 2010, with 40% of men under 55 having MoMHR in 2008, in\u000a      comparison to 20% in 2010.\u000a      It is estimated that this number has halved again in recent years7.\u000a      The Arthritis Research UK\u000a      website provides information on hip resurfacing from experts, and states\u000a      that although metal-on-\u000a      metal hip replacements are still being implanted, predominately in young\u000a      men under the age of 50,\u000a      their general use has reduced \"very sharply\" in the UK in recent years8.\u000a    The full scale of the problem, identified by Professor Murray's team\u000a      almost seven years ago is now\u000a      clearly reflected by the National Joint Registry for England and Wales7\u000a      and other registries12, which\u000a      all show the very high failure rates of MoM replacements. These failures\u000a      are associated with\u000a      considerable patient suffering and expense to the health service.\u000a    Guidelines and Policy\u000a    On the basis of the University of Oxford's research, and the research of\u000a      other groups that have\u000a      followed its lead, strong recommendations have been issued regarding the\u000a      use of MoM\u000a      replacements in the UK. The Medicines and Healthcare products Regulatory\u000a      Agency (MHRA) has\u000a      issued numerous Medical Device alerts for various MoM implants. In\u000a      February 2012 MHRA\u000a      advised that all patients with metal-on-metal hips should be followed up\u000a      annually for five years9.\u000a    This Medical Device alert was replaced in June 2012, with updated\u000a      recommendations stating that\u000a      all patients with MoMHR should be followed up \"annually for the life of\u000a      the implant\"10.\u000a      The British Orthopaedic Association summarised the status of MoMHR in\u000a      2011, highlighting the\u000a      problems of MoM replacements and supporting recommendations to follow up\u000a      MoMHR and restrict\u000a      its use11. The National Joint Registry for England and Wales\u000a      also highlights the high failure rate of\u000a      MoMHR7.\u000a    Similar guidance has also been issued internationally. The Australian\u000a      Orthopaedic Association\u000a      National Joint Replacement Registry, highlights the high failure rate of\u000a      MoMHR in its Hip and Knee\u000a      Arthroplasty 2011 Annual Report12. The Canadian Orthopaedic\u000a      Association (COA) also issued\u000a      similar recommendations in February 201113. In the United\u000a      States, the Food and Drug\u000a      Administration (FDA) also highlighted the safety risks associated with\u000a      MoMHR, and made\u000a      recommendations on patient monitoring14.\u000a    Industry Withdrawals\u000a    DePuy, one of the largest implant manufactures for MoMHR, issued a\u000a      voluntary recall of their\u000a      Articular Surface Replacement ASR™ MOM Hip System in August 2010, and are\u000a      funding revisions\u000a      of this implant15. They and other companies are also involved\u000a      in multi-billion dollar lawsuits16.\u000a    ","ImpactSummary":"\u000a    Metal-on-metal hip resurfacing was developed in the 1990s to provide a\u000a      long-term solution for\u000a      young, active patients with hip disease. After observing severe adverse\u000a      soft tissue reactions\u000a      (pseudotumours) occurring in a growing percentage of patients with\u000a      metal-on-metal resurfacing,\u000a      researchers from the University of Oxford highlighted the problem and\u000a      identified key patient,\u000a      surgical and implant related risk factors. Clinical guidelines have been\u000a      introduced to emphasise the\u000a      risks, and several implants have been withdrawn from the market by the\u000a      manufacturers. This\u000a      research has led to a dramatic decrease in the use of metal-on-metal\u000a      bearings in hip replacement.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Oxford\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Pandit, H. et al. Pseudotumours associated with metal-on-metal\u000a      hip resurfacings. J Bone\u000a        Joint Surg Br 90, 847-851 (2008). doi:\u000a      10.1302\/0301-620X.90B7.20213. Primary paper\u000a          reporting that pseudotumours occur relatively commonly after MoM\u000a          resurfacing and\u000a          can cause major problems.\u000a    \u000a\u000a2. Glyn-Jones, S. et al. Risk factors for inflammatory\u000a      pseudotumour formation following hip\u000a      resurfacing. J Bone Joint Surg Br 91, 1566-1574 (2009).\u000a      doi: 10.1302\/0301-\u000a      620X.91B12.22287. Paper identifying the risk factors for\u000a          pseudotumours after MoM\u000a        resurfacing. \u000a    \u000a\u000a3. Kwon, Y.M. et al. Asymptomatic pseudotumours after\u000a      metal-on-metal hip resurfacing\u000a      arthroplasty: prevalence and metal ion study. J Arthroplasty 26\u000a      511-8 (2011). doi:\u000a      10.1016\/j.arth.2010.05.030. Paper showing that patients with\u000a          asymptomatic MoM\u000a        resurfacings may have developed pseudotumours. \u000a    \u000a\u000a4. Kwon, Y.M. et al. Analysis of wear of retrieved metal-on-metal hip\u000a      resurfacing implants\u000a      revised due to pseudotumours. J Bone Joint Surg Br 92\u000a      356-61 (2010). doi: 10.1302\/0301-\u000a      620X.92B3.23281. Study demonstrating that most pseudotumours are\u000a          caused by high\u000a        wear due to edge loading of the MoM bearing.\u000a    \u000a\u000a5. Kwon, Y.M. et al. Dose-dependent cytotoxicity of clinically\u000a      relevant cobalt nanoparticles and\u000a      ions on macrophages in vitro. Biomed Mater 4, 025018\u000a      (2009) doi: 10.1088\/1748-\u000a      6041\/4\/2\/025018. A paper showing that the metal wear particles kill\u000a          cells.\u000a    \u000a\u000a6. Grammatopoulos, G. et al. Hip resurfacings revised for\u000a      inflammatory pseudotumour have a\u000a      poor outcome. J Bone Joint Surg Br 91, 1019-1024 (2009).\u000a      doi: 10.1302\/0301-\u000a      620X.91B8.22562. Paper demonstrating that poor results are achieved\u000a          following\u000a          revision of MoM resurfacings for pseudotumour.\u000a    \u000aThis research was funded by the British Orthopaedic Association, DePuy,\u000a      the Furlong Foundation\u000a      (now Orthopaedic Research UK), NIHR Research for Patient Benefit, Smith\u000a      & Nephew, Stryker,\u000a      and Wright Medical Technology.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"}],"Sources":"\u000a      \u000a      National Joint Registry for England and Wales. 8th Annual\u000a      Report [online]. Hemel\u000a      Hempstead: National Joint Registry. 2011. Available at:\u000a      http:\/\/www.njrcentre.org.uk\/NjrCentre\/Portals\/0\/Documents\/NJR%208th%20Annual%20Report%202011.pdf\u000a      [Accessed 14 May 2013]Data showing the reduction in MoMHR use\u000a        between 2008 and 2010.\u000a\u000a    Arthritis Research UK. Metal-on-metal hip replacement Q and A. 2013.\u000a      Available at:\u000a      http:\/\/www.arthritisresearchuk.org\/arthritis-information\/surgery\/mom-hip-q-and-a.aspx\u000a      [Accessed 14 May 2013]An article published on the Arthritis Research\u000a          UK website\u000a        indicating the recent drop in MoMHR use in the UK.\u000a\u000a    Medicines and Healthcare products Regulatory Agency (MHRA).All\u000a      metal-on-metal (MOM)\u000a      hip replacements [online] London. 2012. Available at:\u000a      http:\/\/www.mhra.gov.uk\/home\/groups\/dts-bs\/documents\/medicaldevicealert\/con143787.pdf\u000a      [Accessed 14 May 2013] Recommendations made by MHRA in February\u000a          2012,\u000a        indicating that all patients with MoMHR should be followed up\u000a          annually for 5 years.\u000a\u000a    Medicines and Healthcare products Regulatory Agency (MHRA).All\u000a      metal-on-metal (MOM)\u000a      hip replacements [online] London. 2012. Available at:\u000a      http:\/\/www.mhra.gov.uk\/home\/groups\/dts-bs\/documents\/medicaldevicealert\/con155767.pdf\u000a        [Accessed 22 May 2013]\u000a        Updated recommendations by MHRA, released on the 25th\u000a          of June 2012, stating that\u000a        all patients with MoMHR should be followed up \"annually for the life\u000a          of the implant\".\u000a\u000a    British Orthopaedic Association. Metal on Metal Hips [online] London.\u000a      2011. Available at:\u000a      www.boa.ac.uk\/PI\/Pages\/Metal-on-Metal.aspx [Accessed 15 May 2013] A\u000a          summary of the\u000a        problems related to MoMHR from The British Orthopaedic Association\u000a          supporting\u000a        recommendations to follow up MoMHR and restrict its use.\u000a\u000a    The Australian Orthopaedic Association National Joint Replacement\u000a      Registry.Hip and Knee\u000a      Arthroplasty. Annual Report [online] Adelaide: University of Adelaide.\u000a      2011. Available at:\u000a      http:\/\/www.surfacehippy.info\/pdf\/australian-nat-reg-2011.pdf [Accessed 15\u000a      May 2013]\u000a      The Australian Orthopaedic Association National Joint Replacement\u000a          Registry, Hip\u000a        and Knee Arthroplasty Annual Report for 2011, highlighting the high\u000a          failure rate of\u000a        MoMHR.\u000a\u000a    Canadian Orthopaedic Association. Advice to patients with metal-on-metal\u000a      hips [online]\u000a      Available at\u000a      http:\/\/www.coa-aco.org\/images\/stories\/library\/Advice_to_Patients.pdf\u000a      [Accessed\u000a      15 May 2013] Recommendations from The Canadian Orthopaedic\u000a          Association (COA),\u000a        February 2011, highlighting the high failure rate of MoMHR.\u000a\u000a    medicalxpress.com. FDA probing safety of metal-on-metal hip implants\u000a      [online].\u000a      2012.Available at:\u000a      http:\/\/medicalxpress.com\/news\/2012-06-fda-probing-safety-metal-on-metal-hip.html\u000a      [Accessed 15 May 2013] Article about the FDA review\u000a          to assess the\u000a        safety risks associated with MoMHR, and make recommendations on\u000a          patient\u000a        monitoring.\u000a\u000a    DePuy Synthes ASR™ Hip Replacement Recall Guide for Patients [online]\u000a      2013 Available\u000a      at: http:\/\/www.depuy.com\/asr-hip-replacement-recall [Accessed 15 May 2013]\u000a      ASR™ Hip\u000a        Replacement Recall Guide for Patients from the DePuy website. \u000a\u000a    Orthopaedics One. The Case of Metal-on-Metal Implant Recalls - What Have\u000a      We Learned\u000a      [online] 2012.Available at:\u000a      http:\/\/www.orthopaedia.com\/display\/Main\/The+Case+of+Metal-on-Metal+Implant+Recalls+-+What+Have+We+Learned\u000a      [Accessed 15 May 2013] Article\u000a        about MoMHR recalls and lawsuits.\u000a\u000a\u0009\u0009\u000a    ","Title":"\u000a    HIGHLIGHTING THE DANGERS OF METAL-ON-METAL\u000a        HIP REPLACEMENTS\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Conventional total hip replacements (THR) have historically had high\u000a      failure rates in young, active\u000a      patients due to their functional demands. In the 1990s hip resurfacing\u000a      with metal-on-metal (MoM)\u000a      bearings were developed to combat this issue and became a common\u000a      alternative to conventional\u000a      THR in young patients. In 2008 40% of men with hip arthritis, under 55,\u000a      received MoM resurfacing\u000a      rather than conventional THR. Due to the success of MoM resurfacing,\u000a      conventional THR also\u000a      introduced MoM bearings. Worldwide over 1 million MoM bearings have now\u000a      been implanted.\u000a    University of Oxford Professor, David Murray, and other surgeons at the\u000a      Nuffield Orthopaedic\u000a      Centre in Oxford, began implanting MoM resurfacings in 1998. Detailed data\u000a      was collected on\u000a      these patients, and on patients referred to the Nuffield Orthopaedic\u000a      Centre with problems relating\u000a      to MoM bearings. The University of Oxford researchers observed increasing\u000a      numbers of patients\u000a      presenting with a variety of adverse symptoms related to their MoM\u000a      bearings. These patients were\u000a      investigated not only with X-rays, which is the traditional method of\u000a      investigating hip replacements,\u000a      but also with ultrasound scans. The scans revealed that the source of the\u000a      symptoms were solid or\u000a      cystic soft tissue masses. Although not malignant, these lesions resembled\u000a      tumours, leading\u000a      Professor Murray's group to call them pseudotumours.\u000a    Although there have been occasional reports of soft tissue masses\u000a      occurring after hip replacement\u000a      since the 1970s, Professor Murray's group were the first to observe that\u000a      with MoM bearings these\u000a      were relatively common and could be invasive and highly destructive. In\u000a      the group's initial study,\u000a      which was published in 20081, the incidence of pseudotumours\u000a      was higher in women than men,\u000a      with 1% of all resurfacings requiring revision due to pseudotumours.\u000a      Subsequent studies showed\u000a      that incidence increased with time2. In the group's most recent\u000a      study, the incidence at 10 years\u000a      was approximately 1% in men and 20% in women. Asymptomatic patients with\u000a      MoM resurfacings\u000a      were also scanned, revealing that the overall incidence of asymptomatic\u000a      pseudotumours was 4%3.\u000a      With time, a number of asymptomatic lesions became larger, symptomatic and\u000a      required revision.\u000a    In a series of studies investigating the cause of pseudotumours, the\u000a      Oxford group found that the\u000a      majority were caused by excessive wear4 due to edge loading of\u000a      the MoM bearing. This resulted in\u000a      high levels of chromium [Cr] and cobalt [Co] metal ions in the blood. In\u000a        vitro and histological\u000a      studies suggested that metal wear particles killed the cells around the\u000a      implant, resulting in\u000a      extensive soft tissue destruction5. Clinical studies\u000a      demonstrated that women under the age of 40\u000a      with hip dysplasia had a particularly high risk of developing\u000a      pseudotumours2. Surgical risk factors\u000a      included poor acetabular orientation and downsizing of the femoral head,\u000a      and implant risk factors\u000a      included small component size, low clearance and coverage2.\u000a      These, and other factors, such as\u000a      greater flexibility and a different gait pattern, explain why women are\u000a      more likely to edge load their\u000a      resurfacings, and as a result, are at a higher risk of developing\u000a      pseudotumours.\u000a    Further clinical studies demonstrated that revision of MoM resurfacing\u000a      for pseudotumours had a\u000a      high complication rate of 50%, due to severe soft tissue damage6.\u000a    "},{"CaseStudyId":"6296","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The AIRE study, which was conceived, designed and led by staff at Leeds,\u000a      showed for the first time the benefits of early initiation of ACEI\u000a      therapy for high-risk patients with clinical signs of heart failure after\u000a      AMI. This and subsequent research has led to the global introduction of a\u000a      simple and effective treatment, improving survival and quality of life for\u000a      many thousands of patients.\u000a    Impact on health and welfare\u000a    For patients surviving AMI, the debilitating syndrome of heart failure\u000a      secondary to left ventricular dysfunction is a common problem. The body's\u000a      production of angiotensin after AMI act initially as a protective\u000a      mechanism to preserve blood pressure; however, prolonged angiotensin\u000a      production causes cell death. It had been proposed that ACEI therapy would\u000a      mitigate these effects but investigators were cautious about using the\u000a      drugs in these high-risk patients. The AIRE study was the first trial to\u000a      show survival benefits of the ACEI ramipril in these patients. A long-term\u000a      follow up study by Leeds of the trial's UK patients showed that these\u000a      beneficial effects persisted years later.\u000a    The international adoption of the strategy of early ACEI after AMI has\u000a      made it a fundamental part of routine treatment. In addition to\u000a      significantly changing clinical practice, the use of this simple and cost\u000a      effective treatment has contributed to the substantial decline in\u000a      mortality associated with AMI seen over the last two decades. For\u000a      instance, figures from the USA National Registry of Myocardial Infarction\u000a      Investigators indicates that in-hospital mortality after an AMI fell by\u000a      24% from 1990 to 2006 [A]. This trend due to improved care for AMI,\u000a      including the adoption of early secondary prevention such as ACEI\u000a      treatment, is reflected in data from other countries around the world. In\u000a      the UK, a study looking at trends in 3 year mortality in 3 month survivors\u000a      of AMI in the UK, demonstrated that between 1991 and 2002 the use of ACEI\u000a      increased from 11% to 71% and during the same period mortality fell by 28%\u000a      [B]. More recent data from the UK Myocardial Ischaemia National\u000a      Audit Project (covering England, Wales and Belfast) showed a continued\u000a      increase in the prescription of ACEI, from just over 80% of patients with\u000a      AMI in 2003 to 94% of patients with AMI in 2011\/12 [C, figure 15].\u000a      In 2011\/12 there were 79,433 individuals sustaining an AMI; in England,\u000a      95% of patients received ACEI treatment, Wales 90% and Belfast 98% [C;\u000a      table 7]. At a UK population level there has been a year-on-year fall in\u000a      the percentage of patients with AMI who die within 30 days of admission to\u000a      hospital [C; figures 19 and 20]. The observed improvements in\u000a      mortality are not solely attributable to use of ACEI; however, ACEI\u000a      therapy is a fundamental element of modern treatment strategies for AMI [D-F].\u000a      The AIRE study has had major reach and significance, as evidenced by its\u000a      recognition as one of the \"Landmark Heart Failure Treatment Trials\" [D]\u000a      which made \"a fundamental contribution to international clinical\u000a      guidelines, implementation of which has delayed or prevented morbidity and\u000a      death for millions of people worldwide.\" [E]. \"Two decades later\u000a      the results of this study still have a major impact on current guidelines\u000a      underscoring that this study significantly changed treatment of\u000a      cardiovascular high-risk patients.\" [F].\u000a    The importance of AIRE in contributing to the routine adoption of ACEI\u000a      therapy in patients sustaining an AMI is evidenced by the continuing\u000a      citation of this study in international clinical guidelines. The first\u000a      recommendation for the routine adoption of ACEI therapy in patients with\u000a      AMI who develop signs and symptoms of heart failure or who have reduced\u000a      left ventricular ejection fraction, the protocol used in the AIRE study,\u000a      was in the American College of Cardiology\/ American Heart Association\u000a      guidelines in 1996, which cited AIRE as supporting evidence. Since the\u000a      publication of AIRE, ACEI use after AMI has become standard practice\u000a      globally and is established as a class IA recommendation by, for instance,\u000a      the American College of Cardiology Foundation\/American Heart Association [G]\u000a      and the European Society of Cardiology [H] guidelines for\u000a      management of acute myocardial infarction. The AIRE Study is an\u000a      underpinning reference for this therapeutic strategy in both guidelines.\u000a      In the UK, the National Institute for Health and Care Excellence (NICE)\u000a      recommendation for secondary prevention following AMI, published in 2007,\u000a      has guided clinical practice during the current REF period and emphasised\u000a      the prescription of ACEI as a key priority [I, page 10]. This\u000a      guidance cites Leeds research on the efficacy of long term ACEI therapy as\u000a      supporting clinical evidence for the recommendation that: \"After an MI,\u000a      all patients with preserved left ventricular function or with left\u000a      ventricular systolic dysfunction should continue treatment with an ACE\u000a      inhibitor indefinitely, whether or not they have symptoms of heart\u000a      failure.\" [I, page 127]. Furthermore, cost effectiveness analysis\u000a      based on AIRE contributed to the conclusion that long-term ACEI was cost\u000a      effective in patients with and without left ventricular dysfunction [I,\u000a      pages 145-151]. A partial update of these guidelines released in June 2013\u000a      for consultation continues to emphasise ACEI as a key priority in\u000a      secondary prevention in patients with AMI and includes additional priority\u000a      recommendations on correct dosing of ACEI in acknowledgement of their\u000a      ongoing importance [J]. The updated guidance emphasises the\u000a      importance of rapidly achieving the target dose, based on relevant\u000a      clinical evidence, including AIRE, for specific ACEI (e.g. ramipril 10\u000a      mg\/day, as per AIRE): \"Titrate the ACE inhibitor dose upwards at short\u000a      intervals (for example, every 12-24 hours) before the person leaves\u000a      hospital until the maximum tolerated or target dose is reached. If this is\u000a      not possible, this should be completed within 4-6 weeks of hospital\u000a      discharge.\" [J].\u000a    ","ImpactSummary":"\u000a    The Acute Infarct Ramipril Efficacy (AIRE) multicentre international\u000a      trial, conceived, designed, led and coordinated by Leeds was the first to\u000a      show that use of early angiotensin converting enzyme Inhibitor (ACEI)\u000a      therapy in patients with signs and symptoms of heart failure after an\u000a      acute myocardial infarction (AMI) is associated with significantly longer\u000a      survival and better quality of life. Further Leeds research showed the\u000a      beneficial effects persisted long-term. The strategy of early initiation\u000a      of ACEI is now a fundamental and routine part of the management of\u000a      patients after AMI and has contributed to better survival and quality of\u000a      life for patients around the world.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2655984","Name":"Belfast"}],"References":"\u000a    \u000a(1) The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.\u000a      Effect on mortality and morbidity of survivors of acute myocardial\u000a      infarction with clinical evidence of heart failure. Lancet 1993; 342:\u000a      821-28.\u000a      The first study to show the beneficial effect of ACEI in patients\u000a        sustaining an AMI with clinical evidence of heart failure.\u000a    \u000a\u000a(2) Hall AS, Murray GD, Ball SG. Follow-up study of\u000a      patients randomly allocated ramipril or placebo for heart failure after\u000a      acute myocardial infarction: AIRE Extension (AIREX) Study. Acute\u000a      Infarction Ramipril Efficacy. Lancet 1997; 349: 1493-97.\u000a      Research showing long-term beneficial effect of ACEI in patients\u000a        sustaining an AMI with clinical evidence of heart failure.\u000a    \u000a\u000a(3) Flather M, Yusuf S, Kober L, Pfeffer M, Hall AS, Murray G,\u000a      Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E. Long term\u000a      ACE-inhibitor therapy in patients with heart failure or left ventricular\u000a      dysfunction: a systematic overview of data from individual patients.\u000a      Lancet 2000; 355: 1575-81.\u000a    \u000aA systematic review confirming the important role of ACEI post AMI.\u000a      \u000a(4) Cubbon RM, Gale CP, Rajwani A, Abbas A, Morrell C, Das R, Barth JH, Grant\u000a        PJ, Kearney MT, Hall AS. Aspirin and mortality in\u000a      patients with diabetes sustaining acute coronary syndrome. Diabetes Care\u000a      2008; 31: 363-65.\u000a      Data showing beneficial effect of ACEI in patients with and without\u000a        diabetes sustaining an AMI.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    [A] Rogers WJ, et al. Trends in presenting characteristics and hospital\u000a      mortality among patients with ST-elevation and non-ST elevation myocardial\u000a      infarction in the National Registry of Myocardial Infarction from 1990 to\u000a      2006. Am. Heart J 2008; 156: 1026-34.\u000a    [B] Hardoon et al. Trends in longer-term survival following an acute\u000a      myocardial infarction and prescribing of evidenced-based medications in\u000a      primary care in the UK from 1991: a longitudinal population-based study. J\u000a      Epidemiol Community Health. 2011 September; 65(9): 770-774.\u000a    [C] Myocardial Ischaemia National Audit Project (MINAP). How the NHS\u000a      cares for patients with heart attack. Annual public report 2011\/12. http:\/\/www.ucl.ac.uk\/nicor\/audits\/minap\/publicreports\/pdfs\/2012minappublicreportv2.pdf\u000a    [D] Letter of corroboration from Professor of Heart Failure and\u000a      Consultant Cardiologist, Heart Failure Unit, Kings College Hospital,\u000a      London, UK, confirming the AIRE study's fundamental contribution to\u000a      international clinical guidelines, implementation of which has delayed or\u000a      prevented morbidity and death for millions of people worldwide.\u000a    [E] Letter of corroboration from Professor of Vascular Medicine, Service\u000a      d'Hypertension et de Médecine Vasculaire, Hopital Européen Georges\u000a      Pompidou, Paris, France, confirming the AIRE study's fundamental\u000a      contribution to international clinical guidelines.\u000a    [F] Letter of corroboration from Professor of Medicine\/Cardiology,\u000a      Department of Internal Medicine I, University Hospital Aachen, Germany,\u000a      confirming the lasting impact of the AIRE study on current guidelines.\u000a    [G] O'Gara et al. 2013 ACCF\/AHA Guideline for the Management of\u000a      ST-Elevation Myocardial Infarction: A Report of the American College of\u000a      Cardiology Foundation\/American Heart Association Task Force on Practice\u000a      Guidelines. Circulation. 2013;127:e362-e425.\u000a      Available from:\u000a      \u000a        http:\/\/circ.ahajournals.org\/content\/127\/4\/e362.full.pdf+html. ACE\u000a      inhibitor recommendations and reference to AIRE (table 12, p e389; p e390;\u000a      table 14, p e400; AIRE referenced p e412, references 421 and 430).\u000a    [H] Van de Werf F, et al. Management of acute myocardial infarction in\u000a      patients presenting with persistent ST-segment elevation: the Task Force\u000a      on the Management of ST-Segment Elevation Acute Myocardial Infarction of\u000a      the European Society of Cardiology. Eur Heart J 2008; 29: 2909-45.\u000a      Available from: http:\/\/eurheartj.oxfordjournals.org\/content\/29\/23\/2909.full.pdf+html.\u000a      ACE inhibitor recommendations (table 15, p 2924; table 22, p 2933; AIRE\u000a      referenced on p 2944, reference 213)\u000a    [I] The National Institute for Health and Clinical Excellence (NICE). MI:\u000a      secondary prevention. Secondary prevention in primary and secondary care\u000a      for patients following a myocardial infarction (CG48; 2007).\u000a      Available from: http:\/\/guidance.nice.org.uk\/CG48\/Guidance\/pdf\/English.\u000a      ACE inhibitor recommendations (p 10; p 127); Cost effectiveness of ACE\u000a      inhibitors in patients after MI with LV dysfunction including reference to\u000a      AIRE (pp 145-151).\u000a    [J] The National Institute for Health and Clinical Excellence\u000a      (NICE). Post myocardial infarction Secondary prevention in primary and\u000a      secondary care for patients following a myocardial infarction. Partial\u000a      update of NICE CG48: Methods, evidence and recommendations. June 2013\u000a      Available from: http:\/\/www.nice.org.uk\/nicemedia\/live\/13502\/64153\/64153.pdf.\u000a      Updated guidance on ACEI in section 7.3 (pp 219-318). AIRE cited in: table\u000a      49 (p 228); table 61 (p 269) and references to AIRE (reference numbers 16,\u000a      24, 123, 169, 365). \u000a    ","Title":"\u000a    Case Study 1. The Acute Infarct Ramipril Efficacy Study: a simple\u000a      treatment to improve survival after acute myocardial infarction\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Figures from the World Health Organization show that cardiovascular\u000a      disease, in particular acute myocardial infarction (AMI) and its\u000a      complications, is the number one cause of death worldwide (http:\/\/www.who.int\/cardiovascular_diseases\/en\/).\u000a      Despite improved survival from AMI due to modern mechanical reperfusion\u000a      strategies, the debilitating syndrome of heart failure secondary to left\u000a      ventricular dysfunction is a common problem. In the late 1980s, the\u000a      potential benefits of the use ACE inhibitors (ACEI) had been proposed as a\u000a      way of limiting this long-term damage. Yet investigators had been\u000a      reluctant to adopt this strategy because of fears over a negative effect\u000a      of ACEI therapy in high-risk patients.\u000a    Leeds researcher Stephen Ball (British Heart Foundation Professor\u000a      of Cardiology, 1990-2010), conceived, designed, led and co-ordinated the\u000a      Acute Infarct Ramipril Efficacy study (AIRE, named after the river than\u000a      runs through the city). This large prospective randomised controlled trial\u000a      assessed the effect of ACEI therapy on mortality in patients sustaining an\u000a      AMI, who have clinical signs and symptoms of heart failure. This was the\u000a      first trial set up to specifically examine the use of ACEI in this\u000a      population and provided compelling evidence for the use of early and\u000a      prolonged ACEI therapy in patients with post AMI heart failure. Research\u000a      at Leeds has shown ACEI therapy in these patients protects against heart\u000a      failure death, stroke, myocardial infarction and the development of\u000a      resistant heart failure and has fundamentally changed the way patients are\u000a      managed (1,2,3).\u000a    The international multicentre study led from Leeds randomly allocated\u000a      patients to placebo or the ACEI ramipril. A total of 2006 patients meeting\u000a      the criteria, which included a background of optimal therapy, were\u000a      recruited across 14 countries and followed for 15 months. There were 170\u000a      deaths (17%) in the ACEI group compared with 222 deaths (23%) in the\u000a      placebo group. Mortality was reduced from 22.6% to 16.9%, an absolute\u000a      reduction of 5.7% and relative risk reduction of 27% (1).\u000a    A long-term follow up study in which Leeds researchers assessed the\u000a      mortality status of all 603 patients recruited from the 30 UK centres\u000a      involved in the original AIRE Study, showed ongoing benefits of treatment.\u000a      The data showed that after five years, death from all causes had occurred\u000a      in 117 (38.9%) of those treated by placebo and 83 (27.5%) of patients\u000a      assigned ramipril — a relative risk reduction of 36% and an absolute\u000a      reduction in mortality of 11.4%. This corresponded to an extra 114\u000a      patients surviving at 5 years per 1000 treated with ACEI. Treatment of\u000a      nine patients with an ACEI for one year resulted in one patient surviving\u000a      to five years (2). A subsequent systematic review of 12,763 patients,\u000a      including those from AIRE, cemented the beneficial effects of ACEI\u000a      treatment in patients sustaining an AMI confirming clear evidence of early\u000a      benefits which persisted long-term (3).\u000a    More recent work from Leeds (Mark Kearney, Professor of\u000a      Cardiovascular and Diabetes Research 2005- ; Peter Grant,\u000a      Professor of Medicine, 1990-) has shown the benefits of ACEI therapy in\u000a      patients with diabetes after AMI (4).\u000a    "},{"CaseStudyId":"6297","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Research led academically from Leeds University has demonstrated clinical\u000d\u000a      benefit from a new\u000d\u000a      drug, eribulin, for patients with metastatic breast cancer with eribulin\u000d\u000a      now approved for use, being\u000d\u000a      sold worldwide, incorporated into international treatment guidelines and\u000d\u000a      bringing benefits to\u000d\u000a      patients.\u000d\u000a    Dissemination\u000d\u000a      The key eribulin trials described here were reported in high profile, peer\u000d\u000a      reviewed publications\u000d\u000a      (4,5). The EMBRACE study (A) and Study 301 (B) both featured in the ASCO\u000d\u000a      Post, the \"house\u000d\u000a      newspaper\" for the American Society of Clinical Oncologists (which has\u000d\u000a      more than 30,000\u000d\u000a      oncologists as members), as highlights from the annual meeting of the\u000d\u000a      American Society of Clinical\u000d\u000a      Oncology in 2010 and San Antonio Breast Cancer Symposium in 2012. The\u000d\u000a      EMBRACE trial in\u000d\u000a      particular attracted wide attention in the public media (C).\u000d\u000a    Recommendations for use: Professional bodies and guidelines\u000d\u000a      Primarily as a result of the EMBRACE results, showing a clinically and\u000d\u000a      statistically significant\u000d\u000a      increase in median overall survival of 2.49 months in women who had\u000d\u000a      exhausted other approved\u000d\u000a      therapies (5), eribulin has been included in the North American (NCCN) (D)\u000d\u000a      guidelines amongst the\u000d\u000a      \"preferred drugs\" for MBC and the European (ESMO) (E) guidelines as one of\u000d\u000a      the \"new cytotoxic\u000d\u000a      agents\" for the treatment of metastatic breast cancer. Eribulin was on the\u000d\u000a      Cancer Drug Fund\u000d\u000a      \"approved\" list in all 10 English regions; it is on the new National list\u000d\u000a      and expected to continue\u000d\u000a      under new arrangements with the Commissioning Board (F).\u000d\u000a    Changes in policy: Governmental\/regulatory bodies\u000d\u000a      The EMBRACE results showed improved overall survival, an endpoint not\u000d\u000a      achieved by any of the\u000d\u000a      other four single agents approved since 1975 by the FDA for the treatment\u000d\u000a      of MBC. Eribulin\u000d\u000a      (marketed as Halaven) received regulatory approval from the United States\u000d\u000a      FDA in 2010 (G); it\u000d\u000a      was the first cytotoxic to be granted initial approval for refractory\u000d\u000a      metastatic breast cancer on the\u000d\u000a      basis of overall survival data. Subsequently, eribulin was approved in the\u000d\u000a      E.U. by the EMEA (H),\u000d\u000a      and is now approved in 81 countries world-wide.\u000d\u000a    The EMBRACE trial design was unique in using `treatment of physician's\u000d\u000a      choice' as the control arm\u000d\u000a      for a registration trial, there being at the time no standard approved\u000d\u000a      therapy for this group of\u000d\u000a      patients. EMBRACE was also unusual being the first study in MBC to select\u000d\u000a      improved overall\u000d\u000a      survival as the primary endpoint and be successful. The US FDA has since\u000d\u000a      commended the use of\u000d\u000a      `treatment of physician's choice' as the control arm in EMBRACE and the\u000d\u000a      choice of overall survival\u000d\u000a      as a primary endpoint in certain situations (I). Novel aspects of the\u000d\u000a      EMBRACE trial design have\u000d\u000a      been adopted by in registration trials of NKTR-102 (the BEACON trial by\u000d\u000a      Nektar) (J) and T-DM1\u000d\u000a      (the TH3RESA trial by Roche\/Genentech) (J).\u000d\u000a    Changes in practice: treatment, services and commerce\u000d\u000a      Eribulin, and subsequent use of eribulin, have generated commercial\u000d\u000a      impacts. Total sales of\u000d\u000a      eribulin across all regions of the world were £330m, including £72m in the\u000d\u000a      EU, from 2011 to\u000d\u000a      September 2013 (K). Eisai, which is based in the US but with its European\u000d\u000a      office in the UK, has\u000d\u000a      increased its EU workforce from none in 2009 to over 100 in 2013 for the\u000d\u000a      production, distribution\u000d\u000a      and marketing of eribulin both within the UK and internationally (K).\u000d\u000a      Sales of eribulin underpinned\u000d\u000a      R & D investment by Eisai which has a budget of many millions in 2012\u000d\u000a      (K).\u000d\u000a    Changes in health outcomes: patients\u000d\u000a      Sales figures from Eisai show that thousands of women with metastatic\u000d\u000a      breast cancer have been\u000d\u000a      treated with eribulin (K). It is too early to measure directly the impact\u000d\u000a      of eribulin on the survival of\u000d\u000a      women with MBC, and this would be complicated by other changes in care.\u000d\u000a      Given the 2.49 month\u000d\u000a      survival benefit shown by level 1 data from the EMBRACE study, with over\u000d\u000a      40,000 women with\u000d\u000a      MBC having received eribulin to date (K), approaching 10,000 additional\u000d\u000a      life years have been\u000d\u000a      gained from treatment with eribulin.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Clinical trials designed and led by Professor Chris Twelves (University\u000d\u000a      of Leeds) showed eribulin to\u000d\u000a      be the first single agent cytotoxic to prolong survival in women with\u000d\u000a      heavily pre-treated metastatic\u000d\u000a      breast cancer (MBC).\u000d\u000a    Eribulin has been approved by European, U.S. and other regulatory\u000d\u000a      authorities since 2010. Cancer\u000d\u000a      treatment guidelines in the U.S., Europe and elsewhere now recommend\u000d\u000a      eribulin. Sales of eribulin\u000d\u000a      generated many millions of pounds in the first full year following\u000d\u000a      approval. Already tens of\u000d\u000a      thousands of women have been treated with eribulin, who collectively have\u000d\u000a      gained up to ten\u000d\u000a      thousand added life years. The U.S. regulatory authorities have advocated\u000d\u000a      the EMBRACE trial\u000d\u000a      design for future trials.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Leeds\u000d\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4726206","Name":"San Antonio"}],"References":"\u000d\u000a    \u000a1. Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F,\u000d\u000a      Munro A, Bathers S,\u000d\u000a      Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM,\u000d\u000a      Crawford SM, Rea DW,\u000d\u000a      Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves\u000d\u000a      CJ, Cameron D,\u000d\u000a      Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT\u000d\u000a      Investigators and the SCTBG.\u000d\u000a      Adjuvant epirubicin followed by cyclophosphamide, methotrexate and\u000d\u000a      fluorouracil (CMF) vs CMF in\u000d\u000a      early breast cancer: Results with over 7 years median follow-up from the\u000d\u000a      randomised phase III\u000d\u000a      NEAT\/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67.\u000d\u000a      Updated analysis, carried out after Twelves had moved to Leeds, of the\u000d\u000a        UK national trial (on which\u000d\u000a        Twelves was co-CI) that definitively established the benefit of\u000d\u000a        incorporating an anthracycline in\u000d\u000a        adjuvant chemotherapy.\u000d\u000a    \u000a\u000a2. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes\u000d\u000a      G, Fumoleau P,\u000d\u000a      Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S,\u000d\u000a      Leonard R. Superior survival with\u000d\u000a      capecitabine plus docetaxel combination therapy in\u000d\u000a      anthracycline-pretreated patients with\u000d\u000a      advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun\u000d\u000a      15;20(12):2812-23.\u000d\u000a      This trial was one of the first to demonstrate superior survival with\u000d\u000a        the addition of a new agent, in\u000d\u000a        this case capecitabine, to standard therapy in the form of docetaxel as\u000d\u000a        first line chemotherapy for\u000d\u000a        MBC.\u000d\u000a    \u000a\u000a3. Ravaud A, Cerny T, Terret C, Wanders J, Bui BN, Hess D, Droz JP,\u000d\u000a      Fumoleau P, Twelves C\u000d\u000a      Phase I study and pharmacokinetic of CHS-828, a guanidino-containing\u000d\u000a      compound, administered\u000d\u000a      orally as a single dose every 3 weeks in solid tumours: an ECSG\/EORTC\u000d\u000a      study. Eur J Cancer.\u000d\u000a      2005 Mar; 41(5):702-7.\u000d\u000a      One of the Phase I trial by the EORTC through which important links\u000d\u000a        were established between\u000d\u000a        Drs Twelves and Wanders.\u000d\u000a    \u000a\u000a4. Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H,\u000d\u000a      Bachelot T, Awada A,\u000d\u000a      Paridaens R, Goncalves A, Shuster DE, Wanders J, Fang F, Gurnani R,\u000d\u000a      Richmond E, Cole PE,\u000d\u000a      Ashworth S, Allison MA. Phase II study of the halichondrin B analog\u000d\u000a      eribulin mesylate in patients\u000d\u000a      with locally advanced or metastatic breast cancer previously treated with\u000d\u000a      an anthracycline and a\u000d\u000a      taxane. J Clin Oncol. 2010; 28: 2922-28.\u000d\u000a      This large phase II study confirmed the activity of eribulin in women\u000d\u000a        with heavily pre-treated MBC\u000d\u000a        using the dose and schedule that was definitively tested in the EMBRACE\u000d\u000a        trial and Study 301.\u000d\u000a    \u000a\u000a5. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat L, Petrakova K,\u000d\u000a      Chollet P, Manikas A,\u000d\u000a      Dieras V, Delozier T, Vladimorov V, Cardoso F, Koh H, Bougnoux P, Dutcas\u000d\u000a      C, Seegobin S, Mir D,\u000d\u000a      Meneses N, Wanders J, Twelves C. Erubulin monotherapy versus\u000d\u000a      treatment of physician's choice\u000d\u000a      in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label\u000d\u000a      study. Lancet 2011;\u000d\u000a      377: 914-23.\u000d\u000a      Eribulin is the first single agent cytotoxic to improve survival in\u000d\u000a        heavily pre-treated MBC; the\u000d\u000a        benefits of eribulin compared to TPC were apparent across a wide range\u000d\u000a        of patient sub-groups.\u000d\u000a        This study has been central to the increasing use of eribulin in routine\u000d\u000a        clinical practice.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    [A] Helwick C. Novel agent improves survival in women with heavily\u000d\u000a      pre-treated locally recurrent or\u000d\u000a      metastatic breast cancer. The ASCO Post, July 2010, vol 1, issue 2, p 14.\u000d\u000a      http:\/\/issuu.com\/ascopost\/docs\/tap-vol-1-issue-2\u000d\u000a      Article for oncologists describing the EMBRACE trial after its\u000d\u000a        presentation at the American Society\u000d\u000a        of Clinical Oncology in May 2010.\u000d\u000a    [B] Helwick C. Primary endpoint not met for eribulin vs capecitabine in\u000d\u000a      breast cancer. The ASCO\u000d\u000a      Post, February 2013, vol 4, issue 2.\u000d\u000a      http:\/\/www.ascopost.com\/issues\/february-1,-2013\/primary-endpoint-not-met-for-eribulin-vs-\u000d\u000a        capecitabine-in-breast-cancer\u000d\u000a      Article for oncologists describing the Study 301 results after its\u000d\u000a        presentation at the San Antonio\u000d\u000a        Breast Cancer Symposium in May 2012.\u000d\u000a    [C] Marine sponge drug extends breast cancer survival: study. The\u000d\u000a      Independent Online 7th June\u000d\u000a      2010. An example of extensive international coverage of the EMBRACE trial\u000d\u000a      in the general media.\u000d\u000a    [D] NCCN guidelines version 1.2013.\u000d\u000a      http:\/\/www.nccn.org\/professionals\/physicians_gls\/pdf\/breast.pdf.\u000d\u000a      North American guidelines for the treatment of breast cancer that\u000d\u000a        recommend the use of eribulin in\u000d\u000a        women with metastatic disease.\u000d\u000a    [E] Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E, on\u000d\u000a      behalf of the ESMO\u000d\u000a      Guidelines Working Group. Locally recurrent or metastatic breast cancer:\u000d\u000a      ESMO Clinical Practice\u000d\u000a      Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23\u000d\u000a      (suppl 7): vii11-vii19.\u000d\u000a      http:\/\/annonc.oxfordjournals.org\/content\/23\/suppl_7\/vii11.full.\u000d\u000a      European guidelines for the\u000d\u000a        treatment of breast cancer that recommend the use of eribulin in women\u000d\u000a        with metastatic disease.\u000d\u000a    [F] http:\/\/www.commissioningboard.nhs.uk\/about\/\u000d\u000a    [G] US Food and Drug Administration eribulin mesylate approval for\u000d\u000a      granted November 15th 2010.\u000d\u000a      http:\/\/www.fda.gov\/AboutFDA\/CentersOffices\/OfficeofMedicalProductsandTobacco\/CDER\/ucm234\u000d\u000a        527.htm.\u000d\u000a      Documents regulatory approval of eribulin from the United States FDA in\u000d\u000a        2010 (G) and specifically\u000d\u000a        refers to the Phase II trial and to EMBRACE.\u000d\u000a    [H] European Medicines Agency approval for eribulin mesylate granted\u000d\u000a      March 23rd 2011.\u000d\u000a      http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/002084\/human_med_001427.jsp&murl=menus\/medicines\/medicines.jsp&mid=WC0b01ac058001d125.\u000d\u000a      As above (see G) documents approval of eribulin in this case by the\u000d\u000a        European regulators.\u000d\u000a    [I] Cortazar P, Justice R, Johnson J, Sridhara R, Keegan P, Pazdur R. US\u000d\u000a        Food and Drug\u000d\u000a        Administration approval overview in metastatic breast cancer. J Clin\u000d\u000a      Oncol. 2012; 30(14):1705-11.\u000d\u000a      Review describing FDA approvals of drugs in metastatic breast cancer,\u000d\u000a        including eribulin and the\u000d\u000a        EMBRACE trial, that also discusses the use of \"treatment of physician's\u000d\u000a        choice\" and the\u000d\u000a        importance of improved overall survival as an outcome measure.\u000d\u000a    [J] The BEACON Study (Breast Cancer Outcomes With NKTR-102): A Phase 3\u000d\u000a      Open-Label,\u000d\u000a      Randomized, Multicenter Study of NKTR-102 Versus Treatment of Physician's\u000d\u000a      Choice (TPC) in\u000d\u000a      Patients With Locally Recurrent or Metastatic Breast Cancer Previously\u000d\u000a      Treated With an\u000d\u000a      Anthracycline, a Taxane and Capecitabine.\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01492101?term=NKTR-102&rank=6.\u000d\u000a      A Study of Trastuzumab Emtansine in Comparison With Treatment of\u000d\u000a      Physician's Choice in\u000d\u000a      Patients With HER2-Positive Breast Cancer Who Have Received at Least Two\u000d\u000a      Prior Regimens of\u000d\u000a      HER2-Directed Therapy (TH3RESA).\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01419197?term=TH3RESA&rank=1\u000d\u000a      Important clinical trials that incorporate major novel aspects of the\u000d\u000a        EMBRACE trial design,\u000d\u000a        reflecting impact on breast cancer research worldwide.\u000d\u000a    [K] Letter from Global Medical Affairs Director (Oncology), Eisai Europe\u000d\u000a      Limited.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Case Study 2\u000d\u000a    Clinical trials show that the novel cytotoxic drug eribulin prolongs\u000d\u000a      survival in women with heavily\u000d\u000a      pre-treated metastatic breast cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The survival of women with early breast cancer has improved at least in\u000d\u000a      part as a result of trials\u000d\u000a      such as NEAT\/BR9601 (Twelves, co-CI; University of Leeds, Professor\u000d\u000a      of Clinical Cancer\u000d\u000a      Pharmacology and Oncology since 2003), to which Leeds contributed (Perren,\u000d\u000a      University of\u000d\u000a      Leeds, Senior Lecturer in Medical Oncology to 2002 and Professor of\u000d\u000a      Women's Cancers and\u000d\u000a      Oncology since 2013). (1). The treatment of women with MBC remains,\u000d\u000a      however, palliative. Since\u000d\u000a      2000 only 8 new cytotoxic or targeted agents have been approved by the FDA\u000d\u000a      in women with\u000d\u000a      MBC; Twelves was closely involved with the development of two of\u000d\u000a      them, capecitabine (2) and\u000d\u000a      more recently eribulin, both of which prolong survival for women with MBC.\u000d\u000a    As Chair of the EORTC New Drug Development Group from 2002 to 2004, Twelves\u000d\u000a      had\u000d\u000a      previously worked with Dr Jantien Wanders in early drug development (2).\u000d\u000a      Dr Wanders moved (as\u000d\u000a      Executive Director, Oncology) to the Japanese pharmaceutical company Eisai\u000d\u000a      that developed\u000d\u000a      eribulin. This is a novel cytotoxic and synthetic analogue of a product\u000d\u000a      derived from a marine\u000d\u000a      sponge; eribulin inhibits mitosis through action on microtubules, but acts\u000d\u000a      at a binding site different\u000d\u000a      to that of other cytotoxics. Whilst in Leeds, Twelves worked with\u000d\u000a      Dr Wanders and her colleagues\u000d\u000a      at Eisai preparing their November 2005 submission to the European\u000d\u000a      Committee for Medicinal\u000d\u000a      Products for Human Use (CHMP) of initial phase II results with eribulin\u000d\u000a      and participating in the\u000d\u000a      meeting with the CHMP at which they requested three further studies.\u000d\u000a    Between 2006 and 2012, Twelves was played a key role, with Eisai\u000d\u000a      and international co-investigators,\u000d\u000a      in the design, planning, conduct and analysis of these three studies.\u000d\u000a    The first was a larger, confirmatory phase II study with eribulin (Dr\u000d\u000a      Vahdat, Spain, Chief\u000d\u000a      Investigator; Twelves, Co-Investigator and Perren) that\u000d\u000a      substantiated the activity of eribulin in\u000d\u000a      women with heavily pre-treated MBC (4).\u000d\u000a    EMBRACE was the second study and the definitive global phase III trial (Twelves,\u000d\u000a      Co-Chief\u000d\u000a      Investigator with Dr Cortes, Spain) that led to the adoption of eribulin\u000d\u000a      in clinical practice. There\u000d\u000a      being no currently approved standard treatment in heavily pre-treated\u000d\u000a      patients, this was the first\u000d\u000a      pivotal study to incorporate `treatment of physician's choice' (TPC) as\u000d\u000a      the `control' arm. We also\u000d\u000a      challenged the dogma that it was over-ambitious to seek improved overall\u000d\u000a      survival in patients with\u000d\u000a      such advanced disease, using survival as the \"make or break\" primary\u000d\u000a      endpoint rather than a\u000d\u000a      surrogate marker such as progression-free survival. EMBRACE recruited 756\u000d\u000a      women with heavily\u000d\u000a      pre-treated MBC at over 100 centres worldwide (including Leeds, Perren)\u000d\u000a      between 2006 and\u000d\u000a      2008. Survival was significantly longer, by 2.5 months, in women who\u000d\u000a      received eribulin compared\u000d\u000a      to TPC; other efficacy outcomes also favoured eribulin. Toxicities were\u000d\u000a      comparable between\u000d\u000a      treatment arms (5).\u000d\u000a    Finally, the Study 301 phase III trial (Twelves, Co-Chief\u000d\u000a      Investigator with Dr Kaufman, USA)\u000d\u000a      recruited between 2006 and 2009 and compared eribulin with capecitabine in\u000d\u000a      over a thousand\u000d\u000a      women with less heavily pre-treated MBC. There was a trend for improved\u000d\u000a      survival in the eribulin\u000d\u000a      arm, but this did not reach statistical significance; sub-group analyses\u000d\u000a      suggest that women with\u000d\u000a      specific molecular sub-types of MBC (especially \"triple negative\" cancers)\u000d\u000a      may gain particular\u000d\u000a      benefit from eribulin. These data were presented at the 2012 San Antonio\u000d\u000a      Breast Cancer\u000d\u000a      Symposium.\u000d\u000a    "},{"CaseStudyId":"6298","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    CLASICC conclusively demonstrated: the technical and oncological safety\u000a      of laparoscopic colorectal cancer surgery; benefits for patients\u000a      (including improvements to quality of life outcomes) and healthcare\u000a      providers (including health economics needed to guide policy decisions and\u000a      effective criteria for patient selection for laparoscopic surgery).\u000a    Impact on guidance and service delivery\u000a    These outcomes had a direct bearing on the attitudes of surgeons and\u000a      healthcare providers. In 2000, at the time CLASICC was recruiting, NICE\u000a      guidance recommended \"open rather than laparoscopic resection should be\u000a        the preferred surgical procedure\" for patients with colorectal\u000a      cancer [A]. Six years later, CLASICC was one of only 7 RCTs, and the only\u000a      RCT to include rectal cancer, included in a NICE meta-analysis that\u000a      subsequently informed the updated NICE 2006 guidance [B]. The result was a\u000a      step change in recommendation to \"laparoscopic surgery [should now be]\u000a        recommended as an alternative to open resection for individuals with\u000a        colorectal cancer\". The implication was that, where appropriate,\u000a      laparoscopic surgery should be made available throughout the NHS for all\u000a      patients with colorectal cancer. Given that colorectal cancer is the third\u000a      most common cancer in the UK, affecting just under 40,000 people a year,\u000a      this has far reaching implications for the NHS. CLASICC documented the\u000a      potential benefits to health care providers through improved efficiency\u000a      and cost-savings [J], corroborating those outlined in the NICE 2006\u000a      meta-analysis: laparoscopic surgery results in a reduction in hospital\u000a      stay of 1.4 bed-days\/patient, with the potential to increase to 4-10\u000a      bed-days\/patient [B, F]. With ~ 30,000 patients undergoing colorectal\u000a      cancer surgery every year, at a bed-day saving of 1.4 days per patient,\u000a      this equates to ~17,000 bed-days saved per year, or around £7.5M saved per\u000a      annum. Society at large has also benefited with patients and families\u000a      returning to normal activity sooner, and a quicker return to work for\u000a      those in employment.\u000a    Impact on Policy\u000a    CLASICC played an instrumental role in changing healthcare policy\u000a      throughout the UK and internationally. Without the rigorous evaluation of\u000a      all aspects of laparoscopic colorectal cancer surgery (technical,\u000a      oncological, functional, health economics) it is unlikely that its\u000a      implementation would have quadrupled from 10% in 2009 to over 40% in 2012.\u000a      The change in NICE guidance in 2006 persuaded the Department of Health\u000a      (DH) to launch a £20 million initiative in 2008 to promote laparoscopic\u000a      colorectal cancer surgery throughout the NHS (LAPCO) [E]. A letter to NHS\u000a      Chief Executives from the National Cancer Director outlined the need for a\u000a      national training programme, and highlighted the potential cost-savings\u000a      and the obligation of PCTs to fund and to make laparoscopic colorectal\u000a      cancer surgery \"normally available\" [F]. LAPCO has successfully trained\u000a      over 300 colorectal surgeons in laparoscopic colorectal cancer surgery.\u000a    Impact on clinical practice and patient outcomes\u000a    CLASICC has allowed laparoscopic colorectal cancer surgery to be safely\u000a      disseminated throughout the NHS, in accordance with NICE guidance. More\u000a      patients now enjoy the benefits of the laparoscopic approach. Laparoscopic\u000a      resections undertaken in the NHS have increased from 10% in 2009 to 40% by\u000a      2012, which equates to ~9,000 additional patients per annum benefitting\u000a      from the laparoscopic approach; a trend that has been confirmed using\u000a      national NHS HES data [G]. This means that ~9,000 patients per annum are\u000a      recovering quicker from surgery, spending 1 - 2 days less in hospital, and\u000a      returning to normal activities several weeks earlier. Laparoscopic surgery\u000a      for colorectal cancer is fast becoming the standard of care throughout the\u000a      NHS, with the 40% UK adoption rate being one of the highest in the world.\u000a      The realisation that minimally invasive techniques, such as laparoscopic\u000a      surgery, reduces surgical trauma and facilitates patient recovery was\u000a      embraced as a central component of the National Enhanced Recovery\u000a      Programme, supported by the NHS Institute for Innovation and Improvement\u000a      and the NHS Cancer Action Team [H]. The combination of laparoscopic\u000a      surgery and improved perioperative management is considered the current\u000a      gold standard for major colorectal surgery, with the potential to further\u000a      reduce in-patient stays.\u000a    The successful implementation of laparoscopic surgery, supported by\u000a      CLASICC, has lead to the evaluation of other technologies to further\u000a      improve patient outcomes in colorectal cancer surgery. Robotic-assistance\u000a      may improve the capabilities of laparoscopic surgery and increase the\u000a      number of suitable patients. This is currently being tested in a follow-on\u000a      study to CLASICC undertaken by the University of Leeds: the MRC\/EME\/NIHR\u000a      ROLARR trial, a pan-World randomised controlled trial comparing\u000a      robotic-assisted with laparoscopic surgery for rectal cancer [I]. ROLARR\u000a      is at the forefront of surgical clinical trials research and is likely to\u000a      be as influential as CLASICC.\u000a    Impacts on International development\u000a    Internationally, the CLASICC has become a benchmark study for the design\u000a      of other colorectal cancer trials. These included an NCI multi-centre US\u000a      trial to gain further information about laparoscopic surgery in rectal\u000a      cancer [C] and the European COLOR II study. CLASICC has informed policy\u000a      decisions across the globe, for example being cited in the 2012 US\u000a      Position Statement on laparoscopic surgery for curable colon and rectal\u000a      cancer [D]. It has lead to laparoscopic surgery being accepted in many\u000a      different healthcare systems as the preferred treatment for colorectal\u000a      cancer. CLASICC is frequently cited as a point of reference in many\u000a      colorectal cancer publications and continues to be upheld as example of\u000a      rigorous evaluation of surgical technology that influenced surgical cancer\u000a      care.\u000a    ","ImpactSummary":"\u000a    The MRC Conventional versus Laparoscopic-Assisted Surgery In Colorectal\u000a      Cancer trial (CLASICC) is the largest and most successful UK trial of a\u000a      technology applied to general surgery. It addressed an area of huge\u000a      clinical uncertainty, providing a rigorous evaluation of a new technology\u000a      and enabling its safe and widespread implementation. The impact of CLASICC\u000a      has been global, confirming the advantages for patients (quicker recovery)\u000a      and healthcare providers (cost-effectiveness) and so influencing national\u000a      and international policy in favour of the laparoscopic technique. It\u000a      informed NICE guidance and led to a major DH initiative that has seen the\u000a      UK become one of the largest providers in the world of laparoscopic\u000a      colorectal cancer surgery. CLASICC is regarded as a benchmark surgical\u000a      trial, combining high quality trial design with rigorous quality\u000a      assurance, which has informed the design of many subsequent colorectal\u000a      cancer studies.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AHM,\u000a        Heath RM, Brown JM. Short-term endpoints of conventional versus\u000a      laparoscopic-assisted surgery in patients with colorectal cancer (MRC\u000a      CLASICC Trial): multicentre randomised controlled trial. The Lancet 2005;\u000a      365:1718-1726.\u000a       Publication showing that laparoscopic surgery is as\u000a        effective as open surgery for the treatment of colorectal cancer. Unique\u000a        pathological assessment demonstrating high quality laparoscopic\u000a        resections.\u000a    \u000a\u000a2) Jayne DG, Guillou PJ, Thorpe H, Quirke P, Copeland J, Smith AHM,\u000a        Heath RM, and Brown JM. Randomized Trial of Laparoscopic-Assisted\u000a      Resection of Colorectal Carcinoma: 3-Year Results of the UK MRC CLASICC\u000a      Trial Group. J Clin Oncology 2007; 25: 3061-68.\u000a      doi:10.1200\/JCO.2006.09.7758.\u000a      Publication showing that the mid-term\u000a        results of laparoscopic surgery are at least as good as open surgery for\u000a        colorectal cancer. Concerns about higher local recurrence following\u000a        laparoscopic rectal cancer resection disproven.\u000a    \u000a\u000a3) Jayne DG, Thorpe HC, Copeland J, Quirke P, Brown JM, Guillou PJ.\u000a      Five year follow-up of the Medical Research Council CLASICC trial of\u000a      laparoscopically assisted versus open surgery for colorectal cancer. Br J\u000a      Surg. 2010; 97: 1638-45. doi:10.1002\/bjs.7160.\u000a      Publication showing\u000a        that the use of laparoscopic surgery to maximise short-term outcomes for\u000a        colorectal cancer does not compromise long-term oncological results.\u000a        Conversion from laparoscopic to open surgery associated with worse\u000a        overall but not disease-free survival.\u000a    \u000a\u000a4) Franks PJ. Bosanquet N. Thorpe H. Brown JM. Copeland J. Smith AM.\u000a        Quirke P. Guillou PJ. CLASICC trial participants. Short-term costs\u000a      of conventional vs laparoscopic assisted surgery in patients with\u000a      colorectal cancer (MRC CLASICC trial). British Journal of Cancer.\u000a      95(1):6-12, 200. doi:10.1038\/sj.bjc.6603203.\u000a      Publication documenting the short-term cost effectiveness of\u000a        laparoscopic surgery for colorectal cancer.\u000a    \u000a\u000a5) Thorpe H, Jayne DG, Guillou PJ, Quirke P, Copeland J, Brown JM.\u000a      Patient factors influencing conversion from laparoscopic assisted to open\u000a      surgery for colorectal cancer. Br J Surg. 2008; 95: 199-205. PMID:17696215\u000a      Publication identifying those patients most likely to benefit from\u000a        laparoscopic surgery for colorectal cancer. Establishes selection\u000a        criteria for the laparoscopic approach, helping to avoid unplanned\u000a        conversion to open surgery with documented worse overall survival\u000a        (established in [4], above).\u000a    \u000a\u000a6) Jayne DG, Brown JM, Thorpe H, Walker J, Quirke P,\u000a        Guillou PJ. Bladder and sexual function following resection for\u000a      rectal cancer in a randomized clinical trial of laparoscopic versus open\u000a      technique. Br J Surg. 2005; 92(9): 1124-32. PMID:15997446\u000a      Publication highlighting the need for high quality laparoscopic rectal\u000a        cancer surgery to minimise the risk of postoperative bladder and sexual\u000a        dysfunction.\u000a    \u000aFurther successful grant applications which built on the success\u000a      of CLASICC include:\u000a    — MRC: Adhesive complications after open and laparoscopic surgery. (CI: Prof.\u000a        PJ Guillou)\u000a    — MRC\/EME\/NIHR: ROLARR trial: Robotic rectal cancer surgery (CI: Prof.\u000a        D.G.Jayne).\u000a    — MRC\/EME\/NIHR GLiSten trial: Fluorescence guide surgery (CI: Prof.\u000a        D.G.Jayne).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a     [A] NICE Technology Appraisal Guidance TA17. Guidance on the use of\u000a      laparoscopic surgery for colorectal cancer. December 2000. http:\/\/publications.nice.org.uk\/laparoscopic-surgery-for-colorectal-cancer-ta17\u000a      National guidance against the use of laparoscopic surgery for\u000a        colorectal cancer, issued in 2000 prior to the publication of CLASICC.\u000a      (Guidance 1.1)\u000a    [B] NICE Technology Appraisal Guidance TA105. Laparoscopic surgery for\u000a      colorectal cancer. August 2006. National guidance in support of the\u000a        use of laparoscopic colorectal cancer surgery, issued following CLASICC\u000a        - a step change from previous guidance issued in 2000. (Guidance\u000a      1.1)\u000a      http:\/\/publications.nice.org.uk\/laparoscopic-surgery-for-colorectal-cancer-ta105,\u000a        page 4.\u000a    [C] Laparoscopic-assisted resection or open resection in treating\u000a      patients with stage IIA, stage IIIA, or stage IIIB rectal cancer. www.clinicaltrials.gov\u000a        NCT00726622. The US multi-centre trial, set-up in 2008, and\u000a        inspired by CLASICC to evaluate laparoscopic with open surgery for\u000a        rectal cancer.\u000a    [D] Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)\u000a      Evidence-Based Guidelines for the Laparoscopic Resection of Curable Colon\u000a      and Rectal Cancer.\u000a      http:\/\/www.sages.org\/publication\/id\/32\/\u000a      2012 US guidance in support of laparoscopic surgery for colorectal\u000a        cancer, citing CLASICC outcomes.\u000a    [E] LAPCO: National training programme in laparoscopic colorectal surgery\u000a      http:\/\/www.lapco.nhs.uk\/ The\u000a        national training programme in laparoscopic colorectal cancer instigated\u000a        by the National Cancer Director following the reporting of CLASICC and\u000a        evidence of the influence of CLASICC in changing national strategic\u000a        health policy. Over 300 UK colorectal surgeons trained in laparoscopic\u000a        surgery.\u000a    [F] Letter from DH National Cancer Director to NHS Chief Executives - outlining\u000a        the need for a national training programme in laparoscopic colorectal\u000a        cancer surgery based on NICE evidence, the potential cost-savings, and\u000a        the obligation of PCTs to fund the programme to make laparoscopic\u000a        colorectal cancer surgery \"normally available\" (2008). DH gateway\u000a      10945\u000a    [G] Morris,E.J; Jordan,C; Thomas,J.D; Cooper,M; Brown,J.M; Thorpe,H;\u000a      Cameron,D; Forman,D; Jayne,D; Quirke,P; CLASICC trialists Comparison of\u000a      treatment and outcome information between a clinical trial and the\u000a      National Cancer Data Repository. Br J Surg 2011; 98: 299-307. Evidence\u000a        of the trend to increased penetration of laparoscopic colorectal cancer\u000a        surgery performed within the NHS subsequent to CLASICC. PMID:\u000a      20981742\u000a    [H] Department of Health, Enhanced Recovery Programme\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/+\/www.dh.gov.uk\/en\/Healthcare\/Electivecare\/Enhancedrecovery\/index.htm\u000a      Department of Health policy, initiated in 2011, to integrate\u000a        laparoscopic surgery with enhanced recovery programmes for major\u000a        surgery. Highlights the beneficial role of laparoscopic surgery in a\u000a        package as standard of best care.\u000a    [I] Collinson FJ, Jayne DG, Pigazzi A et al. An international,\u000a      prospective, multicentre, randomised, controlled, unblended, parallel\u000a      group trial of robotic-assisted versus standard laparoscopic surgery for\u000a      the curative treatment of rectal cancer. Int J Colorectal Dis. 2012. 27(\u000a      2): 233-241. ROLARR trial protocol. ROLARR builds on the success of\u000a        CLASICC, has only been possible as a result of its success, and will\u000a        likely be as influential as CLASICC. PMID: 21912876\u000a    [J] Franks PJ. Bosanquet N. Thorpe H. Brown JM. Copeland J. Smith\u000a      AM. Quirke P. Guillou PJ. CLASICC trial participants. Short-term costs of\u000a      conventional vs laparoscopic assisted surgery in patients with colorectal\u000a      cancer (MRC CLASICC trial). British Journal of Cancer. 95(1):6-12, 2006. Manuscript\u000a        from CLASICC detailing health economic benefits arising from\u000a        laparoscopic surgery. PMID: 16755298 \u000a    ","Title":"\u000a    Case Study 3. Establishing the effectiveness of laparoscopic surgery for\u000a      colorectal cancer leading to safer implementation into the NHS and\u000a      world-wide for greater a patient benefit.\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The introduction of new technologies into surgical practice is seldom\u000a      based on rigorous scientific evaluation. Such was the case for\u000a      laparoscopic surgery in the 1980's. Although the potential benefits in\u000a      terms of improved patient recovery were not in dispute, concerns were\u000a      expressed regarding its safety, particularly in the treatment of malignant\u000a      disease with early reports of unusual patterns of disease recurrence.\u000a    The MRC CLASICC trial was set up in 1996 to specifically address concerns\u000a      regarding the safety and efficacy of the laparoscopic approach in\u000a      colorectal cancer. Led by Professor P.J.Guillou (Prof. of Surgery\u000a      — retired 2006), facilitated by Professor D.G.Jayne (Leeds\/former\u000a      MRC Clinical Research Fellow), and coordinated by Professor\u000a        J.M.B.Brown (Director, Clinical Trials Research Unit, Leeds), this\u000a      University of Leeds initiated, UK-wide, multicentre clinical trial\u000a      recruited one of the largest cohorts of surgical patients (794 patients)\u000a      to either laparoscopic or conventional open colorectal cancer surgery\u000a      between 1996 and 2002.\u000a    The initial results, reported in the Lancet in 2005 (1), stimulated an\u000a      Editorial and much exchange of international correspondence. Laparoscopic\u000a      surgery was shown to be as safe as open surgery, but with short-term\u000a      benefits for patients, and similar oncological outcomes. CLASICC was\u000a      unique in the rigour of its trial design and quality control, combining\u000a      for the first time centralised pathological review and evaluation of the\u000a      quality of surgery (1, 2); a feature that has been widely adopted in the\u000a      design of subsequent clinical trials and has become standard in routine\u000a      NHS practice. The publication of the 3-year CLASICC results in 2007 (2),\u000a      and subsequently the 5-year results in 2010 (3), confirmed long-term\u000a      oncological safety and further reinforced positive world opinion towards\u000a      laparoscopic surgery. It is now internationally acknowledged that\u000a      laparoscopic surgery has benefits for patients without compromise to\u000a      long-term outcomes. Any previous criticisms towards the laparoscopic\u000a      approach have been dispelled, enabling its safe dissemination into routine\u000a      care [A,B].\u000a    CLASICC was designed as a pragmatic trial, which has been instrumental in\u000a      enabling the translation of its results to the wider surgical community.\u000a      It was also comprehensive in its evaluation, which has enabled valuable\u000a      information to be gained about the broader benefits of the laparoscopic\u000a      approach. It has provided information on cost-effectiveness (4),\u000a      predictors of conversion to open surgery (5), sexual and bladder function\u000a      following rectal resection (6), and benefits of the laparoscopic approach\u000a      in the prevention of adhesive bowel obstruction and incisional herniation.\u000a      The outputs from CLASICC, showing improved cost-effectiveness and better\u000a      functional outcomes, have subsequently been confirmed by other studies.\u000a    Until 2013, CLASICC was the only randomised, multicentre trial to\u000a      evaluate the laparoscopic approach for rectal cancer and thus provided the\u000a      only randomised data to inform healthcare policy. It showed that the\u000a      laparoscopic approach was feasible and potentially beneficial in rectal\u000a      cancer surgery, and that with certain caveats it could be recommended for\u000a      routine application. The findings were endorsed in 2013 with the\u000a      publication of a large, multicentre European study (COLOR II).\u000a    CLASICC set the standard for evaluating new surgical techniques by\u000a      randomised comparison. As the foremost clinical trial in laparoscopic\u000a      colorectal cancer surgery, it set the benchmark in trial design for other\u000a      colorectal cancer studies around the world (NMRC-Singapore trial, European\u000a      COLOR II [L],US NIH ACOSOG-Z6051) [K]. International collaboration led to\u000a      a large transatlantic meta-analysis that revealed the biases present in\u000a      other smaller, single institution studies. The expertise gained from\u000a      CLASICC has been instrumental in developing follow-on research\u000a      initiatives, which include the MRC\/EME\/NIHR ROLARR trial; a pan-World\u000a      randomised controlled trial evaluating robotic-assisted with laparoscopic\u000a      surgery for rectal cancer.\u000a    "},{"CaseStudyId":"6301","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"3865483","Name":"Argentina"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2017370","Name":"Russia"},{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"3190538","Name":"Slovenia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"3895114","Name":"Chile"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Researchers at the University of Leeds clearly identified that widely\u000a      used surgical techniques were associated with local recurrence and death\u000a      in patients with rectal cancer. We developed simple routine methods for\u000a      assessing tumour involvement in the circumferential surgical margin and\u000a      showed how these could be used to predict local recurrence and survival\u000a      and improve surgical performance. Our concepts of the importance of the\u000a      circumferential surgical margin, Leeds dissection methods, photography of\u000a      the quality of surgery, introduction of routine preoperative MRI, and best\u000a      practice total mesorectal excision and extra levator excision methods have\u000a      become the gold standard in the treatment of rectal cancer patients around\u000a      the world.\u000a    Health and welfare\u000a    In the 1990s, patients diagnosed with rectal cancer faced a 20-30% risk\u000a      of local recurrence, which in turn is associated with high rates of\u000a      mortality and can be a very painful and unpleasant way to die.a,b\u000a      We were the first to conclusively show that not properly excising the\u000a      tumour in the circumferential surgical margin strongly influenced local\u000a      recurrence and death, involvement was found in 25% of cases where the\u000a      surgeon believed the operation had been curative. We also highlighted the\u000a      importance of histological assessment in predicting recurrence and\u000a      survival.\u000a    Our work has improved the surgical skills and techniques used in total\u000a      mesorectal excision, abdominoperineal excision and the histology and\u000a      imaging required to support and guide treatment. Through our studies\u000a      showing MRI could be used before surgery to assess the circumferential\u000a      surgical margin and predict outcome, this has become the standard approach\u000a      in Europec and around the world. Patients can now be reassured\u000a      that they are receiving the best possible surgical techniques which can be\u000a      easily monitored and their chance of cure and survival have improved\u000a      dramatically from that seen two decades ago.\u000a    In 2013 our techniques have led to an impressive 40-50% reduction in\u000a      rates of local recurrence in curative surgery across England, Scotland,\u000a      Sweden, Denmark, British Columbia, Slovenia, Belgium Norwayd\u000a      and Spaine and survival in curative cases improved by 8% d.\u000a      This means >1800 fewer patients suffering the consequences of local\u000a      recurrence and >1,000 more surviving each year in the UK.\u000a    Society, culture and productivity\u000a    Between 2003-2006 we received £6 million in Department of Health funding\u000a      to roll out the use of the histological, MRI and surgical techniques we\u000a      had developed to 1,639 individuals from 183\/186 English bowel cancer\u000a      teams.f Professor Quirke led the pathology training, Dr Gina\u000a      Brown MRI and Professor Heald at the Pelican Centre, Basingstoke led on\u000a      the surgery education programme. Between 2011 and 2013 funded by the NHS\u000a      (£1 million) to provide LOw RECtal cancer courses throughout England\u000a      training 1,045 staff of147\/151 English Trusts.\u000a    We conservatively calculate that each local recurrence costs the NHS more\u000a      than £40,000 in direct medical expenses alone f saving\u000a      £60,000,000 per anuum\u000a    NICE has recommended use of our concepts g and the practice\u000a      of all members of the multidisciplinary team in the NHS from surgeons,\u000a      pathologists, radiologists and oncologists has radically changed.\u000a    By defining the planes of surgery seen after operations for rectal cancer\u000a      and showing in a major clinical trial that rapid simple photographic audit\u000a      (using low cost digital cameras or good quality mobile phones) of the\u000a      quality of rectal cancer surgery was possible, we have revolutionised how\u000a      these procedures are performed and assessed. This is now being\u000a      investigated as a tool in other cancers such as pancreas, oesophageal and\u000a      prostate.\u000a    Our methods have now been introduced into many professional guidelines\u000a      around the world - both surgicalh and pathologicali\u000a      and Trial protocols in Englandj and Europe\u000a    In addition, we have actively disseminated these techniques and standards\u000a      on six continents in conjunction with the Pelican Cancer Charity.\u000a      Protocols, trial protocols and educational material have been made freely\u000a      available on the web and by DVD. Countries we have run education\u000a      programmes include many in Europe as well as Argentina, Chile, Russia,\u000a      Toronto, USA with demand continuing to rise.\u000a    ","ImpactSummary":"\u000a    Postoperative local recurrence affects 20-30% of patients with rectal\u000a      cancer. Between 1993 and 2013, University of Leeds researchers identified\u000a      the importance of pathology studies to show a disease-free margin around\u000a      the excised tumour and how to predict this margin routinely and accurately\u000a      using simple histopathology and preoperative MRI.\u000a    We also used photography in the pathological assessment of the quality of\u000a      surgery and were instrumental in the adoption of modern techniques by\u000a      professional organisations around the world.\u000a    Following adoption of our techniques in England and Scotland, local\u000a      recurrence has halved with 10% better survival and cost savings of £60\u000a      million. Our methods have also become the gold standard in the treatment\u000a      of rectal cancer patients around the world.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6167865","Name":"Toronto"}],"References":"\u000a    \u000a[1] Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D,\u000a        Dixon MF, Quirke P. Role of circumferential margin involvement in\u000a      the local recurrence of rectal cancer. Lancet. 1994; 10; 344(8924):\u000a      707-11.\u000a    \u000a\u000a[2] Birbeck KF, Macklin CP, Tiffin NJ, Parsons W, Dixon MF,\u000a      Mapstone NP, Abbott CR, Scott N, Finan PJ, Johnston D, Quirke P.\u000a      Rates of circumferential resection margin involvement vary between\u000a      surgeons and predict outcomes in rectal cancer surgery. Ann Surg. 2002;\u000a      235(4): 449-57.\u000a    \u000a\u000a[3] Quirke P, Steele R, Monson J, Grieve R, Khanna S,\u000a      Couture J, O'Callaghan C, Myint AS, Bessell E, Thompson LC, Parmar M,\u000a      Stephens RJ, Sebag-Montefiore D; NCRI Colorectal Cancer\u000a      Study Group. Effect of the plane of surgery achieved on local recurrence\u000a      in patients with operable rectal cancer: a prospective study using data\u000a      from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet.\u000a      2009; 373(9666): 821-28.\u000a    \u000a\u000a[4] MERCURY Study Group. Diagnostic accuracy of preoperative magnetic\u000a      resonance imaging in predicting curative resection of rectal cancer:\u000a      prospective observational study. BMJ. 2006; 333: 779-78. Quirke P\u000a      lead pathologist.\u000a    \u000a\u000a[5] Marr R, Birbeck K, Garvican J, Macklin CP, Tiffin NJ, Parsons WJ, Dixon\u000a        MF, Mapstone NP, Sebag-Montefiore D, Scott N, Johnston D,\u000a      Sagar P, Finan P, Quirke P. The modern abdominoperineal excision:\u000a      the next challenge after total mesorectal excision. Ann Surg. 2005;\u000a      242(1): 74-82.\u000a    \u000a\u000a[6] West NP, Finan PJ, Anderin C, Lindholm J, Holm T, Quirke\u000a        P. Evidence of the oncologic superiority of cylindrical\u000a      abdominoperineal excision for low rectal cancer. J Clin Oncol. 2008;\u000a      26(21): 3517-22.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    [a] Medical Research Council Rectal Cancer Working Party. Randomised\u000a        trial of surgery alone versus surgery followed by radiotherapy for\u000a        mobile cancer of the rectum. Lancet. 1996 Dec\u000a      14;348(9042):1610-4.\u000a      Describes the low survival and high local recurrence rate in this trial\u000a        before knowledge of the importance of CRM, MRI and improved surgery.\u000a    [b] Kodeda K, Derwinger K, Gustavsson B, Nordgren\u000a        S.Colorectal Dis. 2012 May;14(5):e230-7.\u000a      doi: 10.1111\/j.1463-1318.2011.02895.x.Local recurrence of rectal\u000a        cancer: a population-based cohort study of diagnosis, treatment and\u000a        outcome.\u000a      Describes the severity of local recurrence and the difficulty managing\u000a        it even today if it is not avoided\u000a    [c] Valentini V et al; Scientific Committee. Multidisciplinary Rectal\u000a      Cancer Management: 2nd European Rectal Cancer Consensus\u000a      Conference (EURECA - CC2). Radiother Oncol. 2009 Aug; 92 (2): 148-63.\u000a      European consensus conference mandating our pathology, MRI and TME\u000a        surgery to be updated in 2013\u000a    [d] Bernstein TE, Endreseth BH, Romundstad P, Wibe\u000a        A; Norwegian Colorectal Cancer Registry. Improved local\u000a      control of rectal cancer reduces distant metastases.\u000a      Colorectal Dis. 2012 Oct;14(10):e668-78. doi:\u000a      10.1111\/j.1463-1318.2012.03089.x.\u000a      Description of local recurrence and survival in Norway over this period\u000a        PQ trained Norwegian pathologists in his techniques\u000a    [e] Impact Of A Multidisciplinary Team Training Programme On Rectal\u000a        Cancer Outcomes In Spain. Ortiz H, Wibe A, Ciga MA, Lujan J,\u000a      Codina A, Biondo S; The Spanish Rectal Cancer Project. Colorectal Dis.\u000a      2013 Jan 25. doi: 10.1111\/codi.12141.\u000a      Description of a repeat of the Norwegian project in Spain reproducing\u000a        the improvements in Norway using our Pathogy techniques, MRI and TME\u000a        surgery\u000a    [f] Miller AR, Cantor SB, Peoples GE, Pearlstone\u000a        DB, Skibber JM.\u000a      Dis Colon Rectum. 2000 Dec;43(12):1695-1701; discussion 1701-3. Quality\u000a        of life and cost effectiveness analysis of therapy for locally recurrent\u000a        rectal cancer.\u000a    [g] The National Institute for Health and Clinical Excellence (NICE).\u000a      Colorectal cancer: the diagnosis and management of colorectal cancer.\u000a      2011.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/13597\/56957\/56957.pdf\u000a      Recommends the use of our pathology techniques, preoperative MRI and\u000a        TME surgery\u000a    [h] Practice parameters for the management of rectal cancer\u000a        (revised).\u000a      Monson JR, Weiser MR, Buie WD, Chang GJ, Rafferty JF, Buie\u000a      WD, Rafferty J; Standards Practice Task Force of the American Society of\u000a      Colon and Rectal Surgeons.\u000a      Dis Colon Rectum. 2013 May;56(5):535-50. doi:\u000a      10.1097\/DCR.0b013e31828cb66c.\u000a      Recommends the use of our methods for standard care in USA\u000a    [i] Royal College of Pathologists. Guidelines for dissection and\u000a      reporting of colorectal cancer 2007.\u000a      http:\/\/www.rcpath.org\/resources\/pdf\/G049-ColorectalDataset-Sep07.pdf\u000a        (update due 2013) and College of American Pathologists Protocol for\u000a      the Examination of Specimens From Patients With Primary Carcinoma of the\u000a      Colon and Rectum\u000a      http:\/\/www.cap.org\/apps\/docs\/committees\/cancer\/cancer_protocols\/2012\/Colon_12protocol_3200.pdf\u000a    [j] http:\/\/www.philipquirke.com\u000a      Trial protocols of past and current phase III rectal cancer trials MRC\u000a      Clasicc, MRC CR07, EME Rolar, NCRI Aristotle, NCRI Enrol, Trec, LOREC \u000a    ","Title":"\u000a    Case Study 5. Pathology research led to an international reduction in\u000a      rectal cancer recurrence and death by improving multidisciplinary clinical\u000a      practice\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"},{"GeoNamesId":"2656192","Name":"Basingstoke"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Rectal cancer is common with 14,999 cases annually in the UK and 446,400\u000a      globally. Around 20-30% of patients develop pelvic local recurrence, which\u000a      can lead to a very painful and unpleasant death six to nine months later.\u000a      More than 90% of individuals with pelvic local recurrence die within three\u000a      years of initial surgery.\u000a    In 1994 Phillip Quirke (Professor of Pathology 1982 to present),\u000a      Michael Dixon (Professor of Gastrointestinal Pathology 1970 to\u000a      2001), David Johnston (Professor of Surgery, 1977-1998) and others\u000a      at the University of Leeds published research showing that local\u000a      recurrence of rectal cancers was due to inadequate resection at the\u000a      circumferential surgical margin.1 In this prospective study of\u000a      190 patients with rectal cancer we developed a simple routine dissection\u000a      method for identifying tumour at the circumferential margin and showed\u000a      that it was present in 25% of specimens where the surgeon thought the\u000a      resection was potentially curative and 36% of all cases. This work also\u000a      showed that inadequate resection at the circumferential surgical margin\u000a      predicted local recurrence and survival fell from 66% to 15% and that NHS\u000a      histopathologists could use this method to predict prognosis.\u000a    Subsequent work (also by Professors Quirke, Johnston and Dixon)\u000a      published in 2002 showed that frequency of circumferential surgical margin\u000a      involvement varied between surgeons and was dependent on how well total\u000a      mesorectal excision was performed.2 Our work showed surgical\u000a      skill was associated with rates of local recurrence and individual patient\u000a      survival both of which could be improved with better dissection technique.\u000a    Professor Quirke developed a simple photographic method for\u000a      grading the quality of total mesorectal excision. The MRC CR07 trial in\u000a      2009 showed quality of surgery assessed this way predicted outcomes at\u000a      three years3, and this was confirmed in the Dutch Total\u000a      Mesorectal excision +\/- radiotherapy trial surgical specimens reviewed by\u000a      Quirke.\u000a      In collaboration with Professor Bill Heald and Mr Brendan Moran (Pelican\u000a      Centre, Basingstoke) and Dr Gina Brown (Royal Marsden Hospital, London) we\u000a      conducted the Mercury study showing circumferential surgical margin status\u000a      can be accurately assessed and outcome predicted preoperatively by MRI.4\u000a    One issue that became apparent during these studies in the early 2000s\u000a      was that outcomes in patients with low rectal cancer did not improve with\u000a      improved total mesorectal excision technique. Work by Professors Quirke,\u000a        Johnston and Dixon, showed this was due to on going high rates of\u000a      circumferential surgical margin involvement (20-30%) and high perforation\u000a      rates (20%) during abdominoperineal excision.5 This was\u000a      confirmed in the Mercury trial in tumours < 6cm from anal verge.\u000a    In 2008, Professor Quirke with Paul Finan (Professor of\u000a      Surgery, Leeds Teaching Hospitals NHS Trust [2010-present]) and Nicholas\u000a      West (PhD student\/Lecturer 2009-present) then showed through work in Leeds\u000a      and a collaborative multinational study that a newer more radical approach\u000a      (extralevator abdominoperineal excision) developed by Swedish surgeon\u000a      Torbjorn Holm (Karolinska Hospital, Stockholm) reduced circumferential\u000a      surgical margin positivity and perforations by excising more tissue around\u000a      the tumour.6 The Mercury2 study has shown a relative reduction\u000a      in CRM involvement by 55% based on this approach.\u000a    "},{"CaseStudyId":"6302","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    The use of high-dose melphalan with autologous stem cell rescue and\u000d\u000a      associated combination chemotherapies was a novel clinical intervention\u000d\u000a      which was shown in a trial initiated and led from Leeds and run by the\u000d\u000a      Leeds CTRU (Myeloma VII) to significantly improve outcomes in patients\u000d\u000a      with multiple myeloma (1). The addition of thalidomide and zoledronic acid\u000d\u000a      were shown in a subsequent RCT (Myeloma IX), the largest ever conducted in\u000d\u000a      myeloma, to further improve patient outcome (2). Together this work has\u000d\u000a      transformed the standard management of myeloma.\u000d\u000a    Impact on health and welfare\u000d\u000a      The results of Myeloma VII - that high-dose chemotherapy with ASCT was a\u000d\u000a      significant improvement on standard chemotherapy — was incorporated in UK\u000d\u000a      clinical guidelines, with Morgan and Cook as advisors [A] and\u000d\u000a      international Guidelines [B]. This led to widespread changes in practice\u000d\u000a      as shown by an increase in the uptake of high-dose therapy with autologous\u000d\u000a      stem cell transplants in the UK in the treatment of multiple myeloma\u000d\u000a      rising from 211 in 1999 to 453 in 2005, the increase being sustained in\u000d\u000a      2008 - 2013 [C, D]. These changes were also seen internationally with a\u000d\u000a      doubling of use of this treatment between 2003 (publication of Myeloma\u000d\u000a      VII) and most recent data for all Europe in 2010 [E].\u000d\u000a    The latest cancer survival statistics for patients diagnosed in the\u000d\u000a      period 2005-2009 with their period of survival followed throughout the REF\u000d\u000a      Impact period (2008-2013) show large improvements in survival. In men,\u000d\u000a      one-year relative survival rates for myeloma increased from 35.2% during\u000d\u000a      1971- 1975 to 70.4% during 2005-2009. In women, one-year relative survival\u000d\u000a      rates increased from 40.6% to 72.3% during the same time periods [F]. Meta\u000d\u000a      analysis suggests that the use of high-dose melphalan with ASCT will\u000d\u000a      improve longer term survival in young myeloma patients (1). This is\u000d\u000a      supported by figures which show ten-year relative survival rates for men\u000d\u000a      diagnosed with myeloma increased from 5.3% during 1971-1975 to a predicted\u000d\u000a      19% in those diagnosed in 2007. In women, ten-year relative survival rates\u000d\u000a      increased from 4.8% to a predicted 14.9% during the same time periods [F].\u000d\u000a    Cancer Research UK, the external agency responsible for this analysis say\u000d\u000a      that high-dose treatment is an important component in this improvement in\u000d\u000a      mortality [F]. They observe \"the most marked improvements in five-\u000d\u000a          and ten-year survival have happened since the early 1990s, probably\u000d\u000a          reflecting the effective and widespread use of high-dose chemotherapy\u000d\u000a          and autologous stem cell transplantation\". This was\u000d\u000a      substantially and materially a consequence of Leeds research (Myeloma\u000d\u000a      VII). They add that more recent advances in biological therapies including\u000d\u000a      the use of thalidomide (Myeloma IX) mean that survival rates are\u000d\u000a      continuing to improve rapidly and \"current data may underestimate\u000d\u000a          the survival rates for myeloma patients diagnosed today\" [F].\u000d\u000a      Within the UK healthcare system, recommendations for intensive therapy and\u000d\u000a      for appropriate quality assurance of units delivering this treatment have\u000d\u000a      been developed. Changes in healthcare professional training and\u000d\u000a      professional standards in competence and safety and have been implemented\u000d\u000a      for this treatment [A].\u000d\u000a    The importance of zoledronic acid in myeloma, as shown by Myeloma IX, has\u000d\u000a      been noted by reviewers [G,H] and incorporated into professional\u000d\u000a      guidelines in the USA, Canada and Europe-wide, which recommended that\u000d\u000a      \"given the recent data from the Myeloma IX trial, zoledronic acid is the\u000d\u000a      bisphosphonate of choice in multiple myeloma\" [H,I]. The use of zoledronic\u000d\u000a      acid in myeloma patients in the UK has increased. An independent survey of\u000d\u000a      leading physicians and researchers working in myeloma voted the results on\u000d\u000a      the efficacy of zoledronic acid as the most important publication on\u000d\u000a      myeloma in 2010 [G]. The British Society Committee for Standards in\u000d\u000a      Haematology and the UK Myeloma Forum recommended that zoledronic acid\u000d\u000a      should be given to all patients who have symptomatic multiple myeloma\u000d\u000a      referencing Myeloma IX [A]. The study has also influenced clinical\u000d\u000a      guidelines recommending the use of thalidomide [A,B,I,J]. Subsequent\u000d\u000a      prescribing data from the UK shows uptake has increased as use the drug\u000d\u000a      has become widespread in clinical practice [K]. Leading international\u000d\u000a      opinion confirms the attribution of changes in myeloma practice and\u000d\u000a      outcomes to Leeds research and the MRC Myeloma trials conducted by the\u000d\u000a      Leeds CTRU and led substantially by Leeds based clinical investigators\u000d\u000a      [L].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Two large multicentre clinical trials designed and led by researchers and\u000d\u000a      clinicians in Leeds have resulted in major changes to treatment for\u000d\u000a      patients with multiple myeloma. Myeloma VII clearly established the use of\u000d\u000a      high-dose melphalan supported by autologous stem cell transplant (ASCT)\u000d\u000a      following chemotherapy. Myeloma IX, the largest randomised controlled\u000d\u000a      trial ever in myeloma, showed that zoledronic acid, in addition to\u000d\u000a      reducing skeletal damage, showed an overall survival benefit and\u000d\u000a      introduced the use of thalidomide as an effective yet less toxic therapy.\u000d\u000a      Adoption of these treatment regimens has produced significantly improved\u000d\u000a      outcomes throughout the developed world.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Leeds\u000d\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a(1) Child JA, Morgan GJ, Davies FE, Owen RG, Bell\u000a        SE, Hawkins K, Brown J, Drayson MT, Selby PJ\u000d\u000a      for the Medical Research Council Adult Leukaemia Working Party. High-dose\u000d\u000a      chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N\u000d\u000a      Engl J Med 2003; 348: 1875-1883.\u000d\u000a      This trial led by Child and Selby and performed through Leeds CTRU\u000d\u000a        shows that high-dose chemotherapy with stem cell rescue is better than\u000d\u000a        conventional therapy and led to the use of this treatment strategy for\u000d\u000a        young patients with multiple myeloma across the world.\u000d\u000a    \u000a\u000a(2) Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE,\u000d\u000a      Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S,\u000d\u000a      Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson\u000d\u000a      GH, Child JA, National Cancer Research Institute Haematological\u000d\u000a      Oncology Clinical Study Group. First— line treatment with zoledronic acid\u000d\u000a      as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a\u000d\u000a      randomised controlled trial. Lancet 2010; 376: 1989-1999.\u000d\u000a      This trial led by Child as Chief Investigator and performed through\u000d\u000a        Leeds CTRU shows the superiority of zoledronic acid in reducing bone\u000d\u000a        damage in myeloma patients and improving their survival and has been\u000d\u000a        adopted into therapy.\u000d\u000a    \u000a\u000a(3) Morgan GJ, Child JA, Gregory WM, Szubert AJ, Cocks\u000a        K, Bell SE, Navarro-Coy N, Drayson MT, Owen RG,\u000d\u000a      Feyler S, Ashcroft AJ, Ross FM, Byrne J, Roddie H, Rudin C, Cook G,\u000d\u000a      Jackson GH, Wu P, Davies FE, National Cancer Research Institute\u000d\u000a      Haematological Oncology Clinical Studies Group. Effects of zoledronic acid\u000d\u000a      versus clodronic acid on skeletal morbidity in patients with newly\u000d\u000a      diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a\u000d\u000a      randomised controlled trial. Lancet Oncol 2011; 12(8): 743-752.\u000d\u000a      This paper further analysed Myeloma IX trial showing improved survival\u000d\u000a        not only as a result of delaying damage to bone but possibly because of\u000d\u000a        a direct effect on the tumour.\u000d\u000a    \u000a\u000a(4) Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE,\u000d\u000a      Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL,\u000d\u000a      Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child\u000a        JA, NCRI Haematological Oncology Study Group. Cyclophosphamide,\u000d\u000a      thalidomide, and dexamethasone (CTD) as initial therapy for patients with\u000d\u000a      multiple myeloma unsuitable for autologous transplantation. Blood 2011;\u000d\u000a      118: 1231-1238.\u000d\u000a      In Myeloma IX the use of a simpler initial therapy at the beginning of\u000d\u000a        therapy was shown to be effective and has been widely adopted.\u000d\u000a    \u000a\u000a(5) Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert\u000d\u000a      AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie\u000d\u000a      H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA;\u000d\u000a      National Cancer Research Institute Haematological Oncology Clinical\u000d\u000a      Studies Group. Blood. 2012; 119: 7-15. The role of maintenance thalidomide\u000d\u000a      therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.\u000d\u000a      In Myeloma IX benefits were shown from the use of a simple oral therapy\u000d\u000a        to maintain the effects of the initial chemotherapy. This is widely\u000d\u000a        used.\u000d\u000a    \u000a\u000a(6) Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert\u000d\u000a      AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child\u000a        JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes\u000d\u000a      with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Aug\u000d\u000a      30.\u000d\u000a      This paper confirms the long term impact of zoledronic acid and\u000d\u000a        thalidomide.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    (A) JM Bird, RG Owen, S D'Sa, J Snowden, G Pratt, J Ashcroft, K Yong, G\u000d\u000a      Cook, S Feyler, FE Davies, GJ Morgan, J Cavenagh, E Low, J Behrens. (2011)\u000d\u000a      NICE Guidelines on Myeloma Management. Guidelines for the diagnosis &\u000d\u000a      management of multiple myeloma 2010. British Journal of Haematology; 154:\u000d\u000a      32-75. NICE guidelines clearly indicate that high-dose chemotherapy\u000d\u000a        with autologous stem cell rescue is indicated for younger patients with\u000d\u000a        myeloma and refers to the Myeloma VII trial.\u000d\u000a    (B) Cavo et al. International Myeloma Working Group consensus approach to\u000d\u000a      the treatment of multiple myeloma patients who are candidates for\u000d\u000a      autologous stem cell transplantation. Blood 2011; 117: 6063-73. International\u000a        Myeloma Working Group Guidelines indicate the value of high-dose\u000d\u000a        treatment and stem cell rescue in young patients and reference the Leeds\u000d\u000a        Myeloma VII data.\u000d\u000a    (C) Cook G, Jackson GH, Morgan GJ, Russell NH, Kirkland K, Lee J, Marks\u000d\u000a      DI & Pagliuca A. The outcome of high dose chemotherapy and autologous\u000d\u000a      stem cell transplantation (ASCT) in patients with multiple myeloma: a\u000d\u000a      comparison between two decades and benchmarking against European outcomes.\u000d\u000a      Bone Marrow Transplantation 2011; 46: 1210-18.\u000d\u000a      The UK Transplant Society data shows increasing use of autologous stem\u000d\u000a        cell approaches in myeloma rising from 211 in 1999 to 453 in 2005.\u000d\u000a    (D) British Society for Bone Marrow Transplantation provides by Kieran\u000d\u000a      Kirkland, Head of Data Registry. Myeloma Registry data show increasing\u000d\u000a        uptake of intensive therapy with autologous stem cell support during and\u000d\u000a        after publication of Myeloma VII from Leeds, sustained through to impact\u000d\u000a        period 2008-2013.\u000d\u000a    (E) European Group for Blood and Marrow Transplantation Annual Report\u000d\u000a      2011, p7. This report summarises all EBMT activity. For myeloma high\u000d\u000a        dose therapy with stem cells rise from c 4,000 cases in 2003 to c 8,000\u000d\u000a        cases in 2010.\u000d\u000a    (F) Cancer Research UK data on changing survival in myeloma. http:\/\/www.cancerresearchuk.org\/cancer-info\/cancerstats\/types\/myeloma\/survival\/multiple-myeloma-survival-statistics\u000d\u000a    (G) The Myeloma Beacon survey of most important publications in the field\u000d\u000a      in 2010. Full details at: http:\/\/www.myelomabeacon.com\/news\/2011\/03\/16\/the-top-multiple-myeloma-research-of-2010\/\u000d\u000a      This gives an international authoritative view on the impact of Myeloma\u000d\u000a        IX on clinical practice.\u000d\u000a    (H) Richardson PG, Laubach JP, Schlossman RL, Ghobrial IM, Mitsiades CS,\u000d\u000a      Rosenblatt J, Mahindra A, et al. (2011). The Medical Research Council\u000d\u000a      Myeloma IX trial: the impact on treatment paradigms*. European Journal of\u000d\u000a      Haematology, Myeloma IX: changing treatment paradigms?, 88(1), 1-7. The\u000a        review summarises the conclusive impact of Myeloma IX and its\u000d\u000a        incorporation into guidelines for clinical practice in the USA, Canada\u000d\u000a        and Europe.\u000d\u000a    (I) Clinical Guidelines in Canada (Reece D, Sebag M, White D, Song K. A\u000d\u000a      Canadian perspective on the use of bisphosphonates in the clinical\u000d\u000a      management of multiple myeloma. New Evidence in Oncology, March 2011), the\u000d\u000a      USA (National Comprehensive Cancer Network. NCCN Clinical Practice\u000d\u000a      Guidelines in Oncology: Multiple Myeloma. v.1.2014. Fort Washington, PA:\u000d\u000a      National Comprehensive Cancer Network Inc, 2013) and Europe-wide (Terpos\u000d\u000a      E, Sezer O, Croucher PI, García-Sanz R, Boccadoro M, San Miguel J,\u000d\u000a      Ashcroft J, Bladé J, Cavo M, Delforge M, Dimopoulos MA, Facon T, Macro M,\u000d\u000a      Waage A, Sonneveld P; European Myeloma Network. The use of bisphosphonates\u000d\u000a      in multiple myeloma: recommendations of an expert panel on behalf of the\u000d\u000a      European Myeloma Network. Ann Oncol. 2009 Aug;20(8):1303-17).\u000d\u000a    (J) NICE technology appraisal guidance 228: Bortezomib and thalidomide\u000d\u000a      for the first-line treatment of multiple myeloma. 2011. http:\/\/publications.nice.org.uk\/bortezomib-and-thalidomide-for-the-firstline-treatment-of-multiple-myeloma-ta228\u000d\u000a      This NICE technology appraisal supports the use of thalidomide in the\u000d\u000a        treatment of myeloma indicating the impact of Myeloma IX on clinical\u000d\u000a        practice.\u000d\u000a    (K) NHS Zoledronic acid and thalidomide prescribing data. NHS\u000d\u000a        Zoledronic acid prescribing data for myeloma shows a doubling of\u000d\u000a        prescriptions following the 2011 publication. Thalidomide prescriptions\u000d\u000a        rose during Myeloma IX and were sustained after the trial publication.\u000d\u000a        Data provided by Cellgene.\u000d\u000a    (L) Letter of corroboration from Dr Stewart, Mayo Clinic, the leading US\u000d\u000a      authority on myeloma.\u000d\u000a    ","Title":"\u000d\u000a    Case Study 6. Transforming the treatment of myeloma has produced\u000d\u000a      significant improvement in patient survival: the MRC Myeloma trials\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Multiple myeloma is a malignant disease of bone and bone marrow that\u000d\u000a      causes pain and disability and in the majority of patients is fatal.\u000d\u000a      Conventional chemotherapy had only a modest impact on survival. Peter\u000d\u000a        Selby (Professor of Cancer Medicine, Leeds 1989- ) contributed to\u000d\u000a      early laboratory studies on high-dose chemotherapy in the 1980s at the\u000d\u000a      Royal Marsden Hospital, London. On moving to Leeds, Selby collaborated\u000d\u000a      with Anthony Child (Leeds 1974-, Honorary Professor of\u000d\u000a      Haematology, Leeds 2002-) and Gareth Morgan (Professor of\u000d\u000a      Haematology, Leeds 1990-2006) to initiate and lead a key RCT (MRC Myeloma\u000d\u000a      VII) evaluating both the clinical impact of high-dose chemotherapy using\u000d\u000a      melphalan and the addition of autologous stem cell transplant (1). The\u000d\u000a      trial was designed and delivered through the Leeds Clinical Trials\u000d\u000a      Research Unit, CTRU (Julia Brown, Professor of Clinical Trials\u000d\u000a      Research, Leeds 1990-, Walter Gregory, Professor of Statistical\u000d\u000a      Methodology in Clinical Trials, Leeds 2005-, S Bell, Leeds 1998-,\u000d\u000a      K Hawkins, Leeds 2001-2010, and R Owen, Leeds 1998-,\u000d\u000a      Principal Research Fellows, Leeds). MRC Myeloma VII provided for the first\u000d\u000a      time conclusive evidence that high-dose chemotherapy was effective for\u000d\u000a      myeloma. It showed that high-dose chemotherapy improved survival for\u000d\u000a      patients under 65 years of age by 5% at five years, a finding which was\u000d\u000a      confirmed by a meta-analysis with a simultaneous French trial (1).\u000d\u000a    Building on this evidence, MRC Myeloma IX, also initiated and designed in\u000d\u000a      Leeds and run by the Leeds CTRU (Child, Gordon Cook, Honorary\u000d\u000a      Professor of Haematology and Myeloma Studies, 2003- , Morgan, Brown\u000d\u000a      and Gregory), used the now proven treatments of high-dose\u000d\u000a      chemotherapy with melphalan and ASCT but with the addition of novel oral\u000d\u000a      agent thalidomide to overcome toxicity associated with regimens involving\u000d\u000a      parenteral infusional chemotherapy. The trial showed thalidomide to be an\u000d\u000a      effective oral induction therapy for multiple myeloma associated with\u000d\u000a      fewer toxic effects and has since become primary treatment of choice\u000d\u000a      (4,5,6).\u000d\u000a    Myeloma IX also included a new third-generation bisphosphonate to assess\u000d\u000a      the control of bone damage. Patients were randomised to receive newer drug\u000d\u000a      zoledronic acid or standard bisphosphonate treatment to determine both the\u000d\u000a      anti-osteolytic effects but also possible survival difference. It showed\u000d\u000a      not only that zoledronic acid significantly reduced bone damage in\u000d\u000a      comparison with the previous standard bisphosphonate, clodronate, but also\u000d\u000a      is associated with better survival (2). This too is now considered a\u000d\u000a      standard treatment for multiple myeloma. The six-year median follow-up\u000d\u000a      analysis continued to indicate a late survival benefit. Analyses have\u000d\u000a      shown this is not dependent on the drug's effect in preventing or delaying\u000d\u000a      bone recurrence, and zoledronic acid may have a previously unsubstantiated\u000d\u000a      direct anti-myeloma effect (2,3,4,5,6).\u000d\u000a    The trial also evaluated thalidomide in the maintenance setting and\u000d\u000a      showed benefits of its use to maintain the effects of initial chemotherapy\u000d\u000a      — a strategy now widely used (5). Importantly Myeloma IX included older\u000d\u000a      less fit patients in a non-intensive treatment pathway — a large group\u000d\u000a      clinically but one previously excluded in the trial setting. Treatment\u000d\u000a      incorporating thalidomide appeared to provide a significant benefit in\u000d\u000a      older, less fit patients, with a suggestion of an emerging survival\u000d\u000a      benefit for those patients surviving more than 2 years (4, 5).\u000d\u000a    "},{"CaseStudyId":"6303","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"3865483","Name":"Argentina"},{"GeoNamesId":"2661886","Name":"Sweden"}],"Funders":[],"ImpactDetails":"\u000d\u000a    RA is a chronic, systemic, inflammatory joint disease, affecting 600,000\u000d\u000a      people in the UK and is the largest cause of treatable disability in the\u000d\u000a      Western world. Given its high prevalence in the working population, RA\u000d\u000a      represents a major economic burden through both direct costs of care and\u000d\u000a      through loss of employment, with one in five employed RA patients having\u000d\u000a      to stop work within the first 12 months of illness. Treating RA costs the\u000d\u000a      NHS an estimated £560 million each year, with wider annual costs\u000d\u000a      associated with sick leave and work related disability of £1.8 billion.\u000d\u000a      With inclusion of nursing home costs and private expenditure, the\u000d\u000a      estimated costs are as high as £3.8 billion a year. The research\u000d\u000a      undertaken by the Emery group at Leeds has had a major impact on how the\u000d\u000a      disease is viewed, diagnosed and treated, leading to substantial\u000d\u000a      improvements in the health and quality of life of patients with RA and\u000d\u000a      reduced financial costs, both within the UK and internationally.\u000d\u000a    Impact on health and welfare\u000d\u000a      Research at Leeds has shown the need and impact of early, aggressive care,\u000d\u000a      a model that has been universally adopted in the UK.\u000d\u000a    The National Audit Office's guidelines on the management of RA — a\u000d\u000a      pivotal document commissioned by the House of Lords to review the NHS\u000d\u000a      standards of treatment for patients — cites Leeds work prominently [A].\u000d\u000a      Our work (4) provided the basis for a recommendation that: \"It is\u000d\u000a      important that treatment is started early to minimise damage to joints,\u000d\u000a      and there is increasing evidence that aggressive treatment very soon after\u000d\u000a      the onset of symptoms can lead to remission.\" In the same report, the\u000d\u000a      Rheumatology Service at Leeds is used as an example of excellence in early\u000d\u000a      treatment and multidisciplinary care.\u000d\u000a    Guidelines from the National Institute for Clinical and Health Excellence\u000d\u000a      (NICE) recommended urgent treatment for RA [B]. The full guideline\u000d\u000a      document quotes two Leeds papers which established the superiority of\u000d\u000a      imaging to detect synovitis and the need to identify this early and a\u000d\u000a      further five papers establishing the importance of aggressive treatments\u000d\u000a      particularly in early disease and where the prognosis is poor. Underlining\u000d\u000a      the importance of early diagnosis, the British Society of Rheumatology has\u000d\u000a      recommended banded tariffs to see patients within three weeks of referral\u000d\u000a      [C].\u000d\u000a    Early, aggressive treatment improves patients' quality of life by\u000d\u000a      reducing pain and increasing functional ability and participation in\u000d\u000a      valued activities, including work. Access to early referral is now\u000d\u000a      expected by patients and is part of the Arthritis and Musculoskeletal\u000d\u000a      Alliance \"Standards of Care for Rheumatoid Arthritis\" [D]. This defines\u000d\u000a      appropriate support to enable those with RA to lead independent lives and\u000d\u000a      reach their full health potential. Standard 4 says: \"All people with\u000d\u000a      suspected inflammatory arthritis should be seen by a specialist in\u000d\u000a      rheumatology within 12 weeks of referral from their GP, to confirm\u000d\u000a      diagnosis and enable prompt and effective treatment\" citing Leeds\u000d\u000a      research.\u000d\u000a    Based on the Leeds model, the care of patients with RA has been\u000d\u000a      transformed across the globe [E,F]. Early, aggressive treatment is part of\u000d\u000a      the joint European and American Guidelines [G], which directly influences\u000d\u000a      the care of more than 11.4 million people with RA. Treating to remission\u000d\u000a      is now a target recommended by several international bodies, which cite\u000d\u000a      Leeds research in the evidence, including that of an international\u000d\u000a      taskforce which refers to 17 Leeds papers [G,H]. Through Leeds' highly\u000d\u000a      successful International Fellowship programme, we have hosted over 25\u000d\u000a      clinical fellows from 15 countries, which has directly led to the setting\u000d\u000a      up of arthritis networks in Argentina and Brazil and the Gulf states, in\u000d\u000a      addition to Sweden, Netherlands and Germany.\u000d\u000a    Impact on the economy\u000d\u000a      The National Audit Office estimates that the financial impact to the NHS\u000d\u000a      of adopting the early treatment model is substantial [A]. Figures suggest\u000d\u000a      26,000 newly diagnosed patients in the UK each year, half of whom seek\u000d\u000a      early referral. While earlier, more rapid treatment increases the initial\u000d\u000a      costs, modelling has suggested that these costs would be more than offset\u000d\u000a      by decreases in lost productivity and improved quality of life. It is\u000d\u000a      estimated that by treating those who are seen early is associated with an\u000d\u000a      additional annual cost of £2.2 million but productivity gains of £6.2\u000d\u000a      million.\u000d\u000a    Impact on public policy and services\u000d\u000a      Emery was instrumental in launching the Fit for Work Europe\u000d\u000a      Initiative (www.fitforworkeurope.eu\/),\u000a      an organisation showing that improvements in early intervention, treatment\u000d\u000a      and return to work practices could help people of working age stay in work\u000d\u000a      [I]. This report, launched at the Houses of Parliament in 2009, gained the\u000d\u000a      attention of policymakers and the media, informed Government thinking on\u000d\u000a      early intervention, prompted a debate in the UK parliament and contributed\u000d\u000a      to the initiation of a Government review of the costs and benefits of\u000d\u000a      treatment and care for rheumatoid arthritis patients in the UK. As a\u000d\u000a      result, in September 2010, the Fit for Work Europe Coalition was launched\u000d\u000a      in Brussels to highlight to policymakers and relevant stakeholders the\u000d\u000a      importance of early detection, prevention and management of\u000d\u000a      musculoskeletal disease [I]. The European League Against Rheumatism\u000d\u000a      estimates that this has led to many millions of additional funding\u000d\u000a      allocated to musculoskeletal disease [F].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research in Leeds led by Professor Paul Emery pioneered early\u000d\u000a      diagnosis and treatment for patients with rheumatoid arthritis (RA), with\u000d\u000a      the aim of disease remission rather than reduction of symptoms. This\u000d\u000a      approach has transformed management of RA and is now standard practice for\u000d\u000a      patients worldwide. It has led to greatly improved disease control,\u000d\u000a      increased quality of life and reduced disability as well as direct\u000d\u000a      productivity gains of an estimated £4 million per year to the UK economy.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Leeds\u000d\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2800867","Name":"Bruxelles-Capitale"}],"References":"\u000d\u000a    \u000a1) Devlin J, Gough A, Huissoon A, et al. The acute phase and\u000d\u000a      function in early rheumatoid arthritis. C-reactive protein levels\u000d\u000a      correlate with functional outcome. Journal of Rheumatology 1997; 24: 9-13.\u000d\u000a      This paper provided the rationale for the suppression of inflammation\u000d\u000a        in the treatment of patients with RA showing the first good data that\u000d\u000a        CRP as a surrogate marker correlated with function which was seen as the\u000d\u000a        gold standard measure. \u000d\u000a    \u000a\u000a2) Conaghan PG, O'Connor P, McGonagle D, et al.\u000d\u000a      Elucidation of the relationship between synovitis and bone damage: a\u000d\u000a      randomized magnetic resonance imaging study of individual joints in\u000d\u000a      patients with early rheumatoid arthritis. Arthritis & Rheumatism 2003;\u000d\u000a      48: 64-71.\u000d\u000a      This landmark study simultaneously imaging of synovitis and bone damage\u000d\u000a        in the same patients over 12 months provided the conclusive data that\u000d\u000a        inflammation and joint damage are strongly related and that in the\u000d\u000a        absence of inflammation there was little joint damage. \u000d\u000a    \u000a\u000a3) Quinn MA, Conaghan PG, O'Connor PJ, et al. Very early\u000d\u000a      treatment with infliximab in addition to methotrexate in early,\u000d\u000a      poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging\u000d\u000a      evidence of synovitis and damage, with sustained benefit after infliximab\u000d\u000a      withdrawal: results from a twelve-month randomized, double-blind,\u000d\u000a      placebo-controlled trial. Arthritis & Rheumatism 2005; 52: 27-35.\u000d\u000a      This was the first remission induction study with a TNF inhibitor which\u000d\u000a        showed that patients rapidly reached remission and maintained that state\u000d\u000a        when the biologic was withdrawn. \u000d\u000a    \u000a\u000a4) Emery P, Breedveld FC, Hall S, et al. Comparison of\u000d\u000a      methotrexate monotherapy with a combination of methotrexate and etanercept\u000d\u000a      in active, early, moderate to severe rheumatoid arthritis (COMET): a\u000d\u000a      randomised, double-blind, parallel treatment trial. Lancet 2008; 372:\u000d\u000a      375-82.\u000d\u000a      This international collaboration showed that therapy with combination\u000d\u000a        of a TNF inhibitor and methotrexate was effective but also that serious\u000d\u000a        adverse events were not increased by therapy. It also was the first\u000d\u000a        study to use the now standard outcome of remission as an end point.\u000d\u000a    \u000d\u000a    \u000a\u000a5) Brown AK, Conaghan PG, et al. An explanation for the apparent\u000d\u000a      dissociation between clinical remission and continued structural\u000d\u000a      deterioration in rheumatoid arthritis. Arthritis Rheum 2008; 58: 2958-67.\u000d\u000a      A year-long study of patients in remission at baseline showing for the\u000d\u000a        first time that sensitive imaging with ultrasound and MRI could detect\u000d\u000a        sub-clinical synovitis in patients treated with DMARDs in remission and\u000d\u000a        that sub-clinical disease correlated with significant radiological\u000d\u000a        progression in that individual joints. This formed the basis of current\u000d\u000a        use of high resolution ultrasound.\u000d\u000a    \u000a\u000a6) Bejarano V, Quinn M, Conaghan PG, et al. Effect of the early\u000d\u000a      use of the anti-tumor necrosis factor adalimumab on the prevention of job\u000d\u000a      loss in patients with early rheumatoid arthritis. Arthritis &\u000d\u000a      Rheumatism 2008; 59: 1467-74.\u000d\u000a      A long-term follow up of (4) showing that one year's treatment with\u000d\u000a        biologics produced significant benefits eight years later in a small\u000d\u000a        number of patients. It was the first study to find that early, biologic\u000d\u000a        therapy combined with methotrexate reduced job loss and improved\u000d\u000a        productivity. \u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [A] National Audit Office. Services for people with rheumatoid arthritis\u000d\u000a      (2009).\u000d\u000a      http:\/\/www.nao.org.uk\/wp-content\/uploads\/2009\/07\/0809823.pdf\u000d\u000a      (see pg 11, 28).\u000d\u000a    [B] National Collaborating Centre for Chronic Conditions. Rheumatoid\u000d\u000a      arthritis: national clinical guideline for management and treatment in\u000d\u000a      adults (2009).\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK51812\/pdf\/TOC.pdf\u000d\u000a      (see pg 25, ref 20 (1); pg 32 ref 64 (4) and pg 44 ref 69 (2).\u000d\u000a    [C] British Society of Rheumatology. Best Practice Tariff: Early\u000d\u000a      Inflammatory Arthritis.\u000d\u000a      http:\/\/publications.nice.org.uk\/support-for-commissioning-for-rheumatoid-arthritis-cmg51\/the-commissioning-and-budgeting-tool\u000d\u000a    [D] The Arthritis and Musculoskeletal Alliance Standards of Care for\u000d\u000a      people with Inflammatory Arthritis (2004). (see pg 21 which cites two\u000d\u000a      Leeds studies).\u000d\u000a      http:\/\/www.nras.org.uk\/includes\/documents\/cm_docs\/2012\/a\/arma_standards_of_care_for_ia.pdf\u000d\u000a    [E] Corroborative Letter from British Society of Rheumatology President,\u000d\u000a      Professor Chris Deighton. Available on request.\u000d\u000a    [F] Corroborative Letter from EULAR President, Professor Maurizio Cutolo.\u000d\u000a      Available on request.\u000d\u000a    [G] Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis\u000d\u000a      classification criteria: an American College of Rheumatology\/European\u000d\u000a      League Against Rheumatism collaborative initiative. Annals of the\u000d\u000a      Rheumatic Diseases 69: 1580-88. (see page 1583).\u000d\u000a    [H] Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid\u000d\u000a      arthritis to target: recommendations of an international task force.\u000d\u000a      Annals of the Rheumatic Diseases 69: 631-37.\u000d\u000a    [I] Corroborative Letter from President of WorkFit, Steve Bevan.\u000d\u000a      Available on request. \u000d\u000a    ","Title":"\u000d\u000a    Case Study 7. Changing the treatment paradigm of rheumatoid arthritis:\u000d\u000a      early diagnosis and aggressive treatment to attain remission leads to\u000d\u000a      sustained improvements in health and quality of life.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Treatment for rheumatoid arthritis (RA) had traditionally been\u000d\u000a      conservative, using a step-wise approach to manage the symptoms of the\u000d\u000a      disease as they progressed. Paul Emery (Professor of Rheumatology,\u000d\u000a      Leeds, 1995- ) was the first to turn this model on its head, proposing an\u000d\u000a      ambitious protocol driven by early diagnosis and aggressive treatment with\u000d\u000a      the aim of achieving disease remission defined by complete suppression of\u000d\u000a      synovial and systemic inflammation. In 1995, Emery moved to Leeds to lead\u000d\u000a      a multi-disciplinary research group, who designed and delivered a series\u000d\u000a      of seminal studies to provide the evidence and establish the validity of\u000d\u000a      this proposed treatment model.\u000d\u000a    With Philip Conaghan (Senior Lecturer then Professor of\u000d\u000a      Musculoskeletal Medicine 1997- ), Joe Devlin and Andrew Gough\u000d\u000a      (both Research Fellows 1996-99), Emery showed that early RA\u000d\u000a      patients with a sustained acute phase response suffer irreversible joint\u000d\u000a      damage, resulting in pain and long term functional disability (1). Further\u000d\u000a      work demonstrated the substantial long-term consequences of incomplete\u000d\u000a      suppression of inflammation in early RA, where persistent synovial\u000d\u000a      inflammation led to increased functional disability, osteoporosis and\u000d\u000a      structural joint damage (2).\u000d\u000a    The group then carried out research looking at the effectiveness of early\u000d\u000a      diagnosis and aggressive treatment. Their work established that the\u000d\u000a      greatest predictor of persistence of disease was symptom duration of\u000d\u000a      greater than 12 weeks, a key step in establishing the importance of early\u000d\u000a      treatment. In collaboration with national (Maini, Imperial College London)\u000d\u000a      and international partners (Smolen, Vienna and Breedveld, Lieden), the\u000d\u000a      first international trials of anti-TNF therapy were conducted in patients\u000d\u000a      with RA . The Leeds group were the first to use biologic therapy for\u000d\u000a      remission induction in patients with very early disease and demonstrated\u000d\u000a      significant long benefits at eight years (3). In a subsequent study (4)\u000d\u000a      for the first time remission was used as an endpoint and the effectiveness\u000d\u000a      and lack of side effects demonstrated the feasibility of biologic therapy\u000d\u000a      first line. Consequently, remission has been accepted as the outcome of\u000d\u000a      choice in early therapy.\u000d\u000a    In addition, the Leeds group established the importance of using\u000d\u000a      validated outcome measures, which are both disease specific and reflect\u000d\u000a      what is important to patients. Alongside Richard Wakefield (Senior\u000d\u000a      Lecturer, Leeds 1996- ), they identified that clinical measures of\u000d\u000a      response to treatment are inadequate as subclinical synovitis exists in\u000d\u000a      patients who have satisfied clinical remission criteria, resulting in\u000d\u000a      \"silent\", irreversible joint damage (5). Importantly, the group identified\u000d\u000a      that this sub-clinical inflammation can be detected only through imaging\u000d\u000a      with MRI and ultrasound, questioning the importance of clinically driven\u000d\u000a      criteria as the sole foundation for treatment decisions.\u000d\u000a    With Alan Tennant (Professor of Rehabilitation Studies, 1999- ),\u000d\u000a      the Leeds team developed the RA-WIS, a work instability scale, which was\u000d\u000a      the first instrument designed and validated for the unique needs of\u000d\u000a      patients with RA. This tool is now widely used internationally to assess\u000d\u000a      the impact of RA on individuals' work. The RA-WIS was the primary outcome\u000d\u000a      for a novel randomised controlled trial led by Leeds of early treatment of\u000d\u000a      patients still in work with biologic agent adalimumab (6).\u000d\u000a    Work at Leeds established that the early diagnosis of RA results in\u000d\u000a      suppression of inflammation and leads to higher rates of remission.\u000d\u000a      Following on from this, the group designed a number of novel trials whose\u000d\u000a      primary endpoint was remission. The results of these studies established\u000d\u000a      that importantly, this remission could be sustained without the use of\u000d\u000a      expensive biologics (4). Long-term follow-up at eight years has confirmed\u000d\u000a      the success of this approach and the Leeds group have found that very\u000d\u000a      early treatment to remission results in the ability to cease therapy, and\u000d\u000a      have shown the immunological basis for this, proving the need to treat for\u000d\u000a      remission and not just symptom reduction.\u000d\u000a    "},{"CaseStudyId":"6596","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"927384","Name":"Malawi"},{"GeoNamesId":"2309096","Name":"Equatorial Guinea"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"2300660","Name":"Ghana"},{"GeoNamesId":"2275384","Name":"Liberia"},{"GeoNamesId":"337996","Name":"Ethiopia"},{"GeoNamesId":"934841","Name":"Swaziland"},{"GeoNamesId":"226074","Name":"Uganda"},{"GeoNamesId":"2134431","Name":"Vanuatu"},{"GeoNamesId":"1036973","Name":"Mozambique"},{"GeoNamesId":"3996063","Name":"Mexico"},{"GeoNamesId":"895949","Name":"Zambia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The WHO estimates that insecticide resistance in African malaria vectors,\u000d\u000a      if left unchecked, could potentially result in an additional 120,000\u000d\u000a      childhood deaths, rising to 250,000 as current vector control tools are\u000d\u000a      scaled up [9]. LSTM's research is working to prevent this\u000d\u000a      eventuality. Its approach to resistance analysis has contributed to the\u000d\u000a      greater understanding of insecticide resistance, and has led to proactive\u000d\u000a      decisions being made on insecticide use to avoid control relapses by\u000d\u000a      malaria control programmes in Bioko, Zambia, Mozambique Uganda and\u000d\u000a      Zanzibar. Global Malaria Programme at the World Health Organization has\u000d\u000a      stated \"As part of the global malaria community, LSTM has made significant\u000d\u000a      contribution through their research efforts to the prevention and control\u000d\u000a      measures in addressing the problem of insecticide resistance in the WHO\u000d\u000a      African Region\" leading to the 25% reduction in malaria mortality rates\u000d\u000a      since 2000 and by 33% in the WHO African Region [10].\u000d\u000a    LSTM technical input was sought for the WHO Global Plan for Insecticide\u000d\u000a      Resistance Management in Malaria Vectors 2012 (GPIRM) [9] and the\u000d\u000a      recommendations for action in the GPIRM are substantially based on the\u000d\u000a      research output of LSTM in identifying resistance mechanisms and means to\u000d\u000a      track resistance in the field, and in helping countries to generate an\u000d\u000a      evidence base for resistance management strategies. LSTM managed the only\u000d\u000a      large-scale public health insecticide resistance management programme with\u000d\u000a      a 7-year trial in Mexico, sponsored by industry which demonstrated that\u000d\u000a      Indoor Residual Spraying (IRS) in either an annual rotation system or a\u000d\u000a      village scale mosaic maintained control and extended the useful life of\u000d\u000a      the insecticides.\u000d\u000a    LSTM worked directly with National Malaria Control Programmes in Malawi,\u000d\u000a      Bioko, South Africa, Swaziland, Mozambique and Zambia between 2001 and\u000d\u000a      present day advising on the optimal resistance management strategies.\u000d\u000a      Changes in insecticide use in malaria control have occurred in each of\u000d\u000a      these countries as a direct result. LSTM also supported entomological\u000d\u000a      monitoring and evaluation in a further six African countries (Zanzibar,\u000d\u000a      Liberia, Uganda, DRC, Ethiopia, Ghana, Mozambique and Zambia), through\u000d\u000a      technical assistance to the PMI and, again, several of these countries,\u000d\u000a      including Zanzibar and Uganda, have changed the class of insecticide used\u000d\u000a      in as a direct result. The Co-Chair of the Roll Back Malaria Vector\u000d\u000a      Control Working Group, has highlighted the increased urgency for routine\u000d\u000a      monitoring of resistance and acknowledged LSTM's leading position in\u000d\u000a      driving this forward, in working with country programmes, conducting\u000d\u000a      evidence based monitoring and evaluation and insecticide selection [11].\u000d\u000a    Impact of product development partnership:\u000d\u000a      a. Kits for monitoring insecticide residues on insecticide treated\u000d\u000a        materials. Sub-standard spraying, loss of insecticidal activity in\u000d\u000a      the field and even fake bednets are all major problems facing malaria\u000d\u000a      control programmes. The diagnostic insecticide quantification systems\u000d\u000a      developed by LSTM are undergoing trials by AVIMA Pty (SA) for commercial\u000d\u000a      production in Africa, under the brand name \"Assure\" [12]. They cost\u000d\u000a      <$1, are easy to use and have a unique ability to provide a rapid\u000d\u000a      assessment of spray team performance, so that any problems can be\u000d\u000a      rectified promptly, whether by re-spraying, retraining or improved\u000d\u000a      supervision. The IQK TM have undergone fields trials in Bioko\u000d\u000a      Island (Dec 2010), Vanuatu (Nov 2010) and Ethiopia (Aug 2013). Based on\u000d\u000a      the success of the Bioko trial, approximately 2000 prototype kits were\u000d\u000a      ordered for the subsequent spray rounds in 2011.\u000d\u000a    b. New insecticides. The first longer lasting insecticide\u000d\u000a      formulations (Actellic, Syngenta) became commercially available in 2012\u000d\u000a      and a second set was launched in 2013 (K-Othrine, BayerCropScience). These\u000d\u000a      new formulations increase the residual performance of the insecticide.\u000d\u000a      IVCC and AvecNet funded and managed all of the efficacy trials, both in\u000d\u000a      the Laboratory (LITE) and in the African field trials sites. The new\u000d\u000a      formulations make the insecticide more effective on traditional muds used\u000d\u000a      in house building in rural African communities, and reduces IRS programme\u000d\u000a      costs by increasing the required interval between applications (e.g\u000d\u000a      Syngenta's original formulation, Actellic EC, was effective for two to\u000d\u000a      three months, whereas the new Actellic CS formulation lasts for 4 - 6\u000d\u000a      months). Actellic CS is now being used in Ghana and Zambia. K-Othrine,\u000d\u000a      Bayer's long lasting formulation of Deltamethrin, is now being used in\u000d\u000a      Equatorial Guinea. Syngenta's Actellic CS country registrations are\u000d\u000a      accessible for Ghana, Equatorial Guinea [13]. The IVCC annual\u000d\u000a      report includes further information on industry investment in research and\u000d\u000a      development. [14]\u000d\u000a    c. New software for assessing malaria control programmes. The DDMS\u000d\u000a      software enables managers in countries to monitor interventions and\u000d\u000a      evaluate impact in ways they have not been able to do before. They operate\u000d\u000a      in both resource-poor and resource-rich environments and can be tailored\u000d\u000a      to operate as a single database to an integrated system, combining data\u000d\u000a      from several resources, producing maps, reports and alerts for disease\u000d\u000a      outbreaks. DDMS is being implemented in Ethiopia, Mozambique and Zambia. A\u000d\u000a      Spanish version of the software was produced by LSTM in 2012 and is being\u000d\u000a      used by the Bioko Island Malaria Control Programme, Equatorial Guinea.\u000d\u000a      This highly successful programme has reduced transmission of malaria in\u000d\u000a      Bioko by more than 80% [15].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Malaria kills around 650,000 children a year but can be prevented by\u000d\u000a      killing the mosquito vectors. As mosquitoes become resistant to\u000d\u000a      insecticides the prevention measures can become ineffective. Research at\u000d\u000a      the Liverpool School of Tropical Medicine (LSTM) led by Professor\u000d\u000a      Hemingway FRS has been instrumental in the development of current World\u000d\u000a      Health Organisation (WHO) guidelines to manage resistance, and has led to\u000d\u000a      improved resistance diagnostics and novel monitoring software to integrate\u000d\u000a      entomological and human health outcomes. LSTM's research led to the\u000d\u000a      creation of the Innovative Vector Control Consortium (IVCC) which was\u000d\u000a      established as an independent Product Development Partnership (PDP) in\u000d\u000a      2008. New, longer lasting formulations of insecticides developed by IVCC\u000d\u000a      are now in operational use, and several novel public health insecticides\u000d\u000a      are under development.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Riveron JM, Irving H, Ndula M, Barnes KG, Ibrahim SS, Paine MJ,\u000d\u000a        Wondji CS Directionally\u000a        selected cytochrome P450 alleles are driving the spread of\u000d\u000a        pyrethroidresistance in the major malaria vector Anopheles funestus.\u000d\u000a      (2013) Proc Natl Acad Sci U S A. Jan 2; 110 (1):252-7. Citations: 4 Impact\u000d\u000a      Factor: 9.737\u000d\u000a    \u000a\u000a2. Mitchell SN, Stevenson B, Muller P, Wilding CS,\u000d\u000a      Egyir Lawson A, Field SG, Hemingway J, Paine JI, Ranson\u000d\u000a        H, Donnelly MJ. Identification\u000a        and validation of a gene causing cross-resistance between insecticide\u000d\u000a        classes in Anopheles gambiae from Ghana. (2012) Proceedings of\u000d\u000a      National Academy of Sciences, 109:6417-52. Citations: 20 Impact Factor:\u000d\u000a      9.737\u000d\u000a    \u000a\u000a3. Edi CAV, Koudou BG, Jones CM,Weetman D and Ranson H Multiple\u000a        insecticide resistance in Anopheles gambiae mosquitoes southern Côte\u000d\u000a        d'Ivoire. (2012) Emerging Infectious Diseases. 18(9): 1508-11.\u000d\u000a      Citations: 5 Impact Factor: 5.993\u000d\u000a    \u000a\u000a4. Hemingway J, Vontas J, Poupardin R, Raman J, Lines J,\u000d\u000a      Schwabe C, Matias A. and Kleinschmidt I. Country-level\u000a        operational implementation of the Global Plan for Insecticide Resistance\u000d\u000a        Management (2013) Proceedings of the National Academy of Sciences,\u000d\u000a      Vol 110, Issue 23, pp. 9397-9402. (Equatorial Guinea \/ Bioko). Citations:\u000d\u000a      0 Impact Factor: 9.737\u000d\u000a    \u000a\u000a5. Wondji CS, Coleman M, Kleinschmidt I, Mzilahowa T, Irving\u000d\u000a        H, Ndula M, Rehman A, Morgan J, Barnes KG, Hemingway\u000d\u000a        J. Impact of\u000d\u000a        pyrethroid resistance on operational malaria control in Malawi.\u000d\u000a      (2012) Proc Natl Acad Sci U S A. 2012 Nov 20; 109(47):19063- 70. Epub.\u000d\u000a      Citations: 4 Impact Factor: 9.737\u000d\u000a    \u000a\u000a6. Casimiro S, Coleman M, Mohloai P, Hemingway J, Sharp B: Insecticide\u000a        resistance in Anopheles funestus (Diptera: Culicidae) from Mozambique\u000d\u000a      . (2006) J Med Entomol 43:267-275. Citations: 43 Impact Factor:\u000d\u000a      1.95\u000d\u000a    \u000a\u000a7. Dowd AJ, Steven A, Morou EA, Hemingway J, Vontas J.\u000d\u000a      and Paine MJI. A\u000d\u000a        simple glutathione transferase-based colorimetric endpoint assay for\u000d\u000a        insecticide detection. (2009) Enz and Micro Tech. 45, 164-168.\u000d\u000a      Citations: 5 Impact Factor: 2.638\u000d\u000a    \u000a\u000a8. Eisen L, Coleman M, Lozano-Fuentes S, McEachen N, Orlans M, Coleman\u000a        M Multi-disease\u000a        data management system platform for vector-borne diseases. (2011)\u000d\u000a      PLoS Negl Trop Dis. Mar 29; 5 (3):e1016. Citations: 7 Impact Factor: 4.716\u000d\u000a    \u000aSelected Research Awards\u000d\u000a    2005-2013. Bill & Melinda Gates Foundation. `Innovative\u000d\u000a      Vector Control Consortium (IVCC)'. $50,744,497. Janet Hemingway\u000d\u000a      (PI)\u000d\u000a    2010-2016. Bill & Melinda Gates Foundation. `IVCC\u000d\u000a      Product Development Partnership', $50m Janet Hemingway. (PI)\u000d\u000a    2011-2016. European Commission (FP7). 'African Vector Control: New Tools\u000d\u000a      (AvecNet)'. €11,999,989. Hilary Ranson. (PI)\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"7","Level2":"3","Subject":"Crop and Pasture Production"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section 4 (details of the impact). \u000d\u000a    \u000d\u000a      Global Plan for Insecticide Resistance Management in Malaria Vectors\u000d\u000a        2012 http:\/\/whqlibdoc.who.int\/publications\/2012\/9789241564472_eng.pdf\u000a\u000d\u000a      Contact: Vector Control Unit, Global Malaria Programme at the WHO. To\u000d\u000a        corroborate LSTM's significant contribution to the prevention and\u000d\u000a        control measures in addressing the problem of insecticide resistance in\u000d\u000a        the WHO African Region leading to reduction in malaria mortality in the\u000d\u000a        WHO African Region.\u000d\u000a      Contact: Co-Chair of Roll Back Malaria Vector Control Working Group.\u000d\u000a        To corroborate LSTM's global influence and impact on resistance\u000d\u000a        management strategies used in control programmes.\u000d\u000a      Contact: Director for Avima Pty, the company licensing the IQK in\u000d\u000a        Africa. To corroborate Quantification Kits are in commercial production.\u000d\u000a      Syngenta's Actellic CS country registrations can be provided on\u000d\u000a        request (Ghana, Equatorial Guinea.)\u000d\u000a      IVCC annual report 12\/13, http:\/\/www.ivcc.com\/documents\/IVCCAnnualreport2011-12.pdf\u000a\u000d\u000a      Contact: Senior Officer at Medical Care Development International, who\u000d\u000a        is the PI in the Bioko Island Control Project, confirming DDMS has had a\u000d\u000a        major impact reducing transmission of malaria.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving the Impact of Malaria Prevention Activities\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    This case study encompasses the outputs from five academic staff; Janet\u000d\u000a      Hemingway, (2001-) Director of LSTM, Hilary Ranson (2001-) Professor of\u000d\u000a      Medical Entomology, Martin Donnelly, (2001-) Professor of Evolutionary\u000d\u000a      Genetics, Mark Paine (2006 -) Senior Lecturer, and Charles Wondji (2005-)\u000d\u000a      Research Fellow, leveraging several hundred millions of pounds of research\u000d\u000a      income since 2001.\u000d\u000a    Scale up of insecticide based interventions to target the mosquito\u000d\u000a      vectors that transmit malaria have resulted in a 33% reduction in malaria\u000d\u000a      cases over the last decade in Africa. However, malaria prevention is\u000d\u000a      currently reliant on a very small number of insecticides with only the\u000d\u000a      pyrethroids approved for insecticide treated bednets. Malaria mosquitoes\u000d\u000a      are rapidly developing resistance to these insecticides. There is a\u000d\u000a      critical lack of alternative vector control technologies, and a further\u000d\u000a      impediment to effective malaria control is often the absence of accurate\u000d\u000a      timely information on which to base disease prevention measures, which can\u000d\u000a      result in wasted resources and increased disease burden. New vector\u000d\u000a      control tools, decision support systems and new insecticides are urgently\u000d\u000a      needed to save lives in Africa. If current tools fail due to resistance,\u000d\u000a      the gains in malaria prevention could be quickly eroded.\u000d\u000a    Understanding the mechanisms and spread of insecticide resistance.\u000d\u000a      LSTM leads the malaria control community in understanding the causes and\u000d\u000a      consequences of the evolution of insecticide resistance in malaria\u000d\u000a      vectors. Research into the molecular basis of insecticide resistance has\u000d\u000a      resulted in new resistance monitoring tools and new approaches to measure\u000d\u000a      the speed of spread of resistance [1]. LSTM has characterised a newly\u000d\u000a      emerging resistance mechanism that confers cross resistance to multiple\u000d\u000a      insecticide classes [2], and alerted the community to the presence of a\u000d\u000a      population of malaria vectors in Cote d'Ivoire that has now developed\u000d\u000a      resistance to all available insecticides [3]. The molecular tools\u000d\u000a      developed are now being used in insecticide development to identify new,\u000d\u000a      resistance-breaking chemistries. LSTM has the largest collection of\u000d\u000a      characterised insecticide resistant and susceptible mosquito colonies in\u000d\u000a      the world, maintained by the Liverpool Insect Testing Establishment (LITE;\u000d\u000a      http:\/\/www.lite-testing-facility.com\/).\u000aThis\u000a      facility is being used by a range of commercial partners as part of the\u000d\u000a      insecticide development pipeline.\u000d\u000a    Programmatic monitoring and evaluation\u000d\u000a      LSTM has conducted evidence based monitoring and evaluation strategies for\u000d\u000a      insecticide resistance in multiple countries including defining the types\u000d\u000a      of insecticide resistance that have a major impact on the ability to\u000d\u000a      prevent disease transmission. As an example, research into the mechanisms\u000d\u000a      of resistance in Equatorial Guinea has guided and improved international\u000d\u000a      policy on resistance management [4]. LSTM led a Tropical Disease Research\u000d\u000a      (TDR) network on insecticide resistance in malaria vectors in four\u000d\u000a      countries, establishing protocols for longitudinal resistance monitoring\u000d\u000a      and data evaluation and has worked with the Presidents Malaria Initiative\u000d\u000a      (PMI), and National Malaria Control Programmes to introduce entomological\u000d\u000a      monitoring and evaluation into routine control activities [5, 6]. The EU\u000d\u000a      funded FP7 AvecNet project is working with IVCC and in country partners,\u000d\u000a      setting new standards in quality assurance for evaluation of new\u000d\u000a      insecticides in field trials.\u000d\u000a    Underpinning Research leading to product development.\u000d\u000a    a) LSTM's research on the insect detoxification systems has led to the\u000d\u000a      development of simple, cost-effective and user friendly kits for\u000d\u000a      monitoring insecticide residues on insecticide-treated materials.\u000d\u000a      Pyrethroid Quantification Kits were initially aimed at pyrethroid\u000d\u000a      insecticides used on bednets but the insecticide quantification kits (IQKTM)\u000d\u000a      now also encompasses diagnostics kits to monitor DDT and Carbamates used\u000d\u000a      in indoor residual spraying (IRS) [7].\u000d\u000a    b) New insecticide based products to overcome the rapid selection of\u000d\u000a      pyrethroid resistance in African malaria vectors are under development by\u000d\u000a      IVCC and commercial partners. The LSTM led AvecNet consortium is\u000d\u000a      evaluating these products in the field, including undertaking the first\u000d\u000a      clinical trial of a new dual action bednet.\u000d\u000a    c) Strategic and day to day operational decisions within disease control\u000d\u000a      programmes have to be based on quality information. The Disease Data\u000d\u000a      Management (DDMS) was established to assist in the operational running,\u000d\u000a      monitoring and evaluation of a malaria control\/elimination programme.\u000d\u000a      Development of a software platform that could be configured for any\u000d\u000a      environment was completed in 2011 [8].\u000d\u000a    "},{"CaseStudyId":"6597","Continent":[{"GeoNamesId":"6255150","Name":"South America"}],"Country":[{"GeoNamesId":"3625428","Name":"Venezuela"}],"Funders":[],"ImpactDetails":"\u000a    Policy Impact\u000a    LSTM research findings changed WHO and the CDC strategies, treatment\u000a      guidelines and recommendations. In 2012 the WHO OEPA adopted doxycycline\u000a      for the treatment of residual cases in the North-Eastern focus in\u000a      Venezuela. Attention to operational elements of the river blindness\u000a      programme in the Americas is highly necessary in order to achieve and\u000a      maintain the elimination of transmission. The geographically hard to reach\u000a      location of the affected area coupled with the migratory nature of the\u000a      population make it especially difficult to maintain regular treatments.\u000a      OEPA refers to the use of an alternate antibiotic doxycycline as ensuring\u000a      full elimination of infection and transmission [7].\u000a    The WHO GPELF endorsed the use of doxycycline as a new tool for morbidity\u000a      management of elephantiasis in 2012. The Global Task Force for Health's\u000a      2012 monitoring and evaluation working group on disease specific\u000a      indicators, endorsed the use of doxycycline (6 weeks) for individual\u000a      treatment of adults as an alternative, [8, page 6]. It also refers to the\u000a      use of doxycycline for adults (200 mg\/day) for 6 weeks as an alternative\u000a      and two LSTM studies [4,6]. The sixth meeting of the WHO Strategic and\u000a      Technical Advisory Group for NTD's also states \"for clinical cases, any of\u000a      the following regimens have been proposed and may be considered, for\u000a      adults, doxycycline (200 mg\/day) for 6 weeks is under consideration as an\u000a      alternative\" [9].\u000a    The WHO report from the 2009 Inter-American Conference on Onchocerciasis\u000a      concluded that \"progress towards eliminating river blindness in the region\u000a      of the Americas\" and noted that a 6- week course of daily oral doxycycline\u000a      has been shown to kill adult O. volvulus worms. Doxycycline kills\u000a      endosymbiotic bacteria (Wolbachia) that provide important\u000a      nutritional requirements to the worms; without the bacteria the worms\u000a      become sterile and slowly die. The conference recommended that national\u000a      programmes consider providing doxycycline treatment (but necessarily\u000a      exclude young children and pregnant women) on a selective basis [10].\u000a    CDC recommends doxycycline treatment options for onchocerciasis [11] and\u000a      lymphatic filariasis [12] to health professionals. One objective of the\u000a      A2219WOL programme is to promote advocacy of A2219WOL's outcomes by\u000a      interfacing with CNTD and external scientific advisors to facilitate\u000a      dialogue, representation and engagement with control programmes: the\u000a      African Programme for Onchocerciasis Control (APOC), OEPA and GPELF,\u000a      stakeholder meetings and NTD community forums. The membership of the\u000a      A2219WOL Consortium and the External Scientific Advisory Committee (ESAC)\u000a      in particular is ideally equipped through its excellent networks to\u000a      promote the findings and practical opportunities the A2219WOL project\u000a      provides.\u000a    The AWOL ESAC includes key stakeholder members from APOC, OEPA, GPELF,\u000a      the Mectizan Donation Program [13], Drugs for Neglected Diseases\u000a      initiative (DNDi) and NTD Global Health experts [14] (Prof David\u000a      Molyneux-former LSTM). In addition, the publication of A2219WOL research\u000a      findings in both high impact journals and at international conferences and\u000a      meetings is an ongoing process which adds to the evidence base in order to\u000a      advocate for the implementation of an anti-Wolbachia based approach\u000a      for filariasis therapy.\u000a    CDC Recommended Treatment regime for Onchocerca volvulus-\u000a        based on LSTM research\u000a    \u000a      \u000a        \u000a          Usage\/Drug\u000a          Adult Dose\u000a          Pediatric dose\u000a        \u000a        \u000a          To kill microfilariae:\u000a            ivermectin\u000a          150 mcg\/kg orally in one dose\u000a            every 6 months\u000a          150 mcg\/kg orally in one dose\u000a            every 6 months\u000a        \u000a        \u000a          To kill macrofilariae:\u000a            doxycycline\u000a          200 mg orally daily\u000a            for 6 weeks\u000a          200 mg orally daily\u000a            for 6 weeks\u000a        \u000a      \u000a    \u000a    Commercial Impact\u000a    The breakthrough of anti-wolbachial therapy stimulated the creation of\u000a      both product discovery and development pipelines at LSTM to identify new\u000a      antibiotics which target Wolbachia and could be used to combat\u000a      elephantiasis and river blindness.\u000a    Since 2007, LSTM has been working with industrial partners through\u000a      A2219WOL collaborations [15] with CombinatoRx, Forma Therapeutics,\u000a      Paratek, Inventa Technologies (S) Pte Ltd, Anacor Pharmaceuticals Inc,\u000a      Abbott\/AbbVie, Pfizer Inc, Bio-focus DPI Ltd, SIMM (Shanghai Institute of\u000a      Materia Medica), AstraZeneca, Dupont, Broad Institute, MMV, DNDi, and TB\u000a      Alliance plus others to discover and develop drugs that work to clear the\u000a      Wolbachia symbiont, but can do so in a treatment course of 7 days\u000a      or less and be safe for children and in pregnancy — where a 4-6 week\u000a      course of doxycycline cannot be given.\u000a    LSTM research led, in 2013, to both the A2219WOL Macrofilaricide Drug\u000a      Discovery project, progressing six new chemical series towards\u000a      pre-clinical candidate selection, and the A2219WOL Macrofilaricide Drug\u000a      Development project, taking the best registered and re-purposed drugs from\u000a      LSTM's screening campaign to optimise the best combination of drugs for\u000a      MDA programmes. Both A2219WOL programs include collaboration with\u000a      pharmaceutical companies providing industrial investment to cover the\u000a      entire drug discovery and development process.\u000a    ","ImpactSummary":"\u000a    Scientists at the Liverpool School of Tropical Medicine (LSTM) have\u000a      proven that targeting an essential bacterial symbiont, Wolbachia,\u000a      with a course of antibiotics cures patients of their parasitic worms and\u000a      improves disease pathology. This discovery in 1999 offers superior\u000a      efficacy compared to existing anti-filarial drugs delivering prophylaxis,\u000a      transmission blocking, safe macrofilaricidal activity and improved case\u000a      management therapy. This approach has been endorsed by WHO elimination\u000a      programmes for onchocerciasis, (Onchocerciasis Elimination Programme for\u000a      the Americas, OEPA) and lymphatic filariasis (Global Programme to\u000a      Eliminate Lymphatic Filariasis, GPELF). The Centre for Disease Control\u000a      (CDC), also recommends this new strategy for elimination and morbidity\u000a      management.\u000a    ","ImpactType":"Health","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1796231","Name":"Shanghai Shi"}],"References":"\u000a    \u000a1. Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Hoerauf\u000a      A. Macrofilaricidal\u000a        activity after doxycycline treatment of Wuchereria bancrofti: a\u000a          double-blind, randomised placebo-controlled trial.\u000a      (2005) The Lancet, Volume 365, Issue 9477, Published: 18-24 June 2005,\u000a      Pages 2116-2121 Citations: 112 Impact Factor: 23.878\u000a    \u000a\u000a2. Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K,\u000a      Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A. 'Doxycycline\u000a        reduces plasma VEGF-C\/sVEGFR-3 and improves pathology in lymphatic\u000a        filariasis'. (2006) PLoS Pathogens, Vol 2, Issue 9, 0829-0843.\u000a      Citations: 31 Impact Factor: 6.056\u000a    \u000a\u000a3. Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Lawson B, Taylor\u000a        MJ, Adjei O, Hoerauf A. Reduction\u000a        in levels of plasma vascular endothelial growth factor-A and improvement\u000a        in hydrocele patients by targeting endosymbiotic Wolbachia sp. in Wuchereria\u000a        bancrofti with doxycycline. (2009) Am J Trop Med Hyg. 80(6):\u000a      956-63. Citations: 23 Impact Factor: 2.795\u000a    \u000a\u000a4. Mand S, Debrah AY, Klarmann U, Batsa L, Marfo-Debrekyei Y, Kwarteng A,\u000a      Specht S, Belda-Domene A, Fimmers R, Taylor M, Adjei O, Hoerauf A.\u000a      Doxycycline\u000a        improves filarial lymphedema independent of active filarial infection: a\u000a        randomized controlled trial. (2012) Clinical Infectious Disease.\u000a      55(5):621-30. Citations: 3 Impact Factor: 9.374\u000a    \u000a\u000a5. Turner JD, Tendongfor N, Esum M, Johnston KL, Langley\u000a        RS, Ford L, Faragher B, Specht S, Mand S, Hoerauf A,\u000a      Enyong P, Wanji S, Taylor MJ. Macrofilaricidal\u000a        Activity after Doxycycline Only Treatment of Onchocerca volvulus\u000a        in an Area of Loa loa Co-Endemicity: A Randomized Controlled\u000a        Trial. (2010) PLOS Neglected Tropical Diseases Volume: 4 Issue: 4\u000a      Article Number: e660 Published: APR 2010 Citations: 29 Impact Factor:\u000a      4.752\u000a    \u000a\u000a6. Tamarozzi F, Tendongfor N, Enyong PA, Esum M, Faragher B,\u000a      Wanji S, Taylor MJ. Long\u000aterm\u000a        impact of large scale community-directed delivery of doxycycline for the\u000a        treatment of onchocerciasis. (2012) Parasites & Vectors. 2012\u000a      5:53. Citations: 7 Impact Factor: 3.246\u000a    \u000aKey Research Grants\u000a    2007-2012, Bill & Melinda Gates Foundation, `Anti-Symbiotic\u000a      Treatment of Filariasis' (A- WOL I), $23m, Mark Taylor (PI).\u000a    2013-2016, Bill & Melinda Gates Foundation, `A-WOL II\u000a      Macrofilaricidal Drug Discovery', $5m, Steve Ward (PI, LSTM Deputy\u000a      Director)\u000a    2013-2015, Bill & Melinda Gates Foundation, `A2219WOL II:\u000a      Macrofilaricidal Drug Development' $4m, Mark Taylor (PI)\u000a    2013-2018, DFID `Phase III trial for community doxycycline in\u000a      efficient vector transmission hotspots' £1m,Centre for Neglected\u000a        Tropical Diseases (CNTD), LSTM\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    \u000a      Contact: Director, Onchocerciasis Elimination Program for the Americas\u000a        (OEPA). Confirming they have adopted doxycycline for the treatment of\u000a        residual cases in the North- Eastern focus in Venezuela.\u000a      WHO Global programme to eliminate LF meeting report http:\/\/apps.who.int\/iris\/bitstream\/10665\/78611\/1\/WHO_HTM_NTD_PCT_2013.5_eng.pdf\u000a\u000a      WHO Report of the sixth meeting of the WHO strategic and Technical\u000a        Advisory Group for NTD. http:\/\/www.who.int\/neglected_diseases\/sixth_stag\/en\/index.html\u000a\u000a      Report from the 2009 InterAmerican Conference on Onchocerciasis:\u000a        progress towards eliminating river blindness in the Region of the\u000a        Americas http:\/\/www.who.int\/wer\/2010\/wer8533.pdf\u000a\u000a      Centers for Disease control recommends treatment options for\u000a        onchocerciasis http:\/\/www.cdc.gov\/parasites\/onchocerciasis\/health_professionals\/index.html\u000a\u000a      Centers for Disease Control recommends treatment options for lymphatic\u000a        filariasis http:\/\/www.cdc.gov\/parasites\/lymphaticfilariasis\/treatment.html\u000a\u000a      Contact: Director of the Mectizan Donation Program. Confirming debate\u000a        has been stimulated and informed by research evidence.\u000a      Contact: Director of the River Blindness Program, Lymphatic Filariasis\u000a        Program, confirming debate stimulation and implementation has been and\u000a        informed by research evidence.\u000a      Collaborative agreements with industry can be provided on request.\u000a    \u000a    ","Title":"\u000a    Development of an Effective Cure for River Blindness (Onchocerciasis) and\u000a      Elephantiasis (Lymphatic Filariasis) and a new Tool for Control,\u000a      Elimination and Morbidity Management.\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Mark Taylor established the research at LSTM in 1993 and was\u000a      assisted by Dr Joseph Turner (Lecturer, 2010-), Dr Louise Ford (PDRA,\u000a      2007-) Dr Darren Cook (PDRA, 2005-), Dr Denis Voronin, (PDRA. 2009-), Dr\u000a      Kelly Johnston (PDRA, 2005-) and Dr Helen McGarry (PDRA, 2003-2008) to\u000a      study the filarial parasites which cause elephantiasis (Wuchereria\u000a        bancrofti and Brugia malayi) and river blindness (Onchocerca\u000a        volvulus). Both of these diseases are part of a recent focus on\u000a      neglected tropical diseases (NTDs), recognizing that about a billion more\u000a      people are at risk and millions are infected with NTDs.\u000a    Professor Taylor has made significant progress discovering a previously\u000a      unexpected role of Wolbachia bacterial symbionts as drivers of\u000a      filarial disease, essential contributors to the biology of filarial\u000a      nematodes, and as a target for treatment through antibiotic therapy. He\u000a      has shown that the antibiotic doxycycline can be used to treat patients\u000a      with fewer adverse effects than existing therapies such as ivermectin. New\u000a      drugs are still needed to reduce the treatment course and are being\u000a      developed in partnership with industry. The breakthrough stimulated the\u000a      formation of the 'Anti-Wolbachia' (A·WOL I) consortium in 2007 and A·WOL\u000a      II in 2013, to search for new drugs active against Wolbachia. The\u000a      consortium, led by Taylor, consists of internationally recognised\u000a      researchers in the UK, Germany, Africa and USA and collaborates with\u000a      pharmaceutical companies.\u000a    Professor Taylor's group undertook ten randomised and placebo controlled\u000a      phase II field trials using doxycycline as a novel treatment against\u000a      lymphatic filariasis and onchocerciasis. Field trials were conducted in\u000a      collaboration with A·WOL consortium members in Germany and Africa, with\u000a      the group at LSTM contributing to the planning, protocol design, ethics,\u000a      management and data analysis. A course of doxycycline that depletes the\u000a      bacterial endosymbionts, leads to prolonged reduction in microfilaraemia\u000a      and the death of adult worms (78-92% cure rate) with avoidance of adverse\u000a      events to treatment experienced with standard anti-filarial treatments,\u000a      due to either target species or to co-infections with Loa loa. In\u000a      individuals with disease, a course of treatment can even bring about an\u000a      improvement in the pathology of lymphodema and hydrocele (swollen fluid\u000a      filled scrotal sac) an effect which is retained in patients without active\u000a      infection [1,2,3].\u000a    The new anti-wolbachial therapy provides an alternative to the treatment\u000a      for onchocerciasis and lymphatic filariasis in areas co-endemic with\u000a      loiasis. Previous anti-macrofilarial treatments have resulted in the rapid\u000a      kill of L. loa microfilariae but at the risk of severe\u000a      complications resulting in encephalopathy, coma and death. However, by\u000a      using antibacterial drugs these severe adverse events are avoided because\u000a      L. loa microfilariae do not have Wolbachia symbionts. This\u000a      has potential to overcome a major barrier to the implementation of mass\u000a      drug administration (MDA) programmes.\u000a    Findings by A·WOL of 6 and 8 week courses of doxycycline have been\u000a      reported as a safe and well tolerated treatment for lymphatic filariasis\u000a      with significant activity against adult worms and microfilaraemia [4],\u000a      treatment improves mild to moderate lymphodema independent of on-going\u000a      infection. This benefit expands to the entire population of patients\u000a      suffering from lymphodema. Doxycycline is able to kill the adult worms,\u000a      making doxycycline the first drug already approved for human use that\u000a      controls the parasite and the quality of life of persons with pathology\u000a      [2].\u000a    To test whether a 6-week course of treatment was deliverable through\u000a      community-directed MDA approaches, in 2007 a community trial of treatment\u000a      with doxycycline was carried out in two health districts in Cameroon,\u000a      co-endemic for O. volvulus and L. loa. With 17,519\u000a      eligible subjects, the therapeutic coverage was 73.8% with 97.5%\u000a      compliance, encouraging the feasibility of using doxycycline\u000a      community-directed delivery in restricted populations of this size. The\u000a      evaluation of the effectiveness of this delivery of doxycycline showed\u000a      significant improvements over standard strategies, even up to four years\u000a      after delivery, which is not dependent upon co-administration of\u000a      ivermectin [4, 5]. These findings show that a multi-week course of\u000a      treatment is not a barrier to community-delivery of MDA in restricted\u000a      populations of this size and supports its implementation to complement\u000a      existing control strategies for onchocerciasis [6].\u000a    "},{"CaseStudyId":"6601","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2658434","Name":"Switzerland"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    Approximately 125 million women in malaria-endemic countries become\u000a      pregnant every year, over 32 million of whom live in areas with intense\u000a      transmission of Plasmodium falciparum [1]. This is estimated to\u000a      result in 900,000 preventable LBW births each year and the deaths of\u000a      200,000 newborns and 10,000 mothers. Since 2007, LSTM research has\u000a      contributed significantly to the formulation and maintenance of\u000a      international and national policies specifically designed to reduce this\u000a      risk. Thus, policy makers, mothers and their newborns will have benefited\u000a      from this research as 37 African countries benefited from continued use of\u000a      IPTp (2007-present), and 9 recently updated their policy to more frequent\u000a      doses (2012\/13), which will have greater impact on LBW. [7]\u000a    LSTM's research to better define the global burden of MiP has revised\u000a      WHO's global and region specific estimates of the potential burden of MiP\u000a      [8, page 34] and they are the new default estimates in policy documents\u000a      [9, page 1 ref 1].\u000a    The lack of data on the impact of SP resistance on the effectiveness of\u000a      IPTp was a major concern for policy makers in 2007. The findings of the\u000a      meta-analysis [5] were presented by ter Kuile at WHO's African Regional\u000a      Office (AFRO), Harare in 2005 [10] and at the Technical Expert Group on\u000a      MiP in Geneva, July 2007 [11]. As a direct result, WHO-AFRO issued a\u000a      statement in 2005 on the continued use of SP for IPT during pregnancy\u000a      [10], and in 2007 WHO-Geneva recommended the continued use of IPTp-SP in\u000a      pregnant women, influencing on-going policy in Africa [11], where IPTp\u000a      remains the only drug-based prevention regimen today [12]. It is also\u000a      cited in a 2013 WHO policy brief for implementers and programme managers\u000a      in Africa, stating \"In several countries in Africa, some P. falciparum\u000a        parasites carry quintuple mutations linked to SP resistance — which are\u000a        associated with in vivo therapeutic failure to SP. However, recent\u000a        evidence suggests that IPTp-SP remains effective in preventing the\u000a        adverse consequences of malaria on maternal and fetal outcomes in areas\u000a        where a high proportion of P. falciparum parasites carry these quintuple\u000a        mutations. Therefore, IPTp-SP should still be administered to women in\u000a        such areas\" [13]. The impact of LSTM's research is the formulation\u000a      of policy guidelines that, since 2008, have increased the chances of a\u000a      healthy pregnancy. A recent review using retrospective birth cohort data\u000a      from national cross-sectional datasets in 25 African countries from\u000a      2000-10 estimated that IPTp-SP has reduced neonatal mortality by 18% and\u000a      LBW by 20% under routine programme conditions [14].\u000a    Increasing SP resistance in parts of Africa led to pressure from\u000a      malaria-endemic countries on WHO to provide guidance. LSTM's meta-analysis\u000a      [6] has been crucial in helping WHO update its policy recommendation on\u000a      IPTp in 2012 [13]. Ter Kuile presented the findings at WHO's Evidence\u000a      Review Group (ERG) for MiP in July 2012 who, in turn, presented their\u000a      recommendations to the Malaria Policy Advisory Committee of the WHO in\u000a      September 2012 [15]. This led WHO to update its IPTp policy, subsequently\u000a      communicated to African Member States of the WHO [12]. Several countries\u000a      in East, West and Central Africa have now ratified the updated policy and\u000a      a few have begun implementation.\u000a    One challenge to implementing MiP policies effectively has been lack of\u000a      integration between malaria control and maternal and neonatal health\u000a      programmes at global and country levels. Field studies and reviews of the\u000a      barriers to implementation have been presented by Hill at key meetings\u000a      where the maternal health and malaria communities have come together, many\u000a      of them NGOs seeking guidance to improve practices in endemic countries\u000a      [16,17]. Findings contributed to the policy brief by WHO on the updated\u000a      IPTp policy in terms of appropriate messaging to simplify the guidance\u000a      specifically on the timing, frequency, and safety of taking SP on an empty\u000a      stomach [13]. Hill is a member of the core group of the RBM Partnership on\u000a      MiP, comprised of donors and technical agencies that support countries to\u000a      implement MiP policies, and her research helps develop consensus\u000a      strategies to scale-up MiP interventions [18]. One output is the WHO\/RBM\u000a      consensus statement calling for renewed commitment to fighting MiP, using\u000a      the 3-pronged approach including the updated IPTp policy based on LSTM's\u000a      evidence [9]. The target audience includes national-level policy-makers,\u000a      malaria control and maternal and neonatal health programme managers, and\u000a      other health-care providers. The statement was developed and co-signed by\u000a      19 leading global organisations including WHO, DFID, USAID, UNICEF, BMGF,\u000a      it was co-sponsored by UNDP, World Bank, WHO and UNFPA [9]. Hill has been\u000a      invited by WHO to co-lead the development of a standardized tool to\u000a      evaluate effectiveness of MiP programme [15].\u000a    ","ImpactSummary":"\u000a    Malaria in pregnancy causes the deaths of 200,000 newborns and 10,000\u000a      mothers annually. The Liverpool School of Tropical Medicine is the\u000a      coordinating centre of the global Malaria in Pregnancy Consortium.\u000a      LSTM-led research from 2007 has contributed to the World Health\u000a      Organisation's (WHO) estimates of the global burden of malaria in\u000a      pregnancy, showing that 125M pregnancies are at risk, more than double\u000a      previous estimates. The Consortium has also contributed to a better\u000a      understanding of the low uptake of existing interventions by pregnant\u000a      women, and identification of the best prevention strategies. Consequently,\u000a      WHO updated its policy recommendations in 2007on\u000a      intermittent-preventive-treatment for prevention of malaria in pregnancy,\u000a      adopted in 37 sub-Saharan countries, and in 2012, already adopted in 9\u000a      countries.\u000a    ","ImpactType":"Political","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2660646","Name":"Genève"},{"GeoNamesId":"1105844","Name":"Harare Province"}],"References":"\u000a    \u000a1. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO,\u000a      Quantifying the number of pregnancies at risk of malaria in 2007: a\u000a        demographic study. (2010). PLoS Med 7: e1000221. Citations: 76.\u000a      Impact Factor: 15.617\u000a    \u000a\u000a2. van Eijk AM, Hill J, Alegana VA, Kirui V,\u000a      Gething PW, ter Kuile FO, Snow RW.. Coverage\u000aof\u000a        malaria protection in pregnant women in sub-Saharan Africa: a synthesis\u000a        and analysis of national survey data. (2011) Lancet Infect Dis 11:\u000a      190-207. Citations: 32. Impact Factor: 19.966.\u000a    \u000a\u000a3. van Eijk AM, Hill J, Larsen DA, Webster J, Steketee R,\u000a      Eisele TP, ter Kuile FO.. Coverage\u000a        of intermittent preventive treatment and insecticide-treated nets for\u000a        the control of malaria during pregnancy in sub-Saharan Africa: a\u000a        synthesis and meta-analysis of national survey data, 2009-11. (2013)\u000a      Lancet Infect Dis 13:1029-42. Citations: 0. Impact Factor: 19.966.\u000a    \u000a\u000a4. Hill J, Hoyt J, van Eijk AM, D'Mello-Guyett\u000a        L, Ter Kuile FO, Steketee R, Smith H, Webster J.\u000a\u0009\u0009Factors\u000a        Affecting the Delivery, Access, and Use of Interventions to Prevent\u000a        Malaria in Pregnancy in Sub-Saharan Africa: A Systematic Review and\u000a        Meta-Analysis. (2013). PLoS Med 0(7): e1001488. Citations: 0. Impact\u000a      Factor: 15.253.\u000a    \u000a\u000a5. ter Kuile FO, van Eijk AM, Filler SJ. Effect\u000a        of Sulfadoxine-Pyrimethamine Resistance on the Efficacy of Intermittent\u000a        Preventive Therapy for Malaria Control During Pregnancy: A Systematic\u000a        Review. (2007). JAMA. 297(23):2603-2616. Citations: 133. Impact\u000a      Factor: 25.547.\u000a    \u000a\u000a6. Kayentao K, Garner P, van Eijk AM, Naidoo I,\u000a      Roper C, Mulokozi A, MacArthur JR, Luntamo M, Ashorn P, Doumbo OK, ter\u000a        Kuile FO. Intermittent\u000a        preventive therapy for malaria during pregnancy using 2 vs 3 or more\u000a        doses of sulfadoxine-pyrimethamine and risk of low birth weight in\u000a        Africa: systematic review and meta-analysis. (2013). JAMA 309:\u000a      594-604. Citations: 7. Impact Factor: 29.978.\u000a    \u000aKey Research Grants\u000a    2011-2015. DFID\/MRC\/Wellcome Trust. Intermittent screening and\u000a      treatment or IPT for control of malaria in pregnancy in Indonesia, £2.1m,\u000a      Feiko ter Kuile (PI)\u000a    2010-2015. CDC Atlanta USA. Prevention of Malaria cooperative\u000a      agreement with the Malaria Branch, Centers for Disease Control and,\u000a      £1.67m. Feiko ter Kuile (PI)\u000a    2009-2013. European Developing Countries Clinical Trials Partnership\u000a        (EDCTP). Optimisation of the existing dose and regimen of IPT with\u000a      sulfadoxine-pyrimethamine for the prevention of MiP in the context of high\u000a      coverage of insecticide treated nets and highly seasonal malaria\u000a      transmission, £2.9m, Feiko ter Kuile (PI)\u000a    2007-2014. Bill & Melinda Gates Foundation. Malaria in\u000a      Pregnancy Consortium, a global network of 41 research institutions £15m, Feiko\u000a        ter Kuile (PI)\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    \u000a      Contact: Programme Leader of the Global Malaria Programme at the WHO,\u000a        confirming health impacts as 37 African countries benefited from\u000a        continued use of IPTp (2007-present), and 9 recently updated their\u000a        policy to more frequent doses (post-2012), impacting on LBW. [12]\u000a      WHO Global Malaria Programme, 2012. World Malaria Report 2012 http:\/\/www.who.int\/malaria\/publications\/world_malaria_report_2012\/wmr2012_no_profiles.p\u000a          df. (page 34, better defines the global burden of malaria in\u000a        pregnancy) (in Spanish)\u000a      WHO consensus statement, 2013 http:\/\/www.rbm.who.int\/docs\/2013\/MIP-consensus-\u000a          statement-en.pdf\u000a\u000a      AFRO recommendations on the use of SP for Intermittent Preventive\u000a        Treatment during Pregnancy (IPT) in areas of moderate to high resistance\u000a        to SP in the African Region 2005. http:\/\/www.who.int\/malaria\/publications\/atoz\/who_sp_statement\/en\/\u000a\u000a      WHO Technical Expert Group meeting on IPTp 2007 (meeting report). http:\/\/whqlibdoc.who.int\/publications\/2008\/9789241596640_eng.pdf\u000a\u000a      WHO Malaria Policy Advisory Committee Secretariat, 2012. Conclusions\u000a        and Recommendations of September 2012 meeting. Malar J 11: 424. http:\/\/www.malariajournal.com\/content\/11\/1\/424\u000a\u000a      World Health Organization, 2013. WHO policy brief for the\u000a        implementation of IPTp using sulfadoxine-pyrimethamine (IPTp-SP) April\u000a        2013. http:\/\/www.who.int\/malaria\/publications\/atoz\/Policy_brief_IPTp-\u000a          SP_implementation_11april2013.pdf.pdf\u000a\u000a      Contact: Co-Chair of the RBM Working Group on MiP confirming IPTp with\u000a        SP, resulted in reductions in neonatal mortality (by 18%) and LBW (by\u000a        20%) under routine malaria control programme conditions.\u000a      Malaria Policy Advisory Committee Meeting 11-13 September 2013, WHO\u000a        Evidence Review Group on (IPT) of malaria in pregnancy: Draft\u000a        Recommendations on Intermittent Preventive Treatment in Pregnancy\u000a        (IPTp). http:\/\/www.who.int\/malaria\/mpac\/mpac_sep13_erg_ipt_malaria_pregnancy_report.pdf\u000a\u000a      Maternal Health Task Force, 2012. Malaria in Pregnancy: Bringing the\u000a        maternal Health and malaria communities together (MiP2012). Meeting\u000a        report 26-28 June 2012 Turkey. http:\/\/maternalhealthtaskforce.org\/images\/MiP_Meeting_Report_Final_10-4-12.pdf\u000a        (Results were disseminated at a meeting convened in June 2012.)\u000a      Hill J, 2013. Improving quality of Care. Malaria in pregnancy: What it\u000a        takes to deliver quality health services as a component of comprehensive\u000a        MNCH. Jenny Hill. Available at: https:\/\/meeting.tfigroup.com\/tfi\/frontend\/reg\/titem.csp?pageID=277724&eventID=743&popu\u000a          p=1&eventID=743 (Results were presented at the global MNH\u000a        conference in Arusha)\u000a      Annual Meeting Minutes of the RBM MIP Working Group. Commitment to\u000a        strengthening, accelerating and supporting MIP programming, 13-14 May,\u000a        2013 http:\/\/www.rollbackmalaria.org\/mechanisms\/mpwg.html\u000a\u000a    \u000a    ","Title":"\u000a    The Epidemiology and Control of Malaria in Pregnancy\u000a    ","UKLocation":[{"GeoNamesId":"2644210","Name":"Liverpool"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Liverpool School of Tropical Medicine (LSTM) is the coordinating\u000a      centre of the Malaria in Pregnancy Consortium (MiPc), established in 2007\u000a      and comprises 41 partner institutions in 29 countries. Professor Feiko Ter\u000a      Kuile, LSTM Professor of Tropical Epidemiology (2003-present), is the CEO\u000a      and Jenny Hill (1995-present) is Project Manager; both lead research\u000a      activities. Additional LSTM researchers include: Stephanie Dellicour\u000a      (2007-present), RA in pharmacovigilance; Dr Annemieke van Eijk\u000a      (2009-present), Senior Clinical RA; and Dr Kassoum Kayentao (2010-\u000a      present), LSTM PhD student based at the Malaria Research Training Centre,\u000a      Mali.\u000a    Burden: Malaria is an important health and development challenge\u000a      in Africa, where pregnant women and young children are most at risk. Until\u000a      2010, comprehensive and contemporary estimates of the number of\u000a      pregnancies at risk of malaria and its consequent impact on maternal and\u000a      newborn health were not available. Malaria in pregnancy contributes to a\u000a      vicious cycle of ill-health in Africa, causing babies to be born with low\u000a      birthweight (LBW), which increases the risk of newborn and infant deaths.\u000a      Dellicour and ter Kuile, in collaboration with the University of Oxford,\u000a      derived global estimates of the annual number of women who became pregnant\u000a      in areas with malaria transmission [1], showing that 125m pregnancies are\u000a      at risk, more than double previous World Health Organisation (WHO)\u000a      estimates.\u000a    Increasing access: Hill and ter Kuile conducted field studies in\u000a      Mali and Kenya and together with Van Eijk, compiled data on the progress\u000a      of coverage of intermittent preventative therapy in pregnancy (IPTp) and\u000a      insecticide treated nets (ITNs), the two interventions recommended by WHO\u000a      for the prevention of malaria in pregnancy in sub-Saharan Africa. In two\u000a      sequential meta-analyses in 2011 and 2013 [2,3], they showed that although\u000a      uptake has improved it remains far below the goals set by Roll Back\u000a      Malaria (RBM). Hill [4] identified key interacting barriers to access,\u000a      delivery, and use of IPTp and ITNs and showed that these were relatively\u000a      consistent across countries. Some could be resolved in the short term by\u000a      simplification and standardisation of country IPTp policies and improved\u000a      guidance to health providers, but others are entrenched within weak\u000a      healthcare systems and require medium- to long-term strategies to improve\u000a      antenatal care access and service provision.\u000a    Policy: The 2002 WHO recommendation of 2 doses of\u000a      sulphadoxine-pyrimethamine (SP) as ITPp has been adopted in 37 African\u000a      countries. High level resistance threatens its efficacy in some areas, and\u000a      lack of data on the impact of SP resistance on the effectiveness of IPTp\u000a      became a major concern for policy makers. In 2007, ter Kuile was requested\u000a      by WHO to conduct a meta-analysis to address this question [5]. Findings\u000a      showed that even though SP failed to achieve radical cure in at least 40%\u000a      of children with acute malaria, it still performed very well as preventive\u000a      therapy in semi-immune pregnant women and was associated with marked\u000a      reductions in the risk of LBW, leading to a WHO recommendation to continue\u000a      with IPTp-SP.\u000a    Professor ter Kuile's subsequent meta-analysis of seven randomised\u000a      controlled trials of IPTp compared the standard 2-dose regimen of IPTp-SP\u000a      against regimens providing SP 3 times or monthly. It provided definitive\u000a      evidence that 3 or more doses of SP is far more effective compared to\u000a      2-doses, reducing the risk of severe maternal anaemia in the mother by an\u000a      additional 40% and the risk of LBW by an additional 20%, and was also well\u000a      tolerated and safe [6].\u000a    "},{"CaseStudyId":"6602","Continent":[{"GeoNamesId":"6255146","Name":"Africa"}],"Country":[{"GeoNamesId":"2287781","Name":"Ivory Coast"},{"GeoNamesId":"933860","Name":"Botswana"},{"GeoNamesId":"192950","Name":"Kenya"},{"GeoNamesId":"149590","Name":"Tanzania"},{"GeoNamesId":"337996","Name":"Ethiopia"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    HIV presents a significant health burden in Kenya with an estimated\u000a      104,000 infected children and 1,192,000 persons living with HIV infection\u000a      in 2012 [8]. Early treatment has been associated with a 96% reduction in\u000a      onwards transmission of HIV and theoretical modelling has shown that\u000a      testing scale-up accompanied by treatment could lead to the eradication of\u000a      HIV within a decade. LSTM's research has increased testing, both directly\u000a      through the changes in policy and systems in Kenya and indirectly through\u000a      the scalable quality assured services delivered in institutions like LVCT.\u000a    \u000a\u000a\u000a    Health Impact\u000a    LVCT was founded by Dr Taegtmeyer to exploit the LSTM research findings\u000a      on best practice for the delivery of quality assured HTC. The finding\u000a      shaped the NGO's practice and is maintained today through methodologies\u000a      documented by Taegtmeyer and referenced within the Kenya National\u000a      Voluntary Counselling and Testing (VCT) guidelines in 2010 [9]. LVCT has\u000a      grown into an internationally acclaimed indigenous Kenyan organisation\u000a      (t\/o US$ 9.2m pa). Dr. Kilonzo, Director of LVCT, completed her PhD at\u000a      LSTM. LVCT continues to have a direct reach in HTC services in Kenya, as\u000a      shown in the graph and supports post rape care services in 84 health\u000a      facilities in 2012. The principles established in the early research have\u000a      enabled rapid scale-up including mobile, outreach and home-based testing.\u000a      A sound quality basis has facilitated adaptations to enable services for\u000a      the deaf and other vulnerable groups including MSM and post-rape cases.\u000a      The LVCT annual report [10] documents delivery of quality assured HIV and\u000a      counselling to 1,159,970 clients, with 223,645 children, couples, MSM,\u000a      persons with disabilities and sex workers in 2012. Levels of HIV testing\u000a      have increased with 72% of adults aged 15 to 64 years in 2012 reporting\u000a      ever having been tested for HIV, a significant increase from 34% in 2007.\u000a      HIV prevalence among adults aged 15 to 64 years decreased nationally from\u000a      7.2%, to 5.6% in 2012, as indicated in the Kenya AIDs Indicator Survey\u000a      [8].\u000a    The methodology documented by Taegtmeyer and LVCT was rolled out in 2008\u000a      onwards in other African countries and multiplied through WHO policies and\u000a      guidelines. Partner agencies include the Ministries of Health in Ethiopia\u000a      (focus on access to disadvantaged populations), Cote d'Ivoire (home\u000a      testing) and Botswana and Tanzania [11] (quality assurance). The 2012\u000a      CDC\/WHO handbook for planning, implementing and monitoring home-based HTC\u000a      in high prevalence countries, was developed by Taegtmeyer and is globally\u000a      available [12].\u000a    Policy Impact\u000a    Kenya: Dr Taegtmeyer was part of the editorial team of the first\u000a      national guideline for VCT in Kenya. This was used as the basis for the\u000a      updated guidelines in 2007 and the later second edition in 2010 [9] with a\u000a      focus on provider initiated counselling and testing, quality improvement\u000a      systems and inclusion of the option for HIV self-testing. The guideline\u000a      changed practice and the approach to HTC with the establishment of a QA\u000a      taskforce that developed a QA strategy for HTC linked to the new\u000a      guidelines. The initial Kenyan quality assurance resource pack published\u000a      in 2003 has been the basis of the 2012 National Quality Management\u000a      Guidance Framework [13] for HIV testing and counselling in Kenya 2012.\u000a    International: LSTM research findings on HTC have gained\u000a      considerable attention of international policy makers and significantly\u000a      impacted policy on HTC in the WHO and at the US government's Centres for\u000a      Disease Control (CDC). Taegtmeyer was a member of the PEPFAR counselling\u000a      and testing team from 2007 - 2012. Taegtmeyer was the primary writer of\u000a      WHO's Handbook for Improving HIV Testing and Counselling Services,\u000a      published in 2010, translated into French and Mandarin [14]. Taegtmeyer\u000a      also led the writing of a Practical Handbook on Planning, Implementing and\u000a      Monitoring Home-based HTC [12], and was part of the core writing group of\u000a      the Operational and Service Delivery Guideline Development Group for the\u000a      WHO ART guidelines in 2013 [15]. Recommendations from the WHO on HIV\u000a      re-testing were published in 2010 in French and English [15] and\u000a      Taegtmeyer led on the expert consultation on acute HIV infection in\u000a      Atlanta which was the basis of these recommendations. LSTM initiated the\u000a      first ever international symposium on self-testing for HIV, Taegtmeyer and\u000a      Theobald contributed to the consensus statement agreed by UNAIDS, WHO, and\u000a      the Brocher Foundation in April 2013 [17, page 33], on the legal, ethical,\u000a      gender, human rights and public health implications of HIV self-testing\u000a      scale up. Special acknowledgements were made to Taegtmeyer in the meeting\u000a      report. [17, page 34]\u000a    UK: The research in 2009 led the Liverpool Centre for Sexual\u000a      Health to adopt point of care testing as a direct consequence of the pilot\u000a      and it is now in routine clinical use for HIV same day testing service,\u000a      (730 POCT in 2012) targeting at risk individuals and was presented in a\u000a      national forum that saw the beginning of the scale-up of point of care\u000a      services in a range of sexual health clinics in the UK [18].\u000a    ","ImpactSummary":"\u000a    Research at the Liverpool School of Tropical Medicine (LSTM) has\u000a      developed a successful approach to the rapid scale-up of HIV Testing and\u000a      Counselling (HTC) services in high prevalence countries, a vital component\u000a      of the global HIV response. The model combines comprehensive quality\u000a      assurance with operational research and has led to HTC expansion in\u000a      mobile, home and facility-based settings. It has also allowed for\u000a      responsiveness to local needs leading to post rape care services linked to\u000a      HTC, services for the deaf and HTC for men who have sex with men (MSM) and\u000a      other hidden populations in Africa. The global impact of this model is\u000a      reflected in WHO policy, Ministry of Health HTC guidelines in numerous\u000a      countries in Africa, the on-going work of an indigenous Kenyan NGO and\u000a      expansion of HTC through community outreach in the UK.\u000a    ","ImpactType":"Political","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4180439","Name":"Atlanta"}],"References":"\u000a    \u000a1. Arthur GR, Ngatia G, Rachier C, Mutemi R, Odhiambo J, Gilks\u000a        CF. The\u000a        role for government health centers in provision of same-day voluntary\u000a        HIV counseling and testing in Kenya. (2005) Acquir Immune Defic\u000a      Syndr. Nov 1; 40(3):329-35. Citations: 15 Impact Factor: 3.871\u000a    \u000a\u000a2. Marum E, Taegtmeyer M, Chebet K. Scale\u000a        up of voluntary HIV counselling and testing in Kenya. (2006) JAMA.\u000a      296:859-62. Citations: 41 Impact Factor: 23.175\u000a    \u000a\u000a3. Taegtmeyer M, Doyle V. Quality\u000a        Assurance Resource Pack for Voluntary Counselling and Testing Service\u000a        Providers. Nairobi: Liverpool VCT Centre. (2003)\u000a    \u000a\u000a4. Grabbe KL, Menzies N, Taegtmeyer M, Emukule G, Angala P, Mwega\u000a      I, Musango G, Marum E. Increasing\u000a        access to HIV counselling and testing through mobile services in Kenya:\u000a        strategies, uptake and cost-effectiveness. (2010) J Acquir Immune\u000a      Dedic Syndr. Jul 1; 54 (3):317-23 Citations: 29 Impact Factor: 4.262\u000a    \u000a\u000a5. Kilonzo N, Taegtmeyer M, Molyneux C, Kibaru J, Kamonji V, Theobald\u000a        S. Engendering\u000ahealth\u000a        sector responses to sexual violence and HIV in Kenya: results of a\u000a        qualitative study. (2008) AIDS Care. Feb; 20 (2):188-190. Citations:\u000a      8 Impact Factor: 1.466\u000a    \u000a\u000a6. Taegtmeyer M, Hightower A, Opiyo W, Mwachiro L, Henderson K,\u000a      Angala P, Ngare C, Marum E. Responding\u000a        to the Signs: A peer-led VCT programme for the Deaf in Kenya. (2009)\u000a      Disability and Rehabilitation. 31 (6): 508-14 Citations:11 Impact Factor:\u000a      1.555\u000a    \u000a\u000a7. Taegtmeyer M, Davies A, Mwangome M, van der Elst EM, Graham\u000a      SM, Price MA, Sanders EJ. Challenges\u000a        in providing counselling to MSM in highly stigmatized contexts: results\u000a        of a qualitative study from Kenya. (2013) PLoS One. Jun 7;8(6)\u000a      Citations: 0 Impact Factor: 3.730\u000a    \u000aKey Research Grants\u000a    2013-2014 (1 year). Bill and Melinda Gates Foundation.\u000a      Operational Characteristics of HIV self-test prototypes in lay users in\u000a      sub-Saharan Africa. $187,000. Miriam Taegtmeyer. (PI)\u000a    2013 - 2017 (4 years). FP7 Framework for Health. REACHOUT - close\u000a      to community services. €5.8 m. Miriam Taegtmeyer. (PI)\u000a    2010 - 2015 (5 years). CDC. Institutional collaboration between\u000a      LSTM and CDC and Prevention on Malaria and HIV. $1.8 m. Miriam\u000a        Taegtmeyer. (PI)\u000a    2001 - 2003 (2 years). DFID. VCT scale-up in government health\u000a      facilities in Kenya.. £320,000. Miriam Taegtmeyer (PI)\u000a    2012 - 2015 (3 years). Wellcome Trust. ES Postdoctoral Research\u000a      Fellowship - The social impact of HIV self-testing: reconstructing\u000a      knowledge and re-framing risks associated with HIV prevention. £443,455. David\u000a        G Lalloo & Robert Heyderman (PI's)\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact).\u000a    \u000a      Kenya AIDS Indicator Survey 2012, Preliminary Report,\u000a        http:\/\/nascop.or.ke\/library\/3d\/Preliminary%20Report%20for%20Kenya%20AIDS%20indicator%20survey%202012.pdf\u000a\u000a      National Guidelines for HIV Testing and Counselling in Kenya, 2nd\u000a        Edition, October 2010. http:\/\/nascop.or.ke\/library\/HTC\/National%20Guidelines%20for%20HTC%20in%20Kenya%202010.pdf\u000a\u000a      LVCT Annual Report 2011\/12 http:\/\/www.lvct.org\/images\/pdf\/annual%20report%202012-2013.pdf\u000a\u000a      Tanzania Standard Operating Procedures for HIV Testing and counselling\u000a        services.\u000a        http:\/\/www.jica.go.jp\/project\/tanzania\/001\/materials\/pdf\/vct_10.pdf\u000a\u000a      Home-based HIV counselling and testing: CDC and WHO Practical Handbook\u000a        for planning, implementing and monitoring home-based HTC in high\u000a        prevalence countries (2012)\u000a        http:\/\/www.cdc.gov\/globalaids\/Resources\/prevention\/docs\/HomeBasedHIVTestingAndCounsellingHandbook.pdf\u000a\u000a      National Quality Management Guidance Framework for HIV Testing and\u000a        Counselling in Kenya (2012)\u000a        http:\/\/nascop.or.ke\/library\/HTC\/National%20QMG%20Framework%20Final.pdf\u000a\u000a      WHO Handbook for improving HIV testing and counselling services Nov\u000a        2010. Taegtmeyer, LSTM first author http:\/\/www.who.int\/hiv\/pub\/vct\/9789241500463\/en\/index.html\u000a\u000a      Consolidated guidelines on the use of antiretroviral drugs for\u000a        treating and preventing HIV infection (2013) http:\/\/www.who.int\/hiv\/pub\/guidelines\/arv2013\/en\/\u000a\u000a      Delivering HIV results and messages for re-testing and counselling in\u000a        adults (2010) (French and English). http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241599115_eng.pdf\u000a\u000a      Report with consensus statement, on the first international symposium\u000a        on self-testing for HIV April 2013. http:\/\/apps.who.int\/iris\/bitstream\/10665\/85267\/1\/9789241505628_eng.pdf\u000a\u000a      Contact: Lead Nurse, Liverpool Centre for Sexual Health, Directorate\u000a        of Sexual Health & HIV Medicine, Royal Liverpool and Broadgreen\u000a        University Hospitals, can confirm numbers of Point of Care HIV same day\u000a        testing, now in routine clinical use since 2009.\u000a    \u000a    ","Title":"\u000a    Building and implementing a replicable model for HIV Testing and\u000a      Counselling\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Through a range of collaborations in Africa, Asia and the UK, LSTM has\u000a      led research in the development and scale-up of quality assured, complex\u000a      interventions to increase diagnosis of HIV, prevent transmission and\u000a      improve HIV outcomes especially in generalised HIV epidemic areas and\u000a      amongst adolescents and marginalised groups. LSTM staff who conducted this\u000a      body of research has included Charles Gilks (Prof 1995 - 2002), Gillian\u000a      Arthur (Clinical Lecturer 1999 - 2002), Miriam Taegtmeyer (Senior Clinical\u000a      Lecturer 2001 - present), seconded to Kenya in 2001 - 2004 where she\u000a      founded a local NGO, Liverpool Voluntary Counselling and Testing (LVCT),\u000a      David Lalloo (Dean of Clinical Sciences 1999 - present) and Sally Theobald\u000a      (Reader in Social Science 2001 - present).\u000a    HTC services using rapid diagnostic (20 minutes) HIV tests have helped\u000a      millions of people learn their HIV status, and for those testing positive,\u000a      learn about options for long term care and treatment. These rapid tests\u000a      are highly sensitive and specific, they can be performed with a\u000a      finger-prick blood sample; they do not require electricity or laboratory\u000a      machines and can be performed by a health care worker or trained lay\u000a      counsellor, making them suitable for use outside of health facilities.\u000a      Confirmation through a second rapid test can provide immediate and final\u000a      results, allowing onward referral and linkage to other services. LSTM\u000a      conducted a DfID-funded pilot project in 1999 assessing the feasibility,\u000a      acceptability and cost of integrating these newly available rapid tests\u000a      into three primary health centres in Kenya. Integration was found to be\u000a      both acceptable and feasible, to be associated with behaviour change and\u000a      significantly reduced cost. It represented a significant improvement on\u000a      previous practice where deferred results led to 47-66% of persons tested\u000a      not receiving results [1].\u000a    Research headed by Taegtmeyer during her time in LVCT, led to the first\u000a      published descriptions of translating these pilot studies into the\u000a      scale-up of HTC services in high prevalence countries, a vital component\u000a      of the global HIV response. Firstly describing expansion to 350 sites in\u000a      Kenya [2], and how this was accompanied by a robust quality assurance\u000a      system [3]. Additional operational research compared costs of mobile and\u000a      stand-alone HTC services provided to 62,173 clients [4], discussed human\u000a      resource implications and informed choices in mass media promotion for HTC\u000a      that underpinned policymaker decisions to diversify models for HTC in\u000a      Kenya from 2004 onwards as mobile services were found to be cost\u000a      effective, lay counsellors to provide accurate results through a task\u000a      shifting approach and media promotion that directly mentioned HIV positive\u000a      results to be more successful than that which did not. The demand of\u000a      services from vulnerable groups led to further studies on best approaches\u000a      to deliver HTC services for post-rape care [5], for the deaf [6] and for\u000a      men who have sex with men [7] in Africa as well as on improving linkages\u000a      to HIV care among newly diagnosed positives, for example through home\u000a      initiation of services.\u000a    Qualitative studies in the UK indicated acceptability and feasibility of\u000a      similar approaches to point of care testing for HTC, although impact data\u000a      was required before commissioners in the UK would make this part of\u000a      routine HIV services. LSTM therefore conducted a pilot study in 2009-2010\u000a      in Liverpool using similar training, community entry, supervisory methods\u000a      and radio interview outreach as done in Kenya. This brief 2009 pilot\u000a      resulted in 953 tests and 17 new positives diagnosed and linked to care\u000a      and treatment, an approach that is now funded by commissioners and\u000a      integrated at the Royal Liverpool University Hospital.\u000a    "},{"CaseStudyId":"6605","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d    Research undertaken by the Structural Biology Group at the University of\u000d      Oxford has not only had a broad impact on the programmes of several\u000d      pharmaceutical companies, and the quality of life of those living with\u000d      HIV, it also continues to inform efforts aimed at the development of\u000d      improved anti-HIV compounds 7.\u000d    Commercialisation:\u000d      The GW695634 chemical series, which became the prodrug for GW678248 has\u000d      led to the production of a powerful NNRTI active against efavirenz- and\u000d      nevirapine-resistant HIV-1 viruses. Following phase II trials undertaken\u000d      by GlaxoWellcome in 2005, this NNRTI has since been licensed to a number\u000d      of pharmaceutical companies around the world for drug development. Most\u000d      NNRTIs approved for the clinic from 2000 onwards were optimised based on\u000d      the Stuart Groups structure-based design. These include etravirine, which\u000d      was developed by Johnson & Johnson, and rilpiravine a second\u000d      generation NNRTI with an improved therapeutic index, both of which are\u000d      produced by Tibotec Pharmaceuticals 8. Pfizer, the largest\u000d      pharmaceutical company in the world, replicated the protein constructs and\u000d      crystallization methods from the University of Oxford's Stuart Group,\u000d      using similar structural information to conceive new drug targets. As a\u000d      result Pfizer produced X-ray protein structures of all of their key\u000d      anti-HIV compounds, several of which (including Lersivirine, formally\u000d      known as UK-453,061) advanced into clinical trials, but were never\u000d      licensed for therapy 9. ViiV Healthcare, a specialist HIV\u000d      pharmaceutical company driven by GlaxoSmithKline and Pfizer, is now\u000d      developing Lersivirine in Phase III trials. There are currently 2 more\u000d      NNRTIs in late-stage development; Ardea BioScience's RDEA806 and ViiV's\u000d      GSK-2248761. In addition, global pharmaceutical companies such as Gilead 10\u000d      and Merck11 have all used data from the Stuart Group in their\u000d      NNRTI drug development pipelines. At present there are 5 NNRTIs licensed\u000d      for clinical use. The anti-HIV drug sales market stood at $11.3billion in\u000d      2010 and this is projected to rise yearly by 4.6% (The Global Market for\u000d      AIDS\/HIV testing and Treatment — BCC Research 2011). Globally, there is an\u000d      increase in the use of HAART, which is reflected in these figures.\u000d    Patient Health & Quality of Life\u000d      A recent epidemiological study, evaluating current issues in the\u000d      management of HIV-infected patients, found that the availability of potent\u000d      next-generation NNRTIs might offer improved therapy for\u000d      treatment-experienced patients, particularly those with multi-resistant\u000d      HIV. The study also showed that new NNRTI drugs may reduce HIV\u000d      immunological and clinical progression, and as a result, may also reduce\u000d      treatment costs 12. Median survival time after infection with\u000d      HIV without treatment is 11 years, contrasting with survival time close to\u000d      50 years for an HIV-infected individual treated from age 20 (UNAIDS\u000d      Reference Group for Estimates, Modeling and Projections, 2006). After AIDS\u000d      diagnosis however, untreated individuals survive to 6-19 months post\u000d      diagnosis whereas with treatment many individuals recover to a stable\u000d      latent state of infection with survival rates of ~50 years, approximating\u000d      other HIV-infected individuals (Antiretroviral Therapy Cohort\u000d      Collaboration report, Lancet, 372:293-299, 2008). In a study analysing the\u000d      cost-effectiveness of first line HAART regimens in UK patient groups over\u000d      the period 1996-2006, it was shown that a regimen of 2NRTIs + NNRTI was\u000d      the most effective therapy. In comparison to the alternative regimen of\u000d      2NRTIs + PI (boosted) the study showed that the + NNRTI regimen saved\u000d      £35,194 per annum in HAART treatments 13. Effective HAART\u000d      therapy can now be shown to achieve survival rates for people living with\u000d      HIV equivalent to those in the general population 14,\u000d      emphasizing the success of new generation ART drug regimens.\u000d    Policy and Guidelines\u000d      Clinical guidelines worldwide now recommend NNRTIs in combination with\u000d      NRTIs as the first line therapy for HIV. The standard HAART combination of\u000d      two NRTIs with an NNRTI, is recommended by the World Health Organization\u000d      in their guidelines for antiretroviral therapy for HIV infection in adults\u000d      and adolescents (last revised in 2010) 15. The British HIV\u000d      Association guidelines for the treatment of HIV-infected adults with\u000d      antiretroviral therapy recommend the use of an efavirenz-based regimen as\u000d      the first line choice for patients with HIV 16. They based\u000d      this recommendation on data, which has indicated the efficacy, low\u000d      toxicity and the ease of administration of efavirenz NNRTIs, which were\u000d      developed based on the Stuart Groups structure-based design.\u000d    ","ImpactSummary":"\u000d    Highly Active Anti-Retroviral Therapy (HAART) is a combination of drugs\u000d      used to effectively control HIV infection. Since 1987 Nucleoside Reverse\u000d      Transcriptase Inhibitors (NRTIs) had been used in HAART combinations to\u000d      specifically target HIV-1 reverse transcriptase, however, resistance and\u000d      side effects soon prompted the need for an alternative. In 1998,\u000d      University of Oxford Professors David Stuart and David Stammers provided\u000d      the first detailed structural framework to facilitate the design of a\u000d      highly effective alternative class of drug, the Non-Nucleoside Reverse\u000d      Transcriptase Inhibitors (NNRTIs). NNRTIs have since been developed for\u000d      clinical use, impacting the pharmaceutical industry and profoundly\u000d      improving the quality of life of patients.\u000d    ","ImpactType":"Technological","Institution":"\u000d    The University of Oxford\u000d    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d    \u000a1. Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A. &\u000d      Steitz, T. A. Crystal structure at 3.5 A resolution of HIV-1 reverse\u000d      transcriptase complexed with an inhibitor. Science 256,\u000d      1783-1790 (1992) doi:10.1126\/science.1377403. This paper reports\u000d          the first crystal structure of HIV-1 RT heterodimer at 3.5 A complexed\u000d          with the NNRTI nevirapine, revealing features relating to the\u000d          mechanism of NNRTI inhibition.\u000d    \u000a\u000a2. Ren, J. et al. High resolution structures of HIV-1 RT from\u000d      four RT-inhibitor complexes. Nat. Struct. Biol. 2, 293-302\u000d      (1995). This was the first report from Oxford providing structural\u000d          information of four HIV-RT and NNRTI complexes useful for drug design.\u000d    \u000a\u000a3. Esnouf, R. et al. Mechanism of inhibition of HIV-1 reverse\u000d      transcriptase by non-nucleoside inhibitors. Nat. Struct. Biol. 2,\u000d      303-308 (1995). The 2.35 A structure of the unliganded HIV-1 RT\u000d          from the Oxford group defined the conformational changes required to\u000d          form the NNRTI binding site on RT. This elucidates a common mechanism\u000d          of inhibition by a diverse class of HIV-1 RT inhibitors.\u000d    \u000a\u000a4. Ren, J. et al. The structure of HIV-1 reverse transcriptase\u000d      complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure\u000d      3, 915-926 (1995). This study by the Oxford group suggests\u000d          structural constraints on the repertoire of mutations that can escape\u000d          inhibition without compromising virus viability.\u000d    \u000a\u000a5. Ren, J. et al. Structural mechanisms of drug resistance for\u000d      mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the\u000d      improved resilience of second generation non-nucleoside inhibitors. J.\u000d        Mol. Biol. 312, 795-805 (2001). The crystal\u000d          structures reported from the Oxford group revealed details of\u000d          resistance mechanisms that could be used to formulate general rules\u000d          for drug design of novel inhibitors of HIV-1 RT.\u000d    \u000a\u000a6. Hopkins, A. L. et al. Complexes of HIV-1 reverse transcriptase\u000d      with inhibitors of the HEPT series reveal conformational changes relevant\u000d      to the design of potent non-nucleoside inhibitors. J. Med. Chem. 39,\u000d      1589-1600 (1996). doi: 10.1021\/jm960056x  This paper reports the\u000d          structures of HIV-1 RT with inhibitors of the same class. Details on\u000d          their binding suggested a strategy for designing inhibitors that\u000d          require more than one RT mutation to diminish inhibitor efficacy.\u000d    \u000aThis research was funded by the Medical Research Council's AIDS Directed\u000d      Programme, with Glaxo Wellcome.\u000d    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000d    \u000d      Ren, J. et al. Structural basis for the improved drug resistance\u000d        profile of new generation benzophenone non-nucleoside HIV-1 reverse\u000d        transcriptase inhibitors. J. Med. Chem. 51, 5000-5008 (2008) doi:\u000d        10.1021\/jm8004493\u000d        This paper provides a proof of principle for drug design based on\u000d            the structural features of benzophenone inhibitor binding to HIV-1.\u000a\u000d      Das, K. et al. Roles of conformational and positional adaptability in\u000d        structure-based design of TMC125-R165335 (etravirine) and related\u000d        non-nucleoside reverse transcriptase inhibitors that are highly potent\u000d        and effective against wild-type and drug-resistant HIV-1 variants. J.\u000d        Med. Chem. 47, 2550-2560 (2004) doi: 10.1021\/jm030558s This paper\u000d            cites the elasticity of the NNRTI binding site, resistance mutations\u000d            Tyr 181 and Tyr188 and the structure data from Oxford of HIV-1 RT in\u000d            complex with many inhibitors as key drug design features for novel\u000d            RT inhibitors.\u000a\u000d      Pfizer A Phase 2B Multicenter, Randomized, Comparative Trial Of\u000d        UK-453,061 Versus Etravirine In Combination With Darunavir\/Ritonavir And\u000d        A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of\u000d        Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of\u000d        NNRTI Resistant HIV-1 — Full Text View In: ClinicalTrials.gov Bethesda\u000d        (MD) National Library of Medicine (US) 2000- (Accessed 2013) Available\u000d        at\u000d        http:\/\/clinicaltrials.gov\/show\/NCT00823979\u000d        NLM Identifier: NCT00823979\u000d        This 96 week clinical study (reported August 2012) compares the\u000d            efficacy of lersivirine (UK-453,061) vs etravirine. Although the\u000d            drugs were not ultimately licensed for the clinic, the method of\u000d            structure-based design (developed by the Stuart group) is key to the\u000d            development of these new drugs.\u000a\u000d      Lansdon, E. B. et al. Crystal structures of HIV-1 reverse\u000d        transcriptase with etravirine (TMC125) and rilpivirine (TMC278):\u000d        implications for drug design. J. Med. Chem. 53, 42954299 (2010) doi:\u000d        10.1021\/jm1002233.\u000d        This study recognises the flexible properties in some NNRTI\u000d            structures and the allosteric mechanism of inhibition in the choice\u000d            of pipeline drug targets.\u000a\u000d      Gomez, R. et al. Design and synthesis of pyridone inhibitors of\u000d        non-nucleoside reverse transcriptase. Bioorg. Med. Chem. Lett. 21,\u000d        7344-7350 (2011) doi: 10.1016\/j.bmcl.2011.10.027.\u000d        This paper from Merck describes the design and structural\u000d            characterisation of the pyridone class of NNRTIs. The drug design\u000d            rationale utilised a combination of elements derived from the Oxford\u000d            work.\u000a\u000d      Boyd, M. A. & Hill, A. M. Clinical management of\u000d        treatment-experienced, HIV\/AIDS patients in the combination\u000d        antiretroviral therapy era. Pharmacoeconomics 28 Suppl 1, 17-34 (2010)\u000d        doi: 10.2165\/11587420-000000000-00000.\u000d        This paper reports the improved efficacy of HAART that includes\u000d            next-generation components (PIs, NNRTIs, integrase and\u000d            entry-inhibitors) particularly for patients with existing resistance\u000d            mutations.\u000a\u000d      Beck, E. J. et al. Cost-effectiveness of early treatment with\u000d        first-line NNRTI-based HAART regimens in the UK, 1996-2006. PLoS ONE 6,\u000d        e20200 (2011) doi: 10.1371\/journal.pone.0020200.\u000d        This retrospective study of 7600 people living with HIV in the UK\u000d            analysed the clinical and health economic benefits of 2NRTI + NNRTI\u000d            therapy vs 2NRTI + PI therapy for first-, second- or third-line\u000d            treatment.\u000a\u000d      Obel, N. et al. Impact of non-HIV and HIV risk factors on survival in\u000d        HIV-infected patients on HAART: a population-based nationwide cohort\u000d        study. PLoS ONE 6, e22698 (2011) doi: 10.1371\/journal.pone.0022698.\u000d        This recent study shows that for people living with HIV with no\u000d            other risk factors, effective HAART therapy leads to a mortality\u000d            rate equivalent to that of the general population with no risk\u000d            factors.\u000a\u000d      WHO HIV\/AIDS Programme. Antiretroviral therapy for HIV infection in\u000d        adults and adolescents — recommendations for a public health approach.\u000d        (Accessed 2013). Available at\u000d        http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241599764_eng.pdf\u000d        These WHO HIV\/AIDS Programme guidelines 2010 recommend efavirenz\u000d            or nevirapine as NNRTIs to be added to first-line regimens for\u000d            adults and adolescents, with 2 NRTIs + NNRTI as the preferential\u000d            approach.\u000a\u000d      British HIV Association guidelines for the treatment of HIV-1-positive\u000d        adults with antiretroviral therapy 2012. Doi\u000d        10.1111\/j.1468-1293.2012.01029_1.x. Accessed at\u000d        http:\/\/www.bhiva.org\/documents\/Guidelines\/Treatment\/2012\/hiv1029_2.pdf\u000d        Guidelines recommending the use of an efavirenz-based regimen as\u000d            the first line choice for patients with HIV16. This recommendation\u000d            was based on data developed using the Stuart Group's structure-based\u000d            design.\u000a\u000d    \u000d    ","Title":"\u000d    IMPROVING HIV TREATMENT\u000d    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    For HIV to replicate, it must first convert its RNA genome into DNA. This\u000d      is achieved by the reverse transcriptase (RT) enzyme, which is encoded by\u000d      the HIV genome. The resulting DNA serves as a template for the creation of\u000d      more HIV RNA genomes, which can then be assembled into new viral\u000d      offspring. Reverse transcription is particularly vulnerable to errors.\u000d      Over many generations of viral replication, this leads to high genetic\u000d      diversity, which can in turn lead to drug resistance.\u000d    Nucleoside Reverse Transcriptase Inhibitors (NRTIs) were the first\u000d      antiretroviral drugs developed to control AIDS, but because NRTIs were\u000d      used as monotherapy, HIV soon developed resistance to the drug. Plagued by\u000d      resistance and a number of unpleasant side effects, including fat\u000d      deposition and nausea, the need for an alternative therapy quickly became\u000d      a priority for HIV researchers. Discovered serendipitously in 1989,\u000d      Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) were extremely\u000d      susceptible to resistance via single amino acid changes in HIV-1 RT. The\u000d      mechanism of NNRTI action and the nature of its interactions with the\u000d      target, however, remained unknown. After the crystal structure of HIV-1 RT\u000d      was published in 1992 1, work by the University of Oxford's\u000d      David Stuart refined this model by producing a series of papers in 1995\u000d      describing the first high-resolution structures of NNRTIs and HIV-RT and\u000d      other data, which became the basis for structure-based drug design 2-5.\u000d      The structure of RT-NNRTI complexes identified structural features, which\u000d      correlated with potency, providing an explanation for the mode of action\u000d      of these compounds 3.\u000d    In 1996 Professor David Stammers joined Professor Stuart and his team at\u000d      the University of Oxford. Professor Stammers' spin off company, Arrow\u000d      Therapeutics, assisted the group in delving further into the development\u000d      of NNRTI drug therapy. They then shared this information with\u000d      GlaxoWellcome Pharmaceuticals (now GlaxoSmithKline). The Oxford group\u000d      provided a database of atomic information to GlaxoWellcome, prior to the\u000d      intellectual property becoming public domain, enabling the early\u000d      development of NNRTI drug therapy. This atomic information still comprises\u000d      over 50% of the available data on NNRTIs, while collaborative studies\u000d      involving the University of Oxford's structural biologists have also\u000d      provided detailed explanations for the mechanisms leading to drug\u000d      resistance 4,5. Continuing this collaboration with industry,\u000d      specific chemical series were devised which were outstandingly refractory\u000d      to the development of resistance 6, one of which (GW695634)\u000d      entered phase II clinical trials in 2005. The GW695634 chemical series\u000d      generated the prodrug (a compound modified for active use in the body) of\u000d      GW678248, an NNRTI with potent antiviral activity against efavirenz- and\u000d      nevirapine-resistant HIV-1 viruses. This has led to the development of a\u000d      second-generation of NNRTIs for use in HAART drug combinations.\u000d    "},{"CaseStudyId":"8316","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1168579","Name":"Pakistan"}],"Funders":[],"ImpactDetails":"\u000a    Our research has identified 30 genetic mutations associated with a range\u000a      of inherited disorders\u000a      and enabled us to develop definitive diagnostic tests which have\u000a      subsequently been made\u000a      available by laboratories around the world. Every novel molecular defect\u000a      identified opens up new\u000a      avenues of research for what can be previously undefined or little known\u000a      conditions.\u000a    Impact on health and welfare\u000a    Many thousands of patients have now been tested for mutations in the\u000a      disease genes we have\u000a      identified. We sought to quantify this by contacting directly the labs\u000a      offering tests.\u000a    In total 353 laboratories offering molecular genetics testing are listed\u000a      on the Orphanet web site,\u000a      which is primarily European, while the Genetests website lists over 600\u000a      such laboratories, with a\u000a      greater emphasis on laboratories from the US and elsewhere (data confirmed\u000a      19\/9\/13). There is\u000a      little overlap, with laboratories tending to list on one site or the\u000a      other, and neither list is\u000a      comprehensive. It therefore seems likely that over 1000 laboratories\u000a      around the world offer some\u000a      form of genetic testing. Of these, 268 now offer a screen for GJB2\u000a      (Connexin 26, ref 2). We\u000a      contacted these and 15 responded, including 4 UK, 2 US and 9 European\u000a      laboratories, stating that\u000a      they carry out a total of around 1270 GJB2 tests per year, with\u000a      figures based largely on 2012 [A].\u000a      Recognising that this is a small sample, it does allow us to infer that\u000a      perhaps in the order of 20,000\u000a      GJB2 screens may have been carried out in 2012 internationally, and our\u000a      survey suggests that\u000a      GJB2 screening is increasing [A]. From the same sources above we\u000a      identified 37 laboratories\u000a      providing tests for the other genes noted.\u000a    A definitive diagnosis can be essential for patients who put a premium on\u000a      knowing the cause of\u000a      their condition. It can also have a substantial impact on their future\u000a      care. More than a half of all\u000a      patients with a genetic disease used to wait more than a year for a\u000a      diagnosis, and are frequently\u000a      given incorrect diagnoses [B]. The lack of an accurate test can mean\u000a      fragmented care with\u000a      different specialities and often unnecessary invasive clinical procedures\u000a      [B]. Carrier and prenatal\u000a      testing can hugely reduce the impact on families carrying a defective gene\u000a      by allowing them to\u000a      make informed reproductive choices [B]. A clear genetic diagnosis\u000a      establishes the risks in future\u000a      pregnancies and allows prenatal diagnosis. This is particularly important\u000a      for disorders which are\u000a      fatal\u000a    For many of the genetic conditions for which we have identified the\u000a      cause, genetic diagnosis\u000a      establishes the likely natural history and enables early intervention\u000a      improve the outcome for the\u000a      patient. Important examples include close surveillance for the seizure\u000a      disorders, hearing loss and\u000a      renal failure which are part of East syndrome (KCNJ10) [C]. Early\u000a      identification of children with\u000a      ASPM (microcephaly) mutations established the specific diagnosis in a\u000a      syndrome with a wide\u000a      range of different causes [D]. Deafness is one of the most common major\u000a      abnormalities present at\u000a      birth and a child with undetected hearing loss is at risk of failing to\u000a      develop normal speech and\u000a      language [E]. Presymptomatic identification of children with inherited\u000a      hearing loss, only possible\u000a      through genetic testing in high-risk families, permits the initiation of\u000a      treatment, notably the fitting of\u000a      hearing aids, at a very early age, significantly improving outcome [E].\u000a    The conditions for which we have identified a genetic cause are\u000a      relatively rare. For example\u000a      around 1 in 4000 individuals are affected by autosomal recessive deafness,\u000a      primary microcephaly,\u000a      Aicardi-Goutiere syndrome, and Joubert\/Meckel syndromes. The burden of\u000a      congenital disease in\u000a      some populations and families is approximately doubled due to the practice\u000a      of consanguineous\u000a      marriage. Many characteristics of these conditions are mimicked by\u000a      non—genetic conditions, so\u000a      despite being rare, there are many patients for whom a test provides\u000a      crucial information. For\u000a      example 800 children are born every year in the UK with congenital hearing\u000a      loss, about 25% of\u000a      which is due to mutations in Cx26, but all warrant testing. Microcephaly\u000a      is the presenting complaint\u000a      of a wide variety of neurological disorders but all such cases should be\u000a      tested for mutations in\u000a      ASPM and MCPH1 as the commonest causes of primary microcephaly [D].\u000a      Aicardi-Goutiere\u000a      syndrome can only be distinguished from congenital TORCH infection by\u000a      genetic testing, obviating\u000a      complex invasive clinical tests of doubtful value [F].\u000a    Impact on public policy and services\u000a    In recent years we have been at the forefront in the utilisation of Next\u000a      Generation Sequencing\u000a      (NGS) to identify disease-causing variants. Due to our close links with\u000a      the Yorkshire Regional\u000a      Genetics Service we have been able to facilitate the introduction of NGS\u000a      into the NHS laboratory,\u000a      this is the first NHS laboratory in which NGS analysis has been accredited\u000a      for service provision [G].\u000a    It has always been a key goal of our work to make our research freely\u000a      available. Around 20 years\u000a      ago, efforts were made by US researchers to patent gene sequences to limit\u000a      the widespread\u000a      adoption of clinical testing. We were among the majority of UK and\u000a      European researchers who\u000a      rejected this policy in order to provide genetic testing to as many\u000a      patients as possible. The\u000a      software and data available on our website ( http:\/\/dna.leeds.ac.uk\/)\u000a      is accessed by laboratories\u000a      and researchers around the world. From our website there have been a total\u000a      of 6809 downloads\u000a      from unique IP addresses.\u000a    Impact on commerce\u000a    Around 300 laboratories across Europe, including the UK, are using the\u000a      tests for the genetic\u000a      abnormalities we have identified [A], with many thousands of patients\u000a      offered a vital diagnosis and\u000a      subsequent management for their condition, as outlined above. Diagnostic\u000a      tests we identified are\u000a      also provided in the US, and Australia.\u000a    The original discoveries we have made have been with the help of the\u000a      local Pakistani heritage\u000a      community — a group which has traditionally found it difficult to benefit\u000a      fully from research projects\u000a      which often fail to address their unique medical needs. We have provided\u000a      genetic tests directly to\u000a      families in Pakistan via their healthcare providers. We have provided\u000a      clinical and academic training\u000a      for genetic counselling staff in Pakistan [H].\u000a    ","ImpactSummary":"\u000a    Congenital disorders are causes of major morbidity and mortality\u000a      worldwide. Using autozygosity\u000a      mapping in a local community of Pakistani origin who have high rates of\u000a      inherited recessive\u000a      disorders due to consanguineous unions, we have identified more than 30\u000a      novel disease genes.\u000a      Isolating these previously unknown molecular defects has enabled us to\u000a      develop key diagnostic\u000a      assays, subsequently provided by clinical laboratories globally. Our work\u000a      has provided thousands\u000a      of patients with a definitive diagnosis, removing the need for complex\u000a      clinical testing. Those\u000a      affected can be offered focused management and early therapeutic\u000a      intervention as well as carrier\u000a      and prenatal testing for themselves and family members. Our findings also\u000a      provide new research\u000a      opportunities for previously undefined diseases.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Mueller RF, Bishop DT. Autozygosity mapping, complex consanguinity,\u000a      and autosomal\u000a      recessive disorders. J Med Genet 1993; 30: 798-99.\u000a    \u000a\u000a2) Lench N, Houseman M, Newton V, Van Camp G, and Mueller R. Connexin-26\u000a      mutations in\u000a      sporadic non-syndromal sensorineural deafness. Lancet 1998; 351: 415.\u000a    \u000a\u000a3) Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM,\u000a      Springell K, Mahadevan\u000a      M, Crow YJ, Markham AF, et al. ASPM is a major determinant of cerebral\u000a      cortical size. Nature\u000a      Genetics 2002; 32: 316-20.\u000a    \u000a\u000a4) Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN,\u000a      van Bokhoven H,\u000a      Brunner HG, Hamel BC, et al. Mutations in the gene encoding the 3'-5' DNA\u000a      exonuclease\u000a      TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nature Genetics\u000a      2006; 38: 917-\u000a      20.\u000a    \u000a\u000a5) Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold\u000a      M, Tobin J,\u000a      Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross\u000a      JH, van't Hoff\u000a      W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M,\u000a      Dillon MJ, Heitzmann D,\u000a      Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta\u000a      R. Epilepsy,\u000a      ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl\u000a      J Med 2009; 360:\u000a      1960-70.\u000a    \u000a\u000a6) Sheridan E, Wright J, Small N, Corry PC, Oddie S, Whibley C, Petherick\u000a      ES,Malik T, Pawson\u000a      N, McKinney PA, Parslow RC. Risk factors for congenital anomalyin a\u000a      multiethnic birth cohort:\u000a      an analysis of the Born in Bradford study. Lancet.2013 Jul 3. doi:pii:\u000a      S0140-6736(13)61132-0.\u000a      10.1016\/S0140-6736(13)61132-0.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    [A] Collated information from genetic testing laboratories worldwide,\u000a      detailing numbers of test\u000a      carried out, significance and impact. Orphanet Portal. European reference\u000a      portal for information on\u000a      rare diseases and orphan drugs for all audiences. http:\/\/www.orpha.net\/consor\/cgi-bin\/index.php?lng=EN\u000a    UK Genetic Testing Network (UKGTN). Body which advises the NHS on genetic\u000a      testing.\u000a      http:\/\/www.ukgtn.nhs.uk\/gtn\/Home\u000a    [B] Limb L, Nutt S, Sen A. UK RD. Experiences of Rare Diseases: An\u000a      Insight From Patients and\u000a      Families 2010. http:\/\/www.raredisease.org.uk\/documents\/RDUK-Family-Report.pdf\u000a    [C] Cross JH, Arora R, Heckemann RA, Gunny R, Chong K, Carr L, Baldeweg\u000a      T, Differ AM, Lench\u000a      N, Varadkar S, Sirimanna T, Wassmer E, Hulton SA, Ognjanovic M, Ramesh V,\u000a      Feather S, Kleta\u000a      R, Hammers A, Bockenhauer D. Neurological features of epilepsy, ataxia,\u000a      sensorineural deafness,\u000a      tubulopathy syndrome. Dev Med Child Neurol. 2013 Sep;55(9):846-56.\u000a    [D] Kaindl AM, Titomanlio L, et al. Primary Autosomal Recessive\u000a      Microcephaly. 2009 Sep 1. In:\u000a      Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet].\u000a      Seattle (WA): University\u000a      of Washington, Seattle; 1993-2013. Available from: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK9587\/\u000a    and Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013\u000a      Sep;98(9):707-13.\u000a    [E] Joint Committee on Infant Hearing of the American Academy of\u000a      Pediatrics, Muse C, Harrison J,\u000a      Yoshinaga-Itano C, Grimes A, Brookhouser PE, Epstein S, Buchman C, Mehl A,\u000a      Vohr B, Moeller\u000a      MP, Martin P, Benedict BS, Scoggins B, Crace J, King M, Sette A, Martin B.\u000a      Supplement to the\u000a      JCIH 2007 position statement: principles and guidelines for early\u000a      intervention after confirmation\u000a      that a child is deaf or hard of hearing. Pediatrics. 2013\u000a      Apr;131(4):e1324-49\u000a    and Markides A. Age at fitting of hearing aids and speech\u000a      intelligibility. Br J Audiol 1986; 20: 165-\u000a      67.\u000a    [F] Aicardi J, Crow YJ, Stephenson JBP. Aicardi-Goutières Syndrome. 2005\u000a      Jun 29 [Updated 2012\u000a      Mar 1]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™\u000a      [Internet]. Seattle (WA):\u000a      University of Washington, Seattle; 1993-2013. Available from:\u000a      http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1475\/\u000a    [G] Clinical Pathology Accreditation for the Yorkshire Regional DNA\u000a      Laboratory.\u000a    [H] Bryant LD, Ahmed S, Ahmed M, Jafri H, Raashid Y. 'All is done by\u000a      Allah'. Understandings of\u000a      Down syndrome and prenatal testing in Pakistan. Soc Sci Med. 2011\u000a      Apr;72(8):1393-9\u000a    [I] Letters of corroboration, confirming the impact of Leeds research on\u000a      development of diagnostic\u000a      tests for recessive diseases and consequent improvements for patients and\u000a      families (Chair, British\u000a      Society for Genetic Medicine; Assistant Professor of Pathology, Harvard\u000a      Medical School; Director,\u000a      Genetic Alliance UK)\u000a    \u000a    ","Title":"\u000a    Case Study 8. Transforming the diagnosis and clinical management of\u000a      autosomal recessive\u000a      disease.\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Congenital disorders, while individually rare, are collectively very\u000a      common. The EU estimates as\u000a      many as 6% of the population are affected. Around 75% of these disorders\u000a      affect children and 30%\u000a      of such patients die before the age of five.\u000a    An increased prevalence of recessive disorders is a major local\u000a      healthcare burden in our local\u000a      Pakistani community but has afforded us a unique research opportunity. We\u000a      use autozygosity\u000a      mapping, a technique that enables the identification of the chromosomal\u000a      region that harbours the\u000a      disease-causing gene, as outlined by RF Mueller (Professor of\u000a      Clinical Genetics, Leeds 1995-\u000a      2002) and DT Bishop (Professor of Genetic Epidemiology, Leeds\u000a      1989-present) (1). Applying this\u000a      approach to our local clinical resource, the Yorkshire Regional Genetics\u000a      Service, has resulted in\u000a      the identification of more than 30 novel disease genes, for wide-ranging\u000a      disorders including\u000a      deafness, microcephaly, ciliopathies such as Joubert syndrome and several\u000a      metabolic conditions.\u000a    The techniques we have pioneered generate large and complex datasets\u000a      which in isolation provide\u000a      little understanding. In order to analyse these datasets, Dr I Carr\u000a      (Senior Research Fellow, Leeds\u000a      1999-present) has developed key software packages, which are freely\u000a      available from our website\u000a      (http:\/\/autozygosity.org\/).\u000a    All our research is embedded within the clinical community caring for\u000a      patients with inherited\u000a      disorders and at present led by EG Sheridan (Senior Lecturer in\u000a      Clinical Genetics, Leeds 2006-\u000a      present) and DT Bonthron (Professor of Molecular Medicine, Leeds\u000a      2000-present ) who both hold\u000a      honorary clinical contracts with the Yorkshire Regional Genetics Service.\u000a      Of the 30 previously\u000a      unidentified disease genes we have isolated to date, there are four key\u000a      areas of particular note.\u000a    1995-2002 — Deafness\u000a    Mueller led research to identify mutations in the connexion 26\u000a      (Cx26) gene as the commonest\u000a      genetic cause of deafness, and clarified the role of Cx26 in a range of\u000a      different types of deafness\u000a      (2). We also developed guidelines for the establishment of genetic\u000a      services for the deaf community\u000a      [A].\u000a    1998-2005 — Microcephaly\u000a    AF Markham (Professor of Medicine, Leeds 1990- ) and CG Woods\u000a      (Senior Lecturer in Clinical\u000a      Genetics, Leeds 1998-2005) carried out work on the genetic causes of the\u000a      development of\u000a      pathologically small brains. This included the identification of ASPM and\u000a      MCPH1 as the\u000a      commonest causes of the condition (3).\u000a    2001-present — Intracranial calcification\u000a    YJ Crow (Senior Lecturer in Clinical Genetics, Leeds 2001-2008)\u000a      and Bonthron identified\u000a      mutations in the TREX1 gene in patients with Aicardi-Goutieres syndrome —\u000a      the first of three genes\u000a      to be identified in this group of disorders (4).\u000a    2006-present — Abnormalities in renal tubular function\u000a    Sheridan was joint senior investigator in the detection of a\u000a      fundamental protein involved in renal\u000a      fluid handling in a study, which also defined a novel disorder; EAST\u000a      syndrome. The KCNJ10 gene\u000a      was found to encode a potassium channel expressed in the brain, inner ear,\u000a      and kidney, the\u000a      existence of which had been postulated for 50 years prior to the work (5).\u000a    The 2006 report by the Chief Medical Officer raised the issue of unknown\u000a      healthcare burden which\u000a      results from disorders of this sort. Recent research by Sheridan\u000a      has confirmed that consanguinity\u000a      doubles the risk of congenital anomalies (6). This is an important global\u000a      concern as more than one\u000a      billion people live in societies with consanguinity rates >20%.\u000a    "},{"CaseStudyId":"12327","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3017382","Name":"France"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Patients with venous or arterial thrombosis or with prosthetic metal\u000d\u000a      heart valves are treated with warfarin anticoagulation. Approximately\u000d\u000a      600,000-1,200,000 patients are on warfarin in the UK at any time and\u000d\u000a      6,000-12,000 each year are likely to require emergency reversal of their\u000d\u000a      anticoagulation due to life-threatening bleeding. At the time of our\u000d\u000a      original research most patients with major bleeding on warfarin were\u000d\u000a      treated with fresh frozen plasma (FFP), whilst now the vast majority are\u000d\u000a      treated with prothrombin complex concentrate (PCC), based on our research\u000d\u000a      findings.\u000d\u000a    Impact on national and international clinical guidelines\u000d\u000a    National and international guidelines now recommend the use of PCC for\u000d\u000a      the management of life-threatening bleeding on warfarin.\u000d\u000a    A. The current UK guideline on the use of FFP published by the British\u000d\u000a      Committee for Standards in Haematology (BCSH) states that for reversal of\u000d\u000a      warfarin \"FFP has only a partial effect, is not the optimal treatment, and\u000d\u000a      should never be used for the reversal of Warfarin in the absence of severe\u000d\u000a      bleeding\". The evidence supporting this statement in the guideline is our\u000d\u000a      publication of 1997 (R1). (S1)\u000d\u000a    B. The current UK guideline on the management of patients on warfarin\u000d\u000a      published by the BCSH recommends \"All hospitals managing patients on\u000d\u000a      warfarin should stock a licensed four factor prothrombin complex\u000d\u000a      concentrate. Emergency anticoagulation reversal in patients with major\u000d\u000a      bleeding should be with 25-50µ\/kg for factor prothrombin complex\u000d\u000a      concentrate....... Fresh frozen plasma produces suboptimal anticoagulation\u000d\u000a      reversal and should only be used if prothrombin complex concentrate is not\u000d\u000a      available.\" This guideline lists our 1997 reference (R1) as showing\u000d\u000a      \"Complete and rapid correction of the coagulopathy is more rapidly\u000d\u000a      achieved with PCC than FFP Makris et al 1997\" (S2)\u000d\u000a    C. The use of PCC rather than FFP in patients on warfarin is also\u000d\u000a      recommended by a 2013 guideline on the management of bleeding in patients\u000d\u000a      on antithrombotic agents (S3). This is the BCSH guideline on\u000d\u000a      anticoagulation reversal for all the different anticoagulant drugs.\u000d\u000a    D. In the UK, at the Dudley Group of Hospitals, the policy for reversal\u000d\u000a      of warfarin in patients with intracranial or major bleeding recommends use\u000d\u000a      of PCC and quotes our study R1 to support this recommendation (S4)\u000d\u000a    E. The French national guidelines on the management of major bleeding in\u000d\u000a      patients on vitamin K antagonists, such as warfarin, recommend the use of\u000d\u000a      PCC rather than FFP and quote our study R1 as demonstrating the\u000d\u000a      superiority of PCC over FFP (S5)\u000d\u000a    F. The Italian national guidelines produced by the Italian Society for\u000d\u000a      Transfusion Medicine and Immunohaematology working party also recommend\u000d\u000a      the use of PCC over FFP for treatment of major bleeding on vitamin K\u000d\u000a      antagonists and use all 3 of our studies R1, R2 and R3 to support this\u000d\u000a      recommendation (S6).\u000d\u000a    Impacts on the economy and commerce\u000d\u000a    PCCs were introduced 40 years ago to treat haemophilia B. Initially we\u000d\u000a      used them off-label in our research to treat warfarin related bleeding.\u000d\u000a      PCCs are no longer used to treat haemophilia B.\u000d\u000a    In the last 7 years, however, two international pharmaceutical companies,\u000d\u000a      Octapharma and CSL Behring, have brought concentrates to the market for\u000d\u000a      use in emergency reversal of warfarin (Octaplex and Beriplex\u000d\u000a      respectively). Beriplex, the product licensed in the UK in 2007, was the\u000d\u000a      product first shown by us in 2002 (R3) to be safe and effective. CSL\u000d\u000a      Behring referenced our publications (R1, R3) in the clinical section of\u000d\u000a      their license dossier submitted to the European Medicines Agency (S7).\u000d\u000a    In the Australian Public Assessment Report for Human Prothrombin Complex\u000d\u000a      Concentrate it is stated that our publication R3 was included in the\u000d\u000a      Beriplex license application as supportive evidence (S8).\u000d\u000a    Octapharma and CSL Behring have sold more than 20 million units of\u000d\u000a      Octaplex\/Beriplex in the UK in 2012 (S9).\u000d\u000a    In 2012 CSL Behring has sold in excess of 300 million units of Beriplex\u000d\u000a      internationally (S7). In April 2013, the US Food and Drug Administration\u000d\u000a      approved KCentra™, the first US FDA-approved 4- Factor prothrombin complex\u000d\u000a      concentrate for urgent warfarin reversal in patients with acute bleeding,\u000d\u000a      This is the US name for Beriplex and has enabled CSL Behring to access a\u000d\u000a      new and very large market with the concentrate (S10).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    As a result of University of Sheffield research in 1995-2002, a new gold\u000d\u000a      standard treatment for major bleeding on warfarin has been established,\u000d\u000a      ensuring the more effective treatment of tens of thousands of patients\u000d\u000a      requiring emergency anticoagulation reversal each year in the UK alone.\u000d\u000a      The treatment, using prothrombin complex concentrate (PCC) was\u000d\u000a      demonstrated to be superior to fresh frozen plasma (FFP), the standard\u000d\u000a      alternative at the time, and two PCCs have now been licensed for this\u000d\u000a      indication in the UK.\u000d\u000a    UK and international guidelines now recommend PCC over FFP.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Sheffield\u000d\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Authors working in Sheffield at the time are indicated in bold\u000d\u000a    \u000aR1) Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston\u000a        FE. (1997). Emergency oral anticoagulant reversal: the relative\u000d\u000a      efficacy of infusions of fresh frozen plasma and clotting factor\u000d\u000a      concentrate on correction of the coagulopathy. Thrombosis and Haemostasis.\u000d\u000a      77:477-480\u000d\u000a    \u000aThe key paper that changed the management of reversal of warfarin\u000d\u000a      anticoagulation was carried out in Sheffield and published in 1997. PubMed\u000d\u000a      ID: 9065997\u000d\u000a      [Scopus 275 citations]\u000d\u000a    \u000aR2) Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE.\u000d\u000a      (2001). A comparison of the efficacy of response to oral and intravenous\u000d\u000a      vitamin K in reversal of over-anticoagulation with warfarin. British\u000d\u000a      Journal of Haematology. 115: 145-149\u000d\u000a    \u000aAnother publication from Sheffield, Aberdeen and Cambridge demonstrated\u000d\u000a      that intravenous vitamin K was superior to oral vitamin K for the\u000d\u000a      emergency reversal of warfarin. [Scopus 82 citations]\u000d\u000a    \u000aR3) Preston FE, Laidlaw SL, Sampson B, Kitchen S. (2002). Rapid\u000d\u000a      reversal of oral anticoagulation with warfarin by a prothrombin complex\u000d\u000a      concentrate (Beriplex): efficacy and safety in 42 patients. British\u000d\u000a      Journal of Haematology. 116:619-624\u000d\u000a    \u000aA third publication demonstrated that a PCC called Beriplex used in\u000d\u000a      haemophilia was highly effective for the emergency reversal of warfarin.\u000d\u000a      [Scopus 125 citations].\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    (S1) O'Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for\u000d\u000a      the use of fresh frozen plasma, cryoprecipitate and cryosupernatant.\u000d\u000a      British Journal in Haematology 2004; 126: 11-28.\u000d\u000a    (S2) Keeling D, Baglin T, Tait C et al. Guidelines on oral\u000d\u000a      anticoagulation with warfarin - fourth edition. British Journal of\u000d\u000a      Haematology 2011; 154:311-324\u000d\u000a    (S3) Makris M, van Veen JJ, Tait CR, Mumford AD, Laffan M. Guideline on\u000d\u000a      the management of bleeding in patients on antithrombotic agents. British\u000d\u000a      Journal of Haematology 2013; 160:35-46\u000d\u000a    (S4) http:\/\/www.dwmh.nhs.uk\/sections\/publications\/documents\/FOI28824268083.pdf\u000d\u000a    (S5) Pernod G, Godier A, Gozalo C et al. French clinical practise\u000d\u000a      guidelines on the management of patients on vitamin K antagonists in at\u000d\u000a      risk situations (overdose, risk of bleeding, and active bleeding).\u000d\u000a      Thrombosis Research 2010; 126:e167-e174\u000d\u000a    (S6) Liumbruno G, Bennordello F, Lattanzio A, et al. Recommendations for\u000d\u000a      the use of antithrombin concentrates and prothrombin complex concentrates.\u000d\u000a      Blood Transfusion 2009; 7:325-334\u000d\u000a    (S7) Email from Head of Commercial Operations CSL Behring, on 11th June\u000d\u000a      2013 confirms use of Sheffield research findings in EMA application.\u000d\u000a    (S8) http:\/\/www.tga.gov.au\/pdf\/auspar\/auspar-beriplex.pdf\u000d\u000a    (S9) Email from Director of Serious Hazards of Transfusion (SHOT) on 11th\u000d\u000a      June 2013 confirms sales data.\u000d\u000a    (S10) http:\/\/www.csl.com.au\/docs\/600\/594\/CSL_FINS_2013,1.pdf\u000d\u000a      Page 43 of the CSL financial report corroborates availability of Beriplex\u000d\u000a      in the US, under the name KCentra. \u000d\u000a    ","Title":"\u000d\u000a    A new gold standard treatment for the emergency correction of\u000d\u000a      warfarin-induced coagulopathy\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2638077","Name":"Sheffield"},{"GeoNamesId":"2650839","Name":"Dudley"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Patients who experience venous thrombosis such as deep vein thrombosis\u000d\u000a      and pulmonary embolism, those with atrial fibrillation or who have metal\u000d\u000a      heart valves are anticoagulated with vitamin K antagonists, which in the\u000d\u000a      UK is primarily with warfarin. Approximately 1-2% of the population are on\u000d\u000a      warfarin at any time. Whilst warfarin is highly effective in preventing\u000d\u000a      thrombosis, its main adverse effect is bleeding. The annual risk of\u000d\u000a      bleeding is 1% for major bleeding requiring hospital admission and 0.3%\u000d\u000a      for fatal bleeding. Projected for the UK population over 10,000\u000d\u000a      individuals experience life threatening bleeding annually and in 3,000\u000d\u000a      cases this is fatal.\u000d\u000a    Up to the late 1990s the emergency management of anticoagulation reversal\u000d\u000a      was using fresh frozen plasma (FFP) which was widely available in all UK\u000d\u000a      hospitals. Researchers in the Department of Cardiovascular Science at the\u000d\u000a      University of Sheffield, led by Prof Michael Makris (1991 to present) and\u000d\u000a      Prof Eric Preston (NHS Consultant, Honorary Professor University of\u000d\u000a      Sheffield, now retired) became concerned that the standard treatment with\u000d\u000a      FFP was ineffective or poorly effective and set out to investigate whether\u000d\u000a      an alternative treatment with concentrates (used to treat patients with\u000d\u000a      haemophilia B) was superior. The research confirmed the poor efficacy of\u000d\u000a      FFP and demonstrated the superiority of prothrombin complex concentrate\u000d\u000a      (PCC) leading to a change in clinical practice in the management of\u000d\u000a      life-threatening bleeding in patients on warfarin. It was also\u000d\u000a      demonstrated that the vitamin K that was co-administered had to be given\u000d\u000a      intravenously for maximum efficacy.\u000d\u000a    In the first study (R1), the effect of FFP and PCC in patients with major\u000d\u000a      bleeding on warfarin who required emergency reversal was assessed. All 41\u000d\u000a      patients were treated in Sheffield at the Royal Hallamshire Hospital by\u000d\u000a      University of Sheffield staff. Patients with major bleeding were treated\u000d\u000a      with either FFP or PCC and the research showed that the correction of the\u000d\u000a      coagulopathy achieved by FFP was minor and insufficient for complete\u000d\u000a      reversal, whilst patients treated with PCC achieved very rapid complete\u000d\u000a      reversal of the coagulopathy. The paper concluded that \"Clotting factor\u000d\u000a      concentrates are the only effective option where complete and immediate\u000d\u000a      correction of the coagulation defect is indicated in orally anticoagulated\u000d\u000a      patients with life or limb threatening haemorrhage\".\u000d\u000a    In 2001 the University of Sheffield team collaborated with groups in\u000d\u000a      Aberdeen and Cambridge to show that vitamin K given with the PCC for\u000d\u000a      emergency warfarin reversal was more effective if given intravenously than\u000d\u000a      orally (R2). Approximately a third of the 64 patients studied in this work\u000d\u000a      were from Sheffield.\u000d\u000a    In 2002 a further study from Sheffield, of 42 patients with life\u000d\u000a      threatening bleeding on warfarin and who required immediate reversal,\u000d\u000a      showed that one of concentrates licensed at the time to treat patients\u000d\u000a      with haemophilia B, called Beriplex, was highly efficient and safe in\u000d\u000a      producing immediate reversal of the coagulopathy (R3).\u000d\u000a    "},{"CaseStudyId":"12328","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The Sheffield research, via the spin-out company Simcyp, has delivered\u000d\u000a      commercial and health impact worldwide, thanks largely to its innovative\u000d\u000a      and firmly user-driven business model. Since its inception, all customers\u000d\u000a      have directly steered product development through the Simcyp Consortium,\u000d\u000a      voting on priorities for annual upgrades to ensure the product remains\u000d\u000a      current and closely matched to end-user needs. Consortium members also\u000d\u000a      provide routine data from their own trials, keeping the simulator as\u000d\u000a      accurate as possible through the addition of large volumes of real test\u000d\u000a      data. The accuracy and reliability encouraged several national regulatory\u000d\u000a      bodies to accept Simcyp's modelling as evidence in licensing new drugs.\u000d\u000a      This combination of user-focus, accuracy and regulatory recognition,\u000d\u000a      coupled with the significant commercial benefits described below, has\u000d\u000a      attracted more than 20 of the world's top 25 pharmaceutical companies to\u000d\u000a      buy licences, including AstraZeneca, Eli Lilly, Johnson & Johnson,\u000d\u000a      Merck, Novartis and Pfizer.\u000d\u000a    Commercial\u000d\u000a    Simpcyp was spun out from the University of Sheffield in 2001 (S1).\u000d\u000a      Turnover in 2006 was £1M increasing every year to £4.7M in 2010. This was\u000d\u000a      associated with a £0.2M post-tax profit in 2006 rising to £1.9M in 2011\u000d\u000a      (S2). It was 15th fastest growing UK company in 2009 (S3) and\u000d\u000a      as at 31 July 2011 the number of employees was 47 (S2). In 2012 Simcyp was\u000d\u000a      sold to Certara for $32M (S4, S5).\u000d\u000a    The company also delivers significant benefits for its industrial\u000d\u000a      customers. It can take 12 years and £1 billion to bring a new drug to\u000d\u000a      market. Simcyp allows manufacturers to eliminate dangerous or unsuitable\u000d\u000a      compounds at an early stage and focus solely on potentially viable drugs.\u000d\u000a      By cutting short the early testing phase, they can save time and many\u000d\u000a      millions of dollars that they would otherwise spend testing drugs that\u000d\u000a      would later fail in clinical trials.\u000d\u000a    Simcyp won the Queen's Award for Enterprise in Innovation in 2010 (S6).\u000d\u000a    Health and Wellbeing\u000d\u000a    The extensive use of Simcyp by the industrial pharma community has\u000d\u000a      delivered two distinct impacts on health and wellbeing.\u000d\u000a    Firstly, by optimising the design of trials it has minimised unnecessary\u000d\u000a      drug exposure among human volunteers and animal test subjects. Its\u000d\u000a      contribution to humane research was recognised in 2009 with an OSCAR\u000d\u000a      (Outstanding Scientific Contribution to Animal Replacement, from the UK's\u000d\u000a      leading non-animal medical research charity, The Dr Hadwen Trust for\u000d\u000a      Humane Research [S7].\u000d\u000a    Secondly, the Simcyp Paediatric Simulator provides valuable information\u000d\u000a      relevant to first-time dosing decisions and the design of clinical studies\u000d\u000a      in infants, neonates and children. It also helps pharma companies meet\u000d\u000a      their obligations under EU regulations. A Senior Pharmacist at Sheffield\u000d\u000a      Children's Hospital and Senior Scientist at Simcyp outlines the tool's\u000d\u000a      value:\u000d\u000a    \"Traditional dosing decisions have often been taken under the false\u000d\u000a        assumption that young children are simply little aduts. This model takes\u000d\u000a        into account the many changes in pharmacokinetics which occur as a\u000d\u000a        result of organ maturation and changes in body composition and drug\u000d\u000a        elimination pathways. Fewer than 50% of children's medicines have\u000d\u000a        actually been tested in an appropriate age group. Simpcyp Simulations\u000d\u000a        allow a clinical study in children to become `confirmatory' rather than\u000d\u000a        `exploratory', reducing unnecessary drug exposure. This is crucial now\u000d\u000a        that EU regulations insist that paediatric data be included in all\u000d\u000a        applications for new medicinal products.\"\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research at the University of Sheffield developed pharmacokinetic tools\u000d\u000a      that enable prediction of drug absorption, distribution, metabolism and\u000d\u000a      excretion, and potential drug-drug interactions. In 2001 the University\u000d\u000a      created a spinout company, Simcyp Ltd, to commercialise the technology.\u000d\u000a      The impacts are:\u000d\u000a    \u000d\u000a      Commercial: the company was awarded the Queen's Award for Enterprise\u000d\u000a        in Innovation in 2010 and in February 2012 was sold for $32M to Certara,\u000d\u000a        a leading provider of drug discovery and development software.\u000d\u000a      Commercial: the Simcyp population-based Simulator is now used in drug\u000d\u000a        development by many of the world's leading pharmaceutical companies,\u000d\u000a        saving them time and millions of dollars through more efficient and\u000d\u000a        targeted testing.\u000d\u000a      Health: human and animal test subjects have benefitted by optimisation\u000d\u000a        of the design of trials to minimise unnecessary drug exposure.\u000d\u000a      Health: the Simcyp Paediatric module has improved the care of children\u000d\u000a        by providing reliable evidence to better guide dosage.\u000d\u000a    \u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Sheffield\u000d\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000aR1. Rostami-Hodjegan A, Nurminen S, Jackson PR & Tucker GT. Caffeine\u000d\u000a      urinary metabolite ratios as markers of enzyme activity: a theoretical\u000d\u000a      assessment. Pharmacogenetics. 1996; 6: 121-49. doi: 10.1097\/00008571-199604000-00001\u000d\u000a    \u000a\u000aR2. Rostami-Hodjegan A, Peacey SR, George E, Heller SRR & Tucker GT.\u000d\u000a      Population-based modeling to demonstrate extrapancreatic effects of\u000d\u000a      tolbutamide. Am J Physiol. 1998; 274: E758-E771. PubMed ID: 9575839\u000d\u000a    \u000a\u000aR3. Moghadamnia AA, Rostami-Hodjegan A, Abdul-Manap R, Wright CE, Morice\u000d\u000a      AH, Tucker GT. Physiologically based modelling of inhibition of metabolism\u000d\u000a      and assessment of the relative potency of drug and metabolite:\u000d\u000a      dextromethorphan vs. dextrorphan using quinidine inhibition. Br J Clin\u000d\u000a      Pharmacol. 2003; 56: 57-67. doi: 10.1046\/j.1365-2125.2003.01853.x\u000d\u000a    \u000a\u000aR4. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the\u000d\u000a      clearance of eleven drugs and associated variability in neonates, infants\u000d\u000a      and children. Clinical Pharmacokinetics. 2006; 45: 931-56. doi: 10.2165\/00003088-200645090-00005\u000d\u000a    \u000a\u000aR5. Jamei M, Marciniak S, Feng K, Barnett A, Tucker G &\u000d\u000a      Rostami-Hodjegan. The Simcyp population-based ADME simulator. Expert Opin\u000d\u000a      Drug Metab Toxicol. 2009;5 :211-223. doi: 10.1517\/17425250802691074\u000d\u000a    \u000a\u000aR6. Dickinson GL, Lennard MS, Tucker GT, Rostami-Hodjegan A. The use of\u000d\u000a      mechanistic DM-PK-PD modelling to assess the power of pharmacogenetic\u000d\u000a      studies -CYP2C9 and warfarin as an example. British Journal of Clinical\u000d\u000a      Pharmacology. 2007; 64: 14-26. doi: 10.1111\/j.1365-2125.2007.02850.x\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    S1. Simcyp website gives details of company's history: http:\/\/www.simcyp.com\/\u000d\u000a    S2. Simcyp turnover, post-tax profit and employee number figures\u000d\u000a      2006-2010 from Operations Director, Fusion IP available on file.\u000d\u000a    S3. Reference to 15th fastest growing UK company in 2009. The\u000d\u000a      Business XL Top 50 Rising Stars is an annual ranking of UK-based fast\u000d\u000a      growing companies reporting turnover of between £2.5 million and £100\u000d\u000a      million and profits of at least £300,000 (http:\/\/tinyurl.com\/pwhomqz).\u000d\u000a    S4. Certara media release announcing acquisition of Simcyp (http:\/\/tinyurl.com\/phthryg).\u000d\u000a    S5. Acquisition for $32m confirmed in press (http:\/\/tinyurl.com\/n3xbcor).\u000d\u000a    S6. Media release from Fusion IP announcing award of Queen's Award for\u000d\u000a      Enterprise in Innovation to Simcyp: (http:\/\/www.fusionip.co.uk\/simcyp-wins-queens-award\/).\u000d\u000a    S7. Media release from Simcyp confirming the award of the OSCAR (http:\/\/tinyurl.com\/modur97).\u000a      \u000d\u000a    ","Title":"\u000d\u000a    Commercial and health impacts of drug modelling tools\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2638077","Name":"Sheffield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The handling of a drug by the body can be very complex, as several\u000d\u000a      processes (such as absorption, distribution, metabolism, and elimination)\u000d\u000a      work to alter drug concentrations in tissues and fluids. The perceived\u000d\u000a      failure of new drug development has been blamed in part on deficiencies in\u000d\u000a      understanding how human populations handle such drugs.\u000d\u000a    Prior simulation of the potential exposure of different individuals to a\u000d\u000a      given dose of drug and how they metabolise and react to this drug might\u000d\u000a      help to improve the design of clinical trials. Simplifications of body\u000d\u000a      processes are necessary to predict a drug's behaviour in the body. One way\u000d\u000a      to make these simplifications is to apply mathematical models and computer\u000d\u000a      simulations to the various processes.\u000d\u000a    Professors Tucker (UoS 1972-2009) and Rostami-Hodjegan (UoS 1996-2009)\u000d\u000a      were interested in clinical trial simulation and developed computer\u000d\u000a      programmes to assess how drugs were metabolised in human populations.\u000d\u000a      Using programmes that were developed using FORTRAN they attempted to\u000d\u000a      simulate pharmacokinetic (what the body does to the drug) behaviour in\u000d\u000a      `virtual populations' taking into account demographic, physiological and in\u000a        vitro biochemical data (R1, R2).\u000d\u000a    In 1999, they started to incorporate their algorithms into Windows-based\u000d\u000a      software as part of the Simcyp Simulator Project. The project was a\u000d\u000a      cooperative venture with a consortium of pharmaceutical companies. It had\u000d\u000a      the objective of developing a user-friendly programme and database with\u000d\u000a      simple visual outputs that could be used to predict in vivo\u000d\u000a      pharmacokinetics in virtual adult patient populations (R3). This was also\u000d\u000a      extended to pharmacokinetics in children (R4).\u000d\u000a    The Simcyp Simulator (R5) has evolved to include extensive demographic,\u000d\u000a      physiologic and genomic databases that have allowed the development of\u000d\u000a      algorithms which account for patient variability. This enables drug\u000d\u000a      companies to predict drug behaviour in the virtual patient population, as\u000d\u000a      opposed to a virtual reference man, allowing individuals at extreme risk\u000d\u000a      to be identified. This has facilitated decision making in the early\u000d\u000a      clinical stages of drug development and also minimises unnecessary drug\u000d\u000a      testing on humans and animals. The Simulator continues to evolve and is\u000d\u000a      now used in the investigation of pharmacodynamics (what the drug does to\u000d\u000a      the body, R6).\u000d\u000a    "},{"CaseStudyId":"12329","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2782113","Name":"Austria"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    In the UK alone, osteoporosis results in more than 230,000 fractures,\u000a      including 70,000 hip fractures, every year. Worldwide, it is projected\u000a      that the burden of fractures will more than double by 2050, an increase\u000a      that will be particularly marked in Asia. The need to identify high risk\u000a      individuals for appropriate interventions has been recognised as a global\u000a      health need.\u000a    Impact on skeletal health care in the UK and internationally\u000a    FRAX is the single most important development in osteoporosis management\u000a      since the T-score definition in 1994 (also from the University of\u000a      Sheffield) as it:\u000a    \u000a      Provides an estimate of absolute risk to inform physician and patient\u000a        treatment choice.\u000a      Provides an estimate of risk even in the absence of access to DXA\u000a        technology (Dual-energy X-ray absorptiometry is a means of measuring bone mineral\u000a          density) thus enfranchising management of osteoporosis in a wider\u000a        community.\u000a      Makes more effective use of DXA scanning resources.\u000a      Permits targeting of therapy to highest risk individuals.\u000a      Currently provides assessment of absolute fracture risk for the\u000a        primary care community in 53 countries and 28 languages.\u000a      Has been advocated by NICE in the UK and is incorporated into numerous\u000a        national and international guidelines for osteoporosis.\u000a    \u000a    Since the launch of FRAX in 2008, it has rapidly become the most\u000a      internationally implemented and accepted risk calculator. It is most\u000a      widely available as a free-to-use web-based calculator via the University\u000a      of Sheffield website. The incorporation of a calculation counter (only\u000a      activated by a complete risk calculation rather than a simple visit to the\u000a      website) shows that approximately 6.6 million calculations had passed\u000a      through the website since the counting tool was implemented on 1st June\u000a      2011 (accessed October 16th 2013) (S1). In addition to the web-based tool,\u000a      FRAX is now incorporated into dual X-ray absorptiometry (DXA) scanner\u000a      software, an iPhone app, standalone desktop tools and several paper-based\u000a      calculators. In the UK, it is now available within the TPP SystmOne\u000a      general practitioner software system, used by some 2000 GP practices\u000a      currently with numbers growing. The impact of FRAX on the field of\u000a      osteoporosis has been reflected in the rapid rise of FRAX-related\u000a      publications. In the first year, 2008, there were only 11 FRAX-related\u000a      publications but this increased to 60\/year in 2009 and 2010, 95 in 2011\u000a      and 126 in 2012 (PubMed FRAX in title or abstract excluding Fragile X\u000a      syndrome) (Accessed 13.22 Jan 23rd 2013).\u000a    Prior to FRAX, clinical decision making was largely based on a concept of\u000a      high risk, based on factors such as prior fracture, age, low BMD etc., but\u000a      it was not possible to actually quantify this risk and treatment was\u000a      largely indicated by the finding of BMD-defined osteoporosis. This\u000a      required a BMD scan in virtually all patients with a clinical risk factor\u000a      without any prior assessment of their absolute risk. FRAX can now be used\u000a      to more efficiently target BMD scans to those at or around an intervention\u000a      threshold, an approach endorsed by NICE (S2), and thus improves resource\u000a      use. The major beneficiaries of the FRAX research and development are men\u000a      and women at highest risk of osteoporotic fracture. The reduction in the\u000a      risk of fractures that results from well proven therapies is maximal in\u000a      patients at highest risk with greater absolute risk reductions and reduced\u000a      numbers needed to treat. The tool can also avoid or delay the need for\u000a      therapy in patients previously deemed at high risk by the presence of low\u000a      BMD (e.g. a BMD T-score of -2.5 in a 55 year old woman) but at low\u000a      absolute risk; this improves the risk-benefit ratio of therapies given\u000a      increasing concerns about potential complications of therapy such as\u000a      osteonecrosis of the jaw or atypical femoral fractures.\u000a    To date, the use of FRAX has been endorsed in national\/international\u000a      guidance from the UK (S2), the US (S3), Canada (S4), Europe (S5),\u000a      Switzerland, Japan, Austria and Sweden. In 2008, the National Osteoporosis\u000a      Guideline Group launched a website twinned to the UK FRAX model that gave\u000a      guidance for the use of FRAX results in individuals to guide further\u000a      assessment (e.g. DXA scanning) or intervention (www.shef.ac.uk\/NOGG).\u000a      This guideline was endorsed by many national societies including the Royal\u000a      College of Physicians, Royal College of General Practitioners, Primary\u000a      Care Rheumatology Society, British Geriatrics Society, British Orthopaedic\u000a      Association, Bone Research Society and patient societies including the\u000a      National Osteoporosis Society, Osteoporosis Dorset and Osteoporosis2000.\u000a      It has recently been updated. In the UK, the recently published NICE\u000a      Clinical Guideline endorsed the use of FRAX as one of two risk calculators\u000a      that should be used to target the use of dual X-ray absorptiometry (DXA)\u000a      scans (NICE CG146) (S2) and it has been incorporated in the NHS Map of\u000a      Medicine for osteoporosis, which aims to inform patient choice (S6).\u000a    In 2010, The International Society for Clinical Densitometry (ISCD) and\u000a      the International Osteoporosis Foundation (IOF) convened a FRAX Position\u000a      Development Conference (PDC) resulting in guidelines on the interpretation\u000a      and use of FRAX in clinical practice (S7). In 2011, the US Preventive\u000a      Service Task Force (USPSTF) recommended the use of FRAX to calculate the\u000a      10- year risk for osteoporotic fractures to guide screening decisions for\u000a      women younger than 65 years (S8). In Europe in 2012, FRAX has been\u000a      incorporated into guideline development documents for the management of\u000a      osteoporosis in postmenopausal women as well as glucocorticoid-induced\u000a      osteoporosis in men and women.\u000a    ","ImpactSummary":"\u000a    Research at the University of Sheffield has resulted in FRAX, the first\u000a      internationally-applicable fracture risk calculator that provides\u000a      individualised 10-year probabilities of major osteoporotic fractures from\u000a      readily available clinical risk factors. It has replaced bone mineral\u000a      density (BMD) as the sole quantitative measure of fracture risk, thus\u000a      increasing global access to risk assessment and improving targeting of\u000a      treatment to patients at highest risk. FRAX is incorporated widely into\u000a      national and international guidelines for osteoporosis management.\u000a      Launched in 2008, it now provides country-specific calculations for 53\u000a      nations, in 28 languages. The online tool alone recently processed its 6.6\u000a      millionth calculation.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Sheffield\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000aR1. (1994) Assessment of fracture risk and its application to screening\u000a      for postmenopausal osteoporosis. Report of a WHO Study Group. World Health\u000a      Organ Tech Rep Ser 843:1-129 (available at http:\/\/whqlibdoc.who.int\/trs\/WHO_TRS_843.pdf).\u000a    \u000a\u000aR2. Kanis JA (2002) Diagnosis of osteoporosis and assessment of fracture\u000a      risk. Lancet 359:1929-1936 doi: 10.1016\/S0140-6736(02)08761-5\u000a    \u000a\u000aR3. McCloskey EV, Beneton M, Charlesworth D, et al. (2007) Clodronate\u000a      reduces the incidence of fractures in community-dwelling elderly women\u000a      unselected for osteoporosis: results of a double-blind, placebo-controlled\u000a      randomized study. J Bone Miner Res 22:135-141 doi: 10.1359\/jbmr.061008\u000a    \u000a\u000aR4. Kanis JA, Johnell O, De Laet C, et al. (2004) A meta-analysis of\u000a      previous fracture and subsequent fracture risk. Bone 35:375-382 doi: 10.1016\/j.bone.2004.03.024\u000a    \u000a\u000aR5. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E (2008) FRAX and\u000a      the assessment of fracture probability in men and women from the UK.\u000a      Osteoporos Int 19:385-397 doi: 10.1007\/s00198-007-0543-5\u000a    \u000a\u000aR6. Dawson-Hughes B, Tosteson AN, Melton LJ, 3rd, Baim S, Favus MJ,\u000a      Khosla S, Lindsay RL (2008) Implications of absolute fracture risk\u000a      assessment for osteoporosis practice guidelines in the USA. Osteoporos Int\u000a      19:449-458 doi: 10.1007\/s00198-008-0559-5\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    S1. www.shef.ac.uk\/FRAX\u000a    S2. Osteoporosis: assessing the risk of fragility fracture. NICE Clinical\u000a      Guideline CG146 (Issued: August 2012) (http:\/\/tinyurl.com\/nck8c4l).\u000a    S3. National Osteoporosis Foundation 2013 Clinician's guide to prevention\u000a      and treatment of osteoporosis (http:\/\/tinyurl.com\/nu29v8t)\u000a      Page 22 corroborates the recommendation to use FRAX as well as its\u000a      translation to US norms.\u000a    S4. Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S,\u000a      Hanley DA, Hodsman A, Jamal SA, Kaiser SM, Kvern B, Siminoski K, Leslie WD\u000a      for the Scientific Advisory Council of Osteoporosis Canada. 2010 clinical\u000a      practice guidelines for the diagnosis and management of osteoporosis in\u000a      Canada: summary. CMAJ 2010. doi: 10.1503\/cmaj.100771\u000a      Page 3 corroborates recommendation of FRAX validated in Canadians.\u000a    S5. Endorsement of FRAX in Europe: A framework for the development of\u000a      guidelines for the management of glucocorticoid-induced osteoporosis (http:\/\/tinyurl.com\/ou4dgdx).\u000a    S6. NHS Choices Map of Medicine (http:\/\/tinyurl.com\/k9ycnfk).\u000a    S7. ISCD\/IOF (http:\/\/tinyurl.com\/k2zs6xq).\u000a    S8. U.S. Preventive Services Task Force. Screening for Osteoporosis 2011\u000a      (http:\/\/tinyurl.com\/6fb6zfp).\u000a    ","Title":"\u000a    FRAX, an international tool for the assessment of fracture risk\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The University of Sheffield has a worldwide reputation in the field of\u000a      osteoporosis research, encompassing: epidemiology; diagnostic assessments;\u000a      clinical outcome definitions including vertebral fracture; therapeutic\u000a      developments; and health economics. In 1994, the WHO Collaborating Centre\u000a      for Metabolic Bone Diseases at the University, led by Professor Kanis,\u000a      published a WHO technical report establishing the working definition of\u000a      osteoporosis based on dual x-ray absorptiometry (DXA) measurements of BMD\u000a      (R1). This definition, the T-score threshold of — 2.5, became and remains\u000a      the international standard for the BMD diagnosis of osteoporosis.\u000a      Originally intended as an epidemiological tool, it facilitated assessments\u000a      of the prevalence and burden of osteoporosis across the world for the\u000a      first time. Nationally and internationally, the T-score was subsequently\u000a      incorporated into guidelines for the diagnosis and management of\u000a      osteoporosis, adopted in many countries as a threshold for reimbursement\u000a      of investigations and treatments; it also became widely used as a standard\u000a      for recruitment of patients to studies of new therapies for osteoporosis.\u000a    Whilst osteoporosis remains operationally defined on the basis of the BMD\u000a      T-score, it has long been recognised that the occurrence of fragility\u000a      fractures, the hallmark of osteoporosis, is not dependent on BMD alone.\u000a      Used in isolation, BMD lacks sensitivity for the prediction of future\u000a      fractures (R2). Against this background, a research team within the WHO\u000a      Collaborating Centre at Sheffield led a program of research in 1998 with\u000a      the endorsement of the International Osteoporosis Foundation, the National\u000a      Osteoporosis Foundation (USA), and the International Society for Clinical\u000a      Densitometry and the American Society for Bone and Mineral Research. The\u000a      core team was led by Professors Kanis and McCloskey (2003-date) in\u000a      Sheffield, Professor Johnell in Malmo and Professor Anders Oden and Dr\u000a      Helena Johansson in Gothenburg. The Collaborating Centre aimed to identify\u000a      and validate clinical risk factors for use in fracture risk assessment on\u000a      an international basis, either alone or in combination with BMD. A further\u000a      aim was to incorporate suitably validated risk factors into algorithms for\u000a      risk assessment that were sufficiently flexible to be used in the context\u000a      of many primary care settings, including those where BMD testing was not\u000a      readily available.\u000a    The research program necessitated the centralisation of individual level\u000a      subject data from international cohorts, an achievement in itself that\u000a      reflected the standing of the University of Sheffield in the global\u000a      osteoporosis research community. The University of Sheffield and Professor\u000a      McCloskey also contributed data from a large local cohort recruited to a\u000a      concurrent MRC-funded study of fracture risk factors and prevention in\u000a      elderly women (R3). The central collation of data, comprising\u000a      approximately 250 000 subject-years of follow-up in 60 000 men and women\u000a      with 5000 incident fractures, produced a unique dataset that allowed, for\u000a      the first time, the examination of several individual risk factors for\u000a      fracture and their inter-relationships with other risk variables, notably\u000a      age and BMD. The work gave rise to a series of well-received and highly\u000a      cited meta-analyses, for example of the relationship between prior\u000a      fracture and subsequent fracture (R4), culminating in a provisional\u000a      fracture risk calculator. A subsequent validation study, undertaken in\u000a      external cohorts comprised approximately 230,000 individuals with 1.2\u000a      million subject years of follow-up, including data from Sheffield\u000a      (Professor Richard Eastell, 1995-date). The programme of work culminated\u000a      with the launch of the online FRAX tool (www.shef.ac.uk\/FRAX)\u000a      in April 2008 with simultaneous publication of the UK (R5) and US (R6)\u000a      FRAX tools.\u000a    "},{"CaseStudyId":"12330","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    HEALTHCARE IMPACT\u000a    This research has led to a new drug intervention for osteoporosis.\u000a      Through our research, we demonstrated that Zoledronic acid is effective\u000a      and it was subsequently licensed by the European Medicines Agency in 2007\u000a      [S1].\u000a    The drug was approved based on the phase III clinical trial studies such\u000a      as the HORIZON trial. It was approved in women [S2, S3], men, people with\u000a      hip fractures [S4], and with glucocorticoid-induced osteoporosis. As a\u000a      result of this research, the drug has been licensed in over 100 countries\u000a      and more than 2 million doses of the drugs have been administered since\u000a      2007.\u000a    The main beneficiaries of this research are patients with osteoporosis;\u000a      they receive a well-tolerated and simple to administer treatment that they\u000a      prefer to the alternative (oral alendronate) and have a large reduction in\u000a      their risk of fracture (by 70% for vertebral fracture).\u000a    The development of zoledronic acid as a treatment for osteoporosis is\u000a      original as it is the first (and only) treatment that can be administered\u000a      as infrequently as once a year. This contribution allowed for the\u000a      successful development of this drug by conducting a well-designed trial,\u000a      and allows a clear understanding of the mechanism of action of the drug at\u000a      the molecular and whole body level. The Global Program Head at Novartis\u000a      has recognised the part played by the University of Sheffield in both\u000a      developing the use of zoledronic acid for treatment of osteoporosis, as\u000a      well as sales worth $0.6bn (S3) in 2011 [S5].\u000a    Clinical guidelines have changed as a result of the drug being\u000a      licenced. The Scottish Medicines Consortium has recommended that this\u000a      treatment should be used in patients who are unsuitable for or unable to\u000a      tolerate oral treatment options for osteoporosis [S6]. The treatment has\u000a      not yet been considered by NICE, although treatments for Osteoporosis are\u000a      currently under review by NICE.\u000a    The treatment has been included in international guidelines. Expertise\u000a      gained through our research has been called upon to inform international\u000a      practice which recommends zoledronic acid as best practice.\u000a    Eastell was an advisor on the Endocrine Society panel during 2009-2012\u000a      [S7] in the formation of new international guidelines for male\u000a      osteoporosis, which include the recommendation to use zoledronic acid\u000a      (S5). The treatment has also been included in the International\u000a      Osteoporosis Foundation (IOF) guidelines for glucocorticoid-induced\u000a      osteoporosis and three Sheffield professors were on that panel during\u000a      2009-2012 (John Kanis, Eugene McCloskey and Eastell).\u000a    The use of bone mineral density to identify response in the individual\u000a      patient was the basis for a guideline from the IOF, and Eastell and Kanis\u000a      were two of the members of the panel [S8]. Monitoring of zoledronic acid\u000a      with bone turnover markers and bone mineral density was described in\u000a      guidelines from the IOF on which Kanis and Eastell were members.\u000a    The user experience has improved. According to research into patient\u000a      experience conducted in the USA, 66-79% of patients preferred an annual\u000a      infusion of ZA to weekly oral alendronate [S9], the standard treatment of\u000a      osteoporosis currently recommended by NICE.\u000a    ECONOMIC IMPACT\u000a    The costs of treatment have changed as a result of research-led\u000a      changes in practice. The treatment is the most cost-effective for\u000a      postmenopausal osteoporosis (Scottish Medicines Consortium). Research\u000a      conducted in France found that, for example, treatment with zoledronic\u000a      acid cost €1,216 per hip fracture avoided compared to €1,323 for standard\u000a      treatment [S10].\u000a    Industry has invested in research and development. Novartis has\u000a      funded studies into the efficacy and safety profile through establishing\u000a      clinical trials of more than 11,000 patients for up to 9 years.\u000a    ","ImpactSummary":"\u000a    Research at the University of Sheffield has demonstrated that zoledronic\u000a      acid is an effective and safe treatment for osteoporosis. It resulted in a\u000a      new drug intervention (Aclasta\/Reclast) which has been licensed in more\u000a      than 100 countries and shows increased positive outcomes for patients.\u000a\u0009As a result of the licensing of the drug, clinical guidelines have changed\u000a      globally. For patients, the drug provides a preferred method of treatment,\u000a      evidenced in surveys which show the majority of patients preferred an\u000a      annual infusion of zoledronic acid to the alternative, which is the\u000a      standard treatment of weekly oral alendronate.\u000a    Industry has invested in research and development of the drug. Novartis\u000a      has funded studies into the efficacy and safety profile (up to 2012); in\u000a      2011, sales of Aclasta\/Reclast were US$0.6 billion.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Sheffield\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000a    University of Sheffield researchers in bold\u000a    \u000aR1. Luckman, S. P., Coxon, F. P., Ebetino, F. H., Russell, R. G.,\u000a      and Rogers, M. J. (1998) Heterocycle-containing bisphosphonates cause\u000a      apoptosis and inhibit bone resorption by preventing protein prenylation:\u000a      evidence from structure-activity relationships in J774 macrophages. J.Bone\u000a        Miner.Res. 13, 1668-1678 doi: 10.1359\/jbmr.1998.13.11.1668\u000a    \u000a\u000aR2. Delmas, P. D., Munoz, F., Black, D. M., Cosman, F., Boonen, S.,\u000a      Watts, N. B., Kendler, D., Eriksen, E. F., Mesenbrink, P. G., and Eastell,\u000a        R. (2009) Effects of yearly zoledronic acid 5 mg on bone turnover\u000a      markers and relation of PINP with fracture reduction in postmenopausal\u000a      women with osteoporosis. J.Bone Miner.Res. 24, 1544-1551\u000a      doi: 10.1359\/jbmr.090310\u000a    \u000a\u000aR3. Eastell, R., Black, D. M., Boonen, S., Adami, S., Felsenberg,\u000a      D., Lippuner, K., Cummings, S. R., Delmas, P. D., Palermo, L., Mesenbrink,\u000a      P., and Cauley, J. A. (2009) Effect of once-yearly zoledronic acid five\u000a      milligrams on fracture risk and change in femoral neck bone mineral\u000a      density. J.Clin.Endocrinol.Metab 94, 3215-3225 doi: 10.1210\/jc.2008-2765\u000a    \u000a\u000aR4. Eastell, R., Lang, T., Boonen, S., Cummings, S., Delmas, P.\u000a      D., Cauley, J. A., Horowitz, Z., Kerzberg, E., Bianchi, G., Kendler, D.,\u000a      Leung, P., Man, Z., Mesenbrink, P., Eriksen, E. F., and Black, D. M.\u000a      (2010) Effect of once-yearly zoledronic acid on the spine and hip as\u000a      measured by quantitative computed tomography: results of the HORIZON\u000a      Pivotal Fracture Trial. Osteoporos.Int. 21, 1277-1285 doi:\u000a      10.1007\/s00198-009-1077-9\u000a    \u000a\u000aR5. Black, D. M., Delmas, P. D., Eastell, R., Reid, I. R.,\u000a      Boonen, S., Cauley, J. A., Cosman, F., Lakatos, P., Leung, P. C., Man, Z.,\u000a      Mautalen, C., Mesenbrink, P., Hu, H., Caminis, J., Tong, K.,\u000a      Rosario-Jansen, T., Krasnow, J., Hue, T. F., Sellmeyer, D., Eriksen, E.\u000a      F., and Cummings, S. R. (2007) Once-yearly zoledronic acid for treatment\u000a      of postmenopausal osteoporosis. N.Engl.J.Med. 356,\u000a      1809-1822 doi: 10.1056\/NEJMoa067312\u000a    \u000a\u000aR6. Jacques, R. M., Boonen, S., Cosman, F., Reid, I. R., Bauer, D. C.,\u000a      Black, D. M., and Eastell, R. (2012) Relationship of changes in\u000a      total hip bone mineral density to vertebral and nonvertebral fracture risk\u000a      in women with postmenopausal osteoporosis treated with once-yearly\u000a      zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J.Bone\u000a        Miner.Res. 27, 1627-1634 doi: 10.1002\/jbmr.1644\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    S1. European Medicines Agency European public assessment report variation\u000a      WC500020936 for Aclasta (zoledronic acid) (http:\/\/tinyurl.com\/o6qbwkd)\u000a    S2. FDA Label change for Reclast (zoledronic acid) approving it fo use in\u000a      treatment of osteoporosis in postmenopausal women and treatment of Paget's\u000a      disease of bone in men and women (http:\/\/tinyurl.com\/psgsqw9).\u000a    S3. Press release gives details of approval of drug for use in men (http:\/\/tinyurl.com\/lxskhth).\u000a    S4. Gives details of approval for drug to be used with hip fractures (http:\/\/tinyurl.com\/kqrs7yn).\u000a    S5. E-mail from Global Program Head, Novartis, available on file.\u000a    S6. The Scottish Medicines Consortium recommendation for use of Aclasta (http:\/\/tinyurl.com\/q5klw5n).\u000a    S7. Page 5, recommendation 3.2 corroborates inclusion of zoledronic acid\u000a      as a recommended treatment (http:\/\/tinyurl.com\/m5fkuog).\u000a    S8. Vasikaran, S., Eastell, R., Bruyere, O., Foldes, A. J., Garnero, P.,\u000a      Griesmacher, A., McClung, M., Morris, H. A., Silverman, S., Trenti, T.,\u000a      Wahl, D. A., Cooper, C., and Kanis, J. A. (2011) Markers of bone turnover\u000a      for the prediction of fracture risk and monitoring of osteoporosis\u000a      treatment: a need for international reference standards. Osteoporos.Int.\u000a      22, 391-420 doi: 10.1007\/s00198-010-1501-1\u000a    S9. McClung, M., Recker, R., Miller, P., Fiske, D., Minkoff, J.,\u000a      Kriegman, A., Zhou, W., Adera, M., and Davis, J. (2007) Intravenous\u000a      zoledronic acid 5 mg in the treatment of postmenopausal women with low\u000a      bone density previously treated with alendronate. Bone 41, 122-128 doi: 10.1016\/j.bone.2007.03.011\u000a    S10. Fardellone, P., Cortet, B., Legrand, E., Bresse, X., Bisot-Locard,\u000a      S., Vigneron, A. M., and Beresniak, A. (2010) Cost-effectiveness model of\u000a      using zoledronic acid once a year versus current treatment strategies in\u000a      postmenopausal osteoporosis. Joint Bone Spine 77, 53-57 doi: 10.1016\/j.jbspin.2009.04.009\u000a    ","Title":"\u000a    Health and economic impact of a new drug intervention for osteoporosis\u000a    ","UKLocation":[{"GeoNamesId":"2638077","Name":"Sheffield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Osteoporosis is a major public health problem; there are more than\u000a      230,000 osteoporosis-related fractures annually in the UK, 70,000 of which\u000a      are hip fractures, and these figures are set to rise with the increase in\u000a      the elderly population (www.nos.org.uk).\u000a      Treatments are available that reduce the risk of fracture; the most\u000a      commonly-used treatments are bisphosphonates. Zoledronic acid is a\u000a      bisphosphonate that can be given parenterally once a year and was licensed\u000a      for use in men and women with osteoporosis in 2008.\u000a    Research at the University of Sheffield played a pioneering role in the\u000a      development of the bisphosphonate drugs. Professor Graham Russell\u000a      (Department of Human Metabolism, 1975 to 2000) made a major contribution\u000a      to their early clinical development as well as the understanding of the\u000a      mechanism of action of bisphosphonates at the cellular and molecular level\u000a      which laid the scientific foundation for their current use. In a range of\u000a      research projects, he studied amoebae (Dictyostelium discoideum) and\u000a      immortalised macrophages (J774 cells) and showed that nitrogen-containing\u000a      bisphosphonates induced apoptosis by inhibiting the mevalonate pathway and\u000a      hence post-translational prenylation of GTP-binding proteins (inhibiting\u000a      the enzyme farnesyl diphosphate synthase) and published this in 1998 (R1).\u000a    Professor Richard Eastell (Department of Human Metabolism, University of\u000a      Sheffield, since 1995) developed assays for bone turnover markers,\u000a      evaluated physical measurements of bone and developed methods for defining\u000a      vertebral fractures. Sheffield was funded for this work by peer-review\u000a      organisations. For example, the work on quantitative computed tomography\u000a      was funded by the Medical Research Council (Biomarkers grant) and by\u000a      Arthritis Research UK (project grant). The work on vertebral fracture\u000a      definition was funded by the Medical Research Council (Fellowship) and\u000a      Arthritis Research UK (Project grant).\u000a    Thus, Eastell was able to help design the HORIZON study in 2001 to assess\u000a      the efficacy and safety of zoledronic acid in osteoporosis. This was a\u000a      phase III clinical trial of zoledronic acid sponsored by Novartis and\u000a      Sheffield was a study site. The drug was unique in that it was\u000a      administered as a once a year infusion; the standard approach to giving\u000a      bisphosphonates had been as daily or weekly tablets. The knowledge gained\u000a      from experiments in Sheffield between 1993 and 2001 allowed Eastell, along\u000a      with his fellow members of the trial steering committee (chairman Dr D\u000a      Black), to ensure the following state of the art methods were included in\u000a      the HORIZON trial: bone turnover marker response (R2), bone mineral\u000a      density response (R3), quantitative computed tomography of hip and spine\u000a      response (R4) and the effect of the drug on fracture risk (R5).\u000a    Findings of the HORIZON study showed that the drug reduced vertebral\u000a      fractures by 70%, hip fractures by 41% and non-vertebral fractures by 25%.\u000a      Statistical analysis by Richard Jacques (School of Health and Related\u000a      Research, University of Sheffield, since 2008) allowed a better\u000a      understanding of the link between change in bone mineral density, bone\u000a      turnover markers and fracture risk (R6), and this work provides a target\u000a      for response to zoledronic acid in the individual patient.\u000a    "},{"CaseStudyId":"12331","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Research at the University of Sheffield into ticagrelor has had impact on\u000d\u000a      health and welfare through improved treatment for patients with acute\u000d\u000a      coronary syndromes.\u000d\u000a    In the UK, the National Institute for Health and Care Excellence (NICE)\u000d\u000a      recommended in October 2011 that ticagrelor is a cost-effective and\u000d\u000a      superior alternative to generic clopidogrel in patients with myocardial\u000d\u000a      infarction or moderate-to-high risk unstable angina (S1). The work has\u000d\u000a      supported the introduction of life-saving therapy in these patients since\u000d\u000a      ticagrelor prevents one in five deaths in a broad spectrum of acute\u000d\u000a      coronary syndrome patients compared to standard therapy with clopidogrel.\u000d\u000a    Regulatory approval of ticagrelor has now been achieved in more than 80\u000d\u000a      countries worldwide, including approval by the European Medicines Agency\u000d\u000a      in Europe (2010) (S2) and the Federal Drug Administration in the USA\u000d\u000a      (2011) (S3).\u000d\u000a    Based on the PLATO study results, two European Society of Cardiology\u000d\u000a      guidelines entitled `ESC Guidelines for the management of acute coronary\u000d\u000a      syndromes in patients presenting without persistent ST-segment elevation'\u000d\u000a      (published in 2011) (S4) and `ESC Guidelines for the management of acute\u000d\u000a      myocardial infarction in patients presenting with ST-segment elevation'\u000d\u000a      (published in 2012) (S5) have recommended ticagrelor as first-line\u000d\u000a      treatment in preference to clopidogrel.\u000d\u000a    The recommendations by the ESC and the approval by NICE then led to use\u000d\u000a      of ticagrelor for acute coronary syndrome patients in the UK. Reflecting\u000d\u000a      the leading role that Sheffield played in the development of ticagrelor,\u000d\u000a      the South Yorkshire region, representing a population of over 1.5 million,\u000d\u000a      was the first to adopt ticagrelor as first-line treatment of acute\u000d\u000a      coronary syndromes in preference to generic clopidogrel in February 2012\u000d\u000a      (S6) and other regions of the UK have progressively followed suit, with\u000d\u000a      50% of NHS Trusts in the UK that manage acute coronary syndrome now having\u000d\u000a      adopted ticagrelor (S7).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    This case study describes the healthcare impact arising from the trial\u000d\u000a      and introduction of a new clinical treatment used in patients with acute\u000d\u000a      coronary syndromes. Research at Sheffield provided robust evidence as to\u000d\u000a      the effectiveness of the anti-thrombotic drug ticagrelor, which directly\u000d\u000a      contributed to its approval by global regulatory authorities and its\u000d\u000a      recommendation by the European Society of Cardiology and the National\u000d\u000a      Institute for Health and Care Excellence as a first-line treatment in the\u000d\u000a      management of acute coronary syndromes. South Yorkshire hospitals were\u000d\u000a      early adopters in February 2012 and ticagrelor has been progressively\u000d\u000a      adopted across other parts of the United Kingdom, with over half of UK\u000d\u000a      hospitals now having adopted it. It has also been adopted in over 80 other\u000d\u000a      countries.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Sheffield\u000d\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000aR1. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters\u000d\u000a      G, Storey RF. Safety, tolerability, and initial efficacy of\u000d\u000a      AZD6140, the first reversible oral adenosine diphosphate receptor\u000d\u000a      antagonist, compared with clopidogrel, in patients with non-st-segment\u000d\u000a      elevation acute coronary syndrome: Primary results of the disperse-2\u000d\u000a      trial. J Am Coll Cardiol. 2007;50:1844-1851 doi: 10.1016\/j.jacc.2007.07.053\u000d\u000a    \u000a\u000aR2. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG,\u000d\u000a      Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP.\u000d\u000a      Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12\u000d\u000a      receptor antagonist, compared with clopidogrel in patients with acute\u000d\u000a      coronary syndromes. J Am Coll Cardiol. 2007;50:1852-1856. doi: 10.1016\/j.jacc.2007.07.058\u000d\u000a    \u000a\u000aR3. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C,\u000d\u000a      Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A,\u000d\u000a      Steg PG, Storey RF, Harrington RA, for the PLATO Investigators.\u000d\u000a      Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N\u000d\u000a      Engl J Med. 2009;361:1045-1057 doi: 10.1056\/NEJMoa0904327\u000d\u000a    \u000a\u000aR4. Storey RF, Angiolillo D, Patil S, Desai B, Ecob R,\u000d\u000a      Husted S, Emanuelsson H, Cannon C, Becker R, Wallentin L. Inhibitory\u000d\u000a      effects of ticagrelor compared to clopidogrel on platelet function in\u000d\u000a      patients with acute coronary syndromes: The PLATO PLATELET substudy J Am\u000d\u000a      Coll Cardiol. 2010;56:1456-1462 doi: 10.1016\/j.jacc.2010.03.100\u000d\u000a    \u000a\u000aR5. Storey RF, Becker RC, Harrington RA, Husted S, James SK,\u000d\u000a      Cools F, Steg PG, Khurmi NS, Emanuelsson H, Cooper A, Cairns R, Cannon CP,\u000d\u000a      Wallentin L. Characterisation of dyspnoea in PLATO study patients treated\u000d\u000a      with ticagrelor or clopidogrel and its association with clinical outcomes.\u000d\u000a      Eur Heart J 2011;32:2945-2953 doi: 10.1093\/eurheartj\/ehr231\u000d\u000a    \u000a\u000aR6. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R,\u000d\u000a      Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Paris C, Purdy\u000d\u000a      D, Wilson V, Ledley GS, Storey RF. Randomized double-blind\u000d\u000a      assessment of the onset and offset of the antiplatelet effects of\u000d\u000a      ticagrelor versus clopidogrel in patients with stable coronary artery\u000d\u000a      disease: The ONSET\/OFFSET study. Circulation. 2009;120:2577-2585 doi:\u000d\u000a\u0009  10.1161\/CIRCULATIONAHA.109.912550\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    S1. NICE technology appraisal guidance TA236: Ticagrelor for the\u000d\u000a      treatment of acute coronary syndromes (http:\/\/tinyurl.com\/muuqx9f).\u000d\u000a    S2. European Medicines Agency assessment report for ticagrelor (http:\/\/tinyurl.com\/m9x9vvu).\u000d\u000a    S3. US Federal Drug Administration approved drug products: Ticagrelor\u000d\u000a\u0009(http:\/\/tinyurl.com\/3hhaw).\u000d\u000a    S4. Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H, et al.\u000d\u000a      ESC guidelines for the management of acute coronary syndromes in patients\u000d\u000a      presenting without persistent ST- segment elevation. Eur Heart J. 2011;\u000d\u000a      32:2999-3054 doi: 10.1093\/eurheartj\/ehr236\u000d\u000a    S5. Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, et al.\u000d\u000a      ESC Guidelines for the management of acute myocardial infarction in\u000d\u000a      patients presenting with ST-segment elevation: The Task Force on the\u000d\u000a      management of ST-segment elevation acute myocardial infarction of the\u000d\u000a      European Society of Cardiology (ESC). Eur Heart J 2012;33:2569-2619 doi:\u000d\u000a\u0009  10.1093\/eurheartj\/ehs215\u000d\u000a    S6. Sheffield Teaching Hospitals NHS Foundation Trust guidelines for the\u000d\u000a      management of non- ST-elevation myocardial infarction and ST-elevation\u000d\u000a      myocardial infarction (on Sheffield Teaching Hospitals intranet; copy on\u000d\u000a      file).\u000d\u000a    S7. AstraZeneca. Email on file about number of UK NHS Trusts that have\u000d\u000a      adopted ticagrelor, dated 22 May 2013.\u000d\u000a    ","Title":"\u000d\u000a    New drug for heart attack victims\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2638077","Name":"Sheffield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Platelets play a critical role in most heart attacks. Aspirin is commonly\u000d\u000a      used to prevent heart attack but has a weak antiplatelet effect so\u000d\u000a      clopidogrel, an inhibitor of the platelet P2Y12 receptor, was\u000d\u000a      developed for additional efficacy in patients with acute coronary\u000d\u000a      syndromes (heart attack or unstable angina). Professor Robert Storey\u000d\u000a      (University of Sheffield, since 2002) and his platelet research group\u000d\u000a      focussed on the limitations of clopidogrel and options for improved\u000d\u000a      therapy. In order to address these limitations, ticagrelor was developed\u000d\u000a      by AstraZeneca as a novel reversibly- binding P2Y12 receptor\u000d\u000a      inhibitor. Having previously published research on P2Y12\u000d\u000a      receptor biology and pharmacology, Storey and his group made the following\u000d\u000a      contributions to the development of ticagrelor:\u000d\u000a    DISPERSE-2 study (October 2004 to May 2005): Storey was one of\u000d\u000a      four members of the Executive Committee and the Chief Investigator of the\u000d\u000a      pharmacodynamic substudy for this phase IIb study, comparing ticagrelor\u000d\u000a      (formerly AZD6140) with clopidogrel in patients with acute coronary\u000d\u000a      syndromes. The study established the safety and tolerability of ticagrelor\u000d\u000a      in this population and demonstrated its superior antiplatelet efficacy,\u000d\u000a      providing a foundation for the design of the subsequent phase III PLATO\u000d\u000a      study. Storey led the analyses of and presented the substudy data and was\u000d\u000a      first author on the substudy publication as well as senior author on the\u000d\u000a      main study publication (R1, R2).\u000d\u000a    PLATO study (October 2006 to February 2009): Storey was a member\u000d\u000a      of the executive committee for the 18,624-patient phase III PLATO study\u000d\u000a      and contributed to the study design. He was a co- author on the\u000d\u000a      publication of the main study results that demonstrated that ticagrelor\u000d\u000a      reduces recurrent ischaemic events (relative risk reduction 16%) and\u000d\u000a      all-cause mortality (relative risk reduction 22%) compared to the standard\u000d\u000a      treatment with clopidogrel (R3). He was also the Chief Investigator for\u000d\u000a      the PLATO PLATELET substudy that provided valuable additional information\u000d\u000a      about the pharmacodynamic effects of ticagrelor compared to clopidogrel in\u000d\u000a      the PLATO study (R4) and has also led other publications\u000d\u000a      related to analyses of the PLATO database that guide the use of ticagrelor\u000d\u000a      in acute coronary syndromes. In particular, the extent of the mortality\u000d\u000a      reduction with ticagrelor compared to clopidogrel surpassed expectations\u000d\u000a      since other similar studies, such as clopidogrel compared to placebo or\u000d\u000a      prasugrel compared to clopidogrel in acute coronary syndromes, had not\u000d\u000a      achieved significant mortality reduction. Storey led an analysis providing\u000d\u000a      important characterisation of ticagrelor-related dyspnoea and its benign\u000d\u000a      nature, which is essential information for prescribing clinicians (R5).\u000d\u000a      72% of the patients in PLATO PLATELET were recruited in Sheffield and\u000d\u000a      Storey conducted the analyses, presented and published the data for this\u000d\u000a      substudy.\u000d\u000a    ONSET\/OFFSET study (October 2007 to May 2009): Storey was a senior\u000d\u000a      investigator and UK Chief Investigator for this study, which demonstrated\u000d\u000a      more clearly the pharmacokinetic and pharmacodynamic advantages of\u000d\u000a      ticagrelor compared to clopidogrel in patients with ischaemic heart\u000d\u000a      disease (R6). 30% of the patients were recruited in Sheffield. Storey led\u000d\u000a      the analyses of the cardiopulmonary substudy data, presenting this data\u000d\u000a      and acting as first author on the publication which has provided essential\u000d\u000a      information on ticagrelor-related dyspnoea (European Heart Journal 2010).\u000d\u000a    "},{"CaseStudyId":"12332","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Research at the University of Sheffield into the outcome of treatments\u000a      for patients with congenital adrenal hyperplasia (CAH) has led to a new\u000a      drug treatment being developed, trialled with patients and positive\u000a      outcomes demonstrated. The research has also had commercial impact through\u000a      the creation of a spin-out company, Diurnal Ltd, to commercialise the\u000a      treatment, which has successfully raised investment from both venture\u000a      capitalists and the pharmaceutical industry, and created new jobs and\u000a      major industrial contracts.\u000a    Process to impact:\u000a    In 2005, following a meeting with Ross, the European Medicines Agency\u000a      (EMA) agreed that there was an unmet need for patients with CAH and\u000a      adrenal insufficiency and that Chronocort® could provide a\u000a      significant improvement in treatment, and granted Ross Orphan drug\u000a      designation for Chronocort® to treat CAH (S1) and adrenal\u000a      insufficiency (S2). This designation is to encourage drug development when\u000a      a condition is chronically debilitating, the prevalence is <5 in\u000a      10,000, and the medicine would be of significant benefit to those\u000a      affected. This enabled Phase 1 trials of Chronocort® to go\u000a      ahead. The EMA stated that if use of Chronocort® could\u000a      demonstrate better control of the morning androgen precursor hormones this\u000a      would constitute evidence of significant benefit and would be an\u000a      appropriate primary outcome in clinical trials of patients (S3). This led\u000a      to a Phase 2 clinical trial in CAH patients.\u000a    Following publication in 2010 by the EMA PaeDiatric COmmittee (PDCO) that\u000a      there was no licensed preparation of hydrocortisone for neonates and\u000a      infants with CAH and adrenal insufficiency, the University of Sheffield\u000a      and Diurnal Ltd as an SME partner won a European Framework 7 grant of\u000a      €5.6M to develop a neonatal and infant preparation of hydrocortisone,\u000a      Infacort (S4). Diurnal Ltd then submitted a Paediatric Investigation Plan\u000a      (PIP) to the EMA PDCO — a process usually delivered only by major\u000a      pharmaceutical companies — for the use of Infacort® in neonates\u000a      and infants. The PIP was approved in 2013 (S5), confirming the unmet need\u000a      that Infacort can address and that the clinical development plan was\u000a      appropriate to provide a Paediatric Use Market Authorisation (PUMA). This\u000a      has enabled the manufacture of Infacort® to go ahead and\u000a      Infacort is currently being evaluated in phase 1 clinical studies in\u000a      healthy volunteers.\u000a    Commercial impact\u000a    The spin-out company, Diurnal Ltd, was founded in 2004 with Professor\u000a      Ross as a founding director and subsequently Chief Scientific Officer.\u000a      Diurnal Ltd was created to develop and commercialise the new drug\u000a      Chronocort® based on the research and patents filed by the\u000a      University of Sheffield. Diurnal Ltd licensed the original patent from the\u000a      University of Sheffield and has 15 pending patent applications and 5\u000a      granted patents all filed since 2001. Since 2008, Diurnal Ltd has\u000a      successfully raised over £3.8M investment for development of its drug\u000a      product portfolio from a venture capital consortium including a £461K\u000a      investment from a global pharmaceutical company, through an option to\u000a      licence Chronocort® from Diurnal Ltd (S6). Diurnal Ltd has a\u000a      Cooperative Research and Development Agreement (CRADA) with the National\u000a      Institute of Health (NIH), USA for the development of Chronocort (S7).\u000a      CRADAs signify recognition by NIH of the importance of the drug\u000a      development programme to patients, with NIH agreeing to fund all\u000a      components of the clinical trials performed at NIH. Diurnal Ltd has\u000a      undertaken its drug development and manufacture through both manufacture\u000a      (Penn Ltd, Quay Pharmaceuticals Ltd, GLATT GmbH) and clinical (Simbec\u000a      Research Ltd) research organisations with contracts worth over £2.7M,\u000a      bringing new work and employment to these companies. Diurnal Ltd employs 5\u000a      staff and since 2008 has spent £288K on consultant contracts to help bring\u000a      Chronocort® to market (S6).\u000a    Health impact\u000a    The research has led to the development and manufacture of two new drugs\u000a      for cortisol deficiency: Chronocort® for adults and a neonatal\u000a      and infant formulation, Infacort®. In 2008, oral formulations\u000a      of hydrocortisone, Chronocort®, were generated with a delayed\u000a      and sustained release profile and trialled in 6 healthy volunteers (S8).\u000a      The results demonstrated that it was possible to replace the overnight\u000a      rise in cortisol with Chronocort. In 2009, further phase 1 clinical trials\u000a      were carried out in 28 healthy volunteers and these demonstrated that\u000a      Chronocort® could reproducibly replace overnight circadian\u000a      cortisol levels (S9). In 2010, a 3 month phase 2 trial of Chronocort®\u000a      in 14 adult patients with CAH demonstrated improved overnight disease\u000a      control, using the primary outcome recommended by the EMA (S10). Since\u000a      2010 Diurnal has moved its manufacture to a facility that can optimise the\u000a      formulation and supply phase 3 clinical trial material.\u000a    Public understanding\u000a    The public awareness of the problems for patients with CAH has been\u000a      stimulated by media publicity surrounding the CaH Adult Study Executive\u000a      (CaHASE) publications of poor health outcomes in CAH patients. Patient\u000a      group awareness has been increased through presentations by Ross to\u000a      patient groups including American CAH patient group CARES (5000 Community\u000a      Members), New York 2009; UK CAH patient group, Manchester 2011; and UK\u000a      Addison's Disease Self-Help Group (1400 members), London, 2012. In the USA\u000a      CARES are promoting clinical trials with Chronocort®, and Ross\u000a      has been appointed an Advisor to the American CAH patient support group.\u000a    ","ImpactSummary":"\u000a    Research on Congenital Adrenal Hyperplasia (CAH) at the University of\u000a      Sheffield has resulted in both health and commercial impacts. The research\u000a      has led to a new drug treatment, Chronocort®, being developed\u000a      for CAH. Chronocort® has been tested in CAH patients with the\u000a      positive outcome of improved disease control.\u000a    Commercial impact arose from the creation of a spin-out company, Diurnal\u000a      Ltd, in 2004 which has raised investment of £3.8M since 2008, including\u000a      £0.4M from pharmaceutical industry sources, and (as an SME partner) a\u000a      €5.6M Framework 7 grant to develop a paediatric treatment for CAH. Diurnal\u000a      has created five new jobs and has contracts with six UK companies worth\u000a      £2.7M.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Sheffield\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5128638","Name":"New York"}],"References":"\u000a    University of Sheffield Authors are highlighted in bold.\u000a    \u000aR1. Arlt, W., Willis, D.S., Wild, S.H., Krone, N., Doherty, E.J., Hahner,\u000a      S., Han, T.S., Carroll, P.V., Conway, G.S., Rees, D.A., Stimson, R.H.,\u000a      Walker, B.R., Connell, J.M. & Ross, R.J. (2010) Health status\u000a      of adults with congenital adrenal hyperplasia: a cohort study of 203\u000a      patients. J Clin Endocr Metab. 95, 5110-5121. doi: 10.1210\/jc.2010-0917\u000a    \u000a\u000aR2. Carey, R.M. Adrenal disease update (2011). J Clin Endocr Metab, 96,\u000a      3583-3591. doi: 10.1210\/jc.2011-2162\u000a    \u000a\u000aR3. Mah, P.M., Jenkins, R.C., Rostami-Hodjegan, A., Newell-Price, J.,\u000a        Doane, A., Ibbotson, V., Tucker, G.T. & Ross, R.J. (2004)\u000a      Weight-related dosing, timing and monitoring hydrocortisone replacement\u000a      therapy in patients with adrenal insufficiency. Clinical Endocrinol. 61,\u000a      367-375. doi: 10.1111\/j.1365-2265.2004.02106.x\u000a    \u000a\u000aR4. Merza, Z., Rostami-Hodjegan, A., Memmott, A., Doane, A.,\u000a        Ibbotson, V., Newell-Price, J., Tucker, G.T. & Ross, R.J. (2006)\u000a      Circadian hydrocortisone infusions in patients with adrenal insufficiency\u000a      and congenital adrenal hyperplasia. Clinical Endocrinol. 65, 45-50. doi:\u000a\u0009  10.1111\/j.1365-2265.2006.02544.x\u000a    \u000a\u000aR5. Newell-Price, J., Whiteman, M., Rostami-Hodjegan, A.,\u000a      Darzy, K., Shalet, S., Tucker, G.T. & Ross, R.J. (2008)\u000a      Modified-release hydrocortisone for circadian therapy: a proof-of-\u000a      principle study in dexamethasone-suppressed normal volunteers. Clinical\u000a      Endocrinol. 68, 130-135. doi: 10.1111\/j.1365-2265.2007.03011.x\u000a    \u000a\u000aR6. Debono, M., Ghobadi, C., Rostami-Hodjegan, A., Huatan, H., Campbell,\u000a        M.J., Newell-Price, J., Darzy, K., Merke, D.P., Arlt, W. & Ross,\u000a        R.J. (2009) Modified-release hydrocortisone to provide circadian\u000a      cortisol profiles. J Clin Endocr Metab. 94, 1548-1554. doi: 10.1210\/jc.2008-2380\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    S1. Orphan Designation of Chronocort for CAH (http:\/\/tinyurl.com\/ornrmoh).\u000a    S2. Orphan Designation of Chronocort for Adrenal insufficiency (http:\/\/tinyurl.com\/q3jr5nt).\u000a    S3. Report from EMA meeting on Chronocort on file.\u000a    S4. Treatment of Adrenal Insufficiency in Neonates (TAIN) funded by EU\u000a      FP-7 Grant:\u000a      http:\/\/www.tain-project.org\/\u000a      and http:\/\/cordis.europa.eu\/projects\/rcn\/102053_en.html\u000a    S5. Paediatric Investigation Plan for Infacort programme approved by the\u000a      EMA (http:\/\/tinyurl.com\/mdlmxf7).\u000a    S6. Letter from Diurnal Ltd to University of Sheffield confirming\u000a      investment and spend since 2008.\u000a    S7. Diurnal press release \"Diurnal enters into a Cooperative Research and\u000a      Development Agreement with the National Institute of Health\" (http:\/\/tinyurl.com\/kn64c3w).\u000a    S8. Newell-Price, J., Whiteman, M., Rostami-Hodjegan, A., Darzy, K.,\u000a      Shalet, S., Tucker, G.T. & Ross, R.J. (2008) Modified-release\u000a      hydrocortisone for circadian therapy: a proof-of-principle study in\u000a      dexamethasone-suppressed normal volunteers. Clinical Endocrinology\u000a      68, 130-135. doi: 10.1111\/j.1365-2265.2007.03011.x\u000a    S9. Debono, M., Ghobadi, C., Rostami-Hodjegan, A., Huatan, H., Campbell,\u000a      M.J., Newell-Price, J., Darzy, K., Merke, D.P., Arlt, W. & Ross, R.J.\u000a      (2009) Modified-release hydrocortisone to provide circadian cortisol\u000a      profiles. The Journal of clinical endocrinology and metabolism 94,\u000a      1548-1554. doi: 10.1210\/jc.2008-2380\u000a    S10. Verma, S., Vanryzin, C., Sinaii, N., Kim, M.S., Nieman, L.K.,\u000a      Ravindran, S., Calis, K.A., Arlt, W., Ross, R.J. & Merke, D.P. (2010)\u000a      A pharmacokinetic and pharmacodynamic study of delayed- and\u000a      extended-release hydrocortisone (Chronocort) vs. conventional\u000a      hydrocortisone (Cortef) in the treatment of congenital adrenal\u000a      hyperplasia. Clin Endocrinol (Oxf) 72, 441-447. doi: 10.1111\/j.1365-2265.2009.03636.x\u000a    ","Title":"\u000a    Clinical development and manufacture of a new drug, Chronocort®,\u000a      for treatment of the rare orphan disease congenital adrenal hyperplasia\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"2638077","Name":"Sheffield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In 2000, Professor Richard Ross (University of Sheffield, 1995-date), led\u000a      a UK audit, funded by the Endocrinology Trust, assessing the standard of\u000a      care for adult patients with congenital adrenal hyperplasia (CAH). CAH is\u000a      a condition in which the adrenal gland secretes insufficient amounts of\u000a      the essential stress hormone, cortisol. The audit demonstrated that there\u000a      was no consensus on patient care and that current treatment regimens were\u000a      inadequate. Following presentation of the findings to the British\u000a      Endocrine Society in 2001, the CaH Adult Study Executive (CaHASE), chaired\u000a      by Ross, was formed to investigate the health of patients with CAH across\u000a      17 UK endocrine centres.\u000a    Between 2001 and 2010, CaHASE studied the world's largest cohort of adult\u000a      CAH patients. The research highlighted that these patients have poor\u000a      health outcomes including obesity, osteoporosis, an impaired quality of\u000a      life, poor metabolic profile, and infertility, and that this was related\u000a      to inadequate disease control through a lack of appropriate cortisol\u000a      (hydrocortisone) replacement therapy (R1). The work demonstrated the unmet\u000a      need for new drug treatments and was cited by the Endocrine Society (USA)\u000a      as one of the most influential publications in adrenal disease (R2).\u000a    In 2001, recognising the need for new treatments, Ross examined the\u000a      cortisol rhythm in healthy volunteers and the pharmacokinetics of current\u000a      hydrocortisone therapy in patients with CAH. Cortisol levels in the body\u000a      naturally follow a circadian (around the day) rhythm, rising overnight\u000a      from about 3am to peak on waking and then falling during the day. Thus,\u000a      the main rise in cortisol levels occurs whilst sleeping.\u000a    In 2004, Ross demonstrated that oral tablet hydrocortisone replacement\u000a      therapy cannot replace the overnight rise in cortisol levels because of\u000a      the short plasma half-life of hydrocortisone (R3). The failure of cortisol\u000a      to rise overnight in patients with CAH is critical and the main cause of\u000a      poor control of the disease. CAH results from an enzyme block in the\u000a      production of cortisol from the adrenal gland, and without appropriate\u000a      cortisol replacement at night, precursor hormones accumulate like water\u000a      behind a dam. These precursor hormones are androgens (male hormones) and\u000a      cause precocious puberty, infertility and virilisation of women. To try\u000a      and prevent this overnight rise in androgens, clinicians often over-treat\u000a      patients with potent steroids causing increased cardiovascular risk,\u000a      obesity and osteoporosis.\u000a    In 2006, Ross addressed the failure of treatment in CAH, undertaking\u000a      continuous intravenous infusion studies with hydrocortisone (R4) and\u000a      demonstrating that it was possible to replicate the overnight cortisol\u000a      rise and 24h circadian rhythm with infusions of hydrocortisone. This\u000a      improved the disease control of CAH by preventing the inappropriate rise\u000a      in precursor androgenic hormones without exposing patients to excess\u000a      steroid. Based on this proof of concept work, Ross then developed an oral\u000a      formulation of modified release hydrocortisone, called Chronocort®,\u000a      to replace the normal physiological overnight rise in cortisol levels with\u000a      the aim of improving treatment outcomes for patients with CAH (R5, R6).\u000a    The potential beneficiaries from Chronocort® include those\u000a      patients with cortisol deficiency due to CAH (60-100 cases per million),\u000a      Addison's disease (93-140 cases per million) and pituitary failure\u000a      (150-280 cases per million). Treatment for cortisol deficiency was only\u000a      introduced in the 1950s; prior to that date most patients died. With the\u000a      introduction of treatment there is now a growing cohort of adult patients\u000a      who require on-going therapy.\u000a    "},{"CaseStudyId":"12333","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Sheffield research has led to the development of a routine test for the\u000d\u000a      genetic defect regulating the use of 6-mercaptopurine, a thiopurine drug\u000d\u000a      used to treat childhood leukaemia. Routine tests for this genetic defect\u000d\u000a      are now recommended (and in some cases are mandatory) prior to starting\u000d\u000a      thiopurine drugs. TPMT testing is one of the first pharmacogenetic\u000d\u000a      analyses that has passed from research into routine clinical use and has\u000d\u000a      become a textbook example of pharmacogenomic research.\u000d\u000a    Impact on health and welfare\u000d\u000a    The detection of thiopurine methyltransferase (TPMT) deficiency prior to\u000d\u000a      the start of thiopurine treatment allows the early identification of the 1\u000d\u000a      in 300 genetically disposed to serious side effects from treatment with\u000d\u000a      thiopurine drugs. Identifying TPMT deficiency spares patients painful and\u000d\u000a      potentially life-threatening sepsis\u000d\u000a    In the UK, approximately 400 children and young adults are diagnosed with\u000d\u000a      acute lymphoblastic leukaemia (ALL) per year. All these children are\u000d\u000a      tested for TPMT deficiency prior to the start of thiopurine treatment. The\u000d\u000a      thiopurine drug used is called 6-mercaptopurine; daily oral\u000d\u000a      6-mercaptopurine chemotherapy is taken for two (girls) or three (boys)\u000d\u000a      years. The detection of TPMT deficiency prior to treatment allows\u000d\u000a      immediate thiopurine dose reduction to 10% of the \"normal\" dose and so\u000d\u000a      avoids catastrophic myelosuppression. TPMT-guided dose reduction for the\u000d\u000a      drug 6-mercaptopurine allows the other chemotherapeutic drugs to be given\u000d\u000a      at their maximum tolerated doses and avoids the withdrawal of chemotherapy\u000d\u000a      (and the potential for the re-emergence of the leukaemia) that would have\u000d\u000a      occurred if the full dose of mercaptopurine had been given to the TPMT\u000d\u000a      deficient patient.\u000d\u000a    In addition, children with very high TPMT activities may not respond to\u000d\u000a      standard doses of thiopurine drugs and require protocol-directed dose\u000d\u000a      escalation to accumulate sufficient concentrations of the cytotoxic and\u000d\u000a      immunosuppressive metabolites (called thioguanine nucleotides). Monitoring\u000d\u000a      of drug metabolite concentrations is clinically useful in this situation;\u000d\u000a      assays initially developed by Lennard are now available in Clinical\u000d\u000a      Pathology service laboratories internationally (S1, S2) to measure\u000d\u000a      thiopurine drug metabolites in addition to TPMT genotype and activity.\u000d\u000a      Thiopurine metabolite monitoring enables the child who forms sub-optimal\u000d\u000a      amounts of cytotoxic metabolites due to high inherited TPMT (approximately\u000d\u000a      10% of patients) to be differentiated from the child who lacks thiopurine\u000d\u000a      metabolites for other reasons (e.g. due to tablet taking problems), prior\u000d\u000a      to dose escalation.\u000d\u000a    Changes to trial guidelines\u000d\u000a    The work by Lennard and Lilleyman, to identify the impact of the TPMT\u000d\u000a      genetic polymorphism on the action of thiopurine drugs and the detection\u000d\u000a      of TPMT deficiency, has led to changes in trial guidelines in both the UK\u000d\u000a      and USA (S3, S4). The detection of TPMT deficiency prior to the start of\u000d\u000a      mercaptopurine chemotherapy was incorporated into the protocol for the MRC\u000d\u000a      ALL 2003 (recruitment 2003 to 2011) therapeutic trial for childhood ALL\u000d\u000a      and it is an integral, mandatory, component of the current national trial,\u000d\u000a      UK ALL 2011(recruitment from 2012). The Sheffield Clinical Pharmacology\u000d\u000a      Unit (led by Lennard, funded by Leukaemia and Lymphoma Research; LLR) is\u000d\u000a      responsible for the organisation and implementation of the thiopurine\u000d\u000a      studies within these ALL trials; about 400 children are diagnosed\u000d\u000a      annually.\u000d\u000a    Evidence of enhanced awareness of health risks and benefits by\u000d\u000a          practitioners (NHS consultants)\u000d\u000a    The importance of inherited TPMT to thiopurine treatment outcome,\u000d\u000a      initially demonstrated in children with ALL by Lennard and Lilleyman, has\u000d\u000a      been translated to other disease states (S5). Thiopurine drugs are used\u000d\u000a      extensively to control autoimmune conditions e.g. inflammatory bowel\u000d\u000a      disease which affects approximately 180,000 people in the UK; potentially\u000d\u000a      some 600 patients with TPMT deficiency who can be detected and thus\u000d\u000a      patient care and the quality of life improved by avoiding severe and\u000d\u000a      costly myelosuppressive adverse drug reactions. Overall, 67% of UK\u000d\u000a      consultants test for TPMT prior to starting thiopurine based\u000d\u000a      immunosuppression (S6). The cost of treatment and in-patient care for a\u000d\u000a      severe episode of bone marrow failure due to thiopurine induced\u000d\u000a      myelosuppression is over £9,000. The TPMT genotype test is currently £27\u000d\u000a      per patient thus the cost of detecting 1 patient with TPMT deficiency is\u000d\u000a      slightly less than in-patient treatment, but TPMT testing enables a\u000d\u000a      reduction in treatment-related morbidity and mortality and improved\u000d\u000a      patient care. Treatment guidelines for dermatologists advocate TPMT\u000d\u000a      testing (S7) whilst rheumatologists and hepatologists recommend TPMT\u000d\u000a      testing (S8). The British National Formulary suggests that clinicians\u000d\u000a      should consider TPMT testing.\u000d\u000a    A new diagnostic or clinical technology has been adopted\u000d\u000a    As part of Lennard & Vora's current LLR funding, TPMT genotyping and\u000d\u000a      thiopurine metabolite analysis (and guidelines for clinical\u000d\u000a      interpretation) within the ALL 2011 trial was transferred from research\u000d\u000a      laboratories into laboratories with Clinical Pathology Accreditation (CPA)\u000d\u000a      within the NHS service sector; the transfer was successfully completed in\u000d\u000a      July 2013. The interpretation guidelines for TPMT testing are disease\u000d\u000a      specific (S9). In the UK thiopurine assays are now available at\u000d\u000a      super-regional pathology centres (S2). In addition to the 400 children and\u000d\u000a      young adults diagnosed with ALL per year, adults treated with thiopurine\u000d\u000a      immunosuppression will also be tested, with the current take-up of TPMT\u000d\u000a      testing approximately two thirds of the 180,000 adults diagnosed with\u000d\u000a      inflammatory bowel disease.\u000d\u000a    Impact on public policy and services\u000d\u000a    Decisions by a health service or regulatory authority have been\u000d\u000a        informed by research\u000d\u000a    The US Food and Drug Administration (FDA) directed label modifications\u000d\u000a      for 6-mercaptopurine (July 2004) and azathioprine (July 2005) to reflect\u000d\u000a      the pharmacogenetics of metabolism and recommends TPMT testing prior to\u000d\u000a      initiating thiopurine therapy. Guidance in the UK from the National\u000d\u000a      Formulary recommends that patients have their TPMT status checked prior to\u000d\u000a      starting thiopurine drugs benefiting both the TPMT deficient individual (1\u000d\u000a      in 300) and the 11% of patients who are heterozygotes and are at an\u000d\u000a      increased risk of myelosuppression.\u000d\u000a    Evidence of improved cost-effectiveness\u000d\u000a    The cost-effectiveness of TPMT genotyping, for both UK and European ALL\u000d\u000a      treatment protocols, was demonstrated prior to the widespread introduction\u000d\u000a      of the test (S10). Routine TPMT testing prevents the TPMT precipitated\u000d\u000a      episodes of profound myelosuppression that are caused by standard doses of\u000d\u000a      thiopurine drugs in the TPMT deficient patient. TPMT testing prevents\u000d\u000a      possible death from neutropenia-induced sepsis and thus improves the\u000d\u000a      health-related quality of life. In a child with ALL, current costs (2013)\u000d\u000a      of in-patient care due to thiopurine induced bone-marrow failure is\u000d\u000a      approximately £200 (with drug support running at an additional £50 to £60)\u000d\u000a      per night. Admission to the Intensive Therapy Unit (ITU) would be more\u000d\u000a      expensive. This would be followed by the task of management of the bone\u000d\u000a      marrow failure over a period of 6 to 8 weeks — this would entail the\u000d\u000a      treatment of recurrent infections and associated use of expensive blood\u000d\u000a      products. A total cost of about £10,000, or more, depending on the\u000d\u000a      severity of the bone marrow failure and the recovery time.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    A routine test to screen for patients genetically disposed to serious\u000d\u000a      side effects from treatment with thiopurine drugs has been widely adopted\u000d\u000a      following research by the Academic Unit of Clinical Pharmacology at the\u000d\u000a      University of Sheffield. The test has spared patients painful and\u000d\u000a      potentially life-threatening sepsis, and saved the considerable associated\u000d\u000a      treatment costs which have been estimated to be over £9,000 per patient\u000d\u000a      for a 17 day hospital stay. It has also led directly to a change in\u000d\u000a      clinical guidelines and recommendations in both the USA and UK.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Sheffield\u000d\u000a    ","Institutions":[{"AlternativeName":"Sheffield (University of)","InstitutionName":"University of Sheffield","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007157}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000aR1. Otterness D, Szumlanski C, Lennard L, Klemensdal B, Aarbakke\u000d\u000a      J, Park-Hah J, Iven H, Schmeigelow K, Branum E, O'Brien J, Weinshilboum R.\u000d\u000a      Human thiopurine methyltransferase pharmacogenetics: gene sequence\u000d\u000a      polymorphisms. Clin Pharmacol Ther 1997; 62: 60-73. PubMed ID: 9246020\u000d\u000a    \u000a\u000aR2. Lilleyman JS, Lennard L. 6-Mercaptopurine metabolism and risk\u000d\u000a      of relapse in childhood acute lymphoblastic leukaemia. The Lancet 1994;\u000d\u000a      343: 1188-1190. doi: 10.1016\/S0140-6736(94)92400-7\u000d\u000a    \u000a\u000aR3. Lennard L, Gibson BES, Nicole T, Lilleyman JS.\u000d\u000a      Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine\u000d\u000a      toxicity during treatment for acute lymphoblastic leukaemia. Archives of\u000d\u000a      Disease in Childhood 1993; 69: 577-579. PubMed ID: 8257179\u000d\u000a    \u000a\u000aR4. Lennard L, Lewis IJ, Michelagnoli M, Lilleyman JS.\u000d\u000a      Thiopurine methyltransferase deficiency in childhood lymphoblastic\u000d\u000a      leukaemia: 6-mercaptopurine dosage strategies. Med Ped Oncol 1997; 29\u000d\u000a      252-255. PubMed ID: 9251729\u000d\u000a    \u000a\u000aR5. Lennard L, Singleton HJ. High-performance liquid\u000d\u000a      chromatographic assay of human red blood cell thiopurine methyltransferase\u000d\u000a      activity. J Chromatogr B Biomed Appl. 1994;661:25-33. PubMed ID: 7866549\u000d\u000a    \u000a\u000aR6. Lennard L, Richards S, Cartwright CS, Mitchell C, Lilleyman\u000a        JS, Vora A. The thiopurine methyltransferase genetic polymorphism is\u000d\u000a      associated with thioguanine-related veno- occlusive disease of the liver\u000d\u000a      in children with acute lymphoblastic leukaemia. Clin Pharmacol Ther 2006;\u000d\u000a      80: 375-383. doi: 10.1016\/j.clpt.2006.07.002\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000d\u000a    S1. http:\/\/tinyurl.com\/ll7588u\u000d\u000a      corroborates TPMT testing available in the US\u000d\u000a    S2. http:\/\/www.cityassays.org.uk\/tpmt.html\u000d\u000a      is one of the 2 services in the UK and corroborates TPMT testing routinely\u000d\u000a      available to the NHS.\u000d\u000a    S3. UK ALL2011 trial protocol. United Kingdom trial for children and\u000d\u000a      young adults with acute lymphoblastic leukaemia and lymphoma.\u000d\u000a      International standard randomised controlled trial number (ISRCTN)\u000d\u000a      64515327, Section 7.12.2 and Appendix 21. ALL2003 trial protocol. United\u000d\u000a      Kingdom national randomised trial for children and young adults with acute\u000d\u000a      lymphoblastic leukaemia. ISRCTN 07355119, Appendix C.\u000d\u000a    S4. Relling MV, Gardner EE, Sandborn WJ, Pui C-H, Stein CM, Carrillo M,\u000d\u000a      Evans WE, Klein TE. Clinical pharmacogenetics implementation consortium\u000d\u000a      guidelines for thiopurine methyltransferase genotype and thiopurine\u000d\u000a      dosing. Clin Ther Pharmacol 2011;89:387-391. doi: http:\/\/dx.doi.org\/10.1038\/clpt.2010.320\u000d\u000a    S5. Roblin X, Oussalah A, Chevaux J-B, Sparrow M, Peyrin-Biroulet L. Use\u000d\u000a      of thiopurine testing in the management of inflammatory bowel diseases in\u000d\u000a      clinical practice: A worldwide survey of experts. Inflamm Bowel Dis 2011;\u000d\u000a      17:2480-2487. doi: 10.1002\/ibd.21662\u000d\u000a    S6. Current use of pharmacogenetic testing: a national survey of\u000d\u000a      thiopurine methyltransferase testing prior to azathioprine prescription,\u000d\u000a      Fargher et al, Journal of Clinical Pharmacy and Therapeutics, 32,\u000d\u000a      2:187-195 doi: 10.1111\/j.1365-2710.2007.00805.x\u000d\u000a    S7. Meggitt SJ, Anstey AV, Mustapa MF, Reynolds NJ, Wakelin S. British\u000d\u000a      Association of Dermatologists' guidelines for the safe and effective\u000d\u000a      prescribing of azathioprine 2011. Br J Dermatol 2011; 165: 711-734. doi:\u000d\u000a\u0009  10.1111\/j.1365-2133.2011.10575.x\u000d\u000a    S8. Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG)\u000d\u000a      guidelines for management of autoimmune hepatitis. Gut 2012; 60:1611-1629.\u000d\u000a      doi: 10.1136\/gut.2010.235259\u000d\u000a    S9. Lennard L, Cartwright CS, Wade R, Richards SM, Vora A. Thiopurine\u000d\u000a      methyltransferase genotype-phenotype discordance, and thiopurine active\u000d\u000a      metabolite formation, in childhood acute lymphoblastic leukaemia. British\u000d\u000a      Journal of Clinical Pharmacology, 2013, doi: 10.1111\/bcp.12066 doi: 10.1111\/bcp.12066\u000d\u000a    S10. van den Akker-van Marle M, Gurwitz D, Detmar D, Enzing CM, Hopkins\u000d\u000a      MM, Gutierrez de Mesa E, Ibarreta D. Cost-effectiveness of\u000d\u000a      pharmacogenomics in clinical practice: a case study of thiopurine\u000d\u000a      methyltransferase genotyping in acute lymphoblastic leukaemia in Europe.\u000d\u000a      Pharmacogenomics 2006; 7:783-792. doi: 10.2217\/14622416.7.5.783\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Safer treatment of childhood leukaemia through improved delivery of\u000d\u000a      thiopurine drugs\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2638077","Name":"Sheffield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    During the period 1993 to 2003, Dr Lynne Lennard (Reader in Pharmacology,\u000d\u000a      Department of Human Metabolism, University of Sheffield) together with\u000d\u000a      John Lilleyman (Honorary Professor and Consultant Haematologist, Sheffield\u000d\u000a      Children's Hospital and, from 1995, Professor of Paediatric Haematology,\u000d\u000a      Barts and The London) investigated the wide variations in clinical\u000d\u000a      response to a drug used in the chemotherapy of childhood leukaemia. The\u000d\u000a      drug was called 6-mercaptopurine, a thiopurine drug. A dose of drug that\u000d\u000a      was too toxic in one child could be ineffective in another child. A\u000d\u000a      genetic defect was identified and studied, as part of clinical trials,\u000d\u000a      over the subsequent decade.\u000d\u000a    Research included within these studies includes the description of the\u000d\u000a      genetic defect causing abnormal metabolism of thiopurine drugs at the\u000d\u000a      molecular level, that is the identification of the major defective variant\u000d\u000a      forms of the enzyme thiopurine methyltransferase (TPMT) (R1), the\u000d\u000a      connections between the inheritance of the variant TPMT enzyme, variable\u000d\u000a      mercaptopurine metabolism, drug induced toxicity and the long-term drug\u000d\u000a      effect, i.e. the outcome of treatment (R2), and the development of drug\u000d\u000a      dosage schedules to enable drug therapy in patients with defective TPMT\u000d\u000a      enzyme (R3, R4).\u000d\u000a    Research in Sheffield\u000d\u000a    From 1993 to 2000, Lennard, working with Lilleyman, identified the drug\u000d\u000a      metabolites that caused excess cytotoxicity in children treated with\u000d\u000a      thiopurine drugs as part of their chemotherapy for acute lymphoblastic\u000d\u000a      leukaemia (ALL). Excess production of these toxic metabolites caused bone\u000d\u000a      marrow failure (the bone marrow stops producing blood cells). Lennard\u000d\u000a      developed and published methodologies for the measurement of the enzyme\u000d\u000a      defect for use in routine tests in 1994 (R5), and modified these in 2006\u000d\u000a      (R6). This enabled the development of drug dosage schedules for those\u000d\u000a      patients very sensitive to thiopurine drugs (low TPMT enzyme activity; no\u000d\u000a      drug is removed by the enzyme TPMT and too much drug is then made into\u000d\u000a      toxic metabolites) and those constitutionally resistant to standard drug\u000d\u000a      doses (very high TPMT activities; too much drug is removed by TPMT and\u000d\u000a      insufficient cytotoxic metabolites are made) (R2, R3, R4).\u000d\u000a    Collaborative studies\u000d\u000a    During 1993 to 1997, Lennard worked on a collaborative study with Richard\u000d\u000a      Weinshilboum (Dept Pharmacology, Mayo Clinic, Rochester, USA), and\u000d\u000a      identified the genetic error in the TPMT enzyme (R1). This enabled the\u000d\u000a      establishment of genotype assays to detect TPMT deficiency.\u000d\u000a    Clinical trials\u000d\u000a    From 1997 to date, working within a series of clinical trials with\u000d\u000a      Lilleyman and Vora (from 1995 Honorary Professor of Haematology and\u000d\u000a      Consultant Haematologist, Sheffield Children's Hospital) formal studies\u000d\u000a      were undertaken to establish the links between the amount of inherited\u000d\u000a      TPMT enzyme, the production of cytotoxic drug metabolites and thiopurine\u000d\u000a      drug toxicity and efficacy. The trials were called MRC ALL97 (which ran\u000d\u000a      from 1997 to 2002) and ALL 2003 (2002 to 2011); thiopurine-based treatment\u000d\u000a      lasts for 2 to 3 years, so the last child recruited will finish treatment\u000d\u000a      in 2014. The Sheffield Clinical Pharmacology Unit (led by Lennard, funded\u000d\u000a      by Leukaemia and Lymphoma Research) were responsible for the organisation\u000d\u000a      and implementation of the Thiopurine Studies within these trials.\u000d\u000a      Lilleyman and Vora were the Chief Investigators for ALL97 and ALL2003\u000d\u000a      respectively.\u000d\u000a    "},{"CaseStudyId":"13964","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Leeds research into the factors which determine better outcomes for\u000d\u000a      cancer patients identified multidisciplinary specialised care as important\u000d\u000a      and proposed networks of care as a suitable means to deliver this. This\u000d\u000a      evidence, directly included in the 1995 Calman-Hine report [A],\u000d\u000a      underpinned new government policies, which were systematically\u000d\u000a      implemented, changing guidelines, NHS systems and healthcare practice and\u000d\u000a      leading to improved survival for cancer patients.\u000d\u000a    Creating the impact: an active programme of implementation\u000d\u000a          (1995-2007)\u000d\u000a      Prior to the evidence-based Calman-Hine report which drew heavily on Leeds\u000d\u000a      research, cancer services were fragmented with care often delivered by\u000d\u000a      generalists working in isolation in a single discipline, such as surgery,\u000d\u000a      medicine or radiotherapy. The research at Leeds underpinned the\u000d\u000a      development of the new policy of networks of multidisciplinary teams with\u000d\u000a      specialist services provided at fewer centres. The implementation of this\u000d\u000a      strategy was actively supported and funded by the DH with leadership\u000d\u000a      provided from Leeds (Haward, Mark Baker, Yorkshire Cancer Network\u000d\u000a      Director and Sean Duffy, Leeds 1990- and Yorkshire Cancer Network\u000d\u000a      Director). The plan reconfigured services into Cancer Centres, Cancer\u000d\u000a      Units and Cancer Networks covering specific geographical areas. It\u000d\u000a      involved the designation of appropriate hospitals, consultants and teams\u000d\u000a      to provide specialised services, including major surgery, for patients\u000d\u000a      with rare and intermediate frequency cancers. Cancer Units with adequate\u000d\u000a      patient volumes to provide sufficient multidisciplinary care were\u000d\u000a      identified.\u000d\u000a    This strategy radically changed services in England and Wales affecting\u000d\u000a      over 250,000 new patients every year. Selby and Haward were involved in\u000d\u000a      designing the new services and planning their implementation. A series of\u000d\u000a      service guidance documents developed by Haward determined how services for\u000d\u000a      all the main types of cancer should function and how the component parts\u000d\u000a      fitted together. Improving outcomes guidance, subsequently national cancer\u000d\u000a      guidance, was prepared first for breast cancer and then sequentially in\u000d\u000a      all cancers (from 1995-2006) [B]. These documents make multiple references\u000d\u000a      to Leeds-based research. In breast, colorectal and lung cancer,\u000d\u000a      specialists moved to multidisciplinary team working; in upper GI,\u000d\u000a      urological and gynaecological cancers guidance led to changes in hospital\u000d\u000a      treatment, required multidisciplinary and specialised treatment and\u000d\u000a      defined the minimum caseload necessary for surgeons. Patients with rare\u000d\u000a      cancers were all referred to Cancer Centres. The established principles in\u000d\u000a      the Calman-Hine report were supported by further Leeds research and were\u000d\u000a      incorporated in subsequent policy documents and service guidance [C]. The\u000d\u000a      evidence-base was vital to gain support for radical changes which had the\u000d\u000a      potential to be unpopular. This is likely to have been the first time that\u000d\u000a      volume\/outcome evidence was used in a systematic way to radically change a\u000d\u000a      health system. The result of this systematic evidence-based implementation\u000d\u000a      has been a sustained and ongoing improvement to services and patient\u000d\u000a      outcomes in the impact window 2008-2013.\u000d\u000a    Impact on cancer care services\u000d\u000a      There has been a radical overhaul of the way multidisciplinary care for\u000d\u000a      cancer is delivered and the configuration of services, a national strategy\u000d\u000a      which has remained as a cornerstone of service provision. Since 2008 up to\u000d\u000a      2013 this has ensured that across England and Wales, appropriate teams are\u000d\u000a      in place with adequate degrees of service centralisation and specialised\u000d\u000a      workload. A rolling programme of peer review has been established for each\u000d\u000a      service. Designated requirements are in place for the membership of\u000d\u000a      multidisciplinary teams, the referral of cancer patients and their review\u000d\u000a      in multidisciplinary team meetings, with clear criteria for the service\u000d\u000a      volume requirements for a specialised multidisciplinary team in a Cancer\u000d\u000a      Centre or a Cancer Unit. The National Cancer Peer Review (2010-2013)\u000d\u000a      database [D] records these service changes for all cancer care in England\u000d\u000a      and Wales ensuring these improvements reach all cancer patients and are\u000d\u000a      sustained.\u000d\u000a    Impact on patient survival\u000d\u000a      All cancer patients now receive expert, peer-reviewed, multidisciplinary\u000d\u000a      specialised care. This has been a major factor in the increase in median\u000d\u000a      survival from three years in 1995 to five years for patients diagnosed in\u000d\u000a      2008. The proportion of all cancer patients who survive for five years has\u000d\u000a      increased from 40% in 1995 to over 50% in 2008. This impact is ongoing\u000d\u000a      with survival figures continuing to improve [E,F]. Cancer Research UK have\u000d\u000a      analysed one, five and ten year survival for England prior to Calman-Hine\u000d\u000a      (1991-1995) and in five year cohorts up to 2010 for the 21 most common\u000d\u000a      cancers [F]. Substantial increases in survival of over 5% at 5 years are\u000d\u000a      seen in 16 cancer sites including the common cancers of breast (13%\u000d\u000a      increase), colorectal (12% increase) and prostate (over 15% increase).\u000d\u000a      Important exceptions are cancers of the pancreas (2% increase), lung (4%\u000d\u000a      increase) and brain (4% increase) where even specialised treatments have\u000d\u000a      not led to substantial improvements; testicular cancer where 5 year\u000d\u000a      survival is 97%; and bladder cancer which has not changed. Although other\u000d\u000a      factors have contributed substantially including novel therapies,\u000d\u000a      epidemiological studies and expert opinion have attributed a significant\u000d\u000a      proportion of that improvement to the changes in policy and care practices\u000d\u000a      described here [G,H,I,J]. Multidisciplinary specialised care, Cancer\u000d\u000a      Networks, Centres and Units and peer review driven service delivery and\u000d\u000a      healthcare practices are regarded as important factors in improved patient\u000d\u000a      outcomes [H,I]. If best multidisciplinary specialised practice results in\u000d\u000a      improvements of 5% in 5 year survival as was shown in Leeds research (1,3)\u000d\u000a      a conservative estimate of the impact of specialised multidisciplinary\u000d\u000a      care on 5 year survival across all cancers at 1-2% increased survival on\u000d\u000a      average, would imply many thousands of lives saved every year in England\u000d\u000a      alone before, during, and continuing after the Impact period, 2008-2013.\u000d\u000a    Sir Kenneth Calman, Chief Medical Officer (1991-1997), himself a\u000d\u000a      cancer specialist said: \"The reform of cancer care to ensure all\u000d\u000a        patients were treated by specialists who were working in\u000d\u000a        multidisciplinary teams was of great importance. Dame Deirdre Hine and I\u000d\u000a        were absolutely committed that it should be firmly based on research\u000d\u000a        evidence to ensure the best care and use of resources and to give us an\u000d\u000a        evidence-based platform to persuade clinicians to change their\u000d\u000a        practices. These changes included radical reconfiguration of surgical\u000d\u000a        services for major cancer operations. Leeds oncology\/public health\u000d\u000a        research was critical to our plan and to its successful implementation.\u000d\u000a      [H]\u000d\u000a    Sir Michael Richards, National Cancer Director (1999-2012) said: \"The\u000d\u000a        evidence-based plans for multidisciplinary specialised cancer care and\u000d\u000a        the radical reconfiguration of cancer services have resulted in\u000d\u000a        improvements in care and survival for cancer patients which continue to\u000d\u000a        this day. Leeds research informed the first plan and changes were\u000d\u000a        sustained in the National Cancer Plan of 2000 and the subsequent\u000d\u000a        strategies in 2007 and 2011 and this theme continues up to 2013. The\u000d\u000a        strong evidence base provided by Leeds, incorporated into the planning\u000d\u000a        process, was a critical element of its ongoing success.\" [I]\u000d\u000a    The international impact of the evidence generated by the Leeds team is\u000d\u000a      confirmed from Australia and New Zealand [J]. Professor Jim Bishop,\u000d\u000a      the former Chief Medical Officer of Australia, said \"The initial work\u000d\u000a        done at the University of Leeds by Haward and Selby was an important\u000d\u000a        basis for the recommendations within the report by Calman and Hine on\u000d\u000a        cancer services improvement in the UK. This evidence and subsequent work\u000d\u000a        from Leeds have provided an important part of the much needed evidence\u000d\u000a        base to establish programs to improve the performance of cancer services\u000d\u000a        in Australia. In particular, these data were influential in the\u000d\u000a        development of cancer plans and in the support for multi-disciplinary\u000d\u000a        care.\u000d\u000a    As the Chief Medical Officer for Australia, and Board Member of Cancer\u000d\u000a        Australia (current Chair) the Australian Government Cancer Agency, I\u000d\u000a        note that this evidence was also influential within the policy framework\u000d\u000a        for Cancer Australia especially in promoting multi-disciplinary care in\u000d\u000a        Australia. Cancer Australia has subsequently developed an extensive\u000d\u000a        program of support, evaluation and best practice approaches for\u000d\u000a        multi-disciplinary care in Australia as national standards.\"\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research in Leeds showed, conclusively for the first time, improved\u000d\u000a      outcomes for cancer patients managed in multidisciplinary specialised\u000d\u000a      cancer care teams. Our research and systemic overview provided the\u000d\u000a      evidence for a new government policy to reconfigure cancer care services\u000d\u000a      into Cancer Networks, Centres and Units. This required radical\u000d\u000a      evidence-based changes including centralisation of many cancer surgical\u000d\u000a      services. A rigorous implementation plan based on research evidence, was\u000d\u000a      initiated under Leeds leadership and sustained in subsequent government\u000d\u000a      policies. It changed clinical guidelines and professional standards,\u000d\u000a      altered practice for all UK cancer patients and contributed to improved\u000d\u000a      cancer survival.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Leeds\u000d\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a(1) Sainsbury R, Haward B, Rider L, Johnston C, Round C. Influence of\u000d\u000a      clinician workload and patterns of treatment on survival from breast\u000d\u000a      cancer. Lancet 1995; 20: 345: 1265-70.\u000d\u000a      This study provided compelling evidence to support multidisciplinary\u000d\u000a        team working and specialisation of care with substantial patient volumes\u000d\u000a        per team to improve patient outcome.\u000d\u000a    \u000a\u000a(2) Selby P, Gillis C, Haward R. Benefits from specialised cancer care.\u000d\u000a      Lancet 1996; 348: 313-18.\u000d\u000a      This systematic overview provided the evidence framework underpinning\u000d\u000a        the Calman\/Hine (Expert Advisory Group) Report, 1995 and a shortened\u000d\u000a        version was included in the Report.\u000d\u000a    \u000a\u000a(3) Stefoski Mikeljevic J, Haward RA, Johnston C, Sainsbury R, Forman D.\u000d\u000a      Surgeon workload and survival from breast cancer. Br J Cancer 2003; 89:\u000d\u000a      487-91.\u000d\u000a      This study confirmed with long follow up the importance of surgeon\u000d\u000a        workload in predicting outcomes from breast cancer.\u000d\u000a    \u000a\u000a(4) Downing A, Mikeljevic JS, Haward B, Forman D. Variation in the\u000d\u000a      treatment of cervical cancer patients and the effect of consultant\u000d\u000a      workload on survival: a population-based study. Eur J Cancer 2007; 43:\u000d\u000a      363-70.\u000d\u000a      Analysis showing specialised teams managing substantial numbers of\u000d\u000a        patients with cervical cancer generated better outcomes for patients.\u000d\u000a    \u000a\u000a(5) Morris E, Quirke P, Thomas JD, Fairley L, Cottier B, Forman D.\u000d\u000a      Unacceptable variation in abdominoperineal excision rates for rectal\u000d\u000a      cancer: time to intervene? Gut 2008; 57: 1690.\u000d\u000a      Study showing the variation in outcomes for patients undergoing major\u000d\u000a        surgical resection for rectal cancer was substantial and dependent on\u000d\u000a        surgeon workload.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    [A] A policy framework for commissioning cancer services: A report by the\u000d\u000a      Expert Advisory Group on Cancer to the Chief Medical Officers of England\u000d\u000a      and Wales\/Calman Hine Report 1995.\u000d\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20080814090336\/http:\/\/dh.gov.uk\/en\/Publicationsandstatistics\/Publications\/PublicationsPolicyAndGuidance\/DH_4071083?IdcService=GET_FILE&dID=17110&Rendition=Web\u000d\u000a    This report was the initial step in the impact of the Leeds research\u000d\u000a        and the inclusion of the evidence in the report itself (authored by\u000d\u000a        Selby) demonstrates the contribution to the report.\u000d\u000a    [B] Improving Outcomes in Breast Cancer. July 1996. Produced by\u000d\u000a      Department of Health. Manual Cat.Nos. 96 CC0021 & Research Evidence 96\u000d\u000a      CC0022.\u000d\u000a    National Institute for Clinical Excellence: National Cancer Guidance\u000d\u000a      Steering Group. Improving Outcomes in Urological Cancers. September 2002:\u000d\u000a      NICE. www.nice.org.uk\u000d\u000a    National Cancer Guidance Group. Improving Outcomes in Upper\u000d\u000a      Gastro-intestinal Cancers. Jan 2001: Produced by Department of Health.\u000d\u000a      Manual & Research Evidence 23180 and 23943.\u000d\u000a    National Cancer Guidance Group. Improving Outcomes in Gynaecological\u000d\u000a      Cancers. July 1999: Produced by Department of Health. Manual &\u000d\u000a      Research Evidence 16150.\u000d\u000a    Improving Outcomes in Colorectal cancer. November 1997. Produced by\u000d\u000a      Department of Health. Manual 97CV0119 & Research Evidence 97CC0120.\u000d\u000a    National Institute for Clinical Excellence: National Cancer Guidance\u000d\u000a      Steering Group. Improving Outcomes in Haematological Cancers. October\u000d\u000a      2003: NICE. www.nice.org.uk\u000d\u000a    [C] The DH Cancer Plan 2000; The DH Cancer Reform Strategy 2007; DH\u000d\u000a      Improving Outcomes a Strategy for Cancer 2012. The DH Manual of Cancer\u000d\u000a      Standards 2000 which then became updated in 2004 and 2008 as the DH Manual\u000d\u000a      for Cancer Services 2004, 2008, 2009 and 2011.\u000d\u000a      These were plans which drew on multidisciplinary and specialised care\u000d\u000a        developed through Calman\/Hine and sustained the specific Improving\u000d\u000a        Outcomes Guidance.\u000d\u000a    [D] National Cancer Peer Review (NCPR) database (2010-2013). CQuINS The\u000d\u000a      Cancer Quality Improvement Network System; a web based database used to\u000d\u000a      support the Peer Review process. http:\/\/www.cquins.nhs.uk\/\u000d\u000a    This is a national, Department of Health system and Mr Martin Waugh,\u000d\u000a        Cancer Centre Information Manager has written a note explaining its use\u000d\u000a        in practice.\u000d\u000a    [E] Walters S, Quaresma M, Coleman MP, Gordon E, Forman D, Rachet B.\u000d\u000a      Geographical variation in cancer survival in England, 1991-2006: an\u000d\u000a      analysis by Cancer Network. J Epidemiol Community Health. 2011\u000d\u000a      Nov;65(11):1044-52.\u000d\u000a    [F] Data supplied by Nicholas Ormiston-Smith, Head of Statistics, Cancer\u000d\u000a      Research UK. Survival estimates were provided by the Cancer Research UK\u000d\u000a      Cancer Survival Group, London School of Hygiene and Tropical Medicine on\u000d\u000a      request, 2011. http:\/\/www.lshtm.ac.uk\/eph\/ncde\/cancersurvival\/\u000d\u000a    [G] Autier P, Boniol M, La Vecchia C, et al. Disparities in breast cancer\u000d\u000a      mortality trends between 30 European countries: retrospective trend\u000d\u000a      analysis of WHO mortality database. BMJ 2010 ; 341: c3620. Autier P,\u000d\u000a      Boniol M, Gavin A, Vatten LJ. Breast cancer mortality in neighbouring\u000d\u000a      European countries with different levels of screening but similar access\u000d\u000a      to treatment: trend analysis of WHO mortality database. BMJ 2011; 343:\u000d\u000a      d4411.\u000d\u000a    [H] Letter including quote from ex-Chief Medical Officer, Sir Kenneth\u000d\u000a      Calman, 2 January 2013.\u000d\u000a    [I] Letter including quote from National Cancer Director, Professor Sir\u000d\u000a      Mike Richards.\u000d\u000a    [J] International Corroboration, Professor Jim Bishop, Melbourne,\u000d\u000a      Australia, 9 October 2013.\u000d\u000a      Letter and quotes from Professor Bishop who is an international\u000d\u000a        authority on cancer service developments and former Chief Medical\u000d\u000a        Officer of Australia. International Corroboration, Professor Bridget\u000d\u000a      Robinson, Christchurch, New Zealand, 4 October 2013, who is an\u000d\u000a        international authority on cancer service developments.\u000d\u000a    ","Title":"\u000d\u000a    Case Study 9. Changing cancer services and improving patient outcomes in\u000d\u000a      the UK\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2638235","Name":"Selby"},{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In the early 1990s, cancer survival in the UK was shown to be poor\u000d\u000a      compared with other developed countries. There was a recognised need for\u000d\u000a      radical change and an Expert Advisory Group (EAG) was convened in 1994 by\u000d\u000a      the Chief Medical Officers Sir Kenneth Calman and Dame Deirdre Hine, with\u000d\u000a      Peter Selby, (Leeds 1989- , Professor of Cancer Medicine), as\u000d\u000a      Consultant Advisor, and Bob Haward (Leeds 1995-, Professor of\u000d\u000a      Cancer Studies), as the Public Health representative. While it was clear\u000d\u000a      that cancer services needed to improve, both the EAG and the Department of\u000d\u000a      Health (DH) were determined that policy should be evidence based. Work in\u000d\u000a      Leeds, published in 1995, highlighted the relationship between high\u000d\u000a      clinician workload, a crucial surrogate for specialisation, and\u000d\u000a      multidisciplinary patterns of treatment on survival from breast cancer.\u000d\u000a      This evidence and a key systematic review on the benefits of specialised\u000d\u000a      care also conducted in Leeds and published in 1996 (2) informed new DH\u000d\u000a      policy — the Calman Hine plan — to provide multidisciplinary specialised\u000d\u000a      care in a system of Cancer Networks, Centres and Units.\u000d\u000a    The systematic review of all available evidence (2) drew strongly on data\u000d\u000a      from Leeds and similar work on consultant workload from Glasgow, but also\u000d\u000a      evaluated evidence worldwide. Evidence to support various aspects of\u000d\u000a      specialisation such as training, caseload, and the formation of\u000d\u000a      multidisciplinary teams was strongest for breast cancer, ovarian cancer,\u000d\u000a      and some haematological malignant diseases. The largest number of patients\u000d\u000a      referred to in the review were included in Leeds studies. The review\u000d\u000a      concluded that there was evidence that some specialised care can be\u000d\u000a      successfully delivered by a network of district hospitals and main general\u000d\u000a      or teaching hospitals and does not always require referral to cancer\u000d\u000a      centres, which strongly influenced the recommendations of the EAG and\u000d\u000a      subsequent policies. The review, authored by Selby, was incorporated into\u000d\u000a      the Calman-Hine Plan in 1995 [A].\u000d\u000a    Haward, David Forman (Leeds 1994-2010, Professor of Cancer\u000d\u000a      Epidemiology), Phil Quirke (Leeds 1990- , Professor of Pathology),\u000d\u000a        Eva Morris (Leeds 1999-, Principal Research Fellow) continued to\u000d\u000a      research the relationship between specialised care for colorectal and\u000d\u000a      gynaecological cancers and better survival (3-5). Analysis of\u000d\u000a      cancer-registry data from 12,861 patients with breast cancer treated in\u000d\u000a      Yorkshire showed that patients of surgeons with higher rates of\u000d\u000a      multidisciplinary care indicated by use of chemotherapy and hormone\u000d\u000a      therapy, had improved survival. There was considerable variation between\u000d\u000a      surgeons, 26% of which could be explained by rates of use of chemotherapy\u000d\u000a      and hormone therapy. Had the practice of the surgeons with the best\u000d\u000a      outcomes been followed by all treating clinicians, 5-year survival would\u000d\u000a      have increased by about 4-5% (1-3). Analysis of the differences in\u000d\u000a      survival as a function of consultant caseload showed poorer results\u000d\u000a      amongst those surgeons treating less than 30 new cases of breast cancer\u000d\u000a      per year. Similar Leeds studies on cervical cancer and on colorectal\u000d\u000a      cancer showed variation in outcomes that strongly suggested improved\u000d\u000a      outcomes could be achieved by specialisation and multidisciplinary care\u000d\u000a      (4,5). This work continued to inform DH policy.\u000d\u000a    "},{"CaseStudyId":"15529","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Meningitis C:\u000d\u000a    The studies on meningitis vaccines led by the University of Oxford have\u000d\u000a      had a direct impact on national and international immunisation policy.\u000d\u000a      Trials of the combination Haemophilus influenzae type b-Serogroup C\u000d\u000a      meningococcal meningitis vaccine (Menitorix, GSK vaccines)2\u000d\u000a      supported recommendations for its use in several countries including the\u000d\u000a      UK and Australia7 as a booster dose for toddlers. The\u000d\u000a      quadrivalent meningococcal vaccine (MenACYW, Menveo, Novartis Vaccines)1\u000d\u000a      is now recommended for high-risk groups and travellers by the UK\u000d\u000a      Department of Health following the study in infants conducted by the\u000d\u000a      Oxford Vaccine Group. These recommendations were widely reported8\u000d\u000a      and led to the vaccines' licensure9, and are cited in the US\u000d\u000a      recommendations. In areas where meningitis C vaccines are used, serious\u000d\u000a      disease caused by the targeted bacteria has essentially ceased. Over the\u000d\u000a      past 5 years there have been just 2 deaths in people under 20 years of\u000d\u000a      age, in comparison to 78 deaths in the UK in the year prior to the\u000d\u000a      Department of Health's introduction of these Meningitis C vaccines10.\u000d\u000a      The phase 4 studies designed and conducted at the University of Oxford,\u000d\u000a      which showed that those vaccinated with serogroup C meningococcal vaccine\u000d\u000a      in early childhood can lose immunity, together with data from the Health\u000d\u000a      Protection Agency, led to widespread changes in immunisation policy in\u000d\u000a      those countries using the vaccine11. This also led to\u000d\u000a      widespread media coverage. Adolescent booster doses have been recommended\u000d\u000a      in many countries including the UK11, Canada12 and\u000d\u000a      the USA13, with national recommendations citing studies by the\u000d\u000a      University of Oxford as primary evidence.\u000d\u000a    Meningitis B:\u000d\u000a    Studies on serogroup B meningococcal vaccines have led to major media\u000d\u000a      interest following conference presentations of trials conducted in Oxford\u000d\u000a      including numerous newspaper reports, front page coverage by the\u000d\u000a      Independent (2008), Daily Mail and extensive BBC News reporting. The first\u000d\u000a      infant studies of a new serogroup B vaccine (Bexsero) were conducted in\u000d\u000a      Oxford and have been extensively cited. Professor Pollard was asked to\u000d\u000a      give evidence to the World Health Organization in April 2011 on serogroup\u000d\u000a      B meningococcal vaccines14. In addition, the first phase 3\u000d\u000a      infant study in Europe, led by Oxford University investigators, assembled\u000d\u000a      with data from other global studies, led to licensure of the vaccine by\u000d\u000a      the European Medicines Agency in early 2013. A recommendation in the UK\u000d\u000a      for use of the vaccine among high risk groups and laboratory workers has\u000d\u000a      been made15, and its routine use for children is being\u000d\u000a      considered by the Department of Health16. The design and\u000d\u000a      development of new vaccines for serogroup B meningococcus by Oxford\u000d\u000a      University have led to a number of patents on the candidate vaccines\u000d\u000a      (based on various surface proteins including Opa, PorA and\u000d\u000a      FetA17), which provide a licensing position for the University\u000d\u000a      as these vaccines progress through early phase clinical trials.\u000d\u000a    Conduct of Trials:\u000d\u000a    Studies on plain polysaccharide meningococcal and pneumococcal vaccines\u000d\u000a      provided the first direct demonstration that these vaccines do not induce\u000d\u000a      memory B cells, explaining the phenomenon of hyporesponsiveness (where\u000d\u000a      \"booster\" doses of vaccines do not induce an immune response). This led to\u000d\u000a      a change in policy for vaccine trials, which had previously used plain\u000d\u000a      polysaccharides to test immunological memory. This outcome was cited in a\u000d\u000a      commentary from Novartis Vaccines in 200918.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research performed by the University of Oxford has led to increased\u000d\u000a      protection against meningococcal meningitis, through childhood\u000d\u000a      immunisation in the UK and internationally. Around 600,000 infants each\u000d\u000a      year receive meningococcal vaccines, which prevent up to 1,000 cases of\u000d\u000a      meningitis per annum. Research into the immune responses to polysaccharide\u000d\u000a      conjugate vaccines has changed policy by leading to the introduction of\u000d\u000a      new meningococcal C vaccines in early childhood and booster vaccination in\u000d\u000a      adolescents. Oxford University research has also led to the planned use of\u000d\u000a      vaccines against serogroup B meningococcal disease, which have been\u000d\u000a      licensed and recommended for the prevention of disease in high-risk\u000d\u000a      individuals, and broader use is under consideration.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Oxford\u000d\u000a    ","Institutions":[{"AlternativeName":"Oxford (University of)","InstitutionName":"University of Oxford","PeerGroup":"A","Region":"South East","UKPRN":10007774}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Snape MD et, al. A randomized controlled trial of a novel tetravalent\u000d\u000a      meningococcal glycoconjugate vaccine in infants. JAMA 2008 Jan\u000d\u000a      9;299(2):173-84.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18182599.\u000d\u000a      This was the pivotal study of the quadrivalent ACYW vaccine\u000d\u000a          demonstrating immunogenicity in infants that supported its licensure\u000d\u000a          and policy recommendations.\u000d\u000a    \u000a\u000a2. Pace D, Snape M, Westcar S, Oluwalana C, Yu LM, Begg N, Wysocki J,\u000d\u000a      Czajka H, Maechler G, Boutriau D, Pollard AJ. A novel combined\u000d\u000a      Hib-MenC-TT glycoconjugate vaccine as a booster dose for toddlers: a phase\u000d\u000a      3 open randomised controlled trial. Arch Dis Child. 2008 Nov;\u000d\u000a      93(11):963-70.\u000d\u000a    \u000a\u000a3. Findlow J et, al. Multicentre, open-label, randomised phase II\u000d\u000a      controlled trial of an investigational recombinant meningococcal serogroup\u000d\u000a      B vaccine with and without outer membrane vesicles, administered in\u000d\u000a      infancy, Clin Infect Dis, 2010 Nov 15;51(10):1127-37. Epub 2010 Oct 18\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20954968.\u000d\u000a      The first study ever study in infants of the leading serogroup B\u000d\u000a          meningococcal vaccines.\u000d\u000a    \u000a\u000a4. Gossger N, et, al. European MenB Vaccine Study Group. Immunogenicity\u000d\u000a      and tolerability of recombinant serogroup B meningococcal vaccine\u000d\u000a      administered with or without routine infant vaccinations according to\u000d\u000a      different immunization schedules: a randomized controlled trial. JAMA.\u000d\u000a      2012 Feb 8;307(6):573-82.The Oxford led European phase III trial of\u000d\u000a          the leading serogroup B meningococcal vaccine.\u000d\u000a    \u000a\u000a5. Kelly DF et, al. CRM197-conjugated serogroup C meningococcal capsular\u000d\u000a      polysaccharide, but not the native polysaccharide, induces persistent\u000d\u000a      antigen-specific memory B cells. Blood 2006;108(8):2642-7 http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16675705.\u000d\u000a      The first study to indicate the immunological basis for differences\u000d\u000a          in responses to polysaccharide and conjugate meningococcal vaccines.\u000d\u000a    \u000a\u000a6. Blanchard-Rohner G, et, al. The magnitude of germinal center priming\u000d\u000a      with a protein-polysaccharide conjugate vaccine in human infants\u000d\u000a      determines the persistence of antibody and the intensity of booster\u000d\u000a      response. Journal of Immunology 2008;180(4):2165-73.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18250423.\u000d\u000a      First evidence for a link between early B cell priming in infancy\u000d\u000a          with booster responses in the second year of life.\u000d\u000a    \u000a\u000a7. Snape MD, et, al. Sero-protection against serogroup C meningococcal\u000d\u000a      disease in adolescents in the United Kingdom: an observational study. BMJ\u000d\u000a      2008 Jun 28;336(7659):1487-91. Epub 2008 Jun 5. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18535032.\u000d\u000a      The first study to show that protection against meningitis C had\u000d\u000a          waned among teenagers in the UK leading to calls for boosters to be\u000d\u000a          added.\u000d\u000a    \u000aThis research was funded by the Wellcome Trust, Action Medical Research,\u000d\u000a      Meningitis UK, the NIHR Oxford Biomedical Research Centre, and Novartis\u000d\u000a      Vaccines.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      The Australian Immunisation Handbook, 10th Edition 2013.\u000d\u000a        Meningococcal disease.\u000d\u000a        http:\/\/www.immunise.health.gov.au\/internet\/immunise\/publishing.nsf\/Content\/handbook10-4-10\u000d\u000a        [Accessed 4\/11\/13]. Recommendations for the use of the\u000d\u000a            combination Haemophilus influenzae type b-Serogroup C meningococcal\u000d\u000a            meningitis vaccine as a booster dose for toddlers. Supported by\u000d\u000a            Oxford research.\u000a\u000d\u000a      Combined meningitis vaccine hope http:\/\/news.bbc.co.uk\/1\/hi\/health\/7096522.stm\u000d\u000a        [Accessed 4\/11\/13]. Media reporting on the importance of work in\u000d\u000a            Oxford on a quadrivalent meningitis vaccine.\u000a\u000d\u000a      Recommendations on meningococcal vaccine policy for the UK Dept.\u000d\u000a        Health: Green Bk, Ch 22, Meningococcal\u000d\u000a        https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/223749\/Green_Book\u000d\u000a          _Chapter_22_v2_3.pdf\u000d\u000a         [Accessed 4\/11\/13]. Evidence that studies in Oxford have\u000d\u000a            been used to support UK policy on monovalent serogroup C\u000d\u000a            meningococcal vaccine and quadrivalent ACYW meningococcal vaccines.\u000a\u000d\u000a      Agency, H. P. (n.d.). Vaccination for Meningococcal disease.\u000d\u000a        hpa.org.uk. Health Protection Agency, 7th Floor, Holborn Gate, 330 High\u000d\u000a        Holborn, London, WC1V 7PP, 020 7759 2700 \/ 2701\u000d\u000a        http:\/\/www.hpa.org.uk\/web\/HPAweb&HPAwebStandard\/HPAweb_C\/1296682977081\u000d\u000a        [Accessed 4\/11\/13]. Health Protection Agency (UK) fact sheet\u000d\u000a            featuring information about the decrease in lives lost since the\u000d\u000a            introduction of Meningitis C vaccines.\u000a\u000d\u000a      UK Joint Committee on Vaccines and Immunisation, Meningococcal\u000d\u000a        Sub-Committee, Minute of the meeting held on Friday 18 February 2011.\u000d\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20120907090205\/http:\/www.dh.gov.uk\/prod_consum_dh\u000d\u000a          \/groups\/dh_digitalassets\/@dh\/@ab\/documents\/digitalasset\/dh_128724.pdf\u000d\u000a        [Accessed 4\/11\/13]. Evidence that work on serogroup C\u000d\u000a            meningococcal vaccines in Oxford was used in determining UK\u000d\u000a            immunization policy.\u000a\u000d\u000a      Canadian immunisation Advisory Committee Statement (ACS): National\u000d\u000a        Advisory Committee on Immunization (NACI) Update on the Invasive\u000d\u000a        Meningococcal Disease and Meningococcal Vaccine Conjugate\u000d\u000a        Recommendations. April 2009 http:\/\/www.phac-aspc.gc.ca\/publicat\/ccdr-rmtc\/09vol35\/acs-dcc-3\/index-eng.php\u000d\u000a        [Accessed 4\/11\/13]. Evidence that work on serogroup C\u000d\u000a            meningococcal vaccines in Oxford underpinned policy decisions in the\u000d\u000a            Canada.\u000a\u000d\u000a      United States vaccine policy: Updated Recommendations for Use of\u000d\u000a        Meningococcal Conjugate Vaccines — Advisory Committee on Immunization\u000d\u000a        Practices (ACIP), 2010. January 28, 2011 \/ 60(03); 72-76. www.cdc.gov\/mmwr\/preview\/mmwrhtml\/mm6003a3.htm.\u000d\u000a        [Accessed 4\/11\/13]. Evidence that work on serogroup C\u000d\u000a            meningococcal vaccines in Oxford underpinned policy decisions in the\u000d\u000a            USA.\u000a\u000d\u000a      Evidence to WHO provided by Professor Pollard\u000d\u000a        www.who.int\/immunization\/sage\/DRAFT_AGENDA_Apr_SAGE_with_timings_10_Feb_2011.pdf.\u000d\u000a        [Accessed 4\/11\/13]. Evidence that the expertise in Oxford on\u000d\u000a            meningococcal vaccines is of special interest to WHO.\u000a\u000d\u000a      Joint Committee on Vaccination and Immunisation (JCVI) interim\u000d\u000a        position statement on use of Bexsero® meningococcal B vaccine in the UK\u000d\u000a        July 2013.\u000d\u000a        https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/224896\/JCVI_interim_statement_on_meningococcal_B_vaccination_for_web.pdf [Accessed\u000d\u000a        4\/11\/13]. JCVI interim statement recommending the use of the\u000d\u000a            meningococcal B vaccine among high risk groups and laboratory\u000d\u000a            workers in the UK. This statement directly cites the Gossger N, et,\u000d\u000a            al 2012 paper from Oxford.\u000a\u000d\u000a      Joint Committee on Vaccination and Immunisation (JCVI). Update on the\u000d\u000a        outcome of consultation about use of Bexsero® meningococcal B vaccine in\u000d\u000a        the UK. Published October 2013.\u000d\u000a        https:\/\/www.gov.uk\/government\/publications\/jcvi-update-on-the-use-of-bexsero-meningococcal-b-vaccine\u000d\u000a        [Accessed 4\/11\/13]. Documentation confirming the Department of\u000d\u000a            Health's ongoing consideration for the routine use of the\u000d\u000a            meningococcal B vaccine among children in the UK.\u000a\u000d\u000a      International Patent Application PCT\/GB2005\/005014, which was filed on\u000d\u000a        22nd December 2005 and entitled \"Compositions\". Patent applications\u000d\u000a        directly related to PCT\/GB2005\/005014 are: GB 0428381.8, EP 05843720.3,\u000d\u000a        US 11\/722300, JP 2007-547652. Patent application information\u000d\u000a          for vaccine.\u000a\u000d\u000a      Commentary from Novartis vaccines on hyporesponsiveness: By Michael\u000d\u000a        Broker, Keith Veitch — Quadrivalent meningococcal vaccines:\u000d\u000a        Hyporesponsiveness as an important consideration when choosing between\u000d\u000a        the use of conjugate vaccine or polysaccharide vaccine.\u000d\u000a        http:\/\/ipac.kacst.edu.sa\/eDoc\/2010\/190189_1.pdf\u000d\u000a        [Accessed 4\/11\/13]. Evidence that work to document and\u000d\u000a            characterize the mechanisms of polysaccharide induced\u000d\u000a            hypo-responsiveness has influenced industry perspectives on vaccine\u000d\u000a            development.\u000a\u000d\u000a\u0009\u0009\u0009\u000d\u000a      ","Title":"\u000d\u000a    EFFECTIVE DESIGN, DEVELOPMENT AND EVALUATION OF MENINGITIS VACCINES\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Meningococcal disease is the leading infectious cause of death in\u000d\u000a      children in the UK, and its prevention is a major objective of the Oxford\u000d\u000a      Vaccine Group, directed by Professor Andrew Pollard. During the period\u000d\u000a      from 2001-2013 more than 10,000 volunteers were enrolled in clinical\u000d\u000a      studies in Oxford, mainly children, and the research provided new insight\u000d\u000a      into the design, development and evaluation of novel vaccines for\u000d\u000a      meningitis and specifically meningococcal disease.\u000d\u000a    Clinical Trials of New Meningitis Vaccines\u000d\u000a      The University of Oxford has been at the forefront of the evaluation of\u000d\u000a      novel meningitis candidates in infants and young children. The first\u000d\u000a      global clinical trials in infants of a quadrivalent meningococcal vaccine\u000d\u000a      (MenACYW, Menveo, Novartis vaccines)1, a combination Haemophilus\u000a        influenzae type b-serogroup C meningococcal vaccine (Menitorix, GSK\u000d\u000a      vaccines)2 and the first trials of the leading serogroup B\u000d\u000a      meningococcal candidate vaccine (MenB, Bexsero, Novartis vaccines)3\u000d\u000a      were undertaken in Oxford and Professor Pollard was the chief investigator\u000d\u000a      for the pan-European phase 3 study of the MenB vaccine (1,885 infants\u000d\u000a      enrolled)4. These studies showed that the vaccines were safe\u000d\u000a      and highly immunogenic in infants and toddlers. Oxford researchers have\u000d\u000a      also led the development of novel vaccine candidates for the prevention of\u000d\u000a      serogroup B meningococcal disease. Several different vaccine approaches\u000d\u000a      were evaluated through preclinical development including vaccines that use\u000d\u000a      viral vectors to deliver candidate bacterial proteins, purified protein\u000d\u000a      vaccines, and outer membrane vesicle vaccines. All of these candidates\u000d\u000a      have been designed and produced by the University and tested in\u000d\u000a      preclinical studies and one is in Phase I evaluation.\u000d\u000a    Laboratory Evaluation of Immune Responses\u000d\u000a      New understanding of the development of immunity to bacterial\u000d\u000a      polysaccharide and protein- polysaccharide conjugate vaccines was obtained\u000d\u000a      by the Oxford Vaccine Group, including a major contribution to the\u000d\u000a      understanding of immunological hyporesponsiveness using B cell ELISPOT\u000d\u000a      assays developed by the University. In these studies it was found that\u000d\u000a      antigen-specific B cells were depleted by plain polysaccharide vaccines\u000d\u000a      but not conjugate vaccines4, reducing responsiveness to\u000d\u000a      subsequent vaccine doses. In studies of conjugate vaccines, a strong\u000d\u000a      relationship between germinal centre priming in infants and the magnitude\u000d\u000a      of the immune response was found, suggesting that strategies favouring\u000d\u000a      production of memory B cells might lead to better magnitude and\u000d\u000a      persistence of immune responses6. Evaluation of the serogroup C\u000d\u000a      meningococcal vaccine (introduced in the UK in 1999) demonstrated that\u000d\u000a      immunity after early childhood vaccination does not persist and that the\u000d\u000a      population immunised before 6 years of age have now become susceptible\u000d\u000a      again. Further data collected in Oxford indicate that adolescent booster\u000d\u000a      doses of vaccine appear to overcome this and that adolescents produce far\u000d\u000a      more persistent immune responses leading to new vaccine strategies7.\u000d\u000a    "},{"CaseStudyId":"18319","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    4a. Change in UK breast screening policy\u000d\u000a    The Department of Health (which was aware of the findings of the trial\u000d\u000a      some months before the BMJ publication appeared) issued an Executive\u000d\u000a      Letter in early 1995 requiring all breast screening units to move, within\u000d\u000a      8 months, to two-view mammography for the prevalent screen [4]. There was\u000d\u000a      some uncertainty about whether the full benefit of two views could be\u000d\u000a      realised in practice, especially since the NHS Breast Screening Programme\u000d\u000a      was under workload pressures. For this reason, the introduction of\u000d\u000a      two-view mammography was initially restricted to the prevalent (ie first\u000d\u000a      screening) round while one view was used for incident (ie subsequent\u000d\u000a      screening) rounds [5].\u000d\u000a    In September 2000, the Department of Health published The Cancer\u000d\u000a        Plan, which announced the intention to introduce two views into\u000d\u000a      every attendance at the NHS Breast Screening Programme by December 2003\u000d\u000a      [6].\u000d\u000a    4b. Change in clinical practice\u000d\u000a    Many UK breast screening units adopted the two-view approach back in\u000d\u000a      1995-96 in accordance with the research findings and Executive Letter [4],\u000d\u000a      and the rest followed. By December 2003, 90% of the programmes had\u000d\u000a      achieved the target set out in The Cancer Plan, with the remaining\u000d\u000a      10% projected to do so shortly afterwards [6]. Two-view mammography is now\u000d\u000a      routine in the UK setting.\u000d\u000a    4c. Improved sensitivity and specificity of cancer detection\u000d\u000a    Between 1997 and 2005, the NHS Breast Screening Programme undertook a\u000d\u000a      series of audits of the impact of one- and two-view screening protocols.\u000d\u000a      One audit, for example, compared the cancer detection rates in the\u000d\u000a      incident round of those programmes that had introduced two views at every\u000d\u000a      attendance with the majority of programmes that used single view for the\u000d\u000a      incident round [7]. They found the two-view programmes detected 42% more\u000d\u000a      small invasive cancers (<15mm) — a rate at least as good as, and\u000d\u000a      perhaps even better than, the results obtained from the randomised trial —\u000d\u000a      and also that two views helped to protect against observer error (in which\u000d\u000a      some but not all assessors would be able to detect a small cancer on a\u000d\u000a      single view but far more would detect it on two views). The reduction in\u000d\u000a      recall rate predicted by the trial took some years to establish and may be\u000d\u000a      partly attributable to other influences (eg more double reading of films).\u000d\u000a    An audit of the NHS Breast Screening Programme in 2000-05 showed a 20%\u000d\u000a      increase in overall incident screen cancer detection rate, with the\u000d\u000a      biggest effect seen for small (<15 mm) invasive cancers [8,9]. This\u000d\u000a      increased detection rate was achieved with an 11% drop in recall rate.\u000d\u000a      Similarly, an audit of the Welsh National Breast Screening Programme\u000d\u000a      between 2000 and 2005 [10] compared 98,752 women who had single-view\u000d\u000a      mammography with 95,464 who had two-view. Five hundred and fifty-five\u000d\u000a      cancers were detected with one view and 744 with two, an increased\u000d\u000a      detection rate from 5.6 to 7.8 cancers per 1000 women screened — a 39%\u000d\u000a      increase (p=0.01) [10]. Two hundred and thirty-nine small (ie early,\u000d\u000a      potentially curable) cancers were detected with one view and 323 with two,\u000d\u000a      increasing the detection rate of these cancers from 2.4 to 3.4 per 1000\u000d\u000a      women screened — a 42% increase (p=0.05).\u000d\u000a    In 2004, the Director of the NHS Cancer Screening Programme summed up the\u000d\u000a      benefits of this change in screening practice in the Journal of Medical\u000d\u000a      Screening:\u000d\u000a    \"The move from single view at every round to two views at every round\u000d\u000a        has been an evidence-based, cost-effective quality improvement. It has\u000d\u000a        contributed to the high-quality NHS BSP [Breast Screening Programme]\u000d\u000a        operating currently.\" (page 56) [5].\u000d\u000a    4e. Quantified estimates of benefits continuing during the impact\u000d\u000a        period 2008-13\u000d\u000a    In 2008, a review of advances in breast cancer screening named the\u000d\u000a      introduction of two-view mammography as one of the three most significant\u000d\u000a      advances in breast cancer screening in the previous 20 years [11]. These\u000d\u000a      early improvements in sensitivity and specificity are now beginning to\u000d\u000a      have long-term impacts on morbidity and mortality (because a small breast\u000d\u000a      cancer detected through screening would typically have taken many years to\u000d\u000a      kill the patient had it gone undetected). Thus, whilst the improvements in\u000d\u000a      sensitivity and specificity of national breast screening programmes began\u000d\u000a      before 2008, it has continued and (because of progressively increased\u000d\u000a      uptake around the world) extended further year on year.\u000d\u000a    Two-view mammography remains the national gold standard and this is a\u000d\u000a      direct result of the UKCCCR trial results published in 1995. It continues\u000d\u000a      to have significant health impacts up to the present day, since the same\u000d\u000a      policy and practice remains in place.\u000d\u000a    An audit undertaken by Queen Mary researchers in 2010-12, based on the\u000d\u000a      national cohort of women who were first screened with either one-view or\u000d\u000a      two-view mammography in 2003-04 and\/or in 2004-05 and who were then\u000d\u000a      followed up for up to three years, showed that there was a highly\u000d\u000a      significant reduction in subsequent interval cancers: the incidence of\u000d\u000a      such cancers with two-view mammography was 0.68 relative to the incidence\u000d\u000a      with one-view mammography [12].\u000d\u000a    To illustrate the sustained quantitative benefits of this research, we\u000d\u000a      cite figures from 2010-11 [13]. The NHS Breast Screening Programme\u000d\u000a      screened 2,221,938 women in England, Wales, Northern Ireland and Scotland\u000d\u000a      between April 2010 and March 2011. 17,838 cancers were detected in women\u000d\u000a      of all ages; 80% were invasive. Cancer detection rates for all cancers\u000d\u000a      were 8.0 per 1,000 women screened and for small invasive cancers (<15mm\u000d\u000a      in diameter — the ones that are typically too small to be felt) were 3.3\u000d\u000a      per 1,000 women screened. Using the (relatively conservative) figure of\u000d\u000a      39% for the incremental detection rate with two-view mammography, it is\u000d\u000a      estimated that around 2,500-3,000 invasive cancers are now detected in UK\u000d\u000a      annually (many of them early and treatable) that would have been missed if\u000d\u000a      one-view mammography remained the norm [13].\u000d\u000a    4e. Impact on screening programmes and cancer detection beyond UK\u000d\u000a    The use of two-view mammography in breast screening is now recommended by\u000d\u000a      numerous professional bodies worldwide, including the World Health\u000d\u000a      Organisation's 2006 recommendation, which is still current [14]. The US\u000d\u000a      National Cancer Institute acknowledges the superiority of two-over\u000d\u000a      one-view mammography [15].\u000d\u000a    Two-view mammography is now practised in almost all screening programmes.\u000d\u000a      In EUNICE, a systematic data warehouse on breast cancer screening in\u000d\u000a      Europe, a review in 2012 of 25 national and regional programmes in Europe\u000d\u000a      found that all used two-view mammography at prevalent screen and 64% (16\u000d\u000a      out of 25) used two-view at all screens [16].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    As a result of research at Queen Mary, an estimated 2,500-3,000\u000d\u000a      additional women per year in UK have a breast cancer detected early\u000d\u000a      through two-view mammography at the NHS Breast Screening Programme, and\u000d\u000a      similar country-wide benefits have occurred abroad. From 1988 the NHS\u000d\u000a      Breast Screening Programme offered women aged 50-64 three-yearly one-view\u000d\u000a      mammography. In 1995, results from the UKCCCR Randomised Trial of One and\u000d\u000a      Two View Mammography (led by Queen Mary researchers) showed that including\u000d\u000a      a second view increased breast cancer detection by 24% and reduced recall\u000d\u000a      rate by 15%. On the basis of this evidence, the Department of Health\u000d\u000a      immediately issued an Executive Letter requiring all breast screening\u000d\u000a      units to move to two-view mammography for the prevalent screen. Changes\u000d\u000a      were rapidly and widely implemented. By 2004, two-view mammography had\u000d\u000a      become the policy at all screens, prevalent and incident. Two-view\u000d\u000a      mammography remains national policy and its benefits continue to the\u000d\u000a      present day.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen Mary University of London (QMUL)\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Wald NJ, Murphy P, Major P, Parkes C,\u000d\u000a      Townsend J, Frost C. UKCCCR multicentre randomised controlled\u000d\u000a      trial of one and two view mammography in breast cancer screening. BMJ:\u000d\u000a        British Medical Journal 1995; 311: 1189-93.\u000d\u000a    \u000a\u000a2. Hackshaw AK, Wald NJ, Michell MJ, Field S, Wilson ARM.\u000d\u000a      An investigation into why two-view mammography is better than one-view in\u000d\u000a      breast cancer screening. Clinical Radiology 2000; 55: 454-58.\u000d\u000a    \u000a\u000a3. Duffy SW, Nagtegaal ID, Astley SM, Gillan MG, McGee MA, Boggis\u000d\u000a      CR, Wilson M, Beetles UM, Griffiths MA, Jain AK, Johnson J, Roberts R,\u000d\u000a      Deans H, Duncan KA, Iyengar G, Griffiths PM, Warwick J, Cuzick J,\u000d\u000a      Gilbert FJ. Visually assessed breast density, breast cancer risk and the\u000d\u000a      importance of the craniocaudal view. Breast Cancer Res 2008; 10:\u000d\u000a      R64\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    \u000d\u000a      Winyard G. Executive Letter (95) 7. Quality in the NHS Breast\u000d\u000a          Screening Programme. London: Department of Health, 1995.\u000d\u000a      Patnick J. NHS breast screening: the progression from one to two\u000d\u000a        views. Journal of Medical Screening 2004; 11: 55-56.\u000d\u000a      Department of Health. The Cancer Plan: A Plan for Investment, A\u000d\u000a          Plan for Reform. London, 2000.\u000d\u000a      Blanks RG, Moss SM, Wallis MG. Use of two-view mammography compared\u000d\u000a        with one view in the detection of small invasive cancers: further\u000d\u000a        results from the National Health Service breast screening programme. Journal\u000a          of Medical Screening 1997;4: 98-101.\u000d\u000a      Blanks R, Bennett R, Patnick J, et al. The effect of changing from one\u000d\u000a        to two views at incident (subsequent) screens in the NHS breast\u000d\u000a        screening programme in England: impact on cancer detection and recall\u000d\u000a        rates. Clinical Radiology 2005; 60: 674-80.\u000d\u000a      Bennett R, Blanks R, Patnick J, et al. Results from the UK NHS breast\u000d\u000a        screening programme 2000-05. Journal of Medical Screening 2007;\u000d\u000a        14: 200-204.\u000d\u000a      Osborn G, Beer H, Wade R, et al. Two-view mammography at the incident\u000d\u000a        round has improved the rate of screen-detected breast cancer in Wales. Clinical\u000a          Radiology 2006; 61: 478-82.\u000d\u000a      Hogben RK. Screening for breast cancer in England: a review. Current\u000a          Opinion in Obstetrics & Gynecology 2008; 20: 545-9.\u000d\u000a      Dibden J, Offman J, Parmar D [et al...], Duffy S. Reduction in\u000d\u000a        interval cancer rates following the introduction of two-view mammography\u000d\u000a        in the UK breast screening programme. British Journal of Cancer\u000d\u000a        2013, in press.\u000d\u000a      \u000aNHS Breast\u000d\u000a          Screening Programme Statistical Bulletin (England) 2011 - 2012\u000d\u000a        (www.hscic.gov.uk\/catalogue\/PUB10339).\u000d\u000a      Guidelines for the early detection and screening of breast cancer.\u000d\u000a        World Health Organization, Regional Office for the Eastern\u000d\u000a        Mediterranean, 2006. (see page 36).\u000d\u000a      US National Cancer Institute `PDQ': Breast Cancer Screening —\u000d\u000a        Mammography online guidance. www.cancer.gov\/cancertopics\/pdq\/screening\/breast\/healthprofessional\/page5\u000a\u000d\u000a      Giordano L, von Karsa L, Tomatis M, et al. Mammographic screening\u000d\u000a        programmes in Europe: organisation, coverage and participation. Journal\u000a          of Medical Screening 2012; 19 (S1): 72-82.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved sensitivity of breast cancer screening with two-view\u000d\u000a        mammography\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Breast cancer is by far the commonest female cancer in the UK, accounting\u000d\u000a      for 31% of all new cases of cancer in women; 50,000 new cases are detected\u000d\u000a      annually. Mammography detects most (though not all) breast cancers before\u000d\u000a      they are clinically apparent, allowing treatment to commence earlier and\u000d\u000a      extending long-term survival. Since 1988, the National Breast Cancer\u000d\u000a      Screening Programme has offered three-yearly mammography to women aged\u000d\u000a      50-64 (more recently, those aged 50-70). Over 2 million such women are\u000d\u000a      screened in the UK annually.\u000d\u000a    The original National Breast Screening Programme was based on Swedish\u000d\u000a      research that had used one-view mammography. In the early 1990s, the\u000d\u000a      sensitivity, specificity and cost-effectiveness of one- versus two-view\u000d\u000a      mammography was unknown and there was concern to optimise these metrics.\u000d\u000a      Researchers at the Wolfson Institute for Preventive Medicine at Queen\u000d\u000a      Mary, led by Professor Nick Wald, were commissioned by the UK Coordinating\u000d\u000a      Committee on Cancer Research (UKCCCR) to undertake a trial comparing these\u000d\u000a      options in the prevalent round of breast screening.\u000d\u000a    The UKCCCR Randomised Controlled Trial of One- and Two-View Mammography,\u000d\u000a      which finished recruiting in 1994, was designed to compare one-view\u000d\u000a      mammography (medio-lateral oblique, MLO in Figure 1) and two view\u000d\u000a      (medio-lateral oblique, and cranio-caudal, CC in Figure 1) in breast\u000d\u000a      cancer screening [1]. From nine breast screening centres in England,\u000d\u000a      40,163 women aged 50-64 attending their first breast screening examination\u000d\u000a      were randomised to have one-view, two-view or two-view mammography in\u000d\u000a      which one view was read by one reader and both views were read by another.\u000d\u000a      Readers were blinded to whether a second view existed (to exclude a\u000d\u000a      possible bias due to the reader knowing that a second view was available\u000d\u000a      if they needed it).\u000d\u000a    \u000d\u000aFigure 1: Two different views of the breast taken in mammographic screening: medio-lateral oblique (MLO) and cranio-caudal (CC)\u000d\u000a\u000d\u000a    The results, published in 1995, showed that two-view mammography detected\u000d\u000a      24% more women with breast cancer (95% CI 16% to 31%) than one-view [1].\u000d\u000a      Prevalence of detected cancer was 6.84 per 1,000 women with two-view and\u000d\u000a      5.52 with one-view mammography. The proportion of women recalled for\u000d\u000a      assessment was 15% lower (95% CI 6% to 23%) with two-view (6.97%) than\u000d\u000a      with one view (8.16%) mammography. The cost of two-view screening was\u000d\u000a      higher (£26.46 compared with £22 per examination, 1995 prices) but the\u000d\u000a      average cost per cancer detected was similar (£5,330 compared with £5,310)\u000d\u000a      and the marginal cost per extra cancer detected with two views was similar\u000d\u000a      to the average cost (£5,400).\u000d\u000a    In sum, the study demonstrated conclusively that two-view mammography was\u000d\u000a      medically more effective than one-view; it detected significantly more\u000d\u000a      cancers and reduced recall rates; and it was also similarly cost effective\u000d\u000a      even when only considering short-term costs (ie without taking account of\u000d\u000a      the additional cost savings to the NHS of fewer recalls and fewer\u000d\u000a      late-detected cancers).\u000d\u000a    In a subsequent study to explore the radiographic reasons why two-view\u000d\u000a      mammography was superior to one-view, mammograms from 110 women whose\u000d\u000a      breast cancer had been detected in the screening programme were retrieved\u000d\u000a      from the screening centres and shown to three consultant radiologists\u000d\u000a      (working independently) [2]. Of the 110 women, 87 had their breast cancer\u000d\u000a      detected by both one and two views and in 23 it was missed by one view but\u000d\u000a      detected using two views. Outcome measures were breast size, location and\u000d\u000a      size of the cancer, mammographic features, presence of micro-calcification\u000d\u000a      and overall radiological assessment. Although 23 cancers were missed in\u000d\u000a      the original trial when one view was used, only two were not visible on\u000d\u000a      the oblique view. Cancers missed using a single oblique view (and only\u000d\u000a      detected if the cranio-caudal view was available with the oblique) tended\u000d\u000a      to be smaller by about 4 mm (P = 0.05), centrally located in the breast (P\u000d\u000a      = 0.16), not spiculated or round, (P ≤ 0.001) and lacked\u000d\u000a      micro-calcification (P = 0.15). Other variables were non-significant. The\u000d\u000a      authors concluded that the basis of two-view mammography was the added\u000d\u000a      value of the second view for detecting cancers with these features.\u000d\u000a    More recently, a study led by Queen Mary researchers confirmed that the\u000d\u000a      cranio-caudal view in two-view mammography provides critical information\u000d\u000a      for breast density estimation [3].\u000d\u000a    "},{"CaseStudyId":"18350","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"130758","Name":"Iran"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Royal Society"],"ImpactDetails":"\u000a    4a: Change in management paradigm\u000a    The discovery of ATC has led to the development of a new management\u000a      strategy for patients with trauma-related bleeding — `Damage Control\u000a      Resuscitation'. A central tenet of this paradigm is `Haemostatic\u000a      Resuscitation' that targets ATC. Management has shifted dramatically from\u000a      awaiting and managing late coagulopathy to correcting ATC immediately with\u000a      rapid early administration of clotting factor therapies and avoiding\u000a      haemodilution. This resuscitation strategy has been widely adopted\u000a      internationally, in military and civilian arenas. See for example [8,9].\u000a    4b: Change in survival\u000a    Brohi's findings were first taken up by the British military, who saw\u000a      potential dramatically to reduce mortality rates if treatment was targeted\u000a      at ATC. Studies in the wars in Iraq and Afghanistan, for example, showed\u000a      that this approach appears to reduce mortality in severely bleeding\u000a      patients from 65 per cent to 19 per cent [10]. These are retrospective\u000a      studies but have prompted prospective clinical trials, which are now\u000a      ongoing [11]. Mortality rates for critical trauma patients in shock were\u000a      nearly three times lower at our own (Barts) Major Trauma Centre than\u000a      nationally (20 vs 55 per cent) when using a DCR approach to treatment\u000a      [12]. These findings have been replicated internationally [eg 13].\u000a    4c: Change in policy \/ guidance\u000a    Based on the evidence above, both the USA and UK Surgeon Generals issued\u000a      `general standing orders' during the wars in Iran and Afghanistan that the\u000a      management of severe haemorrhage should target ATC with high-dose\u000a      coagulation therapies. The US Air Force General subsequently testified to\u000a      the US Senate that this resuscitation approach had saved lives [14]. Our\u000a      work in developing a DCR transfusion protocol — called `Code Red' has now\u000a      been adopted by all major trauma centres in London and is being adopted\u000a      nationally and internationally. This coagulation- centric approach has\u000a      been incorporated into UK national transfusion guidelines from the\u000a      Association of Anaesthetists of Great Britain and Ireland [15] and new\u000a      European Guidelines on the management of major haemorrhage [16]. The\u000a      global Advanced Trauma Life Support Manual updated in 2012 includes\u000a      ATC-targeted therapy in its protocols [17]. This approach to bleeding in\u000a      trauma is now also being applied to other forms of bleeding, most notably\u000a      post-partum haemorrhage, another of the world's major causes of death due\u000a      to haemorrhage [18].\u000a    4d: New research directions\u000a    New diagnostic tools\u000a    The work of Brohi's team has shown that ATC cannot be reliably predicted\u000a      from clinical signs and existing tests. There has been renewed interested\u000a      in emergency use of thromboelastography; many hospitals now have these\u000a      devices in their resuscitation rooms. But the current generation of\u000a      thromboelastography devices were not designed for the emergency\u000a      environment. Manufacturers are developing a new generation of devices for\u000a      this purpose and also for pre-hospital care. In particular, one\u000a      manufacturer has developed a `ruggedized' version of their device that has\u000a      been deployed in Camp Bastion in Afghanistan as well as in other conflict\u000a      zones around the world [19]. Major manufacturers have joined a consortium\u000a      with Brohi to develop the next generation of machines and interfaces in\u000a      the EU FP7 programme \"TACTIC\" [20].\u000a    New treatments\u000a    New treatments are being developed and evaluated specifically to treat\u000a      ATC. In simplest form, many hospitals have now put protocols in place to\u000a      have pre-thawed FFP in the trauma receiving room, and this is deployed on\u000a      some helicopters including emergency teams in Afghanistan. Several\u000a      clinical trials of blood-derived coagulation therapies directed at ATC are\u000a      underway. We are conducting the pilot CRYOSTAT trial of early\u000a      cryoprecipitate — the first joint military-civilian randomised controlled\u000a      trial. A large RCT of high-dose platelet therapy is underway in the USA,\u000a      and a trial of fibrinogen therapy delivered en-route in a helicopter is\u000a      underway in Austria. A large international trial of the antifibrinolytic\u000a      tranexamic acid has shown improved survival in bleeding trauma patients\u000a      and is being widely adopted worldwide [21]. Several pharmaceutical\u000a      companies are developing new anti-ATC therapeutics, including Octapharma,\u000a      Astra-Zeneca and CSL-Behring.\u000a    New research\u000a    The name `Acute Traumatic Coagulopathy' was ratified in a consensus\u000a      conference held on this coagulopathy in Chicago in 2008 [22]. A further\u000a      consensus conference on coagulopathy in trauma was subsequently held\u000a      jointly by the US National Institutes for Health (NHLBI) and the\u000a      Department of Defence in Washington DC in 2010 [23], and again in Toronto\u000a      in 2012. This led to several specific grant calls for research into trauma\u000a      haemorrhage, including a large-scale programme from the US Army Combat\u000a      Casualty Care programme. Through such funding, Brohi and others have\u000a      developed experimental models of ATC to determine underlying mechanisms,\u000a      identify new targets for drug discovery and evaluate new treatments.\u000a      Large-scale human studies to elucidate mechanisms and underlying\u000a      propensities for ATC are underway in Europe and USA, and renewed interest\u000a      in bleeding in trauma has led to the development of research networks and\u000a      a general upswing in the volume and quality of trauma research.\u000a    4e: Professional education\u000a    New educational initiatives have been formed for dissemination of these\u000a      findings, including the `PerioperativeBleeding.org' (Austria, Germany),\u000a      the `International Symposium on Critical Bleeding' (Europe and North\u000a      America), `Educational Initiative for Critical Bleeding in Trauma'\u000a      (international) [22], and a `Trauma Coagulopathy & Transfusion\u000a      Masterclass' at the London Trauma Conference.\u000a    4f: Improved public understanding of science\u000a    Brohi's work on ATC and new resuscitation protocols was featured in New\u000a        Scientist \"Code Red\" [24] and in television programmes in the\u000a      Netherlands and Australia. The team have showcased their work to the\u000a      public at the Royal Society's Summer Science event 2011 [25] and the Big\u000a      Bang Fair in Birmingham 2012.\u000a    ","ImpactSummary":"\u000a    The discovery of an early Acute Traumatic Coagulopathy (ATC, a syndrome\u000a      of abnormal clotting after trauma) by Professor Brohi's team in 2000, and\u000a      subsequent work building on that pivotal discovery, has led to [A] a new\u000a      understanding of why patients bleed to death after severe injury and\u000a      resulted in [B] a fundamental change in resuscitation strategy for acute\u000a      bleeding patients (`Damage Control Resuscitation') that has led to [C] a\u000a      250-300 per cent improved survival in massively bleeding trauma patients.\u000a      Discovering the character and mechanism of ATC has led to [D] new research\u000a      in diagnostics and therapeutic opportunities to further improve outcomes.\u000a      These rapid changes have led to [E] new forums for professional education\u000a      and [F] improved public understanding of science and medicine.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6167865","Name":"Toronto"}],"References":"\u000a    \u000a1. Brohi K, Singh J, Heron M, et al. Acute traumatic\u000a      coagulopathy. The Journal of Trauma and Acute Care Surgery 2003;\u000a      54:1127-30. PMID: 12813333.\u000a    \u000a\u000a2. Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard\u000a      S, Johansson PI, Stanworth S, Thiemermann C, Brohi K. Definition\u000a      and drivers of acute traumatic coagulopathy: clinical and experimental\u000a      investigations. Journal of Thrombolysis and Haemostasis 2010; 8:\u000a      1919-25. PMID: 20553376.\u000a    \u000a\u000a3. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet\u000a      JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated\u000a      through the protein C pathway? Annals of Surgery 2007; 245: 812-8.\u000a      PMID: 17457176.\u000a    \u000a\u000a4. Davenport R, Manson J, De'Ath H, Platton S, Coates A, Allard\u000a      S, Hart D, Pearse R, Pasi KJ, MacCallum P, Stanworth S, Brohi\u000a        K. Functional definition and characterization of acute traumatic\u000a      coagulopathy. Critical Care Medicine 2011; 39: 2652-8. PMID:\u000a      21765358.\u000a    \u000a\u000a5. Stanworth SJ, Morris TP, Gaarder C, Goslings JC, Maegele M, Cohen MJ,\u000a      König TC, Davenport RA, Pittet JF, Johansson PI, Allard S, Johnson T, Brohi\u000a        K. Reappraising the concept of massive transfusion in trauma. Critical\u000a        Care 2010; 14: R239. PMID: 21192812.\u000a    \u000a\u000a6. Raza I, Davenport R, Rourke C, Platton S, Stanworth S, MacCallum\u000a        P, Brohi K. The Incidence and Magnitude of Fibrinolytic Activation\u000a      in Trauma Patients. Journal of Thrombolysis and Haemostasis 2013;\u000a      11: 307-314. PMID: 23176206.\u000a    \u000a\u000a7. Rourke C, Curry N, Khan S, Taylor R, Raza I,\u000a        Davenport R, Stanworth S, Brohi K. Fibrinogen levels during\u000a      trauma hemorrhage, response to replacement therapy, and association with\u000a      patient outcomes. Journal of Thrombosis and Haemostasis 2012; 10:\u000a      1342-51. PMID: 22519961.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    \u000a      Holcomb JB, Jenkins D, Rhee P et al. Damage control\u000a        resuscitation: directly addressing the early coagulopathy of trauma. Journal\u000a          of Trauma & Acute Care Surgery 2007; 62: 307-10.\u000a      Holcomb JB, Nunez TC. Damage control resuscitation. In Front Line\u000a          Surgery. Springer, 2011: 47-58.\u000a      Borgman MA, Spinella PC, Perkins JG et al The ratio of blood\u000a        products transfused affects mortality in patients receiving massive\u000a        transfusions at a combat support hospital. J Trauma 2007; 63:\u000a        805-13.\u000a      Examples of ongoing trials that draw on this work: CRYOSTAT (http:\/\/www.controlled-trials.com\/ISRCTN55509212),\u000aPROPPR\u000a        (http:\/\/clinicaltrials.gov\/show\/NCT01545232),\u000aPATCH-TRAUMA\u000a        (http:\/\/researchdata.ands.org.au\/pre-hospital-antifibrinolytics-for-traumatic-coagulopathy-and-haemorrhage-the-patch-study),\u000a        FI in TIC (http:\/\/clinicaltrials.gov\/show\/NCT01475344).\u000a      Davenport RA, Tai N, [...], Lecky F, Walsh MS, Brohi K. A\u000a        major trauma centre is a specialty hospital not a hospital of\u000a        specialties. British Journal of Surgery 2010; 97: 109-17.\u000a      Duchesne JC, Islam TM, Stuke L et al. Hemostatic resuscitation\u000a        during surgery improves survival in patients with traumatic-induced\u000a        coagulopathy. J Trauma. 2009; 67: 33-7.\u000a      Ellen Altman Milhiser, ed. Senate Appropriations Committee Defense\u000a          Subcommittee Hearing. Arlington, VA: Gray and Associates, LC,\u000a        March 18, 2009, p. 3.\u000a      Thomas D, Wee M, Clyburn P, Walker I, Brohi K et al.\u000a        Blood transfusion and the anaesthetist: management of massive\u000a        haemorrhage. Association of Anaesthetists of Great Britain and Ireland.\u000a        Anaesthesia 2010; 65: 1153-1161.\u000a      Spahn DR, Bouillon B, Cerny V, Coats TJ et al. Management of\u000a        bleeding and coagulopathy following major trauma: an updated European\u000a        guideline. Critical Care 2013; 17: R76.\u000a      Advanced Trauma Life Support (ATLS). Student Course Manual 9th\u000a        Edition. Committee on Trauma of American College of Surgeons\u000a        2012.\u000a      Onwuemene O, Green D, Keith L et al. Postpartum hemorrhage\u000a        management in 2012: predicting the future. International Journal of\u000a          Gynaecology Obstetrics 2012; 119: 3-5.\u000a      Rugged ROTEM Delta — Role 2 Support. Available: http:\/\/rotem-aoa.com\/role2.php.\u000a      TACTIC: Targeted Action for Curing Trauma Induced Coagulopathy EU\u000a        Research Projects.\u000a        Available: http:\/\/cordis.europa.eu\/projects\/rcn\/110071_en.html.\u000a      Shakur H, Roberts I, Bautista R et al. Effects of tranexamic\u000a        acid on death, vascular occlusive events, and blood transfusion in\u000a        trauma patients with significant haemorrhage (CRASH-2): a randomised,\u000a        placebo-controlled trial. CRASH-2 trial collaborators. Lancet\u000a        2010; 376: 23-32.\u000a      Bouillon B, Brohi K, Hess JR, Holcomb JB, Parr MJ, Hoyt DB.\u000a        Educational initiative on critical bleeding in trauma: Chicago, July\u000a        11-13, 2008. J Trauma 2010; 68: 225-30.\u000a      National Heart Lung & Blood Institute: Trans-Agency Coagulopathy\u000a        in Trauma Workshop Available: www.nhlbi.nih.gov\/meetings\/workshops\/tactrauma.htm.\u000a      Cohen D. Code Red: Repairing blood in the emergency room. New\u000a          Scientist 2835, 26th October 2011. www.newscientist.com\/article\/mg21228352.900-code-red-repairing-blood-in-the-emergency-room.html#.UjAo9BZurww\u000a\u000a      Trauma: Science of the Bleeding Obvious. Royal Society Summer Science\u000a        2011 Available:\u000a        http:\/\/royalsociety.org\/summer-science\/2011\/trauma-surgery\/.\u000a        Accessed: 10.9.13.\u000a    \u000a    ","Title":"\u000a    Coagulopathy of trauma\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Trauma remains one of the world's biggest contributors to the global\u000a      burden of disease. The increasing burden is highest in young adults and\u000a      children, with 90,000 deaths each year in the EC in people under 30, half\u000a      of which are due to bleeding. The UK mortality for bleeding trauma\u000a      patients requiring a massive transfusion approaches 50 per cent.\u000a    Loss of clotting function in severe bleeding was known about before 2003.\u000a      But up to this point it was thought to be a late phenomenon, primarily due\u000a      to loss or dilution of coagulation factors. Bleeding patients initially\u000a      received intravenous volume resuscitation with packed red cells or\u000a      crystalloid solutions. Later (usually only after a massive transfusion),\u000a      the volume of fluid would lead to a dilutional coagulopathy which would be\u000a      identified using standard laboratory tests of coagulopathy and usually\u000a      treated with a small dose of fresh frozen plasma. We now know that this is\u000a      too little, too late — and Brohi's research has been the main driver for\u000a      this dramatic shift in the management of bleeding trauma patients.\u000a    Discovery of Acute Traumatic Coagulopathy (ATC)\u000a    In 2000, Brohi performed a retrospective study analysing blood samples\u000a      from trauma patients brought in by the Helicopter Emergency Medical\u000a      Service at Barts Hospital. He identified that one in four patients already\u000a      had an established coagulopathy on arrival and that, if present, it was\u000a      associated with a four-fold increase in mortality. This study was\u000a      submitted for publication in 2001. It took two years for Journal of\u000a        Trauma to accept it, primarily because reviewers could not believe\u000a      the results. Eventually published in 2003 [1], this work was subsequently\u000a      replicated in studies in the USA, Europe and Australia. Brohi's team at\u000a      Queen Mary have since focused on understanding the mechanisms underlying\u000a      coagulopathy in trauma, characterisation of ATC, developing diagnostic\u000a      tests for its identification and new therapies, and management strategies\u000a      for its treatment. This work has been supported in part by a £2m NIHR\u000a      Programme Grant for Applied Research.\u000a    Characterisation of ATC\u000a    The Centre for Trauma Sciences, led by Brohi, showed that ATC is an\u000a      endogenous coagulopathy caused by a maladaptive response to severe trauma\u000a      and blood loss [2]. They have discovered that ATC is a unique coagulopathy\u000a      in that it is characterised by a systemic activation of anticoagulation\u000a      and fibrinolysis [2]. Blood clots are therefore poorly formed and rapidly\u000a      broken down. With collaborators, Brohi's team have identified a novel\u000a      mechanism for coagulopathy — activation of the anticoagulant protein C\u000a      pathway, which is a new target for drug discovery [3].\u000a    Diagnosis of ATC\u000a    Standard tests of coagulation in trauma are the laboratory tests of\u000a      clotting activation, such as the prothrombin time (INR). Brohi's team have\u000a      shown that these tests are not available in a timeframe that is able to\u000a      effectively guide management in these rapidly bleeding patients [4]. They\u000a      have also shown that it is impossible reliably to clinically predict who\u000a      will get ATC and need a massive transfusion [5]. Since ATC is primarily a\u000a      problem of clot strength and clot breakdown, standard laboratory clotting\u000a      times are insensitive to its presence. Brohi's group have shown that a\u000a      newer diagnostic device — thromboelastography — can identify patients with\u000a      ATC within five minutes of arrival in the A&E department and have\u000a      determined a diagnostic threshold for this condition. They have also\u000a      discovered, however, that these devices are insensitive to the clot\u000a      breakdown component of ATC and that new diagnostics will be needed in this\u000a      area [6].\u000a    Treatment of ATC\u000a    Discovery of the underlying mechanisms of ATC has led to new therapeutic\u000a      approaches. Research by the Brohi group has shown that fibrinogen\u000a      deficiency is a key early component of ATC. They have shown that this loss\u000a      can be identified rapidly on thromboelastography and has the potential to\u000a      improve clotting function and survival if replaced early [7].\u000a    "},{"CaseStudyId":"18351","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    4a: Change in national and international guidance for hypertension The\u000a        2011 NICE Hypertension Guideline CG127 was a partial update to\u000a      guidance from 2006 and Caulfield served on the Guideline Development Group\u000a      [8]. The 2011 analysis including data derived from ASCOT confirmed that\u000a      beta-blockers were usually less effective than a comparator drug at\u000a      reducing major cardiovascular events, particularly stroke, and showed\u000a      excess rates of new onset diabetes and should be used at step 4.\u000a      Importantly, the results from the ASCOT BP Lowering Arm when combined with\u000a      new data made a strong case for a further modification to the\u000a      Pharmacological Treatment algorithm. This is summarised in section 12.3\u000a      page 208 of that guideline and indicated that a combination of a calcium\u000a      channel blocker and angiotensin converting enzyme inhibitor at step 2\u000a      therapy, first trialled in ASCOT, was superior in preventing\u000a      cardiovascular outcomes [8]. Step 2 of the algorithm was changed to\u000a      reflect this and a meta-analysis showing that calcium channel blockers\u000a      (CCB) were superior to thiazide diuretics in stroke prevention changed\u000a      priority at step 1 for over 55s to CCBs. The NICE Hypertension Guideline\u000a      also cites publications, also based upon ASCOT, showing differential\u000a      effects of antihypertensive treatments on blood pressure variability as an\u000a      independent predictor of clinical outcomes as a further rationale for the\u000a      CCB recommendation at step 1 (CCBs were most effective at reducing\u000a      variability). In the European Society of Hypertension Guideline 2009,\u000a      ASCOT alongside other new data supported the recommendation for equal\u000a      consideration of CCBs and ACE inhibitors [9].\u000a    4b: Change in national and international guidelines for lipid lowering\u000a    ASCOT and CARDS changed lipid-lowering guidance for primary prevention of\u000a      cardiovascular disease in people with hypertension and for those with type\u000a      2 diabetes over 40 years old who (due to lack of peer reviewed evidence)\u000a      had not been offered such drugs previously.\u000a    The Cholesterol Trialists Meta-analysis [10] informed the NICE Technology\u000a      Appraisal (TA094) and Guideline on lipid lowering (CG67) and NCCPC\/RCGP\u000a      revision 2 [11, 12]. Heavily influenced by ASCOT and CARDS, it showed that\u000a      within a year of therapy, people begin to benefit and over 5 years this\u000a      translates into an overall reduction of about one fifth per mmol\/L of LDL\u000a      cholesterol reduction (48 fewer per 1000 having major vascular events\u000a      among those with pre-existing CHD at baseline, compared with 25 per 1000\u000a      if no such history). This benefit is reflected in national (NICE) [13] and\u000a      also international guidance, including American Diabetes Association,\u000a      European Diabetes Association, European Society of Cardiology and Joint\u000a      American and European Societies [14,15].\u000a    4c: Change in patient outcomes\u000a    Hypertension. Following NICE Hypertension Guideline CG34 in 2006\u000a      the most recent Health Survey for England 2011 (chapter 3, figure 3G page\u000a      10 and table 3.12 page 31) shows evidence of improved treatment rate (12%\u000a      improvement in men and 5% in women). The proportion of patients with good\u000a      BP control (<140\/90) has risen from 52% in 2006 to 62% in 2011, and\u000a      older people in particular are more tightly controlled [16]. This\u000a      improvement is likely to be due partly to ASCOT (reflected in NICE CG34)\u000a      and also to the Quality and Outcomes Framework in primary care.\u000a    Cholesterol. From the Health Survey for England, mean levels of\u000a      total serum cholesterol were lower in men than women (5.1 and 5.2 mmol\/L\u000a      respectively) in 2011 [16]. On page 2 in chapter 2 on cardiovascular\u000a      disease the 2011 survey reports 44% of men and 43% of women had total\u000a      cholesterol levels below 5 mmol\/L (the `audit level' for those with CVD,\u000a      diabetes or hypertension who are on drug treatment), while only 14% and12%\u000a      respectively had levels below 4 mmol\/L (current target for same group).\u000a      Since 1998 there has been a fall in mean total cholesterol of 0.5 mmol\/L\u000a      in men and women, accompanied by a rise in prescriptions in England from\u000a      52,190,000 in 2008 to 61,649,000 in 2011 (page 89 Table 3.1 in BHF Heart\u000a      Statistics 2012 [17]). This reflects the influence of lipid lowering\u000a      studies such as ASCOT, CARDS and cholesterol trialists' meta-analysis on\u000a      lipid guidelines and thus on implementation. In Europe, mean cholesterol\u000a      varies between 50-70% above 5.2 mMol\/l and 20-29% above 6.2 mMol\/L which\u000a      means the findings of ASCOT and CARDS if accompanied by prevalence rates\u000a      between 30-40% for hypertension and 6-8% for diabetes have broad impact\u000a      for large numbers of the European population [17].\u000a    4d: Professional education\u000a    Caulfield has been active in promoting continuing professional\u000a      development of health professionals [15]. Hitman and Caulfield have given\u000a      international tours to disseminate the findings of ASCOT and CARDS to\u000a      health professionals and as expert advisors to groups developing national\u000a      guidelines.\u000a    4e: Patient and public engagement\u000a    Caulfield chaired a steering group that produced a National Health\u000a      Service Patient Decision Aid for the Department of Health between\u000a      September 2012-March 2013. This is designed to explain the management of\u000a      blood pressure and specifically the NICE Guidance on Hypertension that\u000a      derives from the ASCOT study. It is intended to answer what patients\u000a      frequently ask and help them to build an understanding of what to expect\u000a      and why it is important. During ASCOT and ILLUMINATE the researchers held\u000a      regular open question and answer \"Town Hall\" meetings with participants\u000a      and their families. The engagement of the patients and public in CV\u000a      research as a direct result of ASCOT and ILLUMINATE at this Centre has led\u000a      to patient production of videos, animations and personal statements to\u000a      encourage participation in new trials. As a direct result of their\u000a      experience in ASCOT, the patients have acted as champions of a national\u000a      electronic volunteering system for trials called Mediguard. Annual\u000a      meetings are held for all participants involved in the ASCOT and\u000a      ILLUMINATE Trials. This has created a highly engaged `patients and public\u000a      engagement' group who propose, advise and support clinical trials at Queen\u000a      Mary.\u000a    ","ImpactSummary":"\u000a    Caulfield co-led and was a principal investigator (PI) on Anglo-Scandinavian\u000a        Cardiac Outcomes Trial (ASCOT). Hitman co-led and was a PI on Collaborative\u000a        AtoRvastatin Diabetes Study (CARDS). These studies dramatically\u000a      changed national and international guidance for diabetes, hypertension and\u000a      cholesterol, leading to widespread and far-reaching changes in management\u000a      of common and potentially fatal risk factors. For example, the proportion\u000a      of hypertensive patients in England with good BP control (<140\/90) rose\u000a      from 52% in 2006 to 62% in 2011; the mean total cholesterol level of the\u000a      population has fallen by 0.5 Mmol\/L between 1998 and 2011.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    This research was reported in a series of papers (>30) from 2002\u000a      onward, mainly in the Lancet and New England Journal of Medicine. The\u000a      papers listed below have been cited between 250 and 3500 times. The\u000a      findings led to changed guidance from 2005 onwards.\u000a    \u000a1. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M et\u000a      al; for the ASCOT investigators. Prevention of cardiovascular events with\u000a      an antihypertensive regimen of amlodipine adding perindopril as required\u000a      versus an atenolol adding thiazide as required in the Anglo-Scandinavian\u000a      Cardiac Outcomes Trial — Blood Pressure Lowering Arm (ASCOT-BPLA): a\u000a      multicentre randomised controlled trial. Lancet 2005; 366: 907-13.\u000a    \u000a\u000a2. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, Caulfield M et\u000a      al; ASCOT Investigators. Role of blood pressure and other variables in the\u000a      differential cardiovascular event rates noted in the Anglo-Scandinavian\u000a      Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet\u000a      2005; 366: 907-13.\u000a    \u000a\u000a3. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M et al;\u000a      ASCOT investigators. Prevention of coronary and stroke events with\u000a      atorvastatin in hypertensive patients who have average or\u000a      lower-than-average cholesterol concentrations in the Anglo-Scandinavian\u000a      Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA): multicentre RCT.\u000a      Lancet 2003;361:1149-58.\u000a    \u000a\u000a4. Sever PS, Chang CL, Gupta AK, Whitehouse A, Poulter NR; ASCOT\u000a      Investigators. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year\u000a      mortality follow-up of the lipid-lowering arm in the U.K. European Heart\u000a      Journal 2011; 32: 2525-32.\u000a    \u000a\u000a5. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA et al; CARDS\u000a      investigators. Primary prevention of cardiovascular disease with\u000a      atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes\u000a      Study (CARDS): multicentre randomised placebo-controlled trial. Lancet\u000a      2004; 364: 685-96.\u000a    \u000a\u000a6. Boekholdt SM, Arsenault\u000a        BJ, Mora\u000a        S, Pedersen\u000a        TR, LaRosa\u000a        JC, Nestel\u000a        PJ, Simes\u000a        RJ, Durrington\u000a        P, Hitman\u000a          GA et al Association of LDL cholesterol, non-HDL cholesterol,\u000a      and apolipoprotein B levels with risk of cardiovascular events among\u000a      patients treated with statins: a meta-analysis. JAMA.\u000a      2012; 307:1302-9\u000a    \u000a\u000a7. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M\u000a      et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at\u000a      high risk for coronary events. New England Journal of Medicine 2007; 22:\u000a      357: 2109-22.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    \u000a      NICE Guideline for Hypertension 2011, update from 2006 (CG34). See\u000a        section 1.4, page 17. http:\/\/www.nice.org.uk\/nicemedia\/pdf\/cg034niceguideline.pdf\u000a\u000a      Mancia G, Laurent S, Agabiti-Rosei E et al., Reappraisal of European\u000a        guidelines on hypertension management: a European Society of\u000a        Hypertension Task Force document. Journal of Hypertension 2009; 18:\u000a        308-347. PMID: 19838131.\u000a      Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and\u000a        safety of cholesterol-lowering treatment: prospective meta-analysis of\u000a        data from 90 056 participants in 14 randomised trials of statins. Lancet\u000a        2005; 366: 1267-78. (update Lancet 2010; 376: 1670-81).\u000a      NICE Lipid Modification Guidance 2008 (CG67) http:\/\/www.nice.org.uk\/nicemedia\/live\/11982\/40742\/40742.pdf\u000a\u000a      NICE Technology Appraisal 2006 (TA094) http:\/\/www.nice.org.uk\/nicemedia\/live\/11564\/33151\/33151.pdf\u000a\u000a      NICE guidance for type 2 diabetes May 2011 and last updated April 2013\u000a        http:\/\/pathways.nice.org.uk\/pathways\/diabetes#path=view%3A\/pathways\/diabetes\/managing-blood-lipids-in-type-2-diabetes.xml&content=close\u000a\u000a      American Diabetes Association Standards of Medical Care in Diabetes\u000a        2013 care.diabetesjournals.org\/content\/36\/Supplement_1\/S11.full\u000a\u000a      International Diabetes Federation guidance on cardiovascular risk http:\/\/www.idf.org\/webdata\/docs\/GGT2D\u000a          12 Cardiovascular risk.pdf (chapter 12)\u000a      Health Survey for England 2011 (see chapter 2 on CVD and 3 on\u000a        hypertension) http:\/\/www.hscic.gov.uk\/catalogue\/PUB09300\u000a\u000a      British Heart Foundation Statistics 2012: Coronary Heart Disease in UK\u000a        http:\/\/www.idf.org\/webdata\/docs\/GGT2D\u000a          12 Cardiovascular risk.pdf and cardiovascular disease in Europe\u000a        (see Chapter 8 Blood pressure and 9 Cholesterol) http:\/\/www.bhf.org.uk\/publications\/view-publication.aspx?ps=1002098\u000a\u000a      NICE Hypertension Guideline Web stream from the British Hypertension\u000a        Society for Health Professionals led by Caulfield (President 2009-11). http:\/\/www.bhsoc.org\/stream\/index.html.\u000a      Patient and public involvement (examples): How to volunteer. http:\/\/www.whri.qmul.ac.uk\/whricrc\/\u000a        Experiences: http:\/\/www.whri.qmul.ac.uk\/whricrc\/takepart\/patientexperiences\/index.html\u000a        e-volunteering for trials: http:\/\/www.whri.qmul.ac.uk\/whricrc\/takepart\/registerwithus\/index.html\u000a\u000a    \u000a    ","Title":"\u000a    Cardiovascular outcomes research: blood pressure and lipid lowering\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Caulfield and Hitman transformed the prevention of cardiovascular disease\u000a      (CVD) by leading seminal RCTs for treatment of high blood pressure (BP)\u000a      and lowering cholesterol in patients with hypertension (25% of adults in\u000a      Western countries) and type 2 diabetes (6% of the UK).\u000a    2a. Using the best drug combinations to lower BP: contribution to\u000a        ASCOT\u000a    The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), an\u000a      independent investigator-led study 1997-2007, tested the impact of\u000a      combinations of anti-hypertensive and lipid lowering drugs on\u000a      cardiovascular outcomes in 19,000 individuals. Caulfield was Co-PI on the\u000a      steering group from 1997. He designed, piloted and actively disseminated\u000a      primary care recruitment procedures. His group optimized the (then novel)\u000a      electronic case record file before UK-wide deployment so data could be\u000a      remotely uploaded in real time. Queen Mary used this as a platform to\u000a      develop an East London partnership of 120 GP practices, serving 500,000\u000a      people, enabling the team to recruit and follow 1157 (making this the\u000a      largest site in the trial) of the 9000 UK ASCOT participants with 33% from\u000a      minority ethnic groups and 99.8% followed up over 5-7 years (income £2M).\u000a    The ASCOT Blood Pressure Arm demonstrated that a combination of\u000a      amlodipine\/ perindopril was superior to a beta blocker\/ thiazide regimen\u000a      in hypertension, with 11% reduction in all cause mortality [1,2]. Over the\u000a      life of the trial, BP fell from a mean of 163\/94 to 136\/77 (fall of\u000a      27-25\/17-16) mm Hg. There was a difference in BP between the two arms of\u000a      2.7\/1.9 mm Hg, reflecting the effectiveness of the amlodipine\/perindopril\u000a      combination relative to the older combination of beta-blocker\/thiazide. At\u000a      the end of ASCOT, 53 percent of non-diabetic people with hypertension\u000a      (over 10,000) had reached the target of <140\/90. After 5.5 years\u000a      follow-up, 82 more people were alive and there were 240 fewer\u000a      cardiovascular events or procedures in the amlodipine\/perindopril arm.\u000a    b) Cholesterol lowering in patients with hypertension and diabetes\u000a        whose LDL cholesterol levels were average or below average. Prior\u000a        to this trial, it was not recommended to treat `normocholesterolaemic'\u000a        patients who had hypertension and\/or diabetes.\u000a    Findings from ASCOT Lipid Lowering Arm (LLA). This arm was\u000a      terminated early at 3.3 years because of a reduced incidence of non-fatal\u000a      myocardial infarction and fatal coronary heart disease by 36% and 27% in\u000a      stroke in those receiving atorvastatin 10 mg [3,4]. From the trial it was\u000a      estimated that the absolute risk reduction was 3.4\/1000 patient years.\u000a      Benefits of atorvastatin were seen at one year into the trial and\u000a      persuaded the Steering Committee that the placebo group and those on\u000a      active treatment should be offered statins because the BP arm was\u000a      continuing and this would allow us to test whether earlier treatment was\u000a      associated with greater benefit. This enabled our subsequent findings:\u000a      individuals receiving statins later in the trial did not get the same\u000a      benefits as those treated early. These ASCOT subjects were previously\u000a      untreated. After a median of 11 years after initial randomization and\u000a      &swungdash;8 years after closure of LLA, follow-up of outcomes shows\u000a      that all-cause mortality (n=520 and 460 in placebo and atorvastatin,\u000a      respectively) remains significantly lower in those originally assigned\u000a      atorvastatin (HR 0.86, CI 0.76-0.98, P=0.02). Cardiovascular deaths were\u000a      fewer, but not statistically significant (HR 0.89, CI 0.72-1.11, P=0.32)\u000a      possibly due to statin treatment in the placebo group; and\u000a      non-cardiovascular deaths were significantly lower (HR 0.85, CI 0.73-0.99,\u000a      P=0.03) in those formerly assigned atorvastatin. It appears that the\u000a      legacy effect of originally being assigned to atorvastatin may contribute\u000a      to long-term benefits on all-cause mortality.\u000a    Contribution to CARDS (Collaborative AtoRvastatin Diabetes Study):\u000a      Hitman was co-PI and rotating chair of the academically led CARDS Study in\u000a      type 2 diabetes [5]. He helped design the study, seek funding from\u000a      Diabetes UK, NHS and Pfizer and had close involvement in the management\u000a      and success of the study. Underpinning research from CARDS involved 2,838\u000a      people with type 2 diabetes and low to moderate cholesterol levels; the\u000a      first such study to focus only on people with diabetes. CARDS was\u000a      terminated at the 2nd interim analysis showing overwhelming\u000a      benefit with atorvastatin that significantly reduced cardiovascular events\u000a      (37%); there was also a 48% reduction in stroke [5]. To date CARDS has\u000a      resulted in 19 peer reviewed publications, including recently in JAMA [6]\u000a      and Lancet, and is consistently quoted as the seminal work on cholesterol\u000a      lowering in diabetes.\u000a    c) The dangers of elevating HDL using Torceptrapib:.As a result of\u000a      the ASCOT study, Caulfield joined the ILLUMINATE steering committee\u000a        for design and leadership of a large-scale pre-license outcome trial\u000a      of the addition of torceptapib to atorvastatin in high-risk patients with\u000a      cardiovascular disease [7]. This drug elevated high-density lipoprotein\u000a      cholesterol levels by blocking Cholesterol Ester Transfer Protein but also\u000a      had the unwanted effect of elevating BP. In 2007 the ILLUMINATE Trial was\u000a      stopped prematurely due to excess cardiac and non-cardiac deaths in the\u000a      torceptrapib arm. This early finding has shaped and enabled continued\u000a      development of this class in other cardiovascular outcome trials.\u000a    "},{"CaseStudyId":"18352","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Publication of the results of the ATAC trial, (five-year follow up in\u000a      2005, 10-year follow up in 2010), supported by results from other\u000a      international trials that confirmed our findings, led to a major change\u000a      worldwide in the treatment of women with postmenopausal oestrogen receptor\u000a      positive breast cancer. This research [a] established beyond doubt the\u000a      most efficacious treatment for preventing recurrence; [b] quantified the\u000a      benefits; [c] documented and quantified the side effects; and [d] showed\u000a      how the major side effects can be most effectively managed in different\u000a      sub-groups of women. The impact of these results can be observed in\u000a      policy\/guidelines; clinical practice; and changes in morbidity and\u000a      mortality.\u000a    4a: Change in policy \/ guidelines\u000a    Three examples are given from numerous policies and guidelines around the\u000a      world:\u000a    \u000a      \u000aUK: In 2009 the NICE guidance for treatment of women with\u000a        hormone receptor-positive breast cancer was changed to five years of an\u000a        aromatase inhibitor as the treatment of choice. See [10,11] and BMJ\u000a        summary reference [12] below.\u000a      \u000aUSA: By 2006, three leading professional organisations (the\u000a        National Comprehensive Cancer Network Breast Cancer Clinical Practice\u000a        Guidelines in Oncology, the American Society of Clinical Oncology\u000a        Technology Assessment on the Use of Aromatase Inhibitors, and the St\u000a        Gallen International Expert Consensus on the Primary Therapy of Early\u000a        Breast Cancer) had all changed their guidance to incorporate the results\u000a        of the ATAC trial. However, at that stage the recommendation reflected\u000a        that no overall increase in survival had yet been shown, and anastrozole\u000a        was considered to be `equivalent' to tamoxifen [13]. In 2010, on\u000a        publication of the 10-year follow-up of ATAC (which did show a\u000a        statistically significant benefit on mortality), the ASCO task force\u000a        updated its guidelines [14], recommending that most postmenopausal women\u000a        with hormone receptor-positive breast cancer consider incorporating\u000a        aromatase inhibitor therapy in adjuvant treatment.\u000a      \u000aAustralia: Government-issued guidance for treatment for\u000a        post-menopausal women with hormone receptor positive early breast cancer\u000a        favours anastrozole over tamoxifen [15].\u000a    \u000a    4b: Change in clinical practice\u000a    Anastrozole is widely used throughout the world, with over 5.9 million\u000a      patient years of medication recorded [16]. For example:\u000a    \u000a      \u000aUK: Standard clinical practice in every oncology unit in the UK\u000a        reflects NICE guidance, which incorporates the ATAC findings. Depending\u000a        on clinical circumstances — eg the individual balance between risk of\u000a        endocrine side effects (commoner with tamoxifen) and bone side effects\u000a        (commoner with anastrozole) — anastrozole is now routinely offered to\u000a        post-menopausal women with hormone receptor-positive breast cancer [17].\u000a      \u000aUSA: Health Maintenance Organisations in USA fund anastrozole\u000a        in suitable patients. See for example [18].\u000a      \u000aAustralia: Anastrozole is now approved (registered and\u000a        subsidised by the Pharmaceutical Benefits Scheme) for use in women with\u000a        hormone receptor-positive breast cancer. More than a million Australian\u000a        women have received this treatment regimen.\u000a      \u000aGermany: A study of prescribing patterns among oncologists and\u000a        gynaecologists in Germany [19] concluded in 2008 that treatment with\u000a        aromatase inhibitors had increased dramatically and had effectively\u000a        replaced the previous gold standard treatment, tamoxifen.\u000a    \u000a    4c: Change in morbidity and mortality (time to recurrence and side\u000a        effects)\u000a    Sine the 10-year follow-up of the ATAC trial was only published in 2010,\u000a      insufficient time has passed to follow up non-trial subjects long-term.\u000a      Over 10 years, around 80% of ATAC participants taking anastrozole were\u000a      still cancer free, compared with 76% of those on the previous gold\u000a      standard treatment of tamoxifen. Anastrozole causes significantly fewer\u000a      side effects than tamoxifen, and is not associated with any increase in\u000a      endometrial cancer, other gynaecologic symptoms or thromboembolic events.\u000a      Extrapolating from the trial data, we anticipate that since around 32,000\u000a      postmenopausal women are diagnosed annually with breast cancer in the UK,\u000a      this is likely to translate to over a thousand fewer women developing a\u000a      recurrence of their breast cancer or experiencing unnecessary side effects\u000a      from their medication each year.\u000a    ","ImpactSummary":"\u000a    Approximately 80% of all breast cancer is hormone receptor positive\u000a      localised cancer in postmenopausal women. For 30 years the universal\u000a      standard adjuvant endocrine treatment for these women was five years of\u000a      tamoxifen, but side effects and recurrences limited its usefulness.\u000a      Results from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial\u000a      led to a major worldwide change in the standard recommended treatment,\u000a      from tamoxifen to anastrozole (an aromatase inhibitor). From 2009 this\u000a      treatment became UK national policy (recommended by NICE), and guidance in\u000a      other countries (eg Australia, USA) has also been revised. Anastrozole is\u000a      now routinely offered to women with hormone receptor positive breast\u000a      cancer in UK and (extrapolating from trial data) we estimate over a\u000a      thousand are spared a recurrence in UK annually.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Nine publications are shown of more than 30 total. QMUL staff in bold.\u000a    \u000a1. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF,\u000a      Hoctin-Boes G, Houghton J, Locker GY, Tobias JS. ATAC Trialists' Group.\u000a      Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial\u000a      after completion of 5 years' adjuvant treatment for breast cancer. Lancet\u000a      2005; 365: 60-62. (Correspondence: Lancet 2005; 365: 1225-1226).\u000a    \u000a\u000a2. Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J,\u000a      Quinn E, Dunbier A, Baum M, Buzdar A, Howell A, Bugarini R, Baehner FL,\u000a      Shak S. Prediction of risk of distant recurrence using the 21-gene\u000a      recurrence score in node-negative and node-positive postmenopausal\u000a      patients with breast cancer treated with anastrozole or tamoxifen: a\u000a      TransATAC study. J Clin Oncol 2010; 28:1829-34\u000a    \u000a\u000a3. The ATAC Trialists' Group: Buzdar A, Howell A, Cuzick J, Wale C,\u000a      Distler W, Hoctin-Boes G, Houghton J, Locker GY, Nabholtz JM.\u000a      Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant\u000a      treatment for early-stage breast cancer: long-term safety analysis of the\u000a      ATAC trial. Lancet Oncology 2006; 7: 633-4\u000a    \u000a\u000a4. Cuzick J, Sestak I, Cella D, Fallowfield L; on behalf of the\u000a      ATAC Trialists' Group. Treatment-emergent endocrine symptoms and the risk\u000a      of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet\u000a        Oncology 2008; 9:1143-48.\u000a    \u000a\u000a5. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M,\u000a      Forbes JF, on behalf of the ATAC\/LATTE investigators. Effect of\u000a      anastrozole and tamoxifen as adjuvant treatment for early-stage breast\u000a      cancer: 10-year analysis of the ATAC trial. Lancet Oncology 2010;\u000a      11: 1109- 10.\u000a    \u000a\u000a6. Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J,\u000a      Beckmann MW & Coleman RE. Long-term effects of anastrozole on bone\u000a      mineral density: 7-year results from the ATAC trial. Annals of\u000a        Oncology 2011; 22: 857-62.\u000a    \u000a\u000a7. Fallowfield L, Cella D, Cuzick J, Francis S, Locker G, Howell\u000a      A. Quality of life of postmenopausal women in the Arimidex, Tamoxifen,\u000a      Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. Journal\u000a        of Clinical Oncology 2004; 22: 4261-71.\u000a    \u000a\u000a8. Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E,\u000a      Zabaglo L, Mallon E, Green AR, Ellis IO, Howell A, Buzdar AU, Forbes JF.\u000a      Prognostic value of a combined estrogen receptor, progesterone receptor,\u000a      Ki-67, and human epidermal growth factor receptor 2 immunohistochemical\u000a      score and comparison with the Genomic Health recurrence score in early\u000a      breast cancer. Journal of Clinical Oncology 2011; 29: 4273-78.\u000a    \u000a\u000a9. Sestak I, Sapunar F, Cuzick J. Aromatase\u000a        inhibitor-induced carpal tunnel syndrome: results from the ATAC trial.\u000a      Journal of Clinical Oncology 2009; 27: 4961-5.\u000a    \u000aFunding\u000a    Astra Zeneca funded the trial and 10-year follow-up, awarding an annual\u000a      grant to Queen Mary from 1998 for statistical support. Additional funding\u000a      was provided by Da Costa and Cancer Research UK.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a      \u000a    NICE Guideline 2009. `Breast cancer (early and locally advanced):\u000a      diagnosis and treatment' www.nice.org.uk\/CG80\u000a      (reviewed 2012 and confirmed still current).\u000a    NICE Guideline 2009 `Advanced breast cancer: diagnosis and treatment' www.nice.org.uk\/CG81\u000a      (reviewed 2012 and confirmed still current).\u000a    Harnett et al. Diagnosis and treatment of early breast cancer,\u000a      including locally advanced disease—summary of NICE guidance. BMJ\u000a      2009; 338: b438. doi: 10.1136\/bmj.b438 www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3266859\/\u000a\u000a    St Gallen Consensus Statement on Breast Cancer Treatment. Journal of\u000a        National Comprehensive Cancer Network 2006; 4: 971-9. www.ncbi.nlm.nih.gov\/pubmed\/17112447\u000a\u000a    Burstein HJ, Prestrud AA, Seidenfeld J. American Society of Clinical\u000a      Oncology Clinical Practice Guideline Update on Adjuvant Endocrine Therapy\u000a      for Women With Hormone Receptor-Positive Breast Cancer. Journal of\u000a        Clinical Oncology 2010; 28: 3784-3796. PMID: 20625130.\u000a    Australian government recommendations for aromatase inhibitors as\u000a      adjuvant endocrine therapy in oestrogen receptor-positive breast cancer:\u000a      http:\/\/guidelines.nbocc.org.au\/guidelines\/adjuvant_endocrine_therapy\/\u000a\u000a    Manufacturer's audit of sales (Astra Zeneca file ADX2810102):\u000a      www.arimdex.net\/arimidex-prescribing-information\/\u000a\u000a    Example of UK-based clinical protocol: Royal Marsden Hospital protocol\u000a      for adjuvant treatment in oestrogen receptor-positive breast cancer\u000a      recommends aromatase inhibitor: www.royalmarsden.nhs.uk\/SiteCollectionDocuments\/gp-education\/20110722\/mark-allen.pdf\u000a\u000a    Example of US Health Maintenance Organization policy on this topic\u000a      (Kaiser Permanente): www.permanente.net\/homepage\/kaiser\/pdf\/66383.pdf\u000a\u000a    Luftner D, Scheller J, Kolm P, Possinger K. Prescription pattern of\u000a      aromatase inhibitors for the adjuvant therapy of breast cancer in Germany\u000a     — Results of the second survey among gynaecologists and medical\u000a      oncologists. Onkologie 2008; 31: 19-25.\u000a\u0009  \u000a    ","Title":"\u000a    Anastrozole for oestrogen receptor positive breast cancer\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Breast cancer is the commonest cancer in the UK, with a substantial\u000a      burden of morbidity and mortality. The ATAC study, the first and largest\u000a      double-blind randomised trial to compare the efficacy and safety of\u000a      anastrozole, tamoxifen or both as treatment for oestrogen receptor\u000a      positive breast cancer in postmenopausal women, was conducted in 381\u000a      centres in 21 countries, and studied 9,366 women over five years.\u000a      Recruitment began in 1996 and closed in 2000. Participants were\u000a      postmenopausal women over 45 who had completed primary surgery and\u000a      chemotherapy for invasive breast cancer and who were candidates for\u000a      hormone therapy. Long-term follow-up showed a 24% reduction in 10-year\u000a      recurrence rates with anastrozole beyond that achieved with tamoxifen. The\u000a      paper presenting the main results, published in the Lancet in 2005, has\u000a      been cited over 1,600 times [1].\u000a    Professor Jack Cuzick (Head of Centre 1998 — present) was the trial\u000a      statistician from the outset, and as a founding member of the Trial\u000a      Steering Committee helped to design the trial. He conducted all analyses\u000a      of the trial data in conjunction with other QMUL staff including\u000a      Christopher Wale (Research Fellow 1998-2010), and Ivana Sestak (Research\u000a      Fellow 2003-present). Professor Cuzick is the Principal Investigator for\u000a      the continued long-term follow-up of this trial. All analyses were\u000a      conducted by Prof Cuzick's group, which was the only group with access to\u000a      treatment codes.\u000a    A significant component of the analytic work for the trial was\u000a      statistical analysis, including major retrospective studies of treatment\u000a      effects. In addition to studies of the primary efficacy end-point (disease\u000a      free survival) [1,2], side effect profile [3,4] and long-term follow-up\u000a      [5], two major sub-studies were conducted within the trial: on bone\u000a      changes [6] and quality of life [7]. In addition, a new prognostic model\u000a      for recurrence has been developed [8].\u000a    The main findings to date can be summarised as follows:\u000a    \u000a      Anastrozole is more effective and better tolerated than tamoxifen in\u000a        preventing recurrence and distant recurrence of breast cancer. ATAC was\u000a        the first study to report this finding in the adjuvant setting [1]. The\u000a        most recent 10-year analysis confirms continued superiority of\u000a        anastrozole over a sustained time interval [5].\u000a      Anastrozole over a 10-year period is substantially more effective than\u000a        tamoxifen in preventing new tumours in the opposite breast (hazard ratio\u000a        0.68 overall, 0.62 for hormone receptor-positive tumours), suggesting\u000a        it could prevent 75% of oestrogen receptor positive cancers in high-risk\u000a        women who do not have cancer [5].\u000a      The combination of anastrozole and tamoxifen is no more effective than\u000a        tamoxifen alone, and significantly less effective than anastrozole alone\u000a        [1,6]. This is due to the agonist properties of tamoxifen (reduces\u000a        oestrogen suppression).\u000a      Bone loss occurs during treatment but recovers soon after stopping, so\u000a        that only women who start with a low bone density need to be given\u000a        bisphosphonate treatment. With this protocol, the risk of increased\u000a        fracture rates in women taking aromatase inhibitors is minimal [6].\u000a      By contrast with tamoxifen, anastrozole is not associated with any\u000a        increase in endometrial cancer, other gynaecologic symptoms, or\u000a        thromboembolic events [3].\u000a      Carpal tunnel syndrome is a rare but real side effect of aromatase\u000a        inhibitor treatment, but most cases are mild, do not need surgery and\u000a        resolve spontaneously after treatment cessation [9].\u000a      Quality of life is similar in patients treated with tamoxifen or\u000a        anastrozole [7].\u000a    \u000a    "},{"CaseStudyId":"18353","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    4a: Change in policy \/ guidelines\u000a    The results of the DCIS trial have had a direct and major impact on\u000a      health policy and guidelines around the world. Examples include:\u000a    \u000a      \u000aUK: The current UK National Institute for Health and Clinical\u000a        Excellence Clinical Guideline on treatment for early and locally\u000a        advanced breast cancer recommends: \"Offer adjuvant radiotherapy to\u000a          patients with DCIS following adequate breast conserving surgery\"\u000a        (paragraph 1.11.2) [5].\u000a      \u000aUSA: Following the publication of long-term follow-up findings\u000a        from the UK\/ANZ trial, the US Agency for Healthcare Research and Quality\u000a        Appropriateness Criteria were amended to include the following\u000a        recommendation: \"Breast conservation therapy (consists of\u000a          breast-conserving surgery to achieve negative margins followed by\u000a          adjuvant radiation therapy to the whole breast) is an acceptable\u000a          treatment alternative to mastectomy for women with localized DCIS\u000a          wishing to conserve their breast.\" [6]\u000a      \u000aUSA: A review by US authors in the International Journal of\u000a        Surgical Oncology in late 2012 stated that for DCIS, \"Postoperative\u000a          radiation therapy in combination with breast-conserving surgery is\u000a          considered the standard of care, with demonstrated decrease in local\u000a          recurrence with the addition of radiation therapy.\" [7]\u000a      \u000aCANADA: According to the Canadian Cancer Society, \"External\u000a          beam radiation therapy is given after breast conserving surgery,\u000a          unless there is a medical condition that prevents a woman from\u000a          receiving radiation\" [8]. Using data from our trial, Canadian\u000a        clinical practice guidelines developed in 2008 and revised in 2012 state\u000a        that for patients with DCIS, following breast conserving surgery,\u000a        adjuvant whole breast radiotherapy is recommended [9]. 2028\u000a    \u000a    4b: Change in clinical practice\u000a    Changes in policy and guidelines have been followed by changes in\u000a      practice. For example:\u000a    \u000a      \u000aUK: British Association of Surgical Oncology audit figures show\u000a        that in 2001-02 only 46% of UK patients with non-invasive breast cancer\u000a        who had undergone breast-conserving surgery received radiotherapy, but\u000a        by 2010-11 this had increased to 60% and the trend was rising (see\u000a        Figure 1 overleaf) [10,11].\u000a      \u000aUSA: An audit of a large US Health Maintenance Organization,\u000a        Kaiser Permanente, in 2010 showed that 57% of 3,000 women treated for\u000a        DCIS in this organisation in the previous 10 years were given adjuvant\u000a        radiotherapy after breast-conserving surgery, and that the odds of a\u000a        woman receiving radiotherapy rose significantly over the time period of\u000a        the study [12].\u000a    \u000a    \u000a    Figure 1: Percentage of non-invasive breast cancers in the NHS\u000a      Breast Screening Programme treated by breast conserving surgery receiving\u000a      radiotherapy\u000a     \u000a    4c: Change in morbidity\u000a    The greatest impact of adjuvant radiotherapy treatment for the affected\u000a      women is decreased morbidity resulting from reduced recurrence rates. In\u000a      the UK each year, around 3,115 of the 4,650 women diagnosed with DCIS opt\u000a      for breast conserving surgery [13]. Without adjuvant radiotherapy 623 of\u000a      these women would face recurrence within ten years, but with adjuvant\u000a      radiotherapy, recurrence risk is reduced by almost 70%. Based on current\u000a      figures, 60% of women who undergo breast-conserving surgery now receive\u000a      adjuvant radiotherapy (1869 women) each year, among whom 261 recurrences\u000a      are prevented.\u000a    ","ImpactSummary":"\u000a    The primary treatment for ductal carcinoma in situ (DCIS, cancer confined\u000a      to the milk ducts of the breast) is surgery, and breast-conserving surgery\u000a      is increasingly preferred over mastectomy. The UK\/ANZ DCIS trial, co-led\u000a      by Queen Mary researchers, showed that following surgery, women with DCIS\u000a      are significantly less likely to develop invasive disease if given\u000a      radiotherapy, and that this protection persists long term. NICE recommends\u000a      that, following adequate breast conserving surgery, adjuvant radiotherapy\u000a      should be offered to patients with DCIS. This recommendation is also\u000a      current in the United States, Canada, Australia, and many European\u000a      countries. Based on current figures, we estimate that in UK alone, around\u000a      260 women each year are spared a recurrence of breast cancer as a result\u000a      of this research.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. UK Coordinating Committee on Cancer Research (UKCCCR) Ductal carcinoma\u000a      in situ (DCIS) Working Party. Radiotherapy and tamoxifen in women with\u000a      completely excised ductal carcinoma in situ of the breast in the UK,\u000a      Australia, and New Zealand: randomised controlled trial. Lancet\u000a      2003; 362: 95-102.\u000a    \u000a\u000a2. Cuzick J, Sestak I, Pinder SE, Ellis IO, Forsyth S, Bundred\u000a      NJ, Forbes JF, Bishop H, Fentiman IS, George WO. Effect of tamoxifen and\u000a      radiotherapy in women with locally excised ductal carcinoma in situ:\u000a      long-term results from the UK\/ANZ DCIS trial. Lancet Oncology\u000a      2011: 12: 21-29.\u000a    \u000a\u000a3. Cuzick J. Treatment of DCIS — results from clinical trials. Surgical\u000a        Oncology 2003; 12: 213-219.\u000a    \u000a\u000a4. Pinder SE, Duggan C, Ellis IO, Cuzick J, Forbes JF, Bishop H,\u000a      Fentiman IS and George WD on behalf of the UK Coordinating Committee on\u000a      Cancer Research (UKCCCR) Ductal Carcinoma in Situ (DCIS) Working Party. A\u000a      new pathological system for grading DCIS with improved prediction of local\u000a      recurrence: results from the UKCCCR\/ANZ DCIS trial. British Journal of\u000a        Cancer 2010; 103: 94-100.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    \u000a      NICE Guideline 2009 `Breast cancer (early and locally advanced):\u000a        diagnosis and treatment www.nice.org.uk\/CG80\u000a        (reviewed 2012 and confirmed still current).\u000a      American College of Radiography Appropriateness Criteria for Ductal\u000a        Carcinoma in Situ. www.guidelines.gov\/content.aspx?id=35163#Section424\u000a\u000a      Lee RJ, Vallow LA, McLaughlin SA, Tzou KS, Hines SL, and Peterson JL.\u000a        Ductal Carcinoma In Situ of the Breast. International Journal of\u000a          Surgical Oncology 2012; doi:10.1155\/2012\/123549\u000a      Canadian Cancer Society recommendations for treating early breast\u000a        cancer. www.cancer.ca\/en\/cancer-information\/cancer-type\/breast\/treatment\/stage-0\/?region=on\u000a\u000a      Alberta Health Services. Clinical Practice Guideline BR-006: Adjuvant\u000a        Radiation Therapy for Ductal Carcinoma In Situ (reviewed April 2012). www.albertahealthservices.ca\/hp\/if-hp-cancer-guide-br006-adjuvant-rt-dcis.pdf\u000a\u000a      NHS Breast Screening Programme and Association of Breast Surgery. An\u000a        Audit of Screen Detected Breast Cancers for the Year of Screening April\u000a        2010 to March 2011. NHS Cancer Screening Programmes 2012.\u000a        www.cancerscreening.nhs.uk\/breastscreen\/publications\/baso2010-2011.pdf\u000a\u000a      NHS Breast Screening Programme and British Association of Surgical\u000a        Oncology Breast Group. An audit of screen detected breast cancers.\u000a        NHS Cancer Screening Programmes 2003, 2004, 2005, 2006, 2007, 2008,\u000a        2009, 2010, 2011, 2012. See previous reference and similar data for past\u000a        years from www.cancerscreening.nhs.uk\u000a\u000a      Haque R, Achacoso NS, Fletcher SW, Nekhlyudov L, Collins LC, Schnitt\u000a        SJ, Quesenberry CP, Jr., Habel LA. Treatment of ductal carcinoma in situ\u000a        among patients cared for in large integrated health plans. The\u000a          American Journal of Managed Care 2010, 16: 351-360.\u000a      McGuire KP, Santillan AA, Kaur P et al. Are mastectomies on\u000a        the rise? A 13-year trend analysis of the selection of mastectomy versus\u000a        breast conservation therapy in 5865 patients. Annals of Surgical\u000a          Oncology 2009; 16: 2682-90.\u000a    \u000a    ","Title":"\u000a    Radiotherapy for ductal carcinoma in situ reduces recurrence\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Ductal Carcinoma In Situ (DCIS), cancer in the milk ducts of the breast,\u000a      is the commonest type of non-invasive breast cancer in the UK with around\u000a      4,650 women diagnosed annually. Following the introduction of the UK\u000a      National Health Service Breast Screening Programme in 1988, there emerged\u000a      a substantial increase in the diagnosis of DCIS, which represents 20-25\u000a      per cent of screen-detected breast cancers in the UK. The primary\u000a      treatment is surgery, with breast conserving surgery preferred over\u000a      mastectomy (which is perceived by many as an over-treatment and is\u000a      unpopular with patients). Survival following treatment is about 98 per\u000a      cent, but the risk of local recurrence and a new cancer in the opposite\u000a      breast is high.\u000a    In the early 1990s the question of which standard treatments should\u000a      follow after breast-conserving surgery for DCIS was uncertain. The UK\/ANZ\u000a      DCIS trial was designed to establish whether adjuvant treatment with\u000a      radiotherapy, tamoxifen, or both tamoxifen and radiotherapy could reduce\u000a      the likelihood of cancer returning after surgery aimed at completely\u000a      removing DCIS. Between 1990 and 1998, 1701 women from the UK, Australia,\u000a      and New Zealand were enrolled in the study. Participants had had complete\u000a      surgical excision of the lesion.\u000a    Professor Jack Cuzick, (Head of Centre 1998 — present) was co-designer of\u000a      the trial, and conducted the data analysis of both the original 2003\u000a      report and the 2010 update. He was lead author of the 2010 long-term trial\u000a      report. The trial was funded in the UK through the UK Coordinating\u000a      Committee on Cancer Research and the Imperial Cancer Research Fund, and by\u000a      grants from the Cancer Research Campaign (C569-A10404), and the Medical\u000a      Research Council.\u000a    In 2003, initial results (median follow-up 4.4 years) published in the\u000a      Lancet suggested that radiotherapy reduced new invasive and local\u000a      recurrences by about half, but no significant effects were noted with\u000a      tamoxifen treatment [1]. The report on the long-term follow up (median\u000a      12.7 years) was published in 2010 [2]. Results showed that radiotherapy\u000a      after surgery reduced the relative risk of developing invasive cancer in\u000a      the same breast by almost 70 per cent and decreased recurrent DCIS in the\u000a      same breast by over 60 per cent, corresponding to an absolute 10-year\u000a      reduction in local cancer recurrences of 12.3 per cent. Treatment with\u000a      radiotherapy had no observed effect on cancer risk in the other breast.\u000a      The trial reported a benefit for tamoxifen in reducing contralateral new\u000a      breast events.\u000a    The UK\/ANZ DCIS trial results confirmed the long-term beneficial effect\u000a      of radiotherapy for women with DCIS treated by complete local excision.\u000a      Women with DCIS are significantly less likely to develop invasive disease\u000a      if they are given radiotherapy after surgery, and the effect is long\u000a      lasting. The results, which have been further analyzed in relation to\u000a      grade of DCIS [3,4], emphasized the importance of radiotherapy for women\u000a      who have had surgery for high-grade (ie more quickly growing and more\u000a      likely to spread) DCIS.\u000a    "},{"CaseStudyId":"18354","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The study findings led directly to a change in guidelines, a change in\u000a      clinical practice and quantifiable improvements in patient morbidity.\u000a    4a: Change to national and international recommendations\u000a    Four examples of clinical guidelines around the world:\u000a    \u000a      \u000aUK: The SLNB technique is now recommended by the UK National\u000a        Institute for Health and Clinical Excellence (NICE) [4]: \"Sentinel\u000a          node biopsy ((SLNB) or axillary four node sampling) should be\u000a          performed to stage the axilla for patients with early invasive breast\u000a          cancer and no evidence of lymph node involvement on ultrasound or a\u000a          negative ultrasound-guided needle biopsy. SLNB is the preferred\u000a          technique.\"\u000a\u000a      \u000aUK: Surgical guidelines in the UK were updated to include the\u000a        recommendation for sentinel node biopsy following the study publication\u000a        in 2005 [5]. \"To minimise morbidity from axillary surgery to obtain\u000a          staging information Sentinel node biopsy using the combined blue\u000a          dye\/radioisotope technique is a recommended axillary staging procedure\u000a          for the majority of patients with early invasive breast cancer\".\u000a      \u000aEurope: The European Society for Medical Oncology\u000a        recommend sentinel node biopsy as the standard of care in early breast\u000a        cancer [6].\u000a      \u000aUSA: SLNB is endorsed as an alternative to ALND for the\u000a        diagnosis of axillary metastases in patients with clinically\u000a        node-negative early breast cancer in guidelines from the American\u000a        Society of Clinical Oncology (ASCO), which cites this trial as evidence\u000a        for the reduction in surgery-related morbidity [7], and by the US\u000a        National Comprehensive Cancer Network Guidelines [8].\u000a      \u000aAustralia: The Australian guidelines on management of breast\u000a        cancer recommend SLNB and explicitly cite this trial as evidence of the\u000a        reduction in side effects [9].\u000a    \u000a    4b: Change to standard clinical practice\u000a    SLNB has become routine in most breast centres. A survey published in\u000a      2010 reported that 69% of breast surgeons in the UK routinely use the\u000a      practice now [10], compared with 10% before this trial was published [11].\u000a      Increasing trends in the use of SLNB have also been reported from Canada\u000a      and Ireland [12,13].\u000a    4c: Development of new surgical training\u000a    Following the trial, successful training programmes have been\u000a      established, aimed primarily at surgical technique, but also incorporating\u000a      multidisciplinary training for nuclear medicine physicians, theatre nurses\u000a      and pathologists [14].\u000a    4d: Reduction in morbidity\u000a    Around 38,000 women are diagnosed with invasive breast cancer in England\u000a      per year. The Second All Breast Cancer Report reported 32% of patients\u000a      receiving sentinel node biopsy in 2007 [15]. However, more than half the\u000a      patients had missing data on axillary surgery in this audit. The audit of\u000a      screen-detected cancers for 2010\/11 reported that 76% of screen-detected\u000a      cancers had sentinel node biopsy [16]. A local audit in Staffordshire\u000a      reported 84% of patients with screen- detected cancers receiving sentinel\u000a      node biopsy [17]. Taking the average of these three figures (probably\u000a      conservative because the proportion is increasing with time), an estimated\u000a      64% of eligible UK patients currently have this procedure. This estimate\u000a      is consistent with a survey of UK surgeons in 2008, which found that 69%\u000a      routinely performed the operation [10].\u000a    The low incidence of lymphoedema observed in cohorts of patients treated\u000a      with SLNB [18] compared with observations in the pre-SLNB era (see for\u000a      example British Journal of Surgery 2000; 87: 1128) is consistent\u000a      with the numbers reported in our study. This translates to 3,405 patients\u000a      per year in UK (0.64 x (0.21-0.07) x 38,000) spared lymphoedema due to\u000a      this procedure.\u000a    4e Extension of the technique to other cancers\u000a    The first cancer for which SLNB was introduced was melanoma. Following\u000a      the success of this approach in breast cancer, researchers have begun to\u000a      explore the use of the technique in other cancers, most notably of the\u000a      head and neck [19].\u000a    ","ImpactSummary":"\u000a    In breast cancer surgery the major physical side effects occur as a\u000a      result of surgery to the axilla. Research at Queen Mary showed\u000a      significantly reduced rates of axillary clearance surgery and physical\u000a      side effects, and significantly improved quality of life, in breast cancer\u000a      patients managed with sentinel lymph node biopsy (SLNB) compared with\u000a      patients undergoing axillary lymph node dissection. As a result, SLNB was\u000a      recommended in NICE guidance and is now routine in most breast centres.\u000a      Previously, only 10% of UK breast surgeons used the procedure, but by 2010\u000a      this had increased to 64%. We estimate around 3,500 patients are spared\u000a      lympheodema in the UK every year as a result of this research.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London (QMUL)\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Purushotham AD, Upponi S, Klevesath MB, Bobrow L, Millar K, Myles\u000a        JP, Duffy SW. Morbidity after sentinel lymph node biopsy in primary\u000a      breast cancer: Results from a randomized controlled trial. Journal of\u000a        Clinical Oncology 2005; 23: 4312-21.\u000a    \u000a\u000a2. Pal A, Provenzano E, Duffy SW, Pinder SE, Purushotham AD. A\u000a      model for predicting non- sentinel lymph node metastatic disease when the\u000a      sentinel lymph node is positive. British Journal of Surgery 2008;\u000a      95: 302-9.\u000a    \u000a\u000a3. Purushotham AD, Bennet Britton TM, Klevesath MB, Chou P,\u000a        Agbaje O, Duffy SW. Lymph node status & breast cancer-related\u000a      lymphoedema. Annals of Surgery 2007; 246: 42-5.\u000a    \u000aThe trial was funded by the Eastern Region R&D Directorate and\u000a      supported by the National Cancer Research Network. Grant holders were\u000a      Purushotham et al, the title was `Sentinel lymphadenectomy in\u000a      breast cancer: a randomised trial', the sponsor was Addenbrookes Hospital,\u000a      Cambridge. The grant ran from 1999 to 2003 and totalled £175,000.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a\u0009\u000a    NICE Guideline 2009 `Breast cancer (early and locally advanced):\u000a      diagnosis and treatment\u000a      http:\/\/www.nice.org.uk\/CG80\u000a      (reviewed 2012 and confirmed still current).\u000a    Association for cancer surgery (BASO): Surgical Guidelines for the\u000a      Management of Breast Cancer. European Journal of Surgical Oncology\u000a      2009, S1-S22. doi:10.1016\/j.ejso.2009.01.008\u000a      http:\/\/www.associationofbreastsurgery.org.uk\/media\/4565\/surgical_guidelines_for_the_management_of_breast_cancer.pdf\u000a\u000a    Aebi S, Davidson T, Gruber G, et al. Primary breast cancer:\u000a      ESMO clinical practice guidelines for diagnosis, treatment and follow-up.\u000a      Annals of Oncology 2011; 22: S6 vi12-vi24.\u000a      http:\/\/www.esmo.org\/education-research\/esmo-clinical-practice-guidelines\/topics\/breast-cancer.html\u000a\u000a    Lyman GH, Giuliano AE, Somerfield MR, et al. American Society\u000a      of Clinical Oncology guideline recommendations for sentinel lymph node\u000a      biopsy in early-stage breast cancer. Journal of Clinical Oncology\u000a      2005; 23: 7703-20.\u000a      http:\/\/jco.ascopubs.org\/content\/23\/30\/7703.long\u000a\u000a    Australian national breast cancer guideline:\u000a      http:\/\/guidelines.nbocc.org.au\/guidelines\/sentinel_node_biopsy\/\u000a\u000a    Glynn RW, Williams L, Dixon JM. A further survey of surgical\u000a      management of the axilla in UK breast cancer patients. Annals of the\u000a        Royal College of Surgeons of England 2010; 92: 506-11.\u000a    Gaston MS,Dixon JM. A survey of surgical management of the axilla in\u000a      UK breast cancer patients. European Journal of Cancer 2004; 40:\u000a      1738-42.\u000a    Quan ML, Hodgson N, Lovrics P et al. National adoption of\u000a      sentinel node biopsy for breast cancer: lessons learned from the Canadian\u000a      experience. The Breast Journal 2008; 14:421-7.\u000a    Heneghan HM, Prichard RS, Devaney A, et al. Evolution of\u000a      breast cancer management in Ireland: a decade of change. BMC Surgery\u000a      2009; 9: 15.\u000a    Somasundaram SK, Chicken DW, Keshtgar MRS. Detection of the sentinel\u000a      lymph node in breast cancer. British Medical Bulletin 2007; 84:\u000a      117-31. (outline training curriculum)\u000a    NHS Cancer Screening Programme and National Cancer Intelligence\u000a      Network. The Second All Breast Cancer Report, 2011. http:\/\/www.ncin.org.uk\/view?rid=612\u000a\u000a    NHS Breast Screening Programme and Association of Breast Surgery. An\u000a      Audit of screen-detected breast cancers for the year of screening April\u000a      2010 to March 2011 (see page 12).\u000a      http:\/\/www.cancerscreening.nhs.uk\/breastscreen\/publications\/baso2010-2011.pdf\u000a\u000a    Apostolopoulos A, Basit A, Kirby RM et al. Conservation of\u000a      the axilla: an audit of sentinel lymph node biopsy after a new start. Clinical\u000a        Breast Cancer 2011; 11: 264-7.\u000a    McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of\u000a      Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node\u000a      Biopsy or Axillary Dissection: Objective Measurements. Journal of\u000a        Clinical Oncology 2008; 26: 5213-9.\u000a    Rigual N, Loree T, Frustino J et al. Sentinel node biopsy in\u000a      lieu of neck dissection for staging oral cancer. JAMA Otolaryngology and\u000a      Head Neck Surgery 2013; 139: 779-782. \u000a\u0009  \u000a    ","Title":"\u000a    Sentinel lymph node biopsy in breast cancer\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Because breast tumours most commonly spread first via the lymph nodes in\u000a      the axilla, removing and checking these for cancer cells is essential for\u000a      staging the tumour and making consequent adjuvant therapeutic decisions.\u000a      Removal of tumour-positive lymph nodes may also have a therapeutic\u000a      benefit, but this is not fully established. Axillary lymph node dissection\u000a      (ALND) is associated with significant morbidity, including loss of arm\u000a      mobility, loss of feeling and lymphoedema (arm swelling), which can be\u000a      prolonged, distressing and disabling. Lymphoedema may lead to ulceration\u000a      or infection if severe.\u000a    \u000a    Figure 1: Lymphoedema of the right arm following axillary lymph node\u000a        dissection\u000a    \u000a    The principle of SLNB is that if the first two or three (sentinel) lymph\u000a      nodes to which the tumour drains are located and have no tumour cells\u000a      present, further surgery to the axilla can be dispensed with, potentially\u000a      minimizing or avoiding these serious side effects. Identification is done\u000a      by injecting a dye, radioisotope or both in the affected breast and\u000a      identifying the nodes to which the marker substance drains. The aim of\u000a      this research was to characterise and quantify physical and psychological\u000a      morbidity after SLNB in the treatment of early breast cancer in a\u000a      randomized controlled trial.\u000a    Between November 1999 and February 2003, 298 patients with early breast\u000a      cancer (tumours measuring 3cm or less on ultrasound examination) who were\u000a      clinically node-negative were recruited from three hospitals in England,\u000a      and randomly allocated to undergo ALND (control group) or SLNB followed by\u000a      ALND if subsequently found to be lymph node positive (study group). A\u000a      detailed assessment of physical and psychological morbidity was performed\u000a      on trial participants during a one-year period postoperatively.\u000a    The main findings from this trial were:\u000a    \u000a      Significant reduction in postoperative arm swelling, rate of seroma\u000a        formation, numbness, and loss of sensitivity to light touch and pinprick\u000a        in the intervention group compared with controls.\u000a      Quality of life and psychological morbidity scores were significantly\u000a        better in the intervention group in the immediate postoperative period,\u000a        with fewer long-term differences.\u000a      The odds of arm lymphoedema were reduced by 75% at six months in the\u000a        study group as a whole, and by 82% in those who were node negative. At\u000a          six months, 21% of participants receiving axillary clearance had\u000a          lymphoedema compared with 7% in those receiving sentinel lymph node\u000a          biopsy.\u000a\u000a      Incidence of seroma formation was reduced from 21% in the control\u000a        group to 14% in the intervention group. In the node-negative cases, the\u000a        difference was greater, at 24% vs 11%. (The effect is greatest in the\u000a        node-negative cases, as these are the cases who do not go on to further\u000a        axillary surgery.)\u000a    \u000a    This trial, published in the Journal of Clinical Oncology in\u000a      2005, concluded that SLNB in patients undergoing surgery for breast cancer\u000a      results in a statistically and clinically significant reduction in\u000a      physical and psychological morbidity [1]. Downstream research within the\u000a      same study identified factors predictive of further tumour cells in the\u000a      axilla in sentinel node positive patients [2]; and showed that in those\u000a      undergoing axillary clearance surgery, those at most risk of arm\u000a      lymphoedema were the node-negative patients [3]. This is of particular\u000a      importance as it is the node-negative patients who will have axillary\u000a      clearance avoided as a result of sentinel node biopsy.\u000a    Stephen Duffy, Professor of Cancer Screening at QMUL, was a co-applicant\u000a      on the trial grant, designed the trial, carried out the randomisation and\u000a      supervised the statistical analysis [1]. A research associate at QMUL, JP\u000a      Myles, carried out the primary statistical analysis under Duffy's\u000a      supervision [1]. A research associate at QMUL, OF Agbaje, and honorary\u000a      research associate at QMUL, P Chou, carried out secondary analyses under\u000a      Duffy's supervision [2, 3].\u000a    "},{"CaseStudyId":"18360","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    4a: Reframing the paradigm of smoking cessation\u000d\u000a    One cumulative impact from 20 years of research at TDRU has been a shift\u000d\u000a      in professional (and, to a lesser extent, public) understanding of the\u000d\u000a      problem of persistent smoking. Doctors and others are now more likely to\u000d\u000a      acknowledge that giving up smoking is not a simple issue of willpower;\u000d\u000a      people who do not quit readily on brief advice are likely to have complex\u000d\u000a      physiological, cognitive or social circumstances that militate against\u000d\u000a      successful quitting. This paradigm shift was recognized in 2008 when the\u000d\u000a      official US guideline on tobacco control was updated: \"Tobacco\u000d\u000a        dependence is a chronic disease that often requires repeated\u000d\u000a        intervention and multiple attempts to quit. Effective treatments exist,\u000d\u000a        however, that can significantly increase rates of long-term abstinence\"\u000d\u000a      [1]. The justification of this statement was argued in a parallel\u000d\u000a      editorial in the Annals of Internal Medicine [2].\u000d\u000a    4b: Improving treatments for dependent smokers\u000d\u000a    This research has contributed to advances in pharmacological and\u000d\u000a      behavioural treatments of dependent smokers used worldwide. For example:\u000d\u000a      pivotal trials contributed to the licensing approvals of nicotine lozenge,\u000d\u000a      varenicline (reference 8 above) and mouth spray; and the trial of\u000d\u000a      varenicline pre-loading (reference 7 above) is changing clinical practice\u000d\u000a      currently. The `Maudsley' Model of intensive stop-smoking treatment\u000d\u000a      refined and piloted within TDRU is now used across NHS-SSS and abroad.\u000d\u000a      More effective treatments of intractable smokers are contributing to the\u000d\u000a      reduction in smoking-related morbidity and mortality in this group.\u000d\u000a      Because tobacco dependence is closely linked to social disadvantage, this\u000d\u000a      is also contributing to reducing health inequalities.\u000d\u000a    4c: Clinical and policy clarity on what does not work\u000d\u000a    Some TDRU trials and reviews have shown negative or ambiguous results,\u000d\u000a      curtailing widespread implementation of ineffective interventions. For\u000d\u000a      example, the RCT of brief intervention in routine hospital admission\u000d\u000a      (reference 5 above) showed no significant improvement in quit rate. A\u000d\u000a      similar study showed negative impact of midwife-led advice in pregnant\u000d\u000a      women. The effect of these negative studies is that, increasingly, busy\u000d\u000a      clinicians are not expected to deliver smoking cessation efforts to\u000d\u000a      persistent smokers in settings where such interventions would be\u000d\u000a      ineffective [3].\u000d\u000a    4d: Change in NICE guidelines and other official advice\u000d\u000a    \u000d\u000a      Hakek was co-opted onto the Programme Development Group for the NICE\u000d\u000a        Public Health Guidance for smoking cessation (PH10). He undertook a\u000d\u000a        rapid review of non-NHS treatments for smoking cessation as part of the\u000d\u000a        guideline development process, incorporating the various reviews done by\u000d\u000a        TDRU and others [4]. PH10 superseded previous NICE reviews of individual\u000d\u000a        therapies and aimed for the first time to review the totality of\u000d\u000a        possible therapies.\u000d\u000a      Hakek advised the guideline development group for Public Health\u000d\u000a        Guidance 34 Quitting Smoking in Pregnancy and Following Childbirth [5].\u000d\u000a        He wrote a 'Rapid review of interventions to prevent relapse in pregnant\u000d\u000a        ex-smokers', which was appended to the NICE guidance.\u000d\u000a      The series of studies on long-term use of nicotine replacement\u000d\u000a        treatments (eg refs 10 and 11 above) were instrumental in relaxing NRT\u000d\u000a        licensing and allowing long-term NRT use. Prior to this research it was\u000d\u000a        believed that NRT should be prescribed only for short periods.\u000d\u000a      Research from TDRU has influenced smoking cessation policy beyond the\u000d\u000a        UK. For example, the World Health Organisation Policy Recommendations\u000d\u000a        cites Hajek's research [6].\u000d\u000a    \u000d\u000a    4d: Policy investment in specialised smoking cessation services\u000d\u000a    This work contributed to significant policy shift towards specialist\u000d\u000a      smoking cessation services. NHS-SSS, established in 1999, is unique\u000d\u000a      internationally as a support for smokers motivated to quit but unable to\u000d\u000a      do so unaided [7]. The service provision framework employed by the smoking\u000d\u000a      cessation clinics was originally based on the Maudsley model developed by\u000d\u000a      Hajek et al and subsequently refined by him at QMUL in\u000d\u000a      collaboration with others. It consists of regular meetings (group or one\u000d\u000a      to one) with a trained adviser using structured, withdrawal-oriented\u000d\u000a      support with smoking cessation medications. The NHS-SSS, which treats\u000d\u000a      800,000 smokers annually, operates in dialogue with a number of specialist\u000d\u000a      teams, including TDRU, who continue to undertake studies whose findings\u000d\u000a      directly inform the refinement and extension of the clinical service.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    There is no `magic bullet' for helping intractable smokers to quit.\u000d\u000a      Rather, the story of this research is one of multiple studies that have\u000d\u000a      built the knowledge base incrementally, allowing Professor of Clinical\u000d\u000a      Psychology Peter Hajek and his team at the Wolfson Institute of\u000d\u000a      Preventative Medicine to produce a targeted, evidence-based model of a\u000d\u000a      specialist treatment that has fed directly into the establishment of the\u000d\u000a      NHS smoking cessation service (NHS-SSS) and national smoking cessation\u000d\u000a      policy (including NICE guidance), and changed clinical practice. The\u000d\u000a      NHS-SSS treats 800,000 smokers per year. The approach is influential\u000d\u000a      globally and has now been used in treating several million smokers and\u000d\u000a      preventing hundreds of thousands of premature deaths.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen Mary University of London (QMUL)\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Hajek P, Stead LF, West R, Jarvis M, Lancaster T. Relapse prevention\u000d\u000a      interventions for smoking cessation. Cochrane Database of Systematic\u000d\u000a        Reviews 2009; CD003999. doi: 10.1002\/14651858.CD003999.pub3\u000d\u000a    \u000a\u000a2. Myers K, Hajek P, Hinds C, McRobbie H. Stopping smoking shortly before\u000d\u000a      surgery and postoperative complications: a systematic review and\u000d\u000a      meta-analysis. Archives of Internal Medicine 2011; 171: 983-989.\u000d\u000a      doi: 10.1001\/archinternmed.2011.97\u000d\u000a    \u000a\u000a3. Hajek P, McRobbie H, Myers K. Efficacy of cytisine in helping smokers\u000d\u000a      quit: systematic review and meta-analysis. Thorax 2013; doi:\u000d\u000a      10.1136\/thoraxjnl-2012-203035.\u000d\u000a    \u000a\u000a4. Farley AC, Hajek P, Lycett D, Aveyard P. Interventions for preventing\u000d\u000a      weight gain after smoking cessation. Cochrane Database of Systematic\u000d\u000a        Reviews 2012; CD006219. doi: 10.1002\/14651858.CD006219.pub3\u000d\u000a    \u000a\u000a5. Hajek P, Taylor TZ, Mills P. Brief intervention during hospital\u000d\u000a      admission to help patients to give up smoking after myocardial infarction\u000d\u000a      and bypass surgery: randomised controlled trial. BMJ 2002; 324:\u000d\u000a      87-89.\u000d\u000a    \u000a\u000a6. Hajek P, West R, Foulds J, Nilsson F, Burrows S, Meadow A. Randomized\u000d\u000a      comparative trial of nicotine polacrilex, a transdermal patch, nasal\u000d\u000a      spray, and an inhaler. Archives of Internal Medicine 1999; 159:\u000d\u000a      2033-8.\u000d\u000a    \u000a\u000a7. Hajek P, McRobbie H, Myers K, Dhanji A, Stapleton J. Use of\u000d\u000a      varenicline for four weeks before quitting smoking. Decrease in ad-lib\u000d\u000a      smoking and increase in smoking cessation rates. Archives of Internal\u000d\u000a        Medicine 2011; 171: 770-7.\u000d\u000a    \u000a\u000a8. Hajek P, Myers K, Dhanji A, McRobbie H. Is a combination of\u000d\u000a      varenicline and nicotine patch more effective in helping smokers quit than\u000d\u000a      varenicline alone? A randomised controlled trial. BMC Medicine\u000d\u000a      2013; 11:140 doi:10.1186\/1741-7015-11-140.\u000d\u000a    \u000a\u000a9. Tonstad S, Tønesen P, Hajek P, Williams K, Billing C, Reeves K. Effect\u000d\u000a      of maintenance therapy with varenicline on smoking cessation: a randomized\u000d\u000a      controlled trial. JAMA 2006; 296: 64-71.\u000d\u000a    \u000a\u000a10. West, R., Hajek, P., Stead, L., & Stapleton, J. (2005). Outcome\u000d\u000a      criteria in smoking cessation trials: proposal for a common standard. Addiction\u000d\u000a      2005; 100: 299-303.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"17","Level2":"1","Subject":"Psychology"}],"Sources":"\u000d\u000a    \u000d\u000a      Treating Tobacco Use and Dependence: 2008 Update. U.S. Department of\u000d\u000a        Health and Human Services. Rockville (MD): Public Health Service; May\u000d\u000a        2008.\u000d\u000a        http:\/\/guideline.gov\/content.aspx?id=12520#Section420\u000a\u000d\u000a      Steinberg MB, Schmelzer AC, Richardson DL, Foulds J: The case for\u000d\u000a        treating tobacco dependence as a chronic disease. Annals of Internal\u000d\u000a          Medicine 2008; 148: 554-556.\u000d\u000a      Fiore MC, Baker B. Should Clinicians Encourage Smoking Cessation for\u000d\u000a        Every Patient Who Smokes? Smoking Cessation for Every Patient Who\u000d\u000a        Smokes. JAMA 2013; 309: 1032-33.\u000d\u000a      NICE Public Health Guidance 10. Smoking Cessation Services (2008).\u000d\u000a        www.nice.org.uk\/PH010\u000a\u000d\u000a      NICE Public Health Guidance 26. Quitting Smoking in Pregnancy and\u000d\u000a        Following Childbirth (2010). http:\/\/guidance.nice.org.uk\/PH26\/Guidance\/pdf\/English\u000a\u000d\u000a      World Health Organization. Policy recommendations for smoking\u000d\u000a        cessation and treatment of tobacco dependence. Geneva: World Health\u000d\u000a        Organization (2003, still current).\u000d\u000a        www.who.int\/tobacco\/resources\/publications\/tobacco_dependence\/en\/\u000a\u000d\u000a      Bauld L, Bell K, McCullough L, Richardson L, Greaves L. The\u000d\u000a        effectiveness of NHS smoking cessation services: a systematic review. Journal\u000a          of Public Health 2010; 32: 71-82.\u000d\u000a      Mardle T, Merrett S, Wright J, Percival F, Lockhart I. Real world\u000d\u000a        evaluation of three models of NHS Smoking Cessation Service in England.\u000d\u000a        BMC Research Notes 2012; 5: 9.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Smoking cessation: treating the intractable smoker\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Despite falling rates in many countries, smoking remains one of the\u000d\u000a      biggest killers globally. It costs the NHS £1.5 billion a year. As smoking\u000d\u000a      becomes less socially acceptable, those who continue to smoke are a\u000d\u000a      self-selecting group for whom simple interventions such as brief advice\u000d\u000a      have repeatedly failed. Since 1993, Hajek's team, the Tobacco Dependence\u000d\u000a      Research Unit (TDRU), at Queen Mary have systematically researched\u000d\u000a      psychological and drug therapies for persistent smokers. Some studies\u000d\u000a      identified effective treatments now used worldwide; others had negative\u000d\u000a      findings, preventing costly but ineffective interventions being\u000d\u000a      implemented.\u000d\u000a    Most smokers in the UK 50 years ago were 'social smokers' who were naïve\u000d\u000a      to health promotion and relatively easily influenced by brief\u000d\u000a      interventions. While some people still respond to brief advice (and this\u000d\u000a      remains a key intervention), many smokers today are nicotine dependent and\u000d\u000a      relatively intractable. A substantial proportion have mental health\u000d\u000a      problems, multi-morbidity and\/or complex social circumstances. They may\u000d\u000a      require specialist services and active (pharmacological and intensive\u000d\u000a      behavioural) interventions — reflected in the emergence of the NHS-SSS in\u000d\u000a      1999.\u000d\u000a    The focus of Hajek's research has been on developing and testing new drug\u000d\u000a      treatments (including balancing the benefits of pharmacotherapies with\u000d\u000a      their potential harms); streamlining complex behavioural interventions so\u000d\u000a      they can be applied on a large scale, and developing and piloting a\u000d\u000a      treatment package that can be disseminated across the NHS.\u000d\u000a    Hajek joined Queen Mary in 1992, bringing along an early version of what\u000d\u000a      was then called the `Maudsley Model' of a specialist smoking cessation\u000d\u000a      intervention developed by himself and colleagues, and establishing the\u000d\u000a      TDRU. TDRU's work since 1992 has focused particularly on developing a\u000d\u000a      practicable treatment model suitable for nationwide dissemination and\u000d\u000a      undertaking randomised controlled trials, systematic reviews and\u000d\u000a      meta-analyses to inform practical provision of smoking cessation\u000d\u000a      treatments. Importantly, and almost by definition, no magic bullet exists\u000d\u000a      for helping intractable smokers to quit. However, significant findings\u000d\u000a      from the body of work at TDRU from 1993 to 2013 have extended the\u000d\u000a      knowledge base in this challenging area. Of a total of over 100 studies by\u000d\u000a      this Group in the past 20 years, we have selected ten key studies (note:\u000d\u000a      these are illustrative of the kind of work they are doing rather\u000d\u000a      than representing the totality of that work).\u000d\u000a    2a: Systematic reviews\u000d\u000a    The team have completed eight major and several smaller reviews, with\u000d\u000a      statistical meta-analyses where appropriate, some in collaboration with\u000d\u000a      the Cochrane Tobacco Addiction Review Group, and some commissioned by NICE\u000d\u000a      and DH. These helped inform UK and international public health policy and\u000d\u000a      the research agenda. They summarised and synthesised the evidence base on\u000d\u000a      the following questions:\u000d\u000a    \u000d\u000a      What is the efficacy of different approaches to preventing relapse\u000d\u000a        after smoking cessation? Main finding: neither skills training nor\u000d\u000a        extended treatment contact has a sufficiently strong evidence base for\u000d\u000a        routine use in smoking cessation clinics. Other potential approaches\u000d\u000a        were identified which are now pursued by proactive NHS and NIHR funding\u000d\u000a        initiatives (2009) [1].\u000d\u000a      Are surgical outcomes worse if smokers quit shortly before elective\u000d\u000a        surgery? Main finding: no significant difference in surgical outcomes\u000d\u000a        between recent quitters and non-quitters (2011) [2].\u000d\u000a      Do any alternative therapies not currently used by the NHS show\u000d\u000a        efficacy or a promise that they might be effective? Main findings:\u000d\u000a        Hypnosis, acupuncture, gradual cessation gadgets and several herbal\u000d\u000a        remedies lack efficacy. The `Alan Carr method' awaits evaluation.\u000d\u000a      What is the efficacy of cytisine in smoking cessation? Main finding:\u000d\u000a        Cytisine is effective. Given its low cost and good safety profile, its\u000d\u000a        licensing should be expedited. (2013) [3]\u000d\u000a      What is the relationship between an individual's rate of nicotine\u000d\u000a        metabolism and their risk of dependence, severity of withdrawal symptoms\u000d\u000a        and chance of successful quitting? Main finding: there is currently\u000d\u000a        limited evidence that individual variation in nicotine metabolism can be\u000d\u000a        used to tailor pharmacotherapy, but further studies are warranted.\u000d\u000a      What is the efficacy and safety of aversive therapy (eg `rapid\u000d\u000a        smoking') as an aid to quitting? Main finding: primary studies were\u000d\u000a        positive but generally of poor quality and publication bias may have\u000d\u000a        occurred, hence the evidence base for this approach is weak.\u000d\u000a      Are there any risks associated with nicotine withdrawal and use of\u000d\u000a        nicotine replacement treatments in secondary care and in pregnancy? Main\u000d\u000a        finding: NRT is safe in secondary care though its use in ICUs to prevent\u000d\u000a        delirium is not warranted. NRT is safer than smoking in pregnancy, but\u000d\u000a        with standard dosing and brief support, it lacks efficacy.\u000d\u000a      What are the optimal treatment approaches for use in secondary care\u000d\u000a        and in pregnancy? Main finding: brief interventions with or without\u000d\u000a        medications are not effective, but treatments providing support for over\u000d\u000a        four weeks have good evidence of efficacy.\u000d\u000a      What is the efficacy and safety of interventions to reduce\u000d\u000a        post-cessation weight gain? Main finding: whilst some pharmacotherapies\u000d\u000a        appear to have short-term success, these benefits are not reliably\u000d\u000a        sustained long term and significant side effects may occur. Dieting in\u000d\u000a        the initial period of cigarette withdrawal may undermine the quit\u000d\u000a        attempt (2012) [4].\u000d\u000a    \u000d\u000a    2b: Randomised controlled trials (RCTs)\u000d\u000a    Hajek's team have published over 20 RCTs since 1993. Selected examples\u000d\u000a      are:\u000d\u000a    \u000d\u000a      Brief interventions vs usual care during routine hospital admissions\u000d\u000a        to promote smoking cessation. Main finding: no advantage over usual\u000d\u000a        care. (2002) [5]\u000d\u000a      Comparison of five different nicotine replacement therapy (NRT)\u000d\u000a        products. Main finding: current NRT products are equally effective and\u000d\u000a        have low abuse potential. (1999) [6]\u000d\u000a      Efficacy of routine stop-smoking and relapse prevention interventions\u000d\u000a        in pregnancy versus usual care. Main finding: brief interventions lack\u000d\u000a        efficacy in this setting.\u000d\u000a      Nicotine lozenge vs placebo in smoking cessation (pivotal trial). Main\u000d\u000a        finding: Nicotine lozenges are effective.\u000d\u000a      Varenicline vs placebo used for 4 weeks prior to quitting. Main\u000d\u000a        finding: Varenicline pre-loading reduces enjoyment of smoking and smoke\u000d\u000a        intake and facilitates smoking cessation. (2011) [7]\u000d\u000a      Combining varenicline with nicotine patch or placebo patch. Main\u000d\u000a        finding: Nicotine patch does not increase varenicline efficacy (2013)\u000d\u000a        [8]\u000d\u000a      Efficacy of nicotine mouth spray vs nicotine lozenges. Main finding:\u000d\u000a        mouth spray was significantly better than lozenges at reducing urge to\u000d\u000a        smoke.\u000d\u000a      Efficacy of nicotine pouch vs placebo (pivotal trial). Nicotine pouch\u000d\u000a        is effective.\u000d\u000a      Ondansetron vs placebo in reducing withdrawal symptoms in smoking\u000d\u000a        cessation. Main finding: no advantage over placebo.\u000d\u000a      Varenicline vs placebo as maintenance following successful abstinence\u000d\u000a        at 3 months (pivotal trial). Main finding: extended treatment improves\u000d\u000a        long-term outcomes. (2006) [9]\u000d\u000a    \u000d\u000a    2c: Cohort studies (17 in total since 1993; below are examples\u000d\u000a      focusing on one research topic pioneered by Hajek's team: long-term use of\u000d\u000a      NRT)\u000d\u000a    \u000d\u000a      Prevalence of long-term use of nicotine chewing gum among smokers\u000d\u000a        treated at routine services. Main finding: 6% use gum at one year,\u000d\u000a        primarily exceptionally heavy smokers who seem to need long-term help to\u000d\u000a        maintain abstinence, gum use reduces weight gain.\u000d\u000a      Effect of NRT cost on long-term use. Main finding: making NRT free had\u000d\u000a        no major effect on the occurrence of their long-term use.\u000d\u000a      Long-term use of different NRT products. Main finding: dependence\u000d\u000a        potential is proportional to the speed of nicotine delivery.\u000d\u000a    \u000d\u000a    2d: Standardisation of outcome measures\u000d\u000a    On the basis of many years' experience summarising different primary\u000d\u000a      studies, Hajek's team proposed a standard set of outcome criteria to be\u000d\u000a      followed by all studies to make comparison and synthesis easier. The\u000d\u000a      standard is increasingly used by researchers worldwide (2005) [10].\u000d\u000a    This work was undertaken mainly by Hajek and his staff at TDRU. The main\u000d\u000a      external collaborator was Prof Robert West at UCL and other members of the\u000d\u000a      UK Centre of Tobacco Control Studies, Public Health Centre of Excellence,\u000d\u000a      of which TDRU is the key member researching treatments for dependent\u000d\u000a      smokers. Funding was from MRC, NIHR, NHS, charities and manufacturers of\u000d\u000a      stop-smoking medication. Researchers on the author lists below who were\u000d\u000a      working at Queen Mary at the time of the research include Hajek, McRobbie,\u000d\u000a      Burrows, Meadow, Taylor, Mills and Myers.\u000d\u000a    "},{"CaseStudyId":"18361","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1168579","Name":"Pakistan"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"130758","Name":"Iran"}],"Funders":["Wellcome Trust","Biotechnology and Biological Sciences Research Council"],"ImpactDetails":"\u000a    Improved clinical practice, diagnostic accuracy and public awareness\u000a        in relation to GJB2\u000a      and hearing loss\u000a    Since GJB2 accounts for up to 50% of genetic hearing loss, most\u000a      clinical genetic services and\u000a      commercial testing companies now offer GJB2 testing, including\u000a      23andMe, University of Chicago\u000a      Genetic Services, University of Iowa, ARUP Laboratories, Greenwood Genetic\u000a      Centre, Knight\u000a      Diagnostic Centre, Harvard Medical School, Athean Diagnostics and\u000a      Centogene. In addition,\u000a      bloodspot-based genetic testing for GJB2 alleles can provide a\u000a      means for rapid confirmation in the\u000a      subset of infants who fail bedside newborn hearing tests [7]. In a US\u000a      study in 2000, eight\u000a      participating laboratories provided GJB2 testing to approximately\u000a      230 families per month [8]. These\u000a      studies have led to a number of additional impacts:\u000a    \u000a      Improved medical and scientific awareness and knowledge of GJB2\u000a        mutations as a major\u000a        underlying cause of congenital hearing loss [9].\u000a      Changes in clinical practice and molecular diagnosis:\u000a      a. Early diagnosis allows for early intervention such as cochlear\u000a        implants in patients with\u000a        GJB2 associated hearing loss. In the UK for example, 1,650 GJB2\u000a        tests were performed in\u000a        2010-2011 according to the Clinical Molecular Genetics Society Audit\u000a        [10]. Delayed\u000a        diagnosis of hearing loss in infants may have a harmful effect on\u000a        social, emotional,\u000a        cognitive, and academic development. A genetic diagnosis provides key\u000a        information for\u000a        genetic counseling, including prognosis and recurrence risk. For\u000a        example, not all GJB2-associated\u000a        hearing loss presents at birth [11].\u000a      b. A positive diagnosis helps rule out other diseases, including Ushers\u000a        Syndrome.\u000a      Genetic testing as described above is now recommended as the gold\u000a        standard by the\u000a        European Molecular Genetics Quality Network, and laboratories that\u000a        follow this guidance can\u000a        seek a formal certificate of quality [12].\u000a      Improved clinical and genetics information on GJB2-associated\u000a        hearing loss for patients with\u000a        hearing loss and their families via websites, leaflets and similar\u000a        material [13].\u000a    \u000a    Improved diagnosis, management, prenatal diagnosis and awareness of\u000a          Harlequin\u000a        ichthyosis\u000a    Kelsell et al's 2005 discovery of recessive ABCA12 mutations as\u000a      the major cause of this\u000a      devastating and often life threatening skin condition has led to a number\u000a      of impacts:\u000a\u0009  \u000a    Molecular diagnosis. The team has developed into a major global\u000a      referral centre for HI in the\u000a      eight-year period since they discovered the HI gene. Over 130 families\u000a      from the UK, Europe,\u000a      Africa and Asia have been sent for ABCA12 genetic analysis to this\u000a      laboratory for molecular\u000a      diagnosis. In 98% of these cases, ABCA12 mutations were identified. For\u000a      many of the samples\u000a      from overseas there is often no financial support for the HI families to\u000a      cover the genetic test\u000a      and in these cases Kelsell's team do the tests at no cost to the family.\u000a      Importantly, they have\u000a      developed genetic screening strategies such as copy number arrays,\u000a      targeted and exome high\u000a      throughput sequencing to increase accuracy of mutation detection and\u000a      increase turnaround\u000a      time (within three months), which is critical for many HI families. Last\u000a      year, they performed\u000a      genetic analysis on eleven HI families, mainly from Pakistan, India and\u000a      Iran. For UK, Europe\u000a      and the US, the ABCA12 genetic test is now an established service in\u000a      general clinical genetic \/\u000a      skin disease laboratories.\u000a    Pre-natal diagnosis (in excess of 20 HI families by this laboratory)\u000a      based on the genetic\u000a      findings. As predicted, in around 75% of cases, the test indicated that\u000a      the mother was carrying\u000a      a child that would not develop HI, and this was of great reassurance to\u000a      the family. Furthermore,\u000a      the team has performed what is believed to be the first case of\u000a      pre-implantation genetic\u000a      diagnosis for this condition, allowing the single genetically unaffected\u000a      embryo to be selected\u000a      from nine fertilised eggs, hence producing a child who was not only\u000a      phenotypically normal but\u000a      who was not even a carrier of the condition. This clinical application was\u000a      published as an online\u000a      communication by Barts Charity [14].\u000a    Data to support specific changes to clinical management. As the team\u000a      had access to a large\u000a      cohort of HI families (due to families requesting genetic testing), the\u000a      team were able to perform\u000a      the first large-scale study of HI, providing important prognostic\u000a      information for clinicians and\u000a      affected families. Previously the only clinical information were\u000a      individual case reports\u000a      describing neonatal lethality. The large number of HI families in this\u000a      study published in the\u000a      Archives of Dermatology (reference 6 above) provided huge insights into\u000a      biology of this severe\u000a      skin disease including that nearly 50% of HI babies in our study survived\u000a      (eg retinoids give\u000a      86% survival).\u000a    Patient and public awareness. Kelsell et al's work on HI has\u000a      been a component in three TV\u000a      documentaries (ITV, Channel 5 and Discovery) shown worldwide [15] and also\u000a      as an\u000a      interactive learning tool within Centre of the Cell, QMUL's interactive\u000a      science education centre\u000a      [16].\u000a\u0009  \u000a    ","ImpactSummary":"\u000a    Research at the Centre for Cutaneous Research at Queen Mary has led to\u000a      gene discovery and\u000a      molecular diagnosis for a number of single gene skin disorders and\u000a      associated syndromes\u000a      including hearing loss, inflammatory bowel disease, cardiomyopathy and\u000a      oesophageal cancer. It\u000a      has identified GJB2 mutations (encoding Cx26) as major cause of\u000a      genetic hearing loss (20-50% of\u000a      all cases) and ABCA12 mutations with the (often fatal) recessive\u000a      skin condition Harlequin\u000a      Ichthyosis. Impacts include: 1) increased medical and scientific\u000a      awareness\/knowledge of the\u000a      inherited basis of these conditions, 2) changes in clinical practice and\u000a      molecular diagnosis, 3)\u000a      improved information for patients, parents and the public.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London (QMUL)\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Kelsell DP, Dunlop J, Stevens HP et al. Connexin 26 mutations\u000a      in hereditary non-syndromic\u000a      sensorineural deafness. Nature 1997; 387, 80-83. PMID: 9139825\u000a    \u000a\u000a2. Scott CA, Kelsell DP. Key functions for gap junctions in skin\u000a      and hearing. Biochemical Journal\u000a      2011; 438: 245-54. PMID: 21834795.\u000a    \u000a\u000a3. Kelsell DP, Norgett EE, Unsworth H et al. Mutations in ABCA12\u000a      underlie the severe congenital\u000a      skin disease Harlequin Ichthyosis. American Journal of Human Genetics\u000a      2005; 76: 794-803.\u000a      PMID: 15756637.\u000a    \u000a\u000a4. Thomas AC, et al and Kelsell DP. Novel and recurring ABCA12\u000a      mutations associated with\u000a      Harlequin Ichthyosis: implications for prenatal diagnosis. British\u000a        Journal of Dermatology 2008;\u000a      158: 611-3. PMID: 17986308.\u000a    \u000a\u000a5. Scott CA et al and Kelsell DP. Targeted sequence capture and\u000a      high-throughput sequencing in\u000a      the molecular diagnosis of ichthyosis and other skin diseases. Journal\u000a        of Investigative\u000a        Dermatology 2012; 133: 573-6. PMID: 22992804.\u000a    \u000a\u000a6. Rajpopat S, et al and Kelsell DP, O'Toole EA. Harlequin\u000a      ichthyosis: a review of clinical and\u000a      molecular findings in 45 cases. Archives of Dermatology 2011; 147:\u000a      681-6. PMID: 21339420.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    GJB2 and hearing loss\u000a    \u000a      \u000a      Schimmenti LA, Warman B, Schleiss MR et al. Evaluation of\u000a        newborn screening bloodspot-based\u000a        genetic testing as second tier screen for bedside newborn hearing\u000a        screening. Genetic\u000a        Medicine 2011; 13:1006-10.\u000a      Kenneson A, Myers MF, Lubin IM, Boyle C. Genetic laboratory practices\u000a        related to testing of\u000a        the GJB2 (Connexin-26) gene in the United States in 1999 and 2000. Genetic\u000a          Testing 2003; 7:\u000a        49-56.\u000a      Ardle BM, Bitner-Glindzicz M. Investigation of the child with\u000a        permanent hearing impairment.\u000a        Archives of Diseases of Childhood (Education and Practice Edition)\u000a        2010; 95: 14-23.\u000a      Clinical Molecular Genetics Society Audit 2010-2011:\u000a          http:\/\/www.cmgs.org\/CMGS%20audit\/2011%20audit\/CMGSAudit10_11_FINAL.pdf\u000a\u000a      Minami SB, Mutai H, Nakano A, Armoto Y et al. GJB2-associated hearing\u000a        loss undetected by\u000a        hearing screening of newborns. Gene 2013 Sep 5, epub ahead of\u000a        print. doi:\u000a        10.1016\/j.gene.2013.08.094.\u000a      Guidelines for testing of DFNB1 as part of EMQN. Hoefsloot LH, Roux\u000a        A-F and Bitner-Glindzicz\u000a        M on behalf of the contributors to the EMQN DFNB1 best practice meeting.\u000a        European Journal\u000a          of Human Genetics advance online publication, 22nd May\u000a        2013. doi: 10.1038\/ejhg.2013.83.\u000a      Example of patient support organisation website for GJB2-related\u000a        deafness.\u000a        https:\/\/www.counsyl.com\/diseases\/gjb2-related-dfnb-1-nonsyndromic-hearing-loss-and-deafness\/\u000a\u000a      ABCA12 and Harlequin Ichthyosis\u000a      First recorded case of pre-implantation genetic diagnosis of HI,\u000a        leading to confirmation that\u000a        fetus was unaffected: www.bartsandthelondoncharity.org.uk\/News\/Detail\/Look-what-we-got-when-we-googled-genetics\u000a\u000a      TV Documentaries, featuring Kelsell et al's research. For\u000a        example: ITV1 `Real Lives' October\u000a        2005; `The Girls with Too Much Skin' www.channel5.com\/shows\/extraordinary-\u000a          people\/episodes\/extraordinary-people-the. This programme was\u000a        short-listed for the Media\u000a        Award for factual Programming at RADAR's People of the Year Human Rights\u000a        Awards 2008.\u000a        Another documentary of this research including gene identification and\u000a        skin models of\u000a        Harlequin Ichthyosis was filmed October 2012 and will be shown in late\u000a        2013 on the Discovery\u000a        Channel.\u000a      Other media coverage: BBC Online http:\/\/news.bbc.co.uk\/1\/hi\/health\/4337009.stm\u000a      Public understanding of science. The School of Medicine and\u000a        Dentistry's Centre of the Cell\u000a        `Find a Gene' interactive exhibit featuring HI: www.centreofthecell.org\/centre\/?page_id=129\u000a\u000a    \u000a    ","Title":"\u000a    Monogenetic diseases\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Basic genetic research in the Centre for Cutaneous Research at Queen Mary\u000a      includes:\u000a    GJB2 and hearing loss (discovery 1996-1997). In 1997, the\u000a      team hypothesised that hearing loss\u000a      in families with autosomal dominant skin disease may be due to an\u000a      unidentified gene mapping in a\u000a      locus for recessive non-syndromic hearing loss on chromosome 13 (termed\u000a      DFNB1). Kelsell et al\u000a      sequenced GJB2 encoding Connexin26 and identified mutations linked\u000a      to hearing loss in this\u000a      family. They then sequenced recessive non-syndromic hearing loss families\u000a      and identified further\u000a      GJB2 mutations. This group (including Professor Irene Leigh) were\u000a      the first to link GJB2 (encoding\u000a      Cx26) mutations with hearing loss. The paper, published in Nature\u000a      in 1997 and cited by over 1,000\u000a      publications since, described the first autosomal non-syndromic deafness\u000a      gene ever identified [1].\u000a      The implication of this finding is that GJB2 mutations account for\u000a      between 20 - 50% of all genetic\u000a      hearing loss in many distinct geographic and ethnic populations. Cochlear\u000a      implants in children with\u000a      GJB2 hearing loss lead to major clinical improvement in hearing\u000a      status, particularly if done in the\u000a      early years of life (eg PMID: 11977173).\u000a    The linking of GJB2 mutation and hearing loss led to further\u000a      studies by the Kelsell group including\u000a      GJB2 mutation screening, the development of molecular assays for\u000a      rapid mutation screening and\u000a      tissue- \/ cell-based functional assays for specific mutations. Dominant\u000a      mutations in GJB2 and other\u000a      connexin encoding genes including Cx31 were also shown to underlie\u0009\u000a      cutaneous conditions with\u000a      and without hearing loss [2]. In addition, the team provided evidence that\u000a      the high carrier frequency\u000a      of recessive GJB2 mutation may be linked to heterozygous\u000a      advantage, conferring protection from\u000a      pathogen-borne disease. Functional studies are revealing new roles for\u000a      loss of functional Cx26\u000a      leading to improved epithelial barriers and impaired bacterial entry into\u000a      epithelial cell, thus another\u000a      potential area of medical benefit.\u000a\u0009\u000a    \u000a    Harlequin Ichthyosis and ABCA12 (discovery 2005-2006).\u000a    \u000a    Harlequin Ichthyosis (HI) is the most severe form of congenital\u000a      ichthyosis. Appearance at birth is\u000a      usually characteristic (left panel above). The whole body is encased in an\u000a      armour of thick white\u000a      plates of scale separated by deep red fissures. The upper and lower\u000a      eyelids are usually retracted,\u000a      causing bilateral ectropion; the lips are parted, causing eclabium. The\u000a      nose is flattened and\u000a      appears rudimentary. Babies who survive infancy and into adulthood develop\u000a      skin changes\u000a      resembling a severe congenital ichthyosiform erythroderma (right panel).\u000a    By 2005, the Kelsell Group at Queen Mary (including Professor Edel\u000a      O'Toole) had identified and\u000a      recruited a number of families worldwide with apparent recessive HI. Using\u000a      the facilities at Barts\u000a      and The London Genome Centre, they implemented a high density Single\u000a      Nucleotide\u000a      Polymorphism (SNP) array \/ homozygosity approach to map the condition to a\u000a      region on\u000a      chromosome 2q35 [3]. Positional candidate gene sequence analysis led them\u000a      to be the first group\u000a      to identify ABCA12 mutations as the cause of this disease. They and others\u000a      screened HI families\u000a      with identifiable biallelic ABCA12 mutations, which account for over 98%\u000a      of cases. Kelsell's centre\u000a      is now a global referral centre for the genetic diagnosis of HI; they have\u000a      now identified ABCA12\u000a      mutations in over 130 families [4-6]. Furthermore, a functional programme\u000a      of work has been\u000a      established with the development of HI keratinocyte cell lines and in\u000a      vitro 3D human HI skin\u000a      models to dissect the cellular pathways disrupted by loss of ABCA12 and\u000a      the development of\u000a      assays which may lead to new therapies.\u000a    Funding: This research has been supported from multiple sources,\u000a      including BBSRC, Barts and\u000a      the London Charity, Wellcome Trust, Action Medical Research, British Skin\u000a      Foundation, Ichthyosis\u000a      Support Group, EU Network consortium (Nanodrug) and SHhIRT (Samuel\u000a      Hardgrave Harlequin\u000a      Ichthyosis Research Trust).\u000a    "},{"CaseStudyId":"18362","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    4a: Paradigm shift in how GH deficiency is conceptualised\u000d\u000a    Prior to mid-1990s, GH deficiency was primarily a paediatric disease\u000d\u000a      focusing on achieving\u000d\u000a      adequate stature. This research, together with other groups and\u000d\u000a      collaborators, demonstrated\u000d\u000a      symptoms and complications of adult GH deficiency, particularly its effect\u000d\u000a      on lipid metabolism and\u000d\u000a      (hence) cardiovascular risk, bone and quality-of-life and shown the\u000d\u000a      importance of replacement after\u000d\u000a      the cessation of linear growth. Professors Monson and Savage have given\u000d\u000a      over 30 plenary\u000d\u000a      lectures and talks on this topic at scientific, clinical and patient care\u000d\u000a      fora 1993-2013, including\u000d\u000a      lectures to GPs, trainees, meetings organised by the Royal College of\u000d\u000a      Physicians and CPD.\u000d\u000a    4b: Change in national policy and clinical management guidelines\u000d\u000a    The team's work in adult and transitional-age GH-deficient patients was\u000d\u000a      critical in informing the\u000d\u000a      NICE guidance on the management of GHD in adults and the optimum treatment\u000d\u000a      of this condition\u000d\u000a      in the transition from childhood to adulthood. The NICE guidance was based\u000d\u000a      on detailed cost\u000d\u000a      effectiveness modelling [10]. The work has informed other national and\u000d\u000a      international clinical\u000d\u000a      guidelines. In particular, our recommendations feature in the 2002 Society\u000d\u000a      for Endocrinology\u000d\u000a      guideline on management of growth hormone deficiency in adults [11].\u000d\u000a    The Growth Hormone Research Society published a critical evaluation of\u000d\u000a      the safety of recombinant\u000d\u000a      HGH administration, which drew on the work of this group [12]. The\u000d\u000a      team's research into thyroxine\u000d\u000a      and glucocorticoid replacement established that patients must be\u000d\u000a      reassessed after initiation of GH\u000d\u000a      treatment. This recommendation is now also incorporated in drug\u000d\u000a      prescribing information both in\u000d\u000a      UK and internationally (see for example this from USA [13]). The new\u000d\u000a      clinical care model, informed\u000d\u000a      by this research, of replacing GH in adolescents so as to optimise peak\u000d\u000a      bone mass and lean body\u000d\u000a      mass, has now become the standard of care for this patient group\u000d\u000a      nationally and internationally as\u000d\u000a      accepted by the European Society of Paediatric Endocrinology [14].\u000d\u000a    4c: Establishing a new `gold standard' service model\u000d\u000a    The formal paediatric-adult endocrine service at Barts led the way in\u000d\u000a      establishing the model for\u000d\u000a      transitional care of complex endocrine disorders, which is consistent with\u000d\u000a      the 2006 Department of\u000d\u000a      Health Guidance publication [15]. This model requires considerably\u000d\u000a      greater collaboration between\u000d\u000a      paediatric and adult endocrinology clinics than was previously the case.\u000d\u000a    4d: Change in clinical practice\u000d\u000a    Following the team's research publications (mostly between 1995 and\u000d\u000a      2001), and the incorporation\u000d\u000a      of their recommendations into NICE guidelines in 2003, prescription rates\u000d\u000a      for GH in the UK\u000d\u000a      increased, as confirmed by Department of Health data (Figure 1) [16].\u000d\u000a\u000d\u000aFigure 1; Number of GH prescriptions in the UK by year. The inflection in the curve\u000d\u000astarting in 2002 reflects the impact of clinical research in hypopituitary adults.\u000d\u000a\u000d\u000a    4e: Improved clinical outcomes (reduced morbidity)\u000d\u000a    GH replacement improves health, psychological well-being and quality of\u000d\u000a      life (reference 3 above).\u000d\u000a      Cardiovascular risk is reduced (reference 1 above) and real-time data from\u000d\u000a      the KIMS database\u000d\u000a      have confirmed that standardised mortality ratios in hypopituitary adults\u000d\u000a      receiving GH replacement\u000d\u000a      are lower than the high rates documented in 1990 (2.0 in men and 3.0 in\u000d\u000a      women) to a mean of 1.2\u000d\u000a      (0.94 in men and 1.56 in women). KIMS data also demonstrate that these\u000d\u000a      improvements translate\u000d\u000a      into a reduction in socio-economic costs (reference 3 above).\u000d\u000a    4f: Establishing a methodological approach to endocrine research in UK\u000d\u000a    This team's initiation and leadership of a combined adult-paediatric\u000d\u000a      endocrinology UK multicentre\u000d\u000a      study focused on the continuation of GH replacement in adolescents in\u000d\u000a      optimising peak bone mass\u000d\u000a      and lean body mass development was the first multi-centre controlled trial\u000d\u000a      of its kind in this\u000d\u000a      condition. Since that trial, other high-quality multi-centre trials of\u000d\u000a      similar design have been initiated\u000d\u000a      and supported by the clinical endocrinology community — see for example\u000d\u000a      [17].\u000d\u000a    4g: Supporting informed choice by patients and informing the public\u000d\u000a    A summary of these research findings is distributed by the Pituitary\u000d\u000a      Foundation in a patient booklet\u000d\u000a      available to download free from their website: `The Pituitary Gland' in\u000d\u000a      2012 [18]. Direct patient\u000d\u000a      comments support the positive effects documented in clinical trials [19].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research at Queen Mary established the beneficial effects of adult growth\u000d\u000a      hormone (GH) replacement.\u000d\u000a      Prof Korbonits' team pioneered careful GH dose titration and adjustment of\u000d\u000a      other concomitant pituitary\u000d\u000a      hormone replacements, both crucial for effective and safe treatment.\u000d\u000a      Collaborative research between\u000d\u000a      adult and paediatric endocrinologists established a new model of GH\u000d\u000a      deficiency treatment between\u000d\u000a      completion of linear growth and full maturity at age 25. Findings led to\u000d\u000a      [a] revised guidelines and policy\u000d\u000a      in UK, Europe and USA; [b] new service models (especially at the\u000d\u000a      paediatric-adult transition); [c]\u000d\u000a      significant changes in clinical practice, [d] improved patient outcomes,\u000d\u000a      notably dramatically improved\u000d\u000a      quality of life, reduced cardiovascular risk and improved survival, [e]\u000d\u000a      reduced costs.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen Mary University of London\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans KA,\u000d\u000a      &Cunningham J. The\u000d\u000a      effect of low dose recombinant human growth hormone replacement on\u000d\u000a      regional fat\u000d\u000a      distribution, insulin sensitivity, and cardiovascular risk factors in\u000d\u000a      hypopituitary adults. Journal of\u000d\u000a      Clinical Endocrinology and Metabolism 1995; 80: 153-159.\u000d\u000a    \u000a\u000a2. Koltowska-Haggstrom M, Mattsson AF, Monson JP, Kind P, Badia X,\u000d\u000a      Casanueva FF, Busschbach\u000d\u000a      J, Koppeschaar H P & Johannsson G. Does long-term GH replacement\u000d\u000a      therapy in hypopituitary\u000d\u000a      adults with GH deficiency normalise quality of life? European Journal\u000d\u000a        of Endocrinology 2006; 155:\u000d\u000a      109-119.\u000d\u000a    \u000a\u000a3. Hernberg-Stahl E, Luger A, Abs R, Bengtsson BA, Feldt-Rasmussen U,\u000d\u000a      Wilton P, Westberg B,\u000d\u000a      Monson JP. Healthcare consumption decreases in parallel with improvements\u000d\u000a      in quality of life\u000d\u000a      during GH replacement in hypopituitary adults with GH deficiency. Journal\u000d\u000a        of Clinical Endocrinology\u000d\u000a        and Metabolism 2001; 86: 5277-5281.\u000d\u000a    4. Drake WM, Coyte D, Camacho-Hübner C, Jivanji NM, Kaltsas G, Wood DF,\u000d\u000a      Trainer PJ, Grossman\u000d\u000a      AB, Besser GM, Monson JP. Optimising growth hormone replacement therapy by\u000d\u000a      dose titration in\u000d\u000a      hypopituitary adults. Journal of Clinical Endocrinology and Metabolism\u000d\u000a      1998; 83: 3913-3919. and\u000d\u000a      Drake WM, Howell SJ, Monson JP, Shalet SM. Optimizing GH therapy in adults\u000d\u000a      and children.\u000d\u000a      Endocrine Reviews 2001; 22: 425-450.\u000d\u000a    \u000a\u000a5. Drake WM, Rodriguez-Arnao J, Weaver JU, James I, Coyte D, Spector T,\u000d\u000a      Besser GM, Monson JP.\u000d\u000a      The influence of gender on the short and long term effects of growth\u000d\u000a      hormone replacement on bone\u000d\u000a      metabolism and bone mineral density in hypopituitary adults — a five year\u000d\u000a      study. Clinical\u000d\u000a        Endocrinology 2001; 54: 525-532.\u000d\u000a    \u000a\u000a6. Carroll PV, Drake WM, Maher KT, Metcalfe K, Shaw NJ, Dunger DB,\u000d\u000a      Cheetham TD, Camacho-Hubner\u000d\u000a      C, Savage MO, Monson JP. Comparison of continuation or cessation of growth\u000d\u000a      hormone\u000d\u000a      (GH) therapy on body composition and metabolic status in adolescents with\u000d\u000a      severe GH deficiency\u000d\u000a      at completion of linear growth. Journal of Clinical Endocrinology and\u000d\u000a        Metabolism 2004; 89: 3890-3895.\u000d\u000a    \u000a\u000a7. Drake WM, Carroll PV, Maher KT, Metcalfe KA, Camacho-Hubner C, Shaw\u000d\u000a      NJ, Dunger DB,\u000d\u000a      Cheetham TD, Savage MO, Monson JP. The effect of cessation of growth\u000d\u000a      hormone (GH) therapy\u000d\u000a      on bone mineral accretion in GH-deficient adolescents at the completion of\u000d\u000a      linear growth Journal of\u000d\u000a      Clinical Endocrinology and Metabolism 2003; 88: 1658-1663\u000d\u000a    \u000a\u000a8. Agha A, Walker D, Perry L, Drake WM, Chew SL, Jenkins PJ, Grossman AB,\u000d\u000a      Monson JP.\u000d\u000a      Unmasking of central hypothyroidism following growth hormone replacement\u000d\u000a      in adult hypopituitary\u000d\u000a      patients. Clinical Endocrinology 2007; 66: 72-77.\u000d\u000a    \u000a\u000a9. Gelding SV, Taylor NF, Wood PJ, Noonan K, Weaver JU, Wood DF, Monson\u000d\u000a      JP. The effect of\u000d\u000a      growth hormone replacement therapy on cortisol-cortisone interconversion\u000d\u000a      in hypopituitary\u000d\u000a      adults: evidence for growth hormone modulation of extrarenal 11\u000d\u000a      beta-hydroxysteroid\u000d\u000a      dehydrogenase activity. Clinical Endocrinology 1998; 48: 153-162.\u000d\u000a    \u000aThe research was supported by the Wellcome Trust, Queen Mary, NHS and\u000d\u000a      visiting Fellowship from\u000d\u000a      Beaumont Hospital and by unrestricted educational pharmaceutical industry\u000d\u000a      grants.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a      \u000d\u000a    NICE Guideline. Growth Hormone Deficiency (Adults) — Human Growth\u000d\u000a      Hormone. TA64\u000d\u000a      (2003).\u000d\u000a        http:\/\/guidance.nice.org.uk\/TA64. Professor Monson is referenced in\u000d\u000a      Appendix B.\u000d\u000a    Society for Endocrinology Guideline on Management of Growth Hormone\u000d\u000a      Deficiency in Adults\u000d\u000a      2002. See pages 28 - 33 for references to 10 papers co-authored by Prof\u000d\u000a      Monson.\u000d\u000a      http:\/\/jcem.endojournals.org\/content\/86\/5\/1868.full\u000a\u000d\u000a    Christiansen JS, Bengtsson BA, Thorner M et al. Critical evaluation of\u000d\u000a      the safety of\u000d\u000a      recombinant human growth hormone administration: statement from the Growth\u000d\u000a      Hormone\u000d\u000a      Research Society. Journal of Clinical Endocrinology and Metabolism 2001;\u000d\u000a      86: 1868-70.\u000d\u000a      http:\/\/jcem.endojournals.org\/content\/86\/5\/1868.full\u000a\u000d\u000a    US Food and Drug Administration safety information: Somatropin [rDNA\u000d\u000a      origin] for injection\u000d\u000a      2012. http:\/\/www.fda.gov\/Safety\/MedWatch\/SafetyInformation\/ucm203732.htm\u000a\u000d\u000a    European Society for Paediatric Endocrinology recommendation of\u000d\u000a      transitional care:\u000d\u000a     http:\/\/www.eurospe.org\/clinical\/Docs\/ManagementGH-treatedAdolescentTransitionAdultCare.pdf\u000a\u000d\u000a    Department of Health guidance on transitional care in complex endocrine\u000d\u000a      disorders 2006 (still\u000d\u000a      current).\u000d\u000a    Department of Health Prescription Cost Analysis publications 2012:\u000d\u000a     http:\/\/webarchive.nationalarchives.gov.uk\/20120104142136\/http:\/\/www.dh.gov.uk\/en\/Publicationsandstatistics\/Statistics\/StatisticalWorkAreas\/Statisticalhealthcare\/DH_4086488\u000a\u000d\u000a    Conway GS, Szarras-Czapnik M, Racz K et al. Treatment for 24 months with\u000d\u000a      recombinant\u000d\u000a      human GH has a beneficial effect on bone mineral density in young adults\u000d\u000a      with childhood-onset\u000d\u000a      GH deficiency. European Journal of Endocrinology 2009; 160: 899-907.\u000d\u000a    Pituitary Foundation information leaflet `The Pituitary Gland' 2012.\u000d\u000a      http:\/\/www.pituitary.org.uk\/information\/publications\/essential-free-publications\/hydrocortisone-advice-pituitary-patient-leaflet\/\u000d\u000a      This leaflet has been downloaded or distributed as hard copies\u000d\u000a      6,297 times in the last three years.\u000d\u000a    Levy,M. Interview with Peter Sonksen. Endocrinologist 2013: Spring; page\u000d\u000a      6-9.\u000d\u000a      http:\/\/www.endocrinology.org\/endocrinologist\/107\/107.pdf#page=6\u000a\u000d\u000a\u0009  \u000d\u000a    ","Title":"\u000d\u000a    Treatment of adult growth hormone deficiency\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Background: Hypopituitarism affects at least 1 in 10,000 people.\u000d\u000a      The commonest cause is pituitary\u000d\u000a      tumours. The observation in 1990 of increased mortality in adult\u000d\u000a      hypopituitary patients on conventional\u000d\u000a      hormone replacement regimens (standardised mortality ratio, SMR,\u000d\u000a      approximately 2:1 and 3:1 in males\u000d\u000a      and females respectively) prompted detailed examination of the metabolic\u000d\u000a      consequences of hormonal\u000d\u000a      deficiencies, especially the impact of GH deficiency and replacement.\u000d\u000a    Aim: To evaluate the impact of GH replacement in adult and adolescence\u000d\u000a        hypopituitary patients,\u000d\u000a        optimise dose regimens, document changes in cardiovascular and bone risk\u000d\u000a        factors and quality\u000d\u000a        of life, and explore how best to adjust other pituitary hormone\u000d\u000a        replacement.\u000d\u000a    Key studies and findings: The Department of Endocrinology at Queen\u000d\u000a      Mary, led by Professor John\u000d\u000a      Monson and including Profs Drake & Gelding, Drs Carroll, Swords, Agha,\u000d\u000a      Brooke and Weaver, was at\u000d\u000a      the forefront of this endeavour in collaboration with paediatric\u000d\u000a      endocrinologist Prof Martin Savage and\u000d\u000a      team. From 1993, using prospective placebo-controlled and observational\u000d\u000a      studies, the team has been\u000d\u000a      made pivotal contributions to the knowledge base on GH deficiency.\u000d\u000a      Highlights include:\u000d\u000a    \u000d\u000a      The team demonstrated that GH deficient patients have a highly adverse\u000d\u000a        cardiovascular risk\u000d\u000a        profile and that this risk could be significantly reduced with GH\u000d\u000a        replacement. In particular, we\u000d\u000a        have shown systematically that GH replacement improves cardiovascular\u000d\u000a        risk factors e.g. it\u000d\u000a        reduces LDL-cholesterol by a mean of 0.4mmol\/l [1].\u000d\u000a      This department was the largest contributor to the major multinational\u000d\u000a        database (KIMS)\u000d\u000a        examining the impact of GH replacement on various indices of well-being\u000d\u000a        and health and these\u000d\u000a        data led to the introduction of the 2003 NICE guidelines on adult GH\u000d\u000a        deficiency. This database\u000d\u000a        has been crucial in documenting the impact of GH replacement on\u000d\u000a        morbidity and mortality in a\u000d\u000a        large cohort of GH deficient patients (see `Impact' below).\u000d\u000a      The research showed that GH replacement significantly improves overall\u000d\u000a        well-being and\u000d\u000a        energy levels, as demonstrated by reduction of the disease-sensitive\u000d\u000a        QoL-AGHDA (Quality of\u000d\u000a        Life — Assessment of GH Deficiency in Adults) score from median 15 to 7\u000d\u000a        [2,3].\u000d\u000a      The team tested a number of approaches to establish the appropriate\u000d\u000a        method of careful dose-optimisation\u000d\u000a        for GH replacement in adults and adolescents [4].\u000d\u000a      The team established optimal management of GH deficiency in the\u000d\u000a        critical period between\u000d\u000a        adolescence and adulthood, when linear growth is complete, which had\u000d\u000a        previously been the\u000d\u000a        subject of much clinical debate [4,5,6,7]. A structured programme of\u000d\u000a        collaborative clinical care\u000d\u000a        led the way in establishing a model for optimal paediatric to adult\u000d\u000a        transitional care of endocrine\u000d\u000a        disorders. The model, sited in the adult endocrine clinic, staffed by\u000d\u000a        paediatric and adult\u000d\u000a        endocrinologists and specialist nurses, was the first of its kind in the\u000d\u000a        UK. Subsequent close\u000d\u000a        paediatric-adult research collaboration led to original data that was\u000d\u000a        pivotal in the 2003 NICE\u000d\u000a        Guidance on GH therapy in GH deficient patients during transition from\u000d\u000a        paediatric to adult care.\u000d\u000a      In addition to the observed bone density improvement in adults [5], in\u000d\u000a        adolescents the team\u000d\u000a        showed, in a multicentre controlled trial co-ordinated from Queen Mary,\u000d\u000a        that GH treatment after\u000d\u000a        completion of linear growth until acquisition of peak bone mass improves\u000d\u000a        bone mineral density\u000d\u000a        by 4% and lean body mass by 4% over 1 year, compared to non-treated\u000d\u000a        controls [6,7].\u000d\u000a      In prospective interventional studies they have demonstrated the\u000d\u000a        important interactions\u000d\u000a        between GH replacement and other hormonal systems, particularly the\u000d\u000a        thyroid axis, and the\u000d\u000a        effect of GH on increasing metabolic clearance of cortisol and the\u000d\u000a        potential adverse effect of\u000d\u000a        this phenomenon in patients with partial ACTH deficiency [8,9].\u000d\u000a      They have shown a reduction on societal and healthcare costs for GH\u000d\u000a        deficient patients [3].\u000d\u000a      The adverse impact of GH deficiency on psychological well-being and\u000d\u000a        energy levels, and the\u000d\u000a        benefits of GH replacement on these aspects were clearly demonstrated.\u000d\u000a        This provided the major\u000d\u000a        evidence base for NICE guidance on the treatment of GH deficiency (see\u000d\u000a        `Impact').\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"18364","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    4a: Laboratory studies led directly to a series of clinical trials in\u000d\u000a        humans.\u000d\u000a    Following on from the initial studies undertaken at Queen Mary by Prof\u000d\u000a      MacDonald's team, further comparisons between enteral nutrition and\u000d\u000a      corticosteroids were carried out. Heushkel and colleagues summarised 5\u000d\u000a      other studies that showed that enteral nutrition was as effective as\u000d\u000a      steroids in inducing remission in paediatric Crohn's disease [6]. In 2006,\u000d\u000a      these results were confirmed in an Italian study [7]. Since then pediatric\u000d\u000a      gastroenterologists have accepted the efficacy of enteral nutrition, and\u000d\u000a      more recent studies have focussed on the type of enteral nutrition [8],\u000d\u000a      partial enteral nutrition [9], and fractionated versus continuous feeding\u000d\u000a      [10].\u000d\u000a    4b: Change in clinical guidelines and policy in UK\u000d\u000a    The use of enteral nutrition as primary therapy for paediatric Crohn's\u000d\u000a      disease was adopted in 2008 in the guidelines of the British Society for\u000d\u000a      Paediatric Gastroenterology, Hepatology and Nutrition [11]; this\u000d\u000a      recommendation was reinforced in 2010 [12]. It is recommended by leading\u000d\u000a      opinion leaders as the primary choice for patients presenting with Crohn's\u000d\u000a      disease and a degree of malnutrition [13]. Consultative NICE guidelines\u000d\u000a      published in October 2012 are strongly supportive of enteral therapy in\u000d\u000a      paediatric Crohn's disease.\u000d\u000a    For example, paragraph 1.4.2 of the consultative NICE guidelines states:\u000d\u000a      \"Enteral nutrition is currently widely used as first-line therapy in\u000d\u000a        children and adolescents to facilitate growth and development.\"\u000d\u000a      Paragraph 4.3 states: \"Consider enteral nutrition as an alternative to\u000d\u000a        a conventional glucocorticosteroid to induce remission for: children in\u000d\u000a        whom there is concern about growth or side effects, and young people in\u000d\u000a        whom there is concern about growth.\" [14]\u000d\u000a    4c: Change in clinical guidelines beyond UK\u000d\u000a    European guidelines changed in 2006 to recommend enteral nutrition as\u000d\u000a      first line therapy in children with Crohn's disease [15].\u000d\u000a    The North American Society for Pediatric Gastroenterology, Hepatology and\u000d\u000a      Nutrition issued new guidelines in 2012 recommending enteral nutrition as\u000d\u000a      first line induction of remission therapy for paediatric Crohn's disease\u000d\u000a      [16].\u000d\u000a    4d: Change in clinical practice worldwide\u000d\u000a    In Sweden, 96% of paediatric IBD units now use enteral nutrition for\u000d\u000a      Crohn's disease, and 65% use exclusive enteral nutrition as primary\u000d\u000a      therapy [17]. Overall in 2003, 62% of European gastroenterologists used\u000d\u000a      enteral nutrition to treat Crohn's disease in children [18], and it is\u000d\u000a      likely that the figure is even higher now, although no recent European\u000d\u000a      data are available. Exclusive enteral nutrition is now being used in\u000d\u000a      Australia [19].\u000d\u000a    In a survey of the use of enteral nutrition in Europe, North America and\u000d\u000a      the Asia-Pacific region, 89% of units used enteral nutrition and polymeric\u000d\u000a      formulae, and by far the majority used two products, Modulen IBD or the\u000d\u000a      lactose free equivalent, Elemental 208 [20].\u000d\u000a    4e: The change in practice produced a change in patient outcomes\u000d\u000a    About 20 per cent of children with Crohn's disease treated with long-term\u000d\u000a      low dose steroid treatment have growth failure. After cessation of\u000d\u000a      steroids, 70 per cent do not show catch up growth [21]. In a two-year\u000d\u000a      follow up of 109 children treated with Modulen IBD, weight and BMI\u000d\u000a      improved markedly during follow up [22]. Height catch-up growth was\u000d\u000a      bimodal, with those patients who responded clinically showing catch-up\u000d\u000a      growth but those who did not, remaining short [22]. In addition, children\u000d\u000a      with Crohn's disease have a markedly impaired quality of life [23].\u000d\u000a      Exclusive treatment with Modulen IBD improves their quality of life [24].\u000d\u000a    An estimated 17,000 new cases of Crohn's disease occur in children across\u000d\u000a      Europe annually, so a conservative estimate is that as a result of our\u000d\u000a      early research, at least 13,000 children a year are being spared steroid\u000d\u000a      therapy.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Corticosteroids are the traditional mainstay of treatment for\u000d\u000a      inflammatory conditions but their side effects are often severe,\u000d\u000a      especially in children. Professor MacDonald's team researched alternatives\u000d\u000a      to corticosteroids in childhood Crohn's disease. With Nestlé they\u000d\u000a      developed a polymeric, milk-based formula feed (Modulen IBD) that was\u000d\u000a      highly effective in inducing clinical remission. NICE guidance have\u000d\u000a      changed to reflect these findings. The treatment is now first-line therapy\u000d\u000a      for childhood Crohn's in UK and the rest of Europe and recommended in\u000d\u000a      clinical guidelines in USA. We estimate that across Europe alone, 13,000\u000d\u000a      new cases of childhood Crohn's annually will be spared steroid therapy as\u000d\u000a      a result of this work.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen Mary University of London\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams\u000a        CB, Domizio P, Walker-Smith JA, MacDonald TT.\u000d\u000a      Tumour necrosis factor-alpha producing cells in the intestinal mucosa of\u000d\u000a      children with inflammatory bowel disease. Gastroenterology 1994;\u000d\u000a      106:1455-1466.\u000d\u000a    \u000a\u000a2. Breese EJ, Michie CA, Nicholls S, Williams CB,\u000d\u000a      Domizio P, Walker-Smith JA, MacDonald TT. The\u000d\u000a      effect of treatment on the frequency of lymphokine-secreting cells in the\u000d\u000a      intestinal mucosa of children with Crohn's disease. Alimentary\u000d\u000a        Pharmacology and Therapeutics 1995; 9:547-552.\u000d\u000a    \u000a\u000a3. Beattie RM, Schiffrin EJ, Donnet-Hughes A, Huggett AC, Domizio\u000a        P, MacDonald TT, Walker-Smith JA. Polymeric\u000d\u000a      nutrition as the primary therapy in children with small bowel Crohn's\u000d\u000a      disease. Alimentary Pharmacology and Therapeutics 1994; 8: 609-15.\u000d\u000a    \u000a\u000a4. Fell JM, Paintin M, Donnet-Hughes A, Arnaud-Battandier F, MacDonald\u000a        TT, Walker-Smith JA. Remission induced by a new specific\u000d\u000a      oral polymeric diet in children with Crohn's disease. Nestlé\u000d\u000a        Nutritional Workshop Series Clinical Performance Programme 1999;\u000d\u000a      2:187-96.\u000d\u000a    \u000a\u000a5. Fell JM, Paintin M, Arnaud-Battandier F, Beattie, RM,\u000d\u000a      Hollis A, Kitching P, Donnet-Hughes A, MacDonald TT, Walker-Smith\u000a        JA. Mucosal healing and a fall in mucosal pro-inflammatory cytokine\u000d\u000a      mRNA induced by a specific oral polymeric diet in paediatric Crohn's\u000d\u000a      disease. Alimentary Pharmacology and Therapeutics 2000; 14: 281-9.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000d\u000a    \u000d\u000a      Heuschkel R, Menache CC, Megerian JT, Baird AE. Enteral nutrition and\u000d\u000a        corticosteroids in the treatment of acute Crohn's disease in children. Journal\u000a          of Paediatric Gastroenterology and Enteral Nutrition 2000; 31:\u000d\u000a        8-15.\u000d\u000a      Canani RB, Terrin G, Borrelli O et al. Short-and long-term therapeutic\u000d\u000a        efficacy of nutritional therapy and corticosteroids in paediatric\u000d\u000a        Crohn's disease. Digestive and Liver Disease 2006; 38: 381-387.\u000d\u000a      Ludvigsson JF. Elemental versus polymeric enteral nutrition in\u000d\u000a        paediatric Crohn's disease: a multicentre randomised trial. Acta\u000d\u000a          Paediatrica 2004; 93: 327-35.\u000d\u000a      Johnson T, Macdonald S, Hill SM, Thomas A, Murphy MS. Treatment of\u000d\u000a        active Crohn's disease in children using partial enteral nutrition with\u000d\u000a        liquid formula: a randomised controlled trial. Gut 2006; 55:\u000d\u000a        356-61.\u000d\u000a      Rubio A, Pigneur B, Garnier-Lengliné H et al. The efficacy of\u000d\u000a        exclusive nutritional therapy in paediatric Crohn's disease, comparing\u000d\u000a        fractionated oral vs continuous enteral feeding. Alimentary\u000d\u000a          Pharmacology and Therapeutics 2011; 33: 1132-39.\u000d\u000a      British Society for Paediatric Gastroenterology, Hepatology and\u000d\u000a        Nutrition Guidelines 2008\u000d\u000a        http:\/\/bspghan.org.uk\/documents\/IBDGuidelines.pdf\u000a\u000d\u000a      Sandhu BK, Fell JME, Beattie RM et al on behalf of the IBD Working\u000d\u000a        Group of the British Society of Paediatric Gastroenterology, Hepatology,\u000d\u000a        and Nutrition. Guidelines for the Management of Inflammatory Bowel\u000d\u000a        Disease in Children in the United Kingdom. Journal of Pediatric\u000d\u000a          Gastroenterology and Nutrition. 2010; 50: S1-S13.\u000d\u000a      Heuschkel R. Enteral nutrition should be used to induce remission in\u000d\u000a        childhood Crohn's disease. Digestive Diseases 2009; 27: 297-305.\u000d\u000a      NICE guideline on management of Crohn's disease, October 2012\u000d\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/13936\/61002\/61002.pdf\u000a\u000d\u000a      Lochs H, Dejong C, Hammarqvist F et al. ESPEN Guidelines on Enteral\u000d\u000a        Nutrition. Gastroenterology 2006; 25:260-74.\u000d\u000a      Critch J, Day AS, Otley A et al on behalf of NASPGAN (North American\u000d\u000a        Society for Pediatric Gastroenterology, Hepatology and Nutrition). Use\u000d\u000a        of enteral nutrition for the control of intestinal inflammation in\u000d\u000a        pediatric Crohn disease. Journal of Pediatric Gastroenterology and\u000d\u000a          Nutrition 2012; 54: 298-305.\u000d\u000a      Grafors JM, Casswall TH Exclusive enteral nutrition in the treatment\u000d\u000a        of children with Crohn's disease in Sweden: a questionnaire survey. Acta\u000a          Pediatrica 2011; 100: 1018-22.\u000d\u000a      Levine A, Milo T, Buller H et al Consensus and controversy in the\u000d\u000a        management of pediatric Crohn's disease: an international study. Journal\u000a          of Pediatric Gastroenterology and Nutrition 2003; 36:464-466.\u000d\u000a      Day AS, Stephenson T, Stewart M, Otley AR. Exclusive enteral nutrition\u000d\u000a        for children with Crohn's disease: use in Australia and attitudes of\u000d\u000a        Australian pediatric gastroenterologists. Journal of Paediatrics and\u000d\u000a          Child Health 2009; 45: 337-41.\u000d\u000a      Whitten KE, Rogers P, Chee KY et al. International survey of enteral\u000d\u000a        nutrition protocols used in children with Crohn's disease. Journal\u000d\u000a          of Digestive Diseases 2012; 13:107-112.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Enteral nutrition in childhood Crohn's disease\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    \u000d\u000a    \u000d\u000a    \u000d\u000a    Nutritional therapy tackles one of the main problems of paediatric\u000d\u000a      Crohn's disease, namely undernourishment leading to growth retardation and\u000d\u000a      delayed puberty, which may be more troublesome and stigmatising than the\u000d\u000a      disease itself. The concept of \"gut rest\" using amino-acid based elemental\u000d\u000a      diets has shown promise for Crohn's disease since the 1980s. Its\u000d\u000a      scientific basis lies in changes in gut microflora. Early elemental diets,\u000d\u000a      such as Flexical (based on hydrolysed casein) were unpalatable, had low\u000d\u000a      energy content and had to be given by nasogastric tube.\u000d\u000a    In the early 1990s, the role of T cells and cytokines as mediators of gut\u000d\u000a      damage in Crohn's disease were identified, principally by MacDonald's\u000d\u000a      research team at Queen Mary. Working with Nestlé, they hypothesised that\u000d\u000a      one of the company's infant milk formulas, called AL110, which contains\u000d\u000a      the immunosuppressive cytokine TGF03b22, might help dampen gut\u000d\u000a      inflammation in Crohn's disease. Importantly, AL110 was palatable. They\u000d\u000a      tested AL110 versus Flexical as a primary therapy in a small group of\u000d\u000a      children with Crohn's disease and found that both were highly effective\u000d\u000a      clinically, dramatically reducing T cell and macrophage derived cytokines\u000d\u000a      from inflamed mucosae [1, 2] along with histological and clinical\u000d\u000a      remission and a catch-up growth spurt in growth-retarded children [3].\u000d\u000a    MacDonald's team developed and tested a more concentrated formulation of\u000d\u000a      the product in larger samples of children with newly-diagnosed Crohn's; 90\u000d\u000a      per cent achieved rapid clinical remission along with histological\u000d\u000a      improvement and reduction in pro-inflammatory cytokines [4,5].\u000d\u000a    Based on these data, Nestle made the new product (CT3211) in a variety of\u000d\u000a      flavours and marketed it as Modulen IBD in the summer of 2001. Modulen IBD\u000d\u000a      is now available as a concentrate at 1.5 Kcal\/ml, so that 1 litre contains\u000d\u000a      1500 calories.\u000d\u000a    "},{"CaseStudyId":"18365","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2661886","Name":"Sweden"}],"Funders":[],"ImpactDetails":"\u000a    In sum, this research [a] quantified the benefit of cervical screening at\u000a      different ages; [b] quantified the benefit of screening at different\u000a      intervals; [c] quantified the harms of screening at different ages. The\u000a      impacts listed below have been divided into impact on policy and guidance;\u000a      impact on practice; reduction in harms; economic impacts; and impact on\u000a      research internationally.\u000a    4a: Change in policy\/guidance\u000a    UK: The cervical screening programme in England changed in 2003 to\u000a      adopt the ages and intervals recommended by Sasieni's team. Policy was\u000a      reviewed in 2009 and remained the same. In 2012, the National Screening\u000a      Committee (representing all four nations of the UK) recommended that\u000a      cervical screening should start at age 25 [11]. This was as a direct\u000a      result of Sasieni's research. Reference [1] was published in July 2003. It\u000a      was discussed by the Advisory Committee on Cervical Screening and, in\u000a      October 2003, the Minister for Public Health announced changes to the\u000a      cervical screening programme in England, including the changes to the\u000a      age-range and screening intervals that the Queen Mary researchers\u000a      recommended [12]. Sasieni spoke at the Minister's press conference to\u000a      explain the research. Sasieni and Cuzick presented their epidemiological\u000a      findings (references 1,2,5,6) and modelling of impact of HPV vaccination\u000a      on cervical screening and cervical cancer in young women (reference 9) to\u000a      an extraordinary meeting of the Advisory Committee on Cervical Screening\u000a      in 2009. In line with their research, the Committee unanimously\u000a      recommended against a proposal to change the age at first screen from 25\u000a      back to 20 [13].\u000a    USA: In 2012, a national guideline produced jointly by the\u000a      American Cancer Society, American Society for Colposcopy and Cervical\u000a      Pathology, and American Society for Clinical Pathology recommended\u000a      changing the screening interval from yearly to 3-yearly in women aged\u000a      21-29 and not screening women under 21 regardless of age of onset of\u000a      sexual activity [14, 15]. The USSPTF made similar recommendations [16].\u000a      This represents a marked change in policy as a result of Sasieni et al's\u000a      research. In 2002, the recommendation in USA was that cervical screening\u000a      should occur from age 18 or soon after the onset of sexual activity.\u000a      Adoption of the recommendations in the USA has taken longer, perhaps\u000a      because of a long tradition of annual screening. Whilst US guidance is\u000a      still not exactly in line with the research evidence, it was influenced by\u000a      the findings of Sasieni's team and represented a shift in a more\u000a      evidence-based direction.\u000a    4b: Change in public health practice\u000a    The percentage of women screened in different age groups in 2002-03 in\u000a      England was 22.4% at age 20-24, 25.6% at age 25-29, and 18.8% at age\u000a      55-59, representing a mix of three- and five-yearly screening from age\u000a      20-64 [17]. In 2010-11 (and 2011-12) those percentages were 2.1% (1.7%)\u000a      (age 20-24), 27.8% (28.3%) (age 25-29), and 15.3% (15.1%) (age 55-59) [18,\u000a      19]. Thus this research has not only resulted in a new policy but that\u000a      policy has been implemented and has had a clear impact on cervical\u000a      screening in England.\u000a    4c: Reduction in harms\u000a    There were some 53,000 abnormal (ie borderline changes or worse)\u000a      screening tests in women aged 20-24 in England in 2002-03 [17]. It is\u000a      reasonable to infer that most of these women would have been anxious. In\u000a      2010-11 there were fewer than 8,000 such tests [18], a reduction of around\u000a      45,000. All women with moderate dyskaryosis or worse (N=9702 aged 20-24 in\u000a      2002-03) were referred to colposcopy and approximately 22% of women with\u000a      borderline changes (N=23,020) and 43% of those with mild dyskaryoisis\u000a      (N=20,950) were referred (after a repeat abnormal test) [17]. Thus it is\u000a      estimated that some 20,000 fewer women aged 20-24 will have been referred\u000a      to colposcopy in 2010-11 compared to 2002-03. At all ages in 2002-03,\u000a      16.8% of women referred with persistent low-grade cytology and 73.4% of\u000a      women referred with moderate dyskaryosis or worse had high-grade disease\u000a      on histology (CIN2 or worse) [17]. Certainly all these women would have\u000a      been offered treatment. Consequently, as a result of this research an\u000a      estimated 8,500 women aged 20-24 will have avoided having unnecessary\u000a      treatment each year. The team has quantified the harms and benefits of\u000a      starting screening at 20 rather than at age 25 and a table laying out the\u000a      numbers affected; this is available on the National Screening Committee\u000a      website [20]. A recent US editorial `Primum non nocere' acknowledged the\u000a      potential harms of cervical screening in inappropriate groups and\/or at\u000a      over-frequent intervals [21].\u000a    4d: Cost savings to the NHS\u000a    The cost saving from not screening some 350,000 women each year is\u000a      approximately £17.5 million [22]. The impact in the USA has been less\u000a      dramatic, but because the population is larger and was previously\u000a      encouraged to have annual screening from age 18, the economic impact has\u000a      been even greater. The Centre for Disease Control and Prevention [23]\u000a      reports that an additional 23-24% of 18 and 19 year old women (i.e. some 1\u000a      million women) have never had a Pap smear and an additional 16% of 20-24\u000a      year old women (about 1.75 million women) have not had a smear in the last\u000a      year. Thus the change in policy had resulted in about 2.75 million fewer\u000a      Pap smears in women aged 18-24 in the year 2010. It is difficult to\u000a      estimate the cost of cervical screening in the USA, but it is likely that\u000a      the annual saving is over $200 million.\u000a    4e: Informing further research internationally\u000a    Soon after the 2003 publication [1], Sasieni was contacted by colleagues\u000a      in Italy and invited to work with them; the following year a paper was\u000a      published broadly confirming the UK finding on Italian data [24]. A\u000a      routine audit of cervical screening has been set up in Sweden [25]. The\u000a      Wolfson team is coordinating an international collaborative audit of\u000a      cervical screening programmes and analysis of routine screening data. The\u000a      design of the cervical screening audit is now being adapted and employed\u000a      to evaluate routine breast colorectal screening [26].\u000a    ","ImpactSummary":"\u000a    Professor Peter Sasieni's team at Queen Mary showed that the efficacy of\u000a      cervical screening was age-dependent. Their recommendations were adopted\u000a      as policy in England in 2003 and led many other countries, including the\u000a      USA, to raise the recommended age of first screening. This research was\u000a      central to the 2009 re-evaluation of the most appropriate age for first\u000a      screening in England, resulting in some 300,000 fewer screening tests per\u000a      year in women aged 20-24, with a cost saving to the NHS of some £15\u000a      million annually. Annually, 45,000 fewer women now have an abnormal\u000a      cervical screening test, of which an estimated 8,500 would have received\u000a      unnecessary surgical treatment. The estimated annual saving to the NHS is\u000a      £17.5 million.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    10 papers listed of 25 relevant from this group (authors from Queen Mary\u000a      in bold):\u000a    \u000a1. Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at\u000a      different ages: evidence from the UK Audit of Screening Histories. British\u000a      Journal of Cancer 2003; 89: 88-93.\u000a    \u000a\u000a2. Szarewski A, Sasieni P. Cervical screening in adolescents - at\u000a      least do no harm. Lancet 2004; 364: 1642-1644.\u000a    \u000a\u000a3. Sasieni PD, Cuzick J, Lynch-Farmery E. Estimating the\u000a      efficiency of screening by auditing smear histories of women with and\u000a      without cervical cancer. British Journal of Cancer 1996; 73: 1001-1005.\u000a    \u000a\u000a4. Sasieni PD. Routine audit is an ethical requirement of\u000a      screening. BMJ 2001; 322:1179.\u000a    \u000a\u000a5. Sasieni P, Castanon A, Louie KS, Eds. NHSCSP Audit of Invasive\u000a      Cervical Cancer National Report 2007-2010. NHS Cancer Screening\u000a      Programmes. Sheffield 2011.\u000a    \u000a\u000a6. Sasieni P, Castanon A, Parkin DM. How many\u000a      cervical cancers are prevented by treatment of screen-detected disease in\u000a      young women? International Journal of Cancer 2009; 124: 461-4.\u000a    \u000a\u000a7. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical\u000a      screening with age: population based case-control study of prospectively\u000a      recorded data. BMJ 2009; 339: b2968. Erratum in BMJ 2009; 339: b3115.\u000a    \u000a\u000a8. Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of\u000a      invasive cervical cancer after treatment of squamous cervical\u000a      intraepithelial neoplasia. International Journal of Cancer 2006; 118:\u000a      2048-55.\u000a    \u000a\u000a9. Cuzick J, Castañón A, Sasieni P. Predicted impact of\u000a      vaccination against human papillomavirus 16\/18 on cancer incidence and\u000a      cervical abnormalities in women aged 20-29 in the UK. British Journal of\u000a      Cancer 2010; 102: 933-939.\u000a    \u000a\u000a10. Sasieni P, Castañón A Cuzick J. The Impact of Cervical\u000a      Screening on Young Women: A Critical Review of the Literature 2002-2009.\u000a      NHSCSP Publication No 31, February 2010. Sheffield, UK: NHS Cancer Screening Programmes, 2010.\u000a    \u000aThe main funder for this work was Cancer Research UK.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    \u000a      UK National Screening Committee. Cervical cancer consultation Q&A.\u000a        http:\/\/www.screening.nhs.uk\/cervicalcancer-qa.\u000a      Advisory Committee on Cervical Screening statement 2003. Modernising\u000a        the NHSCSP:\u000a        Introduction of LBC and change in national policy.\u000a        http:\/\/www.cancerscreening.nhs.uk\/cervical\/news\/009.html\u000a\u000a      Advisory Committee on Cervical Screening statement 2009.\u000a        http:\/\/www.cancerscreening.nhs.uk\/cervical\/cervical-review-minutes-20090519.pdf\u000a\u000a      National guidelines in USA: Saslow DS et al. Guidelines for the\u000a        Prevention and Early Detection of Cervical Cancer. CA Cancer J\u000a        2012; 62: 147-172.\u000a        http:\/\/www.ncbi.nlm.nih.gov\/entrez\/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22422631\u000a\u000a      Kizer N, Peipert JF. Cervical Cancer Screening: Primum Non Nocere. Annals\u000a          of Internal Medicine 2012; 156: 896-897. http:\/\/www.annals.org\/content\/early\/2012\/03\/14\/0003-4819-156-12-201206190-00425.full\u000a\u000a      Moyer VA. Screening for Cervical Cancer: US Preventive Services Task\u000a        Force Recommendation Statement. Annals of Internal Medicine\u000a        2012.\u000a        http:\/\/annals.org\/article.aspx?articleid=1183214\";\u000a      Department of Health Bulletin 2003\/24. Cervical Screening\u000a          Programme, England: 2002-03.\u000a        http:\/\/www.dh.gov.uk\/en\/Publicationsandstatistics\/Statistics\/StatisticalWorkAreas\/Statisticalhealthcare\/DH_4080876\u000a\u000a      The NHS Information Centre. Cervical Screening Programme, England:\u000a          2010-11. 2011.\u000a        http:\/\/www.ic.nhs.uk\/statistics-and-data-collections\/screening\/cervical-screening\/cervical-screening-programme--england-2010-11\u000a\u000a      The Health and Social Care Information Centre. Cervical Screening\u000a          Programme, England:\u000a          2011-12. 2012. http:\/\/www.ic.nhs.uk\/statistics-and-data-collections\/screening\/cervical-screening\/cervical-screening-programme--england-2010-11\u000a\u000a      Sasieni P. Comparison of screening from age 20 and age 25: Table of\u000a        harms and benefits.\u000a        2012. http:\/\/www.screening.nhs.uk\/cervicalcancer\u000a        (see Appendix 2).\u000a      Kizer N, Peipert JF. Cervical Cancer Screening: Primum Non Nocere. Annals\u000a          of Internal Medicine 2012; http:\/\/www.annals.org\/content\/early\/2012\/03\/14\/0003-4819-156-12-201206190-00425.full\u000a\u000a      NHS Cervical Screening Programme. How much does the programme cost and\u000a        how is it funded? http:\/\/www.cancerscreening.nhs.uk\/cervical\/publications\/pm-04.html\u000a\u000a      Centers for Disease Control and Prevention. Cervical Cancer Screening\u000a        Among Women Aged 18-30 Years - United States, 2000-2010. Morbidity\u000a          and Mortality Weekly Report 2013; 61:\u000a        1038-42. http:\/\/www.cdc.gov\/mmwr\/preview\/mmwrhtml\/mm6151a2.htm\u000a\u000a      Zappa M, Visioli CB, Ciatto S, Iossa A, Paci E, Sasieni P. Lower\u000a        protection of cytological screening for adenocarcinomas and shorter\u000a        protection for younger women: the results of a case-control study in\u000a        Florence. British Journal of Cancer 2004; 90: 1784-1786.\u000a        (Analysis of Italian cervical screening data, inspired by Sasieni et\u000a        al's research and which confirmed their findings).\u000a      Andrae B, Kemetli L, Sparen P, Silfverdal L, Strander B, Ryd W et al.\u000a        Screening-preventable cervical cancer risks: evidence from a nationwide\u000a        audit in Sweden. Journal of the National Cancer Institute 2008;\u000a        100: 622-629.\u000a      Research protocol linking cervical with breast and colorectal\u000a        screening in UK.\u000a        http:\/\/prp.dh.gov.uk\/files\/2012\/02\/PRP-commissioned-projects-Feb-2012.pdf\u000a\u000a    \u000a    ","Title":"\u000a    Cervical screening\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Globally, cervical cancer is estimated to be the third commonest cancer\u000a      in women with 530,000 cases and 275,000 deaths annually (Globocan data).\u000a      Unlike other common cancers, it is not a disease of old age: most cases in\u000a      England in 2009 were aged 25-49. Cervical screening has been effective in\u000a      controlling cervical cancer in many countries, but results were mixed:\u000a      whereas cervical cancer incidence fell by 77% in Finland (between 1962-65\u000a      and 1988-93); in England (Birmingham: 1960-66 to 1983-86) and Scotland\u000a      (1963-66 to 1983-87), rates increased slightly (Gustafsson et al 1997).\u000a      Recommendations also varied considerably: In the USA women were advised to\u000a      go for annual screening starting \"within 3 years of onset of sexual\u000a      activity or age 21 (whichever comes first)\" (American Cancer Society);\u000a      whereas Finland recommended 5-yearly screening between ages 30 and 60\u000a      (Anttila, Nieminen EJC 2000). In the UK, there was what the media called a\u000a      \"postcode lottery\". Some women were first invited on their 20th birthday\u000a      and then 3-yearly, others 5-yearly from age 24. In Scotland, women were\u000a      not invited after age 60 but in the rest of the UK screening continued\u000a      until age 64.\u000a    In 2003 Sasieni's group published a paper analysing the screening\u000a      histories of 1305 women with cervical cancer and 2532 age-matched controls\u000a      [1]. Five-yearly screening offered considerable protection (83%) against\u000a      cancer at ages 55-69 years and even annual screening offered only modest\u000a      additional protection (87%). Three-yearly screening offered additional\u000a      protection (84%) over 5-yearly screening (73%) for cancers at ages 40-54\u000a      years, but was almost as good as annual screening (88%). In women aged\u000a      20-39 years, even annual screening was not as effective (76%) as 3-yearly\u000a      screening was in older women. Based on these findings and the observation\u000a      that screening abnormalities were particularly common in women aged 20-24\u000a      but cervical cancer was very rare under age 25, Sasieni et al recommended\u000a      that the screening programme should start at age 25 and comprise 3-yearly\u000a      screening to age 49 and 5-yearly screening from age 50 to 64. This\u000a      publication was the first to suggest that cervical screening worked less\u000a      well in young women, which was both surprising and controversial. The\u000a      findings raised the possibility that cervical screening might do more harm\u000a      than good in some younger women [2].\u000a    The initial study used a case-control design [3]. Sasieni argued that\u000a      this should become a routine systematic audit of the screening programme\u000a      [4]. Since 2007, the audit has covered the whole of England and Wales with\u000a      about 95% completeness - about 85% of cervical cancers are entered in the\u000a      audit within 12 months of diagnosis [5]. Screening histories are extracted\u000a      from prospectively recorded data, eliminating recall bias; controls are\u000a      randomly selected from population lists and anonymously included without\u000a      seeking consent, eliminating selection bias. A similar approach to\u000a      auditing cervical screening has been adopted in Sweden (see reference 25\u000a      below under `Impact').\u000a    The decision not to screen at age 20-24 remained controversial. In 2009,\u000a      the team published two further papers. One addressed the argument that\u000a      screening young women must be beneficial because it leads to the treatment\u000a      of thousands of cases of high-grade CIN [6]. Prof Sasieni's team\u000a      demonstrated that these `high grade CIN' were largely over-treated. The\u000a      second paper looked more closely at the impact of screening in women age\u000a      20-24 [7]. It confirmed that there was no significant benefit from\u000a      screening at ages 20-24 (despite substantial benefit at older ages).\u000a    Other studies undertaken by this team in the area of cervical cancer\u000a      prevention have included\u000a    \u000a      a review of epidemiological studies to establish the optimum interval\u000a        for repeat testing following treatment for cervical intraepithelial\u000a        neoplasia [8]\u000a      a predictive modeling study of the impact of HPV vaccination on cancer\u000a        incidence [9]\u000a      a critical review of the literature on cervical screening in young\u000a        women [10] and\u000a      a national audit of invasive cervical cancer [5]\u000a    \u000a    "},{"CaseStudyId":"18366","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    4a. National implementation and validation of rapid access chest pain\u000a        clinics in hospitals across England and Wales\u000a    The rapid access chest pain clinic established and systematically\u000a      evaluated by Timmis et al in east London led to a radical change\u000a      in health policy when it became the service model for the Cardiovascular\u000a      National Service Framework in the early 1990s [7]. The next decade saw a\u000a      national roll-out of chest pain clinics which gradually became established\u000a      in almost every hospital in England and Wales. Their prognostic validation\u000a      study, which has been cited 68 times (Google Scholar), informed the NICE\u000a      Guideline for Stable Angina (CG126) by providing reliable estimates of\u000a      angina mortality rates [8].\u000a    Rapid access chest pain clinics are now a central component of\u000a      cardiovascular healthcare delivery in the UK, and have been endorsed by\u000a      the Cardiac Tsar: \"Across England, there is now a network of over 160\u000a        rapid-access clinics in which 96% of patients are seen within 2\u000a        weeks of referral.... Sekhri et al from the east London.... vindicate\u000a        the development of the rapid-access model beyond the delivery of\u000a        improved waiting times.\" [9].\u000a    4b: Paradigm change in non-invasive investigation of chest pain\u000a    The exercise ECG had been the most widely used non-invasive test for\u000a      investigation of patients with suspected angina. Timmis et al's BMJ\u000a      2008 study, however, was instrumental in the paradigm change reflected in\u000a      the NICE Guideline on Chest Pain of Recent Onset, which recommended that\u000a      the exercise ECG should no longer be used for diagnosing angina, there\u000a      being a newer generation of more effective diagnostic tests now available\u000a      [10]. In the NICE Guideline on Management of Stable Angina that followed\u000a      soon afterwards, the study informed further recommendations about use of\u000a      prognostic testing in patients with angina [8]. These findings received\u000a      extensive press coverage and generated considerable public interest [11].\u000a    4c: Restoring equity by gender and ethnicity to diagnosis and\u000a        management of angina\u000a    By reporting relations between typicality of symptoms and prognosis by\u000a      gender and ethnicity, the team's 2008 Canadian Medical Association\u000a        Journal paper [6] destroyed the longstanding myth that symptoms are\u000a      commonly \"atypical\" in women and south Asian patients with suspected\u000a      angina. This myth has almost certainly played a damaging role in the\u000a      widely reported under-treatment of women and south Asian patients, which\u000a      in turn must have contributed to unnecessary morbidity and mortality.\u000a    Based on those findings, the 2010 NICE Guideline on Chest Pain of Recent\u000a      Onset now states: \"Do not define typical and atypical features of\u000a        anginal and non-anginal chest pain differently in men and women (or) in\u000a        ethnic groups\" [10].\u000a    The findings have received strong professional endorsement. For example,\u000a      Tony Delamonthe, Deputy Editor of BMJ, said in response to the\u000a      team's 2008 BMJ paper: \"in some cases, it's reasonable to\u000a        conclude, these inequalities kill\" [12].\u000a    4d. National recognition\u000a    Timmis' work in utilising electronic registry data for evaluating chest\u000a      pain clinics has resulted in:\u000a    \u000a      2009 — Short-listed for the BMJ Group Award for Outstanding\u000a        Achievement in Evidence-Based Healthcare [13]\u000a      2009 — Chair NICE Guideline group for Investigation of Chest Pain [10]\u000a      2011 — Chair NICE Guideline group for Management of Stable Angina [8]\u000a    \u000a    4e: International spread (examples)\u000a    Australia's first public rapid assessment clinic for chest\u000a      pain has reduced outpatient waiting times from months to days, the clinic\u000a      claims. Based at MonashHeart, in south-east Melbourne, the clinic opened\u000a      in July 2012. Director, Professor Ian Meredith, said more than 1,500\u000a      patients had been treated in the 12 months of its operation. \"There\u000a        are certainly instances where lives have unequivocally been saved and\u000a        heart attacks have been prevented,'' he said [14].\u000a    Canada. \"Rapid assessment chest pain clinics... have\u000a        proven effective in expediting consultation with reduction in hospital\u000a        admissions for patients with atypical pain syndromes\" [15].\u000a    ","ImpactSummary":"\u000a    Timmis' collaborative research group (straddling four major institutions)\u000a      focuses on healthcare delivery as it affects cardiovascular outcomes. The\u000a      group's research in patients with suspected angina has delivered four key\u000a      impacts:\u000a    a. National implementation and validation of rapid access chest pain\u000a      clinics in hospitals in England and Wales — a model that has been\u000a      replicated widely in other countries;\u000a    b. Paradigm change in diagnostic testing that has informed national\u000a      guidelines;\u000a    c. Identification of inequity in access to healthcare and healthcare\u000a      decisions that has informed national guidelines; and\u000a    d. New research to restore equitable management of patients with\u000a      suspected angina.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2158177","Name":"Melbourne"}],"References":"\u000a    Six papers listed of >30 relevant from this group 1993-2013. Queen\u000a      Mary researchers in bold.\u000a    \u000a1. Sekhri N, Feder G, Junghans C, Hemingway H, Timmis\u000a        AD. How effective are rapid access chest pain clinics? Prognosis of\u000a      incident angina and non-cardiac chest pain in 8762 consecutive patients. Heart\u000a      2007; 93: 458-63.\u000a    \u000a\u000a2. Sekhri N, Feder G, Junghans C, Eldridge S,\u000a      Umaipalan A, Madhu R, Hemingway H, Timmis AD. Incremental\u000a      prognostic value of the exercise electrocardiogram in the initial\u000a      assessment of patients with suspected angina: cohort study. BMJ.\u000a      2008; 337: a2240.\u000a    \u000a\u000a3. Sekhri N, Timmis AD, Hemingway H, Walsh N, Eldridge S,\u000a      Junghans C, Feder G. Is access to specialist assessment of chest\u000a      pain equitable by age, gender, ethnicity and socioeconomic status? An\u000a      enhanced ecological cohort analysis. BMJ Open 2012; 2: e001025.\u000a    \u000a\u000a4. Sekhri N, Timmis A, Chen R, Junghans C, Walsh N, Zaman\u000a      J, Eldridge S, Hemingway H, Feder G. Does inequity of\u000a      access to investigation affect clinical outcomes? A prognostic study of\u000a      coronary angiography for suspected stable angina pectoris. BMJ\u000a      2008; 336: 1058-61\u000a    \u000a\u000a5. Hemingway H, Chen R, Junghans C, Timmis A, Eldridge S, Black\u000a      N, Shekelle P, Feder G. Appropriateness criteria for coronary\u000a      angiography in angina: reliability and validity. Annals of Internal\u000a        Medicine 2008; 149: 221-31.\u000a    \u000a\u000a6. Zaman MJ, Junghans C, Sekhri N, Chen R, Feder GS, Timmis\u000a        AD, Hemingway H. Presentation of stable angina pectoris among women\u000a      and South Asian people. Canadian Medical Association Journal 2008;\u000a      179: 659-67.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    \u000a      Department of Health. National Service Framework for Coronary Heart\u000a        Disease: Modern standards and service models. London: Department of\u000a        Health, 2000.\u000a        www.gov.uk\/government\/publications\/quality-standards-for-coronary-heart-disease-care\u000a\u000a      NICE Guideline 2008: Management of Stable Angina (CG126).\u000a        http:\/\/publications.nice.org.uk\/management-of-stable-angina-cg126\u000a\u000a      Boyle RM. Value of rapid-access chest pain clinics. Heart\u000a        2007; 93: 415-416.\u000a       NICE Guideline 2010: Chest Pain of Recent Onset (CG 95). www.nice.org.uk\/guidance\/cg95\u000a\u000a      Public engagement on investigation of chest pain (examples from\u000a        extensive press coverage):\u000a      \u000a\u000a        \u000aDaily Telegraph March 2010: NHS told to replace outdated\u000a          tests that miss patients at risk of heart attacks. www.telegraph.co.uk\/health\/healthnews\/7504376\/NHS-told-to-replace-outdated-\u000a          tests-that-miss-patients-at-risk-of-heart-attacks.html\u000a\u000a        ABC News (USA): November 2008: EKG not a strong predictor of heart\u000a          disease\u000a          http:\/\/abcnews.go.com\/Health\/Healthday\/story?id=6250728&page=2\u000a\u000a        CBC News (Canada) November 2008: ECG tests no better than physical\u000a          for predicting heart disease www.cbc.ca\/news\/health\/story\/2008\/11\/13\/heart-ecg.html?ref=rss\u000a\u000a      \u000a      Delamothe T. How the NHS measures up. BMJ 2008; 336: 1469.\u000a      BMJ Group Awards 2009:\u000a        www.cawt.com\/Site\/11\/Documents\/News\/BMJWinnersBrochure2009.pdf\u000a\u000a      `Clinic cuts chest pains waiting times. Canberra Times,\u000a        Australia. July 26 2012.\u000a        www.canberratimes.com.au\/national\/clinic-cuts-chest-pains-waiting-time-20120725-22ras.html\u000a\u000a      Knudtson ML, Beanlands R, Brophy JM, et al. Treating the right\u000a        patient at the right time:\u000a        Access to specialist consultation and noninvasive testing. Canadian\u000a          Journal of Cardiology 2006; 22: 819-24.\u000a    \u000a    ","Title":"\u000a    Improving clinical services for coronary artery disease\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    2a: Background\u000a    Coronary artery disease remains the leading cause of premature death in\u000a      the UK and elsewhere in the developed world. In the UK, mortality is\u000a      particularly high among people of south Asian origin (Indian, Pakistani,\u000a      Bangladeshi, Sri Lankan), though whether this reflects increased\u000a      susceptibility to coronary disease, increased case fatality, or both, has\u000a      been a subject of intense debate. Less contentious has been the benefits\u000a      of treatment which, regardless of ethnicity, are greater the earlier after\u000a      diagnosis it is started.\u000a    The relevance of this in east London during the 1990s, where South Asians\u000a      accounted for more than a third of the catchment population, was reflected\u000a      in the long waiting times for outpatient appointments in people with\u000a      suspected angina and the inevitable treatment delays this implied. Timmis\u000a      responded by piloting a one-stop chest pain clinic in 1995, but while this\u000a      accelerated diagnosis by provision of same day testing, it did little to\u000a      reduce outpatient waiting times, which were the major determinant of\u000a      diagnostic delay. Timmis took the decision to abandon the conventional\u000a      appointment system and instead to provide a novel open-access service,\u000a      allowing patients with suspected angina a consultant opinion within 24-48\u000a      hours of referral. So was established one of the first rapid access chest\u000a      pain clinics in 1997, which provided the starting point for national\u000a      implementation and an extended programme of outcomes research.\u000a    2b: Multicentre prognostic validation of rapid access chest pain\u000a        clinics\u000a    The electronic registry Timmis designed for the new rapid access chest\u000a      pain clinic at Newham was made available to five other clinics across UK\u000a      and provided the data source for an SDO-funded multi-centre validation\u000a      study in 2002-4 incorporating over 8,000 patients [1]. The study showed\u000a      that cumulative mortality rates over five-year follow-up were\u000a      significantly higher in patients diagnosed with angina compared with\u000a      non-cardiac chest pain, confirming the efficacy of rapid access chest pain\u000a      clinics for risk stratifying new referrals. Less reassuring was that 32%\u000a      of all cardiovascular events occurred in patients diagnosed with\u000a      \"non-cardiac chest pain\" — often after a normal exercise ECG — indicating\u000a      much scope for improving the diagnostic process.\u000a    2c: Exercise ECG for prognostic assessment in rapid access chest pain\u000a        clinics\u000a    The exercise ECG has been the most widely used non-invasive test for risk\u000a      assessment in patients with suspected angina. In Timmis et al's\u000a      multicentre study of rapid access chest pain clinics, it was used in about\u000a      half of all patients. Having shown that many patients with normal exercise\u000a      ECGs went on to experience coronary events, the research team undertook a\u000a      new prognostic study, which on the one hand confirmed previous reports\u000a      that an abnormal exercise ECG is predictive of increased risk, but on the\u000a      other showed that it added almost nothing to the prognostic information\u000a      provided by simple clinical assessment [2]. They concluded that better\u000a      tests were needed to improve risk stratification among patients with\u000a      suspected angina, a conclusion that was soon reflected in national\u000a      guidelines (see below).\u000a    2d: Rapid access chest pain clinics: inequity by gender and ethnicity\u000a    One of the group's key research findings was how inequity blights every\u000a      stage of the management pathway from initial referral, through patient\u000a      selection for coronary angiography, and on to patient uptake of coronary\u000a      bypass surgery. Their recent ecological cohort analysis showed inequitable\u000a      access to treatment in rapid access chest pain clinics [3]. They confirmed\u000a      important inequity in the way patients were managed in these clinics by\u000a      showing that patients appropriate for diagnostic coronary angiography,\u000a      using expert criteria were only half as likely to receive it if they were\u000a      South Asian or female [4]. The potential for harm was reflected in a\u000a      multivariate analysis showing that patients appropriate for angiography\u000a      who did not receive it were around twice as likely to suffer fatal and\u000a      non-fatal coronary events compared to patients appropriately investigated.\u000a    Timmis et al have responded proactively to these findings by\u000a      incorporating a contemporary set of appropriateness criteria into a\u000a      decision tool for guiding investigation of patients with chest pain. They\u000a      have conducted an electronic simulation study showing that the decision\u000a      tool, blind to gender and ethnicity, contributed positively to clinical\u000a      judgement [5] and are now taking this tool into the clinical setting in a\u000a      NIHR-funded validation pilot. A further contribution has been an\u000a      examination of the fixed beliefs of physicians about differences in the\u000a      symptomatic expression of angina by ethnicity and gender. Contrary to\u000a      conventional teaching, the prognostic correlates of typical and atypical\u000a      chest pain in South Asians and women were no different from whites and men\u000a      in a cohort recruited from the rapid access chest pain clinic, reminding\u000a      clinicians that presenting symptoms should be interpreted independently of\u000a      ethnicity and gender in this setting [6]. This advice has now been\u000a      incorporated into international guidelines.\u000a    2e: Ongoing research\u000a    Timmis' research into chest pain clinics utilizing electronic patient\u000a      records represents the start of an ongoing programme for which his group\u000a      has received substantial funding. Through linkage of national electronic\u000a      registries recording primary care, heart attack (MINAP), hospital\u000a      admission (HES) and mortality (ONS) data the research has now extended to\u000a      embrace the lifetime progression of coronary disease from first symptom to\u000a      death. Exemplar studies, all in preparation for publication, include the\u000a      first risk model for stable angina developed in real-world practice,\u000a      analysis of inter-hospital variation in 30-day heart attack mortality and\u000a      international comparison of heart attack mortality (UK vs Sweden). New\u000a      grants include 2008 NIHR Improving quality of care in angina and heart\u000a      attack (£1.8 million); 2008 Wellcome Insights into CVD from linking\u000a      datasets (£1.2 million); and 2012 MRC eHealth Informatics (£4.3 million).\u000a    "},{"CaseStudyId":"18367","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"660013","Name":"Finland"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"3202326","Name":"Croatia"},{"GeoNamesId":"102358","Name":"Saudi Arabia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2623032","Name":"Denmark"}],"Funders":[],"ImpactDetails":"\u000a    4a: Rapid and widespread incorporation into national policy in UK\u000a    The findings from this research were rapidly adopted in official\u000a      guidelines, for example:\u000a    \u000a       The National Screening Committee Model of Best Practice (MOBP) for\u000a        England 2003 (still current) was based largely on the results of the\u000a        SURUSS study [7];\u000a       UK National Screening Committee in 2007 summarised the above and\u000a        recommended a flexible strategy with patient choice based on SURUSS [8];\u000a        update in 2012 endorsed the 2003 MOBP recommendations with some changes\u000a        in cutoff levels [9]\u000a       Genetics White Paper 2003 `Our inheritance, our future' incorporated\u000a        the recommendations from the SURUSS study (this policy is still current)\u000a        [10];\u000a       NICE Guidance 2008 (updated from 2003): recommendations were based on\u000a        SURUSS and subsequent work undertaken by Queen Mary researchers and\u000a        others, and recommended Combined test for women presenting before 15\u000a        weeks and Triple or Quadruple test for those presenting at 15-20 weeks,\u000a        and also that patients should be given accurate information about\u000a        detection and false positive rates based on SURUSS results [11].\u000a    \u000a    4b: Change in practice\u000a    The SURUSS study prompted most UK antenatal centres to introduce one of\u000a      the recommended combination of tests for Down's routinely [12]. The\u000a      Genetics White Paper Review 2008 found almost all NHS maternity units in\u000a      the UK offer at least one of the screening tests shown in the SURUSS study\u000a      to have acceptable detection and false positive rates for detection of\u000a      Down's syndrome [10].\u000a    4c: Improved information for parents\u000a    Information for patients provided by the NHS, other public bodies and\u000a      third-sector organisations is based predominantly on results of the SURUSS\u000a      study [13].\u000a    4d: Staff training\u000a    Training and professional development for midwives has been provided by\u000a      the Wolfson Institute at Queen Mary in the form of study days A total of\u000a      34 study days have been held from 2008 to 2013, with over 500 midwives\u000a      attending [14].\u000a    4e: Improved outcomes: antenatal diagnoses and terminations\u000a    The proportion of Down's cases diagnosed antenatally in UK rose from\u000a      30.6% in 1989-90 to 60.3% in 2008-9 and has remained at over 60% in\u000a      2008-13 [15]. While the proportion of antenatally diagnosed cases which\u000a      were terminated remained constant at 91.5% throughout this period, the\u000a      number of Down's fetuses terminated annually rose from 307 in 1989-90 to\u000a      1,032 in 2008-9 [15].\u000a    4f: Cost savings to the NHS and beyond\u000a    The advances in screening practice have been shown to be cost effective\u000a      and led to overall economic savings. A cost analysis in the SURUSS report\u000a      [1] showed, for example, that to screen 100,000 women, the second\u000a      trimester double test was estimated to cost £5.8 million at a 90%\u000a      detection rate, compared with £4.6 million for the Combined test and £3.0\u000a      million for the Integrated test; the cost of measuring extra markers in\u000a      the latter two tests being more than offset by the reduction in the number\u000a      and associated cost of performing diagnostic procedures. These relatively\u000a      modest costs clearly outweigh the economic costs of long-term care and\u000a      support for the Down's syndrome individuals that would otherwise have been\u000a      born (not to mention the human cost).\u000a    4g: Influence on professional knowledge and further research by others\u000a    The research is highly cited by fellow academics, with the main outputs\u000a      being cited hundreds of times. They have taken this work forward in a\u000a      number of policy-relevant directions. Uptake outside UK, and particularly\u000a      in north America, was accelerated by the confirmatory results of the\u000a      FASTER study on which we collaborated with US colleagues (reference 2\u000a      above). The SURUSS dataset was used by research teams in several countries\u000a      to develop statistical and economic models intended to inform national\u000a      policy decisions. For example researchers in:\u000a    \u000a       the USA used SURUSS data to show the superiority of Quadruple\u000a        over Triple test in a Californian population and introduce the\u000a        Integrated test in statewide programmes [16,17];\u000a       Canada used SURUSS data to justify using the Integrated test\u000a        [18];\u000a       Saudi Arabia used SURUSS data to model a national screening\u000a        programme and recommended the Quadruple test [19]; and\u000a       China used SURUSS data to produce ROC curves and economic\u000a        models to inform national screening policy and recommended the Triple\u000a        test as most cost-effective [20].\u000a    \u000a    4h: Change in screening policy beyond UK\u000a    SURUSS data, either directly or via further modelling work in the\u000a      countries concerned (see previous point) influenced advice from\u000a      professional bodies and\/or national screening policy in numerous other\u000a      countries. For example:\u000a    \u000a       The American College of Obstetricians and Gynecologists, and US\u000a        National Institute of Child Health and Human Development (NICHD) and US\u000a        Society for Maternal-Fetal Medicine proposed first-trimester screening\u000a        for Down's syndrome (flexibly depending on circumstances and patient\u000a        choice) based on SURUSS data [21];\u000a       The European Union EUROCAT (European Surveillance of Congenital\u000a        Abnormalities) programme report 2010 suggests that SURUSS findings have\u000a        influenced current antenatal screening policy in Croatia, Denmark,\u000a        Finland, France, Italy, Netherlands, Spain, and Switzerland [22]. Most\u000a        other European countries have no systematic screening programme and\/or\u000a        have significant legal or religious bars to termination of pregnancy.\u000a    \u000a    ","ImpactSummary":"\u000a    This research significantly improved the accuracy of antenatal screening\u000a      for Down's syndrome and the extent to which maternal choices are informed\u000a      by robust evidence. Tests developed by Professor Nick Wald's team at Queen\u000a      Mary's Wolfson Institute of Preventive Medicine and validated in the\u000a      SURUSS (Serum Urine and Ultrasound Screening Study) study were adopted as\u000a      national UK policy in 2003 and remain an established gold standard\u000a      worldwide. As a result, most Down's syndrome babies in UK are now born\u000a      through parental informed choice, and (using age-adjusted figures)\u000a      approximately 3,000 fewer babies with the syndrome were born between 2008\u000a      and 2013. Screening programmes in numerous countries are based on this\u000a      research.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Six papers selected of 35 publications from this stream of research (also\u000a      see reference 15 in s.5 below describing a major national audit by Morris\u000a      et al under `Sources to corroborate the impact'):\u000a    \u000a1. Wald NJ, Rodeck C, Hackshaw AK, Walters J,\u000a      Chitty L, Mackinson AM. First and second trimester antenatal screening for\u000a      Down's syndrome: the results of the Serum, Urine and Ultrasound Screening\u000a      Study (SURUSS). Journal of Medical Screening 2003; 10: 56-104. A\u000a        longer version of this paper was published as Health Technology\u000a        Assessment report: Wald NJ, Kennard A, Hackshaw AK, McGuire A. Antenatal\u000a        Screening for Down's Syndrome. London: NHS R&D Health Technology\u000a        Assessment Programme; 1998. Report No: Vol 2: no.1.\u000a    \u000a\u000a2. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R,\u000a      Berkowitz RL et al [Hackshaw, Wald]. First- and\u000a      Second-Trimester Evaluation of Risk (FASTER) Research Consortium.\u000a      First-trimester or second-trimester screening, or both, for Down's\u000a      syndrome. New England Journal of Medicine 2005; 353: 2001-11.\u000a    \u000a\u000a3. Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening\u000a      for Down's syndrome with the quadruple test. Lancet 2003; 361:\u000a      835-6.\u000a    \u000a\u000a4. Wald NJ, Huttly WJ, Rudnicka AR. Prenatal screening for Down\u000a      syndrome: the problem of recurrent false-positives. Prenatal Diagnosis\u000a      2004; 24: 389-92.\u000a    \u000a\u000a5. Wald NJ, Rudnicka AR, Bestwick JP. Sequential and contingent\u000a      prenatal screening for Down syndrome. Prenatal Diagnosis 2006; 26:\u000a      769-777.\u000a    \u000a\u000a6. Wald NJ, Huttly WJ, Murphy KW, Ali K, Bestwick JP, Rodeck CH.\u000a      Antenatal screening for Down's syndrome using the Integrated test at two\u000a      London hospitals. Journal of Medical Screening 2009; 16: 7-10.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    See reference 6 in section 3 above, plus:\u000a    \u000a       National Screening Committee Model of Best Practice (MOBP) for Down's\u000a        syndrome screening in England 2003.\u000a       UK National Screening Committee. Fetal Anomaly Screening Programme:\u000a        Screening for Down's syndrome. In: NSC Policy Recommendations 2007-2010:\u000a        Model of Best Practice. London, Department of Health, 2008.\u000a       UK National Screening Committee. Fetal Anomaly Screening Programme:\u000a        Screening for Down's syndrome. In: NSC Policy Recommendations 2011-2014:\u000a        Model of Best Practice. London, Department of Health, 2012.\u000a       Genetics White Paper 2003 `Our inheritance, our future: Realising the\u000a        potential of genetics in the NHS' (still current). See page 13.\u000a        www.geneticseducation.nhs.uk\/downloads\/0070DH_White_paper_review.pdf\u000a\u000a       NICE Guidance 2008: Antenatal care: Routine care for the healthy\u000a        pregnant woman (CG62, updated from 2003). See Section 1.7.2, page 29. www.nice.org.uk\/CG62\u000a\u000a       Ward P. From ad hoc Down's syndrome screening to a functional\u000a        uniform national screening programme. Ultrasound 2011; 19:\u000a        151-153.\u000a       Information for NHS patients\/parents based on SURUSS (examples):\u000a        Example of NHS hospital website explaining Down's screening using SURASS\u000a        data:\u000a        www.bartsandthelondon.nhs.uk\/our-services\/maternity-service\/for-women-and-families\/your-\u000a          pregnancy\u000a        NHS Choices patient advice on screening for Down's syndrome\u000a        www.nhs.uk\/Planners\/pregnancycareplanner\/Pages\/Downsscreening.aspx\u000a        Patient UK leaflet on screening for Down's syndrome:\u000a        www.patient.co.uk\/doctor\/Antenatal-Screening-for-Down%27s-Syndrome.htm\u000a\u000a       Wolfson Institute website (includes patient information site and\u000a        details of study days for clinicians). www.wolfson.qmul.ac.uk\/epm\/screening\u000a\u000a       Morris JK, Alberman E. Trends in Down's syndrome live births and\u000a        antenatal diagnoses in England and Wales from 1989 to 2008: analysis of\u000a        data from the National Down Syndrome Cytogenetic Register. BMJ\u000a        2009; doi: 10.1136\/bmj.b3794.\u000a       American College of Obstetrics and Gynecology Practice Bulletin\u000a        No.77. Screening for Fetal Chromosomal Abnormalities Obstetrics and\u000a          Gynecology 2007; 109: 217-227.\u000a       Kazerouni NN et al. Detection rate of quadruple-marker\u000a        screening determined by clinical follow-up and registry data in the\u000a        statewide California program, July 2007 to February 2009. Prenatal\u000a          Diagnosis 2011; 31: 901-906.\u000a       Okun N, Summers AM, Hoffman Bet al. Prospective experience with\u000a        integrated prenatal screening and first trimester combined screening for\u000a        trisomy 21 in a large Canadian urban center. Prenatal Diagnosis\u000a        2008; 28: 987-992.\u000a       Habib FA. Antenatal Screening Strategies for Down Syndrome: Analysis\u000a        of Existing Protocols and Implications in the Kingdom of Saudi Arabia. British\u000a          Journal of Medicine and Medical Research 2011; 1: 105-121.\u000a       Hong Q et al. A perspective study and financial analysis of\u000a        different protocols of second trimester maternal serum screening for\u000a        Down's syndrome. Chinese Journal of Reproductive Medicine 2010\u000a        (19): z2. http:\/\/d.wanfangdata.com.cn\/periodical_szyxzz2010z2003.aspx\u000a\u000a       Reddy U, Mennuti M. Incorporating First-Trimester Down Syndrome\u000a        Studies Into Prenatal Screening: Executive Summary of the National\u000a        Institute of Child Health and Human Development Workshop. Obstetrics\u000a          & Gynecology 2006; 107: 167-173. See also statewide\u000a        recommendations operationalizing these eg California Department of\u000a        Public Health www.cdph.ca.gov\/programs\/PNS\/Pages\/default.aspx\u000a\u000a       EUROCAT report on prenatal screening policies in Europe www.eurocat-network.eu\/content\/Special-Report-Prenatal-Screening-Policies.pdf\u000a\u000a    \u000a    ","Title":"\u000a    Antenatal screening for Down's syndrome\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Down's syndrome is the commonest genetic disorder in the UK. It produces\u000a      moderate to severe mental impairment with or without physical\u000a      abnormalities, as well as early-onset dementia. Almost all individuals\u000a      with this syndrome require lifelong care. Down's syndrome affects one in\u000a      500 fetuses in mothers under 20 years' old but rises sharply with maternal\u000a      age to one in 40 in mothers over 45. Over 90% of couples choose to\u000a      terminate a pregnancy if they know their fetus is affected. Those who\u000a      choose not to terminate prefer to know the diagnosis in advance of the\u000a      birth. No non-invasive test yet allows diagnosis of Down's syndrome at a\u000a      sufficiently early stage of pregnancy to offer the choice of termination\u000a      with 100% accuracy. Amniocentesis and chorionic villous sampling, while\u000a      highly accurate, carry a risk of miscarriage and fetal harm. False\u000a      negative and false positive tests place significant stress on the couple\u000a      and have ethical implications.\u000a    Since 1993, the Wolfson Institute at Queen Mary has undertaken a series\u000a      of research studies to find the most effective, safe and cost-effective\u000a      test for antenatal detection of Down's syndrome and ensure the results are\u000a      taken up in policy and practice. The challenge in developing any screening\u000a      test is maximising sensitivity (the proportion of all cases detected),\u000a      while minimising the false-positive rate, and ensuring that tests are\u000a      acceptable and feasible to patients and busy clinicians. Each study in\u000a      this programme has generated a new test or combination of tests that\u000a      further improved sensitivity for any given false positive rate, reducing\u000a      the need for invasive tests.\u000a    In particular, the multicentre study SURUSS (Serum Urine and Ultrasound\u000a      Screening Study), was based on data collected from 25 maternity units on\u000a      47,053 singleton pregnancies in 1999-2002, including 101 with Down's\u000a      syndrome, and compared five tests or test combinations, of which the\u000a      Integrated test (first and second trimester tests combined in a single\u000a      estimate, which detects over 90% of Down's fetuses with a 2% false\u000a      positive rate) was the most accurate; but the first-trimester Combined\u000a      test (involving only a single visit) had better feasibility and\u000a      cost-effectiveness [1].\u000a    Results from SURUSS were independently corroborated on a large cohort of\u000a      pregnancies in USA (FASTER study [2]). This built on work carried out at\u000a      Queen Mary since 1998, including studies to develop and validate Triple,\u000a      Combined and Quadruple screening tests [1,3-5]. Subsequent work by other\u000a      groups has built on the SURUSS findings to improve screening performance\u000a      further (eg combining first and second trimester blood tests with\u000a      ultrasound scan), achieving detection rates of around 95% for false\u000a      positive rates of 2%. A team at Queen Mary have demonstrated the efficacy\u000a      and acceptability of these screening methods in a national audit of almost\u000a      11,000 pregnant women through the National Down Syndrome Cytogenetic\u000a      Register: 98% of women accepted the Integrated test and of these, 94%\u000a      completed both stages of the test [6].\u000a    The SURUSS HTA research programme began in 1999 and the initial results\u000a      were published in 2003; related work continues. The key researchers were\u000a      Nicholas Wald, Allan Hackshaw and Jocelyn Walters (Wolfson Institute), and\u000a      Charles Rodeck, Lynn Chitty and Ann-Marie Mackinson (from UCLH). Funding\u000a      was from the NHS Health Technology Assessment Group. Audit work on\u000a      implementation and uptake was led by Joan Morris (Wolfson).\u000a    "},{"CaseStudyId":"18368","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1252634","Name":"Bhutan"}],"Funders":[],"ImpactDetails":"\u000a    4a. Change in perception of risk by policymakers and the public\u000a    The Department of Health, having commissioned the work, promptly accepted\u000a      the Queen Mary team's conclusions on the risk and the size of the effect.\u000a      Legislation banning smoking in public places was advocated in 1998 by the\u000a      government's Scientific Committee on Tobacco and Health, of which\u000a      Professor Wald was a member [8]. The publication of the original\u000a      meta-analyses led to widespread media coverage. Professor Law appeared on\u000a      BBC and ITV news, and was interviewed together with a tobacco industry\u000a      representative by John Humphrys on the Today Programme.\u000a    4b. Change in policy and legislation in UK\u000a    A ban on smoking in public places was proposed by the Chief Medical\u000a      Officer Sir Liam Donaldson, in his annual public health report for 2002\u000a      [9]. A Public Health White Paper, Choosing Health, published in\u000a      2004, announced a total ban on smoking in public places [10]. Following\u000a      this, there was considerable discussion in parliament on whether the ban\u000a      on smoking in public places should be partial (eg with private clubs\u000a      exempt and taking account of a possible adverse effect on businesses and\u000a      the hospitality industry) or total, including a widely publicised threat\u000a      by Sir Liam to resign if a total ban was not upheld. Legislation, which\u000a      had already come into force in Scotland in 2006 [11], was passed in\u000a      England and Wales in 2007 [12].\u000a    4c. [Failed] attempts by the tobacco lobby to rebut the research\u000a        findings\u000a    The tobacco industry undertook a sophisticated lobbying campaign, much of\u000a      it indirectly by funding the hospitality industry, in an effort to\u000a      discredit the work of Queen Mary (and other) researchers [13]. These\u000a      efforts contributed to the delay in definitive legislation in UK until\u000a      2006-7. But ultimately, clear messages from the Department of\u000a      Health-commissioned Queen Mary meta-analyses about the serious health risk\u000a      (Figure 1) outweighed speculative (and as it turned out, unfounded)\u000a      arguments about potential loss of revenue and collapse of hospitality\u000a      businesses [14,15].\u000a    4d. Change in practice: smoking bans were effectively implemented\u000a    Contrary to predictions that this law would be widely flouted, it proved\u000a      highly effective from the outset, with (for example) an estimated 98%\u000a      compliance from businesses within six months of its introduction in\u000a      England and Wales [16]. As a direct result, levels of tobacco-related\u000a      toxic chemicals (`fine particulate matter') in ambient air of bars fell by\u000a      91%, and cotinine levels in the saliva of non-smoking bar and restaurant\u000a      workers by 76%, in the same period in England [16]. Similar findings were\u000a      documented in Scotland [17]. A Cochrane review synthesised 30 studies of\u000a      exposure to second hand smoke from across the world, 19 of which measured\u000a      this using biomarkers, and confirmed a consistent and significant\u000a      reduction following the introduction of smoking bans [18]. Importantly,\u000a      there was no evidence of compensatory increases in smoking in the home —\u000a      indeed some studies documented a decline in children's exposure to tobacco\u000a      smoke at home [19, 20].\u000a    4e. Change in policy and the law beyond the UK\u000a    Smoke-free legislation is now widespread. For example, all EU Member\u000a      States have some form of regulation aimed at limiting exposure to\u000a      second-hand smoke [21,22]; most US states have also introduced such bans,\u000a      as have some low-income countries such as Vietnam and Bhutan.\u000a    4e. Reduction in smoking-related morbidity and mortality in UK and\u000a        worldwide\u000a    Smoking bans in public places have had widespread and dramatic impacts on\u000a      human health [15]. The following examples were selected from dozens of\u000a      potentially relevant ones:\u000a    \u000a      Reduced hospital admissions for acute coronary syndrome \/ myocardial\u000a        infarction. We cite a BMJ study based on English data and an\u000a        international meta-analysis of 10 studies that estimates a 17% reduction\u000a        in the incidence of acute myocardial infarction as a result of smoking\u000a        bans [23,24];\u000a      Reduced hospital admissions for childhood asthma [25]; and\u000a      Reduced pregnancy complications (preterm delivery and small for\u000a        gestational age) [26].\u000a    \u000a    4f. Changes in public attitudes to smoking\u000a    Acknowledging a background trend of declining public support for smoking\u000a      in bars, workplaces and other public places, there is evidence that even\u000a      citizens initially opposed to the bans showed a shift in attitudes over\u000a      time, with a growing perception of the personal, health and environmental\u000a      benefits of smokefree policies [27-29]. Short-term quit rates reported by\u000a      the NHS Stop Smoking Service showed a 23% increase following the\u000a      introduction of the smoking ban, though rates of sustained quitting\u000a      attributable to the ban are harder to document [15].\u000a    ","ImpactSummary":"\u000a    Epidemiological research at Queen Mary, commissioned by the Department of\u000a      Health, demonstrated a clear and causal link between exposure to\u000a      environmental tobacco smoke and both ischaemic heart disease and lung\u000a      cancer. The evidence contributed significantly to public and political\u000a      debates on whether to ban smoking in public places. It informed the\u000a      rebuttal of heavy tobacco industry lobbying and had a pivotal influence on\u000a      changes in the law in Scotland (2006), England and Wales (2007), and\u000a      Northern Ireland (2007), as well as in many countries outside UK, which\u000a      led to highly significant reductions in environmental pollution from\u000a      secondhand smoke. Many health benefits were subsequently attributed to the\u000a      ban, notably a 17% reduction in incidence of acute myocardial infarction.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen Mary University of London\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Law MR, Hackshaw AK. Environmental tobacco smoke. British\u000a        Medical Bulletin 1996; 52: 22-34.\u000a    \u000a\u000a2. Law MR, Morris J, Wald NJ. Environmental tobacco smoke\u000a      exposure and ischaemic heart disease: an evaluation of the evidence. BMJ\u000a      1997; 315: 973-80.\u000a    \u000a\u000a3. Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung\u000a      cancer and environmental tobacco smoke. BMJ 1997; 315: 980-88.\u000a    \u000a\u000a4. Hackshaw A. Lung cancer and passive smoking. Statistical\u000a        Methods in Medical Research 1998; 7: 119-36.\u000a    \u000a\u000a5. Law MR, Wald NJ. Environmental tobacco smoke and\u000a      ischemic heart disease. Progress in Cardiovascular Diseases 2003;\u000a      46.1: 31-38.\u000a    \u000a\u000a6. Vineis P, Alavanja M, Buffler P, Fontham E, Franceschi S, Gao Y, Gupta\u000a      P, Hackshaw A, Matos E, Samet J. Tobacco and cancer: recent\u000a      epidemiological evidence. Journal of the National Cancer Institute\u000a      2004; 96: 99-106.\u000a    \u000a\u000a7. Nebot M, López MJ, Gorini G, Neuberger M, Axelsson S, Pilali M,\u000a      Fonseca C, Abdennbi K, Hackshaw A, Moshammer H. Environmental\u000a        tobacco smoke exposure in public places of European cities. Tobacco\u000a      control 2005; 14: 60-63.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    \u000a      Poswillo DC. Report of the Scientific Committee on Tobacco and Health.\u000a        London: The Stationery Office, 1998. (ISBN 011322124x.)\u000a      Annual Report of the Chief Medical Officer 2002. London, Department of\u000a        Health, 2003, p. 24.\u000a      Department of Health. Choosing Health: Making Healthier Choices\u000a          Easier. London, Stationery Office, 2004.\u000a      \u000aThe Prohibition of Smoking in Certain Premises (Scotland)\u000a          Regulations 2006.\u000a        www.legislation.gov.uk\/ssi\/2006\/90\/pdfs\/ssi_20060090_en.pdf\u000a\u000a      \u000aHealth Act 2006. Includes Smoke-free (Premises and\u000a          Enforcement) Regulations 2006. http:\/\/www.legislation.gov.uk\/ukpga\/2006\/28\/pdfs\/ukpga_20060028_en.pdf\u000a\u000a      Dearlove JV, Bialous SA, and Glantz SA. Tobacco industry manipulation\u000a        of the hospitality industry to maintain smoking in public places.\u000a        Tobacco Control 2002; 11: 94-104.\u000a      Drope J, Chapman S. Industry efforts at discrediting scientific\u000a        knowledge of environmental tobacco smoke: a review of internal industry\u000a        documents. Journal of Epidemiology and Community Health 2001;\u000a        55: 588-594.\u000a      Bauld L. Impact of smokefree legislation in England: Evidence review.\u000a        University of Bath, 2011. www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/216319\/dh_124959.pdf\u000a\u000a      Department of Health. Smokefree England — One year on. London,\u000a        Stationery Office 2008.\u000a      Semple S, van Tongeren M, Gee I, Galea K, MacCalman L. Ayres J.\u000a        Smokefree bars 07: Changes in bar workers' and customers' exposure to\u000a        second-hand smoke, health and attitudes. Final report to the Department\u000a        of Health. University of Aberdeen, the Institute of Occupational\u000a        Medicine and Liverpool John Moores University, 2009.\u000a      Callinan JE, Clarke A, Doherty K and Kelleher C. Legislative smoking\u000a        bans for reducing secondhand smoke exposure, smoking prevalence and\u000a        tobacco consumption. Cochrane Database of Systematic Reviews\u000a        2010; 4: CD005992. DoI: 0.1002\/14651858.CD005992.pub2.\u000a      Holliday J, Moore G and Moore L. Changes in child exposure to\u000a        secondhand smoke after implementation of smoke-free legislation in\u000a        Wales: a repeated cross-sectional study. BMC Public Health 2009;\u000a        9: 430. DoI: 10.1186\/1471- 2458-9-430.\u000a      Akhtar PC, Currie DB, Currie CE et al. Changes in child\u000a        exposure to environmental tobacco smoke (CHETS) study after\u000a        implementation of smoke-free legislation in Scotland: national cross\u000a        sectional survey. BMJ 2007; 335: 545-9.\u000a      European Commission. Towards a Europe free from tobacco smoke: policy\u000a        options at EU level, Directorate C: public health and risk assessment.\u000a        Brussels, European Commission, 2007. http:\/\/ec.europa.eu\/health\/ph_determinants\/life_style\/Tobacco\/Documents\/gp_smoke_en.pdf\u000a\u000a      EU countries that limit second-hand smoke: www.smokefreepartnership.eu\/smokefreemap\u000a\u000a      Sims M, Maxwell R, Bauld L & Gilmore A. The short-term impact of\u000a        smokefree legislation in England: a retrospective analysis on hospital\u000a        admissions for myocardial infarction. BMJ 2010; 340: c2161. doi:\u000a        10.1136\/bmj.c2161.\u000a      Meyers DG, Neuberger JS, He J. Cardiovascular effect of bans on\u000a        smoking in public places. A systematic review, meta-analysis. Journal\u000a          of American College of Cardiology 2009;54:1249-55.\u000a      Mackay D, Haw S, Ayres JG, Fischbacher C, Pell JP. Smoke-free\u000a        legislation and hospitalizations for childhood asthma. New England\u000a          Journal of Medicine 2010;363:1139-45.\u000a      Mackay DF, Nelson SM, Haw SJ, Pell JP. Impact of Scotland's smoke-free\u000a        legislation on pregnancy complications: retrospective cohort study. PLoS\u000a          medicine. 2012;9(3):e1001175.\u000a      Ritchie D, Amos A, Martin C. Public places after smoke-free — a\u000a        qualitative exploration of the changes in smoking behaviour. Health\u000a          & place. 2010; 16: 461-9.\u000a      Hargreaves K, Amos A, Highet G, Martin C, Platt S, Ritchie D and White\u000a        M. The social context of change in tobacco consumption following the\u000a        introduction of `smokefree' England legislation: a qualitative,\u000a        longitudinal study. Social Science and Medicine 2010; 71:\u000a        459-66.\u000a      Martin C, Ritchie D and Amos A. Evaluation of the smoke-free\u000a        legislation in Scotland: qualitative community study: Final Report.\u000a        Report submitted to Health Scotland 2008. www.healthscotland.com\/scotlands-health\/evidence\/smokefreelegislation\/studydetailsqualitativecommunitystudy.aspx\u000a\u000a    \u000a    ","Title":"\u000a    The evidence base for harms from environmental tobacco smoke\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Wolfson Institute of Preventive Medicine at Queen Mary has a long\u000a      tradition of undertaking policy-relevant research (empirical studies and\u000a      systematic reviews and meta-analyses) to identify environmental harms with\u000a      a view to informing changes in policy and legislation. Here, we describe\u000a      the most significant programme of work since 1993, which built the\u000a      evidence base on passive smoking and informed the far-reaching legislative\u000a      changes banning smoking in public places.\u000a    In 1996, the Department of Health (DH) (England) commissioned Professor\u000a      Wald's team to prepare a report to evaluate the strength of evidence on\u000a      the harmful effects of environmental tobacco smoke and quantify the risk.\u000a      A background paper [1] and two shorter BMJ publications resulted [2,3].\u000a    Particularly innovative was the paper on ischaemic heart disease [2]. In\u000a      this meta-analysis, Wolfson researchers included all 19 acceptable\u000a      published studies of heart disease risk in lifelong non-smokers who lived\u000a      with a smoker and in those who lived with a non-smoker, five large\u000a      prospective studies of smoking and ischaemic heart disease, studies of\u000a      platelet aggregation and studies of diet according to exposure to tobacco\u000a      smoke. The relative risk of ischaemic heart disease with exposure to\u000a      environmental tobacco smoke was 1.30 (95% CI 1.22 to 1.38) at age 65. At\u000a      the same age, the estimated relative risk associated with smoking one\u000a      cigarette per day was similar at 1.39 (1.18 to 1.64), while for 20 per day\u000a      it was 1.78 (1.31 to 2.44).\u000a    The researchers were the first to recognise that this result from several\u000a      large rigorous cohort studies established that the dose-response\u000a      relationship between tobacco smoke intake and risk of ischaemic heart\u000a      disease was non-linear, indicating that the seemingly disproportionately\u000a      large effect of passive smoking was not surprising. Two separate analyses\u000a      indicated that non-smokers who live with smokers eat a diet that places\u000a      them at a 6% higher risk of ischaemic heart disease, so the direct effect\u000a      of environmental tobacco smoke was to increase risk by 23% (14% to 33%).\u000a      Platelet aggregation provided a plausible and quantitatively consistent\u000a      mechanism for this low dose effect. The increase in platelet aggregation\u000a      produced experimentally by exposure to environmental tobacco smoke would\u000a      be expected to have acute effects that increased the risk of ischaemic\u000a      heart disease by 34%.\u000a    Whilst many primary studies already existed, fewer than half had produced\u000a      a definitive result and there was controversy about the significance of\u000a      `positive' studies, especially in relation to whether and how confounding\u000a      variables such as diet had been accounted for. In contrast, the findings\u000a      from the Queen Mary meta-analysis were definitive and compelling (Figure\u000a      1): breathing other people's smoke is an important cause of ischaemic\u000a      heart disease, increasing a non-smoker's risk by almost a quarter. The\u000a      potential impact on exposed individuals of avoiding environmental tobacco\u000a      smoke was equivalent in magnitude to someone with hypertension taking a\u000a      blood pressure-lowering drug.\u000a    The meta-analysis on environmental tobacco smoke and lung cancer [3]\u000a      followed a similar design, synthesising findings from 37 published studies\u000a      in lifelong non-smokers who lived with a current smoker or lifelong\u000a      non-smoker. The risk estimate was compared with that from linear\u000a      extrapolation of the risk in smokers using seven studies of biochemical\u000a      markers of tobacco smoke intake. Results were similar: the excess risk of\u000a      lung cancer was 24% (95% CI 13% to 36%) in non-smokers who lived with a\u000a      smoker (P < 0.001). Adjustment for the effects of bias (positive and\u000a      negative) and dietary confounding had little overall effect; the adjusted\u000a      excess risk was 26% (7% to 47%). Furthermore, the dose-response relation\u000a      of the risk of lung cancer with both the number of cigarettes smoked by\u000a      the spouse and the duration of exposure was significant, and\u000a      tobacco-specific carcinogens were found at significant levels in the blood\u000a      and urine of non-smokers exposed to environmental tobacco smoke. Again,\u000a      the conclusion was definitive and compelling: breathing other people's\u000a      cigarette smoke is a significant and preventable cause of lung cancer.\u000a    \u000a    Figure 1 (reproduced from reference 2 below), showing how\u000a        meta-analysis by Wolfson researchers reduced uncertainty on the relation\u000a        between environmental tobacco smoke and ischaemic heart disease\u000a    \u000a   Further research referenced below includes a detailed exposition of the\u000a      statistical methodology used for these analyses [4] and later work in\u000a      collaboration with other research teams worldwide to update the evidence\u000a      base, partly in response to lobbying from the tobacco industry, who\u000a      initially strongly rejected the findings of the early meta-analyses\u000a      [5,6,7].\u000a    "},{"CaseStudyId":"18369","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1643084","Name":"Indonesia"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"1814991","Name":"China"}],"Funders":["Economic and Social Research Council"],"ImpactDetails":"\u000d\u000a    4a: Sphincter reconstruction and neuromodulation: ESGN, SNS and PTNS.\u000d\u000a      The development of an ESGN to replace an absent or severely damaged anal\u000d\u000a      sphincter has allowed many patients who were destined to life with a\u000d\u000a      permanent stoma to avoid this fate. The innovator of ESGN (Prof Williams\u000d\u000a      from Queen Mary) won the Nessim Habif Prize from University of Geneva in\u000d\u000a      1995 and the Galen Medal of the Worshipful Company of Apothecaries in\u000d\u000a      2003. National Specialist Commissioning Advisory Group (NSCAG) funding in\u000d\u000a      1997 enabled the establishment of the Colorectal Development Unit (CDU)\u000d\u000a      for trialling new procedures. ESGN was approved by NICE in 2003 [7] and\u000d\u000a      reviewed by Health Technology Assessment NHS R&D HTA programme in 2005\u000d\u000a      [8]. Clinical Commissioning Groups receive funding if patients are\u000d\u000a      referred for ESGN. Over 100 procedures had been performed in UK in 2005\u000d\u000a      [8] with many more since and the procedure is conducted in other European\u000d\u000a      centres and Southeast Asia [9;10].\u000d\u000a    This advanced and complex procedure was never intended as first-line\u000d\u000a      therapy for uncomplicated FI but has transformed the lives of the most\u000d\u000a      severely affected individuals (e.g. when the sphincter is entirely absent\u000d\u000a      or has been severely traumatised) for whom no effective treatment was\u000d\u000a      previously available. The lessons learnt in the development of ESGN paved\u000d\u000a      the way (conceptually and technically) for the development of sacral nerve\u000d\u000a      stimulation (SNS), which is now the mainstay of neuromodulatory therapy\u000d\u000a      for bowel disease internationally (Medtronics sales of $1 billion to 2012\u000d\u000a      for SNS [11]: NICE guidelines 2007 and 2011 [12]). The trial of SNS in\u000d\u000a      patients with RED (see above) is changing the paradigm of patient\u000d\u000a      selection for this procedure [1]. The uptake of PTNS by NHS pelvic floor\u000d\u000a      services has spread nationally (UK) as a result with a recent NICE\u000d\u000a      guideline [13] and 7 recently reported case series.\u000d\u000a    4b: Anal fistula procedures. The snug seton method is now a\u000d\u000a      standard technique for certain fistulas, adopted worldwide, and described\u000d\u000a      in the most popular UK postgraduate textbook of coloproctology [14] and is\u000d\u000a      part of the Great Britain and Ireland guidelines [15]. A multicentre\u000d\u000a      European trial (the first of its type in fistula surgery) assessing the\u000d\u000a      efficacy of collagen paste is testament to the enthusiasm with which it is\u000d\u000a      being greeted by the surgical community [16].\u000d\u000a    4c: Rectal augmentation to improve FI in patients with rectal\u000d\u000a        hypersensitivity. This procedure is used in extreme cases and has\u000d\u000a      provided important data that has helped elucidate the cause of rectal\u000d\u000a      hypersensitivity in faecal urgency and visceral pain. Drug development has\u000d\u000a      followed this observation and allied observations in other viscera\u000d\u000a      particularly in respect to TRPV1 antagonists by GSK [17].\u000d\u000a    4d Vertical reduction rectoplasty (VRR) and colonic conduit for rectal\u000d\u000a        evacuation disorders (RED). Patients with RED represent the majority\u000d\u000a      of those investigated for chronic constipation. Our research, utilising\u000d\u000a      new investigative tools such as ambulatory manometry, rectal barostat\u000d\u000a      compliance measurements and rectal sensitivity tests has shown that we can\u000d\u000a      identify a certain subgroup who can benefit from VRR an innovative\u000d\u000a      procedure we have designed. These procedures are now included in textbooks\u000d\u000a      [18] with recent resurgence especially toward the use of anterograde\u000d\u000a      continence procedures.\u000d\u000a    4e: The APPEAR (Anterior Perineal PlanE for ultra-low Anterior\u000d\u000a        Resection). APPEAR retains gastrointestinal continuity and preserves\u000d\u000a      acceptable continence in patients who would otherwise require a permanent\u000d\u000a      stoma. In Europe the total number of stomas constructed each year is\u000d\u000a      160,000 with an annual cost to the NHS (appliances etc) of £250 million.\u000d\u000a      The first paper in 2008 having demonstrated feasibility, a multicentre\u000d\u000a      trial commenced in 2009 with uptake to date in UK, Germany, China, Iran,\u000d\u000a      Indonesia and South America [19]. This new procedure has reduced the need\u000d\u000a      for permanent stoma in two thirds of patients. Results have been\u000d\u000a      replicated in the other centres cited. Externally quantified economic\u000d\u000a      benefits of stoma prevention can be calculated as £50,000 based on 2 QALYs\u000d\u000a      and £12,000 p.a. in avoided stoma management costs [20]. The innovative\u000d\u000a      stapler design and grasper designed and patented for the APPEAR was\u000d\u000a      awarded the Worshipful Company of Cutlers' Surgical Prize 2011 [21]. The\u000d\u000a      IPR (held by the inventor NS Williams and Queen Mary) has been\u000d\u000a      commercialised internationally (patents WO2012032302 and WO2012032303)\u000d\u000a      [22].\u000d\u000a    4f: Procedures designed to prevent parastomal hernias. Parastomal\u000d\u000a      hernias are a major problem for patients who undergo stoma formation and\u000d\u000a      affect some 50% of all ostomates over 10 years, of whom 1\/3 require\u000d\u000a      further, often unsuccessful surgery. The new technique SMART (Stapled Mesh\u000d\u000a      Stoma Reinforcement Technique) is now the subject of a randomised,\u000d\u000a      multicentre, international trial (commenced 2011). The stapling equipment\u000d\u000a      that enables SMART also won the Cutlers' Surgical Prize for 2011 [21] and\u000d\u000a      is part of a collaborative commercial venture with Frankenman\u000d\u000a      International (Queen Mary receives royalties on the product) [23].\u000d\u000a    4g: Process development. After a national competition, Williams'\u000d\u000a      group were designated as one of only two pilot NIHR Healthcare Technology\u000d\u000a      Cooperatives (HTCs) in 2007. The remit was to facilitate interactions\u000d\u000a      between healthcare and industry to develop technology for patient benefit\u000d\u000a      in the field of bowel disorders. The initial funding was renewed for a\u000d\u000a      further 3 years in 2009 (circa £900,000) by a programme board (of TSB and\u000d\u000a      NIHR). The HTC was favourably reviewed by RAND [20] and had leveraged £1.6\u000d\u000a      million in further funding. The team was invited to bid for more funding\u000d\u000a      as part of a policy to extend the HTC concept and was successful in being\u000d\u000a      awarded a grant of £800K (2012-14) after open competition.\u000d\u000a    Among the achievements of the HTC (now called Enteric) has been the\u000d\u000a      development of a de novo specialty specific network of over 20 colorectal\u000d\u000a      surgical centres through which national multicentre trials are already\u000d\u000a      underway e.g. HTA-funded CONFIDeNT study of PTNS [24]. Furthermore the\u000d\u000a      group has raised charitable income (circa £3million) including a Wolfson\u000d\u000a      Foundation Grant to develop a National Centre for Bowel Research and\u000d\u000a      Surgical Innovation that opened in March 2012.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Professor Norman Williams and colleagues, based at Queen Mary, developed\u000d\u000a      innovative surgical procedures for patients with anorectal diseases to\u000d\u000a      preserve function, reduce morbidity, eliminate the need for a permanent\u000d\u000a      stoma and reduce its complications. They tested these in clinical trials\u000d\u000a      and showed them to be effective and improve quality of life. The APPEAR\u000d\u000a      procedure (designed to preserve continence in patients who would otherwise\u000d\u000a      require a permanent stoma) is now used internationally and electrically\u000d\u000a      stimulated gracilis muscle (ESGN) is well established as a treatment for\u000d\u000a      end-stage faecal incontinence (FI). The team has harnessed the science of\u000d\u000a      neuromodulation to provide minimally invasive methods of treating FI and\u000d\u000a      developed robust processes for technological development, training and\u000d\u000a      dissemination. Two patents have been filed for innovative surgical\u000d\u000a      instruments and these have been developed commercially.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen Mary University of London\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen Mary, University of London","InstitutionName":"Queen Mary, University of London","PeerGroup":"A","Region":"London","UKPRN":10007775}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2660646","Name":"Genève"}],"References":"\u000d\u000a    \u000a1. George BD, Patel J, Watkins ES, Williams NS, Swash M.\u000d\u000a      Physiological and histochemical adaptation of the electrically stimulated\u000d\u000a      gracilis muscle to neoanal sphincter function. British Journal of\u000d\u000a        Surgery 1993; 80:1342-46 (Winner, Moynihan Prize Association of\u000d\u000a      Surgeons 1993)\u000d\u000a    \u000a\u000a2. Knowles CH, Thin N, Gill K, Bhan C, Grimmer K, Lunniss PJ, Williams\u000a        NS, Scott M. Prospective randomized double-blind study of sacral\u000d\u000a      nerve stimulation in patients with rectal evacuatory dysfunction and\u000d\u000a      rectal hyposensitivity. Annals of Surgery 2012; 255: 643-9.\u000d\u000a    \u000a\u000a3. Murphy J, Chan CLH, Vasudevan SP, Scott SM, Lunniss PJ, Williams\u000d\u000a        NS. Rectal Augmentation: Short and mid term evaluation of a novel\u000d\u000a      procedure for severe faecal urgency and incontinence. Annals of\u000d\u000a        Surgery 2008; 247: 421-427.\u000d\u000a    \u000a\u000a4. Chan CLH, Facer P, Davis JB, Smith GD, Egerton\u000a        J, Bountra C, Williams NS, Anand P. Sensory fibres\u000d\u000a      expressing capsaicin receptor TRPV1 in patients with rectal\u000d\u000a      hypersensitivity and faecal urgency. Lancet 2003; 361: 385-391.\u000d\u000a    \u000a\u000a5. Williams NS, Hughes SF, Stuchfield B. Continent colonic\u000d\u000a      conduit for rectal evacuation in severe constipation. Lancet 1994;\u000d\u000a      343: 1321-1324.\u000d\u000a    \u000a\u000a6. Williams NS, Murphy J, Knowles CH. Anterior perineal\u000d\u000a      plane for ultra-low anterior resection of the rectum (the APPEAR\u000d\u000a      technique): a prospective clinical trial of a new procedure. Annals of\u000d\u000a        Surgery 2008; 24:750-758.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      NICE Guideline. Stimulated Graciloplasty for Faecal Incontinence (IPG\u000d\u000a        159) www.nice.org.uk\/nicemedia\/live\/11024\/30589\/30589.pdf\u000d\u000a        200 still current\u000d\u000a      Tillin T, Chambers M, Feldman R. Outcomes of electrically stimulated\u000d\u000a        gracilis neosphincter surgery. Health Technology Assessment\u000d\u000a        2005; Vol 9 No 28.\u000d\u000a      Contact to endorse SNS: a professor who pioneered SNS for faecal\u000d\u000a        incontinence and can ratify the importance of this expansion of the\u000d\u000a        technique.\u000d\u000a      Rosetrees Prize for Surgical Research awarded to Emma Carrington 2011\u000d\u000a        www.rcseng.ac.uk.\u000d\u000a      \u000aTransforming for Growth: Innovating for Life. Medtronics Annual\u000d\u000a        Report 2012. http:\/\/www.medtronic.com\/wcm\/groups\/mdtcom_sg\/@mdt\/@corp\/documents\/documents\/ar12_annual_report_final.pdf\u000a\u000d\u000a      NICE Guideline. Sacral\u000a          Nerve Stimulation for Faecal Incontinence (IPG99) www.nice.org.uk\/nicemedia\/live\/11079\/30919\/30919.pdf\u000d\u000a        November 2004 (still current).\u000d\u000a      NICE Guideline. Percutaneous\u000a          Tibial Nerve Stimulation for Faecal Incontinence. (IPG 395). www.nice.org.uk\/nicemedia\/live\/13159\/54562\/54562.doc\u000d\u000a        May 2011.\u000d\u000a      Textbook & Guidelines: A Companion to Specialist Surgical\u000d\u000a        Practice. Colorectal Surgery. 4th. Edn 2009. WB Saunders, London,\u000d\u000a        Chapter 14, p 223 - 242.\u000d\u000a      The treatment of anal fistula: ACPGBI Position Statement. Colorectal\u000d\u000a        Disease 2007; 9 (Supplement 4): 18 - 50.\u000d\u000a      Study protocol. A Prospective, Multi-center, Observational Study of\u000d\u000a        the Use of Permacol™ Collagen Paste to Treat Anorectal Fistulas.\u000d\u000a        NCT01624350. http:\/\/clinicaltrials.gov\/show\/NCT01624350\u000a\u000d\u000a      Holzer P. Transient receptor potential (TRP) channels as drug targets\u000d\u000a        for diseases of the digestive system. Pharmacological Therapeutics\u000d\u000a        2011; 131: 142-70.\u000d\u000a      O'ConnellPR, Madoff RD, Solomon M. Rob & Smith's Operative\u000d\u000a          Surgery of the Colon, Rectum and Anus. Hodder Arnold; 6th Revised\u000d\u000a        edition: 2012.\u000d\u000a      Williams NS, Murphy J, Knowles CH. Anterior perineal plane for\u000d\u000a        ultra-low anterior resection of the rectum (the APPEAR technique): a\u000d\u000a        prospective clinical trial of a new procedure. Annals of Surgery\u000d\u000a        2008; 24: 750-758.\u000d\u000a      Kryl D, Marjanovic S, Chonaill SN, Ridsdale H, Yaqub O. Healthcare\u000d\u000a          Technology Co-operatives: Filling a niche in the English R&D\u000d\u000a          landscape. Prepared for the Department of Health (England). RAND\u000d\u000a        Corporation 2011. www.rand.org\/pubs\/technical_reports\/TR932.html\u000a\u000d\u000a      Worshipful Company of Cutlers' Surgical Prize 2011 www.cutlerslondon.co.uk\u000a\u000d\u000a      Published patents:\u000d\u000a      a) Williams, N S and Weng, Z `Method and Apparatus for Forming Stoma\u000d\u000a        Trephines and Anastomoses' WO20120 2 02, Filed by Queen Mary and\u000d\u000a        Frankenman International Ltd, 15.03.2012.\u000d\u000a      b) Williams, N S and Weng, Z `Forceps Comprising a Trocar Tip' WO20120\u000d\u000a        2 0 , Filed by Queen Mary and Frankenman International Ltd, 15.03.2012\u000d\u000a      Contact to endorse collaboration with Frankenman International:\u000d\u000a        Director of R&D at Frankenman International Limited.\u000d\u000a      Enteric: The Bowel Function Healthcare Technology Co-operative. www.bowelfunctionhtc.org.uk\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Development and validation of innovative colorectal surgery procedures\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The research described below took place at Queen Mary between 1993 and\u000d\u000a      2013, led by Professor Norman Williams who is currently President of the\u000d\u000a      Royal College of Surgeons.\u000d\u000a    Anorectal disease is common, burdensome, and may produce complications\u000d\u000a      that are costly to manage. Traditional treatments included mutilating\u000d\u000a      surgery with significant physical and psychological side effects.\u000d\u000a      Incorporation of new technologies and rigorous research methods have\u000d\u000a      recently produced a range of promising new treatments:\u000d\u000a    2a: Sphincter Reconstruction and Neuromodulation. Before ESGN was\u000d\u000a      shown to be viable clinically, it was necessary to demonstrate that the\u000d\u000a      fast twitch gracilis muscle could be converted to slow twitch muscle\u000d\u000a      capable of functioning as a sphincter. Studies in animals and man showed\u000d\u000a      that physiological and biochemical properties of striated muscle could be\u000d\u000a      modified by specific stimulation parameters [1]. Having shown in man that\u000d\u000a      ESGN was a viable anal sphincter replacement, its use was extended for\u000d\u000a      Total Anorectal Reconstruction in patients with anorectal agenesis or\u000d\u000a      previous complete anorectal excision [Williams 1993-; 3 MD Research\u000d\u000a      Fellows (RFs) 1995-1998]. Despite the evolution of sacral nerve\u000d\u000a      stimulation (SNS) over a 10-year period, there had been almost no robust\u000d\u000a      controlled evaluations of this therapy alone or against newer, less\u000d\u000a      invasive neuromodulatory therapies, and its mechanism of action was yet to\u000d\u000a      be established. Studies of the effects of SNS on rectal sensory function\u000d\u000a      [2] and cortical processing thereof provided a rationale for use in\u000d\u000a      patients with abnormal rectal sensation with a GB \/ Ireland multicentre\u000d\u000a      trial to optimise electrode insertion technique based on cortical\u000d\u000a      responses. Four further national multicentre trials (three NIHR \/ HTA) are\u000d\u000a      in progress to assess the impact of less invasive techniques e.g.\u000d\u000a      Percutaneous Tibial Nerve Stimulation (PTNS) in patients with FI or RED\u000d\u000a      [Knowles 2009-; Carrington (RF) 2009-12; Thin (RF) 2010-13; Horrocks (RF)\u000d\u000a      2011-13].\u000d\u000a    2b: Anal Fistula Eradication. The development of the `snug seton'\u000d\u000a      method which allows a slow (over months) controlled division of enclosed\u000d\u000a      sphincter muscle to effect fistulotomy has resulted in published\u000d\u000a      acceptable continence preservation. The use of biomaterials in anal\u000d\u000a      fistula management has evolved by exploration of host-xenograft\u000d\u000a      interactions between man and acellular porcine dermal cross-linked\u000d\u000a      collagen. Pilot studies of the use of collagen, either as a solid implant\u000d\u000a      or as a suspension held within fibrin glue, as a definitive treatment\u000d\u000a      yielded good success rates with no functional compromise as assessed\u000d\u000a      clinically and manometrically, and at long follow-up [Lunniss PJ (SenLect)\u000d\u000a      1997-. Hammond TM MD Res 2000-2002].\u000d\u000a    2c: Rectal Augmentation. The use of small intestine to increase\u000d\u000a      rectal capacity (Rectal Augmentation) [3] resulted from studies\u000d\u000a      demonstrating that patients with rectal hypersensitivity and FI exhibited\u000d\u000a      reduced rectal compliance, low rectal volumes and high pressure\u000d\u000a      propagating rectal contractions on ambulatory motility studies (Williams,\u000d\u000a      Scott SM Physiologist 1990- , Lunniss PJ Senior Lecturer 1995-2011, Chan\u000d\u000a      CLH RF 2003-6). Collaboration with the Peripheral Nerve Unit at Imperial\u000d\u000a      (Prof P Anand) showed that rectal hypersensitivity was related to neuronal\u000d\u000a      sprouting and an increase in TRPV1 receptors [4].\u000d\u000a    2d: Vertical Reduction Rectoplasty and Colonic Conduit:\u000d\u000a      Physiological investigations showed that patients with megarectum and\u000d\u000a      rectal hyposensitivity may have both afferent neuropathy and increased\u000d\u000a      compliance (laxity of the rectal wall). Vertical Reduction Rectoplasty was\u000d\u000a      devised to correct the specific physiological abnormalities in the second\u000d\u000a      group [Gladman MA PhD thesis 2002-5]. Colonic conduit was developed as an\u000d\u000a      antegrade enema solution in adults with severe RED without their native\u000d\u000a      appendix [5].\u000d\u000a    2e: The APPEAR Procedure: This technique, designed to excise the\u000d\u000a      distal part of the anorectum and preserve continence, was developed\u000d\u000a      following study of the physiology of the anorectal reflexes responsible\u000d\u000a      for continence and appreciation that receptors responsible were sited in\u000d\u000a      the pelvic floor musculature [6]. Physiological and imaging studies before\u000d\u000a      and after APPEAR demonstrate that this is an effective technique that\u000d\u000a      should reduce the present permanent stoma rate significantly [Murphy J\u000d\u000a      & El-Gendy K (RFs) 2008-10, Bryant CH (RF) 2010].\u000d\u000a    2f: Prevention of Parastomal Herniation. A collagen implant was\u000d\u000a      investigated to examine its interaction with human tissue and determine if\u000d\u000a      reinforcement of the stoma trephine could reduce incidence of parastomal\u000d\u000a      hernia. Results showed the approach to be feasible The pilot study\u000d\u000a      provided vital information on host\/implant interaction that assisted in\u000d\u000a      modifying the material for other clinical uses. Further studies\u000d\u000a      investigated whether a stapling technique (SMART) could be combined with\u000d\u000a      the collagen implantation to simultaneously create the trephine and\u000d\u000a      reinforcement. These studies have now led to a multicentre international\u000d\u000a      trial [Hotouras A (RF) 2010- , Thaha M (Clinical Fellow) 2009-11].\u000d\u000a    "},{"CaseStudyId":"19548","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"3017382","Name":"France"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    Lung transplants represent the last hope for cystic fibrosis patients\u000a      with end-stage lung disease.\u000a      By demonstrating that colonisation of the airways with the majority of the\u000a      closely related\u000a      Burkholderia species of bacteria does not adversely affect the\u000a      outcome of lung transplant,\u000a      Newcastle research has resulted in many seriously ill young people now\u000a      being offered transplants\u000a      that had previously been considered too risky. The mean survival rate for\u000a      these patients is as\u000a      good as that of non-infected patients. In a situation where median\u000a      lifespan is around 37 years,\u000a      good-quality lifespan post-transplant can exceed five years (EV a).\u000a    Approach to patient treatment in major research centres\u000a    As noted above, in the 1990s most centres stopped listing cystic fibrosis\u000a      patients for transplant if\u000a      they had any Burkholderia infection because of the risk to the\u000a      patient's life. However, some large\u000a      research centres, including Newcastle and centres in France, the US,\u000a      Canada and Australia,\u000a      continued to consider for transplant patients colonised by these bacteria.\u000a      Since 2001, all patients\u000a      in Newcastle have been assessed for risk posed by Burkholderia\u000a      infection by ensuring that those\u000a      carrying the dangerous Burkholderia cenocepacia infection are\u000a      identified (R1).\u000a    If the dangerous Burkholderia cenocepacia was found then a revised\u000a      pre- and post-transplant\u000a      treatment protocol was implemented. Over time the protocol changed as\u000a      virulence factors were\u000a      identified (R4) and researchers sought to improve results for their\u000a      patients. In 2008, the continued\u000a      poor outcomes for these patients, even with the amended treatment, led\u000a      Newcastle and most of\u000a      the other centres finally to stop transplanting patients with the\u000a      dangerous Burkholderia\u000a        cenocepacia (see R5). Nonetheless, patients with non-cenocepacia\u000a      infections continued to be\u000a      transplanted during this period (1990s-2008), but only in the large\u000a      research-active centres.\u000a    The significance of the Newcastle findings (R1-R4), especially the good\u000a      outcomes for patients with\u000a      non-cenocepacia infection, has been disseminated widely through\u000a      professional networks and via\u000a      the guidelines of the International Society for Heart and Lung\u000a      Transplantation, of which Corris was\u000a      an author (EV b).\u000a    Guidelines into practice\u000a    The publication of the International Society for Heart and Lung\u000a      transplantation guidelines in 2006\u000a      brought Newcastle research findings to the attention of transplant centres\u000a      worldwide. Transplant\u000a      centres that had stopped listing patients with any Burkholderia\u000a      infection for transplant began to\u000a      revise their policies after 2008. The Medical Director of the Texas\u000a      Transplant Centre confirmed,\u000a    `Implementation of the recommendations suggested, with risk\u000a        stratification in 2008, led to\u000a        significant and meaningful changes, not only in our clinical practice,\u000a        but for the rest of the\u000a        North American Continent in lung transplantation.' (EV c)\u000a    Further evidence of the Newcastle approach to risk stratification\u000a      affecting global practice has come\u000a      from a number of organisations. The President of the International Society\u000a      for Heart and Lung\u000a      Transplantation has confirmed that:\u000a    `Since the ISHLT guidelines were published the majority of transplant\u000a        centres have, to the\u000a        best of my knowledge, implemented them in practice. Hence it is fair to\u000a        say that the current\u000a        local, and International, policy and clinical practice in relation to\u000a        lung transplantation of\u000a        cystic fibrosis patients has largely been informed by the Newcastle\u000a        research.' (EV d)\u000a    The President of the European Cystic Fibrosis Society in 2013 confirms:\u000a    `The incorporation of [Newcastle] research findings into the\u000a        ISHLT Guidelines, and the\u000a        subsequent implementation of risk stratification by the majority of\u000a        transplantation centres in\u000a        the past 5 years has led to significant changes in clinical practice\u000a        throughout Europe. This\u000a        stratification of B. cenocepacia patients, who have very poor\u000a        outcomes compared to\u000a        patients with B. multivorans and other species, has ensured that\u000a        the precious resource of\u000a        transplanted lungs are directed effectively.' (EV e)\u000a    The Chair of the Association of Lung Transplant Physicians UK has also\u000a      confirmed that `Most if not\u000a        all European Transplant centres' stratify patient risk based on\u000a      Newcastle's research and noted:\u000a    `This important finding has been instrumental in informing listing and\u000a        organ allocation\u000a        practices in an era of continuing critical donor organ shortage to\u000a        ensure better use of this\u000a        scarce resource and effective transplantation in people with Cystic\u000a        fibrosis. Having\u000a        previously been denied access to transplantation, many cystic fibrosis\u000a        patients with non-\u000a        cenocepacia infection have since undergone successful surgery.' (EV\u000a      f)\u000a    While work continues to help patients identified as having the\u000a        dangerous Burkholderia\u000a        cenocepacia, the Newcastle findings have largely benefited cystic\u000a      fibrosis patients with non-\u000a      cenocepacia Burkholderia complex infections. The Newcastle research\u000a      paper from 2010 (R5)\u000a      highlighted the success of transplanting such patients and this data\u000a      (disseminated widely in\u000a      abstract form from 2008, the year the paper was first submitted to the\u000a      journal) has proved\u000a      influential. The President of the International Society for Heart and Lung\u000a      Transplantation has\u000a      confirmed that,\u000a    `The ISHLT registry does not record infection data stratified by\u000a        organism, however studies\u000a        by ISHLT members revealed the prevalence of Burkholderia complex\u000a        species among cystic\u000a        fibrosis patients on transplant lists to be around 10%. Just under half\u000a        of these will be\u000a        colonised by Burkholderia species other than B. cenocepacia.\u000a        Consequently it would be\u000a        reasonable to conservatively estimate that more than 30 patients (adults\u000a        and children)\u000a        worldwide per year now receive transplants who would otherwise not have\u000a        been listed, the\u000a        majority of those who could benefit.' (EV d, EV g)\u000a    ","ImpactSummary":"\u000a    Lung transplants represent the last hope for cystic fibrosis patients\u000a      with end-stage lung disease.\u000a      However, since the mid-1990s, other than in large research centres, some\u000a      cystic fibrosis patients\u000a      were not offered this treatment because of the variable and often poor\u000a      outcome of surgery. This\u000a      patient group carried a difficult to treat bacterial infection caused by\u000a      the Burkholderia genus. In\u000a      2001 researchers in Newcastle published findings that demonstrated that\u000a      one particular species,\u000a      Burkholderia cenocepacia, was responsible for the poor outcomes and\u000a      that other species of\u000a      Burkholderia were not as dangerous. This finding was incorporated\u000a      into international guidelines\u000a      and since 2008 most transplant centres worldwide have adopted a risk\u000a      stratification approach to\u000a      listing patients for transplant. Consequently, more than 30 people per\u000a      year worldwide now get\u000a      transplants that would otherwise have been denied.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4736286","Name":"Texas"}],"References":"\u000a    (Citations as at July 2013, key Newcastle researchers in bold.)\u000a    \u000aR1. De Soyza A, McDowell A, Archer L, Dark JH, Elborn SJ,\u000a      Mahenthiralingam E, Gould K,\u000a      Corris PA. Burkholderia cepacia complex genomovars and\u000a      pulmonary transplantation outcomes in\u000a      patients with cystic fibrosis. Lancet 2001 Nov 24, 358(9295):\u000a      1780-1. doi:10.1016\/S0140-6736(01)06808-8. cited by 93.\u000a    \u000a\u000aR2. De Soyza A and Corris PA. Lung transplantation and the Burkholderia\u000a        cepacia complex. The\u000a        Journal of Heart and Lung Transplantation 2003, 22(9): 954-8.\u000a      doi:10.1016\/S1053-2498(03)00024-\u000a      X. Cited by 21.\u000a    \u000a\u000aR3. De Soyza A, Ellis CD, Anjam Khan CM, Corris PA and Demarco de\u000a        Hormaeche R.\u000a      Burkholderia cenocepacia lipopolysaccharide, lipid A and\u000a        proinflammatory activity. American\u000a        Journal of Respiratory and Critical Care Medicine 2004, 170: 70-7.\u000a      doi: 10.1164\/rccm.200304-592OC. Cited by 35.\u000a    \u000a\u000aR4. De Soyza A, Morris K, McDowell A, Doherty C, Archer L,\u000a      Perry J, Govan JR, Corris PA,\u000a        Gould K. Prevalence and clonality of Burkholderia cepacia\u000a      complex genomovars in UK patients\u000a      with cystic fibrosis referred for lung transplantation. Thorax\u000a      2004, 59(6): 526-8. doi:\u000a      10.1136\/thx.2003.010801. Cited by 28.\u000a    \u000a\u000aR5. De Soyza A, Meachery G, Hester KL, Nicholson A, Parry G, Tocewicz\u000a        K, Pillay T, Clark\u000a        S, Lordan JL, Schueler S, Fisher AJ, Dark JH, Gould FK, Corris PA.\u000a      Lung transplantation for\u000a      patients with cystic fibrosis and Burkholderia cepacia complex\u000a      infection: a single-center\u000a      experience. The Journal of Heart and Lung Transplantation 2010,\u000a      29(12): 1395-404. doi:\u000a      10.1016\/j.healun.2010.06.007. Cited by 22.\u000a    \u000aKey funding\u000a    Wellcome Trust, The Role of Genomovars in B.Cepacia Proinflammatory\u000a        Activity 01\/10\/2001 to\u000a      30\/09\/2003, £111,442.00.\u000a    The Newcastle upon Tyne Hospitals NHS Charities, Studies of Host\u000a        Epithelial Cell-Pathogen\u000a        Interactions in Cystic Fibrosis Patients Infected with Burkholderia\u000a        Cepacia, 01\/04\/2005 to\u000a      31\/03\/2006, £38,620.00.\u000a    Higher Education Funding Council for England: New Blood Senior\u000a      Lectureship, Dr. Anthony De\u000a      Soyza, 2007-12; £300,000\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    EV a. Data on post-transplant survival obtained from International\u000a      Society for Heart and Lung\u000a      Transplantation registry. Summary available in the Journal of Heart\u000a        and Lung Transplantation\u000a      2012, 31(10): 1073-97. Hard copy available on request. DOI:\u000a      10.1016\/j.healun.2012.08.004\u000a    EV b. The 2006 International Guidelines for the Selection of Lung\u000a        Transplant Candidates are\u000a      available at http:\/\/www.sciencedirect.com\/science\/article\/pii\/S1053249806002518.\u000a      DOI:\u000a      10.1016\/j.healun.2006.03.011 The guidelines have been cited in 412 papers\u000a      relating to both\u000a      research and clinical practice.\u000a    EV c. Correspondence from the Medical Director of the Texas Transplant\u000a      Centre is available and\u000a      he has agreed to be contacted to discuss matters further.\u000a    EV d. Correspondence from the President of the International Society for\u000a      Heart and Lung\u000a      Transplantation is available and he has agreed to be contacted to discuss\u000a      matters further.\u000a    EV e. Correspondence from the President of the European Cystic Fibrosis\u000a      Society is available.\u000a    EV f. Correspondence from the Chair of the Association of Lung Transplant\u000a      Physicians UK is\u000a      available.\u000a    EV g. Details of the manner in which this estimate was reached are\u000a      available on request and the\u000a      President of the International Society for Heart and Lung Transplantation\u000a      has agreed to be\u000a      contacted to discuss this calculation.\u000a    \u000a    ","Title":"\u000a    How better risk stratification for lung transplant has benefitted cystic\u000a      fibrosis\u000a      patients\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle University researchers\u000a    Professor Paul Corris and Dr. Anthony De Soyza originated the research:\u000a      Corris then acted as De\u000a      Soyza's doctoral supervisor. Professor Gould developed the microbial\u000a      repository and provided\u000a      input to study design and analysis. Professors Dark and Fisher contributed\u000a      to analysis, and, with\u000a      Corris and Gould, the clinical service. All worked jointly between\u000a      Newcastle University and the\u000a      Newcastle upon Tyne Hospitals NHS Trust.\u000a    Background\u000a    The condition: Cystic fibrosis is an inherited condition,\u000a      affecting both sexes, that has an impact on\u000a      many systems in the body, but respiratory problems are the most common\u000a      cause of illness and\u000a      death. The incidence of cystic fibrosis in the UK is around 1 in 2,500\u000a      newborns per year. The\u000a      Cystic Fibrosis Trust report that around 10,000 people in the UK live with\u000a      the condition. In end-\u000a      stage cystic fibrosis, often the only viable means of prolonging a\u000a      good-quality life is by\u000a      transplanting both lungs with healthy donor organs.\u000a    Transplantation: The International Society for Heart and Lung\u000a      Transplantation reported that 178\u000a      centres worldwide conducted 3,519 lung transplants in 2010 (the latest\u000a      full year for which there are\u000a      data). Of these, 620 were cystic fibrosis patients (17% of total). The\u000a      British Transplantation\u000a      Society estimated that on average around 9 out of 10 people will survive\u000a      for at least a year after a\u000a      transplant and 5 out of 10 will survive for at least five years.\u000a    Infection: Worldwide, it is reported (R5 and Boussaud et al 2008\u000a      PMID: 18408050) around 5 - 10%\u000a      of cystic fibrosis patients become colonised with a bacterium known until\u000a      recently as Burkholderia\u000a        cepacia (around 500 patients in the UK). Such infection was, and\u000a      remains, difficult to treat and can\u000a      cause the clinical syndrome of necrotising pneumonia with associated\u000a      septicaemia. This is life\u000a      threatening. From the early 1990s, centres worldwide reported that cystic\u000a      fibrosis lung transplant\u000a      patients with Burkholderia cepacia infection had variable and\u000a      generally worse outcomes compared\u000a      to patients without the pathogen. Consequently, many centres stopped\u000a      transplanting such\u000a      patients.\u000a    By the late 1990s, research revealed a complex of nine different, closely\u000a      related, species of\u000a      bacteria. These included Burkholderia cepacia, Burkholderia\u000a        multivorans and Burkholderia\u000a        cenocepacia. `Burkholderia cepacia complex' infections\u000a      continued to be a contra-indication for\u000a      transplant in most centres worldwide.\u000a    Research in Newcastle\u000a    One strand of research in Newcastle focussed on risk stratification for\u000a      lung transplant in cystic\u000a      fibrosis patients. Approximately 20 lung transplants for cystic fibrosis\u000a      are conducted per year at\u000a      Newcastle; the highest by volume in the UK. Many more patients are, of\u000a      course, referred but a\u000a      number of factors are taken into account before listing a patient for\u000a      transplant. The number of\u000a      transplants is limited by donor lung availability.\u000a    In 2001, Newcastle researchers published the first results (R1) which\u000a      showed that one particular\u000a      species in the Burkholderia complex, Burkholderia cenocepacia,\u000a      was associated with poor\u000a      outcome of transplantation in cystic fibrosis patients. This was confirmed\u000a      by studies in North\u000a      Carolina and France. In 2003, De Soyza and Corris reviewed the\u000a      then-current state of knowledge\u000a      (R2) and drew the conclusion that accurate identification of the\u000a      particular Burkholderia species\u000a      carried by each patient was important, as the weight of evidence suggested\u000a      that patients without\u000a      the dangerous Burkholderia cenocepacia species could be\u000a      transplanted successfully.\u000a    Newcastle researchers published an `important first step'\u000a      (Editorial comment,\u000a      http:\/\/ajrccm.atsjournals.org\/content\/170\/1\/6)\u000a      in 2004, identifying factors underlying the virulence of\u000a      the dangerous Burkholderia cenocepacia (R4). In 2010, Newcastle\u000a      researchers published a\u000a      retrospective study (R5) of their experiences of lung transplant in 216\u000a      cystic fibrosis patients over\u000a      20 years. They noted that 22 patients had confirmed pre-operative Burkholderia\u000a      complex infection,\u000a      with 12 of these being Burkholderia cenocepacia. Nine of these cenocepacia-infected\u000a      recipients\u000a      died within the first year; however patients infected with other Burkholderia\u000a      species had\u000a      significantly better outcomes, with post-transplantation survival\u000a      comparable to other transplant\u000a      recipients with cystic fibrosis.\u000a    "},{"CaseStudyId":"20066","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    As a result of our work, which provided an evidence base for the efficacy\u000d\u000a      of self-management in LUTS, nearly all evidence-based practice guidelines\u000d\u000a      recommend self-management as the initial form of therapy for all men\u000d\u000a      presenting with LUTS. It has therefore become a global standard of care.\u000d\u000a    \u000d\u000a      NICE guideline CG97 (2010), on Lower urinary tract symptoms in men,\u000d\u000a        recommends self- management in the text and in the therapeutic\u000d\u000a        algorithms. The BMJ RCT is referenced [a]. Emberton acted as\u000d\u000a        expert advisor to the group that produced the guidelines.\u000d\u000a      2011 guidelines issued by the European Association of Urology on\u000d\u000a        treatment of non-neurogenic male LUTs (on which the majority of the\u000d\u000a        national guidelines are based) cite our evidence that \"self-management\u000a          as part of watchful waiting reduces both symptoms and progression\".\u000a        Accordingly, they recommend that \"men with mild symptoms are\u000d\u000a          suitable for watchful waiting...Men with LUTS should be offered\u000d\u000a          lifestyle advice prior to or concurrent with treatment.\" The table\u000d\u000a        from Brown et al 2007 is cited directly and the recommendation is\u000d\u000a        attributed a level of Evidence of 1b; Grade A [b].\u000d\u000a    \u000d\u000a    Self-management is now widely recommended to patients, for example on the\u000d\u000a      patient.co.uk website [c] and on NHS Choices [d]. Private\u000d\u000a      healthcare providers now recommend self- management according to the NICE\u000d\u000a      guidelines (e.g. Benenden Healthcare [e]) and it is widely used in\u000d\u000a      NHS Continence Services [f]. A survey of GPs in 2011 showed that\u000d\u000a      46% had implemented the guidance, and 80% of those had seen a reduction in\u000d\u000a      referral costs [g].\u000d\u000a    The impacts of our work on patients are as follows:\u000d\u000a    \u000d\u000a      \u000aFewer men require drug therapy: our RCT demonstrated both a\u000d\u000a        reduction in symptoms equivalent to that achieved by surgery and a\u000d\u000a        reduction in the need for treatment whether it be medication or surgery\u000d\u000a      \u000aMore effective therapy: Our intervention arm was standard care\u000d\u000a        plus self-management. Men receiving drug therapy who were randomised to\u000d\u000a        the intervention arm had greater and more sustained symptom improvement.\u000d\u000a      \u000aFewer referrals: Self-management is being applied in primary\u000d\u000a        care and is being promoted through self-help groups. The resolution of\u000d\u000a        symptoms without recourse to medication or surgery leads to fewer\u000d\u000a        referrals to secondary care.\u000d\u000a    \u000d\u000a    The impacts on patients also provide economic benefits to the healthcare\u000d\u000a      system through a reduced cost of care. Our work has shown that once the\u000d\u000a      self-management skills are taught the benefits are sustained. This has not\u000d\u000a      been the case in other self-management programmes. A conservative\u000d\u000a      estimate, abstracting from our data, is that men using self-management\u000d\u000a      have a 3-fold reduction in risk of requiring therapy or progressing\u000d\u000a      symptomatically. Estimates of the cost of treating LUTS in the UK are\u000d\u000a      approximately £120m per year. Modelling of the effect size and uptake of\u000d\u000a      self-management as an initial strategy produces an estimate of a £20m\u000d\u000a      annual saving, largely derived as a result of fewer referrals to secondary\u000d\u000a      care and to reduced drug costs.\u000d\u000a    Kaiser Permanente, the largest managed care organisation in the United\u000d\u000a      States covering a population of 3.6 million, is in the process of adapting\u000d\u000a      and implementing self-management as a standard intervention based on the\u000d\u000a      work published by our team and the recommendations in international\u000d\u000a      clinical practice guidelines. They state that it is \"exactly the type\u000d\u000a        of innovative, impactful work that can help us break out of the\u000d\u000a        traditional means of delivering health care, and help contain burgeoning\u000d\u000a        costs while at the same time, improve the quality of care.\" [h].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Lower Urinary Tract Symptoms (LUTS) in men is a chronic disease of ageing\u000d\u000a      that causes significant quality of life impairment in one third of men\u000d\u000a      over the age of 60. Traditional management comprises a step-up regimen of\u000d\u000a      drugs and surgical interventions aimed at relieving symptoms. At UCL we\u000d\u000a      conceived, developed, evaluated and implemented a self-management\u000d\u000a      intervention that results in greater symptom reduction than that achieved\u000d\u000a      by medication, reduction in the use of medication and of referrals to\u000d\u000a      secondary care, and reduced costs. The intervention is now a global\u000d\u000a      standard of care.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Brown CT, Van Der Meulen J, Mundy AR, Emberton M. Lifestyle and\u000d\u000a      behavioral interventions for men on watchful waiting with uncomplicated\u000d\u000a      lower urinary tract symptoms: a national multidisciplinary survey. BJU\u000d\u000a      Int. 2003 Jul;92(1):53-7. http:\/\/dx.doi.org\/10.1046\/j.1464-410X.2003.04268.x\u000d\u000a    \u000a\u000a[2] Lane T, Brown C, Emberton M. Behavioural\u000a        approaches are helpful in overactive bladder. BMJ. 2003 Aug\u000d\u000a      2;327(7409):291. http:\/\/dx.doi.org\/10.1136\/bmj.327.7409.291\u000d\u000a    \u000a\u000a[3] Brown CT, Van Der Meulen J, Mundy AR, Emberton M. Lifestyle\u000a        and behavioural interventions for men on watchful waiting with\u000d\u000a        uncomplicated lower urinary tract symptoms: a national multidisciplinary\u000d\u000a        survey. BJU Int. 2003 Jul;92(1):53-7. http:\/\/dx.doi.org\/10.1046\/j.1464-410X.2003.04268.x\u000d\u000a    \u000a\u000a[4] Brown CT, van der Meulen J, Mundy AR, O'Flynn E, Emberton M. Defining\u000a        the components of a self-management programme for men with uncomplicated\u000d\u000a        lower urinary tract symptoms: a consensus approach. Eur Urol. 2004\u000d\u000a      Aug;46(2):254-62; discussion 263.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/j.eururo.2004.02.008\u000d\u000a    \u000a\u000a[5] Brown CT, Yap T, Cromwell DA, Rixon L, Steed L, Mulligan K, Mundy A,\u000d\u000a      Newman SP, van der Meulen J, Emberton M. Self-management\u000a        for men with lower urinary tract symptoms: randomised controlled trial.\u000d\u000a      BMJ. 2007 Jan 6;334(7583):25.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/bmj.39010.551319.AE\u000d\u000a    \u000a\u000a[6] Yap TL, Brown C, Cromwell DA, van der Meulen J, Emberton M. The\u000a        impact of self- management of lower urinary tract symptoms on\u000d\u000a        frequency-volume chart measures. BJU Int. 2009 Oct;104(8):1104-8. http:\/\/dx.doi.org\/10.1111\/j.1464-410X.2009.08497.x\u000d\u000a      \u000aThis work was supported by a BUPA Foundation award.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"10","Subject":"Nursing"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Lower urinary tract symptoms in men. National Institute of health and\u000d\u000a      Clinical Excellence. NICE Clinical Guideline 97, 2010. http:\/\/www.nice.org.uk\/nicemedia\/live\/12984\/48557\/48557.pdf\u000d\u000a    [b] Guidelines on the treatment of non-neurogenic male LUTs. European\u000d\u000a      Association of Urology, 2011. These guidelines place self-management as an\u000d\u000a      important intervention (Grade A) http:\/\/www.uroweb.org\/gls\/pdf\/12_Male_LUTS.pdf\u000d\u000a    [c] Patient.co.uk recommendations on LUTS: http:\/\/www.patient.co.uk\/doctor\/lower-urinary-tract-symptoms-in-men\u000d\u000a    [d] NHS Choices guidelines on non-surgical treatment for urinary\u000d\u000a      incontinence:\u000d\u000a      http:\/\/www.nhs.uk\/Conditions\/Incontinence-urinary\/Pages\/Treatment.aspx\u000d\u000a    [e] Advice on continence provided by Beneden Health: https:\/\/www.benenden.co.uk\/healthcare-membership\/personal-healthcare\/healthcare-services\/continence-care\/\u000d\u000a    [f] E.g. Brighton and Sussex University Hospitals — Department of Urology\u000d\u000a      guidance on LUTS. Copy available on request.\u000d\u000a    NHS Evidence Update for lower urinary tract symptoms in men, 2012:\u000d\u000a      http:\/\/arms.evidence.nhs.uk\/resources\/hub\/691207\/attachment\u000d\u000a    [g] http:\/\/www.medicalnewstoday.com\/releases\/228342.php\u000d\u000a    [h] Personal communication from Director of Research for Kaiser\u000d\u000a      Permanente Southern California. Available on request. \u000d\u000a    ","Title":"\u000d\u000a    Self-management intervention for men with lower urinary tract symptoms:\u000d\u000a      development, phased evaluation and global adoption\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In about 2003 Emberton observed that many men were adopting informal\u000d\u000a      strategies that would allow them to `manage' their symptoms as an\u000d\u000a      alternative to pharmacotherapy [1]. These were sometimes learnt by\u000d\u000a      trial and error, and at other times they were acquired through the\u000d\u000a      informal network of men with symptoms and, very occasionally, taught by a\u000d\u000a      growing constituency of continence advisors and nurse specialists. These\u000d\u000a      strategies included: fluid management, caffeine avoidance, timed\u000d\u000a      toileting, urethral milking, double voiding and bladder re-training. We\u000d\u000a      conducted a survey of urologists, nurse practitioners and continence\u000d\u000a      advisors to determine the use of these strategies, and the results showed\u000d\u000a      that these interventions are indeed advised by many in such circumstances\u000d\u000a      [2]. However, there was a wide variation in their use, and no\u000d\u000a      supporting evidence base, so we felt that it was necessary to test their\u000d\u000a      effectiveness.\u000d\u000a    We began by assembling a multi-disciplinary research team (patients,\u000d\u000a      urologists, continence advisors, specialist nurses, health services\u000d\u000a      researchers and health psychologists) that was representative of the\u000d\u000a      expertise necessary to address the research question. A systematic review\u000d\u000a      of the literature confirmed that the evidence to support life-style\u000d\u000a      modification was either weak or absent. A formal survey of UK practice\u000d\u000a      indicated that the use of lifestyle interventions was infrequent but that\u000d\u000a      professional groups would be receptive, if they were shown to be effective\u000d\u000a      [3]. We conducted a needs assessment (qualitative methods\u000d\u000a      comprising semi-structured interviews\/surveys) that confirmed an unmet\u000d\u000a      need from the patients' perspective and no barriers to adoption from the\u000d\u000a      professions or pharmaceutical industry [1]. We defined the\u000d\u000a      intervention prospectively using formal consensus methodology (RAND)\u000d\u000a      through the process of item generation and item reduction in two rounds of\u000d\u000a      scoring. [4]. The defined intervention was piloted in a single\u000d\u000a      centre (UCLH). The pilot demonstrated good uptake by patients, adherence\u000d\u000a      to the programme and provided a strong preliminary signal of efficacy.\u000d\u000a      This pilot informed the design and conduct of an RCT that compared\u000d\u000a      standard care to standard care plus the self-management intervention using\u000d\u000a      a reduction in patient-reported symptom score as the primary outcome. This\u000d\u000a      study demonstrated a reduction in symptoms equivalent to that achieved by\u000d\u000a      surgery and a reduction in the need for medical and surgical treatment [5,6].\u000d\u000a    "},{"CaseStudyId":"20951","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Our ongoing programme of basic science, translational and clinical\u000d\u000a      research has underpinned substantial advances in understanding vascular\u000d\u000a      complications of SSc and has directly informed the development of new\u000d\u000a      effective therapies. The best example for this is the targeting of\u000d\u000a      endothelin receptors. ET-1 is a vasoconstrictor peptide implicated in SSc\u000d\u000a      pathogenesis and ERAs have been developed that are now licensed therapies\u000d\u000a      for PAH in SSc and also for digital ulcer disease. The latter represents\u000d\u000a      the first ever SSc-specific licensing indication.\u000d\u000a    Use of ERAs for PAH in SSc\u000d\u000a    PAH is a complication that affects about 10% of SSc patients. As a result\u000d\u000a      of the research described above, use of ERAs has become standard practice\u000d\u000a      in the management of PAH related to connective tissue disease\u000d\u000a      (specifically complicating SSc) [a]. Our work specifically defined\u000d\u000a      tolerability and efficacy in SSc cases with PAH. The FDA and EMA approvals\u000d\u000a      of Bosentan in 2002 were dependent on the BREATHE-1 study to which we\u000d\u000a      contributed [b, c]. The use of Bosentan is now recommended in\u000d\u000a      European guidelines [d] and our studies provided key evidence used\u000d\u000a      in guideline development.\u000d\u000a    Worldwide, many thousands of patients have now benefitted from treatment\u000d\u000a      with bosentan for PAH. Actelion (the company that markets bosentan)\u000d\u000a      reported that in one year alone (2012) 44,000 patients were currently\u000d\u000a      receiving the therapy. It is estimated that around a quarter of PAH\u000d\u000a      patients have connective tissue disease (see Badesch et al. 2010), so we\u000d\u000a      can assume that around 11,000 of these treatments were for SSc patients [e].\u000d\u000a    Endothelin antagonism with bosentan in SSc patients with PAH reduces\u000d\u000a      death rate by 30%. Thus the average survival for pulmonary arterial\u000d\u000a      hypertension in SSc has improved from less than two years to more than\u000d\u000a      five years from diagnosis [f]. This can be estimated to have saved\u000d\u000a      around 30 lives a year in our cohort of SSc cases and perhaps 150 lives\u000d\u000a      per year in the UK [g]. Furthermore, there is an important benefit\u000d\u000a      in terms of quality of life and symptom burden as most patients with PAH\u000d\u000a      treatment improve their functional class to grade II, representing minor\u000d\u000a      breathlessness that allows them to participate in normal activities. This\u000d\u000a      benefit was demonstrated by the improvement in the heath transition domain\u000d\u000a      of the SF-36 heath status measure in the TRUST clinical trial that our\u000d\u000a      centre led [see reference 4 above]. This has been possible due to\u000d\u000a      the pivotal work that our centre undertook in defining a role for ET-1 in\u000d\u000a      pathogenesis and also in defining benefit in terms of mortality and\u000d\u000a      efficacy of ERA.\u000d\u000a    Licensing of bosentan for digital ulcer disease\u000d\u000a    Digital ulcers are a significant complication of SSc. They are painful,\u000d\u000a      and may take between three and 15 months to heal. Secondary infections may\u000d\u000a      occur in 50% of cases, and recurring ulcers can be a major source of\u000d\u000a      disability, interfering with the patient's daily activities and capacity\u000d\u000a      to work. Digital ulcers can also lead to the chronic use of analgesics and\u000d\u000a      antibiotics, and sometimes to hospitalisation and surgery (including\u000d\u000a      digital amputation) [h]. In May 2007, Bosentan was licensed by the\u000d\u000a      European Medicines Agency (EMA) as a preventative treatment to reduce the\u000d\u000a      number of new digital ulcers in patients with systemic sclerosis and\u000d\u000a      ongoing digital ulcer disease. As well as the research provided above,\u000d\u000a      Black and Denton made the presentation to the EMA on the clinical impact\u000d\u000a      of digital ulcer disease that underpinned the approval [i].\u000d\u000a    Our work defined the patients most likely to benefit from this high cost\u000d\u000a      therapy, in order to facilitate targeting of appropriate cases where\u000d\u000a      clinical impact and economic considerations are favourable. This treatment\u000d\u000a      is now recommended in consensus guidelines issued by the UK Scleroderma\u000d\u000a      working group [j].\u000d\u000a    European League Against Rheumatism (EULAR) and the EULAR Scleroderma\u000d\u000a      Trials and Research Group (EUSTAR) recommend: \"Bosentan has confirmed\u000d\u000a        efficacy in two high-quality randomised controlled trials to prevent\u000d\u000a        digital ulcers in diffuse systemic sclerosis patients, in particular\u000d\u000a        those with multiple digital ulcers. Bosentan should be considered in\u000d\u000a        diffuse systemic sclerosis with multiple digital ulcers after failure of\u000d\u000a        calcium antagonists and, usually, prostanoid therapy\" [d].\u000d\u000a      In 2012, Actelion (manufacturers of Bosentan) reported that over 5,000 DU\u000d\u000a      patients were currently on this therapy [k].\u000d\u000a    Trial results showed that the use of bosentan for digital ulcers reduced\u000d\u000a      the incidence in SSc patients by 50% [l]. A 50% reduction in new\u000d\u000a      digital ulcer formation is a tangible impact on a non- lethal burden of\u000d\u000a      SSc that affects up to 50% of cases. It has been shown in recent work from\u000d\u000a      the DUO register that ulcer number correlates with inability to undertake\u000d\u000a      employed work and also the need for paid help, specifically that having\u000d\u000a      more than two digital ulcers is associated with reduced work participation\u000d\u000a      [m].\u000d\u000a    Reduction in need for hospital admission for intravenous prostcyclin has\u000d\u000a      been a specific benefit of the availability of oral therapies for severe\u000d\u000a      digital ulcers in SSc. This is exemplified by the approved algorithm for\u000d\u000a      ulcer use that defines the need for three or more annual admissions for\u000d\u000a      inpatient treatment as a threshold for funding application for ERA. This\u000d\u000a      is based upon predicted per patient annual saving of around £3,600. Thus,\u000d\u000a      with around 30 cases per year in our centre fulfilling this standard, that\u000d\u000a      has now been adopted by UK Scleroderma Study Group (chaired by Denton) as\u000d\u000a      part of their \"best practice recommendations\" in 2012, would save the NHS\u000d\u000a      in our hospital an estimated £100,000 and nationally a predicted £500,000\u000d\u000a      per year.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The research described below has made a major contribution to the\u000d\u000a      clinical and preclinical development of endothelin receptor antagonists\u000d\u000a      (ERAs) for the treatment of systemic sclerosis (SSc). As a result, ERAs\u000d\u000a      are now standard management for pulmonary arterial hypertension related to\u000d\u000a      connective tissue disease and specifically complicating SSc. This work has\u000d\u000a      also led to the licensing of bosentan (one of the ERAs) for digital ulcer\u000d\u000a      disease, a major non-lethal complication of SSc that impacts on quality of\u000d\u000a      life, employment status and the major economic cost of SSc management. By\u000d\u000a      2012, more than 16,000 patients with SSc had been treated worldwide with\u000d\u000a      these therapies, with numbers increasing every year.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Abraham DJ, Vancheeswaran R, Dashwood MR, Rajkumar VS, Pantelides P,\u000d\u000a      Xu SW, du Bois RM, Black CM. Increased levels of endothelin-1 and\u000d\u000a      differential endothelin type A and B receptor expression in\u000d\u000a      scleroderma-associated fibrotic lung disease. Am J Pathol. 1997\u000d\u000a      Sep;151(3):831-41. http:\/\/europepmc.org\/abstract\/MED\/9284832\u000d\u000a    \u000a\u000a[2] Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for\u000d\u000a      pulmonary arterial hypertension related to connective tissue disease: a\u000d\u000a      subgroup analysis of the pivotal clinical trials and their open-label\u000d\u000a      extensions. Ann Rheum Dis. 2006 Oct;65(10):1336-40. http:\/\/dx.doi.org\/10.1136\/ard.2005.048967\u000d\u000a    \u000a\u000a[3] Williams MH, Das C, Handler CE, Akram MR, Davar J, Denton CP, Smith\u000d\u000a      CJ, Black CM, Coghlan JG. Systemic sclerosis associated pulmonary\u000d\u000a      hypertension: improved survival in the current era. Heart. 2006\u000d\u000a      Jul;92(7):926-32. http:\/\/dx.doi.org\/10.1136\/hrt.2005.069484\u000d\u000a    \u000a\u000a[4] Denton CP, Pope JE, Peter HH, Gabrielli A, Boonstra A, van den Hoogen\u000d\u000a      FH, Riemekasten G, De Vita S, Morganti A, Dölberg M, Berkani O, Guillevin\u000d\u000a      L; TRacleer Use in PAH associated with Scleroderma and Connective Tissue\u000d\u000a      Diseases (TRUST) Investigators. Long-term effects of bosentan on quality\u000d\u000a      of life, survival, safety and tolerability in pulmonary arterial\u000d\u000a      hypertension related to connective tissue diseases. Ann Rheum Dis. 2008\u000d\u000a      Sep;67(9):1222-8. http:\/\/dx.doi.org\/10.1136\/ard.2007.079921\u000d\u000a    \u000a\u000a[5] Williams MH, Handler CE, Akram R, Smith CJ, Das C, Smee J, Nair D,\u000d\u000a      Denton CP, Black CM, Coghlan JG. Role of N-terminal brain natriuretic\u000d\u000a      peptide (N-TproBNP) in scleroderma-associated pulmonary arterial\u000d\u000a      hypertension. Eur Heart J. 2006 Jun;27(12):1485-94.\u000d\u000a      http:\/\/dx.doi.org\/10.1093\/eurheartj\/ehi891\u000d\u000a    \u000a\u000a[6] Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E,\u000d\u000a      Rich E, Carpentier P, Molitor J, Seibold JR, Hsu V, Guillevin L,\u000d\u000a      Chatterjee S, Peter HH, Coppock J, Herrick A, Merkel PA, Simms R, Denton\u000d\u000a      CP, Furst D, Nguyen N, Gaitonde M, Black C. Digital ulcers in systemic\u000d\u000a      sclerosis: prevention by treatment with bosentan, an oral endothelin\u000d\u000a      receptor antagonist.\u000d\u000a      Arthritis Rheum. 2004 Dec;50(12):3985-93. http:\/\/dx.doi.org\/10.1002\/art.20676\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    [a] Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ,\u000d\u000a      Sitbon O, Tapson VF, Galiè N. Updated evidence-based treatment algorithm\u000d\u000a      in pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1\u000d\u000a      Suppl):S78-84. http:\/\/dx.doi.org\/10.1016\/j.jacc.2009.04.017.\u000d\u000a    [b] FDA approval: http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2001\/21-290_Tracleer.cfm\u000d\u000a      (see approval letters — 2nd page of PDF document)\u000d\u000a    [c] EMA approval:\u000d\u000a      http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/000401\/hu\u000a        man_med_001100.jsp&mid=WC0b01ac058001d124\u000d\u000a    [d] Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak\u000d\u000a      L, Clements P, Denton C, Farge D, Fligelstone K, Földvari I, Furst DE,\u000d\u000a      Müller-Ladner U, Seibold J, Silver RM, Takehara K, Toth BG, Tyndall A,\u000d\u000a      Valentini G, van den Hoogen F, Wigley F, Zulian F, Matucci- Cerinic M;\u000d\u000a      EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic\u000d\u000a        sclerosis: a report from the EULAR Scleroderma Trials and Research group\u000d\u000a        (EUSTAR). Ann Rheum Dis. 2009 May;68(5):620-8. http:\/\/dx.doi.org\/10.1136\/ard.2008.096677\u000d\u000a    [e] Actelion annual report 2012 states that 44,000 patients on Tracleer\u000d\u000a      (bosentan) at that time (all PAH) http:\/\/annualreport2012.actelion.com\/en\/ar2012\/business-strategy-and-operations\/our-products.html\u000d\u000a      US registry study reports that 25% of patients with PAH associated with\u000d\u000a      connective tissue diseases: Badesch DB, Raskob GE, Elliott CG, Krichman\u000d\u000a      AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S,\u000d\u000a      Feldkircher K, Miller DP, McGoon MD.Pulmonary arterial hypertension:\u000d\u000a      baseline characteristics from the REVEAL Registry. Chest. 2010\u000d\u000a      Feb;137(2):376-87. http:\/\/dx.doi.org\/10.1378\/chest.09-1140\u000d\u000a    [f] Galia N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A.\u000d\u000a      A meta-analysis of randomized controlled trials in pulmonary arterial\u000d\u000a      hypertension. Eur Heart J. 2009 Feb;30(4):394-403. http:\/\/dx.doi.org\/10.1093\/eurheartj\/ehp022\u000d\u000a    [g] Patient data used to make calculation available from UK National PH\u000d\u000a      audit online at http:\/\/www.hscic.gov.uk\/ph\u000d\u000a    [h] http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Scientific_Discussion_-_Variation\/human\/000401\/WC500041601.pdf\u000d\u000a      See page 3\u000d\u000a    [i] \u000d\u000ahttp:\/\/www.medicines.org.uk\/emc\/medicine\/20423\/SPC\/Tracleer+%28bosentan%29+125mg+film-coated+tablets\u000d\u000a      See section 5.1\u000d\u000a    [j] \u000d\u000a\u0009http:\/\/www.rheumatology.org.uk\/includes\/documents\/cm_docs\/2012\/0\/0945_complications_of_scleroderma_vasculopathy_raynauds_phenomenon_digital_ulcers_and_critical_digital.pdf\u000d\u000a    [k] Actelion 2012 annual report:\u000d\u000ahttp:\/\/annualreport2012.actelion.com\/en\/ar2012\/business-strategy-and-operations\/our-products.html\u000d\u000a    [l] Dhillon S. Bosentan: a review of its use in the management of digital\u000d\u000a      ulcers associated with systemic sclerosis. Drugs. 2009 Oct\u000d\u000a      1;69(14):2005-24. http:\/\/doi.org\/bv65w3\u000d\u000a    [m] Guillevin L, Hunsche E, Denton CP, Krieg T, Schwierin B, Rosenberg D,\u000d\u000a      Matucci-Cerinic M; DUO Registry Group. Functional impairment of systemic\u000d\u000a      scleroderma patients with digital ulcerations: results from the DUO\u000d\u000a      Registry. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):71-80. http:\/\/www.clinexprheumatol.org\/pubmed\/find-pii.asp?pii=23910613\u000d\u000a    ","Title":"\u000d\u000a    Targeting endothelin in systemic sclerosis — improved survival in\u000d\u000a      pulmonary arterial hypertension (PAH) in systemic sclerosis and licensing\u000d\u000a      of the first drug specifically for digital ulcers in systemic sclerosis\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Research conducted by the Centre for Rheumatology & Connective Tissue\u000d\u000a      Disease, UCL Division of Medicine, has underpinned the development of\u000d\u000a      endothelin receptor antagonists (ERA) as treatment for systemic sclerosis\u000d\u000a      (SSc). In 1993 we made the key observation that endothelin-1 (ET-1) in the\u000d\u000a      plasma was increased in SSc. Over the following years we published a\u000d\u000a      number of seminal papers in the field that delineated the association\u000d\u000a      between ET-1 and vasculopathy and fibrosis in SSc [1].\u000d\u000a    As a result of this early work, a number of studies took place in\u000d\u000a      different centres, building on our original observations, and these led to\u000d\u000a      licensing of the first ERA (bosentan) for pulmonary hypertension in\u000d\u000a      connective tissue disease. This was founded upon the observation that\u000d\u000a      pulmonary arterial hypertension (PAH) in SSc was very similar to\u000d\u000a      idiopathic and familial forms of PAH and this led to the inclusion of PAH\u000d\u000a      cases associated with connective tissue disease, especially SSc, in trials\u000d\u000a      for licensing purposes. The first study, led from North America, looked at\u000d\u000a      non-scleroderma associated PAH and was so successful that a further\u000d\u000a      clinical trial — BREATHE-1 — was fast-tracked. UCL researchers played an\u000d\u000a      instrumental role in this study. Leading on from this, we undertook a\u000d\u000a      sub-group analysis of both trials, which showed that the scleroderma\u000d\u000a      patients had responded as well as others to the treatments — an\u000d\u000a      observation which provided an impetus to develop these therapies for\u000d\u000a      scleroderma patients [2]. Following licensing of the drugs, we\u000d\u000a      were the first to show that this treatment improved survival [3].\u000d\u000a    The second phase of research in this area refined and extended our early\u000d\u000a      work, demonstrating the class effect of several drugs, and defining the\u000d\u000a      differences between them. Our patients with PAH have been enrolled into\u000d\u000a      major studies of bosentan and other ERAs (e.g. ambrisentan, sitaxentan)\u000d\u000a      and we have explored differences between these agents in ways that would\u000d\u000a      not be possible in commercial trials. We have led the largest recent study\u000d\u000a      of SSc-PAH that explored long-term benefit of bosentan on quality of life\u000d\u000a      [4]. We defined mortality benefit of ERA therapy using data from\u000d\u000a      our cohort and also developed new and better assessment for PAH including\u000d\u000a      the first study of the biomarker NT-pro-BNP in PAH-SSc that included\u000d\u000a      robust haemodynamics and longitudinal sampling [5].\u000d\u000a    Our centre has led on research to extend the use of bosentan for digital\u000d\u000a      ulcer disease, another complication of SSc for which there were previously\u000d\u000a      no treatments available, or scientific rationale for treatments. Our\u000d\u000a      observation that patients taking part in clinical trials seemed to have\u000d\u000a      fewer digital ulcers led to a pivotal trial (RAPIDS-1) being set up, which\u000d\u000a      we led [6]. Along with a further trial (RAPIDS-2), to which we\u000d\u000a      made a significant contribution, this led to the licensing of bosentan for\u000d\u000a      digital ulcers — the first ever drug for the condition, and in fact the\u000d\u000a      first ever specific therapy for SSc.\u000d\u000a    We have provided academic leadership to the Digital Ulcers Outcome (DUO)\u000d\u000a      register of cases recruited across Europe with digital ulcer disease in\u000d\u000a      SSc and this is providing a unique resource for academic study of this\u000d\u000a      important complication that contributes major morbidity. A positive\u000d\u000a      outcome of this work has been better care for digital ulcers in SSc and\u000d\u000a      harmonisation of good practice across many major centres in Europe.\u000d\u000a    "},{"CaseStudyId":"21063","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000a    Patient Benefits\u000a    The research at Newcastle has had a significant impact on the health and\u000a      welfare of patients with MND, and the randomised controlled trial (RCT)\u000a      has led to changes in clinical guidelines and clinical practice. The work\u000a      has provided one of only two evidence-based treatments for patients with\u000a      MND in recent decades, with Riluzole being the other. However, Riluzole\u000a      offers only a modest survival benefit, with no improvement in symptom\u000a      control. As testified by an Associate Professor at the Respiratory\u000a      Institute of the Cleveland Clinic, Ohio, the Newcastle studies `...have\u000a        shown that the magnitude of the survival impact of noninvasive\u000a        ventilation exceeds that of pharmacologic intervention (with riluzole),\u000a        such that future trials have to factor in the survival benefit of NIPPV\u000a      [non-invasive positive pressure ventilation]' [EV a].\u000a    The Newcastle RCT was considered Class 1 research when reviewed within\u000a      guidelines on the treatment of patients with MND, produced by both the\u000a      American Academy of Neurology [EV b] and the European Federation of\u000a      Neurological Societies [EV c], and it was the only RCT selected as\u000a      fulfilling the rigorous criteria for entry into a Cochrane review of the\u000a      subject of mechanical ventilation for MND patients [EV d]. The research\u000a      clearly demonstrated the survival benefit offered by non-invasive\u000a      ventilation to those patients with good bulbar function compared to\u000a      standard non-ventilatory treatment. It also demonstrated a significant and\u000a      sustained improvement of quality of life for patients treated by\u000a      non-invasive ventilation. Respiratory muscle weakness causes\u000a      hypoventilation and sleep disruption and, as a consequence, patients with\u000a      MND often suffer from morning headaches, lethargy, fatigue, poor\u000a      concentration, and poor appetite [EV e]. Non-invasive ventilation can\u000a      significantly reduce these symptoms, such that the longer survival of MND\u000a      patients given non-invasive ventilation is accompanied by improved\u000a      symptoms. Since non-invasive ventilation is provided through a portable\u000a      ventilator, patients are treated in their own homes [EV e] with support\u000a      from specialist home ventilation services, which are available in the UK\u000a      and elsewhere.\u000a    The potential benefits of non-invasive ventilation are recognised by the\u000a      MND Association, who quoted the Newcastle-based research in a press\u000a      release [EV e] ahead of a Westminster Hall debate in 2009 on the\u000a      availability of non-invasive ventilation to people with MND. The RCT [R4,\u000a      section 2] was directly referred to during the debate [EV f].\u000a      Specifically, it was stated that: `Clinical research published in 2006\u000a        showed that non-invasive ventilation typically increased the median\u000a        survival period for people with motor neurone disease by seven months'\u000a      and `...the typical survival period is 14 months, so seven months would\u000a        be a material change in someone's survival, and a major change in their\u000a        quality of life and that of their carers' [EV f].\u000a    Clinical Practice\u000a    The Newcastle led survey carried out in 2009 found that the number of MND\u000a      patients referred for non-invasive ventilation within the UK had increased\u000a      2.6-fold compared to the number of referrals in 2000 (from 234 to 612),\u000a      and the number of patients successfully established on non-invasive\u000a      ventilation had increased 3.4-fold (from 126 to 444) [R5, section 3].\u000a      Since the incidence of MND has remained stable over that time, these\u000a      figures indicate that there has been a substantial change in clinical\u000a      practice and an improvement in the referrals process [R5, section 3]. In\u000a      addition, the access to non-invasive ventilation services by neurologists\u000a      has improved, as 10.1% reported no service available in 2000 compared with\u000a      only 1% in 2009 [R5, section 3]. In 2010, NICE published guidelines on the\u000a      use of NIV in the management of MND, with Dr Bourke on the guideline\u000a      development group [EV g]. Within the UK, the wider implementation of these\u000a      guidelines continues to increase the use of non-invasive ventilation for\u000a      MND and addresses any current variations in clinical practice. This is\u000a      evidenced by two surveys carried out by the MND Association on patients\u000a      living with MND in England, Wales and Northern Ireland. Data from patient\u000a      questionnaires showed that NIV use by MND patients has increased from\u000a      13.2% (62 out of 469 patients) in 2009 to 24.6% (192 out of 779 patients)\u000a      in 2013 [EV h].\u000a    The clinical impact of this research is clearly evident beyond the UK;\u000a      the use of non-invasive ventilation in patients with MND has expanded in\u000a      the US, Australia and across Europe, where clinical guidelines now include\u000a      evidence-based recommendations for its use. As identified by the clinical\u000a      and academic director of the national referral centre for chronic\u000a      respiratory failure and home ventilation at St Thomas' hospital `...the\u000a        trial by Bourke et al has driven forward the use of non-invasive\u000a        ventilation in both the European and North American Centres' [EV i].\u000a    The American Academy of Neurology cite the work by the Newcastle\u000a      group in the opening paragraph of their 2009 Practice Parameter update (an\u000a      influential US clinical practice guideline), stating that since the\u000a      publication of the previous guidelines `...there have been some\u000a        important new studies, including a randomized controlled trial of\u000a        non-invasive ventilation in ALS.2' (where `2'\u000a      refers to R4 in Section 3) [EV b].\u000a    The RCT also has an important position in the European Federation of\u000a        Neurological Societies 2012 guidelines for the diagnosis and\u000a        management of ALS [EV c], in which NIV is advised for the management\u000a      of respiratory dysfunction in all MND (ALS) patients with good bulbar\u000a      function [EV c, p.371]. The following quote and recommendation are taken\u000a      directly from the guidelines (in which `[140]' refers to R4 in\u000a      section 2): `Non-invasive positive-pressure ventilation increases\u000a        survival and improves patients' quality of life and is the preferred\u000a        therapy to alleviate symptoms of respiratory insufficiency [47, 49,\u000a        137-142] (of which [140] is Class I)' [EV c, p.372]. Further, it is\u000a      stated in the recommendations that `NIPPV [non-invasive\u000a        positive-pressure ventilation] can prolong survival for many months' and\u000a        `...may improve the patient's quality of life' [EV c, p.372].\u000a    In addition, guidelines published in 2010 by the New South Wales\u000a        Agency for Clinical Innovation highlight that \"...the role of NIV\u000a        remained unclear until a randomised controlled study by Bourke et al\u000a        [139]\" (where [139] refers to the RCT) and that `...nocturnal\u000a        ventilation is used in patients with motor neurone disease to improve\u000a        symptoms and quality of life', (again citing R4, section 3) [EV j,\u000a      p.39-40]. The objective of these guidelines is to provide information to\u000a      optimise the management of individuals with disorders likely to lead to\u000a      the development of chronic respiratory failure and aims to assist\u000a      clinicians in informed decision-making [EV j].\u000a    ","ImpactSummary":"\u000a    Motor neuron disease (MND) is a devastating and debilitating disease with\u000a      poor prognosis; most patients die from progressive respiratory failure\u000a      within three years of onset. A randomised controlled trial conducted in\u000a      Newcastle provided robust evidence that non-invasive ventilation for\u000a      patients with MND can significantly improve quality of life and increase\u000a      survival (216 days with non-invasive ventilation compared to 11 days\u000a      without). Findings from this trial underpinned recommendations concerning\u000a      the use of non-invasive ventilation in MND in clinical guidelines\u000a      internationally, and use in clinical practice has increased in the UK,\u000a      across Europe, and in the US and Australasia. In the UK, the number of MND\u000a      patients successfully established on non-invasive ventilation in 2009 had\u000a      increased 3.4-fold since 2000 and since 2009 has further increased almost\u000a      two-fold.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5165418","Name":"Ohio"},{"GeoNamesId":"2155400","Name":"State of New South Wales"}],"References":"\u000a\u0009\u000a\u0009(Newcastle researchers in bold.\u000a      Citation count from Scopus, July 2013)\u000a    \u000aR1. Bourke SC, Shaw PJ, Gibson GJ. Respiratory function\u000a      vs. sleep-disordered breathing as predictors of QOL in ALS. Neurology\u000a      2001; 57:2040-4. DOI:10.1212\/WNL.57.11.2040. Cited by 67.\u000a    \u000a\u000aR2. Bourke SC, Williams TL, Bullock RE, Gibson\u000a        GJ, Shaw PJ. Non-invasive ventilation in motor neuron disease:\u000a      current UK practice. Amyotrophic Lateral Sclerosis and Other Motor Neuron\u000a      Disorders 2002; 3:145-149. DOI:10.1080\/146608202760834157. Cited by\u000a        21.\u000a    \u000a\u000aR3. Bourke SC, Bullock RE, Williams TL, Shaw PJ,\u000a      Gibson GJ. Non-invasive ventilation in ALS: indications and effects\u000a      on quality of life. Neurology 2003; 61:171-7. DOI:\u000a      10.1212\/01.WNL.0000076182.13137.38. Cited by 136.\u000a    \u000a\u000aR4. Bourke SC, Tomlinson M, Williams TL, Bullock\u000a        RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation\u000a      on survival and quality of life in patients with amyotrophic lateral\u000a      sclerosis: a randomised controlled trial. Lancet Neurology 2006; 5:140-7.\u000a      DOI: org\/10.1016\/S1474-4422(05)70326-4. Cited by 209.\u000a    \u000a\u000aR5. O'Neill CL, Williams TL, Peel ET, McDermott CJ, Shaw PJ, Gibson\u000a        GJ, Bourke SC. Non-invasive ventilation in motor neurone\u000a      disease: an update of current UK practice. Journal of Neurology,\u000a      Neurosurgery and Psychiatry 2012; 83:371-376. DOI:\u000a      10.1136\/jnnp-2011-300480. Cited by 10.\u000a    \u000aSelected funding awards\u000a    \u000a      1999-2000 Sleep disordered breathing & the impact of nocturnal\u000a        ventilatory support & quality of life in motor neurone disease — a\u000a        pilot study. The Newcastle upon Tyne Hospitals NHS Charities — £41,387\u000a      2000-2002 Sleep Disordered Breathing and the Impact of Nocturnal\u000a        Non-Invasive Ventilatory Support on Quality of Life in Motor Neurone\u000a        Disease. NHS Executive — Northern & Yorkshire — £82,480\u000a    \u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    EV a. Testimonial: Associate Professor of Medicine, Cleveland Clinic,\u000a      Ohio, USA. (Held at Newcastle, available on request)\u000a    EV b. Miller RG et al. Practice parameter update: the care of the patient\u000a      with amyotrophic lateral sclerosis: drug, nutritional, and respiratory\u000a      therapies (an evidence-based review): report of the Quality Standards\u000a      Subcommittee of the American Academy of Neurology. Neurology 2009;\u000a      73:1218-26. DOI: 10.1212\/WNL.0b013e3181bc0141\u000a    EV c. EFNS guidelines on the clinical management of amyotrophic lateral\u000a      sclerosis (MALS) — revised report of an EFNS task force. European Journal\u000a      of Neurology 2012;19:360-75. DOI:10.1111\/j.1468-1331.2011.03501.x\u000a    EV d. Radunovic, A et al. Mechanical ventilation for amyotrophic lateral\u000a      sclerosis\/motor neuron disease (Review).The Cochrane Collaboration, 2009;\u000a      4:CD004427. DOI: 10.1002\/14651858.CD004427.pub2\u000a    EV e. http:\/\/centrallobby.politicshome.com\/members\/member-press\/member-press-details\/newsarticle\/the-benefits-of-non-invasive-ventilation-systems-1\/\/\/sites\/motor-neurone-disease-association\/\u000a    EV f.\u000a        http:\/\/www.publications.parliament.uk\/pa\/cm200809\/cmhansrd\/cm090331\/halltext\/90331h0\u000a        001.htm\u000a    EV g. National Institute for Health and Clinical Excellence. Motor\u000a      neurone disease — the use of non-invasive ventilation in the management of\u000a      motor neurone disease, 2010. www.nice.org.uk\/cg105\u000a    EV h. Motor Neurone Disease Association: Tracking Surveys, 2009 and 2013\u000a      (July). (Copies held and available on request. Contact: Director of Care\u000a      (South), MND Association)\u000a    EV i. Testimonial: Clinical & Academic Director, Lane Fox Respiratory\u000a      Unit, St Thomas' Hospital; National referral centre for chronic\u000a      respiratory failure\/home ventilation, UK. (Held at Newcastle, available on\u000a      request).\u000a    EV j. ACI, NSW Agency for Clinical Innovation. Domiciliary non-invasive\u000a      ventilation in adult patients — a consensus statement.\u000a        http:\/\/www.aci.health.nsw.gov.au\/search-results?mode=results&queries_keyword_query=non+invasive&x=0&y=0\u000a        \u000a    ","Title":"\u000a    Use of non-invasive ventilation to improve survival and quality of life\u000a      in patients with motor neuron disease\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle researchers\u000a      (Where people left\/joined the University in the period 1993-2013, years\u000a      are given in brackets)\u000a    SC Bourke (1999-2002 & 2005 onwards), Clinical Research Associate\u000a      1999-2002, Honorary Clinical Lecturer 2005-2010, then Associate Clinical\u000a      Lecturer; GJ Gibson, Honorary Professor 1990-2000, Professor of\u000a      Respiratory Medicine 2000-2009, then Emeritus Professor, TL Williams (2001\u000a      onwards), Clinical Lecturer\/Senior Lecturer; RE Bullock, Clinical\u000a      Lecturer.\u000a    Background\u000a    Motor neuron disease (MND), is one of the most prevalent\u000a      neurodegenerative diseases of adulthood, with amyotrophic lateral\u000a      sclerosis (ALS) being the most common form of MND. The International\u000a      Alliance of ALS\/MND Associations reports that around 120,000 people are\u000a      diagnosed worldwide with MND each year. In the UK, two in 100,000 people\u000a      are diagnosed with MND annually, and seven out of every 100,000 people\u000a      currently live with MND in the UK, equating to around 4,300 people. It is\u000a      a devastating and debilitating disease with a poor prognosis. Progressive\u000a      weakness of muscles, including those of the limbs, trunk, mouth and\u000a      respiratory system, and eventual death of the muscle cells results in\u000a      disability; and ultimately most patients die from respiratory failure\u000a      within three years of onset. There is currently no cure for MND, and\u000a      treatment aims only to alleviate suffering and compensate for the\u000a      progressive loss of bodily functions, including swallowing and breathing.\u000a      The only drug available for treatment of MND is Riluzole, which offers a\u000a      modest mean survival benefit of 2-3 months, with no improvement in symptom\u000a      control.\u000a    Research\u000a    Respiratory muscle weakness affects most MND patients, causing\u000a      breathlessness and sleep disruption [R1]. Newcastle research identified\u000a      this as a strong independent predictor of quality of life in MND patients.\u000a      Non-invasive ventilation assists breathing via a fitted face-mask through\u000a      which air is pushed into the trachea of the patient, which in turn means\u000a      that tracheostomies (surgical opening of the windpipe and insertion of a\u000a      tube to facilitate breathing) can be avoided. The research, performed by\u000a      Dr Stephen Bourke and Professor John Gibson in collaboration with\u000a      colleagues in neurosciences (Professor Pamela Shaw at Sheffield and Dr\u000a      Timothy Williams) and anaesthesia (Dr Robert Bullock) focused on the\u000a      long-term use of non-invasive ventilation in MND. While previous\u000a      nonrandomised studies had suggested that NIV may improve survival and\u000a      symptom control in patients with MND, these studies were on selected\u000a      populations and\/or did not account for clinical factors such as bulbar\u000a      function (controls swallowing, breathing and speech), which is known to\u000a      affect tolerance of non-invasive ventilation, and independently influences\u000a      survival in patients with MND. Thus, it remained unclear whether\u000a      non-invasive ventilation per se improved patient survival, or if\u000a      this was due to pre-existing favourable prognostic features. It was also\u000a      not clear if non-invasive ventilation improved patients' quality of life\u000a      [R1].\u000a    In 2000, the Newcastle team carried out the first nationwide survey of UK\u000a      practice on the use of non-invasive ventilation in MND [R2].\u000a      Questionnaires were sent to all practising neurologists in the UK, which\u000a      revealed that only 5.5% of MND patients under review at that time were\u000a      receiving gnon-invasive ventilation [R2]. Subsequently, 22 patients were\u000a      included in a non-randomised pilot study, which compared different\u000a      criteria (including symptoms, lung function, and indices of sleep\u000a      disordered breathing) for the initiation of non-invasive ventilation [R3].\u000a      This study showed significant improvements in patient mental health,\u000a      quality of life and sleep. It was also reported that orthopnoea\u000a      (breathlessness when lying flat) was the best predictor of quality of life\u000a      benefits [R3].\u000a    In the subsequent, and first, randomised controlled trial (RCT) to assess\u000a      the effect of non-invasive ventilation on survival and quality of life in\u000a      MND, 41 patients (studied between September 2000 and December 2004) were\u000a      randomly assigned either to receive non-invasive ventilation or to\u000a      continue without ventilatory support. Overall, 85% of the patients were\u000a      also receiving riluzole. Initially, patients were monitored closely at\u000a      regular intervals and were only randomly assigned to a study group when\u000a      they met one or both of the following criteria: (1) breathlessness lying\u000a      flat with maximum respiratory pressure (a measurement of muscle strength)\u000a      less than 60% of that predicted, and (2) suffering from hypercapnia\u000a      (abnormally high carbon dioxide in the blood due to inadequate breathing)\u000a      [R4]. Randomisation of patients was performed by a computer programme that\u000a      included all relevant prognostic factors in its model, e.g. rate of\u000a      disease progression and bulbar function, in order to ensure that these\u000a      were similar in the two groups. The findings showed significantly better\u000a      patient mental health, quality of life and sleep in those treated with\u000a      NIV, compared to patients that weren't treated with NIV. In addition, for\u000a      those patients with good bulbar function, median survival was 216 days\u000a      (once established on non-invasive ventilation), compared to only 11 days\u000a      in patients treated without ventilatory support [R4].\u000a    A follow up UK survey carried out in 2009 to assess any changes in\u000a      respiratory care of MND patients following the trial showed a 3.4-fold\u000a      increase in the proportion being treated with NIV [R5].\u000a    "},{"CaseStudyId":"21067","Continent":[],"Country":[],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d    Surveying current practice in the UK\u000d    To determine the extent of clinical adoption in the UK of UVB and\u000d      azathioprine on treatment of adult patients with refractory\u000d      moderate-to-severe atopic eczema outwith an acute flare, a survey of\u000d      current clinical practice was conducted. This was done in June 2013 by\u000d      Newcastle University researchers, through the UK Translational Research\u000d      Network in Dermatology and the UK Dermatology Clinical Trials Network (Ev\u000d      a). The design and implementation of the survey instrument was validated\u000d      by an independent consultant. The 61 completed responses from 310\u000d      consultant dermatologists surveyed were in line with expectations for this\u000d      type of research. Survey outcomes are discussed below for each of the\u000d      treatments and should be seen in the context of the estimated number of\u000d      new adult referrals in the UK per year. Responses from the consultant\u000d      dermatologists surveyed revealed an estimated 28,400 new referrals for\u000d      refractory moderate-to-severe atopic eczema in adults per year across the\u000d      UK.\u000d    Narrowband UVB in guidelines and clinical practice\u000d    In 2012 a number of European dermatology societies, including the\u000d      European Academy of Dermatology and Venereology, European Task Force on\u000d      Atopic Dermatitis and European Society of Pediatric Dermatology, published\u000d      a consensus set of guidelines on treatment of atopic eczema. On UV\u000d      phototherapy they state:\u000d    `There is evidence that UV-therapy can be used in AE [atopic\u000d      eczema] to relieve pruritus [itch]. Narrowband UVB seems to be\u000d        most preferable' (Ev b)... `Narrow-band UVB was more\u000d        effective than UVA' (Ev b).\u000d    That recommendation cites and is largely based on Farr and Reynolds' 2001\u000d      trial results (R2): it is the only randomised controlled trial cited in\u000d      support, and Reynolds' was a significantly larger study than the other two\u000d      half-body comparison studies (which also reported later).\u000d    The results of the 2013 Newcastle run survey of UK practice indicated\u000d      that phototherapy (using any one of a number of wavelengths of ultraviolet\u000d      radiation) was the most popular first-line treatment option for\u000d      moderate-to-severe refractory atopic eczema that was not controlled by\u000d      topical treatment. Phototherapy was chosen by just under half (46%) of\u000d      respondents, probably reflecting the widespread availability of\u000d      phototherapy units. Of those considering this approach, over 93% selected\u000d      narrowband UVB as their first choice, indicating that UVB phototherapy\u000d      (trialled by Newcastle) has been widely adopted across the UK as a\u000d      treatment for refractory atopic eczema. Based on the reported numbers of\u000d      patients treated by the consultant dermatologists in the survey, it is\u000d      estimated that about 8,200 patients are treated with or referred for\u000d      narrowband UVB phototherapy each year in the UK.\u000d    Azathioprine in guidelines and clinical practice\u000d    The British National Formulary (BNF) is a standard resource for UK\u000d      clinicians, aiding decisions on which drug to use when treating a\u000d      particular disease. A full entry on azathioprine first appeared in the\u000d      skin section of the Formulary in edition 59, March 2010 (Ev\u000d      c). It states that azathioprine should be considered for severe refractory\u000d      eczema, and there is accompanying dosing guidance based on the thiopurine\u000d      methyl transferase (TPMT) activity of individuals, as first used by\u000d      Newcastle researchers. TPMT is an enzyme present in humans that\u000d      metabolises azathioprine and similar drugs. Genetic variation in the\u000d      population means that the drug is broken down at different rates by\u000d      different individuals. Patients with no TPMT activity should not receive\u000d      the drug. The dosing guidance of 1-3mg\/kg\/day for normal or high TPMT\u000d      activity, 0.5-1mg\/kg\/day for low TPMT activity reflects the doses used in\u000d      the Newcastle University-led trial (R3). A British National Formulary\u000d      clinical writer has stated,\u000d    `I can confirm that the paper by Meggitt SJ, et al .... Lancet 2006)\u000d        was used, among others, to inform this content change [the BNF entry\u000d      on azathioprine for atopic eczema]' (Ev c).\u000d    In 2011 the British Association of Dermatologists published guidelines on\u000d      the safe and effective prescription of azathioprine for a variety of\u000d      dermatological conditions. On use of the drug for atopic eczema, the\u000d      guidelines state:\u000d    `Although azathioprine is not licensed for use in atopic eczema, there\u000d        is now strong evidence (from two RCTs) for a statistically significant\u000d        and clinically meaningful response to azathioprine. Both studies used\u000d        the drug as oral monotherapy in moderate-to-severe, refractory disease.'\u000d      (Ev d)\u000d    The Newcastle University trial (R3) was the larger of the two studies\u000d      referred to and was the only one to employ dosing based on the TPMT\u000d      activity of patients. The guidelines specifically highlight the importance\u000d      of TPMT assessment in the clinic for avoiding drug toxicity. This trial\u000d      was also cited as significant underpinning evidence in an influential 2011\u000d      systematic review of several studies in which azathioprine had been used\u000d      off-label for treatment of skin diseases. The review contains a `strong\u000a        clinical recommendation ... for azathioprine in atopic dermatitis'\u000d      on the basis of high-quality level A evidence (Ev e).\u000d    The Newcastle run 2013 survey of UK dermatologists (Ev a) indicated that\u000d      azathioprine has been widely adopted in the UK as a treatment of\u000d      moderate-to-severe refractory atopic eczema. Systemic therapy was the most\u000d      popular second-line treatment option chosen by 49% of respondents, and it\u000d      was also the second most popular first-line treatment option, chosen by\u000d      36% of respondents. Of those considering systemic therapy, azathioprine\u000d      was the most popular first-line choice of drug (46% of respondents). There\u000d      is evidence that because of its better safety profile than ciclosporin,\u000d      azathioprine is facilitating longer-term control of symptoms (for example\u000d      suppression of itching) in patients. Thus, the median length of\u000d      azathioprine treatment reported in the survey was 13 - 24 months compared\u000d      with three to six months for ciclosporin — the next most commonly used\u000d      drug. Almost 95% of respondents agreed\/strongly agreed that TPMT level at\u000d      baseline should guide the choice of initial dose, a dosing strategy\u000d      pioneered by Newcastle. Based on the reported numbers of patients treated\u000d      by the consultant dermatologists in the survey, it can be estimated that\u000d      about 4,470 patients begin treatment with azathioprine each year in the\u000d      UK.\u000d    Beyond the UK, the 2012 European guidelines on treatment of atopic eczema\u000d      recommend that azathioprine be considered for moderate-to-severe disease.\u000d      They state (citing R3 as supporting evidence):\u000d    `Azathioprine may be used (off label) in AE [atopic eczema]\u000d        patients, if ciclosporin is either not effective or contraindicated.\u000d        Patients should be screened for TPMT activity before starting\u000d        azathioprine therapy to reduce the risk for bone marrow toxicity by dose\u000d        adaptation. The suggested dose range is 1-3 mg2044 kg bw 2044 day.' (Ev\u000d        f)\u000d    There is little data on the extent of use of azathioprine in the adult\u000d      patient population across Europe, but a recently published survey of\u000d      paediatric dermatologists across the continent found that the drug was\u000d      prescribed as a first-line treatment in a fifth of cases of severe eczema\u000d      in children (Ev g).\u000d    ","ImpactSummary":"\u000d    Atopic eczema is a disabling long-term skin condition affecting ~2% of\u000d      the UK adult population. The mainstay of treatment remains topical\u000d      steroids and moisturisers, but many adult patients with atopic eczema have\u000d      resistant disease that can significantly impair quality of life. Newcastle\u000d      University researchers conducted clinical trials that showed both\u000d      whole-body ultraviolet B phototherapy and systemic (tablet) treatment with\u000d      the immunosuppressant drug azathioprine were effective treatments for\u000d      adults with atopic eczema resistant to standard topical treatments. UK and\u000d      European guidelines written after 2008 recommend UVB phototherapy and\u000d      azathioprine for atopic eczema, and survey data indicate that both are now\u000d      widely used to treat the disease in the UK.\u000d    ","ImpactType":"Health","Institution":"\u000d    Newcastle University\u000d    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000d    (Newcastle authors in bold. Citations from Scopus, July 2013.)\u000d    \u000aR1. Hudson-Peacock MJ, Diffey BL & Farr PM (1996).\u000d      Narrow-band UVB phototherapy for severe atopic dermatitis. British\u000d        Journal of Dermatology 135(2):332. DOI:\u000d      10.1111\/j.1365-2133.1996.tb01179.x 27 citations.\u000d    \u000a\u000aR2. Reynolds NJ, Franklin V, Gray JC, Diffey BL & Farr PM\u000d      (2001). Narrow-band ultraviolet B and broad-band ultraviolet A\u000d      phototherapy in adult atopic eczema: a randomised controlled trial. The\u000a        Lancet 357(9273):2012-2016. DOI: 10.1016\/S0140-6736(00)05114-X.\u000d      113 citations.\u000d    \u000a\u000aR3. Meggitt SJ, Gray JC & Reynolds NJ (2006).\u000d      Azathioprine dosed by thiopurine methyltransferase activity for\u000d      moderate-to-severe atopic eczema: a double-blind, randomised controlled\u000d      trial. The Lancet 367(9513):839-846. DOI: 10.1016\/S0140-6736(06)68340-2.\u000d      81 citations.\u000d    \u000aKey funding\u000d    NHS Research and Development, Northern and Yorkshire, UK.1994-7. £28,153.\u000d      Ultraviolet light (UV) therapy for atopic dermatitis: double blind,\u000d        randomized trial of narrow band UVB (TLO1) versus UVA versus placebo.\u000d    British Skin Foundation. Clinical Research Fellowship to Dr Meggitt.\u000d      2000-1. £40,372. Randomised double blind controlled trial of\u000d        azathioprine in moderate-to-severe atopic eczema.\u000d    In 2007, Dr Meggitt was awarded the British Skin Foundation prize for the\u000d      best British Skin Foundation funded research conducted in the previous 10\u000d      years.\u000d    Wellcome Trust. Funding for Professor Reynolds and Dr Meggitt. 2001-4.\u000d      £462,884. Regulation of the calcineurin\/NFAT pathway in human\u000d        keratinocytes and inflammatory skin disease\u000d    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d    Ev a. Survey of UK dermatologists that were members of the UK\u000d      Translational Research Network in Dermatology or the UK Dermatology\u000d      Clinical Trials Network (June 2013).\u000d    Ev b. Journal of the European Academy of Dermatology and Venereology\u000d      (2012): Guidelines for treatment of atopic eczema (atopic dermatitis) -\u000d      Part I. DOI: http:\/\/dx.doi.org\/10.1111\/j.1468-3083.2012.04635.x\".\u000d      (Quotation from page 1053, column 2.)\u000d    Ev c. Statement from a science writer at the British National Formulary.\u000d    Ev d. British Journal of Dermatology (2011): British Association of\u000d      Dermatologists' guidelines for the safe and effective prescribing of\u000d      azathioprine. \u000dhttp:\/\/www.bad.org.uk\/Portals\/_Bad\/Guidelines\/Clinical%20Guidelines\/Azathioprine%20guidelines%202011.pdf.\u000d      (Quotation from page 714, column 2.)\u000d    Ev e. Schram ME, Borgonjen RJ, Bik CM, van der Schroeff JG, van\u000d      Everdingen JJ, & Spuls PI (2011). Off-label use of azathioprine in\u000d      dermatology: a systematic review. Archives of dermatology 147(4):\u000d      474-88. DOI: http:\/\/dx.doi.org\/10.1001\/archdermatol.2011.79.\u000d      (Quotation from page 474, column 2.)\u000d    Ev f. Journal of the European Academy of Dermatology and Venereology\u000d      (2012): Guidelines for treatment of atopic eczema (atopic dermatitis) —\u000d      Part II. DOI: \u000d        href=\"http:\/\/dx.doi.org\/10.1111\/j.1468-3083.2012.04636.x\".\u000d      (Quotation from page 1180, column 1.)\u000d    Ev g. Proudfoot LE, Powell AM, Ayis\u000a        S, Barbarot\u000a        S, Baselgatorres\u000a        E, Søndergaard\u000a        Deleuran M, Fölster-Holst\u000a        R, Gelmetti\u000a        C, Hernández-Martin\u000a        A, Middelkamp-Hup\u000a        MA, Oranje\u000a        AP, Patrizi\u000a        A, Rovatti\u000a        G, Schofield\u000a        O, Spuls\u000a        P, Svensson\u000a        A, Vestergaard\u000a        C, Wahlgren\u000a        CF, Schmitt\u000a        J, C;\u000d      The\u000a        European Dermato-Epidemiology Network (EDEN). The European treatment\u000d      of severe atopic eczema in children taskforce (TREAT) survey. Br J\u000d      Dermatol. (2013) doi: http:\/\/dx.doi.org\/10.1111\/bjd.12505\u000d    \u000d    ","Title":"\u000d    Increased range and adoption of evidence-based treatments for refractory\u000d      moderate-to-severe atopic eczema\u000d    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    Key Newcastle University researchers\u000d    The research was conceived and carried out by Professor Nick Reynolds (as\u000d      Clinical Senior Lecturer and Professor from 2001); Dr Simon Meggitt\u000d      (Honorary Clinical Lecturer and from 2005 Senior Clinical Fellow); and\u000d      Professor Peter Farr, who at the time of the research was an Honorary\u000d      Clinical Lecturer in the Department of Dermatology.\u000d    Background\u000d    Although often considered a disease of childhood, around 2% of adults in\u000d      the UK have atopic eczema (dermatitis) (Herd et al 1996 PMID:8776352),\u000d      representing over a third of all patients with the condition (Sandström\u000d      Falk & Faergemann 2006 PMID:16648916). While many adult patients\u000d      respond to treatment with topical steroids and moisturisers, a significant\u000d      percentage have refractory disease although the prevalence of refractory\u000d      moderate-to-severe atopic eczema in the UK has not been defined. In\u000d      adults, refractory moderate-to-severe atopic eczema usually runs a\u000d      prolonged and protracted course (Barker et al 2006 PMID:16990802) and is\u000d      characterised by skin barrier dysfunction and chronic inflammation,\u000d      typically affecting over 40% of the body surface area (R2, R3). The\u000d      itching, associated loss of sleep and skin infections that accompany\u000d      moderate-to-severe disease significantly impair quality of life.\u000d    Adults with moderate-to-severe atopic eczema refractory to topical\u000d      treatments (including calcinuerin inhibitors) may be considered for\u000d      phototherapy or systemic drug treatments. Currently ciclosporin is the\u000d      only oral drug with a product licence for refractory atopic eczema. It\u000d      should be used only for a limited period (the British National Formulary\u000d      recommends two months maximum) because prolonged use is associated with\u000d      hypertension, renal impairment and risk of cancer. However, symptoms recur\u000d      within weeks when ciclosporin is discontinued.\u000d    In 2000 an independent systematic review (Hoare et al. 2000\u000d      PMID:11134919) highlighted the lack of therapeutic options for patients\u000d      with refractory atopic eczema and underscored the need for scientifically\u000d      robust testing of a range of treatments for the disease.\u000d    Newcastle research\u000d    Researchers in Newcastle University sought to address the issues\u000d      highlighted by Hoare et al. and conducted trials of two distinct\u000d      therapeutic approaches.\u000d    Ultraviolet B phototherapy: As narrowband ultraviolet B (UVB) is\u000d      widely used to treat psoriasis, most dermatology units are equipped with\u000d      phototherapy units though its efficacy for treating atopic eczema was\u000d      previously unknown. In 1996, Farr led an open pilot study of narrowband\u000d      UVB phototherapy for moderate-to-severe atopic eczema in adults (R1).\u000a      That small study informed the design, by Farr and Reynolds, of the first\u000d      randomised controlled trial (69 patients) comparing narrowband UVB to\u000d      broadband UVA (as used in commercial sunbeds) and visible-light (placebo)\u000d      for the treatment of refractory moderate-to-severe atopic eczema in\u000d      adults. The results (R2) showed that narrowband UVB was an\u000d      effective, well-tolerated treatment and the benefits were maintained for\u000d      several months after treatment ended. Over the course of 24 treatments,\u000d      mean total disease activity (the sum of clinical scores of five clinical\u000d      signs of eczema at six body sites) reduced by around one-third from\u000d      baseline in UVB-treated patients, which was a statistically significant\u000d      change when compared to placebo. In contrast, the reduction in disease\u000d      activity after UVA treatment was smaller and not significant. The\u000d      effectiveness of narrowband UVB was also reflected by improvements in the\u000d      extent of disease and patient reported symptoms, as 90% of the UVB treated\u000d      patients reported a reduction in itch over the treatment course, compared\u000d      to 11% of the placebo group (R2).\u000d    Azathioprine: Following an open pilot study (the results of which\u000d      were published in a review; Meggitt and Reynolds (2001) PubMed ID:\u000d      11488818), Reynolds and Meggitt designed and led the first parallel-group\u000d      randomised controlled trial of azathioprine for moderate-to-severe atopic\u000d      eczema in adults. This regional multi-centre trial was also the first to\u000d      use pharmacogenetic-based dosimetry for a dermatological condition.\u000d      Patient doses of azathioprine were based on their levels of the enzyme\u000d      thiopurine methyl transferase (TPMT) which reflects their ability to\u000d      metabolise the drug. The results were published in the Lancet in\u000d      2006 (R3). 63 patients participated in the trial, with 42 receiving\u000d      azathioprine. Azathioprine significantly improved disease activity by 37%\u000d      over 12 weeks of treatment compared to a 20% reduction in the placebo\u000d      group. Again, objective improvements in disease activity were matched by\u000d      improvements in body surface area affected, patient-oriented symptoms and\u000d      quality of life scores. For example, itch scores reduced significantly (by\u000d      46%) in patients who received azathioprine compared to those who received\u000d      placebo (R3). TPMT-based dosimetry reduced the dose administered to a\u000d      subset of patients with no loss of efficacy and potential safety benefits\u000d      (R3).\u000d    "},{"CaseStudyId":"21084","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1733045","Name":"Malaysia"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000a    The pGALS (paediatric Gait, Arms, Legs, Spine) examination\u000a    Developed by researchers in Newcastle, pGALS is a quick but sensitive\u000a      screening examination of the musculoskeletal system applicable to the\u000a      school-aged child, taking less than three minutes to perform. The findings\u000a      of the examination need to be considered in the context of a history taken\u000a      at the same time. First, a general assessment looks for joint swelling,\u000a      any physical asymmetry, flexion deformities or rashes. The child is\u000a      observed walking (gait); the arms, legs and spine are then sequentially\u000a      examined through a series of specific movements made by the child and\u000a      physical examination by the clinician. These tests enable rapid and\u000a      accurate assessment of the flexibility and symmetry of joint movements and\u000a      indicate whether or not referral to a specialist is in order.\u000a    Having developed and validated the pGALS examination, Foster and\u000a      colleagues entered into a collaboration with a leading UK charity in order\u000a      to disseminate knowledge about pGALS to practicing clinicians, parents\u000a      and, importantly, to those teaching medical students.\u000a    Collaborations with Arthritis Research UK\u000a    Newcastle researchers collaborated with the UK's leading charity in the\u000a      field, Arthritis Research UK, on the production of teaching aids.\u000a      Both a video of a pGALS examination of a child and a pdf booklet\u000a      describing and illustrating the method were developed. Arthritis\u000a        Research UK's Education Manager has confirmed that in 2013 around\u000a      100 copies of the DVD are requested per month, with 15,600 copies\u000a      distributed in total since it was first made. Web-streaming is also\u000a      popular: with `5,012 unique views in 2012 and 3,764 unique views in\u000a        the first 5 months of 2013' and `pGALS video clips viewed ... on\u000a        YouTube — upwards of 40,000 views since April 2012.' (Ev a)\u000a    Further collaborations have included surveys (in 2009 and 2013) of\u000a      current practice in teaching paediatric musculoskeletal examination. The\u000a      methodology and results of the 2009 survey were reported in R3 and R4. The\u000a      2013 survey was led from Newcastle and the design was validated by an\u000a      independent consultant. Surveys sought the views of lead paediatric\u000a      teachers (paediatric rheumatology consultants and trainees who teach (100%\u000a      response rate) and general paediatric consultants (39% response rate)).\u000a      Additionally, lead adult musculoskeletal teachers were surveyed (62%\u000a      response rate). The survey received responses representing 23 UK medical\u000a      schools (Ev b).\u000a    Impact on medical school teaching\u000a    In 2008, pGALS was introduced as a core clinical skill for paediatric\u000a      musculoskeletal assessment at Newcastle University Medical School (it is\u000a      also taught in Newcastle's NuMed course in Malaysia) and other\u000a      institutions in the UK have followed suit. The impact on teaching beyond\u000a      Newcastle has been significant and approached through two routes;\u000a      awareness raising amongst specialists who teach paediatrics and\u000a      contribution to core medical teaching texts.\u000a    Raised awareness impacts on teaching. The 2009 survey received\u000a      replies from 23 of the 32 UK medical schools (72%) and indicated that only\u000a      six medical schools were teaching pGALS.\u000a    The 2013 survey also received responses from 23 medical schools and\u000a      indicated that pGALS was being taught in 15 medical schools, with all\u000a      using the Arthritis Research UK pGALS DVD or web streaming\u000a      service. Importantly, a significant improvement since 2009 is that 14\u000a      medical schools allowed students to practice pGALS on children and 13\u000a      medical schools gave students the opportunity to examine children with\u000a      musculoskeletal problems.\u000a    Core clinical skills are acquired at medical school. Since pGALS now\u000a      reaches undergraduate students in at least 15 medical schools in the UK,\u000a      this begins to address the problem of clinicians' lack of confidence in\u000a      musculoskeletal examination identified by Newcastle research.\u000a    Raised awareness through textbooks. Foster and Jandial were\u000a      invited in 2008 to contribute a chapter on children's musculoskeletal\u000a      problems, including a description of pGALS, to one of the most popular\u000a      paediatrics student textbooks, `The Illustrated textbook of Paediatrics',\u000a      Lissauer and Clayden (eds). Amazon.co.uk report that this textbook\u000a      is its best seller in paediatrics texts (Ev c). Evidence from a\u000a      number of medical school libraries indicated that this text is also\u000a      generally the most frequently borrowed by students (Ev d).\u000a    The pGALS examination has been described in several other textbooks. `Training\u000a        in Paediatrics: The Essential Curriculum' (2009) Gardiner, Eisen and\u000a      Murphy (eds), `MRCPCH Clinical: Short Cases, History Taking and\u000a        Communication Skills' (2011) Bedwani, Anderson and Beattie, `Rheumatology\u000a        in Primary Care' (2012) Wagh (ed) and the `Pocket Tutor\u000a        Paediatric Clinical Examination' (2012) Brugha, Marlais and\u000a      Abrahamson (eds). In February 2012 Oxford University Press\u000a      requested permission to use photographs of the pGALS examination produced\u000a      by Arthritis Research UK in their `Oxford Specialist Handbooks\u000a        on Paediatric Rheumatology'.\u000a    Impact on paediatrician training\u000a    Foster is Chair of the Royal College of Paediatrics and Child Health\u000a      (RCPCH) College Advisory Committee for higher specialist training in\u000a      paediatric rheumatology in the UK. She was able to use her position to\u000a      lobby the Board of Examiners, backed by the evidence-base provided by the\u000a      Newcastle research, to address the lack of confidence and competence in\u000a      the paediatric musculoskeletal examination skills reported by\u000a      paediatricians in the UK. In 2009, Foster was successful in persuading the\u000a      RCPCH to include paediatric musculoskeletal assessment in the competency\u000a      framework for training and also, most importantly, included in the\u000a      clinical part of the MRCPCH examination (a mandatory examination for all\u000a      paediatricians in the UK) and pGALS was included as a minimum basic skill\u000a      (Ev e). Consequently, all paediatricians trained in the UK are now aware\u000a      of pGALS. Supplementary resources for trainees and examiners have also\u000a      been developed by Foster and Jandial at the request of the RCPCH and are\u000a      available on the RCPCH website (Ev f).\u000a    International impact\u000a    In May 2013 the Intellectual Property coordinator for the American\u000a      Academy of Family Physicians sought copyright permission to use the pGALS\u000a      materials and the Arthritis Research UK Education Manager has\u000a      confirmed that, `Examples of recent requests to reproduce the\u000a        description of how to perform the screening examination [pGALS] include:\u000a        ... \"The Pediatric Clinics of North America\" (Canadian request, November\u000a        2011) [and] \"General Practice at a Glance\" textbook (request\u000a        from Wiley-Blackwell, July 2011).' (Ev a)\u000a    The Director of Paediatrics of a major hospital in Mumbai, India, has\u000a      confirmed the use of pGALS in practice there, stating, `[pGALS] is\u000a        routinely used in clinical practice in our country ... Hands On — a\u000a        document prepared by the authors [Foster and Jandial] and the\u000a        video demonstrating pGALS are popular teaching tools and are routinely\u000a        used by my colleagues and me in our training and teaching sessions.'\u000a      (Ev g). An Emeritus Professor of Pediatric Rheumatology in Canada has also\u000a      noted that pGALS `has filled a significant gap in medical education\u000a        and has been widely adopted world-wide' (Ev h).\u000a    ","ImpactSummary":"\u000a    pGALS (paediatric Gait, Arms, Legs, Spine) is a quick, accurate and\u000a      child-friendly examination technique that identifies children who need to\u000a      be referred to a paediatric rheumatology specialist. pGALS has been widely\u000a      disseminated since 2008 and integrated into both undergraduate medical\u000a      student teaching and the membership examination for the Royal College of\u000a      Paediatrics and Child Health. pGALS was developed by Newcastle researchers\u000a      in response to their findings of a self-reported lack of confidence among\u000a      clinicians when conducting musculoskeletal examinations of children.\u000a      Research also showed that delays and inappropriate investigations were\u000a      being conducted before the child was referred to a specialist. pGALS is\u000a      now taught in at least 15 of the 32 medical schools in the UK and has been\u000a      described in a number of leading textbooks. It is becoming known and used\u000a      worldwide, adapted for local cultural and social contexts.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1275339","Name":"Mumbai"}],"References":"\u000a    \u000aR1. Foster HE, Eltringham MS, Kay LJ, Friswell M, Abinun M, Myers A.\u000a      Delay in access to appropriate care for children presenting with\u000a      musculoskeletal symptoms and ultimately diagnosed with juvenile idiopathic\u000a      arthritis. Arthritis Care and Research 2007, 57(6), 921-927. DOI:\u000a        http:\/\/dx.doi.org\/10.1002\/art.2282. Cited by 19\u000a    \u000a\u000aR2. Myers A, McDonagh JE, Gupta K, Hull R, Barker D, Kay LJ, Foster HE.\u000a      More 'cries from the joints': Assessment of the musculoskeletal system is\u000a      poorly documented in routine paediatric clerking. Rheumatology\u000a      2004, 43(8), 1045-1049. DOI: http:\/\/dx.doi.org\/10.1093\/rheumatology\/keh245.\u000a      Cited by 31\u000a    \u000a\u000aR3. Jandial S, Myers A, Wise E, Foster HE. Doctors Likely to Encounter\u000a      Children with Musculoskeletal Complaints Have Low Confidence in Their\u000a      Clinical Skills. Journal of Pediatrics 2009, 154(2), 267-271. DOI:\u000a      http:\/\/dx.doi.org\/10.1016\/j.jpeds.2008.08.013.\u000a      Cited by 20\u000a    \u000a\u000aR4. Jandial S, Rapley T, Foster H. Current teaching of paediatric\u000a      musculoskeletal medicine within UK medical schools — a need for change. Rheumatology\u000a      2009, 48(5), 587-590. DOI: http:\/\/dx.doi.org\/10.1093\/rheumatology\/kep038.\u000a      Cited by 7\u000a    \u000a\u000aR5. Foster HE, Kay LJ, Friswell M, Coady D, Myers A. Musculoskeletal\u000a      screening examination (pGALS) for school-age children based on the adult\u000a      GALS screen. Arthritis Care and Research 2006, 55(5), 709-716.\u000a      DOI:\u000a        http:\/\/dx.doi.org\/10.1002\/art.22230. Cited by 31\u000a    \u000a\u000aR6. Goff\u000a        I, Bateman\u000a        B, Myers\u000a        A, Foster\u000a        H. Acceptability and practicality of musculoskeletal examination in\u000a      acute general pediatric assessment. The Journal of Pediatrics.\u000a      2010 Apr; 156(4):657-62. DOI: http:\/\/dx.doi.org\/10.1016\/j.jpeds.2009.10.047.\u000a      Cited by 9\u000a    \u000aKey funding\u000a    Arthritis Research UK. Foster HE, LJ Kay, TR Rapley, CR May. A study\u000a        to develop Regional Musculoskeletal examination for use in school aged\u000a        children. 2005-2011, £121,758\u000a    Arthritis Research UK. Foster HE (Principal Investigator), Rapley TR, Kay\u000a      LJ, May CR. Exploring the barriers to care for children with suspected\u000a        Juvenile Idiopathic Arthritis. 2008-2012, £141,874\u000a    Arthritis Research UK. Jandial S, Kay LJ, Stewart J, Foster HE. Improving\u000a        musculoskeletal clinical skills in medical students. 2007 - 2011,\u000a      £128,015\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    Ev a. Information supplied by the Education Manager of Arthritis Research\u000a      UK, whose contact details are available on request. The video is available\u000a      at http:\/\/www.arthritisresearchuk.org\/health-professionals-and-students\/video-resources\/pgals.aspx\u000a    Ev b. The survey was undertaken in June\/July 2013 using Survey Monkey and\u000a      the methodology was similar to the previous study by Newcastle\u000a      researchers. The response rate was acceptable for a questionnaire of this\u000a      type and the instrument was validated and optimized by established\u000a      strategies. Contact details for the independent consultant are available\u000a      on request.\u000a    Ev c. Data from Amazon.co.uk shows `The Illustrated textbook of\u000a        Paediatrics', Lissauer and Clayden (eds), published by Mosby, to be\u000a      the bestseller in the category Books > Scientific, Technical &\u000a        Medical > Medicine & Nursing > Medical Sciences A-Z >\u000a        Paediatrics http:\/\/www.amazon.co.uk\/ILLS-TXTBK-PAEDIATRICS-4ESTUDENTCONSULT\/dp\/0723435650\u000a    Ev d. Lending data provided by Newcastle University library staff who\u000a      conducted a survey amongst colleagues. Data from five English medical\u000a      school libraries was obtained indicating that only a `Crash course'\u000a      paediatrics text was more frequently borrowed.\u000a    Ev e. The Royal College of Paediatrics and Child Health have produced a\u000a      guide for candidates and examiners that references pGALS on page 33. It is\u000a      available at the RCPCH website or a pdf copy can be provided on request. http:\/\/www.rcpch.ac.uk\/training-examinations-professional-development\/assessment-and-examinations\/examinations\/clinical-e-3\u000a    Ev f. Supplementary resources are available at http:\/\/www.rcpch.ac.uk\/training-examinations-professional-development\/postgraduate-training\/sub-specialty-training\/paediatr\u000a    Ev g. Correspondence is available from the Director of Paediatrics Jaslok\u000a      Hospital and Research Centre, Mumbai, India. Contact details are available\u000a      on request.\u000a    Ev h. Correspondence is available from the Professor Emeritus, Division\u000a      of Rheumatology, Department of Pediatrics, University of British Columbia,\u000a      and British Columbia's Children's Hospital, Vancouver, Canada. Contact\u000a      details are available on request. \u000a    ","Title":"\u000a    pGALS: a novel and simple approach for musculoskeletal examination of\u000a      children\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key researchers.\u000a    The Newcastle University researchers involved throughout the period of\u000a      the research were Professor Helen Foster (project lead), Dr Tim Rapley\u000a      (social scientist, qualitative methodology) and Dr Sharmila Jandial\u000a      (education research fellow, now a consultant in paediatric rheumatology).\u000a    Background.\u000a    Paediatric musculoskeletal problems are extremely common, occurring in up\u000a      to 30% of young persons and accounting for 3% of hospital day case\u000a      attendances. The challenge for clinicians is identifying those children\u000a      who have significant disease and doing so early in its course.\u000a    One such disease with significant long term consequences is juvenile\u000a      idiopathic arthritis. This is defined as inflammation of one or more\u000a      joints for at least six weeks, in a child under the age of 16 years in\u000a      whom other known causes of arthritis have been excluded. The inflamed\u000a      joint is often swollen, warm, has lost normal movement and is stiff in the\u000a      mornings. Pain is not always a major feature and so it can be difficult\u000a      for parents and doctors to detect arthritic joints in young children. The\u000a      UK annual incidence is approximately 1 in 10,000 and at any one time there\u000a      are about 12,000 affected children in the UK. Juvenile idiopathic\u000a      arthritis can start at any age from birth to adolescence, but the peak age\u000a      of onset is six years. It is more common in girls than boys. Joint damage\u000a      occurs early in the disease progression and the risk of associated\u000a      blindness (due to associated eye inflammation) is greatest in the first\u000a      months of arthritis onset. Evidence supports early and aggressive\u000a      intervention to obtain the optimal outcome.\u000a    Research\u000a    Research conducted by Foster and colleagues (R1, R2) showed that it was\u000a      common for many children presenting in primary and secondary care settings\u000a      with musculoskeletal complaints to experience delay in being referred to\u000a      paediatric rheumatology services. The researchers found complex referral\u000a      pathways from their primary care doctor to different secondary care\u000a      services, via general paediatrics, orthopaedics, and accident and\u000a      emergency. In addition to delaying the critical referral to a paediatric\u000a      rheumatologist, such complexity often resulted in children being subjected\u000a      to inappropriate, costly and unnecessary invasive investigations, such as\u000a      magnetic resonance imaging (for which many young children need a general\u000a      anaesthetic) and removal of fluid from the joints (often also requiring\u000a      anaesthetic). Further Newcastle-led research (R3) identified a general\u000a      lack of assessment of a child's musculoskeletal system by trainee and\u000a      consultant general paediatricians, despite other systems, such as\u000a      cardiovascular or gastrointestinal, being routinely assessed regardless of\u000a      the complaint with which the child presented. This was linked to a,\u000a      self-reported, low confidence in their ability to conduct musculoskeletal\u000a      assessment of children. Foster and colleagues identified (R4) a lack of\u000a      teaching of musculoskeletal clinical skills in medical schools, a\u000a      potential explanation for this poor confidence in clinical assessment.\u000a    In order to improve the confidence of clinicians conducting\u000a      musculoskeletal assessment of children and thus alleviate the delay in\u000a      diagnosis of conditions such as juvenile idiopathic arthritis, Newcastle\u000a      researchers developed a new method for examination of children's joints.\u000a      Foster and colleagues reported the development and validation of pGALS\u000a      (paediatric Gait Arms Legs and Spine) in 2006 (R5). This was tested in the\u000a      clinic and found to have excellent sensitivity when compared with expert\u000a      diagnosis and did not lead to false negative results. Further work by the\u000a      group (R6) showed that the pGALS approach can be useful as a diagnostic\u000a      tool in the acute (ie non-rheumatological) paediatric setting and can be\u000a      used by non-specialists.\u000a    "},{"CaseStudyId":"21692","Continent":[],"Country":[],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    The Newcastle research demonstrating the feasibility of preventing the\u000a      transmission of mitochondrial disease using PNT has led to a chain of\u000a      impacts in the spheres of public policy and public debate resulting in a\u000a      Government commitment to change the law in the UK.\u000a    The Human Fertilisation and Embryology Act 1990 (as amended in 2008),\u000a      only permits eggs and embryos that have not had their nuclear or\u000a      mitochondrial DNA altered to be used for treatment. However, the Act\u000a      allows for regulations to be passed by Parliament that will legally allow\u000a      such alterations in order to prevent the transmission of serious\u000a      mitochondrial disease. The sequence of events leading to the proposed\u000a      introduction of these regulations, on which Newcastle research and\u000a      researchers had an impact, is outlined below.\u000a    Impacts on public policy debates: the regulator.\u000a    In 2005 the regulator (the HFEA) licensed Newcastle researchers to\u000a      conduct research: Mitochondrial DNA Disorders: Is there a way to\u000a        prevent transmission? (EV a) and in April 2010 the results of\u000a      research on pronuclear transfer were published online in Nature\u000a      [R2]. The Parliamentary Under-Secretary of State for Health, in a\u000a      2013 debate, noted, `In 2010, Newcastle researchers approached the\u000a        Department of Health and, in the light of their progress, requested that\u000a        we consider introducing regulations to allow mitochondria replacement in\u000a        treatment.' (EV b). As a consequence of this, the HFEA Scientific\u000a        and Clinical Advances Advisory Committee met in May 2010 to consider\u000a      developments and Newcastle researchers were invited to present evidence\u000a      (EV c). In February 2011 The Secretary of State for Health asked the HFEA\u000a      to carry out a formal scientific review and in April 2011 they reported\u000a      (EV d). Newcastle provided two of only seven experts who were invited to\u000a      give evidence. The review recommended a minimum set of experiments that\u000a      were critical to a decision about the safety of the methods, including\u000a      work on PNT in both humans and non-human primates. As a consequence of R2,\u000a      the human PNT research on normally-fertilised oocytes formed a substantial\u000a      part of the research plan for the Wellcome Trust Mitochondrial Research\u000a      Centre, established in Newcastle in April 2011. This work and the analysis\u000a      in R2 were reported to the HFEA Scientific and Clinical Advances\u000a        Advisory Committee in 2013, Professors Turnbull, Herbert and Murdoch\u000a      having been invited to participate in the first core panel meeting (EV d).\u000a      As a result of this research and that of others showing a lack of success\u000a      of PNT in macaque monkeys, the Committee removed the requirement for\u000a      further work in non-human primates in 2013 (EV d contains both the 2011\u000a      and 2013 findings).\u000a    Meanwhile, in June 2011 the HFEA Ethics and Law Committee\u000a      considered the ethical and legal aspects of PNT and MST to combating\u000a      mitochondrial disease. The result of this was a paper, published in 2012\u000a      and incorporating information derived from Newcastle research, which was\u000a      circulated to inform debate and discussion within the HFEA and more\u000a      broadly among external stakeholders (EV e).\u000a    Impact on society: Consultation exercises stimulate public debate\u000a        2012-13.\u000a    In January 2012 the Secretaries of State for Health and for Business,\u000a      Innovation and Skills jointly asked the HFEA to seek public views on new\u000a      techniques to prevent the transmission of mitochondrial disease. The\u000a      public consultation ran from July - December 2012 and the final report\u000a      noted that 90 participants engaged in deliberative workshops and that\u000a      other activities, including schools events, engaged with at least 2,967\u000a      members of the public (EV f).\u000a    January 2012 also saw the Nuffield Council on Bioethics open a call for\u000a      evidence that ran through January and February 2012 for a report on the\u000a      ethics of novel techniques to prevent mitochondrial diseases. In total, 92\u000a      organisations and individuals contributed evidence and several Newcastle\u000a      researchers are cited in the full report, published in June 2012 (EV g).\u000a    Impact on Parliamentary debate.\u000a    In March 2013 the Parliamentary Office for Science and Technology\u000a      published a POSTNote (an accessible review for Parliamentarians) on new\u000a      techniques for preventing mitochondrial disease. This referenced both the\u000a      Newcastle Nature paper (R2) and the Nuffield Council on Bioethics report\u000a      to which Newcastle researchers contributed (EV h).\u000a    The issues raised in the various sources of information and advice given\u000a      to parliamentarians were aired in a Westminster Hall adjournment debate in\u000a      June 2013, initiated by a Newcastle MP. In the debate, the Parliamentary\u000a      Under-Secretary of State for Health said,\u000a    I pay great tribute to researchers at the International Centre for\u000a        Life in Newcastle [the building in which the PNT research takes\u000a      place] ... it is a fine institution. They have been developing their\u000a        groundbreaking expertise for many years. In anticipation of significant\u000a        advances in this field, the Human Fertilisation and Embryology Act 1990\u000a        was amended in 2008 to introduce a regulation-making power that, if\u000a        implemented, would enable mitochondria replacement to take place in\u000a        treatment. (EV b, col: 64.)\u000a    The Parliamentary Under-Secretary of State for Health went on to make\u000a      clear that the Government would consider the issue, led by the Chief\u000a      Medical Officer. The decision was announced in late June 2013 that draft\u000a      legislation that will be brought forward to permit the use of PNT in\u000a      treatment. The Chief Medical Officer noted that about 10 families each\u000a      year could be affected and said,\u000a    Scientists have developed ground-breaking new procedures which could\u000a        stop these diseases being passed on, bringing hope to many families\u000a        seeking to prevent their future children inheriting them. It's only\u000a        right that we look to introduce this life-saving treatment as soon as we\u000a        can. (EV i)\u000a    Newcastle University researchers, as the only group in the UK licensed to\u000a      conduct PNT research have thus been at the heart of developments in public\u000a      policy and law in what remains a challenging and ethically sensitive\u000a      research area.\u000a    ","ImpactSummary":"\u000a    Research at Newcastle University, the only centre licenced in the UK, has\u000a      shown that the in vitro fertilisation-based technique of\u000a      pronuclear transfer to prevent the transmission of mitochondrial disease\u000a      from mother to child is feasible. As a consequence the UK Government asked\u000a      the regulator responsible, the Human Fertilisation and Embryology\u000a      Authority (HFEA), to conduct both a scientific safety review of the\u000a      techniques in which Newcastle research was widely referenced and to\u000a      undertake a public consultation exercise. The findings from both these\u000a      consultations and from a separate Nuffield Council on Bioethics report\u000a      were supportive, to the extent that in June 2013 the UK's Chief Medical\u000a      Officer announced that the Government would bring forward draft\u000a      legislation to change the law in the UK to allow embryos created using the\u000a      Newcastle approach to be used for the treatment of affected couples.\u000a    ","ImpactType":"Political","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Newcastle researchers in bold. Citation counts from Scopus as at July\u000a      2013.)\u000a    \u000aR1. Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor\u000a        RW, Chinnery PF, Turnbull DM. (2008) Prevalence of Mitochondrial DNA\u000a      Disease in Adults. Annals of Neurology 63, 35-39. doi:\u000a      10.1002\/ana.21217 Cited by 154.\u000a    \u000a\u000aR2. Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree\u000a        LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M and\u000a        Turnbull DW. (2010) Pronuclear transfer in human embryos to prevent\u000a      transmission of mitochondrial DNA disease. Nature, 465, 82-85.\u000a      doi: 10.1038\/nature08958 Cited by 61.\u000a    \u000a\u000aR3. Samuels DC, Wonnapinij P and Chinnery PF. (2013) Preventing\u000a      the transmission of pathogenic mitochondria DNA mutations: can we achieve\u000a      long-term benefits from germ-line transfer? Human Reproduction\u000a      28(3) 554-9. doi: 10.1093\/humrep\/des439 Not yet cited\u000a    \u000aKey funding\u000a    Project Grant- Muscular Dystrophy Campaign. Mitochondrial DNA disorders:\u000a      is there a way to prevent transmission? 01\/01\/2005 - 30\/09\/2008 (PI:\u000a      Professor DM Turnbull) £166,896\u000a    Project Grant- Muscular Dystrophy Campaign. Mitochondrial DNA Disorders:\u000a      is there a way to prevent transmission? 01\/10\/2008 - 31\/05\/2012 (PI:\u000a      Professor DM Turnbull) £199,993\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    EV a. Documentary evidence: HFEA reference R0153. Both a lay summary and\u000a      further details of the licensed research, together with details of how the\u000a      licence was granted, are available at\u000a      http:\/\/www.hfea.gov.uk\/1564.html\u000a    Ev b. Hansard record of Westminster Hall debate. (HC Deb 4 25 Jun 2013,\u000a      vol 565, part 23 Cols 60WH - 67WH). The first quote is in Column 65WH, the\u000a      second in Col 64WH. Available at:\u000a      http:\/\/www.publications.parliament.uk\/pa\/cm201314\/cmhansrd\/cm130625\/halltext\/130625h0002.htm#13062568000002\u000a    Ev c. Documentary evidence: HFEA. Scientific and Clinical Advances\u000a      Advisory Committee meeting minutes, 2010. Available at http:\/\/www.hfea.gov.uk\/5906.html\u000a    Ev d. Documentary evidence: HFEA. Review of scientific methods to\u000a        avoid mitochondrial disease 2011 (including 2013 update). The\u000a      documents available at the following link cite evidence supplied by\u000a      Newcastle researchers and include the HFEA Scientific reviews of 2011\u000a        and 2013 and the Core panel meeting: non-confidential minutes (2013)\u000a      referencing R2 above. Available at\u000a      http:\/\/www.hfea.gov.uk\/6372.html\u000a    Ev e. Documentary evidence: HFEA, Ethics and Law Advisory Committee\u000a      paper. Available at\u000a      http:\/\/www.hfea.gov.uk\/ELAC-November-2012.html\u000a    Ev f. Documentary evidence: HFEA and Office for Public Management.\u000a      Information on the public consultation (launch, methodology and findings)\u000a      can be accessed at\u000a      http:\/\/www.hfea.gov.uk\/6896.html\u000a    Ev g. The Nuffield Council on Bioethics report can be accessed at\u000a      http:\/\/www.nuffieldbioethics.org\/publications\u000a    Ev h. The UK Parliamentary Office for Science and Technology POSTNote can\u000a      be accessed at\u000a      http:\/\/www.parliament.uk\/briefing-papers\/POST-PN-431\u000a    Ev i. The Chief Medical Officer for the UK and the Department for Health.\u000a      A press release describing the decision reached and including the\u000a      quotation used can be accessed at\u000a      https:\/\/www.gov.uk\/government\/news\/innovative-genetic-treatment-to-prevent-mitochondrial-disease\u000a    \u000a    ","Title":"\u000a    Towards prevention of mitochondrial diseases: changing government policy\u000a      and influencing public debate.\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key researchers.\u000a    Professors Mary Herbert and Douglass Turnbull of Newcastle University led\u000a      the research on pronuclear transfer (PNT). Professor Alison Murdoch of the\u000a      Newcastle Fertility Centre led the clinical care of the women who donated\u000a      eggs. Professor Patrick Chinnery studied the likelihood of\u000a      intergenerational transfer of diseased mitochondria after PNT.\u000a    Background.\u000a    Mitochondria provide about 90% of the body's energy requirements\u000a      and are the only cellular structures other than the nucleus that contain\u000a      DNA. Each mitochondrion contains multiple copies of this DNA and each cell\u000a      has many mitochondria.\u000a    Mitochondrial diseases result when mitochondria do not function\u000a      correctly and many arise because of mutations in the mitochondrial DNA.\u000a      Mutations may arise spontaneously or be inherited and may affect all or\u000a      only some of the mitochondria. Inherited mitochondrial diseases pass down\u000a      the female line only, since all the mitochondria of a new embryo derive\u000a      from those present in the egg cell. The incidence of early onset\u000a      mitochondrial disease is 1 in 16,129 births per year (Sklaldal et al. 2003\u000a      PubMed ID: 12805096) implying around 50 new cases per year in the UK.\u000a      Research in Newcastle on the prevalence of mitochondrial DNA disease in\u000a      adults indicated a minimum prevalence of 1 in 10,870 meaning that more\u000a      than 4,600 people are living with such disease in the UK (R1). There are\u000a      no effective treatments available for mitochondrial disease, which can\u000a      result in serious medical conditions, including blindness, heart failure,\u000a      liver failure, learning disabilities and diabetes. Many conditions lead to\u000a      death in early infancy. Genetic advice to affected couples planning a\u000a      family is difficult because of the variable nature of the severity with\u000a      which many such diseases affect individuals.\u000a    In vitro fertilisation is a technique developed to help couples\u000a      who, for whatever reason, cannot conceive. It involves hormonal\u000a      stimulation of the ovaries and surgical retrieval of eggs. Fertilisation\u000a      is then attempted in vitro. Fertilised eggs are cultured for a few\u000a      days before the highest quality embryos are transferred to the woman in\u000a      the hope of establishing a pregnancy.\u000a    The legal position on research on sperm, eggs and embryos in the\u000a      UK is dictated by the Human Fertilisation and Embryology Act (1990),\u000a      amended in 2008. All research must be licensed by the HFEA. The UK\u000a      approach to regulation of research on human embryos has been adopted by\u000a      many countries around the world.\u000a    Approaches to preventing the transmission of mitochondrial disease\u000a    There are two approaches that show promise to prevent the maternal\u000a      transmission of mitochondrial disease to offspring. Both involve\u000a      transferring the human genome of the parents into a donated egg that\u000a      contains a healthy mitochondrial genome. Maternal spindle transfer (MST)\u000a      is an approach in which the chromosomes from the egg of a woman with\u000a      mitochondrial disease are transferred to a donor egg from which the\u000a      chromosomes have been removed. The egg is then fertilised to provide the\u000a      paternal contribution to the offspring's genome (Tachibana et al. 2013\u000a      PubMed ID: 23103867). Pronuclear transfer (PNT) involves removing the\u000a      maternal and paternal genomes (pronuclei) from the patient's egg that has\u000a      been fertilised in vitro and placing them into a donor egg that\u000a      contains only the mitochondria of the donor (an enucleated egg) (McGrath\u000a      and Solter 1983 PMID: 6857250). Both approaches result in offspring that\u000a      are genetically identical to an embryo that would arise from normal\u000a      fertilisation, but that no longer carry a dysfunctional mitochondrial\u000a      genome.\u000a    Newcastle is the only centre in the UK licenced to conduct research that\u000a      addresses the safety and efficacy of PNT.\u000a    Work by others (McGrath and Solter 1983 PMID: 6857250) using mice had\u000a      shown that transfer of pronuclei from one egg to another immediately after\u000a      in vitro fertilization led to normal development to adulthood and ensuing\u000a      fertility in offspring. It was later shown, again in the mouse, that signs\u000a      of mitochondrial disease could be safely eradicated by transferring the\u000a      pronuclei from the disease-affected fertilised egg to an egg with healthy\u000a      mitochondria, from which nuclear DNA had been removed (Sato, et al. 2005\u000a      PMID: 16275929).\u000a    Newcastle research\u000a    Newcastle researchers wished to test the technical feasibility of\u000a      pronuclear transfer in humans. This was a challenge because the pronuclei\u000a      of human eggs are several times larger than those of mouse eggs and\u000a      therefore required new transfer techniques to be developed to avoid damage\u000a      to the egg's plasma membrane. In 2005 they were granted a licence by HFEA\u000a      to carry out the work. The study used abnormally fertilised eggs obtained\u000a      with consent from a donor, a patient undertaking in vitro fertilisation. A\u000a      new method of introducing the pronuclei into the recipient eggs was\u000a      developed and shown to be successful, in that eggs with transplanted\u000a      pronuclei developed normally to blastocysts (the latest developmental\u000a      stage at which they can legally be kept in the laboratory in the UK). Thus\u000a      the Newcastle research demonstrated the feasibility of PNT in humans (R2).\u000a    The carry-over of mitochondria from the disease-affected egg to the\u000a      healthy egg along with the pronuclei was a major concern in the\u000a      development of the technique, as it was possible that damaged mitochondria\u000a      might be transmitted across generations. Further Newcastle-led research\u000a      has determined that this is unlikely (R3).\u000a    "},{"CaseStudyId":"21693","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"732800","Name":"Bulgaria"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"798544","Name":"Poland"},{"GeoNamesId":"719819","Name":"Hungary"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"3077311","Name":"Czech Republic"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Multidisciplinary care\u000d\u000a    The guidelines for care of DMD-affected individuals produced in 2010 by\u000d\u000a      the group led by Bushby\u000d\u000a      and published in Lancet Neurology (hereafter the Guidelines), describe\u000d\u000a      best practice for\u000d\u000a      multidisciplinary care that has become the expected standard for these\u000d\u000a      patients globally.\u000d\u000a    Since DMD affects a number of body systems, coordination of clinical care\u000d\u000a      is a crucial component\u000d\u000a      of best practice for the management of DMD. This is best provided in a\u000d\u000a      multidisciplinary care\u000d\u000a      setting in which the DMD-affected individual and their family can access\u000d\u000a      the range of expertise\u000d\u000a      needed for the multisystem management of DMD. The expertise required falls\u000d\u000a      into eight\u000d\u000a      categories and the focus of the system is the patient.\u000d\u000a    \u000d\u000a      Diagnostics. Including Genetic testing and muscle biopsy and\u000d\u000a        interventions such as\u000d\u000a        genetic counselling and family support.\u000d\u000a      Rehabilitation management. Assessments of strength, posture etc and\u000d\u000a        interventions such\u000d\u000a        as providing adaptive equipment and physiotherapy.\u000d\u000a      Orthopaedic management. Various assessments are conducted and\u000d\u000a        interventions such as\u000d\u000a        tendon surgery and posterior spinal fusion offered.\u000d\u000a      Psychosocial management. Assessments of speech and language and how\u000d\u000a        the patient\u000d\u000a        and family are coping are made and interventions can include\u000d\u000a        psychotherapy and other\u000d\u000a        supportive care.\u000d\u000a      Cardiac management. Monitoring the heart is important and standard\u000d\u000a        medical interventions\u000d\u000a        are offered as appropriate.\u000d\u000a      Pulmonary management. Monitoring lung function is another key tool in\u000d\u000a        multisystem\u000d\u000a        management and interventions such as home nocturnal ventilation have\u000d\u000a        been shown to\u000d\u000a        have significant benefit.\u000d\u000a      Gastrointestinal, speech\/swallowing, nutrition. Upper and lower GI\u000d\u000a        investigations are\u000d\u000a        conducted and medical or surgical interventions offered as necessary.\u000d\u000a      Corticosteroid management. The patient's age, stage of disease and\u000d\u000a        risk factors for side-\u000d\u000a        effects are considered and affect the choice of drug regimen.\u000d\u000a    \u000d\u000a    (For more detail see R3, page 79.)\u000d\u000a    Influencing public debate, policy and practice\u000d\u000a    In 2009, while the DMD Care Considerations Working Group research was\u000d\u000a      ongoing, Newcastle\u000d\u000a      researchers gave evidence to the UK All Party Parliamentary Group for\u000d\u000a      Muscular Dystrophy. The\u000d\u000a      subsequent Walton Report stated: `We praise the work of the\u000d\u000a        Newcastle Muscle Centre, which well\u000d\u000a        deserves its international reputation for excellence in all aspects of\u000d\u000a        research, diagnosis, care and\u000d\u000a        support for children and adults with neuromuscular conditions' (Ev\u000d\u000a      a, p48). The report also notes;\u000d\u000a    `...the clinical audit data from the South West region which show the\u000d\u000a        mean age of death at\u000d\u000a        19 years of age for patients with Duchenne Muscular Dystrophy compares\u000d\u000a        starkly with\u000d\u000a        published survival data showing the average of death for similar\u000d\u000a        patients in the North East\u000d\u000a        region has reached 30 years of age ... In any decent, civilised society\u000d\u000a        these variances are\u000d\u000a        unacceptable and we cite them here as evidence of service failures that\u000d\u000a        must be addressed\u000d\u000a        with the utmost urgency.' (Ev a, p11).\u000d\u000a    In evidence to the All Party Parliamentary Group, representatives from a\u000d\u000a      number of health\u000d\u000a      authorities, including the South West of England, noted that they were\u000d\u000a      conducting reviews of their\u000d\u000a      services (Ev a, p47-51).\u000d\u000a    In 2011, the robustness of the guidelines on multidisciplinary care was\u000d\u000a      accredited for the NHS by\u000d\u000a      NICE (Ev b), resulting in the first such accredited guidelines for\u000d\u000a      neuromuscular diseases and,\u000d\u000a      indeed, for rare diseases in general. The guidelines are thus established\u000d\u000a      in the UK, until at least\u000d\u000a      2016, as the standard of care required for patients with DMD.\u000d\u000a    National and international implementation of care guidelines\u000d\u000a    UK regions outside the North East of England are implementing the\u000d\u000a      multidisciplinary care\u000d\u000a      approach, following reviews of services. In Northern Ireland the\u000d\u000a      Guidelines have been\u000d\u000a      implemented through the combined efforts of a parent-activist and a\u000d\u000a      paediatric consultant following\u000d\u000a      visits to Newcastle. The Guidelines formed the basis of a case made to the\u000d\u000a      Northern Irish\u000d\u000a      Assembly seeking improved investment in care for patients with\u000d\u000a      neuromuscular disease. The\u000d\u000a      parent-activist has stated that the Guidelines `greatly strengthened\u000d\u000a        the case we presented'. The\u000d\u000a      care network in Northern Ireland has subsequently grown to a\u000d\u000a      multidisciplinary team (Ev c).\u000d\u000a    The wider reach of the guidelines is under active examination. The\u000d\u000a      European Commission\u000d\u000a      Executive Agency for Health and Consumers funded a large multinational\u000d\u000a      project, CARE-NMD, to\u000d\u000a      study the implementation of the Guidelines throughout the UK and in\u000d\u000a      Denmark, Germany, Czech\u000d\u000a      Republic, Bulgaria, Poland and Hungary. Interim findings from CARE-NMD\u000d\u000a      show that boys\u000d\u000a      attending the centres of expertise in each nation, (i) have greater access\u000d\u000a      to services due to the\u000d\u000a      implementation of the Guidelines within the centres and (ii) report\u000d\u000a      greater satisfaction with their\u000d\u000a      treatment (Ev d). The Guidelines have been summarised and made available\u000d\u000a      to American\u000d\u000a      clinicians via the National Guideline Clearinghouse of the US\u000d\u000a      Department for Health and Human\u000d\u000a      Services (Ev e). The Centers for Disease Control and Prevention\u000d\u000a      have recently funded a study,\u000d\u000a      led by the University of Rochester Medical Center, New York State, to\u000d\u000a      examine the implementation\u000d\u000a      of the Guidelines in the USA and will begin data collection in late 2013.\u000d\u000a    In Southern India, a service based on the Guidelines was established in\u000d\u000a      2011, with Bushby's help.\u000d\u000a      The Director of the Molecular Diagnostics, Counseling, Care & Research\u000d\u000a      Centre, Coimbatore has\u000d\u000a      described how the Newcastle approach to multidisciplinary care was\u000d\u000a      implemented, saying; `The\u000d\u000a        Lancet Guidelines have stood as the basic framework on which we have\u000d\u000a        based our assessments\u000d\u000a        and recommendations... and the confidence we give [parents] that\u000d\u000a        whatever is available\u000d\u000a        internationally we offer our kids is a great sense of relief [for\u000d\u000a      them]' (Ev f). The implementation of\u000d\u000a      DMD care in Australia is also based on the Guidelines (Ev g).\u000d\u000a    Helping professionals, patients and their carers\u000d\u000a    The CARE-NMD website includes open access to a `training toolkit',\u000d\u000a      developed in 2011 from the\u000d\u000a      Guidelines by the Newcastle team, and colleagues, for the benefit of the\u000d\u000a      neuromuscular\u000d\u000a      community and wider public (Ev e).\u000d\u000a    The EU-funded Network of Excellence projects, TREAT-NMD (Chair:\u000d\u000a      Lochmuller) and CARE-\u000d\u000a      NMD, within which the Newcastle Muscle Group lead implementation in the\u000d\u000a      UK, in 2011 produced\u000d\u000a      an English language family-friendly version of the Guidelines entitled `A\u000d\u000a        Guide for Families' in\u000d\u000a      collaboration with patient groups. The source file has been distributed to\u000d\u000a      organisations around the\u000d\u000a      world, such as the US Centers for Disease Control and Prevention, for\u000d\u000a      further dissemination and\u000d\u000a      translations have been produced by recipients. By 2013 it had been\u000d\u000a      translated into 26 other\u000d\u000a      languages covering developed and developing nations (Ev h). These are\u000d\u000a      available on the TREAT-NMD\u000d\u000a      and CARE-NMD websites and have been downloaded over 3000 times (Ev i).\u000d\u000a      Physical\u000d\u000a      copies are printed locally where required and so there is scant data on\u000d\u000a      distribution, though it has\u000d\u000a      been reported that around 5,000 Japanese language guides have been printed\u000d\u000a      and distributed\u000d\u000a      throughout Japan (Ev i). The guide has also been disseminated by national\u000d\u000a      and international\u000d\u000a      patient groups. The Vice President of the American organization Parent\u000d\u000a      Project Muscular\u000d\u000a      Dystrophy has provided evidence that the guide has been viewed or\u000d\u000a      downloaded 4865 times since\u000d\u000a      2011. They have also mailed 869 copies to individuals and have provided\u000d\u000a      750 copies of the\u000d\u000a      document to clinics since 2010 (Ev j).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    In the 1960s boys with Duchenne muscular dystrophy would die at around\u000d\u000a      the age of 14 to 15\u000d\u000a      years; by the 1990s survival had risen to around 19 years. Young men with\u000d\u000a      this condition can now\u000d\u000a      live to around 30 years of age. This significant improvement is possible\u000d\u000a      where patient\u000d\u000a      management involving coordinated multidisciplinary care is implemented.\u000d\u000a      Such an approach was\u000d\u000a      developed as a result of research and clinical practice pioneered by the\u000d\u000a      Newcastle Muscle Group.\u000d\u000a      Guidelines for the care of patients with Duchenne muscular dystrophy,\u000d\u000a      published in 2010, were\u000d\u000a      developed by an international working group led by Professor Kate Bushby\u000d\u000a      of Newcastle\u000d\u000a      University. These guidelines achieved NICE process accreditation in the UK\u000d\u000a      and have been\u000d\u000a      adopted globally as the definition of best practice.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Newcastle University\u000d\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5128638","Name":"New York"},{"GeoNamesId":"1273865","Name":"Coimbatore"}],"References":"\u000d\u000a    (Citation counts from Scopus at July13, Newcastle authors in bold.)\u000d\u000a    \u000aR1. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby\u000d\u000a        K. Survival in\u000d\u000a      Duchenne muscular dystrophy: improvements in life expectancy since 1967\u000d\u000a      and the impact of\u000d\u000a      home nocturnal ventilation. Neuromuscul Disord. 2002\u000d\u000a      Dec;12(10):926-9. doi: 10.1016\/S0960-8966(02)00140-2.\u000d\u000a      Cited by 257\u000d\u000a    \u000a\u000aR2. Eagle M, Bourke J, Bullock R, Gibson M, Mehta J, Giddings D,\u000d\u000a        Straub V, Bushby K.\u000d\u000a      Managing Duchenne muscular dystrophy--the additive effect of spinal\u000d\u000a      surgery and home nocturnal\u000d\u000a      ventilation in improving survival. Neuromuscul Disord. 2007\u000d\u000a      Jun;17(6):470-5. doi:\u000d\u000a      10.1016\/j.nmd.2007.03.002. Cited by 65\u000d\u000a    \u000a\u000aR3. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe\u000d\u000a      L, Kaul A, Kinnett K,\u000d\u000a      McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD\u000d\u000a      Care\u000d\u000a      Considerations Working Group. Diagnosis and management of Duchenne\u000d\u000a      muscular dystrophy,\u000d\u000a      part 1: diagnosis, and pharmacological and psychosocial management. Lancet\u000d\u000a        Neurol. 2010\u000d\u000a      Jan;9(1):77-93. doi: 10.1016\/S1474-4422(09)70271-6. Cited by 178\u000d\u000a    \u000a\u000aR4. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe\u000d\u000a      L, Kaul A, Kinnett K,\u000d\u000a      McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD\u000d\u000a      Care\u000d\u000a      Considerations Working Group. Diagnosis and management of Duchenne\u000d\u000a      muscular dystrophy,\u000d\u000a      part 2: implementation of multidisciplinary care. Lancet Neurol.\u000d\u000a      2010 Feb;9(2):177-89. doi:\u000d\u000a      10.1016\/S1474-4422(09)70272-8. Cited by 102\u000d\u000a    \u000aResearchers and funding.\u000d\u000a    Together with the key researchers named above, Drs Michelle Eagle, Elaine\u000d\u000a      McColl, John Bourke\u000d\u000a      and Rob Bullock also contributed significantly.\u000d\u000a    Funding came from public sources in the EU, USA and UK and charities,\u000d\u000a      notably the Muscular\u000d\u000a      Dystrophy Campaign.\u000d\u000a    The Newcastle Muscle Centre grant support 2008-2011 in total was\u000d\u000a      £339,421.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    Ev a. The Walton report is available online at:\u000d\u000a      http:\/\/www.specialisedservices.nhs.uk\/document\/access-to-specialist-neuromuscular-care-walton-report-2009\/search:true\u000d\u000a    Ev b. The listing for the accreditation is available online, guidance is\u000d\u000a      titled \"Duchenne Muscular\u000d\u000a      Dystrophy Working Group — diagnosis and management of duchenne muscular\u000d\u000a      dystrophy\"\u000d\u000a    http:\/\/www.nice.org.uk\/aboutnice\/accreditation\/AccreditationDecisions.jsp\u000d\u000a    A pdf document of the final accreditation report is available from this\u000d\u000a      link or on request.\u000d\u000a    Ev c. Correspondence is available from the parent\/activist (who is also a\u000d\u000a      GP), which details the\u000d\u000a      impact the Newcastle Muscle Team and the Guidelines for care have had in\u000d\u000a      developing the service\u000d\u000a      offered to Duchenne muscular dystrophy patients and their families in\u000d\u000a      Northern Ireland.\u000d\u000a    Ev d. The CARE NMD project is ongoing and the PI has agreed to be\u000d\u000a      contacted to discuss the\u000d\u000a      interim findings on the implementation of the multidisciplinary approach\u000d\u000a      to DMD care in Europe.\u000d\u000a    Ev e. The summary for clinicians is available at the following URL and\u000d\u000a      the Guidelines (R3 & R4)\u000d\u000a      are the first two entries listed in a general search for DMD.\u000d\u000a      http:\/\/www.guideline.gov\/search\/search.aspx?term=duchenne+muscular+dystrophy\u000d\u000a    Ev f. Correspondence from the Director, Molecular Diagnostics,\u000d\u000a      Counseling, Care & Research\u000d\u000a      Centre, Coimbatore, India is available and contact details can be made\u000d\u000a      available on request.\u000d\u000a    Ev g. For examples, see the Australian Neuromuscular Network: http:\/\/www.ann.org.au\/duchenne-muscular-dystrophy\/.\u000d\u000a      The Guidelines also featured in Australian Neuromuscular Network\u000d\u000a      newsletters (300 members).\u000d\u000a    Ev h. The CARE-NMD project website is: http:\/\/en.care-nmd.eu\/.\u000d\u000a      The `training toolkit' is available\u000d\u000a      by clicking the `Resources' tab and the Family Guide and a full list of\u000d\u000a      the languages in which it is\u000d\u000a      available can be found at http:\/\/en.care-nmd.eu\/international\/family-guide\/\u000d\u000a    Ev i. The TREAT-NMD Web Development Officer is able to corroborate the\u000d\u000a      number of downloads.\u000d\u000a      Contact details available on request.\u000d\u000a    Ev j. Contact details for the vice president of the patient organisation\u000d\u000a      Parent Project Muscular\u000d\u000a      Dystrophy in the USA are available on request.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving the quality and length of the lives of Duchenne muscular\u000d\u000a      dystrophy\u000d\u000a      patients through the application of multidisciplinary care\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Key researchers\u000d\u000a    The research was led by Professor Kate Bushby, in collaboration with:\u000d\u000a      Professor Volker Straub,\u000d\u000a      co-PI on TREAT-NMD; and Professor Hanns Lochmuller, co-investigator on\u000d\u000a      TREAT-NMD and\u000d\u000a      CARE-NMD.\u000d\u000a    Background\u000d\u000a    Duchenne muscular dystrophy (DMD) is a rare inherited disorder that\u000d\u000a      affects only boys. The\u000d\u000a      incidence is 1 in 3,500 live male births. Prevalence data (Orphanet)\u000d\u000a      suggests that around 1,500\u000d\u000a      boys\/young men are living with the condition in the UK. Without\u000d\u000a      intervention, affected boys will\u000d\u000a      lose the ability to walk by the age of 13 years, develop severe postural\u000d\u000a      problems and respiratory\u000d\u000a      and cardiac failure, leading to an average age at death of 19 years.\u000d\u000a    Research\u000d\u000a    While there is no cure for DMD, it was recognised by the Newcastle Muscle\u000d\u000a      Group that patients\u000d\u000a      treated in the North East of England were surviving better (longer and\u000d\u000a      with higher quality of life)\u000d\u000a      than was reported elsewhere in the UK and abroad. This was the impetus to\u000d\u000a      establish and publish\u000d\u000a      evidence for this observation, and then for the group to ascertain,\u000d\u000a      implement and evaluate best\u000d\u000a      practice recommendations in a systematic way to promote care worldwide.\u000d\u000a    A retrospective study (R1) reviewed the treatment and management of DMD\u000d\u000a      in Newcastle between\u000d\u000a      1967 and 2002. In the 1960s, age at death averaged 14.4 years and by 1990\u000d\u000a      this had risen to 19\u000d\u000a      years. This research was the first to demonstrate the significant positive\u000d\u000a      impact of home nocturnal\u000d\u000a      ventilation (mechanical help with breathing during sleep) on survival of\u000d\u000a      patients in the care of the\u000d\u000a      Newcastle Muscle Group, at a time when few centres worldwide offered this\u000d\u000a      support. By 2002\u000d\u000a      survival was 25 years in ventilated patients. In 2007 a study of long-term\u000d\u000a      data (R2) revealed\u000d\u000a      further improvements in survival following the inclusion of spinal surgery\u000d\u000a      within a comprehensive\u000d\u000a      multidisciplinary approach, with average survival age in Newcastle now 30\u000d\u000a      years.\u000d\u000a    In 2008, Professor Bushby was selected by her peers to manage a large\u000d\u000a      scale international\u000d\u000a      research project, the `Duchenne Muscular Dystrophy Care Considerations\u000d\u000a      Working Group', funded\u000d\u000a      and supported by the USA's Centers for Disease Control and Prevention\u000d\u000a      to develop care\u000d\u000a      recommendations for this condition. The research effort involved\u000d\u000a      evaluation of the assessment\u000d\u000a      and interventions used worldwide in the management of a wide range of\u000d\u000a      aspects of DMD. The\u000d\u000a      results of this study were presented in two Lancet Neurology papers (R3,\u000d\u000a      R4). These articles\u000d\u000a      provide a framework for: (i) recognising the multisystem primary\u000d\u000a      manifestations of DMD and the\u000d\u000a      secondary complications that can arise; and (ii) the positive benefits of\u000d\u000a      providing coordinated\u000d\u000a      multidisciplinary care to those boys affected.\u000d\u000a    "},{"CaseStudyId":"21694","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    While the cause of aHUS was unknown, Newcastle researchers realised that\u000a      an effective treatment was more likely to be developed if the underlying\u000a      molecular mechanisms of the condition were understood. Treatment for aHUS\u000a      was limited, with patients reaching end stage kidney failure and requiring\u000a      lifelong dialysis while living with the risk of early death. Newcastle\u000a      research established that abnormalities in complement (a key component of\u000a      the immune system that allows the body to distinguish between itself and\u000a      foreign cells) were found in the majority of aHUS patients and that some\u000a      of the mutations affected products of the liver.\u000a    Genetic testing\u000a    As most of the abnormalities were shown to have a genetic basis, an NHS\u000a      diagnostic service was established within the Northern Molecular Genetics\u000a      Laboratory at the Centre for Life in Newcastle in 2002 (Ev a). All aHUS\u000a      mutation screening for the UK is provided by the Newcastle laboratory.\u000a      Between 2002 and 2007 16 samples were tested for three genes, CFH, CFI and\u000a      CD46; genes being tested sequentially. From 2008, 612 samples were tested\u000a      for these three genes with analysis being simultaneous and in 2011 testing\u000a      extended to five genes simultaneously, adding another 337 samples by July\u000a      2013 (Ev b).\u000a    Best practice: diagnosis and treatment of aHUS\u000a    In 2009 Goodship, on behalf of the Renal Association, the British\u000a      Committee for Standards in Haematology and the British Transplantation\u000a      Society, led the development of national clinical practice guidelines for\u000a      the management of aHUS in the UK (Ev c).\u000a    Genetic testing. Initial diagnosis and management of aHUS includes\u000a      the recommendation that screening for the genes identified by\u000a      Newcastle-led research be conducted in order to determine the best\u000a      treatment for the patient. The value of genetic testing to the patient is\u000a      that by identifying the exact abnormalities they carry, treatment options\u000a      can be directed to their particular manifestation of the disease.\u000a    Kidney transplant. Accurate genetic testing can now identify those\u000a      patients who would benefit from a kidney transplant and those who would\u000a      not.\u000a    Combined liver-kidney transplant. Two of the genes associated with\u000a      aHUS (CFH and CFI), identified by Newcastle-led research,\u000a      encode complement regulators produced by the liver. Finding mutations in\u000a      these genes in a particular patient indicates that the patient is at high\u000a      risk of a kidney transplant failing. For such patients a combined\u000a      liver\/kidney transplant might be a treatment option. This procedure has\u000a      been undertaken successfully and to date 25 such double transplants have\u000a      been performed worldwide, including three in the UK (Ev d).\u000a    Eculizumab: optimal treatment for aHUS\u000a    There is, however, a significant question of patient benefit in combined\u000a      liver-kidney transplant. With a one year mortality rate of 25% it is,\u000a      understandably, not an option chosen by many patients. This very high risk\u000a      meant that the researchers continued exploring other treatment options.\u000a      Goodship and colleagues identified a complement inhibitor, the drug\u000a      eculizumab (an anti-C5 humanised monoclonal antibody made by Alexion\u000a      Pharmaceuticals (Ev e)) as a good candidate for repurposing to treat aHUS\u000a      patients.\u000a    Two clinical trials, for which Goodship was the UK Chief Investigator,\u000a      were conducted (results in R6, Goodship joint senior author). Based on the\u000a      results, eculizumab was approved in 2011 by both the FDA (Ev f) in the USA\u000a      and the European Medicines Agency (Ev g) for the treatment of aHUS. There\u000a      are no other approved treatments for the disease.\u000a    Funding treatment. Evidence of the efficacy of eculizumab in\u000a      treating aHUS led to the submission of an application for the\u000a      establishment of a National Specialised Service for aHUS in Newcastle with\u000a      funding for the drug. This was reviewed by the Advisory Group for National\u000a      Specialised Services (AGNSS) in June 2012.\u000a    AGNSS considered that Eculizumab for aHUS was a life-saving and\u000a        life-transforming product that despite the very high cost should be\u000a        available in England to patients with aHUS. ... With the exception of a\u000a        single member, AGNSS agreed that the combination of the factors\u000a      [detailed earlier in the document] justified recommending this\u000a        high-cost product. (Ev h)\u000a    The annual cost per aHUS patient, per year of eculizumab, has been\u000a      calculated as £327,600 for an adult and £163,800 for a child (Ev i).\u000a    This high cost led to Government concerns about its affordability and so\u000a      the National Institute for Health and Care Excellence (NICE) were\u000a      asked to report. However, in 2013 NHS England implemented an interim\u000a      policy whereby eculizumab will be funded for aHUS patients. The Public\u000a      Health Adviser, Specialised Services Team, NHS England has confirmed,\u000a    As a consequence of the findings from recent clinical trials of the\u000a        terminal complement inhibitor eculizumab, on 1st\u000a        April 2013 NHS England adopted an interim policy of funding this drug\u000a        for those patients who had received it in the clinical trial and any new\u000a        patient who would benefit from it. (Ev j)\u000a    In practice this means that around 20 patients per year will receive the\u000a      drug and the interim policy is expected to be extended to aHUS patients\u000a      who receive kidney transplants in September 2013. The significance of this\u000a      decision is that no child or adult in the UK should now progress to end\u000a      stage kidney failure caused by aHUS.\u000a    ","ImpactSummary":"\u000a    Research conducted by Professor Tim Goodship and co-workers at Newcastle\u000a      has had a profound effect on the prognosis for patients with atypical\u000a      haemolytic uraemic syndrome (aHUS). By engaging in research on the genetic\u000a      factors underlying the disease they developed an understanding of the\u000a      molecular mechanisms responsible. Identifying that the majority of\u000a      patients with aHUS have either acquired or inherited abnormalities of the\u000a      regulation of complement (part of the immune system) led to the\u000a      establishment of a UK national service for genetic screening and treatment\u000a      with the complement inhibitor eculizumab. As eculizumab is now available\u000a      to patients in England, the progression to end-stage renal failure can be\u000a      prevented and patients already on dialysis will soon be successfully\u000a      transplanted.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000aR1. Warwicker P, Goodship THJ, Donne RL, Pirson Y, Nicholls A,\u000a      Ward RM, Goodship JA. Genetic studies into inherited and sporadic\u000a      haemolytic uraemic syndrome. Kidney Int. 1998;53:836-844. doi:\u000a      10.1111\/j.1523-1755.1998.00824.x Cited by 267.\u000a    \u000a    \u000a      \u000a        \u000a          Research\u000a              funding\u000a          £\u000a        \u000a        \u000a          Charitable foundations\u000a          503,449 (around half from AMRC charities)\u000a        \u000a        \u000a          MRC\u000a          655,975\u000a        \u000a        \u000a          Northern Counties Kidney Research Fund\u000a          193,992\u000a        \u000a        \u000a          Total\u000a          1,353,416\u000a        \u000a      \u000a    \u000a    Details of the impact\u000a    While the cause of aHUS was unknown, Newcastle researchers realised that\u000a      an effective treatment was more likely to be developed if the underlying\u000a      molecular mechanisms of the condition were understood. Treatment for aHUS\u000a      was limited, with patients reaching end stage kidney failure and requiring\u000a      lifelong dialysis while living with the risk of early death. Newcastle\u000a      research established that abnormalities in complement (a key component of\u000a      the immune system that allows the body to distinguish between itself and\u000a      foreign cells) were found in the majority of aHUS patients and that some\u000a      of the mutations affected products of the liver.\u000a    Genetic testing\u000a    As most of the abnormalities were shown to have a genetic basis, an NHS\u000a      diagnostic service was established within the Northern Molecular Genetics\u000a      Laboratory at the Centre for Life in Newcastle in 2002 (Ev a). All aHUS\u000a      mutation screening for the UK is provided by the Newcastle laboratory.\u000a      Between 2002 and 2007 16 samples were tested for three genes, CFH, CFI and\u000a      CD46; genes being tested sequentially. From 2008, 612 samples were tested\u000a      for these three genes with analysis being simultaneous and in 2011 testing\u000a      extended to five genes simultaneously, adding another 337 samples by July\u000a      2013 (Ev b).\u000a    Best practice: diagnosis and treatment of aHUS\u000a    In 2009 Goodship, on behalf of the Renal Association, the British\u000a      Committee for Standards in Haematology and the British Transplantation\u000a      Society, led the development of national clinical practice guidelines for\u000a      the management of aHUS in the UK (Ev c).\u000a    Genetic testing. Initial diagnosis and management of aHUS includes\u000a      the recommendation that screening for the genes identified by\u000a      Newcastle-led research be conducted in order to determine the best\u000a      treatment for the patient. The value of genetic testing to the patient is\u000a      that by identifying the exact abnormalities they carry, treatment options\u000a      can be directed to their particular manifestation of the disease.\u000a    Kidney transplant. Accurate genetic testing can now identify those\u000a      patients who would benefit from a kidney transplant and those who would\u000a      not.\u000a    Combined liver-kidney transplant. Two of the genes associated with\u000a      aHUS (CFH and CFI), identified by Newcastle-led research,\u000a      encode complement regulators produced by the liver. Finding mutations in\u000a      these genes in a particular patient indicates that the patient is at high\u000a      risk of a kidney transplant failing. For such patients a combined\u000a      liver\/kidney transplant might be a treatment option. This procedure has\u000a      been undertaken successfully and to date 25 such double transplants have\u000a      been performed worldwide, including three in the UK (Ev d).\u000a    Eculizumab: optimal treatment for aHUS\u000a    There is, however, a significant question of patient benefit in combined\u000a      liver-kidney transplant. With a one year mortality rate of 25% it is,\u000a      understandably, not an option chosen by many patients. This very high risk\u000a      meant that the researchers continued exploring other treatment options.\u000a      Goodship and colleagues identified a complement inhibitor, the drug\u000a      eculizumab (an anti-C5 humanised monoclonal antibody made by Alexion\u000a      Pharmaceuticals (Ev e)) as a good candidate for repurposing to treat aHUS\u000a      patients.\u000a    Two clinical trials, for which Goodship was the UK Chief Investigator,\u000a      were conducted (results in R6, Goodship joint senior author). Based on the\u000a      results, eculizumab was approved in 2011 by both the FDA (Ev f) in the USA\u000a      and the European Medicines Agency (Ev g) for the treatment of aHUS. There\u000a      are no other approved treatments for the disease.\u000a    Funding treatment. Evidence of the efficacy of eculizumab in\u000a      treating aHUS led to the submission of an application for the\u000a      establishment of a National Specialised Service for aHUS in Newcastle with\u000a      funding for the drug. This was reviewed by the Advisory Group for National\u000a      Specialised Services (AGNSS) in June 2012.\u000a    AGNSS considered that Eculizumab for aHUS was a life-saving and\u000a        life-transforming product that despite the very high cost should be\u000a        available in England to patients with aHUS. ... With the exception of a\u000a        single member, AGNSS agreed that the combination of the factors\u000a      [detailed earlier in the document] justified recommending this\u000a        high-cost product. (Ev h)\u000a    The annual cost per aHUS patient, per year of eculizumab, has been\u000a      calculated as £327,600 for an adult and £163,800 for a child (Ev i).\u000a    This high cost led to Government concerns about its affordability and so\u000a      the National Institute for Health and Care Excellence (NICE) were\u000a      asked to report. However, in 2013 NHS England implemented an interim\u000a      policy whereby eculizumab will be funded for aHUS patients. The Public\u000a      Health Adviser, Specialised Services Team, NHS England has confirmed,\u000a    As a consequence of the findings from recent clinical trials of the\u000a        terminal complement inhibitor eculizumab, on 1st\u000a        April 2013 NHS England adopted an interim policy of funding this drug\u000a        for those patients who had received it in the clinical trial and any new\u000a        patient who would benefit from it. (Ev j)\u000a    In practice this means that around 20 patients per year will receive the\u000a      drug and the interim policy is expected to be extended to aHUS patients\u000a      who receive kidney transplants in September 2013. The significance of this\u000a      decision is that no child or adult in the UK should now progress to end\u000a      stage kidney failure caused by aHUS.\u000a    Sources to corroborate the impact\u000a    Ev a. UK Genetic Testing Network. aHUS associated gene dossier.\u000a      http:\/\/www.ukgtn.nhs.uk\/ukgtn\/LabFileDownload.do?uniqueIdentifier=3343B60250578360016F7C9E263999CF\u000a    Ev b. The Associate Director of the Northern Molecular Genetics Service\u000a      can be contacted to corroborate the information regarding genetic tests\u000a      for aHUS.\u000a    Ev c. Taylor CM, Machin S, Wigmore SJ, Goodship TH. Clinical Practice\u000a      Guidelines for the management of atypical Haemolytic Uraemic Syndrome in\u000a      the United Kingdom. Br. J. Haematol. 2010;148(1):37-47\u000a    Ev d. Information about transplants can be found in Journal of the\u000a      American Society of Nephrology 2009, 20(5): 940-9. http:\/\/jasn.asnjournals.org\/content\/20\/5\/940\u000a      DOI: 10.1681\/ASN.2008080906. (Citations = 59)\u000a    Ev e. Soliris product information (includes results of clinical trials).\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/000791\/WC500054208.pdf\u000a    Ev f. FDA approves Soliris for rare paediatric blood disorder: Orphan\u000a      drug receives second approval for rare disease\u000a      http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/2011\/ucm272990.htm\u000a    Ev g. EMA approval. Soliris (eculizumab) changes since initial\u000a      authorisation of medicine\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Summary_of_opinion\/human\/000791\/WC500112852.pdf\u000a    Ev h. AGNSS; Meeting minutes. April 2011.\u000a      www.specialisedservices.nhs.uk%2Flibrary%2F34%2FAGNSS_minutes_of_meeting___1st_Aprill_2011.pdf\u000a    Ev i. The Independent: article on aHUS and eculizumab, including an\u000a      interview with a Newcastle based patient. http:\/\/www.independent.co.uk\/life-style\/health-and-families\/health-news\/at-what-cost-lifesaving-drug-withheld-8632371.html\u000a    Ev j. Correspondence from the Public Health Adviser, Specialised Services\u000a      Team, NHS England, who has agreed to be contacted to corroborate the\u000a      impact of Newcastle-led research on the interim funding policy for\u000a      eculizumab, is available on request.\u000a    Annotations\u000a    Articles\u000a    \u000a      \u000a        \u000a          Reference\u000a          Year\u000a          DOI\u000a        \u000a        \u000a          Warwicker P, Goodship THJ, Donne RL, Pirson Y, Nicholls A,\u000a            Ward RM, Goodship JA. Genetic studies into inherited and\u000a            sporadic haemolytic uraemic syndrome. Kidney Int.\u000a            1998;53:836-844. doi: 10.1111\/j.1523-1755.1998.00824.x Cited\u000a              by 267.\u000a          1998\u000a          10.1111\/j.1523-1755.1998.00824.x\u000a        \u000a        \u000a          Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC,\u000a            Tielemans CL, Goodship JA, Goodship THJ. Factor H mutations\u000a            in hemolytic uremic syndrome cluster in exons 18-20, a domain\u000a            important for host cell recognition. Am. J. Hum. Genet.\u000a            2001;68(2):485-490. doi: 10.1086\/318203 Cited by 181.\u000a\u000a          2001\u000a          10.1086\/318203\u000a        \u000a        \u000a          \u000aKavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS,\u000a            Warwick G, Richards A, Ward R, Goodship JA, Goodship TH.\u000a            Mutations in complement factor I predispose to development of\u000a            atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol.\u000a            2005;16(7):2150-5. doi: 10.1681\/ASN.2005010103 Cited by\u000a              132.\u000a\u000a          2005\u000a          10.1681\/ASN.2005010103\u000a        \u000a        \u000a          Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship\u000a              THJ, Remuzzi G. Outcome of renal transplantation in patients\u000a            with non-shiga toxin-associated hemolytic uremic syndrome:\u000a            Prognostic significance of genetic background. Clin. J. Am. Soc.\u000a            Nephrol. 2006;1(1):88-99. doi: 10.2215\/CJN.00050505 Cited\u000a              by 75.\u000a\u000a          2006\u000a          10.2215\/CJN.00050505\u000a        \u000a        \u000a          Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS,\u000a            Remuzzi G, Strain L, Goodship THJ. Favorable long-term\u000a            outcome after liver-kidney transplant for recurrent hemolytic uremic\u000a            syndrome associated with a factor H mutation. Am. J. Transplant\u000a            2006;6(8):1948-52. doi: 10.1111\/j.1600-6143.2006.01375.x Cited\u000a              by 65.\u000a\u000a          2006\u000a          10.1111\/j.1600-6143.2006.01375.x\u000a        \u000a        \u000a          Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C,\u000a            Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T,\u000a            Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, KarpmanD,\u000a            LebranchuY, Mariat C, MenneJ, MoulinB, Nurnberger J, Ogawa M,\u000a            Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS,\u000a            Trivelli A, Zimmerhackl LB, Goodship T and Loirat C.\u000a            Terminal Complement Inhibitor Eculizumab in Atypical\u000a            Hemolytic-Uremic Syndrome. The New England Journal of Medicine\u000a            2013; 368: 2169-81. DOI:10.1056\/NEJMoa1208981 (Drs. Legendre,\u000a                Licht, Muus, Goodship, and Loirat contributed equally to this\u000a                article as joint senior authors.)\u000a          2013\u000a          10.1056\/NEJMoa1208981\u000a        \u000a      \u000a    \u000a    \u000a\u000a\u000aR2. Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC,\u000a      Tielemans CL, Goodship JA, Goodship THJ. Factor H mutations in\u000a      hemolytic uremic syndrome cluster in exons 18-20, a domain important for\u000a      host cell recognition. Am. J. Hum. Genet. 2001;68(2):485-490. doi:\u000a      10.1086\/318203 Cited by 181.\u000a    \u000a\u000aR3. Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS,\u000a      Warwick G, Richards A, Ward R, Goodship JA, Goodship TH. Mutations\u000a      in complement factor I predispose to development of atypical hemolytic\u000a      uremic syndrome. J. Am. Soc. Nephrol. 2005;16(7):2150-5. doi:\u000a      10.1681\/ASN.2005010103 Cited by 132.\u000a    \u000a\u000aR4. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship\u000a        THJ, Remuzzi G. Outcome of renal transplantation in patients with\u000a      non-shiga toxin-associated hemolytic uremic syndrome: Prognostic\u000a      significance of genetic background. Clin. J. Am. Soc. Nephrol.\u000a      2006;1(1):88-99. doi: 10.2215\/CJN.00050505 Cited by 75.\u000a    \u000a\u000aR5. Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS,\u000a      Remuzzi G, Strain L, Goodship THJ. Favorable long-term outcome\u000a      after liver-kidney transplant for recurrent hemolytic uremic syndrome\u000a      associated with a factor H mutation. Am. J. Transplant 2006;6(8):1948-52.\u000a      doi: 10.1111\/j.1600-6143.2006.01375.x Cited by 65.\u000a    \u000a\u000aR6. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C,\u000a      Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D,\u000a      Furman RR, Gaber O, Herthelius M, Hourmant M, KarpmanD, LebranchuY, Mariat\u000a      C, MenneJ, MoulinB, Nurnberger J, Ogawa M, Remuzzi G, Richard T,\u000a      Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship\u000a        T and Loirat C. Terminal Complement Inhibitor Eculizumab in Atypical\u000a      Hemolytic-Uremic Syndrome. The New England Journal of Medicine\u000a      2013; 368: 2169-81. DOI:10.1056\/NEJMoa1208981 (Drs. Legendre, Licht,\u000a          Muus, Goodship, and Loirat contributed equally to this article as\u000a          joint senior authors.)\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    Ev a. UK Genetic Testing Network. aHUS associated gene dossier.\u000a      http:\/\/www.ukgtn.nhs.uk\/ukgtn\/LabFileDownload.do?uniqueIdentifier=3343B60250578360016F7C9E263999CF\u000a    Ev b. The Associate Director of the Northern Molecular Genetics Service\u000a      can be contacted to corroborate the information regarding genetic tests\u000a      for aHUS.\u000a    Ev c. Taylor CM, Machin S, Wigmore SJ, Goodship TH. Clinical Practice\u000a      Guidelines for the management of atypical Haemolytic Uraemic Syndrome in\u000a      the United Kingdom. Br. J. Haematol. 2010;148(1):37-47\u000a    Ev d. Information about transplants can be found in Journal of the\u000a      American Society of Nephrology 2009, 20(5): 940-9. http:\/\/jasn.asnjournals.org\/content\/20\/5\/940\u000a      DOI: 10.1681\/ASN.2008080906. (Citations = 59)\u000a    Ev e. Soliris product information (includes results of clinical trials).\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/000791\/WC500054208.pdf\u000a    Ev f. FDA approves Soliris for rare paediatric blood disorder: Orphan\u000a      drug receives second approval for rare disease\u000a      http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/2011\/ucm272990.htm\u000a    Ev g. EMA approval. Soliris (eculizumab) changes since initial\u000a      authorisation of medicine\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Summary_of_opinion\/human\/000791\/WC500112852.pdf\u000a    Ev h. AGNSS; Meeting minutes. April 2011.\u000a      www.specialisedservices.nhs.uk%2Flibrary%2F34%2FAGNSS_minutes_of_meeting___1st_Aprill_2011.pdf\u000a    Ev i. The Independent: article on aHUS and eculizumab, including an\u000a      interview with a Newcastle based patient. http:\/\/www.independent.co.uk\/life-style\/health-and-families\/health-news\/at-what-cost-lifesaving-drug-withheld-8632371.html\u000a    Ev j. Correspondence from the Public Health Adviser, Specialised Services\u000a      Team, NHS England, who has agreed to be contacted to corroborate the\u000a      impact of Newcastle-led research on the interim funding policy for\u000a      eculizumab, is available on request.\u000a    ","Title":"\u000a    Uncovering the genetic basis of atypical haemolytic uraemic syndrome\u000a      leads to improved treatment.\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Researchers and funding\u000a    Professor Tim Goodship led this research. Co-investigators at Newcastle\u000a      University were: Professor Judith Goodship and Dr David Kavanagh. Funding\u000a      of around £1.3M was obtained from a number of charitable sources and the\u000a      Medical Research Council.\u000a    Background\u000a    Haemolytic uraemic syndrome is a condition in which small blood vessels\u000a      are blocked by blood clots. It predominantly affects children and is the\u000a      most common cause of acute kidney failure in children. The overall\u000a      incidence of the condition is estimated at 2.1 cases per 100,000 persons\u000a      per year and it is usually associated with infection by the bacterium E.\u000a        coli O157. However, there is also a rare, chronic, severe form known\u000a      as atypical haemolytic uraemic syndrome (aHUS), which can be either\u000a      inherited or arise spontaneously and again predominantly affects children.\u000a      aHUS represents 5-10% of haemolytic uraemic syndrome cases at\u000a      presentation, which equates to around 200 people being affected in the UK.\u000a      The prognosis for affected individuals is poor: there is 8% mortality\u000a      around the time of presentation and 50% of survivors will require\u000a      long-term dialysis within two years. The outcome of kidney transplantation\u000a      in aHUS affected individuals is poor, with a high risk of disease\u000a      recurrence and subsequent transplant loss. The overall five year\u000a      transplant survival for aHUS patients is only 51% and outcome is even\u000a      worse (30% five year survival) in patients known to have an underlying\u000a      genetic abnormality (Le Quintrec et al. 2013, PubMed ID: 23356914). For\u000a      all patients undergoing kidney transplant for any indication, the five\u000a      year survival is ~77% (Gondos et al. 2013 PubMed ID: 23060279).\u000a    Research\u000a    In the early 1990s Goodship began caring for an individual from a family\u000a      in the North East of England within which multiple generations had been\u000a      affected by aHUS. At this time nothing was known about the cause of the\u000a      disease but help from this family offered an opportunity to identify the\u000a      underlying molecular mechanisms of the disease. In 1998 Goodship and\u000a      colleagues at Newcastle University were the first (R1) to establish\u000a      linkage of aHUS to a specific region on chromosome 1 that includes the\u000a      gene for complement regulator factor H (CFH) and identified two mutations.\u000a      (Complement is a group of proteins that play a pivotal role in the immune\u000a      system, allowing the body to distinguish between host and foreign cells or\u000a      pathogens). Subsequently, the Newcastle group demonstrated the clustering\u000a      of such mutations in the C terminal exons (regions important for host\u000a      recognition), identified other genes associated with aHUS (such as\u000a      complement factor I (CFI) and membrane cofactor protein CD46) and were the\u000a      first to identify factor H autoantibodies in association with complement\u000a      gene mutations (R2, R3). They demonstrated that inherited or acquired\u000a      abnormalities affecting components of the alternative complement pathway\u000a      were present in ~70% of aHUS patients.\u000a    Building on this research, Goodship collaborated with Professor Giuseppe\u000a      Remuzzi (Mario Negri Institute, Bergamo, Italy) to show that the\u000a      underlying mutation in aHUS was a strong predictor of kidney transplant\u000a      outcome. In aHUS patients with a factor H mutation there is an 80% risk of\u000a      losing a transplanted kidney within two years (R4). Further research\u000a      demonstrated that combined liver and kidney transplantation was associated\u000a      with better outcomes in such cases (R5). Genetic testing is therefore\u000a      clearly an essential tool to facilitate the appropriate treatment of aHUS\u000a      patients.\u000a    As complement plays a central role in the pathogenesis of aHUS, further\u000a      research has been conducted on complement inhibitors as potentially\u000a      effective treatments for the disease. Two clinical trials (37 patients) of\u000a      the anti-C5 humanised monoclonal antibody eculizumab (brand name Soliris)\u000a      have been undertaken, with substantial contributions provided by Goodship.\u000a      The results of these trials (R6) showed that treatment with eculizumab\u000a      resulted in improved kidney function: in one trial patient improvement was\u000a      such that dialysis was discontinued in 4 of the 5 patients in the trial on\u000a      dialysis and earlier intervention with the drug was associated with\u000a      greater patient improvement.\u000a    "},{"CaseStudyId":"21696","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The research initiated at Newcastle in the 1990s not only led to the\u000a      first in class trial of a PARP inhibitor but also played a key role in\u000a      establishing the translational research routes of development of this\u000a      class of agents. When the project was first established, PARP was not\u000a      considered a viable target, particularly by the pharmaceutical industry,\u000a      but the Newcastle team championed it and drove the project to clinical\u000a      proof-of-principle. PARP has now been adopted as a key cancer drug target\u000a      by the global pharmaceutical industry, and has reached cancer patients\u000a      across Europe, the Americas, Australasia and Asia, with eight PARP\u000a      inhibitors currently in clinical trial development worldwide and at least\u000a      eight cancer types being treated through clinical trials [EV a].\u000a    In 2010, Cancer Research UK formally recognised the research underpinning\u000a      the discovery and development of PARP inhibitors, awarding their inaugural\u000a      Translational Cancer Research Prize to the Newcastle PARP team. This prize\u000a      was awarded `...in recognition of the discovery and development of\u000a        novel PARP inhibitors, specifically the achievement of the team in\u000a        driving an initial scientific concept through medicinal chemistry and\u000a        preclinical work, to first-in-man clinical studies.' [EV b]. The\u000a      successful exploitation of PARP as a drug target builds on many decades of\u000a      basic research on DNA damage and repair by many scientists and clinicians.\u000a      In so doing, it demonstrates the importance of academia as a resource for\u000a      new targets in drug discovery. Notably, numerous other DNA damage and\u000a      repair targets are now being evaluated; based largely on the PARP\u000a      inhibitor paradigm.\u000a    Commercial Impact\u000a    The research has had a significant impact on the UK and global\u000a      pharmaceutical industry, with the following companies investing heavily in\u000a      clinical trials and clinical PARP inhibitor programmes: AstraZeneca,\u000a      Clovis, SanofiAventis, Abbott, Merck, Biomarin, Eisai, Cephalon and\u000a      Genentech [EV a]. It is clear that since the initial Newcastle trial\u000a      (2003-2005), in which patients were treated with a PARP inhibitor for the\u000a      first time, and the demonstration of synthetic lethality in BRCA-deficient\u000a      cancers, there has been a marked increase in the commencement of trials\u000a      testing PARP inhibitors [data extracted from EV a]:\u000a\u000a\u000a\u000a    In the period May 2008- May 2013, 33 cancer trials involving PARP\u000a      inhibitors were completed and an additional 52 trials are currently open,\u000a      totalling 50 Phase I, 33 Phase II and 2 Phase III trials in this period\u000a      [EV a]. In 2011 the average per patient cost associated with a Phase I, II\u000a      and III trial in Oncology were reported to be $21,883, $73,303 and $65,900\u000a      respectively [EV c]. An estimate of the investment by companies into PARP\u000a      inhibitor trials is summarised in the following table:\u000a    \u000a      \u000a        \u000a          Phase\u000a          No.\u000a              of Trials\u000a          No.\u000a              of patients\u000a          Average\u000a              Total cost\u000a        \u000a        \u000a          I\u000a          50\u000a          3,173\u000a          $69.4 million\u000a        \u000a        \u000a          II\u000a          33\u000a          3,160\u000a          $231.6 million\u000a        \u000a        \u000a          III\u000a          2\u000a          1,299\u000a          $85.6 million\u000a        \u000a      \u000a    \u000a    Impact on Patients\u000a    Since the initial Phase I trial (2003), clinical trials involving PARP\u000a      inhibitors have enrolled around 7,000 patients (approx. 750 of which were\u000a      recruited to more than one trial phase), with around 5,600 patients having\u000a      enrolled in trials opening January 2008 onwards [EV a, d]. From the\u000a      outset, the potential of PARP inhibitors was clear and two out of the 33\u000a      patients treated for malignant melanoma in the Phase I trial and five out\u000a      of the 40 patients treated in the Phase II trial (2005) (both outlined in\u000a      Section 2) are today (October 2013) alive and in remission [EV e]. When\u000a      recruited into the trials, all of these patients were diagnosed with\u000a      incurable disease with a life expectancy of just a few months.\u000a    A recent Phase II trial of the PARP inhibitor olaparib in BRCA-deficient\u000a      advanced breast cancer has shown not only that this drug is well\u000a      tolerated, but also a significant reduction in tumour size in 38% of\u000a      patients (9 of 24 patients) [EV f]. Similarly, a Phase II trial showed\u000a      that this drug was well tolerated in BRCA-deficient ovarian cancer\u000a      patients, with 33% (11 of 33 patients) showing reduced tumour size [EV g].\u000a      BRCA proteins play a major role in the response to and repair of\u000a      DNA double strand breaks through the homologous recombination repair\u000a      pathway, while PARP inhibitors play a crucial role in DNA single-strand\u000a      break repair. Harmful mutations in BRCA genes produce a hereditary\u000a      breast-ovarian cancer syndrome in affected families. According to the\u000a      National Cancer Institute between 1 in 400 and 1 in 800 women will have a\u000a      BRCA mutation, which equates to a conservative estimate of around\u000a      40,000 women (1 in 800) in the UK; of these approx. 60% (24,000 women)\u000a      will develop breast cancer, and 15-40% (6,000-16,000 women) will develop\u000a      ovarian cancer. The PARP inhibitor olaparib could therefore have a\u000a      significant impact on the lives of women diagnosed with breast- or ovarian\u000a      cancer. Furthermore, PARP inhibitors offer the potential for\u000a      chemo-prevention, thereby allowing breast cancer patients to avoid\u000a      disfiguring surgery such as bilateral mastectomy and oophorectomy [EV d].\u000a      In addition, a recent small study demonstrated promising results in\u000a      patients with BRCA mutations after treatment with a new PARP inhibitor,\u000a      BMN 673; 18 out of 42 (42%) patients with ovarian or breast cancer showed\u000a      signs of tumour shrinkage after treatment [EV f].\u000a    ","ImpactSummary":"\u000a    Newcastle research selected the DNA repair enzyme poly(ADP-ribose)\u000a      polymerase (PARP) as a promising target for cancer therapy. The\u000a      first-in-class PARP inhibitor, rucaparib, was developed at Newcastle, in\u000a      collaboration with Cancer Research UK and Agouron Pharmaceuticals, and\u000a      subsequently became the first PARP inhibitor to be used to treat a cancer\u000a      patient in a clinical trial. Currently, at least 8 PARP inhibitors are\u000a      being developed and major pharmaceutical companies have to date invested\u000a      around $385 million in clinical trials, and over 7,000 patients worldwide\u000a      have been treated with PARP inhibitors in trials since 2008, demonstrating\u000a      the importance of basic and translational research in universities to drug\u000a      discovery by pharmaceutical companies.\u000a    ","ImpactType":"Technological","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Newcastle researchers in bold. Citation count from Scopus, July 2013)\u000a    \u000aR1. Griffin RJ, Srinivasan S, Bowman K, Calvert\u000a        AH, Curtin NJ, Newell DR, Pemberton LC, Golding\u000a        BT. Resistance-modifying agents. 5. Synthesis and biological\u000a      properties of quinazolinone inhibitors of the DNA repair enzyme\u000a      poly(ADP-ribose) polymerase (PARP). (1998) Journal of Medicinal Chemistry,\u000a      41(26):5247-56. DOI: 10.1021\/jm980273t. Cited by 79\u000a    \u000a\u000aR2. Calabrese CR, Almassy R, Barton S, Batey MA,\u000a      Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf\u000a      RA, Kyle S, Li J, Maegley K, Newell DR, Notarianni E,\u000a      Stratford IJ, Skalitzky D, Thomas HD, Wang LZ, Webber SE,\u000a      Williams KJ, Curtin NJ. Anticancer chemosensitization and\u000a      radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor\u000a      AG14361. (2004) Journal of the National Cancer Institute, 96:56-67. DOI:\u000a      10.1093\/jnci\/djh005. Cited by 216\u000a    \u000a\u000aR3. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez\u000a      E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific\u000a      killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)\u000a      polymerase. (2005) Nature, 434:913-917. DOI:10.1038\/nature03443. Cited\u000a        by 982\u000a    \u000a\u000aR4. Plummer R, Jones C, Middleton M, Wilson R, Evans J,\u000a      Olsen A, Curtin N, Boddy A, McHugh P, Newell D,\u000a      Harris A, Johnson P, Steinfeldt H, Dewji R, Wang D, Robson L, Calvert\u000a        H. Phase I study of the poly(ADP-ribose) polymerase inhibitor,\u000a      AG014699, in combination with temozolomide in patients with advanced solid\u000a      tumors. (2008) Clinical Cancer Research, 14:7917- 7923. DOI:\u000a      10.1158\/1078-0432.CCR-08-1223. Cited by 128\u000a    \u000a\u000aR5. Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson\u000a      RH, Mulligan E, Curtin N, Wang D, Dewji R, Abbattisya A,\u000a      Gallo J, Calvert H. A phase II study of the potent PARP inhibitor,\u000a      Rucaparib (PF-01367338, AG014699), with temozolomide in patients with\u000a      metastatic melanoma demonstrating evidence of chemopotentiation (2013)\u000a      Cancer Chemotherapy Pharmacology, 71:1191-1199. DOI:\u000a      10.1007\/s00280-013-2113-1. (Published in May 2013; not yet cited)\u000a    \u000a\u000aR6. Drew Y, Mulligan EA, Vong WT, Thomas HD,\u000a      Kahn S, Kyle S, Mukhopadhyay A, Los G, Hostomsky Z,\u000a      Plummer ER, Edmondson RJ, Curtin NJ. Therapeutic\u000a      potential of poly(ADP- ribose) polymerase inhibitor AG014699 in human\u000a      cancers with mutated or methylated BRCA1 or BRCA2. (2011) Journal of the\u000a      National Cancer Institute, 103:334-346. DOI: 10.1093\/jnci\/djq509. Cited\u000a        by 47\u000a    \u000aSelected funding awards\u000a    • 1993-1996 The synthesis and evaluation of inhibitors of poly-ADP\u000a        ribose polymerase and nucleoside transport to potentiate the activity of\u000a        cytotoxic drugs. The North of England Cancer Research Campaign —\u000a      £72,000.\u000a    • 1998-2002 An investigation into the interactive effects of poly\u000a        (ADP-ribose) polymerase and DNA-dependent protein kinase. CRUK —\u000a      £70,016\u000a    • 1998-1999 Poly (ADP) Ribose Polymerase Inhibitors. Agouron\u000a      Pharmaceuticals — £531,956.\u000a    • 2001-2002 Development of pharmacodynamic assays for the clinical\u000a        evaluation of novel PARP inhibitors, and pre-clinical investigations of\u000a        backup compounds. Agouron Pfizer GRD — £220,000\u000a    • 2002-2003 NECRC Cancer Research Unit Core Grant. Cancer\u000a      Research UK — £504,404 • 2002-2005 Phase 1 Trial of the Novel PARP\u000a        Inhibitor, AG14699, in Combination with Temozolomide. CRUK —\u000a      £178,595\u000a    • 2007-2010 Therapeutic potential of PARP inhibitors in cancers\u000a        defective in BRCA1, BRCA2 or other defects contributing to a BRCAness\u000a        phenotype. Pfizer Inc. USA — £104,940.61\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    EV a. www.clinicaltrials.gov\u000a      (Search term `PARP inhibitor',\u000a        excluding withdrawn and terminated trials. For patient\u000a        numbers, trials not yet recruiting were also excluded.)\u000a    EV b. Inaugural Cancer Research UK Translational Research Team Prize in\u000a      2010\u000a      http:\/\/www.cancerresearchuk.org\/science\/funding\/find-grant\/all-funding-schemes\/translational-cancer-research-prize\/past-winners\/\u000a    EV c. http:\/\/www.pharmalive.com\/clinical-trial-costs-are-rising-rapidly\u000a    EV d. Plummer R. Perspective on the pipeline of drugs being developed\u000a      with DNA damage as a target. Clinical Cancer Research (2010) 16,\u000a      4527-4531. DOI: 10.1158\/1078-0432.CCR-10- 0984\u000a    EV e. Patient survival data; corroborating e-mail.\u000a    EV f. Tutt, A et al. Phase II trial of the oral PARP inhibitor olaparib\u000a      in BRCA-deficient advanced breast cancer. Journal of Clinical Oncology,\u000a      2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No\u000a      18S (June 20 Supplement).\u000a      http:\/\/meeting.ascopubs.org\/cgi\/content\/abstract\/27\/18S\/CRA501\u000a    EV g. Audeh, MW et al. Phase II trial of the oral PARP inhibitor olaparib\u000a      (AZD2281) in BRCA- deficient advanced ovarian cancer. Journal of Clinical\u000a      Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol\u000a      27, No 15S (May 20 Supplement).\u000a      http:\/\/meeting.ascopubs.org\/cgi\/content\/abstract\/27\/15S\/5500\u000a    ","Title":"\u000a    The development of a novel class of anticancer drugs, PARP inhibitors,\u000a      has attracted multi-million dollar investments in clinical trials by nine\u000a      pharmaceutical companies\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle researchers and their roles at the time of the research\u000a      (Where people left\/joined the university in the period 1993-2013, years\u000a      are given in brackets)\u000a    AH Calvert (1990-2009), professor of medical oncology; NJ Curtin,\u000a      lecturer\/senior lecturer 1998- 2006, then professor of experimental cancer\u000a      therapeutics; BW Durkacz (1982-2010) was the project originator; she was a\u000a      reader 1984-2008, then professor of experimental cancer therapeutics; BT\u000a      Golding, professor of organic chemistry 1983-2006, then senior research\u000a      investigator; RJ Griffin, reader in cancer therapy 1991-2001, then\u000a      professor of medicinal chemistry; DR Newell, professor of cancer\u000a      therapeutics; R Plummer (2001 onwards), clinical lecturer 2001- 2004,\u000a      clinical senior lecturer of oncology 2004-2008, then clinical professor of\u000a      experimental cancer medicine.\u000a    Background\u000a    DNA repair pathways can enable cancerous cells to survive the DNA damage\u000a      induced by radiation therapy and chemotherapy. Thus, inhibitors of these\u000a      pathways could enhance the effect of these treatments. Basic research at\u000a      Newcastle instigated by Prof Barbara Durkacz selected the DNA repair\u000a      enzyme poly(ADP-ribose) polymerase (PARP) as a promising target for cancer\u000a      therapy. Multiple pathways contribute to the repair of DNA and PARP is a\u000a      key enzyme in the repair pathway. Early PARP inhibitors, the benzamides,\u000a      were developed in the 1980s, but lacked the potency and specificity\u000a      required for pre-clinical evaluation.\u000a    Research\u000a\u0009Since 1995, the work of a multidisciplinary team at\u000a      Newcastle has resulted in the development of novel and potent PARP\u000a      inhibitors (1000 times more potent than benzamides) that selectively\u000a      inhibit the enzyme [R1, R2, R3]. These were developed using\u000a      structure-based drug design, in collaboration with Agouron Pharmaceuticals\u000a      and Cancer Research UK. The chemo- and radio- potentiating abilities of\u000a      these inhibitors were evaluated in animal models and cell cultures and\u000a      they were demonstrated to have a cellular activity that increases the DNA\u000a      damage induced by cytotoxic anticancer drugs and ionising radiation [e.g.\u000a      R2].\u000a    Cancer Research UK selected the potent PARP inhibitor rucaparib\u000a      (AG014699, CO-338) for clinical trials, and the first cancer patients in\u000a      the world to receive a PARP inhibitor were treated at Newcastle in 2003 as\u000a      part of a Phase I study [R4]. With 33 patients, the study demonstrated\u000a      that rucaparib in combination with the chemotherapeutic drug temozolomide,\u000a      was well tolerated by patients, and confirmed PARP inhibition in all\u000a      patients [R4]. Subsequently a Phase II study with 40 patients demonstrated\u000a      that temozolomide efficacy was increased when used in combination with\u000a      rucaparib [R5].\u000a    In parallel, the research undertaken at Newcastle stimulated widespread\u000a      interest, both in industry and academia, in PARP as a target in cancer\u000a      therapies, with more than 10 compounds subsequently selected for\u000a      development. In collaboration with Sheffield (Prof Thomas Helleday), the\u000a      Newcastle group also demonstrated the synthetic lethality of PARP\u000a      inhibitors towards cells with mutations in the BRCA genes, the underlying\u000a      cause of many inherited breast and ovarian cancers [R3, R6]. Synthetic\u000a      lethality is defined as the lethal effect of inactivating two enzymes or\u000a      pathways when inactivation of either alone is tolerated [6].\u000a    "},{"CaseStudyId":"21697","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    It is estimated that over 14,000 people are diagnosed worldwide with\u000a      malignant pleural\u000a      mesothelioma each year, around 2,500 of which are in the UK. This disease\u000a      most commonly\u000a      develops between the ages of 50 and 70 years, affecting five times more\u000a      men than women.\u000a      Symptoms include shortness of breath, chest pains, fatigue, and weight\u000a      loss. There is no cure and\u000a      the prognosis is poor; over 2,000 people die annually from the disease in\u000a      the UK.\u000a    Impact on Patients\u000a    If not for the Newcastle research and collaboration with Eli Lilly\u000a      Pharmaceuticals, pemetrexed\u000a      toxicity, which includes severe bone marrow suppression, vomiting,\u000a      fatigue, shortness of breath,\u000a      and anaemia, would have led to its clinical development being discontinued\u000a      [EV a]. Instead, it was\u000a      demonstrated for the first time that pemetrexed could be used safely in\u000a      patients and that the\u000a      toxicity and side effects could be reduced by supplementation with not\u000a      only folic acid, but also\u000a      vitamin B12. A Vice President of Eli Lilly at the time the research was\u000a      carried out confirms that\u000a      during their collaborative work with the Newcastle group:\u000a    `...the identification of biomarkers related to folic acid and other\u000a        vitamins [including\u000a      homocysteine] has been fundamental to understand the toxicity of\u000a        Pemetrexed. High levels of\u000a        homocysteine were associated to higher risk of developing severe\u000a        toxicity and in some\u000a        instances toxic deaths. The supplementation of folic acid and vitamin\u000a        B12, currently part of the\u000a        label of Pemetrexed commercialized with the name of Alimta is the result\u000a        of this collaboration'\u000a      [EV a].\u000a    Continuing, he says that this ultimately permitted `...the completion\u000a        of the development of\u000a        Pemetrexed' [EV a]. The supplementation treatment means that\u000a      patients are better able to tolerate\u000a      the drug and stand to benefit from this treatment.\u000a    Following the Newcastle Phase I trial, the collaborative retrospective\u000a      study with Eli Lilly, and\u000a      incorporating vitamin B12 supplementation in a Phase II trial [R2, R3,\u000a      Section 2], a Phase III trial\u000a      [R4, Section 2] included the supplementation treatment and 500 mg\/m2\u000a      body surface pemetrexed.\u000a      This is recognised in the 2008 National Institute for Health and Care\u000a      Excellence (NICE) guidelines\u000a      for the treatment of malignant pleural mesothelioma, which states that `...with\u000a        effect from the date\u000a        of the protocol change, all patients received supplementation' [EV\u000a      b, p. 8]. The trial confirmed that\u000a      when pemetrexed was supplemented with folic acid and vitamin B12,\u000a      incidences of severe toxicity,\u000a      which include drug-related death, neutropenia (white blood cell\u000a      reduction), febrile neutropenia, and\u000a      diarrhoea, were significantly reduced, compared to when it was not [R4,\u000a      Section 2; EV b].\u000a      Supplemented pemetrexed treatment combined with cisplatin also resulted in\u000a      a significant increase\u000a      in patients' quality of life by reducing disease symptoms, including pain,\u000a      fatigue, anorexia, and\u000a      cough [R4, Section 2; EV b].\u000a    Using pemetrexed with cisplatin also resulted in a significant survival\u000a      benefit for patients with\u000a      malignant pleural mesothelioma. In fully supplemented patients with\u000a      advanced disease, median\u000a      survival was 13.2 months when pemetrexed and cisplatin were administered,\u000a      versus 8.4 months\u000a      for patients given cisplatin alone [EV b]. Pemetrexed also increased\u000a      tumour response rates to\u000a      cisplatin (41.3% with pemetrexed versus 16.7%\u000a      without) and the median time to progressive disease\u000a      (defined as at least 20% growth in tumour size since\u000a      the start of treatment) was significantly longer for\u000a      patients who received pemetrexed and cisplatin as\u000a      compared with patients who received just cisplatin (5.7\u000a      months versus 3.9 months, respectively) [EV b].\u000a      Notably, there has been a marked increase in the\u000a      number of cancer (predominantly MPM) patients in the\u000a      UK receiving pemetrexed treatment following the\u000a      release of the 2008 NICE guidelines (bar chart) [EV c].\u000a\u0009  \u000a      \u000a     \u000a    Impact on Clinical Practice\u000a    In accordance with the 2008 NICE guidelines [EV b, p. 8], pemetrexed with\u000a      cisplatin is currently the\u000a      only chemotherapy regimen licensed for treatment of malignant pleural\u000a      mesothelioma. The\u000a      guidelines cite the Phase III trial [R4, Section 2] which adopted vitamin\u000a      B12 with folic acid\u000a      supplementation into its protocol as a result of the collaborative work\u000a      between Newcastle and Eli\u000a      Lilly [R2, Section 3] as the only identified randomised controlled\u000a      pemetrexed trial in malignant\u000a      pleural mesothelioma. The NICE guidelines clearly state that `...in\u000a        order to reduce toxicity, patients\u000a        treated with pemetrexed must receive folic acid and vitamin B12\u000a        supplementation' [EV b, p. 6]. This\u000a      is also clearly stated in the 2004 FDA and EMEA approvals for pemetrexed\u000a      (Alimta) and in its\u000a      prescription information, and the maximum tolerated dose of 500 mg\/m2\u000a      body surface area [EV d].\u000a      Notably, the US National Guideline Clearinghouse website provides a link\u000a      to the NICE guidelines\u000a      [EV e]. A Phase II trial on the treatment of patients with malignant\u000a      pleural mesothelioma with\u000a      pemetrexed and carboplatin, recently reported that 70% of the 76 patients\u000a      enrolled exhibited\u000a      clinical improvement after just two courses and that the pemetrexed dose\u000a      of 500 mg\/m2 body\u000a      surface area was well tolerated [EV f].\u000a    The former Vice President of Eli Lilly states that to date:\u000a    `...Alimta has been used globally by hundreds of thousands of patients\u000a        and it is standard of\u000a        care in [mesothelioma and non small cell lung cancer]. The\u000a        collaboration [between Newcastle\u000a      University and Eli Lilly] has been crucial for the advancement of the\u000a        knowledge in this field and\u000a        the achievement of the introduction of a medicine that changed the\u000a        modality of treatment for\u000a        mesothelioma and lung cancer' [EV a].\u000a    Pemetrexed treatment with folic acid and vitamin B12 supplementation was\u000a      also adopted into the\u000a      NICE guidelines for non-squamous non-small cell lung cancer (comprises\u000a      most lung cancers) in\u000a      December 2010 [EV g] and for maintenance treatment of this disease in 2012\u000a      [EV h].\u000a    Clinical Trials\u000a    There are currently 361 clinical trials (either open or completed in\u000a      2008-2013) registered on\u000a      clinicaltrials.gov that use pemetrexed in accordance with the FDA and Eli\u000a      Lilly guidelines. These\u000a      include trials on malignant pleural mesothelioma, non-small cell lung\u000a      cancer, squamous cell head\u000a      and neck cancer, advanced urothelial carcinoma, ovarian carcinoma, and\u000a      thyroid cancer, and\u000a      involve over 58,000 patients [EV i].\u000a    ","ImpactSummary":"\u000a    Malignant pleural mesothelioma (MPM) is a treatable but incurable cancer\u000a      that originates in the\u000a      cells lining the lungs. Over 14,000 people worldwide are diagnosed\u000a      annually with MPM. Antifolates\u000a      are often used in cancer therapy, but side effects are a major issue. A\u000a      retrospective analysis of\u000a      cancer trials and phase 1 trial of MPM patients, carried out by Newcastle\u000a      in collaboration with Eli\u000a      Lilly Pharmaceuticals, determined that plasma homocysteine levels were a\u000a      good predictor of drug\u000a      toxicity in cancer patients treated with the antifolate pemetrexed, and\u000a      that this drug was well\u000a      tolerated by patients with low homocysteine levels. It was also determined\u000a      that pemetrexed\u000a      treatment should be supplemented with vitamin B12 as well as folic acid,\u000a      to reduce drug toxicity.\u000a      Ultimately, this permitted the continued development of pemetrexed, which\u000a      otherwise would have\u000a      been too toxic for clinical use. It is now the only licensed drug for MPM\u000a      treatment in combination\u000a      with platinum-based chemotherapy.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Newcastle researchers in bold. Citation count from Scopus, July 2013)\u000a    \u000aR1. Smith PG, Marshman E, Newell DR, Curtin\u000a        NJ. Dipyridamole potentiates the in vitro activity\u000a      of MTA (LY231514) by inhibition of thymidine transport. Br J Cancer. 2000\u000a      Feb;82(4):924-30.\u000a      DOI: 10.1054\/bjoc.1999.1020. Cited by 23.\u000a    \u000a\u000aR2. Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ,\u000a      Stabler SP, Paoletti P,\u000a      Calvert AH, Allen RH. Homocysteine and methylmalonic acid: markers\u000a      to predict and avoid\u000a      toxicity from pemetrexed therapy. Mol Cancer Ther. 2002 May;1(7):545-52.\u000a      PMID: 12479273\u000a      Cited by 186.\u000a    \u000a(Prof Calvert was senior co-author for this paper and provided the\u000a      oncology and antifolate\u000a      expertise. He was a major driver of the study and a long-standing advisor\u000a      to Eli Lilly for the\u000a      development of pemetrexed and other antifolates.)\u000a    \u000aR3. Hughes A, Calvert P, Azzabi A, Plummer R,\u000a      Johnson R, Rusthoven J, Griffin M, Fishwick\u000a      K, Boddy AV, Verrill M, Calvert H. Phase I\u000a      clinical and pharmacokinetic study of pemetrexed\u000a      and carboplatin in patients with malignant pleural mesothelioma. J Clin\u000a      Oncol. 2002\u000a      Aug;20(16):3533-44. DOI: 10.1200\/JCO.2002.10.073. Cited by 118.\u000a    \u000a\u000aR4. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie\u000a      P, Gatzemeier U,\u000a      Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III Study of\u000a      Pemetrexed in\u000a      Combination With Cisplatin Versus Cisplatin Alone in Patients with\u000a      Malignant Pleural\u000a      Mesothelioma. J Clin Oncol. 2003; 21(14):2636-2644. DOI:\u000a      10.1200\/JCO.2003.11.136. Cited\u000a        by 1149.\u000a    \u000aSelected Funding Awards\u000a    \u000a      1999-2003 NECRC Cancer Research Unit Core Grants 2-5. Cancer\u000a        Research UK- £3,427,742\u000a    \u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    EV a. Testimonial letter: Former VP of Eli Lilly Pharmaceuticals (Letter\u000a      held at Newcastle).\u000a    EV b. NICE technology appraisal guidance 135 (2008): Pemetrexed for the\u000a      treatment of\u000a      malignant pleural mesothelioma. http:\/\/guidance.nice.org.uk\/TA135\/Guidance\/pdf\/English\u000a    EV c. Patient numbers extracted from NHS prescription data for\u000a      pemetrexed:\u000a      http:\/\/www.hscic.gov.uk\/searchcatalogue?q=pemetrexed&area=&size=10&sort=Relevance\u000a      in conjunction with statement in NICE guidelines on cost\/patient for a\u000a      course of pemetrexed\u000a      treatment (EV a, p. 7).\u000a    EV d. Prescription information: http:\/\/www.lilly.com\/products\/human\/Pages\/human.aspx\u000a    EV e. http:\/\/guideline.gov\/search\/search.aspx?term=pemetrexed\u000a    EV f. Castagneto, B et al. Phase II study of pemetrexed in combination\u000a      with carboplatin in\u000a      patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008,\u000a      19:370-3. DOI:\u000a      10.1093\/annonc\/mdm501.\u000a    EV g. NICE technology appraisal guidance 181 (2010): Pemetrexed for the\u000a      first-line treatment of\u000a      non-small-cell lung cancer. PDF at:\u000a      http:\/\/guidance.nice.org.uk\/TA181\/Guidance\/pdf\/English\u000a    EV h. NICE technology appraisal guidance 190 (2012): Pemetrexed for the\u000a      maintenance\u000a      treatment of non-small-cell lung cancer. PDF at:\u000a      http:\/\/guidance.nice.org.uk\/TA190\/Guidance\/pdf\/English\u000a    EV i. Data extracted from: http:\/\/www.clinicaltrials.gov\u000a      (Search words `pemetrexed' `alimta', `500\u000a      mg\/m2`; show results for trials open or completed 2008-2013)\u000a    ","Title":"\u000a    Reducing the toxicity of pemetrexed treatment in malignant pleural\u000a      mesothelioma.\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle researchers\u000a    (Where people left\/joined the university in 1993-2013, years are given in\u000a      parentheses)\u000a    AV Boddy (1998 onwards), lecturer\/senior lecturer 1998-2006, then\u000a      professor of cancer\u000a      pharmacology; AH Calvert (1990-2009), professor of medical oncology; NJ\u000a      Curtin, lecturer\/senior\u000a      lecturer 1998-2006, then professor of experimental cancer therapeutics; DR\u000a      Newell, professor of\u000a      cancer therapeutics; R Plummer (2001 onwards), clinical lecturer\/senior\u000a      lecturer of oncology 2001-2008,\u000a      and then clinical professor of experimental cancer medicine.\u000a    Background\u000a    Malignant pleural mesothelioma (MPM) is a cancer that originates in the\u000a      pleura (the lining of the\u000a      lungs). Over 14,000 people worldwide are diagnosed annually with this\u000a      incurable disease, which is\u000a      most often caused by past exposure to asbestos. It is therefore\u000a      particularly prominent in\u000a      industrialised regions closely connected with shipbuilding, mining, and\u000a      construction.\u000a    Antifolates are drugs that are toxic to rapidly dividing cells such as\u000a      malignant cells; therefore, many\u000a      are used in cancer therapy. However, a major problem with antifolates is\u000a      significant side effects,\u000a      which include severe bone marrow suppression (leading to reduced immunity\u000a      and thus increased\u000a      risk of infection) and gastrointestinal toxicity: a combination that\u000a      carries a high mortality risk.\u000a    Research\u000a    Antifolate use in cancer treatment has been a major research area for\u000a      some time. Newcastle\u000a      research into the cellular activity of a multitargeted antifolate\u000a      (LY231514), now known as\u000a      pemetrexed or Alimta [e.g. R1], led to supportive laboratory studies being\u000a      performed and an\u000a      important early-phase clinical trial of pemetrexed.\u000a    Pemetrexed prevents cell replication by interfering with folate-dependent\u000a      processes; thus, it also\u000a      affects normal cells; side effects include low white and red blood cell\u000a      counts, nausea, fatigue,\u000a      shortness of breath, and anaemia. It was recognised that the ability to\u000a      predict patients more likely\u000a      to experience drug-associated toxicity could lead to significant\u000a      improvements in the management\u000a      of this problem. Thus, in a collaborative study, Newcastle and Eli Lilly\u000a      Pharmaceuticals\u000a      retrospectively analysed plasma samples from 246 patients treated with\u000a      pemetrexed, combined\u000a      with folic acid in Phase I and II trials (1995) for cancers other than\u000a      malignant pleural mesothelioma.\u000a      The aim was to identify potentially predictive factors of severe drug\u000a      toxicity [R2]. This analysis\u000a      identified a positive correlation between plasma homocysteine levels and\u000a      pemetrexed toxicity,\u000a      suggesting that measuring pre-treatment homocysteine levels could identify\u000a      patients likely to\u000a      experience severe toxicity. These findings were incorporated into the\u000a      protocol of an Eli Lilly-sponsored\u000a      Phase I clinical trial of MPM therapy, which began at the same time as the\u000a      retrospective\u000a      analysis [R3]. This trial determined the safe dose of pemetrexed with\u000a      carboplatin. The study\u000a      enrolled patients with malignant pleural mesothelioma, and was the first\u000a      prospective study to use\u000a      homocysteine levels as a marker to predict the potential adverse toxicity\u000a      of an antifolate [R3]. This\u000a      ensured that patients that were particularly vulnerable to pemetrexed\u000a      toxicity could be excluded\u000a      from the trial, leaving 27 eligible patients out of 40. The trial proved\u000a      that pemetrexed was well\u000a      tolerated in the trial patients at 500 mg\/m2 body surface area.\u000a      There was also a substantial clinical\u000a      benefit: significant tumour responses (size decrease) and rapid marked\u000a      improvement of debilitating\u000a      symptoms, e.g. shortness of breath and chest pain, in 84% of the patients\u000a      [R3]. The Newcastle\u000a      Phase l trial demonstrated that pemetrexed could be administered safely to\u000a      patients in a platinum\u000a      chemotherapy combination and, ultimately this was the first therapy to be\u000a      approved by the Food\u000a      and Drug Administration (FDA) and the European Medicines Agency (EMEA) in\u000a      2004 for the\u000a      treatment of malignant pleural mesothelioma.\u000a    At the time of the retrospective analysis and Phase I trial, it was known\u000a      that folic acid\u000a      supplementation could potentially reduce antifolate toxicity, but the\u000a      underlying mechanism was\u000a      unclear. However, the retrospective analysis, which included vitamin\u000a      deficiency markers from\u000a      patients, also demonstrated that high pemetrexed toxicity correlated with\u000a      low folate and vitamin\u000a      B12 levels [R2]. As folates and vitamin B12 are required for homocysteine\u000a      metabolism, this offered\u000a      an explanation of why increased homocysteine levels were correlated with\u000a      increased drug toxicity;\u000a      gastrointestinal pathology is thought to be present in the majority of\u000a      patients with B12 deficiency. It\u000a      was therefore inferred that these patients, with their background of\u000a      gastrointestinal pathology might\u000a      experience greater antifolate toxicity, as antifolates also have\u000a      deleterious gastrointestinal side\u000a      effects. These findings suggested that pemetrexed treatment should not\u000a      only be supplemented\u000a      with folic acid, but also vitamin B12, to reduce the toxic side effects of\u000a      antifolates [R2]. Preliminary\u000a      data of vitamin B12 intervention in a Phase II pemetrexed trial confirmed\u000a      that administering folic\u000a      acid and vitamin B12 reduced homocysteine levels and in turn significantly\u000a      reduced the toxicity\u000a      associated with pemetrexed therapy while maintaining, or even improving,\u000a      efficacy [R2].\u000a    As a direct consequence of the retrospective analysis, all patients given\u000a      pemetrexed in\u000a      mesothelioma trials were also subsequently given folic acid and vitamin\u000a      B12. Eli Lilly\u000a      Pharmaceuticals supported a large multi-centre Phase III clinical trial\u000a      and Newcastle was one of\u000a      the participating centres [R4]. The protocol for this trial, which\u000a      involved 456 patients, was revised in\u000a      December 1999 to include supplementation treatment, thus 117 patients were\u000a      not given folic acid\u000a      and vitamin B12 and 339 patients were. This trial, which also incorporated\u000a      the pemetrexed dose of\u000a      500 mg\/m2 body surface area, demonstrated the benefit of\u000a      combining pemetrexed with cisplatin\u000a      (another platinum drug similar to carboplatin) in patients with malignant\u000a      pleural mesothelioma. It\u000a      also confirmed that the addition of folic acid and vitamin B12\u000a      significantly reduced toxicity without\u000a      affecting drug efficacy [R4].\u000a    "},{"CaseStudyId":"21698","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":["Research Councils UK"],"ImpactDetails":"\u000d\u000a    As a result of the underpinning research detailed above, Newcastle has\u000d\u000a      become a leading centre for studying the pharmacology of drugs used to\u000d\u000a      treat children's cancer and so has had a significant impact on the conduct\u000d\u000a      of national and European clinical trials. Crucially, these trials equate\u000d\u000a      to standard treatment approaches for most childhood cancers, and trial\u000d\u000a      protocols act as clinical guidelines. Approximately 90% of neuroblastoma\u000d\u000a      patients are enrolled in clinical trials.\u000d\u000a    Benefits to Patients treated with Carboplatin\u000d\u000a    Newcastle is now established as the national centre for pharmacology\u000d\u000a      studies in childhood cancer, coordinating patient recruitment in 18 UK\u000d\u000a      treatment centres [EV a]. A blood testing service offered by the Newcastle\u000d\u000a      laboratory has been used routinely by 12 of the UK's major treatment\u000d\u000a      centres for children with cancer since 2008, including all of the largest\u000d\u000a      centres, e.g. Alder Hey, Birmingham Children's Hospital and Great Ormond\u000d\u000a      Street [EV a]. The following figure graphically represents the use of\u000d\u000a      carboplatin in treating neuroblastoma patients, in accordance with the\u000d\u000a      protocol for the European High-Risk Neuroblastoma Trial [EV b; Trial\u000d\u000a      NCT01704716] and other challenging patient populations of various tumour\u000d\u000a      types. It shows how the Newcastle blood testing service, alongside the\u000d\u000a      provision of dosing tables by the Newcastle group, has had a direct impact\u000d\u000a      on the treatment of children with carboplatin:\u000d\u000a\u000d\u000a\u000d\u000a\u000d\u000a    The blood testing service is used to determine individualised dosing for\u000d\u000a      the treatment of children with high dose carboplatin chemotherapy and\u000d\u000a      other patients where drug dosing is particularly challenging, including\u000d\u000a      very young children and those without functional kidneys, thus protecting\u000d\u000a      them from experiencing excessive drug exposures. This is a vital tool, and\u000d\u000a      one of the Consultant Paediatric Oncologists at Alder Hey hospital states\u000d\u000a      that through using this service they have `...observed the need for\u000d\u000a        significant dose adjustment in several patients' [EV c].\u000d\u000a      Furthermore, a Consultant Paediatric Oncologist at Birmingham Children's\u000d\u000a      Hospital, confirms that overdosing patients with carboplatin `...significantly\u000a        increases the chances of death from non haematological end organ\u000d\u000a        toxicity during these procedures' and that `...under dosing\u000d\u000a        patients increases the chance of relapse from their malignant tumours'\u000d\u000a      [EV d]. He goes on to say that: `...using the real-time Carboplatin\u000d\u000a        pharmacokinetically guided dosing has allowed both reductions and\u000d\u000a        increases in the predicted total dose of carboplatin of more than 20%\u000d\u000a        and this service has improved both safety and efficacy for our patients'\u000d\u000a      [EV d].\u000d\u000a    A Consultant Paediatric Oncologist at Great Ormond Street also confirms\u000d\u000a      that the Newcastle drug monitoring service `...has been invaluable for\u000d\u000a        the treatment of patients receiving high dose chemotherapy and infant\u000d\u000a        patients where the risk of drug toxicity is a real concern' [EV e].\u000d\u000a    Through involvement with the Children's Cancer and Leukaemia Group, the\u000d\u000a      Newcastle dosing tables for carboplatin are routinely included in clinical\u000d\u000a      trial protocols for various types of childhood cancer, including\u000d\u000a      neuroblastoma and brain tumours [EV b]. Between Jan 2008 and July 2013\u000d\u000a      there were four open clinical trials using the Newcastle dosing tables,\u000d\u000a      with an estimated enrolment of 2,400 children [EV b], all of whom benefit\u000d\u000a      from a more uniform drug exposure to carboplatin. In addition, since 2008\u000d\u000a      the blood testing service has been used to guide dosing in 54 children\u000d\u000a      outside of clinical trials, with dose changes implemented in approximately\u000d\u000a      75% of these patients [EV a, EV f]. Notably, the carboplatin dosage tables\u000d\u000a      have been incorporated into a European High-Risk Neuroblastoma Trial\u000d\u000a      (HR-NBL-1\/SIOPEN), which to date has recruited over 2,000 children at 115\u000d\u000a      sites across Europe and Australia [EV b; Trial NCT01704716]. Furthermore,\u000d\u000a      Newcastle provides one of only three reference laboratories for this trial\u000d\u000a      [EV b; Trial NCT01704716].\u000d\u000a    As noted in Section 2, carboplatin has important advantages over cisplatin\u000a      in terms of reduced long-term toxicity. Now, thanks to the drug monitoring\u000d\u000a      approaches developed at Newcastle carboplatin-toxicity can also be\u000d\u000a      appropriately controlled, even in clinical studies where high doses of\u000d\u000a      carboplatin are necessary. This has ultimately resulted in improved care\u000d\u000a      of children being treated for a number of tumour types. Recently, use of\u000d\u000a      the Newcastle drug monitoring approach has also allowed a curative\u000d\u000a      carboplatin regimen for retinoblastoma to be used safely in the context of\u000d\u000a      maturing renal function in a neonate who was diagnosed with the disease at\u000d\u000a      35 weeks (gestational age) [EV f]. This highlighted a clinical situation\u000d\u000a      where carboplatin therapeutic drug monitoring represented the only\u000d\u000a      feasible treatment approach to ensure an appropriate drug exposure,\u000d\u000a      leading to a successful treatment outcome [EV f].\u000d\u000a    Benefits to Patients treated with 13-cis Retinoic\u000a        Acid\u000d\u000a    Since 2008, and following the establishment of the carboplatin dosing\u000d\u000a      approach, the Newcastle group have been leading therapeutic drug\u000d\u000a      monitoring studies for an additional 11 important chemotherapeutics [EV\u000d\u000a      g]. The Newcastle-led national study on dosing of 13-cis retinoic\u000d\u000a      acid (13-cisRA) in high-risk neuroblastoma patients (R6 in section\u000d\u000a      3) reported that some children are receiving potentially sub-therapeutic\u000d\u000a      doses and therefore may be less likely to benefit from treatment. 13-cisRA\u000a      is a key drug used in maintenance treatment for high-risk neuroblastoma;\u000d\u000a      combining bone marrow transplantation with 13-cisRA treatment\u000d\u000a      results in an 18% increase in 5 year survival rates compared to bone\u000d\u000a      marrow transplantation alone [EV h], highlighting the clinical importance\u000d\u000a      of this drug. As a result of the Newcastle findings, published online in\u000d\u000a      October 2012, children weighing less than 12kg now no longer receive\u000d\u000a      reduced drug doses in clinical trials across Europe [EV b; Trial\u000d\u000a      NCT01704716, EV i], and recommended increased dose levels for children\u000d\u000a      unable to swallow capsules have also been adopted [EV b; Trial\u000d\u000a      NCT01704716, EV i]. These improved dosing guidelines have an impact on\u000d\u000a      over two-thirds of high-risk neuroblastoma patients and allow for optimal\u000d\u000a      administration of 13-cisRA across Europe, as highlighted in a\u000d\u000a      recent editorial published in Clinical Cancer Research [EV j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Clinical pharmacology studies conducted at Newcastle have led to\u000d\u000a      optimisation of the administration of the chemotherapy drug carboplatin in\u000d\u000a      children with neuroblastoma and other cancers. The research provided the\u000d\u000a      rationale for carboplatin dosing based on patient renal function, with\u000d\u000a      individualised dosing resulting in increased drug efficacy and reduced\u000d\u000a      toxicity. This approach is now in widespread use in national and European\u000d\u000a      treatment protocols, benefitting over 2,500 children. Similar drug\u000d\u000a      monitoring approaches are being implemented for an increasing number of\u000d\u000a      important drugs. Following a recent Newcastle-led national clinical trial,\u000d\u000a      new dosing guidelines for the drug 13-cis retinoic acid have been\u000d\u000a      adopted for high-risk neuroblastoma patients across Europe.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Newcastle University\u000d\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    (Newcastle researchers in bold. Citation count from Scopus, July 2013)\u000d\u000a    \u000aR1. Newell DR, Pearson ADJ, Balmanno K, Price L, Wyllie RA, Keir\u000d\u000a      M, Calvert AH, Lewis IJ, Pinkerton CR, Stevens MCG. Carboplatin\u000d\u000a      pharmacokinetics in children: The development of a pediatric dosage\u000d\u000a      formula. Journal of Clinical Oncology (1993). 11: 2314-2323. Cited by\u000d\u000a        104 (PMID:8246021)\u000d\u000a    \u000a\u000aR2. Ghazal-Aswad S, Calvert AH, Newell DR. A single-sample assay\u000d\u000a      for the estimation of the area under the free carboplatin plasma\u000d\u000a      concentration versus time curve. Cancer Chemotherapy and Pharmacology\u000d\u000a      (1996). 37: 429-434. DOI: 10.1007\/s002800050408\u000d\u000a        Cited by 4\u000d\u000a    \u000a\u000aR3. Thomas HD, Boddy AV, English MW, Hobson R, Imeson J, Lewis I,\u000d\u000a      Morland B, Pearson ADJ, Pinkerton R, Price L, Stevens M, Newell\u000a        DR. Prospective validation of renal function-based carboplatin\u000d\u000a      dosing in children with cancer: a United Kingdom Children's Cancer Study\u000d\u000a      Group trial. Journal of Clinical Oncology (2000). 18: 3614-21. Cited\u000d\u000a        by 36 (PMID:11054434)\u000d\u000a    \u000a\u000aR4. Wright J, Boddy AV, Highley M, Fenwick J, McGill A, Calvert AH.\u000d\u000a      Estimation of glomerular filtration rate in cancer patients. British\u000d\u000a      Journal of Cancer (2001). 84: 452-459. DOI: 10.1054\/bjoc.2000.1643.\u000d\u000a        Cited by 94\u000d\u000a    \u000a\u000aR5. Veal GJ, Errington J, Tilby MJ, Pearson ADJ, Foot ABM,\u000d\u000a      McDowell H, Ellershaw C, Pizer B, Nowell GM, Pearson DG, Boddy AV\u000d\u000a      on behalf of the UKCCSG Pharmacology Working Group. Adaptive dosing and\u000d\u000a      platinum-DNA adduct formation in children receiving high dose carboplatin\u000d\u000a      for the treatment of solid tumours. Br J Cancer (2007). 96: 725-731. DOI:\u000d\u000a      10.1038\/sj.bjc.6603607. Cited by 14\u000d\u000a    \u000a\u000aR6. Veal\u000a          GJ, Errington J, Rowbotham SE, Illingworth NA, Malik G, Cole M, Daly\u000d\u000a          AK, Pearson AD, Boddy AV. Adaptive dosing approaches\u000d\u000a      to the individualization of 13-cis-retinoic acid (isotretinoin) treatment\u000d\u000a      for children with high-risk neuroblastoma. Clinical Cancer Research (2013)\u000d\u000a      19(2):469-79. DOI: 10.1158\/1078-0432.CCR-12-2225. Cited by 1\u000d\u000a    \u000aKey funding awards\u000d\u000a    • 2000-2010 Pharmacology Studies in Paediatric Oncology, CRUK\u000d\u000a      Programme grant — £900,000\u000d\u000a    • 2004-2008 Pharmacology of retinoids in neuroblastoma, CRUK PhD\u000d\u000a      Studentship - £100,000\u000d\u000a    • 2005-2010 Academic Fellowship in patient-oriented medical research,\u000d\u000a      RCUK - £125,000\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    EV a. List of UK Centres Utilising Newcastle Real-Time Carboplatin\u000d\u000a      Monitoring \/ Dose Adjustment Service, including patient numbers, supplied\u000d\u000a      by the Blood Sampling Service (Contact provided, and list available on\u000d\u000a      request).\u000d\u000a    EV b. Data and protocols sourced from clinicaltrials.gov.uk.Trial refs:\u000d\u000a      NCT01704716, NCT00047138, NCT00025103 and NCT00274950\u000d\u000a      (Collated table of trials, and full protocol for NCT01704716 available on\u000d\u000a      request)\u000d\u000a    EV c. Letter from Consultant Paediatric Oncologist (Alder Hey Hospital,\u000d\u000a      Liverpool)\u000d\u000a    EV d. Letter from Consultant Paediatric Oncologist (clinical lead for\u000d\u000a      chemotherapy) (Birmingham Children's Hospital)\u000d\u000a    EV e. Letter from Consultant Paediatric Oncologist (Great Ormond Street\u000d\u000a      Hospital, London)\u000d\u000a    EV f. Picton et al. Therapeutic monitoring of carboplatin dosing in a\u000d\u000a      premature infant with retinoblastoma. Cancer Chemother Pharmacol (2009)\u000d\u000a      63:749-752. DOI: 10.1007\/s00280-008-0787-6.\u000d\u000a    EV g. Literature search; trials using drug-monitoring approaches for\u000d\u000a      chemotherapeutic drugs other than carboplatin. Table, including\u000d\u000a      references, available on request.\u000d\u000a    EV h. Matthay KK et al. Long-Term Results for Children with High-Risk\u000d\u000a      Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy\u000d\u000a      Followed by 13-cis-Retinoic Acid: A Children's Oncology Group\u000d\u000a      Study. J Clin Oncol (2009). 27(7):1007-13. DOI: 10.1200\/JCO.2007.13.8925.\u000d\u000a    EV i. Long Term Continuous Infusion ch14.18\/CHO Plus s.c. Aldesleukin\u000d\u000a      (IL-2) (LTI):\u000d\u000a      http:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT01701479\u000d\u000a    EV j. Matthay KK. Targeted isotretinoin in neuroblastoma: Kinetics,\u000d\u000a      Genetics or Absorption. Clin Cancer Res (2013) 19(2):311-3. DOI:\u000d\u000a      10.1158\/1078-0432.CCR-12-3313 \u000d\u000a    ","Title":"\u000d\u000a    Optimising the treatment of childhood cancer through therapeutic drug\u000d\u000a      monitoring\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"},{"GeoNamesId":"2655603","Name":"Birmingham"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Key Newcastle researchers\u000d\u000a      (Where individuals left or joined the university in the period 1993-2013,\u000d\u000a      years are given in brackets)\u000d\u000a    AV Boddy (1998 onwards), lecturer\/senior lecturer 1998-2006, then\u000d\u000a      Professor of Cancer Pharmacology; AH Calvert (1990-2009), professor of\u000d\u000a      medical oncology; DR Newell, professor of cancer therapeutics and senior\u000d\u000a      pharmacologist; ADJ Pearson (1989-2005), Professor of Paediatric Oncology;\u000d\u000a      GJ Veal (1998-onwards) research associate\/senior research associate\u000d\u000a      1998-2005, research fellow 2005-2010 then lecturer\/senior lecturer.\u000d\u000a    Background\u000d\u000a    Cancer is the leading cause of death from disease in children aged 1-14\u000d\u000a      years of age, accounting for approximately 20% of all deaths in this age\u000d\u000a      group in the UK. Neuroblastoma is the most common paediatric malignant\u000d\u000a      solid tumour outside the central nervous system, with approximately 100\u000d\u000a      cases diagnosed annually in the UK and around 900 cases in Europe. The\u000d\u000a      median age at diagnosis is 22 months and the most common type of\u000d\u000a      neuroblastoma is high risk neuroblastoma. This is incurable in over 50% of\u000d\u000a      cases, which in the UK accounts for approx. 15% of cancer related deaths\u000d\u000a      in childhood.\u000d\u000a    The platinum agent cisplatin has been used since the 1970s as a\u000d\u000a      chemotherapeutic drug. Whilst highly effective in the treatment of\u000d\u000a      neuroblastoma and other childhood cancers, the associated long-term\u000d\u000a      toxicity and side effects, including hearing loss (Brock et al. 2012,\u000d\u000a      PMID: 22547603) and kidney damage (Skinner et al. 2009, PMID: 19850470),\u000d\u000a      have encouraged the development of less toxic platinum analogues, leading\u000d\u000a      to the introduction of carboplatin for clinical use. Work in Newcastle and\u000d\u000a      elsewhere had led to a detailed understanding of the pharmacokinetics (the\u000d\u000a      fate of a drug from administration to the point when it is eliminated from\u000d\u000a      the body) of carboplatin in adults. However, there were essentially no\u000d\u000a      data available in children on the pharmacokinetics of carboplatin, a drug\u000d\u000a      used in induction and consolidation chemotherapy regimens for intermediate\u000d\u000a      and high-risk neuroblastoma, when Newcastle initiated these studies [R1].\u000d\u000a    Research\u000d\u000a    The Newcastle group identified two key factors relevant to\u000d\u000a      carboplatin-treatment in children. Firstly, removal of carboplatin from\u000d\u000a      the body was shown to be almost exclusively via elimination of unchanged\u000d\u000a      drug in the urine, with drug clearance found to be closely related to the\u000d\u000a      glomerular filtration rate of the patient. Secondly, exposure (a\u000d\u000a      pharmacokinetic measure that is derived from the drug concentration in the\u000d\u000a      blood and the time it remains in the body) to carboplatin was shown to be\u000d\u000a      more closely correlated than dose of drug administered to both toxicity\u000d\u000a      and clinical response (reduction in tumour size) [R1]. In order to improve\u000d\u000a      standard clinical practice and achieve target drug exposures, Newcastle\u000d\u000a      researchers devised equations to determine the most appropriate\u000d\u000a      carboplatin dose to be administered to individual patients; producing\u000d\u000a      dosing tables and developing appropriate blood sampling strategies to\u000d\u000a      facilitate the monitoring of drug levels in patients [R1, R2]. Subsequent\u000d\u000a      research led by Newcastle, as part of a national multi-centre study,\u000d\u000a      demonstrated in a randomised controlled trial that dosing patients\u000d\u000a      according to renal function resulted in more uniform drug exposure drug\u000d\u000a      [R3]. This ground-breaking research led to a shift from conventional\u000d\u000a      dosing based on body size or surface area to a more rational\u000d\u000a      individualised dosing approach based on renal function. This is\u000d\u000a      particularly pertinent in a paediatric setting, since there is significant\u000d\u000a      variation in renal function throughout childhood.\u000d\u000a    Further studies on methods for estimation of renal function in children\u000d\u000a      and the impact of total nephrectomy (kidney removal) and dialysis (removal\u000d\u000a      of waste from the blood) on the elimination of carboplatin [R4] have\u000d\u000a      allowed the drug to be administered safely in a variety of challenging\u000d\u000a      clinical settings. Perhaps most importantly, using a combination of\u000d\u000a      renal-function estimation and therapeutic drug monitoring, where\u000d\u000a      concentrations of the drug are measured in plasma to inform future dosing\u000d\u000a      decisions, the Newcastle group has pioneered an approach to the\u000d\u000a      safe use of high-dose carboplatin for resistant tumours [R5].\u000d\u000a    Since the carboplatin dosing approach was established, similar\u000d\u000a      therapeutic drug monitoring studies have been carried out with 13-cis\u000d\u000a      retinoic acid (13-cisRA) [R6]. This is a key drug used in\u000d\u000a      maintenance treatment for high-risk neuroblastoma patients. Recently\u000d\u000a      published data from a Newcastle-led national study indicated that children\u000d\u000a      who weigh less than 12kg, who receive a reduced dose of 13-cisRA,\u000d\u000a      are more likely to experience sub-therapeutic drug exposures and therefore\u000d\u000a      may be less likely to benefit from treatment [R6]. In addition, children\u000d\u000a      who are unable to swallow 13-cisRA capsules whole due to their\u000d\u000a      young age, for whom the drug has to be extracted and mixed with food, are\u000d\u000a      also at risk of experiencing low drug exposures [R6].\u000d\u000a    "},{"CaseStudyId":"21706","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Introduction of pharmacogenetic information to warfarin dosing advice\u000a    Several groups around the world made contributions to the body of\u000a      evidence about the role of genetics in determining the warfarin\u000a      sensitivity of patients, however it was the work published by Daly, Kamali\u000a      and others in Newcastle that has been recognised as being fundamental. The\u000a      Medical Director of the Barnes-Jewish Hospital Anticoagulation Service\u000a      (who is also Professor of Medicine at Washington University, St Louis,\u000a      USA) has said, `The seminal paper published by Ann Daly at Newcastle\u000a        University in 1999 [R1] ignited the field of\u000a        pharmacogenetic-based therapy' (Ev a). The importance of the 2005\u000a      study [R2] has also been acknowledged, with the University of Illinois\u000a      Hospital and Health Services Centre confirming that it `formed a\u000a        significant part of the evidence base that ultimately led to\u000a        international clinical trials of gene-guided dosing of anticoagulants\u000a        (including warfarin) being carried out' (Ev b).\u000a    Official guidance: By late 2007 (and so having an impact on\u000a      practice from 2008 onwards) the US Food and Drug Administration had judged\u000a      that the evidence on warfarin pharmacogenetics was sufficiently strong to\u000a      warrant a change to the approved medication guide of warfarin (marketed as\u000a      Coumadin). Since approximately one third of the population carries at\u000a      least one genetic polymorphism that slows the breakdown of warfarin, there\u000a      was a significant opportunity to apply the research findings and protect\u000a      patient health by avoiding overdose. The regulator issued a safety alert\u000a      that stated:\u000a    `FDA approved updated labeling to include pharmacogenomics information\u000a        to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION\u000a        sections of the prescribing information for the widely used\u000a        blood-thinning drug, Coumadin. This new information explains that\u000a        people's genetic makeup may influence how they respond to the drug.\u000a        Specifically, people with variations in two genes may need lower\u000a        warfarin doses than people without these genetic variations. The two\u000a        genes are called CYP2C9 and VKORC1' (Ev c)\u000a    In 2010 a substantial change was made to the drug medication guide that\u000a      is included in the drug packaging when, at the request of the US Food and\u000a      Drug Administration, a table displaying three ranges of warfarin doses\u000a      based on CYP2C9 and VKORC1 genotype information was added (Ev d and Ev e).\u000a    Assisting practitioners: In 2009 the international standard\u000a      algorithm for warfarin dosing was published in the New England Journal\u000a        of Medicine (Ev f). The algorithm was a product of the work of the\u000a      International Warfarin Pharmacogenetics Consortium. Newcastle University\u000a      researchers Daly, Kamali and Sconce all contributed data to the paper that\u000a      outlined the algorithm. Sources at centres in Chicago and Seattle have\u000a      confirmed that the international standard algorithm was `significantly\u000a        underpinned' (Ev b) by Newcastle research (R2) and that the\u000a      Newcastle researchers had published `the first algorithm on CYP2C9 and\u000a        VKORC1 gene-guided dosing of warfarin' (Ev g).\u000a    Application in the clinic\u000a    Interest in the pharmacogenetic approach to warfarin prescribing is\u000a      increasing in clinics across the US, with large academic medical centres\u000a      leading implementation. Since autumn 2010 the Vanderbilt University\u000a      Medical Center in the US has been running the PREDICT programme, which\u000a      aims to embed pharmacogenetic information in its approach to healthcare.\u000a      So far the programme `has included >12,500 subjects and\u000a        warfarin-CYP2C9\/VKORC1 is one of five drug-gene interactions currently\u000a      [being] targeted.'(Ev h)\u000a    The University of Illinois at Chicago has also provided a statement\u000a      concerning practice at its medical centre:\u000a    `beginning in August 2012, all patients newly starting warfarin during\u000a        hospitalization at our medical center are automatically genotyped for\u000a        clinical care to assist with warfarin dosing. Nearly 300 patients have\u000a        been genotyped to date.' (Ev b)\u000a    Large-scale clinical trials\u000a    Clinical trials of gene-based dosing of warfarin, together involving\u000a      thousands of people in the US and Europe, are currently in progress. Daly\u000a      and Kamali contributed to the major European trial, EU-PACT (R6), which\u000a      involved 455 patients. In the US, two large studies are ongoing: the\u000a      WARFARIN study (approximately 3,800 patients, started August 2011) and the\u000a      COAG study (around 1,020 patients, started September 2009) (Ev i).\u000a    The US Food and Drug Administration has estimated that gene-based dosing\u000a      of warfarin will prevent 85,000 serious bleeding events and 17,000 strokes\u000a      a year in the US (Ev j).\u000a    ","ImpactSummary":"\u000a    Warfarin is an anti-coagulant drug prescribed to tens of millions of\u000a      people in the UK and US who are at high risk of developing blood clots.\u000a      Because individual sensitivity to warfarin varies in the population there\u000a      is a risk of overdosing the drug and causing serious bleeding and even\u000a      stroke in many people when starting treatment. In 1999 researchers at\u000a      Newcastle University were the first to demonstrate a statistically\u000a      significant link between a person's genotype and the appropriate dose of\u000a      warfarin. In 2010 the US Food and Drug Administration (FDA) mandated\u000a      inclusion of a table of dose recommendations based on genotype in the\u000a      warfarin prescribing information leaflet accompanying the drug. Newcastle\u000a      research forms the basis of the 2009 international standard algorithm for\u000a      gene-guided dosing of warfarin. This approach has been adopted by large US\u000a      medical centres and the FDA states that it will prevent 17,000 strokes a\u000a      year in the US.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5809844","Name":"Seattle"},{"GeoNamesId":"4896861","Name":"Illinois"},{"GeoNamesId":"4407066","Name":"St. Louis"}],"References":"\u000a    (Newcastle authors shown in bold. Citations from Scopus as at July 2013.)\u000a    \u000aR1. Aithal GP, Day CP, Kesteven PJL & Daly\u000a        AK (1999). Association of polymorphisms in the cytochrome P450\u000a      CYP2C9 with warfarin dose requirement and risk of bleeding complications.\u000a      Lancet 353:717-719. DOI: 10.1016\/S0140-6736(98)04474-2. 807\u000a        citations.\u000a    \u000a\u000aR2. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood\u000a        P, Kesteven P, Daly AK & Kamali F (2005). The impact of CYP2C9\u000a      and VKORC1 genetic polymorphism and patient characteristics upon warfarin\u000a      dose requirements: proposal for a new dosing regimen. Blood\u000a      106:2329-2333. DOI: 10.1182\/blood-2005-03-1108. 506 citations.\u000a    \u000a\u000aR3. The International Warfarin Pharmacogenetics Consortium (2009).\u000a      Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N\u000a        Engl J Med 360:753-764. DOI: 10.1056\/NEJMoa0809329. 558\u000a        citations\u000a    \u000a\u000aR4. Howard R, Leathart JBS, French DJ, Krishan E, Kohnke H,\u000a      Wadelius M, van Schie R, Verhoef T, Maitland-van der Zee A-H, Daly AK\u000a      & Barallon R (2011). Genotyping for CYP2C9 and VKORC1 alleles by a\u000a      novel point of care assay with HyBeacon (R) probes. Clinica Chimica\u000a        Acta 412:2063-2069. DOI: 10.1016\/j.cca.2011.07.013. 10\u000a        citations. (Daly is the corresponding author)\u000a    \u000a\u000aR5. Avery PJ, Jorgensen A, Hamberg A, Wadelius M, Pirmohamed M\u000a      & Kamali F (2011). A Proposal for an individualized\u000a      pharmacogenetics-based warfarin initiation dose regimen for patients\u000a      commencing anticoagulation therapy. Clinical Pharmacology and\u000a        Therapeutics 90:701-706. DOI: 10.1038\/clpt.2011.186. 10\u000a        citations. (Kamali is the corresponding author and the first author\u000a      is Senior Lecturer, Department of Mathematics and Statistics, Newcastle\u000a      University.)\u000a    \u000a\u000aR6. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson\u000a      T, Kesteven P, Christersson C, Wahlström B, Stafberg C, Zhang E, Leathart\u000a      JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery\u000a        P, Kamali F, Wadelius M (2013). A Randomized Trial of\u000a      Genotype-Guided Dosing of Warfarin. N Engl J Med (publication\u000a      online Nov 2013). (Kamali is joint senior author with Wadelius)\u000a    \u000aKey research grants\u000a    European Commission Biomedical Programme. 1996-8. £33 512. Eurohepatotox.\u000a    GenoType Ltd. 2001-4. £35 000. A Study of Genetic Factors Affecting\u000a        Warfarin Dose Requirements.\u000a    European Commission FP7. 2007-13. £250 000 to Newcastle University. European\u000aPharmacogenetics\u000a        of Anti-Coagulant Therapy (EU-PACT) study design.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    Ev a. Correspondence from a Professor of Medicine, Washington University\u000a      Medical School, St Louis is available and contact details are available on\u000a      request.\u000a    Ev b. Correspondence from an Associate Professor at the Department of\u000a      Pharmacy Practice, University of Illinois at Chicago is available and\u000a      contact details are available on request.\u000a    Ev c. US Food and Drug Administration (August 2007): Warfarin (marketed\u000a      as Coumadin) — safety alert.\u000a      http:\/\/www.fda.gov\/Safety\/MedWatch\/SafetyInformation\/SafetyAlertsforHumanMedicalProducts\/ucm152972.htm\u000a    Ev d. US Food and Drug Administration (January 2010): Coumadin (warfarin\u000a      sodium) tablet and injection. Detailed View: Safety Labeling Changes\u000a      Approved By FDA Center for Drug Evaluation and Research (CDER).\u000a      http:\/\/www.fda.gov\/Safety\/MedWatch\/SafetyInformation\/ucm201100.htm\u000a    Ev e. Bristol-Myers Squibb website: Coumadin (warfarin) drug medication\u000a      guide.\u000a      http:\/\/packageinserts.bms.com\/pi\/pi_coumadin.pdf\u000a      (Dosing table on page 2, column 2.)\u000a    Ev f. The International Warfarin Pharmacogenetics Consortium (2009).\u000a      Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N\u000a        Engl J Med 360:753-764. DOI:\u000a      10.1056\/NEJMoa0809329. 558 citations\u000a    Ev g. Correspondence from a Professor and Chair of Medicinal Chemistry at\u000a      the Department of Medicinal Chemistry, University of Washington, Seattle\u000a      is available and contact details are available on request.\u000a    Ev h. Correspondence from the Director of the Oates Institute for\u000a      Experimental Therapeutics at the Vanderbilt School of Medicine is\u000a      available and contact details are available on request.\u000a    Ev i. Trial information at clinicaltrials.gov\u000a      EU-PACT http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01119300\u000a      WARFARIN http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01305148\u000a      COAG http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00839657\u000a    Ev j. US Food and Drug Critical Path Initiative: Warfarin Dosing.\u000a      http:\/\/www.fda.gov\/ForConsumers\/ConsumerUpdates\/ucm077473.htm\u000a    \u000a    ","Title":"\u000a    Developing gene-guided dosing of warfarin to improve patient safety\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle University researchers\u000a    At the time of the research Professors Ann Daly and Farhad Kamali were\u000a      both Senior Lecturers in the Department of Pharmacological Sciences.\u000a    Background\u000a    Warfarin is an anti-coagulant drug used to prevent and treat many\u000a      clotting disorders, that otherwise can lead to severe outcomes such as\u000a      stroke. It is very commonly prescribed: over 10.1 million prescriptions of\u000a      warfarin were written in 2012 in England, with approximately 1% of the UK\u000a      population being prescribed this drug at any given time. 33.9 million\u000a      prescriptions of the drug were dispensed in 2011 at retail pharmacies in\u000a      the US (data from the NHS Information Centre and IMS Health).\u000a    It has long been known that age, race, gender, weight, and the presence\u000a      or absence of co-morbidities (and associated medications) all influence\u000a      patient sensitivity to warfarin. Choosing the correct starting dose of\u000a      warfarin is a complex decision and once started, the dose will be adjusted\u000a      to the optimum level by closely monitoring the clotting ability of the\u000a      patient's blood over the course of several weeks. Overdosing a patient\u000a      with warfarin dramatically increases the risk of bleeding, and can\u000a      potentially also cause a stroke. Such overdosing is most likely in the\u000a      first few months of treatment. The Food and Drug Administration reported\u000a      in 2007 that warfarin was the second most common drug (insulin was the\u000a      first) implicated in emergency room visits in the US, amounting to tens of\u000a      thousands of trips per year (Lesko 2008 PMID: 18714317). Newcastle\u000a      University researchers, in collaboration with American colleagues,\u000a      realised that variable patient sensitivity to warfarin might have a\u000a      genetic component and explored this in a clinical study.\u000a    Underpinning research\u000a    Newcastle University researchers were partners in the first clinical\u000a      study, led by the National Cancer Institute in the USA, which explored the\u000a      association between warfarin sensitivity and one variant allele of the\u000a      gene CYP2C9 (which encodes a liver enzyme that breaks down warfarin).\u000a      Although the results (Furuya et al. 1995 PMID: 8747411) did not reach\u000a      statistical significance they showed an association between genotype and\u000a      warfarin dose requirement. Subsequent research revealed that there are\u000a      actually two common variant alleles relevant to warfarin sensitivity.\u000a    These findings led Daly and others to refine the clinical study\u000a      methodology and explore more clearly the link between genotype and\u000a      warfarin sensitivity. By focussing on a group of patients with a\u000a      requirement for low doses of the drug they were, in 1999, the first to\u000a      demonstrate a statistically significant association between CYP2C9\u000a      genotype and sensitivity to warfarin (R1). The study also confirmed that\u000a      this group of patients needing a low dose of warfarin were significantly\u000a      more likely to have suffered serious bleeding events whilst taking the\u000a      drug.\u000a    In a 2005 study of 297 patients, each of whom was on a stable maintenance\u000a      dose of warfarin, Newcastle researchers assessed the genetic contribution\u000a      of sensitivity to the drug, relative to known factors of age and body\u000a      size. Consistent with their previous findings, patients with two copies of\u000a      the most common allele of CYP2C9 required significantly higher doses than\u000a      those possessing one or more variant alleles. The same study also reported\u000a      a significant association between allelic variants of another gene -\u000a      VKORC1 (which encodes the target of warfarin) - and warfarin dose\u000a      requirement. On the basis of these results a novel warfarin dosing regimen\u000a      incorporating CYP2C9 and VKORC1 genotype information, age and body size\u000a      was developed and validated (R2). Newcastle researchers were then closely\u000a      involved with the International Warfarin Pharmacogenetics Consortium in\u000a      the production of a refined algorithm, published in 2009, following a\u000a      trial involving 4,043 patients (R3).\u000a    Research involving Newcastle has continued, with Kamali and Daly leading\u000a      work packages within the EU-PACT European multi-site randomised controlled\u000a      trial of the safety and utility of genotype-guided dosing of\u000a      anticoagulants involving 455 patients. Newcastle University researchers\u000a      contributed to patient recruitment for the trial and led on (i) developing\u000a      and validating a rapid (~2hr) point of care test for genotyping (R4) and\u000a      (ii) developing an algorithm for genotype-guided dosing appropriate for\u000a      the study (R5). The EU-PACT study has shown that patients dosed with\u000a      warfarin based on CYP2C9 and VKORC1 genotype had on average a coagulation\u000a      rate within the desired range for 67.4% of measurements in the first 3\u000a      months of treatment compared with 60.3% of measurements in the controls\u000a      who received conventional dosing (R6). This difference was highly\u000a      significant (p<0.001). Genotyped patients exceeded the safe clotting\u000a      time in 2.3% of samples monitored, while the value for controls was 5.3%\u000a      (p<0.001). The study found that genotyping improves the safety of\u000a      warfarin treatment during initial dosing when adverse events are most\u000a      common; time to stable dosage was 44 days for genotyped patients and 59\u000a      days in controls (p<0.003) (R6).\u000a    "},{"CaseStudyId":"21709","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    The challenge of liver disease\u000a    Non-alcoholic fatty liver disease (NAFLD) is the most common liver\u000a      disease in the developed world\u000a      with a prevalence of 20-25% in the general population. It is closely\u000a      associated with obesity,\u000a      diabetes and other features of the metabolic syndrome with a prevalence of\u000a      more than 90% in\u000a      obese populations and more than 70% in patients with type 2 diabetes.\u000a      Although the first stage of\u000a      NAFLD — simple steatosis — has a benign outcome, patients with more\u000a      advanced, fibrotic, disease\u000a      can progress to cirrhosis, liver failure and hepatocellular cancer as well\u000a      as an increased risk of\u000a      cardiovascular disease. As expected, patients with fibrotic NAFLD have an\u000a      increased overall, liver-\u000a      and cardiovascular-related mortality compared to the age- and gender\u000a      matched population. In light\u000a      of these different prognoses, it is vital to differentiate the vast\u000a      majority of NAFLD patients with\u000a      steatosis from the minority (10-20%) with advanced fibrotic NAFLD, since\u000a      this latter group require\u000a      careful monitoring and treatment with emerging therapies. At the outset of\u000a      the research, the only\u000a      accurate way to determine the severity of NAFLD was by liver biopsy (EV\u000a      a), an expensive\u000a      procedure which is invasive and associated with morbidity and occasional\u000a      mortality. For example,\u000a      minor pain is experienced in around 10% of cases, major pain in 1% and\u000a      death in 0.1% (EV a, b).\u000a      Furthermore, since a sample represents only 1\/50,000 of the whole liver\u000a      and lesions are scattered\u000a      throughout the organ, biopsy is prone to sampling error and may lead to\u000a      misdiagnosis (EV d).\u000a    The identification of predictive variables of fibrosis and subsequent\u000a      validation of the NAFLD\u000a      Fibrosis Score (NFS), in studies led by the Newcastle Liver Group has\u000a      provided a safe and reliable\u000a      non-invasive alternative to liver biopsy for the vast majority (up to 75%)\u000a      of patients with NAFLD,\u000a      markedly reducing associated morbidity.\u000a    As evidence of the impact of the NFS, it has now been incorporated into policy,\u000a      forming part of two\u000a      international guidelines and is now routinely used in clinical\u000a        practice in the UK, with associated\u000a      patient benefit and reduced cost for the NHS.\u000a    Policy\u000a    Firstly, the 2010 European Association for the Study of Liver (EASL)\u000a    position statement on\u000a    NAFLD (EV c) includes the NFS as one of three \"simple clinical scores\"\u000a    and cites R1. Secondly,\u000a    the 2012 Guidelines from the American Association for the Study of Liver\u000a      Diseases,\u000a    American College of Gastroenterology, and the American Gastroenterological\u000a    Association (EV a)\u000a    state: \"NAFLD Fibrosis Score is a clinically useful tool for identifying\u000a      NAFLD patients with higher\u000a      likelihood of having bridging fibrosis and\/or cirrhosis\" (pg 2010).\u000a    The recommendation is level 1\u000a    (strong) under the GRADE system.\u000a    Practice\u000a    The NAFLD score has been taken up and used in practice nationwide. Of the\u000a      major UK liver units\u000a      that responded to the request for a statement, all were positive. Some\u000a      examples include:\u000a    \u000a      \u000a\"It's made a big difference to my practice. I use the NFS [NAFLD\u000a          Fibrosis Score] in my\u000a          modified map of medicine to allow GPs to triage their referrals for\u000a          NAFLD. This was agreed\u000a          with the commissioners. [We] currently have 5 new and 20-25 reviews\u000a          per week in the\u000a          NAFLD clinic\" (EV e)\u000a      \"I use the NAFLD score. It is reliable and easy to use.\"(EV\u000a        f)\u000a      \u000a\"NAFLD Fibrosis Score is embedded in our chronic liver disease\u000a          database.\" (EV g)\u000a    \u000a    Two websites have been set up (EV h, i) that allow simple calculation of\u000a      NAFLD score using the\u000a      formula set out in the paper by Angulo et al. (R1). The creator of\u000a      the gihep.com calculator (EV h),\u000a      states \"We appreciate the NAFLD calculator and many of our faculty use\u000a        this on a regular basis at\u000a        Indiana University and from the usage statistics (~25 uses\/day) from\u000a        around the world. It has been\u000a        on the site since October 2011.\" The calculator at nafldscore.com\u000a      was created in early 2009 and is\u000a      used to calculate a NAFLD score approximately 5000 times per month (EV i).\u000a    Patient and NHS benefit\u000a    Liver biopsy is associated with pain, occasionally mortality and sampling\u000a      error (EV a, b, c). Since\u000a      the NAFLD Fibrosis Score identifies those patients who do not need a\u000a      biopsy, it allows up to 75%\u000a      of biopsies to be spared (R1), decreasing patient risk and saving time. In\u000a      financial terms, avoiding\u000a      liver biopsy also represents cost savings to the NHS. The June 2013 NICE\u000a      costing template (EV j)\u000a      states that a liver biopsy costs £535, and a 2013 audit (EV b) of UK liver\u000a      biopsy stated that 3500\u000a      biopsies were carried out in 2008 by the 87 radiology departments that\u000a      responded, out of a total of\u000a      210. This means that using the NFS to spare liver biopsy would have saved\u000a      the NHS £1,872,500\u000a      annually across these departments alone. Since the NFS score is based on\u000a      patient data that are\u000a      routinely available to liver doctors and GPs, costs are minimised and the\u000a      NHS benefits from\u000a      financial savings.\u000a    In summary, Newcastle research has validated a non-invasive test\u000a      for non-alcoholic fatty liver\u000a      disease that spares the need for liver biopsy, an invasive, painful and\u000a      costly process.\u000a    ","ImpactSummary":"\u000a    Non-alcoholic fatty liver disease (NAFLD) is the most common liver\u000a      disease in the developed world\u000a      with a prevalence of 20-25% in the general population. Until Newcastle\u000a      validated its new\u000a      diagnostic, the only accurate way to determine the severity of NAFLD was\u000a      by liver biopsy, an\u000a      expensive and invasive procedure which is associated with morbidity and\u000a      occasional mortality.\u000a      Studies lead by Professor Day in Newcastle have established a non-invasive\u000a      fibrosis scoring\u000a      system, the NAFLD Fibrosis Score (NFS), which is capable of accurately\u000a      differentiating patients\u000a      with and without fibrosis. The NFS has now been incorporated into two\u000a      international guidelines,\u000a      allows biopsy to be avoided in up to 75% of patients and could save the\u000a      NHS nearly £2m annually.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Scopus citation data at as 31.7.13, Newcastle researchers\u000a      highlighted in bold)\u000a    \u000aR1. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC,\u000a      Enders F, Saksena S,\u000a      Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench\u000a      J, Therneau TM,\u000a      Day CP. (2007). The NAFLD fibrosis score: a noninvasive system that\u000a      identifies liver\u000a      fibrosis in patients with NAFLD. Hepatology.;45:846-854. DOI:\u000a      10.1002\/hep.21496. Cited\u000a        by 299\u000a    \u000a\u000aR2. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP.\u000a      Simple non-invasive fibrosis\u000a      scoring systems can reliably exclude advanced fibrosis in patients with\u000a      non-alcoholic fatty\u000a      liver disease (2010). Gut; 59:1265-1269. DOI:\u000a      10.1136\/gut.2010.216077. Cited by 50,\u000a      Editor's Choice.\u000a    \u000aRelevant funding award\u000a    \u000a      2010-2013. Commission of the European Communities. £1,002,729. Neptune\u000a          \/ FLIP\u000a          Project.\u000a\u000a    \u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    EV a. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K,\u000a      Charlton M, Sanyal AJ.\u000a      (2012) The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease:\u000a      Practice\u000a      Guideline by the American Association for the Study of Liver Diseases,\u000a      American College\u000a      of Gastroenterology, and the American Gastroenterological Association. Hepatology\u000a      (55):\u000a      6, 2005-2023.\u000a    EV b. Howlett DC, Drinkwater KJ, Lawrence D, Barter S, Nicholson T.\u000a      (2013) Findings of the UK\u000a      national audit evaluating image-guided or image-assisted liver biopsy.\u000a      Part II. Minor and\u000a      major complications and procedure-related mortality. Radiology.\u000a      266(1):226-35.\u000a    EV c. Ratziu V, Bellentani S, Cortez-Pinto H, Day CP, Marchesini G.\u000a      (2010) A position\u000a      statement on NAFLD\/NASH based on the EASL 2009 Special Conference. The\u000a        Journal of\u000a        Hepatology; 53:372-84.\u000a    EV d. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E,\u000a      Grimaldi A, Capron F,\u000a      Poynard T; LIDO Study Group. (2005). Sampling Variability of Liver Biopsy\u000a      in\u000a      Nonalcoholic Fatty Liver Disease. Gastroenterology. 128\u000a      (7):1898-906.\u000a    EV e. Statement from the Senior Lecturer in Hepatology and Clinical\u000a      Director of the Birmingham\u000a      University Stem Cell Centre, contact details available on request\u000a    EV f. Statement from the Wellcome Trust Intermediate Clinical Fellow\u000a      (Honorary Consultant) at\u000a      University College London, contact\u000a        details available on request.\u000a    EV g. Statement from the Honorary Clinical Senior Lecturer, University of\u000a      Glasgow, contact\u000a      details available on request.\u000a    EV h. Online NAFLD score calculator run by the Gastroenterology and\u000a      Medical Informatics\u000a      Fellow, Indiana University School of Medicine, contact details available\u000a      on request.\u000a      http:\/\/gihep.com\/calculators\/hepatology\/nafld-fibrosis-score\/,\u000a    EV i. Online NAFLD score calculator run by The Wellcome Trust Clinical\u000a      Research Fellow and\u000a      Honorary Specialist Registrar in Hepatology, contact details available on\u000a      request.\u000a      http:\/\/nafldscore.com\/\u000a    EV j. NICE costing template: CG165 Hepatitis B (chronic). Available at\u000a      www.nice.org.uk\/nicemedia\/live\/14191\/64226\/64226.xls\u000a        under tab 4: unit costs\u000a    \u000a    ","Title":"\u000a    Simple, non-invasive, diagnosis of liver fibrosis severity in\u000a      non-alcoholic fatty\u000a      liver disease (NAFLD)\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle researchers\u000a    Professors Christopher Day (Senior Lecturer 1997-2000, Professor of Liver\u000a      Medicine 2000-2008,\u000a      Pro-Vice-Chancellor\/Provost of the Faculty of Medical Sciences 2008-date)\u000a      and Alastair Burt\u000a      (Professor of Hepatopathology 1989-2012).\u000a    Validation of the NFS as a non-invasive measure of advanced liver\u000a        fibrosis\u000a    Between 2000 and 2003, working with collaborators in Italy, Australia and\u000a      the US (Mayo Clinic),\u000a      Professors Christopher Day and Alastair Burt of Newcastle University\u000a      collected the clinical data\u000a      and routine laboratory tests of 733 patients with biopsy-proven, definite\u000a      NAFLD of different fibrosis\u000a      severities (R1). Patients were divided into two groups to construct\u000a      (n=480) and validate (n=253) a\u000a      scoring system, the NAFLD Fibrosis Score (NFS). Routinely available\u000a      demographic, clinical and\u000a      laboratory variables were analyzed by multivariate modelling to predict\u000a      the presence or absence of\u000a      advanced fibrosis (either stage 3, bridging fibrosis, or stage 4,\u000a      cirrhosis). Six variables were found\u000a      to be independent indicators of advanced liver fibrosis: age,\u000a      hyperglycemia, body mass index,\u000a      platelet count, albumin, and the ratio of two liver enzymes (AST:ALT).\u000a      This scoring system was\u000a      found to have an accuracy of 0.88 and 0.82 in the estimation and\u000a      validation groups, respectively.\u000a    By applying the high cut-off score, the presence of advanced fibrosis\u000a      could be diagnosed with high\u000a      accuracy (positive predictive value of 90% and 82% in the estimation and\u000a      validation groups,\u000a      respectively). Applying this model would have spared liver biopsy in 549\u000a      (75%) of the 733 patients,\u000a      with correct prediction in 496 (90%). By applying the low cut-off score,\u000a      advanced fibrosis could be\u000a      excluded with high accuracy (negative predictive value of 93% and 88% in\u000a      the estimation and\u000a      validation groups, respectively). This means that the great value of the\u000a      NFS is in negative\u000a      prediction of NAFLD — identifying those patients who do not require\u000a      biopsy, and thus sparing a\u000a      painful and invasive procedure.\u000a    Comparison of the NAFLD Fibrosis Score to other non-invasive tests\u000a    A second study performed entirely in Newcastle on an independent cohort\u000a      of biopsy-proven\u000a      NAFLD patients (n=145) demonstrated that the NFS had a higher positive\u000a      predictive value (79%)\u000a      and an equivalent negative predictive value (92%) to the other four\u000a      available simple non-invasive\u000a      scoring systems for the diagnosis of advanced fibrotic NAFLD (R2). The\u000a      high accuracy in both high\u000a      and low cut-off score makes this tool a robust mechanism to justify the\u000a      clinical decision to biopsy a\u000a      patient.\u000a    "},{"CaseStudyId":"21717","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Impact on UK policy and practice\u000a      The impact of the Newcastle University-led research has been significant\u000a      in the UK. First, as a matter of policy, almost all newly diagnosed CGD\u000a      patients are now listed for bone marrow transplant. This is because\u000a      transplantation as soon as possible after diagnosis is preferred since\u000a      delay lengthens the period in which infections or inflammatory problems\u000a      can become established. Such problems were shown by Newcastle research to\u000a      be major risk factors for serious complications around the time of the\u000a      transplant. Second, transplantation with bone marrow from a matched\u000a      unrelated donor is now considered acceptable when matched sibling donors\u000a      are not available. This means that many more transplants are possible than\u000a      was previously the case. This approach to the treatment of new CGD cases\u000a      pioneered at Newcastle has been adopted by the other UK specialist centre\u000a      — Great Ormond Street Hospital. The Director of the Bone Marrow\u000a      Transplantation Unit there has confirmed that practice at that hospital\u000a      has changed as a result of Newcastle University research, saying,\u000a    `Undoubtedly up to 2009 we had a different approach to BMT [bone\u000a      marrow transplantation] in CGD between the two NCG units\u000a      [Newcastle and Great Ormond Street] with a much more conservative\u000a        approach at GOS compared to Newcastle. Also without doubt your\u000a        presentations at the NCG audit meetings and your publication of the\u000a        excellent outcome of the Newcastle single centre experience of MSD\/MUD*\u000a        for CGD, convinced us to change our strategy to match yours.' (Ev a)\u000a      [*matched sibling donor and matched unrelated donor transplantation]\u000a    The effect of the changes in policy and practice are demonstrated in the\u000a      number and type of bone marrow transplants carried out in the UK on\u000a      patients with CGD (Ev b) and shown in table 1.\u000a    Table 1. Number of bone marrow transplants at the two UK centres,\u000a      categorised by type.\u000a    \u000a      \u000a        \u000a          \u000a          Matched\u000a          sibling\u000a          Matched\u000a          unrelated\u000a          Totals\u000a          \u000a        \u000a        \u000a          Years\u000a          Newcastle\u000a          GOS\u000a          Newcastle\u000a          GOS\u000a          Newcastle\u000a          GOS\u000a        \u000a        \u000a          1998-2002\u000a          9\u000a          2\u000a          2\u000a          2\u000a          11\u000a          4\u000a        \u000a        \u000a          2003-2007\u000a          1\u000a          1\u000a          6\u000a          3\u000a          7\u000a          4\u000a        \u000a        \u000a          2008-2012\u000a          2\u000a          2\u000a          21\u000a          11\u000a          23\u000a          13\u000a        \u000a      \u000a    \u000a    As shown in table 1, the Newcastle centre has led on the practice of\u000a      transplanting patients with CGD. What is also striking is the shift from\u000a      using bone marrow from matched sibling donors to using that from matched\u000a      unrelated donors. The effect of this has been to increase the total number\u000a      of transplants carried out (a larger pool of available donors) and this is\u000a      particularly notable in the data from Great Ormond Street. Of the 36\u000a      transplants between 2008 and 2013 32 children are alive and cured of the\u000a      disease. It is thus clear that many children now have a significantly\u000a      better quality of life, than would otherwise have been the case.\u000a    Impact on international guidelines and practice\u000a      The European Society for Immunodeficiencies and European Group for Blood\u000a      and Marrow Transplantation published guidelines in 2011 on bone marrow\u000a      transplantation for treatment of primary immunodeficiencies, a class of\u000a      diseases that includes CGD. The guidelines recommend a more conservative\u000a      approach (a default position of anti-microbial prophylaxis) than that\u000a      taken in the UK but they nonetheless incorporated Newcastle University\u000a      research findings, describing excellent outcomes after transplants with\u000a      matched unrelated donor material. The guidelines state that either of the\u000a      inherited forms of CGD can be cured with transplants from matched sibling,\u000a      matched unrelated and mis-matched unrelated donors (Ev c, p19). Two\u000a      Newcastle research papers (R1 & R2) are listed among the five\u000a      supporting references in the chronic granulomatous disease section of the\u000a      guidelines document.\u000a    In the United States bone marrow transplantation is now increasingly\u000a      preferred as a treatment for children with CGD. In a 2011 paper,\u000a      clinicians at the National Institutes of Health cited the European and UK\u000a      experience of transplantation (including R1 and R2) and concluded:\u000a    `allogeneic transplantation has improved dramatically over the last\u000a        decade.... It has become a successful and sensible option for many\u000a        patients with CGD that will likely treat and prevent both infectious and\u000a        inflammatory complications.' (Ev d)\u000a    Engagement with patient group\u000a      With a base in London, the UK CGD Society attracts members from all over\u000a      the world (59% are from outside the UK). Around 150 people are now\u000a      registering with the society each year. Their website www.cgdsociety.org\u000a      is a source of information about the science of CGD, diagnosis, disease\u000a      management and treatment, and acts as a portal to facilitate access of\u000a      patients and their families to support services. Gennery has contributed\u000a      significantly to material on the society website that explains bone marrow\u000a      transplantation, including presenting a video in which he sets out to\u000a      demystify bone marrow transplantation. There have been over 1200 page\u000a      views on the bone marrow transplantation section of the society's website.\u000a      A representative from the society has described the impact of the\u000a      Newcastle University research on patients:\u000a    `More families with young children are now actively considering\u000a      [bone marrow transplant (BMT)] as a treatment option for CGD when their\u000a        child is well rather than when they become seriously ill. This is a\u000a        significant step forward and has been made possible by the advances and\u000a        increased success of BMT for all primary immunodeficiencies, including\u000a        CGD. Dr Gennery... has also added important knowledge about the impact\u000a        of CGD on the quality of life of those affected and demonstrated how\u000a        this and the growth and development of children returns to normal post\u000a        BMT.' (Ev e)\u000a    The change in approach by clinicians in the UK towards treatment of the\u000a      disease is reflected in the information provided by the UK CGD Society to\u000a      patients and their families. The society's An introduction to bone\u000a        marrow transplantation for parents, which was approved in July 2013\u000a      by the CGD Society and a Specialty Doctor in bone marrow transplant at\u000a      Great Ormond Street Hospital, states:\u000a    `A bone marrow transplant is now the recommended course of treatment\u000a        for any child diagnosed with CGD. As with every medical procedure, there\u000a        is a level of risk associated with a BMT. However, in most cases,\u000a        experts consider this risk to be manageable.' (Ev f)\u000a    Although the numbers of patients being treated is small, the two centres\u000a      together have had a significant impact on CGD in the UK, reaching all\u000a      those in need and contributing to the improved health and wellbeing of not\u000a      only the children themselves, but also their wider families.\u000a    ","ImpactSummary":"\u000a    Chronic granulomatous disease is a rare but very serious inherited\u000a      disorder of the immune system that leaves sufferers vulnerable to\u000a      potentially fatal bacterial and fungal infections. Researchers at\u000a      Newcastle University demonstrated very high survival and cure rates\u000a      following bone marrow transplantation for the disease and good quality of\u000a      life for successfully transplanted patients. This led to a change in\u000a      national clinical policy, and doctors at both specialist disease centres\u000a      in the UK now recommend transplantation to families where previously they\u000a      would not have done so. In the five years prior to 2008 there were only 11\u000a      transplants for chronic granulomatous disease in the UK and in the\u000a      following five years, 36 transplants. 32 children are alive and cured of\u000a      the disease.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Newcastle researchers in bold. Citations from Scopus as at July 2013)\u000a    \u000aR1. Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di\u000a      Bartolomeo P, Flood T, Landais P, Müller S, Ozsahin H, Passwell JH, Porta\u000a      F, Slavin S, Wulffraat N, Zintl F, Nagler A, Cant A, Fischer A\u000a      (2002). Treatment of chronic granulomatous disease with myeloablative\u000a      conditioning and an unmodified hemopoietic allograft: a survey of the\u000a      European experience, 1985-2000. Blood 100(13):4344-50. DOI:\u000a      10.1182\/blood-2002-02-0583. 110 citations.\u000a    \u000aCant had a significant role in producing output R1. He contributed about\u000a      a third of the patient data to the study and to drafting the manuscript.\u000a    \u000aR2. Soncini E, Slatter MA, Jones LB, Hughes S, Hodges S, Flood TJ, Barge\u000a      D, Spickett GP, Jackson GH, Collin MP, Abinun M, Cant AJ, Gennery AR\u000a      (2009). Unrelated donor and HLA- identical sibling haematopoietic stem\u000a      cell transplantation cure chronic granulomatous disease with good\u000a      long-term outcome and growth. British Journal of Haematology.\u000a      145(1):73-83. DOI: 10.1111\/j.1365-2141.2009.07614.x. 28 citations.\u000a    \u000a\u000aR3. Cole T, McKendrick F, Titman P, Cant AJ, Pearce\u000a        MS, Cale CM, Goldblatt D, Gennery AR (2013). Health related\u000a      quality of life and emotional health in children with chronic\u000a      granulomatous disease: a comparison of those managed conservatively with\u000a      those that have undergone haematopoietic stem cell transplant. Journal\u000a        of Clinical Immunology. 33(1):8-13. DOI: 10.1007\/s10875-012-9758-0.\u000a    \u000aKey research grants\u000a    Newcastle upon Tyne Hospitals NHS Foundation Trust. Continuous funding\u000a      (including for research) for the Supra-Regional Paediatric Bone Marrow\u000a      Transplant Unit.\u000a    Bubble Foundation UK. 2009-10. £66 008. Pre-Doctoral Fellowship.\u000a\u0009   National Institute for Health Research. 2010-14. £248 459. Chronic\u000a       Granulomatous Disease: Clinical course, quality of life, cognitive\u000a       outcome and cost benefit with conservative or curative treatment.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    Ev a. Statement from the Director of Bone Marrow Transplantation, Great\u000a      Ormond Street Hospital.\u000a    Ev b. Transplant figures available from the BMT data manager,\u000a      Newcastle-upon-Tyne Hospitals Trust.\u000a    Ev c. EBMT\/ESID guidelines for haematopoietic stem cell transplantation\u000a      for primary immunodeficiencies (2011). http:\/\/www.esid.org\/downloads\/BMT_Guidelines_2011.pdf\u000a      (Quotation from page 19.)\u000a    Ev d. Kang EM, Marciano BE, DeRavin S, Zarember KA, Holland SM, Malech HL\u000a      (2011). Chronic granulomatous disease: overview and hematopoietic stem\u000a      cell transplantation. J Allergy Clin Immunol. 2011 Jun;127(6):1319-26;\u000a      quiz 1327-8. DOI: 10.1016\/j.jaci.2011.03.028.\u000a    Ev e. Statement from the Research and Support Programme Manager, CGD\u000a      Society.\u000a    Ev f. CGD Society (2013): An introduction to bone marrow transplantation.\u000a      A guide for parents of children under the age of 18 who are affected by\u000a      CGD. (Quotation from page 2. Supplied by the Society, available on\u000a      request.) \u000a    ","Title":"\u000a    Curing chronic granulomatous disease in children through early bone\u000a      marrow transplant\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"},{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle University researchers\u000a      Dr Andrew Gennery, initially a Clinical Senior Lecturer and from 2009\u000a      Consultant and Clinical Reader and Professor Andrew Cant, then an Honorary\u000a      Clinical Lecturer, led the studies in Newcastle and contributed to\u000a      collaborative work as described below.\u000a    Background\u000a      Chronic granulomatous disease (CGD) is a severe inherited disorder of the\u000a      immune system that usually becomes clinically apparent in the first few\u000a      months of life. It is rare, with an incidence of 4 - 5 cases per million\u000a      live births in Europe, so about four children are newly diagnosed each\u000a      year in the UK and Ireland. Because of the rarity of the disease, patients\u000a      are diagnosed at national specialised centres. In the UK these are the\u000a      Great North Children's Hospital in Newcastle and Great Ormond Street\u000a      Hospital in London. The disease results from any one of a number of\u000a      defects in genes encoding subunits of the enzyme NADPH oxidase that result\u000a      in loss of its catalytic activity. In healthy people the enzyme has an\u000a      important role in the production of toxic oxygen species by immune\u000a      phagocytes (principally neutrophils), a process that is required to kill\u000a      many pathogenic bacteria and fungi. Patients with CGD are therefore very\u000a      vulnerable to serious infection by these micro-organisms. Even for those\u000a      patients who comply fully with the prophylactic regimen of anti-bacterial\u000a      and anti-fungal drugs, rates of morbidity and mortality are high. A report\u000a      published in 2008 on outcomes in UK patients estimated mortality to be 45%\u000a      by age 30 years (Jones et al. (2008) PMID: 18410635).\u000a    Research\u000a      In 2002 several European centres, including Newcastle, published a survey\u000a      of outcomes of bone marrow transplantation for CGD, covering procedures\u000a      carried out at between 1985 and 2000 (R1). It was a project jointly\u000a      conceived by Professor Andrew Cant, Professor Reinhard Seger (University\u000a      Children's Hospital, Zurich) and Dr Alain Fischer (Necker Hospital,\u000a      Paris). Cant contributed about a third of the patient data in the report.\u000a      The report demonstrated high survival and cure rates following\u000a      myeloablative transplantation (complete destruction of the recipient's own\u000a      bone marrow before transplant) with matched sibling donors. Success rates\u000a      were particularly high in younger patients and in those without\u000a      established infection. The authors concluded that while bone marrow\u000a      transplantation had previously been considered a risky intervention, only\u000a      to be used in those patients where (in spite of prophylactic treatment)\u000a      disease had become established on a severe course, it was now an\u000a      appropriate option to consider early for affected children with matched\u000a      sibling donors.\u000a    In 2009 Gennery and colleagues published an analysis of outcomes of bone\u000a      marrow transplantation for the disease, this time covering a later period\u000a      (1998 to 2007) and including patients transplanted with bone marrow from\u000a      matched unrelated as well as matched sibling donors (ten people in each\u000a      group) (R2). Of the 20 patients transplanted, 18 were cured of the\u000a      disease. Significantly, long term outcomes were comparable for those\u000a      patients receiving marrow from matched unrelated donors and those from\u000a      matched sibling donors. Complications during and after transplant only\u000a      tended to occur in patients with pre-existing infection and\/or\u000a      inflammation. In 2009 Gennery led a pioneering study into the\u000a      under-researched area of the quality of life of CGD patients comparing\u000a      those cured by bone marrow transplantation with patients managed\u000a      conservatively (R3). The researchers looked at the quality of life of 47\u000a      patients, approximately half of whom were pre-transplant (median age 9\u000a      years) and the others post-transplant (median age 10 years). A validated\u000a      paediatric quality of life questionnaire approach was used, involving both\u000a      children and their parents. Across several domains, including physical,\u000a      emotional, social and school functioning, children with the disease who\u000a      had not been transplanted (n = 34) and their parents (n = 47) had\u000a      significantly poorer quality of life than a control group of healthy\u000a      children\/parents. By comparison, transplanted children cured of the\u000a      disease, and their parents, had a comparable quality of life to healthy\u000a      controls.\u000a    "},{"CaseStudyId":"21721","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000aApproximately 37% of neuroblastoma patients are prospectively classified as low-risk. These low\u000d\u000arisk patients are children aged ≤18 months with localised (ie non-metastatic) neuroblastoma where\u000d\u000aimmediate surgery is precluded and children aged ≤12 months with disseminated neuroblastoma\u000d\u000abut without bone, pleura, lung or central nervous system disease (EV a).\u000d\u000aThe discovery that 17q gain is a strong predictor of progressive neuroblastoma and the inclusion of\u000d\u000a17q gain detection into a clinical trial protocol have played significant roles in changing the way in\u000d\u000awhich patients are diagnosed and treated. Treatment for low-risk neuroblastoma patients is now\u000d\u000astratified across Europe and Australia according to whether a segmental chromosomal abnormality\u000d\u000a(SCA) is present or not. The presence of an SCA identifies children that have progressive disease\u000d\u000aand who therefore require immediate chemotherapy, while chemotherapy may be reduced or\u000d\u000aindeed not required for children without SCAs.\u000d\u000aImpact on patients: Treatment stratification via clinical trials\u000d\u000aOn their website, The Children's Neuroblastoma Cancer Foundation highlight the role played by\u000d\u000aclinical trial protocols as guidelines for paediatric oncologists in their treatment of all neuroblastoma\u000d\u000apatients:\u000d\u000a`Clinical trials are the standard of care for children with neuroblastoma: virtually all children\u000d\u000a[approximately 90%] treated for intermediate- and high-risk disease as well as many low-risk NB [neuroblastoma] patients are enrolled on a clinical trial or treated ` per' [as if they\u000d\u000awere enrolled in] a clinical trial. The treatment is the same in either case, but only the\u000d\u000aoutcomes of those enrolled are included in the final trial results.'\u000d\u000a(http:\/\/www.cncfhope.org\/Neuroblastoma_Clinical_Trials)\u000d\u000aThe protocol for the pan-European Low and Intermediate Risk Neuroblastoma Study (LINES)\u000d\u000astratifies treatment in accordance with the findings of Newcastle research. This trial opened in\u000d\u000aseven European countries and Australia in 2012 (EV b, c, d) and it is due to open in another 12\u000d\u000aEuropean countries in the near future, aiming to enrol 685 patients in five years (EV a, b). The trial\u000d\u000a`...groups together in a single protocol the treatment of all patients with \"non high risk\"\u000d\u000aneuroblastoma (NB), with stratification into two groups: low risk and intermediate risk' (EV a, p.26).\u000d\u000aLINES is the first trial in which genetic abnormalities other than MYCN are being used to stratify\u000d\u000atreatment in low-risk neuroblastoma patients. Specifically, the presence of an SCA in these\u000d\u000apatients identifies children that have progressive disease, and a higher risk of relapse, and thus\u000d\u000arequire upfront chemotherapy (EV d). Notably, 17q gain is confirmed as being the most frequently\u000d\u000aoccurring SCA in these patients (EV b, c, d). The UK Chief Investigator of LINES, confirms that:\u000d\u000a`...the work undertaken at Newcastle University regarding 17q gain in neuroblastoma has\u000d\u000ahad significant implications in improving treatment for patients with low risk neuroblastoma\u000d\u000athat have now been translated into the current European low risk neuroblastoma clinical\u000d\u000atrial' (EV d).\u000d\u000aOptimising treatment for each patient is not only crucial for increasing the chances of survival, but\u000d\u000aalso for reducing the detrimental side effects associated with chemotherapy and radiotherapy\u000d\u000a(http:\/\/www.macmillan.org.uk). In LINES, genomic profiling is performed before drugs are\u000d\u000aadministered. The principal investigator of the trial has stated that: `Some patients without [SCAs]\u000d\u000acan now be given minimal treatment in the knowledge that their tumour is very unlikely to reoccur,\u000d\u000awhereas for others whose tumours do harbour SCA, more treatment will be proposed upfront in\u000d\u000aorder to reduce the risk of relapse.' (EV c).\u000d\u000aBeyond Europe and Australia, the co-chair of the International Neuroblastoma Risk Group task\u000d\u000aforce has confirmed that in North America:\u000d\u000a`...the next Intermediate-Risk Neuroblastoma Children's Oncology Group Trial will stratify\u000d\u000atreatment intensity according to the presence or absence of [SCAs] including 17q gain. For\u000d\u000apatients with intermediate-risk neuroblastoma with one or more [abnormalities] including\u000d\u000a17q gain, treatment will be intensified with increased numbers of chemotherapy cycles in an\u000d\u000aeffort to improve the event-free survival of this \"higher risk\" group of patients. In addition,\u000d\u000areduced treatment will be administered to patients [lacking SCAs] in an effort to maintain\u000d\u000ahigh cure rates with decreased toxicity from treatment.' (EV e).\u000d\u000aThe US National Cancer Institute (NCI) also cites the Newcastle research in their information\u000d\u000asummary, a resource that informs and assists clinicians who care for neuroblastoma patients by\u000d\u000aproviding comprehensive, peer-reviewed, evidence-based information about the treatment of\u000d\u000aneuroblastoma (EV f). The NCI recognises the importance of 17q gain as a prognostic factor,\u000d\u000areporting that it `...independently predicts a poor prognosis', citing R3. The NCI also refer to the\u000d\u000athree different progressive tumour types described by the Newcastle group, citing R5 (EV f).\u000d\u000aThe LINES trial is not yet open in the UK, but guidelines for the treatment of low and intermediate\u000d\u000arisk neuroblastoma patients are in place. These guidelines follow the protocol of the LINES trial\u000d\u000aand recommend stratification of treatment for low-risk neuroblastoma patients in accordance with\u000d\u000awhether or not an SCA, including 17q gain, is identified (EV g). These were published in 2011 and\u000d\u000aare accessible to paediatric oncologists via the Children's Cancer and Leukaemia Group. A recent\u000d\u000aaudit of 19 UK Children's Cancer & Leukaemia Group principal treatment centres found that in the\u000d\u000aperiod August 2011- July 2013, 12 out of 12 responding centres adhere to these guidelines when\u000d\u000adiagnosing and treating children with low-risk neuroblastoma (EV h).\u000d\u000aImpact on clinical practice by improved detection of SCAs\u000d\u000aThe detection of SCAs, including 17q, as markers of progressive disease, is rapidly becoming\u000d\u000astandard of care for all patients with neuroblastoma. Multiplex ligation-dependent probe\u000d\u000aamplification (MLPA) was applied specifically to neuroblastoma for the first time by the Newcastle\u000d\u000ateam. Through dissemination of their work, and collaborative work with the International Society of\u000d\u000aPaediatric Oncology European Neuroblastoma Research Network (EV i and EV j) and MRC\u000d\u000aHolland, a neuroblastoma-specific MLPA kit was developed for use worldwide. The International\u000d\u000aNeuroblastoma Risk Group recommend the use of MLPA as a diagnostic tool that will reliably and\u000d\u000aaccurately detect segmental chromosomal abnormalities, reporting that `...[the] robust nature of the\u000d\u000aresults and the relatively low cost of the MLPA kits make this technique attractive for routine\u000d\u000aneuroblastoma analysis' (EV j).\u000d\u000a","ImpactSummary":"\u000d\u000aNeuroblastoma is a paediatric cancer that arises from the sympathetic nervous system. The\u000d\u000aaverage age at diagnosis is 18 months and the disease accounts for approximately 15% of all\u000d\u000achildhood cancer-related deaths. Determining optimal treatment for individual patients is crucial for\u000d\u000aincreasing chances of survival and for reducing side effects of chemotherapy and radiotherapy.\u000d\u000aNewcastle-led research identified unbalanced 17q gain as the most common segmental\u000d\u000achromosomal abnormality (SCA) in patients with neuroblastoma; this was present in more than\u000d\u000a50% of patients. Gain of 17q is now one of the key SCAs used to determine treatment for patients\u000d\u000ain a European neuroblastoma trial and in UK treatment centres. Newcastle research also led to the\u000d\u000adevelopment of a simple diagnostic test for the detection of the main SCAs in neuroblastoma.\u000d\u000a","ImpactType":"Health","Institution":"\u000d\u000aNewcastle University\u000d\u000a","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a(Citation count from Scopus, July 2013; Newcastle researchers shown in bold)\u000d\u000a\u000aR1. Lastowska M, Roberts P, Pearson ADJ, Lewis I, Wolstenholme J, Bown N. Promiscuous\u000d\u000atranslocations of chromosome arm 17q in human neuroblastoma. Genes Chromosomes\u000d\u000aCancer 1997;19:143-49. DOI: 10.1002\/(SICI)1098-2264(199707)19:3<143::AID-GCC2>3.0.CO;2-Y. Cited by 52.\u000d\u000a\u000a\u000aR2. Bown N, Cotterill S, Lastowska M, O'Neill S, Pearson AD, Plantaz D, Meddeb M, Danglot G,\u000d\u000aBrinkschmidt C, Christiansen H, Laureys G, Speleman F, Nicholson J, Bernheim A, Betts DR,\u000d\u000aVandesompele J, Van Roy N. Gain of chromosome arm 17q and adverse outcome in patients\u000d\u000awith neuroblastoma. N Engl J Med 1999;340:1954-61. DOI: 10.1056\/NEJM199906243402504.\u000d\u000aCited by 272.\u000d\u000a\u000a\u000aR3. Lastowska M, Cotterill S, Bown N, Cullinane C, Variend S, Lunec J, Strachan T, Pearson\u000d\u000aADJ, Jackson MS. Breakpoint position on 17q identifies the most aggressive neuroblastoma\u000d\u000atumours. Genes Chromosome Cancer 2002;34:428-36. DOI: 10.1002\/gcc.10089. Cited by 36.\u000d\u000a\u000a\u000aR4. Bown N, Lastowska M, Cotterill S, O'Neill S, Ellershaw C, Roberts P, Lewis I, Pearson ADJ.\u000d\u000a17q gain in neuroblastoma predicts adverse clinical outcome. Med Ped Oncology 2001;36:14-19. DOI: 10.1002\/gcc.10089. Cited by 27.\u000d\u000a\u000a\u000aR5. Lastowska M, Cullinane C, Variend S, Cotterill S, Bown N, O'Neill S, Mazzocco K, Roberts P,\u000d\u000aNicholson J, Ellershaw C, Pearson ADJ, Jackson MS. Comprehensive genetic and\u000d\u000ahistopathologic study reveals three types of neuroblastoma tumors. J Clin Oncol\u000d\u000a2001;19:3080-90. (PMID:11408505) Cited by 71.\u000d\u000a\u000a\u000aR6. Ambros IM, Brunner B, Aigner G, Bedwell C, Beiske K, Benard J, Bown N, Combaret V,\u000d\u000aCouturier J, Defferrari R, Gross N, Jeison M, Lunec J, Marques B, Martinsson T, Mazzocco K,\u000d\u000aNoguera R, Schleiermacher G, Speleman F, Stallings R, Tonini GP, Tweddle DA, Valent A,\u000d\u000aVicha A, Roy NV, Villamon E, Ziegler A, Preuner S, Drobics M, Ladenstein R, Amann G,\u000d\u000aSchuit RJ, Potschger U, Ambros PF. A multilocus technique for risk evaluation of patients with\u000d\u000aneuroblastoma. Clin Cancer Res 2011;17:792-804. DOI: 10.1158\/1078-0432.CCR-10-0830.\u000d\u000aCited by 16.\u000d\u000a\u000aNewcastle researchers made a substantial contribution to the conception, design and\u000d\u000aexecution of the study (including data acquisition); the analysis and interpretation of data;\u000d\u000aand drafting the output and critiquing the output for important intellectual content.\u000d\u000aKey funding awards\u000d\u000a• 1999-2002 Analysis of Chromosome 17q in Neuroblastoma Progression. North of England\u000d\u000aChildren's Cancer Research Fund - £136,444\u000d\u000a• 2003-2006 Identification of Candidate Genes from 17q and Other Chromosomal Regions\u000d\u000aInvolved in Neuroblastoma Progression. Neuroblastoma Society - £173,443\u000d\u000a• 2004-2006 Provision of a national UK Children's Cancer Study Group (UKCCSG) facility for\u000d\u000aneuroblastoma molecular investigations for European clinical trials. Cancer Research UK —\u000d\u000a£77,393\u000d\u000a• 2006-2008 Provision of a national service for neuroblastoma molecular investigations for\u000d\u000aclinical trials. Department of Health - £238,847\u000d\u000a• 2008-2011. The National Reference Centre for Neuroblastoma Biology. Neuroblastoma\u000d\u000aSociety of Great Britain, project grant - £166,055\u000d\u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000aEV a. A SIOPEN study: European Low and Intermediate Risk Neuroblastoma.\u000d\u000ahttp:\/\/clinicaltrials.gov\/ct2\/show\/NCT01728155 Full protocol available on request (held at\u000d\u000aNewcastle)\u000d\u000aEV b. Testimonial; co-chief investigator of LINES, Instituto de Investigacion Sanitaria La Fe\u000d\u000a(Spain).\u000d\u000aEV c. Testimonial; co-chief investigator of LINES, Institut Curie (France).\u000d\u000aEV d. Testimonial; UK chief investigator of LINES, Oxford University Hospitals (UK)\u000d\u000aEV e. Testimonial; co-chair of the International Neuroblastoma Risk Group task force\u000d\u000aEV f. http:\/\/www.cancer.gov\/cancertopics\/pdq\/treatment\/neuroblastoma\/HealthProfessional\u000d\u000aEV g. UK guidelines for treatment of low- and intermediate risk neuroblastoma. Copy held at\u000d\u000aNewcastle and available on request.\u000d\u000aEV h. Audit of 19 (12 responding) UK Children's Cancer & Leukaemia Group principal treatment\u000d\u000acentres: Adherence to guidelines published on the CCLGNB website on treatment of low-and intermediate risk neuroblastoma. Contact: UK chief investigator of LINES.\u000d\u000aEV i. https:\/\/www.siopen-r-net.org\/\u000d\u000aEV j. Ambros et al. International consensus for neuroblastoma molecular diagnostics: report from\u000d\u000athe International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 2009;\u000d\u000a100: 1471-82.\u000d\u000a\u000d\u000a","Title":"\u000d\u000aIdentification of a chromosomal abnormality now used to stratify treatment in\u000d\u000achildren with neuroblastoma.\u000d\u000a","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aKey researchers\u000d\u000a(Where individuals left or joined the university in the period 1993-2013, years are given in brackets)\u000d\u000aN Bown, Research Associate 1987-1996, then Lecturer; DA Tweddle (1996 onwards), Clinical\u000d\u000aResearch Associate 1996-1999, Clinician Scientist 2002-2004, Clinical Senior Lecturer\/Consultant\u000d\u000a2004-2011, then Professor of Paediatric Oncology; ADJ Pearson (1989-2005), Professor of\u000d\u000aPaediatric Oncology; M Lastowska (1999-2010), Research Associate\/Senior Research Associate;\u000d\u000aMS Jackson (1998 onwards), Lecturer\/Senior Lecturer; J Lunec (1998 onwards), Senior Lecturer\u000d\u000a1998-1999, Reader in Molecular Oncology 1999-2007, then Professor of Molecular Oncology.\u000d\u000aBackground\u000d\u000aNeuroblastoma is a paediatric cancer that arises from the sympathetic nervous system. Around\u000d\u000a100 children are diagnosed with neuroblastoma every year in the UK, and incidence rates are\u000d\u000asimilar across Europe, Australia and America. The average age at diagnosis is 18 months. The\u000d\u000aChildren's Neuroblastoma Cancer Foundation states that 37% of all neuroblastoma cases are low\u000d\u000arisk, 18% are intermediate risk and 45% are high risk (based on the risk of relapse following\u000d\u000atreatment), accounting for approximately 15% of cancer-related deaths in childhood. Patients can\u000d\u000abe prospectively assigned to a risk category on diagnosis based on age, on whether the tumour\u000d\u000acan be removed surgically and whether tumour cells have spread to other parts of the body.\u000d\u000aThe hallmarks of neuroblastoma are (a) its clinical variability, ranging from rapid malignant\u000d\u000aprogression to spontaneous regression and (b) its biological variability, as seen in the complexity of\u000d\u000athe genetic abnormalities acquired by the tumour cells, many of which are powerful prognostic\u000d\u000amarkers. Being able to identify the genetic abnormalities of each individual patient aids in risk\u000d\u000astratification and decisions regarding treatment, usually as part of a clinical trial.\u000d\u000aResearch\u000d\u000aStratified treatment of neuroblastoma patients began in the 1980s, with more intensive treatment\u000d\u000abeing given to those with an MYCN (gene that encodes a protein that is critical for normal brain\u000d\u000adevelopment) amplification. However, around 80% of patients with neuroblastoma do not have\u000d\u000aMYCN amplification. Other genetic prognostic markers were needed.\u000d\u000aNewcastle-based research involving the analysis of primary tumours resulted in the identification of\u000d\u000aseven previously unknown structural chromosomal rearrangements that result in 17q gain (that is,\u000d\u000aextra copies of genetic information on one arm of chromosome 17) (R1). Furthermore, a\u000d\u000aNewcastle-led study of 313 patients at six European centres identified 17q gain as the most\u000d\u000acommon chromosomal abnormality (SCA) in neuroblastoma, present in 53.7% of the patients\u000d\u000astudied (R2). In addition, knowledge of the breakpoint position on 17q was found to enable\u000d\u000adiagnosis of the tumour's level of aggressiveness (R3). In a subsequent collaborative study by UK\u000d\u000acytogenetics centres, 17q gain was found in 69 out of 104 neuroblastoma tumours (R4). This study\u000d\u000arevealed a strong association between 17q gain and advanced-stage disease, in which 17q gain\u000d\u000awas a significant predictor of adverse outcome: 84.4% of patients with 17q gain had less than five\u000d\u000ayears relapse-free survival, compared to 24.8% of patients without 17q gain (R4). A further study\u000d\u000ainvolving 108 neuroblastoma patients was carried out to determine the relationship between\u000d\u000agenetic abnormalities, tumour morphology and prognosis (R5). Four tumour types were defined:\u000d\u000aone regressing type and three progressing types. Although a number of genetic abnormalities were\u000d\u000afound in progressing tumour types, 17q gain was the only feature common to all. 17q gain was\u000d\u000ashown to be a critical genetic alteration associated with metastatic and\/or invasive neuroblastoma\u000d\u000aand a more powerful prognostic marker for this disease than any other genetic abnormality or\u000d\u000ahistological and clinical factor analysed (R5).\u000d\u000aThe discovery that SCAs are a valuable prognostic marker in non-MYCN amplified neuroblastoma\u000d\u000aled to the need for a cost-effective and robust method of detecting them. 17q gain proved difficult\u000d\u000ato detect using then standard laboratory techniques such as fluorescence in situ hybridisation and\u000d\u000aso testing for 17q gain in patients outside of research centres was rare. The Newcastle group\u000d\u000aapplied a polymerase chain reaction-based multiplex ligation-dependent probe amplification\u000d\u000a(MLPA) technique for detecting the relevant chromosomal alterations in neuroblastoma (R6).\u000d\u000a"},{"CaseStudyId":"21968","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    Streptococcus Pneumoniae is an important cause of infection at the\u000a      extremes of life. In the United Kingdom the incidence of invasive\u000a      pneumococcal disease (IPD) is 37-48 per 100,000 for children under 1 year\u000a      and 21-36 per 100,000 for adults >65 years. In the period July 1996 to\u000a      June 2006 (prior to vaccine introduction) there were 52,579 cases of IPD\u000a      identified through the UK laboratory- based surveillance system. This does\u000a      not take into account the majority of pneumonia and otitis media cases [a].\u000a    The first pneumococcal conjugate vaccine containing seven of the most\u000a      prevalent serotypes (PCV7) was licensed in 2000 as a four-dose schedule.\u000a      Adding a new vaccine to the relatively crowded UK infant immunisation\u000a      schedule in the early 2000s presented significant difficulties, as infants\u000a      were already receiving two injections at each immunisation visit (at 2, 3\u000a      and 4 months of age). Our demonstration that three doses were\u000a      immunologically broadly equivalent to four gave the Department of Health\u000a      the evidence base to introduce PCV into the routine infant immunisation\u000a      programme vaccine with doses at 2, 4 and 12 months (\"2+1\" schedule). An\u000a      initial catch-up campaign was conducted in 2006\/7 with routine\u000a      immunisation beginning in 2008 [b].\u000a    The introduction of PCV in the UK has had a clear impact on pneumococcal\u000a      disease. Prior to its introduction, deaths from IPD in children under five\u000a      had peaked at 797 cases\/year. In 2011\/12 (the last year for which there\u000a      are complete data) this had reduced by 50% to 340 deaths. Notably, cases\u000a      of IPD due to the seven serotypes included in the vaccine have fallen\u000a      dramatically, as the following table shows:\u000a     Table 1: Serotype specific IPD cases for under fives in England and Wales\u000a      prior to and following the introduction of PCV7 into the infant\u000a      immunisation programme [c]\u000a    \u000a      \u000a        \u000a          Serotype\u000a          2003\/4\u000a          2011\/12\u000a        \u000a        \u000a          4\u000a          15\u000a          0\u000a        \u000a        \u000a          6B\u000a          52\u000a          1\u000a        \u000a        \u000a          9V\u000a          31\u000a          1\u000a        \u000a        \u000a          14\u000a          142\u000a          2\u000a        \u000a        \u000a          18C\u000a          38\u000a          4\u000a        \u000a        \u000a          19F\u000a          49\u000a          5\u000a        \u000a        \u000a          23F\u000a          25\u000a          1\u000a        \u000a      \u000a    \u000a    On the basis of early experience with PCV7, Goldblatt worked with\u000a      international colleagues to define the first correlates of protection and\u000a      then helped to draw up WHO guidelines for how PCVs should be subsequently\u000a      licensed (WHO TRS 927) [d]. These guidelines were used to license\u000a      10- and 13-valent formulations approved in 2009\/10. In 2010 the 13-valent\u000a      vaccine was introduced in the UK. This vaccine addressed the burden of\u000a      disease caused by the additional serotypes included in the PCV13 vaccine.\u000a    In addition to the direct impact of the vaccine on disease in the\u000a      vaccinated infants, the PCV vaccine reduces the carriage of pneumococci in\u000a      the nasopharynx, which thus reduces the spread of the pneumococci and\u000a      impacts on invasive disease in other age groups. The figure below (adapted\u000a      from HPA data [c]) illustrates the impact of infant vaccination on\u000a      vaccine type IPD in all age groups in the UK.\u000a\u0009  \u000a\u0009  \u000a\u0009  \u000a    The \"2+1\" schedule has been highly efficacious and is also more cost\u000a      effective, as it uses fewer doses. For these reasons, many countries\u000a      worldwide have implemented it. In 2013, WHO reports that in Europe and the\u000a      Americas 23 countries are using PCV according to the schedule we developed\u000a      [e].\u000a    Our work has also contributed to global efforts to reduce mortality from\u000a      pneumococcal disease in developing countries. Half a million children\u000a      under five die each year from the condition, making it the leading\u000a      vaccine-preventable cause of death among young children. In response to\u000a      this issue, WHO and the GAVI alliance have initiated an innovative\u000a      financing process — the Advanced Market Commitment (AMC) [f] —\u000a      designed to make effective and affordable pneumococcal vaccines available\u000a      for children in developing countries. Goldblatt chaired the committee that\u000a      defined the minimum product specification (TPP) for the vaccine. This\u000a      report was published in February 2008 [g] and in March 2010,\u000a      UNICEF entered into agreements with GSK and Pfizer to supply 30 million\u000a      doses annually for 10 years [h]. An independent report into the\u000a      AMC process reported that: \"Several interviewees praised the TPP for\u000a        striking an appropriate balance between setting a high bar to ensure\u000a        vaccine effectiveness and still allowing low-cost producers to compete.\u000a        The TPP also proved useful in inspiring and supporting similar guidance\u000a        for other prospective vaccines\" [i]. Since 2010, over 25\u000a      countries have begun to roll out pneumococcal vaccines under this\u000a      programme; by July 2013, it was estimated that GAVI and its partners have\u000a      immunised more than 10 million children [j]. GAVI aims to increase\u000a      this to 45 countries by 2015, projecting that this will prevent more than\u000a      half a million deaths in this period.\u000a    ","ImpactSummary":"\u000a    A programme of work undertaken jointly between the UCL Institute of Child\u000a      Health (ICH) Vaccine Evaluation Laboratory headed by Professor David\u000a      Goldblatt and the Health Protection Agency (now Public Health England\u000a      [PHE]) led by Professor Liz Miller, has led directly to the introduction\u000a      of pneumococcal conjugate vaccines (PCV) into the UK infant immunisation\u000a      schedule. These vaccines have reduced the burden of invasive disease in\u000a      the UK saving many lives and reducing morbidity from these devastating\u000a      infections. This work has also provided the evidence for other countries\u000a      to introduce PCV with fewer than the originally recommended doses, thus\u000a      improving cost effectiveness and hastening the implementation of these\u000a      vaccines worldwide. Goldblatt has also contributed to a WHO programme to\u000a      roll out PCV in developing countries; by July 2013 this programme had\u000a      vaccinated around 10 million children.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Plikaytis BD, Goldblatt D, Frasch CE, Blondeau C, Bybel MJ,\u000a      Giebink GS, Jonsdottir I, Kayhty H, Konradsen HB, Madore DV, Nahm MH,\u000a      Schulman CA, Holder PF, Lezhava T, Elie CM, Carlone GM. An analytical\u000a      model applied to a multicenter pneumococcal enzyme-linked immunosorbent\u000a      assay study. J Clin Microbiol. 2000 Jun;38(6):2043-50. http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC86724\/\u000a    \u000a\u000a[2] Jodar L, Butler J, Carlone G, Dagan R, Goldblatt D, Kayhty H,\u000a      Klugman K, Plikaytis B, Siber G, Kohberger R, Chang I, Cherian T.\u000a      Serological criteria for evaluation and licensure of new pneumococcal\u000a      conjugate vaccine formulations for use in infants. Vaccine. 2003 Jul\u000a      4;21(23):3265-72. http:\/\/dx.doi.org\/10.1016\/S0264-410X(03)00230-5\u000a    \u000a\u000a[3] Goldblatt D, Plikaytis BD, Akkoyunlu M, Antonello J, Ashton\u000a      L, Blake M, Burton R, Care R, Durant N, Feavers I, Fernsten P, Fievet F,\u000a      Giardina P, Jansen K, Katz L, Kierstead L, Lee L, Lin J, Maisonneuve J,\u000a      Nahm MH, Raab J, Romero-Steiner S, Rose C, Schmidt D, Stapleton J, Carlone\u000a      GM. Establishment of a new human pneumococcal standard reference serum,\u000a      007sp. Clin Vaccine Immunol. 2011 Oct;18(10):1728-36. http:\/\/dx.doi.org\/10.1128\/CVI.05252-11\u000a    \u000a\u000a[4] Goldblatt D, Southern J, Ashton L, Richmond P, Burbidge P,\u000a      Tasevska J, Crowley-Luke A, Andrews N, Morris R, Borrow R, Cartwright K,\u000a      Miller E. Immunogenicity and boosting after a reduced number of doses of a\u000a      pneumococcal conjugate vaccine in infants and toddlers. Pediatr Infect Dis\u000a      J. 2006 Apr;25(4):312-9 http:\/\/dx.doi.org\/10.1097\/01.inf.0000207483.60267.e7\u000a    \u000a\u000a[5] Goldblatt D, Southern J, Ashton L, Andrews N, Woodgate S,\u000a      Burbidge P, Waight P, Miller E. Immunogenicity of a reduced schedule of\u000a      pneumococcal conjugate vaccine in healthy infants and correlates of\u000a      protection for serotype 6B in the United Kingdom. Pediatr Infect Dis J.\u000a      2010 May;29(5):401-5. http:\/\/dx.doi.org\/10.1097\/INF.0b013e3181c67f04\u000a    \u000a\u000a[6] Scott JA, Ojal J, Ashton L, Muhoro A, Burbidge P, Goldblatt D.\u000a      Pneumococcal conjugate vaccine given shortly after birth stimulates\u000a      effective antibody concentrations and primes immunological memory for\u000a      sustained infant protection. Clin Infect Dis. 2011 Oct;53(7):663-70. http:\/\/dx.doi.org\/10.1093\/cid\/cir444\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    [a] http:\/\/www.hpa.org.uk\/web\/HPAweb&Page&HPAwebAutoListName\/Page\/1203409671876.\u000a    [b] The Green Book, chapter 25:\u000a      https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/216088\/Green-Book-Chapter-25-v4_0.pdf (References Goldblatt et al 2006; book page\u000a      311, pdf page 17)\u000a    [c] Data provided by Public Health England. Contact details provided.\u000a    [d]. http:\/\/www.who.int\/entity\/biologicals\/areas\/vaccines\/pneumo\/Pneumo_final_23APRIL_2010.pdf.\u000a    (International Reference Materials, page 6; Authors and Acknowledgements,\u000a    page 34; Reference 23, page 37).\u000a    [e] WHO vaccine-preventable diseases: monitoring system. 2013 global\u000a      summary\u000a      http:\/\/apps.who.int\/immunization_monitoring\/globalsummary\/schedules.\u000a    [f] GAVI alliance website detailing the pneumococcal Advance Market\u000a      Commitment\u000a      http:\/\/www.gavialliance.org\/funding\/pneumococcal-amc\/about\/\u000a    [g] Target Product Profile (TPP) for the Advance Market Commitment (AMC)\u000a      for Pneumococcal Conjugate Vaccines: www.who.int\/immunization\/sage\/target_product_profile.pdf.\u000a      (Vaccine dosage schedule page 22, Contributors page 29, References 66 and\u000a      75).\u000a    [h] GSK press release: http:\/\/www.gsk.com\/media\/press-releases\/2010\/gsk-joins-global-vaccine-\u000aalliance-to-help-prevent-millions-of-children-from-contracting-pneumococcal-disease-in-the-worlds-poorest-countries.html\u000a    [i] The Advance Market Commitment for Pneumococcal Vaccines: Process and\u000a      Design Evaluation. February 15, 2013. Dalberg Global Development Advisors.\u000a      http:\/\/www.gavialliance.org\/library\/documents\/gavi-documents\/evaluations\/amc-process-and-design-evaluation-full-report\/. (quote page 12).\u000a    [j] http:\/\/www.gavialliance.org\/support\/nvs\/pneumococcal\/\u000a    Contact details\u000a    [c] Liz Miller, Public Health England. liz.miller@hpa.org.uk\u000a      [Provided [c] data on serotype specific IPD cases for under fives in\u000a        England and Wales prior to and following the introduction of PCV7 into\u000a        the infant immunisation programme] \u000a    ","Title":"\u000a    Evaluating and introducing pneumococcal conjugate vaccines (PCV) into the\u000a      UK infant immunisation programme\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Since 1993, the Goldblatt laboratory has had a leading role in global\u000a      efforts aimed at establishing and standardising pneumococcal assays for\u000a      the purpose of assessing and licensing pneumococcal vaccines [1].\u000a    In 2002 the laboratory was designated one of only two World Health\u000a      Organisation (WHO) Reference Laboratories for Pneumococcal Serology in\u000a      recognition of its role in standardising pneumococcal assays and\u000a      establishing correlates of protection to license second generation\u000a      pneumococcal conjugate vaccines [2]. The WHO funded the laboratory\u000a      to develop assays, teach and train staff from organisations around the\u000a      world in the conduct of such assays and to transfer materials and\u000a      technology to other laboratories to facilitate global efforts to rapidly\u000a      introduce pneumococcal vaccines in areas of the world most in need. The\u000a      laboratory has just finished leading an international effort to develop a\u000a      new Pneumococcal Standard Reference serum to replace the dwindling stocks\u000a      of an existing standard. The new Standard will enable assays to be\u000a      quality-controlled for the next 50 years [3].\u000a    The first PCV, a seven-valent formulation, was licensed in 2000 but\u000a      initially only used in the USA where it was administered, according to a\u000a      four-dose schedule. In collaboration with PHE, we were the first in the\u000a      world to formally assess the utility of a three-dose, rather than the\u000a      licensed four-dose schedule and to predict the efficacy of the reduced\u000a      schedule based on the data generated in this study [4]. A\u000a      three-dose schedule was desirable in the UK to facilitate introduction\u000a      into an already crowded immunisation programme and to address the issue of\u000a      cost-effectiveness. The results of this study led directly to the decision\u000a      in the UK to introduce PCV into the infant immunisation schedule with only\u000a      three doses (September 2006).\u000a    ICH and PHE subsequently proceeded to establish the immunological basis\u000a      for the effectiveness of the response to a three-dose schedule and to\u000a      refine the understanding of pneumococcal correlates of protection [5].\u000a    Underpinning research at ICH continues to inform the evolving use of PCV.\u000a      The Goldblatt laboratory has led a study of PCV administration with the\u000a      first dose at birth, to assess safety and likely efficacy of early\u000a      vaccination in developing countries where up to a quarter of pneumococcal\u000a      deaths under the age of 2 years occur before infants are eligible for\u000a      their first vaccine [6].\u000a    "},{"CaseStudyId":"21969","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"3144096","Name":"Norway"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000d    Guidelines and adoption \u000d    The research on non-invasive prenatal diagnosis (NIPD) contributed to a\u000d      report from the PHG Foundation in 2009, giving a service-based overview of\u000d      the implications for the NHS of implementing this technology [a].\u000d      We also produced a opinion paper on NIPD using cell free fetal DNA in\u000d      maternal blood for the Royal College of Obstetricians and Gynaecologists\u000d      (RCOG) in 2009 which was supported by their scientific advisory committee\u000d      [b]. We then led the Gene Dossier submission to the UKGTN which was\u000d      approved formally in April 2011 [c]. Furthermore from 2012 the\u000d      approval of Gene Dossiers for Achondroplasia and Thanatophoric dysplasia\u000d      was gained [d, e]. Chitty has also co-led the FP7 work package of\u000d      Eurogentest 2, which has developed and published guidelines for service\u000d      delivery in Europe [f]. The technology has attracted further\u000d      interest from policy makers, including a report on genomic technology in\u000d      healthcare by the Human Genomics Strategy Group for the Department of\u000d      Health [g].\u000d     Service provision and patient benefit \u000d    NIPD for fetal sex determination is now the recognised standard of\u000d      practice in UK genetic services allowing equity of access for all women in\u000d      the UK at high risk of sex-linked disorders. The service at Great Ormond\u000d      Street Hospital (GOSH) performs >100 tests per annum (Table 1) and,\u000d      using samples in the RAPID sample bank, has helped other laboratories\u000d      establish this as a standard of care, with Manchester offering this test\u000d      from 2010, Birmingham from 2011 and Cambridge, Edinburgh and Salisbury\u000d      from 2013. Fetal sex determination using NIPD is now the most common\u000d      prenatal molecular test performed in the UK [h] and has reduced\u000d      the invasive testing rate by nearly50% for women at high risk of\u000d      sex-linked disorders. \u000d    We have established a large unique\/comprehensive bank of samples that is\u000d      a resource for academic and commercial collaborators, which has already\u000d      helped establish NIPD for sex determination in four other UK laboratories,\u000d      and is being used to develop NIPD for Duchenne Muscular Dystrophy,\u000d      Tuberous Sclerosis and Huntingdon Disease in Birmingham, Cambridge and\u000d      Edinburgh regional genetics centres, as well as developing non-invasive\u000d      prenatal testing for aneuploidy and other chromosomal rearrangements. We\u000d      are the only public service laboratory offering a clinical service for\u000d      NIPD for single gene disorders - not just in UK, but beyond, and we\u000d      receive referrals from Europe, Canada and North America (Table 1). \u000d    \u000d    \u000d      \u000d        \u000d          \u000a\u000d          \u000d          \u000aNIPD for fetal sex\u000d              determination\u000d          \u000d          \u000aPrenatal tests for\u000d              Achondroplasia\u000d          \u000d          \u000aPrenatal tests for\u000d              Thanatophoric dysplasia\u000d          \u000d          \u000a\u000d          \u000d          \u000a\u000d          \u000d        \u000d        \u000d          \u000a\u000d          \u000d          \u000a\u000d          \u000d          Invasive\u000d            \u000d          NIPD\u000d          Invasive\u000d            \u000d          NIPD\u000d            \u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2008\u000a                        - 9 \u000d                  \u000d                \u000d              \u000d            \u000d          \u000d          96\u000d          21\u000d          \u000a\u000d          \u000d          4\u000d          \u000a\u000d          \u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2009\u000a                        - 10 \u000d                  \u000d                \u000d              \u000d            \u000d          \u000d          118\u000d          28\u000d          \u000a\u000d          \u000d          16\u000d          \u000a\u000d          \u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2010\u000a                        - 11 \u000d                  \u000d                \u000d              \u000d            \u000d          \u000d          103\u000d          27\u000d          13\u000d          21\u000d          0\u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2011\u000a                        - 12 \u000d                  \u000d                \u000d              \u000d            \u000d          \u000d          124\u000d          28\u000d          14\u000d          25\u000d          2\u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2012\u000a                        - 13 \u000d                  \u000d                \u000d              \u000d            \u000d          \u000d          163\u000d          20\u000d          22\u000d          17\u000d          11\u000d        \u000d        \u000d          \u000d            \u000d              \u000d                \u000d                  \u000d                    2013\u000a                        –\u000d                      now\u000a                         \u000d                \u000d              \u000d            \u000d          \u000d          79\u000d          10\u000d          4\u000d          4\u000d          11\u000d        \u000d        \u000d          \u000a\u000d          \u000d        \u000d        \u000d          \u000aOther tests performed\u000d               clinically\u000d          \u000d          Apert syndrome (n=7)        \u000d               Osteogenesis Imperfecta (n=1)\u000d                                      \u000a            Torsion dystonia\u000d            (n=4)          \u000d            Fraser's syndrome (n=1)  \u000d            Autosomal Recessive Polycystic Kidney Disease (n=1)\u000d          \u000d        \u000d        \u000d          \u000aSources of referrals\u000d          \u000d          UK, USA, Canada, Netherlands, Italy, Norway,\u000d            Switzerland\u000d          \u000d        \u000d      \u000d    \u000d    \u000d     Table 1. Details of clinical NIPD tests performed by our Regional\u000d        Genetics Laboratory (figures given by financial year). Note the steady\u000d        increase in numbers of tests done over time, with the trend to decreased\u000d        invasive testing following gene dossier approval in 2012 [i].\u000d      \u000d     These tests can be offered earlier in pregnancy further relieving\u000d      parental anxiety. The benefits are summed up by the supporting statement\u000d      one patient gave us when we submitted our application for an NIHR\u000d      programme grant to further develop this work and has been further\u000d      supported in our work with patients who have undergone NIPD [reference 4\u000d      in section 3 above]: \u000d     \"It is only three weeks since the termination, though the experience\u000d        is stil raw I wanted to share with you that the pain is very much mixed\u000d        with a great sense of gratitude for the opportunity of having early\u000d        non-invasive testing. Having experienced both procedures, I am\u000d        enormously appreciative of developments in cffDNA diagnosis. Even with\u000d        its unfortunate outcome, my second testing experience was a\u000d        significantly less distressing process than the CVS with extended\u000d        waiting period and associated risks. I would sincerely love to see the\u000d        service and support I experienced expanded as far as possible, so that\u000d        others can benefit as I did\" [j]. \u000d     Patient and Practitioner Engagement\u000d     Our third impact is the engagement with practitioners and\u000d      patients, particularly through our website www.rapid.nhs.uk\u000a        which provides an information resource required to implement this\u000d      safer approach to prenatal testing whilst maintaining the informed patient\u000d      consent. In partnership with the National Genetics Education and\u000d      Development Centre, Birmingham (RAPID co-applicants) and lay organisations\u000d      such as Genetic Al iance UK, Sickle Cell Association and Antenatal Results\u000d      and Choices (ARC) using information acquired from patient interviews and\u000d      surveys, we have developed health information packages, including\u000d      e-learning modules [k]. We have also contributed to\u000d      practitioner-facing journals [l]. \u000d    ","ImpactSummary":"\u000d    Until recently, prenatal diagnosis of genetic conditions required\u000d      analysis of fetal genetic material obtained following invasive testing,\u000d      with a risk of miscarriage. Non-invasive prenatal diagnosis (NIPD) using\u000d      cell-free fetal DNA in maternal plasma has transformed prenatal diagnosis\u000d      for many women. Testing the maternal blood sample avoids the miscarriage\u000d      risk. At UCL, we have led the implementation into clinical practice of\u000d      NIPD for serious sex-linked and autosomal dominant disorders. After a\u000d      successful application for UK Gene Testing Network (UKGTN) Gene Dossier\u000d      approval for fetal sex determination in 2011, this is now the standard of\u000d      care across the UK. \u000d    ","ImpactType":"Health","Institution":"\u000d     University College London \u000d    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1105844","Name":"Harare Province"}],"References":"\u000d    \u000a[1] Hyett JA, Gardener G, Stojilkovic-Mikic T, Finning KM, Martin PG,\u000d      Rodeck CH, Chitty LS.Reduction in diagnostic and therapeutic interventions\u000d      by non-invasive determination of fetal sex in early pregnancy. Prenat\u000d      Diagn. 2005 Dec;25(12):1111-6.\u000d        http:\/\/doi.org\/fbpfq9 \u000d    \u000a\u000a[2] Hil M, Taffinder S, Chitty LS, Morris S. Incremental cost of\u000d      non-invasive prenatal diagnosis versus invasive prenatal diagnosis of\u000d      fetal sex in England. Prenat Diagn. 2011 Mar;31(3):267-73.\u000d        http:\/\/dx.doi.org\/10.1002\/pd.2680  \u000d    \u000a\u000a[3] Hil M, Finning K, Martin P, Hogg J, Meaney C, Norbury G, Daniels G,\u000d      Chitty L. Non-invasive prenatal determination of fetal sex: translating\u000d      research into clinical practice. Clin Genet. 2011 Jul;80(1):68-75.\u000d        http:\/\/dx.doi.org\/10.1111\/j.1399-0004.2010.01533.x  \u000d    \u000a\u000a[4] Lewis C, Hil M, Skirton H, Chitty LS: Non-invasive prenatal diagnosis\u000d      for fetal sex determination - benefits and disadvantages from the service\u000d      users' perspective. Eur J Hum Genet. 2012 Nov;20(11):1127-33.\u000d        http:\/\/dx.doi.org\/10.1038\/ejhg.2012.50  \u000d    \u000a\u000a[5] Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, Cole\u000d      TJ. New aids for the non-invasive prenatal diagnosis of achondroplasia:\u000d      dysmorphic features, charts of fetal size and molecular confirmation using\u000d      cell free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol.\u000d      2011 Mar;37(3):283-9.\u000d        http:\/\/dx.doi.org\/10.1002\/uog.8893  \u000d    \u000a\u000a[6] Lench N, Barrett A, Fielding S, McKay F, Hil M, Jenkins L, White H,\u000d      Chitty LS. The clinical implementation of non-invasive prenatal diagnosis\u000d      for single gene disorders: challenges and progress made. Prenat Diagn.\u000d      2013 Jun;33(6):555-62.\u000d        http:\/\/dx.doi.org\/10.1002\/pd.4124  \u000d    \u000a\u000a[7] Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole T. Safer,\u000d      accurate prenatal diagnosis of thanatophoric dysplasia using ultrasound\u000d      and cell free fetal DNA. Prenat Diagn. 2013 May;33(5):416-23.\u000d        http:\/\/dx.doi.org\/10.1002\/pd.4066  \u000d    NIHR Programme Grant: RAPID- Reliable Accurate Prenatal\u000a      non-Invasive Diagnosis RP-PG-0707-10107, sponsor GOSH\u000d      2009-2014, £2 million \u000d    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"}],"Sources":"\u000d     [a] PHG foundation Steering Group Wright, C. Cell-free fetal nucleic\u000d      acids for non-invasive prenatal\u000d      diagnosis, Report of the UK expert working group, PHG Foundation (2009): http:\/\/www.phgfoundation.org\/download\/ffdna\/ffDNA_report.pdf\u000a         \u000d    [b] Chitty LS, Crolla JC. Non-invasive prenatal diagnosis using cell free\u000d      fetal DNA in maternal blood. Scientific Advisory Committee Opinion Paper\u000d      15, RCOG June 2009: http:\/\/www.rcog.org.uk\/files\/rcog-corp\/uploaded-files\/SIP_No_15.pdf\u000a         \u000d    [c] Gene Dossier submission to the UKGTN which was approved formally in\u000d      April 2011 Approval:http:\/\/ukgtn.nhs.uk\/find-a-test\/search-by-disorder-gene\/test-service\/x-linked-conditions-excluding-haemophilia-nipd-602\/\u000a        \u000d     Best Practice guidelines: \u000d     http:\/\/ukgtn.nhs.uk\/fileadmin\/uploads\/ukgtn\/Documents\/Resources\/Library\/NIPD\/BPCAREPATWAYSNIPDCAHFINAL.pdf\u000a        \u000d    [d] Approval of Gene Dossiers for Achondroplasia and Thanatophoric\u000d      dysplasia: \u000d    \u000d       \u000d          http:\/\/ukgtn.nhs.uk\/find-a-test\/search-by-disorder-gene\/test-service\/achondroplasia-nipd-600\/\u000a           \u000d       http:\/\/ukgtn.nhs.uk\/uploads\/tx_ukgtn\/Achondroplasia_FGFR3_TC_Sept_12.pdf\u000a\u000d      \u000a\u000d        \u000dhttp:\/\/ukgtn.nhs.uk\/find-a-test\/search-by-disorder-gene\/test-service\/thanatophoric-\u000a\u000d       dysplasia-nipd-599\/\u000a           \u000d       http:\/\/ukgtn.nhs.uk\/uploads\/tx_ukgtn\/TD12_FGFR3_TC_Sept_12.pdf\u000a          \u000a\u000d    \u000d    [e] Corroboration of our impact on the approval of the gene dossiers is\u000d      available from the Chair of UKGTN Clinical and Scientific Advisory Group.\u000d      Contact details provided. \u000d     [f] Skirton H, Goldsmith L, Jackson L, Lewis C, Chitty L. Offering\u000d      prenatal diagnostic tests:European guidelines for clinical practice\u000d      guidelines. Eur J Hum Genet.\u000d        http:\/\/doi.org\/pds \u000d     [g] Building on our inheritance: Genomic technology in healthcare. A\u000d      report by the Human Genomics Strategy Group. January 2012 gives NIPD as an\u000d      example that needs to be developed (quotes and Chitty acknowledged for\u000d      contribution): http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/@dh\/@en\/documents\/digitalasset\/dh_132382.pdf\u000a         \u000d    [h] CMGS audits 2010-11 and 11-12:\u000d        www.cmgs.org\/CMGS%20audit\/cmgs_audit.htm  \u000d    \u000d    \u000d     \u000d      Fig 1a. Histogram showing increase use of NIPD for fetal\u000d          sex determination \u000d     \u000d      Fig 1b. Molecular prenatal tests performed\u000d    \u000d    \u000d     [i] Data can be confirmed by Lead Scientist NIPD section, North East\u000d      Thames Regional Genetics Service, Great Ormond Street Hospital NHS\u000d      Foundation Trust. Contact details provided. \u000d     [j] Anonymised patient feedback available on request from Great Ormond\u000d      Street Hospital.Contact details provided. Further quotes from interviewed\u000d      patients who have undergone NIPD and these are published in Lewis C, Hil\u000d      M, Skirton H, Chitty LS. Fetal sex determination using cell-free fetal\u000d      DNA: service users' experiences of and preferences for service delivery.\u000d      Prenat Diagn. 2012; 32(8):735-41 and Lewis C, Hil M, Chitty LS:\u000d      Non-invasive prenatal diagnosis for single gene disorders: experience of\u000d      patients. Clin Genet 2013. http:\/\/doi.org\/pdt\u000d       \u000d     [k] See www.rapid.nhs.uk. Activities\u000a      include: \u000d    \u000d      \u000d         RAPID dissemination meetings at ICH for laboratory and clinical\u000d          staff across England - July2009, January 2010, November 2011, November\u000d          2012 \u000d      \u000d    \u000d    \u000d      \u000d         RAPID laboratory workshop on free fetal DNA Extraction methods\u000d          involved 13 NHS labs from around the UK \u000d      \u000d    \u000d     [l] Director, Antenatal Results and Choices can vouch for support and\u000d      dissemination to patients.Contact details provided. \u000d     [m] Rafi I, Chitty L. Cell-free fetal DNA and non-invasive prenatal\u000d      diagnosis. Br J Gen Pract. 2009 May;59(562):e146-8.\u000d        http:\/\/dx.doi.org\/10.3399\/bjgp09X420572. \u000d    ","Title":"\u000d    Delivery of new methods for safer prenatal diagnosis: non-invasive\u000d      testing using cell free fetal DNA in maternal blood \u000d    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"},{"GeoNamesId":"2655603","Name":"Birmingham"},{"GeoNamesId":"2650225","Name":"Edinburgh"},{"GeoNamesId":"2646393","Name":"Huntingdon"},{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    Work led by Lyn Chitty at the UCL Institute of Child Health from 2005-10\u000d      was initially focussed on determining the clinical impact of NIPD for\u000d      fetal sex determination in women considering an invasive diagnostic test\u000d      because they were at risk of carrying a baby with a serious sex-linked\u000d      disorder (e.g. Duchenne muscular dystrophy) or might require dexamethasone\u000d      treatment because of a risk of congenital adrenal hyperplasia (CAH). The\u000d      established approach to prenatal diagnosis requires an invasive test (e.g.\u000d      chorionic vil ous sampling) to obtain fetal genetic material for analysis,\u000d      procedures associated with a 0.5-1% risk of miscarriage. NIPD allows\u000d      analysis of cell-free fetal DNA (cffDNA) in the blood of pregnant mothers.\u000d      Our early clinical work, funded by an EU FP6 award, clearly showed that\u000d      NIPD reduced the rate of invasive testing by 46% as well as reducing\u000d      unnecessary administration of dexamethasone to some mothers [1].\u000d      These results led to the delivery of NIPD for fetal sex determination on a\u000d      research basis from 2006. \u000d    We also established a bank of plasma samples collected from parents with\u000d      pregnancies at risk of aneuploidy or genetic disorders. This now contains\u000d      >11,000 samples and is a resource which has underpinned the\u000d      developments described here. In 2009, Chitty was awarded an NIHR programme\u000d      grant (RAPID: Reliable Accurate Prenatal non-Invasive Diagnosis) to\u000d      investigate the feasibility of wider use of cffDNA and to develop\u000d      standards for implementation into NHS clinical practice. Since then, the\u000d      RAPID team has led the development of laboratory standards and performed a\u000d      national evaluation of NIPD for fetal sex determination that demonstrated\u000d      a high sensitivity and specificity for the method [2]. \u000d    We subsequently showed that it is cheaper than traditional invasive\u000d      testing [3], and that it is highly valued by patients [4].\u000d      This research formed the basis for the development of the standards\u000d      required for formal approvals necessary to implement NIPD for fetal sex\u000d      determination for serious sex-linked disorders as a clinical test. From\u000d      2009 onwards we also developed and implemented NIPD for single gene\u000d      disorders including achondroplasia, thanatophoric dysplasia, and apert\u000d      syndrome as well as developing several tests on a bespoke per patient\u000d      basis [5, 6, 7]. \u000d    "},{"CaseStudyId":"22019","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000aImpact on patients\u000d\u000aThe majority of our patients are well and off all prophylactic therapy. One SCID-X1 patient who\u000d\u000awas atypical (adolescent at time of treatment and had previously undergone HSCT, which was\u000d\u000afailing) was treated on compassionate grounds, but did not reconstitute. As discussed, we have\u000d\u000ahad one serious adverse event (leukaemia). This patient was successfully treated by\u000d\u000achemotherapy and HSCT [a].\u000d\u000aThe only alternative treatment for our patients would have been HSCT. Many patients who have\u000d\u000aundergone this treatment suffer from additional complications such as long-term effects related to\u000d\u000achemotherapy, usually with alkylating agents (e.g. lack of growth, compromised fertility, secondary\u000d\u000amalignancy, hearing loss, hypodontia). Our recent study suggests a high incidence of cognitive and\u000d\u000abehavioural abnormalities in SCID patients following HSCT. Since many of our gene therapy\u000d\u000apatients have not received chemotherapy we can reasonably expect to see a reduction in the\u000d\u000aappearance of such debilitating side effects and a consequent improved quality of life compared to\u000d\u000apatients who have had chemotherapy.\u000d\u000aOne parent whose child underwent gene therapy said:\u000d\u000a\"Guy is now doing brilliantly; he can do all of the things his friends can do and more. He is\u000d\u000aable to play football and ride a pony. He wouldn't be here if it wasn't for the option of gene\u000d\u000atherapy treatment. We are incredibly grateful to the whole team at Great Ormond Street\u000d\u000aHospital, but especially Adrian Thrasher and Bobby Gaspar who pioneered this work. To\u000d\u000aother parents who find themselves in our situation we would say `go for it'\" [b].\u000d\u000aEconomic benefits\u000d\u000aThe cost of gene therapy compared to the only other comparable treatment, HSCT, is reduced\u000d\u000abecause the patient has a significantly shorter stay in hospital (4-6 weeks for gene therapy\u000d\u000acompared to 8 weeks on average for HSCT). The cost of enzyme replacement for ADA-SCID is\u000d\u000aestimated at £350,000 p.a. minimum cost for the life-time of a patient. A significant number of our\u000d\u000apatients are now off enzyme replacement treatment, with gene therapy thus offering an overall total\u000d\u000acost saving of £5 million to date.\u000d\u000aInput into guidelines and policy\u000d\u000aGaspar has been Chairman of the BMT and Gene Therapy Working Party of European Society for\u000d\u000aImmunodeficiencies (ESID), Chairman of the Inborn Errors Working Party of the European Blood\u000d\u000aand Marrow Transplantation Society (EBMT). He has been involved in developing the current\u000d\u000aguidelines for the treatment of PIDs [c, d]. In 2006 we contributed to the European Primary\u000d\u000aImmunodeficiency Consensus Conference and their guidelines, which are still current [e].\u000d\u000aThrasher has acted in an advisory capacity to the US Recombinant DNA Advisory Committee\u000d\u000a(RAC), the US Federal Drugs Administration (FDA), the UK Gene Therapy Advisory Committee\u000d\u000a(GTAC) [f], the Medicines Control Agency (MCA) and the European Medicines Evaluation Agency\u000d\u000a(EMEA).\u000d\u000aPublic engagement\u000d\u000aWe have worked extensively with national and international patients' groups including the Primary\u000d\u000aImmunodeficiency Association (PIA) [g], the CGD Society, the International Patient Organisation\u000d\u000afor Primary Immunodeficiency (IPOPI) and Rare Disease UK [h]. This has included speaking at\u000d\u000atheir meetings and contributing to newsletters. For example, Gaspar is Chairman of the IPOPI\u000d\u000aMedical Advisory panel and is a member of the advisory panels for PID-UK and the Ataxia\u000d\u000aTelangiectasia society.\u000d\u000aWe have publicised our work to the general public through our interactions with the GOSH\u000d\u000aChildren's Charity fundraising work, through talks, films and other promotional material. We have\u000d\u000aalso worked closely with the Jeans for Genes Campaign in schools and at other fundraising\u000d\u000aevents, speaking and appearing in films to raise awareness of our work. Our work has been\u000d\u000apresented as part of a living exhibition to promote the public understanding of science. The\u000d\u000aexhibition, \"Health Matters\", has been on continuous display in the Science Museum throughout\u000d\u000athe 2008-13 period. Our work also appears as part of a science exhibition at Bristol Museum.\u000d\u000aWe have worked extensively with the media to publicise our work. We have promoted our research\u000d\u000athrough films, newspapers and television, including BBC News, Newsnight and Radio 4, ITN News\u000d\u000aand Channel 4 News and also in numerous scientific documentaries, including BBC Horizon [i].\u000d\u000aWe have worked with the Science Media Centre in educating journalists about our work.\u000d\u000aWe are very active in scientific societies which relate to our work such as the British Society for\u000d\u000aGene and Cell Therapy (BSGCT). Thrasher has recently retired as the President of the BSGCT,\u000d\u000aand has organised education days for junior scientists and the general public. We are hosting at\u000d\u000atent at the forthcoming Bloomsbury Festival to showcase our work. We have talked about our work\u000d\u000ain schools, to students of all ages from primary through to `A' Level students. We have hosted\u000d\u000aschool children to visit our labs and to hear presentations on our work. We offer one week work\u000d\u000aexperience placements to students in our labs on a biannual basis.\u000d\u000a","ImpactSummary":"\u000d\u000aResearch at the UCL Institute of Child Health (ICH) has led to the successful treatment of children\u000d\u000awith primary immunodeficiency diseases for whom there was little chance of \"cure\" by the only\u000d\u000aother possible means: haematopoietic stem cell transplantation (HSCT). Beginning in 2002, we\u000d\u000ahave treated 32 patients with four different primary immunodeficiency disorders. In total we have\u000d\u000atreated 12 patients with severe combined immunodeficiency (SCID-X1), 13 patients with adenosine\u000d\u000adeaminase deficient severe combined immunodeficiency (ADA-SCID), 5 patients with chronic\u000d\u000agranulomatous disease (CGD) and 2 patients with Wiskott-Aldrich syndrome (WAS). Most of the\u000d\u000apatients have been successfully treated and are at home, off all therapy. We are now starting to\u000d\u000adevelop this technology to treat a wider range of related disorders.\u000d\u000a","ImpactType":"Health","Institution":"\u000d\u000aUniversity College London\u000d\u000a","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a\u000a[1] Vetrie D, Vorechovský I, Sideras P, Holland J, Davies A, Flinter F, Hammarström L, Kinnon C,\u000d\u000aLevinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a\u000d\u000amember of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226-33.\u000d\u000ahttp:\/\/dx.doi.org\/10.1038\/361226a0\u000d\u000a\u000a\u000a[2] Thrasher AJ, Casimir CM, Kinnon C, Morgan G, Segal AW, Levinsky RJ. Gene transfer to\u000d\u000aprimary chronic granulomatous disease monocytes. Lancet. 1995 Jul 8;346(8967):92-3.\u000d\u000ahttp:\/\/dx.doi.org\/10.1016\/S0140-6736(95)92116-8\u000d\u000a\u000a\u000a[3] Demaison C, Brouns G, Blundell MP, Goldman JP, Levinsky RJ, Grez M, Kinnon C, Thrasher\u000d\u000aAJ. A defined window for efficient gene marking of severe combined immunodeficient-repopulating cells using a gibbon ape leukemia virus-pseudotyped retroviral vector. Hum Gene\u000d\u000aTher. 2000 Jan 1;11(1):91-100. http:\/\/dx.doi.org\/10.1089\/10430340050016184\u000d\u000a\u000a\u000a[4] Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von\u000d\u000aKalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL,\u000d\u000aLevinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined\u000d\u000aimmunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004 Dec 18-31;364(9452):2181-7. http:\/\/dx.doi.org\/10.1016\/S0140-6736(04)17590-9\u000d\u000a\u000a\u000a[5] Gaspar HB, Bjorkegren E, Parsley K, Gilmour KC, King D, Sinclair J, Zhang F, Giannakopoulos\u000d\u000aA, Adams S, Fairbanks LD, Gaspar J, Henderson L, Xu-Bayford JH, Davies EG, Veys PA,\u000d\u000aKinnon C, Thrasher AJ. Successful reconstitution of immunity in ADA-SCID by stem cell gene\u000d\u000atherapy following cessation of PEG-ADA and use of mild preconditioning. Mol Ther. 2006\u000d\u000aOct;14(4):505-13. http:\/\/dx.doi.org\/10.1016\/j.ymthe.2006.06.007\u000d\u000a\u000a\u000a[6] Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman\u000d\u000aMH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL,\u000d\u000aStaal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK,\u000d\u000aSchmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with\u000d\u000aacquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1\u000d\u000apatients. J Clin Invest. 2008 Sep;118(9):3143-50. http:\/\/dx.doi.org\/10.1172\/JCI35798\u000d\u000a\u000a\u000a[7] Thornhill SI, Schambach A, Howe SJ, Ulaganathan M, Grassman E, Williams D, Schiedlmeier\u000d\u000aB, Sebire NJ, Gaspar HB, Kinnon C, Baum C, Thrasher AJ. Self-inactivating gammaretroviral\u000d\u000avectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther. 2008\u000d\u000aMar;16(3):590-8. http:\/\/dx.doi.org\/10.1038\/sj.mt.6300393\u000d\u000a\u000aSelected research grant support\u000d\u000aWellcome Trust Senior Fellowship in Clinical Science. Development of novel therapeutic\u000d\u000aapproaches for primary immunodeficiency. 1999-2014. Over £4 million. Thrasher\u000d\u000aDepartment of Health. Clinical trials of gene therapy for primary immunodeficiency. 2005-10.\u000d\u000a£1,033,723. Thrasher, Kinnon & Gaspar\u000d\u000aMRC Project Grant. Clinical trial of self-inactivating vectors for gene therapy of X-linked severe\u000d\u000acombined immunodeficiency (SCID-X1). 2006-12. £727,647. Thrasher & Gaspar\u000d\u000a","ResearchSubjectAreas":[{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a[a] Patient data can be verified by Senior Consultant Immunologist, Chair of Research\u000d\u000aGovernance Advisory Committee, GOSH. Contact details provided.\u000d\u000a[b] Patient testimonies available from Senior Press Officer, Great Ormond Street Hospital. Contact\u000d\u000adetails provided.\u000d\u000a[c] http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2766674\/?tool=pubmed\u000d\u000a[d] http:\/\/www.esid.org\/downloads\/BMT_Guidelines_2011.pdf\u000d\u000a[e] http:\/\/ec.europa.eu\/health\/ph_projects\/2005\/action1\/docs\/action1_2005_frep_01_en.pdf\u000d\u000a[f] Corroboration can be obtained from former Chair of the Gene Therapy Advisory Committee\u000d\u000a(GTAC). Contact details provided.\u000d\u000a[g] Letter of testimony from David Webster, past Chairman of Trustees of the Primary\u000d\u000aImmunodeficiency Association available on request.\u000d\u000a[h] Corroborating testimony as to our work with patient groups can be obtained from the Chronic\u000d\u000aGranulomatous Disease Society (CGD Society). Contact details provided.\u000d\u000a[i] Media coverage:\u000d\u000a\u000d\u000a2011 article marking 10 years since the boy received treatment : http:\/\/bbc.in\/pqXemg\u000a\u000d\u000ahttp:\/\/www.bbc.co.uk\/news\/health-11451810\u000d\u000ahttp:\/\/www.bbc.co.uk\/news\/health-17209287\u000d\u000a\u000ahttp:\/\/www.channel4.com\/news\/has-a-cure-been-found-for-boy-in-the-bubble-syndrome\u000d\u000a2011 report on overall trial results and Science Translational Medicine paper\u000d\u000ahttp:\/\/www.gosh.org\/gen\/news\/latest-news\/2011-archive\/gene-therapy-success-for-children-born-without-functioning-immune-system\/\u000d\u000aYouTube video discussing the Science Translational Medicine paper\u000d\u000ahttp:\/\/www.youtube.com\/watch?v=3IGKoh6-o7I [578 views at 22 Sep 2013]\u000d\u000aYouTube video `Rhys' story - a Genetic Disorders UK \/ Jeans for Genes Day film'\u000d\u000ahttp:\/\/www.youtube.com\/watch?v=8fcXB0cf9DU [10,529 views at 22 Sep 2013]\u000d\u000a\u000d\u000a\u000d\u000a","Title":"\u000d\u000aGene therapy for immunodeficiency diseases\u000d\u000a","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aPrimary immunodeficiency disorders are a heterogeneous group of rare, inherited diseases, where\u000d\u000achildren are born with defective immune systems. In the most severe forms children are unable to\u000d\u000afight off even very mild infections and, without treatment, will usually die within the first 2 years of\u000d\u000alife.\u000d\u000aWith the discovery of the causative genes for several primary immunodeficiencies by our group\u000d\u000aand others came the possibility of developing new and improved forms of treatment for these life-threatening diseases [1]. Although earlier clinical trials of gene therapy had been conducted, these\u000d\u000ahad been largely unsuccessful.\u000d\u000aOur strategy was to develop efficient methods for introducing therapeutic genes into\u000d\u000ahaematopoietic stem cells (HSCs). To this end we developed gammaretroviral vectors to transduce\u000d\u000aHSCs, using technology that we had developed in-house (selection of HSCs using anti-CD34\u000d\u000amonoclonal antibodies and novel vectors). Using CGD as a model disorder, we showed functional\u000d\u000acorrection of the defect in in vitro models [2]. At the same time we developed immunodeficient\u000d\u000amouse models for testing functional correction in vivo. By 2000 we had developed gammaretroviral\u000d\u000avectors that were capable of delivering therapeutic genes under the control of constitutive viral\u000d\u000apromoters that could transduce HSCs with high efficiency and which could be used for clinical trials\u000d\u000aof gene therapy [3].\u000d\u000aFollowing scale-up of these methods we initiated our first clinical trial of gene therapy for SCID-X1,\u000d\u000afollowed by clinical trials for ADA-SCID and CGD using gammaretroviral vectors in the early 2000s.\u000d\u000aBy measuring the quantity and quality of immune reconstitution using cellular and molecular\u000d\u000atechniques we evaluated the success of these treatments, comparing them to the only other\u000d\u000aalternative, HSCT. We have also analysed these patients using novel molecular methods for\u000d\u000ainvestigating and mapping gene integration sites to assess the efficiency of transduction [4, 5].\u000d\u000aOverall these clinical trials have been judged to be largely successful. However, following the\u000d\u000adevelopment of a T-cell leukaemia-like disease in 4 of 10 SCID-X1 patients in a French clinical\u000d\u000atrial, there were concerns regarding the safety profile of the use of gammaretroviral vectors. Of\u000d\u000athese patients 3 were successfully treated by chemotherapy and HSCT while unfortunately 1\u000d\u000apatient died. One of our patients was similarly affected but responded to chemotherapy treatment.\u000d\u000aThese studies demonstrated that while gene correction of autologous HSCs was highly effective,\u000d\u000athe use of gammaretroviral vectors utilising the viral promoter had a finite risk of insertional\u000d\u000amutagenesis [6].\u000d\u000aFurther research has shown that relatively simple modifications to design, such as the use of self-inactivating (SIN) vectors in which viral promoters are deleted and transcription is under the control\u000d\u000aof an internal mammalian promoter, may significantly improve safety [7]. To this end, we have\u000d\u000adeveloped new SIN gammaretroviral vectors which incorporate additional safety features, including\u000d\u000aself-inactivation and tissue specific promoters, and we have also developed SIN lentiviral vectors\u000d\u000abased on HIV. Current clinical trials using these new vectors are being conducted for SCID-X1,\u000d\u000aADA-SCID, CGD and WAS.\u000d\u000a"},{"CaseStudyId":"22135","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Background to limb-girdle muscular dystrophy type 2A\u000d\u000a    Limb-girdle muscular dystrophy type 2A is a rare progressive\u000d\u000a      muscle-wasting disease caused by\u000d\u000a      mutation(s) in the CAPN3 gene that result in reduction of protein\u000d\u000a      expression or loss of protein\u000d\u000a      function. The disease, which usually becomes symptomatic at between 10 and\u000d\u000a      30 years of age,\u000d\u000a      manifests as progressive weakening of muscles in the hips and shoulders,\u000d\u000a      causing a slow\u000d\u000a      reduction in mobility, balance, and the ability to lift objects. A patient\u000d\u000a      typically becomes wheelchair\u000d\u000a      bound 20 - 30 years after disease onset. A study carried out in north-east\u000d\u000a      England estimated the\u000d\u000a      prevalence there of all the limb-girdle muscular dystrophies to be 2.27\u000d\u000a      per 100,000 individuals;\u000d\u000a      limb-girdle muscular dystrophy type 2A is the most common type with a\u000d\u000a      prevalence of 0.6 per\u000d\u000a      100,000 (Norwood et al. (2009) PubMed ID: 19767415). A\u000d\u000a      separate study carried out in north-east\u000d\u000a      Italy yielded an estimated prevalence of 0.95 per 100,000 individuals\u000d\u000a      (Fanin et al. (2005) PubMed\u000d\u000a      ID: 15725583).\u000d\u000a    Why diagnosis is important\u000d\u000a    While limb-girdle muscular dystrophy type 2A is incurable, diagnosis does\u000d\u000a      benefit the patient in\u000d\u000a      other ways. Health monitoring can be customised to the patient: the 2A\u000d\u000a      subtype, compared with\u000d\u000a      the other limb-girdle muscular dystrophies, is associated with a\u000d\u000a      relatively low incidence of cardiac\u000d\u000a      and respiratory problems, and so the affected person can be reassured and\u000d\u000a      given low-key health\u000d\u000a      surveillance. Diagnosis also means that the patient can be given access to\u000d\u000a      the disease-specific\u000d\u000a      registry, and potentially a chance to participate in clinical trials of\u000d\u000a      future therapies. Further, as it is\u000d\u000a      known that limb-girdle muscular dystrophy type 2A is an autosomal\u000d\u000a      recessive disorder, precise\u000d\u000a      genetic counselling can be given to the patient and family members and\u000d\u000a      prenatal testing can be\u000d\u000a      done if requested. In addition, diagnosis often has a positive\u000d\u000a      psychological effect on patients, who\u000d\u000a      welcome official recognition of their condition and the ability to share\u000d\u000a      their experiences with others\u000d\u000a      with the disease (e.g. Bird (1999) PubMed ID: 12194381).\u000d\u000a    Diagnosis of limb-girdle muscular dystrophy type 2A\u000d\u000a    Typically the diagnostic approach for the disease is multi-faceted.\u000d\u000a      Initial tests include symptom\u000d\u000a      assessment (pattern of affected muscles), measurement of creatine kinase\u000d\u000a      levels in the blood and\u000d\u000a      muscle histopathology.\u000d\u000a    If limb-girdle muscular dystrophy type 2A is suspected on the basis of\u000d\u000a      these test results, calpain 3\u000d\u000a      immunoblot analysis is performed on a muscle biopsy sample (Ev a). A\u000d\u000a      reduction in the level of\u000d\u000a      calpain 3, when considered in the context of amounts of other muscle\u000d\u000a      proteins (for example\u000d\u000a      dysferlinopathy is associated with reductions in the amount of calpain 3\u000d\u000a      and dysferlin), is usually\u000d\u000a      sufficient for confident diagnosis of limb-girdle muscular dystrophy type\u000d\u000a      2A to be made. About one-fifth\u000d\u000a      of limb-girdle muscular dystrophy type 2A patients have normal amounts of\u000d\u000a      calpain 3 protein,\u000d\u000a      and for them sequencing of the CAPN3 gene needs to be performed after the\u000d\u000a      protein test for a\u000d\u000a      diagnosis to be reached.\u000d\u000a    In 2007 the European Federation of Neurological Societies published a\u000d\u000a      guideline on diagnosis and\u000d\u000a      management of limb-girdle muscular dystrophies. It states (citing research\u000d\u000a      that used the Newcastle\u000d\u000a      University CALP antibodies):\u000d\u000a    \"Immunoblotting [for calpain 3] has been the accepted test required\u000d\u000a        for the diagnosis of LGMD2A\"\u000d\u000a      (Ev b)\u000d\u000a    Use of the Newcastle calpain 3 antibodies in Europe and the United\u000d\u000a        States\u000d\u000a    All muscle biopsies from suspected limb-girdle muscular dystrophy cases\u000d\u000a      in England, Wales and\u000d\u000a      Scotland are tested at the NHS Specialised Service Rare Neuromuscular\u000d\u000a      Disorders laboratory in\u000d\u000a      Newcastle, which was established in 2001 (Ev c). The Newcastle unit\u000d\u000a      performed calpain 3\u000d\u000a      immunoblots using the Newcastle CALP antibodies on 186 samples in the year\u000d\u000a      2008\/9 and on 164\u000d\u000a      samples in the year 2009\/10, yielding molecular confirmation of\u000d\u000a      limb-girdle muscular dystrophy\u000d\u000a      type 2A in nine and six individuals respectively in those years (Ev\u000d\u000a      d). There is also evidence of the\u000d\u000a      usage of CALP antibodies in Europe; in Paris 90 diagnostic tests were\u000d\u000a      performed in the last year,\u000d\u000a      (47 had calpain defects) (Ev e) and in Milan 52 samples were\u000d\u000a      tested in the last two years (3 were\u000d\u000a      calpain-deficient) (Ev f).\u000d\u000a    The antibodies are also used in the United States to diagnose the\u000d\u000a      disease. Dr Melissa Spencer is a\u000d\u000a      Professor of Neurology and the Co-Director of the Center for Duchenne\u000d\u000a      Muscular Dystrophy at\u000d\u000a      UCLA, Chair of the Scientific Advisory Board of the Coalition to Cure\u000d\u000a      Calpain 3, and an authority in\u000d\u000a      US on the science and treatment of the disease. She has stated that:\u000d\u000a    \"Dr Anderson generated and characterized several monocolonal\u000d\u000a        antibodies ... and these\u000d\u000a        antibodies are widely used in calpain 3 research and are considered to\u000d\u000a        be the `gold standard\".\u000d\u000a    \"While there are a number of distinct mutations in the CAPN3 gene\u000d\u000a        which can cause LGMD2A, not\u000d\u000a        all of which result in a reduction or abolition of calpain 3 protein, or\u000d\u000a        an altered proteolytic\u000d\u000a        degradation profile, blotting for the protein in muscle biopsy lysates\u000d\u000a        using the antibodies developed\u000d\u000a        by Louise Anderson at Newcastle University is now a routine part of the\u000d\u000a        process — in the US and\u000d\u000a        worldwide — leading to diagnosis of LGMD2A.\" (Ev g)\u000d\u000a    Worldwide sales of the Newcastle CALP antibodies\u000d\u000a    The Newcastle University CALP antibodies were initially sold through the\u000d\u000a      local university spin-out\u000d\u000a      company Novocastra Laboratories. However, since 2009 a licensing agreement\u000d\u000a      has been in place\u000d\u000a      with the international bioscience company Leica Biosystems and they now\u000d\u000a      sell significant\u000d\u000a      quantities of the antibodies worldwide — including in North America,\u000d\u000a      Europe, Asia and Australasia\u000d\u000a      (Ev h).\u000d\u000a    Unit sales for the UK and Ireland\u000d\u000a    [text removed for publication]\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Limb-girdle muscular dystrophy type 2A is a rare (about six cases per\u000d\u000a      million individuals) and\u000d\u000a      incurable muscular disorder with a genetic basis. Although diagnosis is a\u000d\u000a      multi-step process, which\u000d\u000a      includes symptom assessment and histopathology of affected muscle, it\u000d\u000a      invariably involves\u000d\u000a      measurement of the amount of protein calpain 3 in muscle biopsy samples.\u000d\u000a      This is performed in\u000d\u000a      diagnostic laboratories worldwide using the two monoclonal antibodies\u000d\u000a      CALP-12A2 and CALP-2C4,\u000d\u000a      which were developed by researchers at Newcastle University in the late\u000d\u000a      1990s. In 2009\u000d\u000a      Newcastle University signed a licensing agreement with the international\u000d\u000a      bioscience company\u000d\u000a      Leica Biosystems that currently sells the antibodies to institutions\u000d\u000a      worldwide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Newcastle University\u000d\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2988507","Name":"Paris"},{"GeoNamesId":"3173435","Name":"Milan"}],"References":"\u000d\u000a    (Newcastle researchers in bold. Citation count from Scopus, July 2013)\u000d\u000a    \u000aR1. Spencer MJ, Tidball JG, Anderson LV, Bushby KM, Harris\u000d\u000a        JB, Passos-Bueno MR, Somer\u000d\u000a      H, Vainzof M, Zatz M (1997). Absence of calpain 3 in a form of limb-girdle\u000d\u000a      muscular\u000d\u000a      dystrophy (LGMD2A). J Neurol Sci. 146(2):173-8. DOI:\u000d\u000a      10.1016\/S0022-510X(96)00304-8.\u000d\u000a      32 citations.\u000d\u000a    \u000aHarris, Bushby and Anderson were involved in the conception,\u000d\u000a          organisation and\u000d\u000a          prosecution of the study that led to output R1. They were also\u000d\u000a          involved in drafting the\u000d\u000a          manuscript. Harris is corresponding author.\u000d\u000a    \u000aR2. Anderson LV, Davison K, Moss JA, Richard I,\u000d\u000a      Fardeau M, Tomé FM, Hübner C, Lasa A,\u000d\u000a      Colomer J, Beckmann JS (1998). Characterization of monoclonal antibodies\u000d\u000a      to calpain 3 and\u000d\u000a      protein expression in muscle from patients with limb-girdle muscular\u000d\u000a      dystrophy type 2A. Am\u000d\u000a        J Pathol. 153(4):1169-79. DOI: 10.1016\/S0002-9440(10)65661-1. 117\u000d\u000a        citations.\u000d\u000a     \u000aAnderson was the principal researcher and is the corresponding\u000d\u000a          author.\u000d\u000a    Select research grants\u000d\u000a    • Muscular Dystrophy Group of Great Britain. 1991 - 1994. £76 000. Expression\u000d\u000a        of dystrophin\u000d\u000a        and related proteins in normal and diseased tissues\u000d\u000a    • Muscular Dystrophy Group of Great Britain. 1960s - 1990s. ~ £100 000\u000d\u000a      per year. Centre\u000d\u000a      grant, supporting the staffing costs (including Anderson) at the Muscular\u000d\u000a      Dystrophy Centre,\u000d\u000a      based at Newcastle General Hospital.\u000d\u000a    • Novocastra Laboratories. Royalties (received from 1997) from sales of\u000d\u000a      dystrophin and other\u000d\u000a      antibodies produced by Newcastle were recycled back into research leading\u000d\u000a      to development of\u000d\u000a      the calpain 3 monoclonal antibodies.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    Ev a. GeneReviews (NCBI Bookshelf): Calpainopathy.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1313\/#lgmd2a.Diagnosis\u000d\u000a    Ev b. Norwood F, De Visser M, Eymard B, Lochmüller H, Bushby K (2007).\u000d\u000a      EFNS guideline on\u000d\u000a      diagnosis and management of limb girdle muscular dystrophies. European\u000d\u000a        Journal of\u000d\u000a        Neurology 14(12):1305-1312.\u000d\u000a    Ev c. NHS Specialised Services: Rare Neuromuscular Disorders.\u000d\u000a      http:\/\/www.specialisedservices.nhs.uk\/service\/rare-neuromuscular-disorders\u000d\u000a    Ev d. Statement from the NHS Specialised Service Rare Neuromuscular\u000d\u000a      Disorders Diagnostic\u000d\u000a      Laboratory, Newcastle, UK.\u000d\u000a    Ev e. Statement from the Laboratory of Biochemistry and Molecular\u000d\u000a      Genetics, Cassini Hopital\u000d\u000a      Cochin, Paris, France.\u000d\u000a    Ev f. Statement from the Neuromuscular Diseases and Neuroimmunology Unit,\u000d\u000a      Fondazione\u000d\u000a      IRCCS Istituto Neurologico, Milan, Italy.\u000d\u000a    Ev g. Statement from a Professor at the UCLA Department of Neurology\u000d\u000a    Ev h. Leica Biosystems: confidential sales information. (Data tab.)\u000d\u000a    ","Title":"\u000d\u000a    Diagnostic test for the rare muscular disorder limb-girdle muscular\u000d\u000a      dystrophy type 2A\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Key Newcastle University researchers\u000d\u000a    (Where people left or joined the university in the period 1993-2013,\u000d\u000a      years are given in brackets)\u000d\u000a    \u000d\u000a      Dr Louise Anderson, Lecturer in the Department of Neurobiology\u000d\u000a        (1992-2005).\u000d\u000a      Professor John Harris, Professor of Experimental Neurology.\u000d\u000a      Professor Kate Bushby, initially a Clinical Research Associate, then\u000d\u000a        Senior Lecturer (1997-1999),\u000d\u000a        Reader in Human Genetics (1999-2001), and subsequently Professor of\u000d\u000a        Neuromuscular\u000d\u000a        Genetics.\u000d\u000a    \u000d\u000a    Background\u000d\u000a    In the early 1990s the genetic defects underlying the limb-girdle\u000d\u000a      muscular dystrophies, a group of\u000d\u000a      rare muscle disorders, were discovered. One disease subtype, limb-girdle\u000d\u000a      muscular dystrophy type\u000d\u000a      2A, was found to be caused by mutations in the CAPN3 gene, which encodes\u000d\u000a      the skeletal muscle\u000d\u000a      protein calpain 3. Genetic analyses of samples from several limb-girdle\u000d\u000a      muscular dystrophy type\u000d\u000a      2A patients revealed a number of distinct disease-causing mutations within\u000d\u000a      CAPN3, making a\u000d\u000a      simple genetic test difficult to develop. An effort was mounted to come up\u000d\u000a      with a protein-based\u000d\u000a      diagnostic test for the disease.\u000d\u000a    A biomarker for limb-girdle muscular dystrophy type 2A\u000d\u000a    Anderson, Bushby and Harris, in a collaboration with researchers at the\u000d\u000a      University of California Los\u000d\u000a      Angeles, published a key paper in 1997 showing that the protein calpain 3\u000d\u000a      was absent in muscle\u000d\u000a      biopsies taken from three patients with limb-girdle muscular dystrophy\u000d\u000a      type 2A but present in all 12\u000d\u000a      control samples of healthy muscle. The researchers also found that calpain\u000d\u000a      3 was clearly\u000d\u000a      detectable in samples from nine patients suffering from muscle diseases\u000d\u000a      other than limb-girdle\u000d\u000a      muscular dystrophy type 2A, suggesting that the marker was highly specific\u000d\u000a      — and therefore\u000d\u000a      potentially of diagnostic use (R1).\u000d\u000a    Development and validation of monoclonal antibodies against calpain 3\u000d\u000a      In the 1997 study (R1) that identified calpain 3 protein as a potential\u000d\u000a      diagnostic marker for limb-girdle\u000d\u000a      muscular dystrophy type 2A, the researchers used affinity-purified\u000d\u000a      polyclonal antisera (a preparation containing several kinds of antibody, each with a slightly\u000d\u000a      different specificity) to detect\u000d\u000a      the protein. Following that study, Anderson led a project at Newcastle\u000d\u000a      University to generate highly\u000d\u000a      specific monoclonal antibodies against two regions of calpain 3. Three\u000d\u000a      monoclonal antibodies,\u000d\u000a      clones CALP-2C4, -11B3 and -12A2, were made, and they were described in a\u000d\u000a      paper published in\u000d\u000a      the American Journal of Pathology in 1998 (R2). The antibodies were\u000d\u000a      validated with samples from\u000d\u000a      33 healthy controls, 70 disease controls (muscle diseases other than\u000d\u000a      limb-girdle muscular\u000d\u000a      dystrophy type 2A) and nine people with limb-girdle muscular dystrophy\u000d\u000a      type 2A. The controls\u000d\u000a      0(healthy and other disease) all yielded a normal calpain profile, and\u000d\u000a      seven of nine limb-girdle\u000d\u000a      muscular dystrophy type 2A samples showed a clear reduction in amount of\u000d\u000a      full-length calpain 3. In\u000d\u000a      the other two LGMD2A samples there were normal levels of full-length\u000d\u000a      protein but reduced levels\u000d\u000a      of two calpain 3 degradation products (R2).\u000d\u000a    "},{"CaseStudyId":"23093","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3017382","Name":"France"}],"Funders":[],"ImpactDetails":"\u000d\u000a    In developing the device, Singer worked closely with the manufacturer\u000d\u000a      (formerly Doptex, now\u000d\u000a      Deltex Medical), a British company based in Chichester. This close\u000d\u000a      collaboration allied his clinical\u000d\u000a      and translational expertise with their engineering and technical skills.\u000d\u000a      The device, now marketed as\u000d\u000a      the CardioQ, has \"changed the way in which doctors can care for\u000d\u000a        patients having major surgery or\u000d\u000a        in intensive care. It allows doctors to intervene quickly and safely\u000d\u000a        based on small changes in\u000d\u000a        circulating blood volume and so avoid the dangers of reduced oxygen\u000d\u000a        delivery\" [a].\u000d\u000a    To date, more than 500,000 patients have benefitted from the use of the\u000d\u000a      CardioQ in surgery and in\u000d\u000a      intensive care. By the end of 2012, a total of 926 monitors had been\u000d\u000a      installed in the UK and\u000d\u000a      monitors have been sold widely in many other countries including the US,\u000d\u000a      Canada, South America\u000d\u000a      and Continental Europe [a]. In the period 2008-13 this amounted to\u000d\u000a      over £33m in sales for Deltex\u000d\u000a      [b]. The company employs around 65 people, mostly in the UK, and\u000d\u000a      the CardioQ is their sole\u000d\u000a      product.\u000d\u000a    The outcome benefits (reduced complications, shorter ICU and hospital\u000d\u000a      stay) accruing from the\u000d\u000a      perioperative optimisation studies were evaluated and endorsed\u000d\u000a      independently by the US Agency\u000d\u000a      for Healthcare Research and Quality [c] and the NIHR Health\u000d\u000a      Technology Assessment\u000d\u000a      Programme [d]. In March 2011 NICE published its Medical\u000d\u000a      Technologies Guidance (MTG3)\u000d\u000a      recommending the use of oesophageal Doppler monitoring (ODM) in high-risk\u000d\u000a      surgery. NICE\u000d\u000a      estimated that its use could save around £1,000 each time it is used for\u000d\u000a      high-risk surgery, and up\u000d\u000a      to £400m per year for the NHS as a whole [e].\u000d\u000a    In the same year, the NHS Innovative Technology Adoption Procurement\u000d\u000a      Programme (ITAPP)\u000d\u000a      selected oesophageal Doppler-guided intra-operative fluid management as\u000d\u000a      one of three\u000d\u000a      technologies for wider adoption by the NHS in England [f]. Later\u000d\u000a      that year, the NHS Innovation\u000d\u000a      Health & Wealth Review named ODM as one of six high impact innovations\u000d\u000a      and called for the\u000d\u000a      widespread implementation of ODM for fluid management in surgery, stating\u000d\u000a      that this technology\u000d\u000a      \"can reduce mortality rates for elective procedures, improve the\u000d\u000a        quality of care for more than\u000d\u000a        800,000 patients a year, and save the NHS at least £400m annually\" [g].\u000d\u000a      This was reported in the\u000d\u000a      media at the time, including on the BBC News website [h].\u000d\u000a    In May 2012, the NHS National Technology Adoption Centre published its\u000d\u000a      Intraoperative Fluid\u000d\u000a      Management Technologies (IOFMT) Adoption Pack to encourage adoption\u000d\u000a      throughout the NHS as\u000d\u000a      a recommended High Impact Innovation [i]. Hospital trusts have to\u000d\u000a      implement ODM at projected\u000d\u000a      target levels in 2013\/14 or lose access to their CQUIN payments, which\u000d\u000a      make up 2.5% of their\u000d\u000a      budget.\u000d\u000a    Looking outside the UK, the device has been adopted or is under formal\u000d\u000a      evaluation by health\u000d\u000a      regions\/large hospital groups in the USA, France, Spain, and Canada. The\u000d\u000a      Entralgo Agency in\u000d\u000a      Spain have evaluated the device and confirmed its utility. In April 2013,\u000d\u000a      the US Centres for\u000d\u000a      Medicare and Medicaid Services (CMS) granted ODM its own unique code for\u000d\u000a      physician\u000d\u000a      reimbursement. In addition, CMS set a standard amount of $101 that it will\u000d\u000a      reimburse US doctors\u000d\u000a      for each use of an ODM probe in either surgery for patients requiring\u000d\u000a      intra-operative fluid\u000d\u000a      optimisation or for ventilated patients in intensive care. This is a very\u000d\u000a      significant development for\u000d\u000a      the ODM in the USA and very rare that the CMS grant an individual\u000d\u000a      technology with such a code\u000d\u000a      (especially to a small British company) [j].\u000d\u000a    In May 2013, the professional body for anaesthetists in France Société\u000d\u000a      Française d'Anesthésie et\u000d\u000a      de Réanimation ('SFAR') published new guidelines setting out recommended\u000d\u000a      fluid management\u000d\u000a      best practice for its members. These guidelines make it clear that\u000d\u000a      ODM-guided fluid management\u000d\u000a      should be used in all high risk surgery in France, estimated to cover\u000d\u000a      circa 750,000 patients a year.\u000d\u000a      All of these recommendations are graded in the highest category '1+',\u000d\u000a      meaning that SFAR\u000d\u000a      members are expected to comply because the evidence level is high, and\u000d\u000a      that future evidence is\u000d\u000a      unlikely to change the conclusions from the current evidence. In France\u000d\u000a      clinical guidelines from\u000d\u000a      professional societies determine the standards expected of their members\u000d\u000a      based on clinical\u000d\u000a      benefit. The recommendations are based on the ODM evidence and the\u000d\u000a      guidelines make it clear\u000d\u000a      that this evidence should not be assumed to apply to alternative\u000d\u000a      technologies. The\u000d\u000a      recommendations apply to all high risk surgery, defined as surgery with an\u000d\u000a      increased risk of post-\u000d\u000a      operative complications due to either the health of the patient or the\u000d\u000a      nature of the surgery; typically\u000d\u000a      this excludes minor day-case surgery and surgery lasting fewer than two\u000d\u000a      hours with low levels of\u000d\u000a      post-operative complication [k].\u000d\u000a    Deltex Medical won the National Outstanding Achievement category in the\u000d\u000a      2013 UK Healthcare\u000d\u000a      Business Awards held at the NHS Healthcare Innovation Expo [l].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    As a result of research undertaken by Professor Mervyn Singer and\u000d\u000a      colleagues at UCL, the\u000d\u000a      oesophageal Doppler haemodynamic monitoring device is now a standard of\u000d\u000a      care in intensive care\u000d\u000a      units and operating theatres. The research underpinned the development of\u000d\u000a      the CardioQ\u000d\u000a      Oesophageal Doppler Monitor that guides optimisation of the circulation in\u000d\u000a      critically ill and\u000d\u000a      perioperative patients. In multiple studies its use has led to significant\u000d\u000a      reductions in postoperative\u000d\u000a      complication rates and length of stay in patients undergoing high-risk\u000d\u000a      surgery. Over 500,000\u000d\u000a      patients have now benefitted from this technology that, between 2008-13,\u000d\u000a      generated over £33m in\u000d\u000a      sales for its manufacturer, Deltex Medical. The device is recommended in\u000d\u000a      NICE guidance and has\u000d\u000a      been identified by the Department of Health as one of six high impact\u000d\u000a      innovations to be\u000d\u000a      implemented fully across the NHS.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Mythen MG, Webb AR. Perioperative plasma volume expansion reduces the\u000d\u000a      incidence of gut\u000d\u000a      mucosal hypoperfusion during cardiac surgery. Arch Surg. 1995\u000d\u000a      Apr;130(4):423-9.\u000d\u000a      http:\/\/dx.doi.org\/10.1001\/archsurg.1995.01430040085019\u000d\u000a    \u000a\u000a[2] Sinclair S, James S, Singer M. Intraoperative intravascular volume\u000d\u000a      optimisation and length of\u000d\u000a      hospital stay after repair of proximal femoral fracture: randomised\u000d\u000a      controlled trial. BMJ. 1997\u000d\u000a      Oct 11;315(7113):909-12. http:\/\/dx.doi.org\/10.1136\/bmj.315.7113.909\u000d\u000a    \u000a\u000a[3] Poeze M, Ramsay G, Greve JW, Singer M. Prediction of postoperative\u000d\u000a      cardiac surgical\u000d\u000a      morbidity and organ failure within 4 hours of intensive care unit\u000d\u000a      admission using esophageal\u000d\u000a      Doppler ultrasonography. Crit Care Med. 1999 Jul;27(7):1288-94.\u000d\u000a      http:\/\/dx.doi.org\/10.1097\/00003246-199907000-00013\u000d\u000a    \u000a\u000a[4] McKendry M, McGloin H, Saberi D, Caudwell L, Brady AR, Singer M.\u000d\u000a      Randomised controlled\u000d\u000a      trial assessing the impact of a nurse delivered, flow monitored protocol\u000d\u000a      for optimisation of\u000d\u000a      circulatory status after cardiac surgery. BMJ. 2004 Jul 31;329(7460):258.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/bmj.38156.767118.7C\u000d\u000a    \u000a\u000a[5] Dark PM, Singer M. The validity of trans-esophageal Doppler\u000d\u000a      ultrasonography as a measure of\u000d\u000a      cardiac output in critically ill adults. Intensive Care Med. 2004\u000d\u000a      Nov;30(11):2060-6.\u000d\u000a      http:\/\/dx.doi.org\/10.1007\/s00134-004-2430-2\u000d\u000a    \u000a\u000a[6] Atlas G, Brealey D, Dhar S, Dikta G, Singer M. Additional hemodynamic\u000d\u000a      measurements with an\u000d\u000a      esophageal Doppler monitor: a preliminary report of compliance, force,\u000d\u000a      kinetic energy, and\u000d\u000a      afterload in the clinical setting. J Clin Monit Comput. 2012\u000d\u000a      Dec;26(6):473-82.\u000d\u000a      http:\/\/dx.doi.org\/10.1007\/s10877-012-9386-5\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Deltex Medical website: http:\/\/www.deltexmedical.com\/index.html\u000d\u000a      and 2012 annual report\u000d\u000a      http:\/\/www.deltexmedical.com\/downloads\/2012report&accounts.pdf\u000d\u000a    [b] Sales figures supplied by Deltex — available on request.\u000d\u000a    [c] Agency for Healthcare Research and Quality Technology Assessment\u000d\u000a      Program. Esophageal\u000d\u000a      Doppler Ultrasound-Based Cardiac Output Monitoring for Real-Time\u000d\u000a      Therapeutic Management\u000d\u000a      of Hospitalised Patients; January 2007 http:\/\/www.cms.gov\/medicare-coverage-\u000d\u000adatabase\/details\/technology-assessments-details.aspx?TAId=45&bc=BAAgAAAAAAAA&\u000d\u000a      (See\u000d\u000a      refs 10, 47, 48 which are papers in section 2 above; also refs 1 and 64\u000d\u000a      are work done at UCL\u000d\u000a      by the same individuals).\u000d\u000a    [d] Mowatt G, Houston G, Hernández R, et al. Systematic review of the\u000d\u000a      clinical effectiveness and\u000d\u000a      cost-effectiveness of oesophageal Doppler monitoring in critically ill and\u000d\u000a      high-risk surgical\u000d\u000a      patients. Health Technol Assess. 2009; 13: iii-iv, ix-xii, 1-95\u000d\u000a      http:\/\/www.hta.ac.uk\/fullmono\/mon1307.pdf\u000d\u000a    [e] CardioQ-ODM (oesophageal Doppler monitor) (MTG3) http:\/\/guidance.nice.org.uk\/MTG3\u000d\u000a      (accessed 21st May 2012)\u000d\u000a    [f] See, for example, plans for adoption in the East Midlands, which\u000d\u000a      explain the wider national\u000d\u000a      context: http:\/\/www.tin.nhs.uk\/innovation-nhs-east-midlands\/product-and-technology-adoption-campaigns\/the-oesophageal-doppler\/\u000d\u000a    [g] Innovation, Health and Wealth 2011\u000d\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consu\u000d\u000a        m_dh\/groups\/dh_digitalassets\/documents\/digitalasset\/dh_134597.pdf\u000d\u000a    [h] BBC News coverage: http:\/\/www.bbc.co.uk\/news\/health-12899316\u000d\u000a    [i] NHS Technology Adoption Centre:\u000d\u000a      http:\/\/www.ntac.nhs.uk\/Publications\/TechnologyAdoptionPacks\/Intra_Operative_Fluid_Manage\u000d\u000a        ment\/Intra_Operative_Fluid_Management.aspx\u000d\u000a    [j] Press release from Deltex Medical giving details of the newly\u000d\u000a      announced physician\u000d\u000a      reimbursement in USA http:\/\/www.deltexmedical.com\/announcements\/2013_04_10.pdf\u000d\u000a    [k] Vallet B, Blanloeil Y, Cholley B, Orliaguet G, Pierre S, Tavernier B.\u000d\u000a      Stratégie du remplissage\u000d\u000a      vasculaire périopératoire (Guidelines for perioperative haemodynamic\u000d\u000a      optimization). Ann Fr\u000d\u000a      Anesth Reanim. 2013 Jun;32(6):454-62 http:\/\/dx.doi.org\/10.1016\/j.annfar.2013.04.013\u000d\u000a    [l] UK Healthcare Business awards: http:\/\/www.sehta.co.uk\/2013\/03\/13\/deltex-wins-medilinkuk-national-outstanding-achievements-award\/\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved surgical outcomes achieved through perioperative circulatory\u000d\u000a      optimisation guided by oesophageal Doppler\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2653192","Name":"Chichester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In the late 1980s, the CardioQ Oesophageal Doppler Monitor was conceived\u000d\u000a      by Mervyn Singer\u000d\u000a      while a registrar at Mount Vernon Hospital. He then validated the device\u000d\u000a      and performed proof-of-concept\u000d\u000a      studies during his research fellowship at St George's Hospital Medical\u000d\u000a      School. Work at\u000d\u000a      UCL by Singer (as Lecturer\/Senior Lecturer\/Reader\/Professor) between 1993\u000d\u000a      and 2004 further\u000d\u000a      validated the device and, crucially, assessed its utility through a series\u000d\u000a      of studies, including three of\u000d\u000a      the early perioperative outcome RCTs. This work done at UCL underpinned\u000d\u000a      the commercial\u000d\u000a      development of the device and its widespread adoption since.\u000d\u000a    The device utilises a Doppler ultrasound probe inserted via the mouth\u000d\u000a      into the oesophagus. The\u000d\u000a      probe is connected to a monitor that displays flow velocity waveforms of\u000d\u000a      blood being pumped down\u000d\u000a      the descending thoracic aorta. Correct focussing of the probe is readily\u000d\u000a      and reliably achieved within\u000d\u000a      just a few minutes, and can be performed by either a doctor or nurse.\u000d\u000a      Integral software,\u000d\u000a      incorporating a nomogram developed by Singer, computes in real time a\u000d\u000a      close estimate of absolute\u000d\u000a      left ventricular cardiac output and, from the waveform shape, considerable\u000d\u000a      information on left\u000d\u000a      ventricular filling, contractility and afterload. These data can be used\u000d\u000a      to quickly detect any\u000d\u000a      deterioration in circulatory status, and to guide optimal fluid and drug\u000d\u000a      therapy.\u000d\u000a    Ten studies have been performed at UCL, including assessments of the\u000d\u000a      circulatory stress induced\u000d\u000a      by chest physiotherapy, transurethral prostatectomy and cardiac surgery\u000d\u000a      (with demonstration of its\u000d\u000a      prognostic utility), and optimisation of mechanical ventilation settings.\u000d\u000a      Importantly, three of the\u000d\u000a      studies were single-centre, randomised controlled trials (RCTs) in\u000d\u000a      patients undergoing\u000d\u000a      haemodynamic optimisation either during [1] or after [2]\u000d\u000a      cardiac surgery, or during intraoperative\u000d\u000a      repair of fractured hips [3]. The first study was performed by\u000d\u000a      Monty Mythen (then Clinical Research\u000d\u000a      Fellow, now Professor at UCL) and the latter two were led by Singer. All\u000d\u000a      three studies reported\u000d\u000a      significant reductions in postoperative complications and hospital stay in\u000d\u000a      patients optimised by\u000d\u000a      oesophageal Doppler, as compared to patients receiving standard-of-care.\u000d\u000a    A recent systematic review\/meta-analysis of perioperative optimisation\u000d\u000a      studies reported on nine\u000d\u000a      oesophageal Doppler perioperative optimisation studies, demonstrating a\u000d\u000a      major reduction in post-operative\u000d\u000a      complications through its use (odds ratio [95% CI] 0.41 [0.30-0.57])\u000d\u000a      (Hamilton et al).To\u000d\u000a      assess the generalisability of these results, the NHS Technology Adoption\u000d\u000a      Centre organised a\u000d\u000a      before-after study in three UK hospitals (including the Whittington\u000d\u000a      Hospital, London) comparing\u000d\u000a      outcomes in 649 surgical patients after implementation of the CardioQ\u000d\u000a      technology against 658\u000d\u000a      matched cases before implementation. Total length of stay was reduced by\u000d\u000a      3.7 days across each\u000d\u000a      site (Kuper et al).\u000d\u000a    All of the UCL studies were funded internally with the exception of Ref 3\u000d\u000a      below where Deltex\u000d\u000a      Medical (the manufacturer of CardioQ) provided an unrestricted educational\u000d\u000a      grant.\u000d\u000a    "},{"CaseStudyId":"23094","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Clinical practice and patient benefit\u000d\u000a    As a result of the neuroimaging work described above, we have\u000d\u000a      increased the number of children\u000d\u000a      who can be considered for surgery. This approach has underpinned the\u000d\u000a      development of the\u000d\u000a      epilepsy surgery programme at Great Ormond Street Hospital (GOSH), now one\u000d\u000a      of the largest\u000d\u000a      epilepsy surgery units in Europe and the largest in the UK. Numbers of\u000d\u000a      patients per year have\u000d\u000a      increased from 40\/year in 2004 to 70\/year in 2012 [a].\u000d\u000a    The benefit of this surgery to the patients is reduction if not abolition\u000d\u000a      of seizures. Children are\u000d\u000a      carefully evaluated to determine whether the seizures are coming from one\u000d\u000a      area, and whether that\u000d\u000a      area can be removed without further functional compromise. Secondary\u000d\u000a      benefits that have been\u000d\u000a      suggested have included optimisation of neurodevelopmental progress and\u000d\u000a      behavioural\u000d\u000a      improvement. We have evaluated outcome in several groups of children, and\u000d\u000a      demonstrated benefit\u000d\u000a      over time [b, c].\u000d\u000a    Since 2001, Cross has led the International League Against Epilepsy Task\u000d\u000a      Force for Paediatric\u000d\u000a      Epilepsy Surgery which has established referral guidelines for children\u000d\u000a      with epilepsy for surgery\u000d\u000a      [d], with recent evaluation of newer technologies and the\u000d\u000a      development of an evaluation protocol\u000d\u000a      [e]. The team has also contributed evidence and participated in the\u000d\u000a      working groups of the Safe and\u000d\u000a      Sustainable Paediatric Neurosurgical review currently being undertaken in\u000d\u000a      England and Wales with\u000d\u000a      the recent development of the national Children's Epilepsy Surgery Service\u000d\u000a      (CESS), launched in\u000d\u000a      November 2012, for which GOSH is the lead of four centres, and Professor\u000d\u000a      Cross is Clinical\u000d\u000a      Advisor [f]. The organisation Epilepsy Action report that: \"Professor\u000d\u000a        Cross's work identifying both a\u000d\u000a        shortfall in the number of operations undertaken in the UK and also the\u000d\u000a        benefits of early surgery on\u000d\u000a        neurodevelopmental and psychosocial outcomes has greatly assisted in the\u000d\u000a        campaign to improve\u000d\u000a        children's surgery in England. The outcome of our (and others)\u000d\u000a        campaigning, underscored by\u000d\u000a        Professor Cross's work, led to the NHS in England agreeing in 2012 to\u000d\u000a        nationally commission\u000d\u000a        children's epilepsy surgery [the CESS]\" [g].\u000d\u000a    Following our establishment of an evidence base for the ketogenic\u000d\u000a        diet, our study is now widely\u000d\u000a      quoted in service developments and the numbers of children who have been\u000d\u000a      initiated and\u000d\u000a      sustained on the diet in the UK have increased considerably. The ketogenic\u000d\u000a      diet service at Great\u000d\u000a      Ormond Street Hospital has been established and funded since 2008 with a\u000d\u000a      clinical consultant\u000d\u000a      lead, two dieticians and epilepsy nurse support, taking referrals from the\u000d\u000a      North London area and\u000d\u000a      linking in with other London centres [i]. A clinical network has\u000d\u000a      been established amongst other\u000d\u000a      centres now set up in the South East; Evelina Children's Hospital, St\u000d\u000a      Georges Hospital and\u000d\u000a      Addenbrookes Hospital. A recent EME NIHR grant has been achieved involving\u000d\u000a      nine centres\u000d\u000a      across the UK for a randomised controlled trial of diet utilisation for\u000d\u000a      the treatment of epilepsy in\u000d\u000a      children under two years of age, led by Cross and GOSH.\u000d\u000a    Cross has worked for many years with a parent support group, Matthew's\u000d\u000a      Friends, which was\u000d\u000a      launched by a parent involved in our ketogenic diet study in 2004. The CEO\u000d\u000a      of this organisation\u000d\u000a      reports that: \"We have seen a huge increase in ketogenic services\u000d\u000a        throughout the UK and globally\u000d\u000a        and the trial results proved to be a major part of successful business\u000d\u000a        cases being made for centres\u000d\u000a        to set up a service. Without this evidence proving the efficacy of the\u000d\u000a        treatment then I very much\u000d\u000a        doubt we would have as many people using the diet as there are currently.\u000d\u000a      Professionals from all\u000d\u000a        over the world quote the results from this trial and have publically\u000d\u000a        thanked the team for carrying out\u000d\u000a        such a trial as the information from it has furthered their own services\u000d\u000a        and allowed them to treat\u000d\u000a        more patients in their own healthcare systems\" [j].\u000d\u000a    Cross is Chair of the Medical Board of the charity and works with them to\u000d\u000a      support parents and\u000d\u000a      professionals considering and implementing the ketogenic diet. She has\u000d\u000a      been involved in several\u000d\u000a      parent and professional information days, as well as preparation of\u000d\u000a      material to help implementation\u000d\u000a      of the diet. She was on the scientific committee of two of the three\u000d\u000a      global conferences on dietary\u000d\u000a      therapy of epilepsy and neurological disorders (co-organised with Matthews\u000d\u000a      Friends in Edinburgh\u000d\u000a      in 2010) and is leading on organisation of the meeting to be held in 2014.\u000d\u000a      All have resulted in\u000d\u000a      publications as supplements to peer-reviewed journals, one of which Cross\u000d\u000a      co-edited in 2012 [k].\u000d\u000a      From expertise and experience gleaned from the research, she has recently\u000d\u000a      jointly edited a guide\u000d\u000a      and cookery book for utilisation by parents with colleagues from Australia\u000d\u000a      [l].\u000d\u000a    In 2012, NICE guidelines on the diagnosis and management of the\u000d\u000a      epilepsies in adults and\u000d\u000a      children in primary and secondary care (for which Cross was on the\u000d\u000a      Guideline Development\u000d\u000a      Group) made the following recommendation: \"Refer children and young\u000d\u000a        people with epilepsy\u000d\u000a        whose seizures have not responded to appropriate AEDs to a tertiary\u000d\u000a        paediatric epilepsy specialist\u000d\u000a        for consideration of the use of a ketogenic diet.\" The guideline\u000d\u000a      made specific reference to the\u000d\u000a      underpinning research described above as supporting evidence for this\u000d\u000a      recommendation [m].\u000d\u000a      Cross was also integral to the international consensus guidelines for\u000d\u000a      optimal management of\u000d\u000a      children utilising the ketogenic diet, published in 2009 [n].\u000d\u000a    Media and public engagement\u000d\u000a    As a result of this work, we have contributed to various newspaper and\u000d\u000a      television news articles and\u000d\u000a      supplements including the Daily Mail, Daily Express, Sunday Times, Times\u000d\u000a      and BBC. The epilepsy\u000d\u000a      surgery and ketogenic diet programmes have also been the focus of TV\u000d\u000a      documentaries and news\u000d\u000a      features, the most recent at the launch of the CESS programme in 2012.\u000d\u000a      Following development of\u000d\u000a      the CESS, Cross has worked with Epilepsy Action on information documents\u000d\u000a      about the CESS\u000d\u000a      programme for parents and professionals, and the results of research\u000d\u000a      performed have ensured\u000d\u000a      accuracy of information [g]. She has also worked with Young\u000d\u000a      Epilepsy, a charitable organisation\u000d\u000a      working towards improving the lives of children and young people with\u000d\u000a      epilepsy [o]. Young\u000d\u000a      Epilepsy through their information and education unit, with advice from\u000d\u000a      Cross, run training days for\u000d\u000a      both parents and professionals, disseminating information about the\u000d\u000a      benefits of surgery and early\u000d\u000a      referral.\u000d\u000a    Training\u000d\u000a    In addition to the training above, the unit has developed an\u000d\u000a      international reputation for training\u000d\u000a      clinical fellows from around the world. Great Ormond Street is the lead\u000d\u000a      for the development of the\u000d\u000a      National Epilepsy Surgery Programme. Cross has been integral to the\u000d\u000a      development of\u000d\u000a      standardised epilepsy training courses through the British Paediatric\u000d\u000a      Neurology Association. Over\u000d\u000a      3,000 paediatricians have now passed through the courses and Cross remains\u000d\u000a      Chair of the\u000d\u000a      Steering Committee [p].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Our research on alternatives to medication in the treatment of childhood\u000d\u000a      epilepsy has resulted in\u000d\u000a      increasing rates of surgery with better outcomes, and a new clinical\u000d\u000a      service — the national\u000d\u000a      Children's Epilepsy Surgery Service (CESS) — being commissioned in England\u000d\u000a      and Wales. We\u000d\u000a      have also developed an evidence base for ketogenic dietary therapy,\u000d\u000a      resulting in an increase in\u000d\u000a      service provision. Many more patients are benefiting from this therapy,\u000d\u000a      which is now recommended\u000d\u000a      in NICE guidelines. Throughout our programme of research we have engaged\u000d\u000a      with charities and\u000d\u000a      patient groups to disseminate the results of our research as widely as\u000d\u000a      possible.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2650225","Name":"Edinburgh"}],"References":"\u000d\u000a    \u000a[1] Hartley LM, Gordon I, Harkness W, Harding B, Neville BG, Cross JH.\u000d\u000a      Correlation of SPECT\u000d\u000a      with pathology and seizure outcome in children undergoing epilepsy\u000d\u000a      surgery. Dev Med Child\u000d\u000a      Neurol. 2002 Oct;44(10):676-80. http:\/\/dx.doi.org\/10.1111\/j.1469-8749.2002.tb00269.x\u000d\u000a    \u000a\u000a[2] De Tiège X, Laufs H, Boyd SG, Harkness W, Allen PJ, Clark CA,\u000d\u000a      Connelly A, Cross JH. EEG-fMRI\u000d\u000a      in children with pharmacoresistant focal epilepsy. Epilepsia. 2007\u000d\u000a      Feb;48(2):385-9.\u000d\u000a      http:\/\/dx.doi.org\/10.1111\/j.1528-1167.2006.00951.x\u000d\u000a    \u000a\u000a[3] D'Argenzio L, Colonnelli MC, Harrison S, Jacques TS, Harkness W,\u000d\u000a      Vargha-Khadem F, Scott\u000d\u000a      RC, Cross JH. Cognitive outcome after extratemporal epilepsy surgery in\u000d\u000a      childhood. Epilepsia.\u000d\u000a      2011 Nov;52(11):1966-72. http:\/\/dx.doi.org\/10.1111\/j.1528-1167.2011.03272.x\u000d\u000a    \u000a\u000a[4] Skirrow C, Cross JH, Cormack F, Harkness W, Vargha-Khadem F, Baldeweg\u000d\u000a      T. Long-term\u000d\u000a      intellectual outcome after temporal lobe surgery in childhood. Neurology.\u000d\u000a      2011 Apr\u000d\u000a      12;76(15):1330-7. http:\/\/dx.doi.org\/10.1212\/WNL.0b013e31821527f0\u000d\u000a    \u000a\u000a[5] Eltze CM, Chong WK, Cox T, Whitney A, Cortina-Borja M, Chin RF, Scott\u000d\u000a      RC, Cross JH. A\u000d\u000a      population-based study of newly diagnosed epilepsy in infants. Epilepsia.\u000d\u000a      2013 Mar;54(3):437-45.\u000d\u000a      http:\/\/dx.doi.org\/10.1111\/epi.12046\u000d\u000a    \u000a\u000a[6] Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G,\u000d\u000a      Whitney A, Cross\u000d\u000a      JH. The ketogenic diet for the treatment of childhood epilepsy: a\u000d\u000a      randomised controlled trial.\u000d\u000a      Lancet Neurol. 2008 Jun;7(6):500-6. http:\/\/dx.doi.org\/10.1016\/S1474-4422(08)70092-9\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] http:\/\/www.specialisedservices.nhs.uk\/document\/report-unit-visits-james-steers-sharon-stower\u000d\u000a    [b] Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha-Khadem\u000d\u000a      F, Neville BG.\u000d\u000a      Clinical outcomes of hemispherectomy for epilepsy in childhood and\u000d\u000a      adolescence. Brain. 2003\u000d\u000a      Mar;126(Pt 3):556-66. http:\/\/dx.doi.org\/10.1093\/brain\/awg052\u000d\u000a    [c] Dunkley C, Kung J, Scott RC, Nicolaides P, Neville B, Aylett SE,\u000d\u000a      Harkness W, Cross JH.\u000d\u000a      Epilepsy surgery in children under 3 years. Epilepsy Res. 2011\u000d\u000a      Feb;93(2-3):96-106.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/j.eplepsyres.2010.11.002\u000d\u000a    [d] Cross JH, Jayakar P, Nordli D, Delalande O, Duchowny M, Wieser HG,\u000d\u000a      Guerrini R, Mathern\u000d\u000a      GW; International League against Epilepsy, Subcommission for Paediatric\u000d\u000a      Epilepsy Surgery;\u000d\u000a      Commissions of Neurosurgery and Paediatrics. Proposed criteria for\u000d\u000a        referral and evaluation\u000d\u000a        of children for epilepsy surgery: recommendations of the Subcommission\u000d\u000a        for Pediatric\u000d\u000a        Epilepsy Surgery. Epilepsia. 2006 Jun;47(6):952-9. http:\/\/doi.org\/cjxnqm\u000d\u000a    [e] Jayakar P, Gaillard WG, Tripathi M, Libenson M, Mathern GW, Cross JH\u000d\u000a      on behalf of the Task\u000d\u000a      Force for Paediatric Epilepsy Surgery, Commission for Paediatrics, and the\u000d\u000a      Diagnostic\u000d\u000a      Commission of the International League Against Epilepsy. Diagnostic\u000d\u000a        Test Utilization in\u000d\u000a        Evaluation for Resective Epilepsy Surgery in Children; Recommendations\u000d\u000a        on behalf of\u000d\u000a        the Task Force for Paediatric Epilepsy Surgery (of the Commission\u000d\u000a      for Paediatrics) * and\u000d\u000a      the Diagnostic Commission of the ILAE. Submitted to Epilepsia. Available\u000d\u000a      on request.\u000d\u000a    [f] www.specialisedservices.nhs.uk\/safe_sustainable\/childrens-neurosurgical-services\u000d\u000a      Impacts\u000d\u000a      can be corroborated by Chair of the Epilepsy National Clinical\u000d\u000a      Coordinating Group. Contact\u000d\u000a      details provided.\u000d\u000a    [g] http:\/\/www.epilepsy.org.uk\/info\/treatment\/epilepsy-surgery\/children\u000d\u000a      Corroborating statement\u000d\u000a      provided by Deputy Chief Executive, Epilepsy Action. Also explains Cross's\u000d\u000a      work as co-clinical\u000d\u000a      lead and work to develop NHS England-approved referral guidelines and\u000d\u000a      patient guidelines,\u000d\u000a      and public awareness work. Copy available on request and contact details\u000d\u000a      provided.\u000d\u000a    [h] Lord K, Magrath G. Use of the ketogenic diet and dietary practices in\u000d\u000a      the UK. J Hum Nutr Diet.\u000d\u000a      2010 Apr;23(2):126-32. http:\/\/dx.doi.org\/10.1111\/j.1365-277X.2010.01040.x\u000d\u000a    [i] \u000d\u000ahttp:\/\/www.gosh.nhs.uk\/health-professionals\/clinical-guidelines\/the-ketogenic-diet-in-the-management-of-epilepsy\/\u000d\u000a    [j] Supporting statement from CEO, Matthew's Friends (http:\/\/www.matthewsfriends.org).\u000d\u000a      Copy\u000d\u000a      available on request and contact details provided.\u000d\u000a    [k] Kossoff E, Cross JH eds. Special Issue on Dietary treatments for\u000d\u000a      epilepsy & neurological\u000d\u000a      disorders. Epilepsy Research. 2012;100(3):203-346.\u000d\u000a      http:\/\/www.sciencedirect.com\/science\/journal\/09201211\/100\u000d\u000a    [l] Nation J, Cross JH, Scheffer IE. Ketocooking: A Practical Guide to\u000d\u000a      the Ketogenic Diet. The\u000d\u000a      Homewood Press, 2012. Available on request.\u000d\u000a    [m] Guidelines on the diagnosis and management of the epilepsies in\u000d\u000a      primary and secondary care\u000d\u000a      National Institute of Health and Clinical Excellence, 2004, update 2012\u000d\u000a      http:\/\/guidance.nice.org.uk\/CG137\/Guidance\/pdf\/English\u000d\u000a      (see refs 359 and 361, and p.482)\u000d\u000a    [n] Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina\u000d\u000a      Bergqvist AG, Blackford\u000d\u000a      R, Buchhalter JR, Caraballo RH, Cross JH et al; Charlie Foundation,\u000d\u000a      Practice Committee of the\u000d\u000a      Child Neurology Society; Practice Committee of the Child Neurology\u000d\u000a      Society; International\u000d\u000a      Ketogenic Diet Study Group. Optimal clinical management of children\u000d\u000a        receiving the\u000d\u000a        ketogenic diet: recommendations of the International Ketogenic Diet\u000d\u000a        Study Group.\u000d\u000a      Epilepsia. 2009 Feb;50(2):304-17. http:\/\/dx.doi.org\/10.1111\/j.1528-1167.2008.01765.x\u000d\u000a    [o] http:\/\/www.youngepilepsy.org.uk\u000d\u000a      Impact can be corroborated by the CEO of Young Epilepsy.\u000d\u000a    [p] http:\/\/www.bpna.org.uk\/pet\/\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Alternatives to medication improve quality of life for children with\u000d\u000a      epilepsy\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Epilepsy affects 112,000 children and young people in the UK, of whom two\u000d\u000a      thirds will respond to\u000d\u000a      antiepileptic medication, or go into spontaneous remission. For the\u000d\u000a      remaining third, however,\u000d\u000a      seizures persist, and are associated with a reduced quality of life.\u000d\u000a      Therefore, since 1993, research\u000d\u000a      at the UCL Institute of Child Health's Neurosciences Unit has investigated\u000d\u000a      alternative approaches\u000d\u000a      to medication, with a particular emphasis on the roles of surgery and\u000d\u000a      dietary treatments as\u000d\u000a      alternatives to antiepileptic drugs.\u000d\u000a    Epilepsy surgery, targeted at removing the source of seizures, can\u000d\u000a      lead to long-term seizure relief\u000d\u000a      where medication has been unsuccessful. Our initial research evaluated\u000d\u000a      newer imaging\u000d\u000a        techniques in the detection of brain abnormalities in children with\u000d\u000a      focal epilepsy utilising MRI, as\u000d\u000a      well as relating these areas to seizure onset utilising functional imaging\u000d\u000a      e.g. single photon emission\u000d\u000a      computed tomography [1]. Further work in collaboration with the\u000d\u000a      departments of Clinical\u000d\u000a      Neurophysiology and Developmental Cognitive Neuroscience has developed functional\u000d\u000a        MRI, both\u000d\u000a      for determining areas of motor and language cortex in relation to the\u000d\u000a      epileptic focus to be removed,\u000d\u000a      as well as more recently linking electrical to structural brain\u000d\u000a      abnormality for determining the source\u000d\u000a      of seizures [2]. We have also performed outcome studies\u000d\u000a      demonstrating the relative merits of early\u000d\u000a      surgery in carefully selected populations, with at least maintained\u000d\u000a      cognitive ability following\u000d\u000a      surgery, suggesting a maintained developmental trajectory [3].\u000d\u000a      More recent work has\u000d\u000a      demonstrated long-term improvements in cognition associated with\u000d\u000a      weaning-off medication [4]. An\u000d\u000a      epidemiological community-based cohort study has outlined the consequence\u000d\u000a      of early onset\u000d\u000a      epilepsy with uniformly poor outcomes, and has enabled the delineation of\u000d\u000a      neurodevelopment in\u000d\u000a      children with ongoing seizures by which the impact of intervention can be\u000d\u000a      compared [5].\u000d\u000a    For some patients, including those for whom surgery may not be an option,\u000d\u000a      treatment may involve\u000d\u000a      the ketogenic diet. This is a high fat diet designed to mimic the\u000d\u000a      metabolic effects of starvation.\u000d\u000a      Although this dietary treatment has been used in the treatment of\u000d\u000a      childhood epilepsy for many\u000d\u000a      years, our group undertook the first randomised controlled trial of its\u000d\u000a      use in childhood epilepsy, and\u000d\u000a      established its benefit equivalent to any new anti-epileptic drug with no\u000d\u000a      difference between types of\u000d\u000a      diet applied [6]. Collaborative work with UCL's Department of\u000d\u000a      Clinical Chemistry and Institute of\u000d\u000a      Neurology is now being undertaken to determine a possible mechanism of\u000d\u000a      action for its effect with\u000d\u000a      plans for translation to clinical practice through clinical trials.\u000d\u000a    "},{"CaseStudyId":"23128","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    The underpinning research described above has had a major impact in\u000d\u000a      transforming the management and identification of patients with FH. The\u000d\u000a      three specific impacts described below are: (1) development and validation\u000d\u000a      of screening methods which are now in use throughout the UK; (2)\u000d\u000a      contribution of research to the development of NICE guidelines (CG71); (3)\u000d\u000a      impact on the design of the NHS's Vascular Checks programme to increase\u000d\u000a      the reach of our work.\u000d\u000a    FH is one of the most common Mendelian disorders, affecting 1 in 500\u000d\u000a      members of the general population — or approximately 120,000 people in the\u000d\u000a      UK. People with FH have very high levels of low density lipoprotein\u000d\u000a      cholesterol (LDL-C) from birth and are at extremely high risk of\u000d\u000a      developing early heart disease. This can be prevented by early treatment\u000d\u000a      with a high intensity lipid-lowering therapy such as statins.\u000d\u000a      Unfortunately, only 15,000 FH patients have been identified to date and\u000d\u000a      are being adequately treated. Since FH is a monogenic disorder, the best\u000d\u000a      way to find new FH patients is by identifying the genetic mutation in the\u000d\u000a      proband and \"cascade testing\" all their first degree relatives, 50% of\u000d\u000a      whom will also be carriers.\u000d\u000a    DNA screening methods we developed have been used commonly in DNA\u000d\u000a      diagnostic laboratories throughout the UK. The identification and\u000d\u000a      characterisation of the common mutations in LDLR, APOB and PCSK9 in FH\u000d\u000a      patients in the UK led to the development of a DNA test kit which was\u000d\u000a      commercialised by Tepnel (now Geneprobe) during the Department of\u000d\u000a      Health-funded London IDEAS Genetic Knowledge Park of which Professor\u000d\u000a      Humphries was CEO. Although now superseded by new technologies, the\u000d\u000a      availability of the Elucigene FH20 kit allowed labs to take on FH genetic\u000d\u000a      testing and offer it widely and therefore led to the identification of the\u000d\u000a      molecular cause of FH in a large number of patients. This information was\u000d\u000a      then used for testing their relatives. In 2008, Humphries also contributed\u000d\u000a      to the first UK Genetic Testing Network \"Gene Dossier\" for FH obtained by\u000d\u000a      the GOSH DNA laboratory [a].\u000d\u000a    The demonstration of the feasibility, acceptability and\u000d\u000a      cost-effectiveness of FH cascade testing carried out at UCL was a major\u000d\u000a      part of the evidence that was presented to the NICE Guideline Development\u000d\u000a      Group, which led to their recommendation that DNA testing should be\u000d\u000a      offered to all FH patients to confirm their diagnosis and to use the DNA\u000d\u000a      information for cascade testing in their relatives [b]. The NICE\u000d\u000a      guidelines (CG71) for the identification and management of FH patients\u000d\u000a      were published in 2008 and Humphries was the Lead Clinical Advisor for\u000d\u000a      these guidelines. Implementation guidelines and costing tools were also\u000d\u000a      part of the NICE work, along with further NICE Quality Standards,\u000d\u000a      published in August 2013.\u000d\u000a    Progress in implementing these guidelines was examined in a pilot audit,\u000d\u000a      again led by Humphries and run through the Royal College of Physicians,\u000d\u000a      which reported in 2009 [c]. This was followed by a national audit\u000d\u000a      of 140 Lipid Clinics in the UK which reported in December 2010. The audit\u000d\u000a      revealed that DNA and cascade testing had been implemented well in\u000d\u000a      Scotland, Northern Ireland and Wales but almost not at all in England.\u000d\u000a      Nevertheless, 26% of patients seen over a 5-month period at the surveyed\u000d\u000a      clinics were offered a DNA test. At that time, only 21% of trusts reported\u000d\u000a      that they had access to a family cascade testing system for FH, but where\u000d\u000a      individuals had a DNA test, the process of cascade testing was initiated\u000d\u000a      in 72% of adults and 54% of paediatric cases [d]. According to the\u000d\u000a      Clinical Molecular Genetics Society Audit of Data for the year 2011-2012,\u000d\u000a      a total of 3,235 DNA tests for FH were performed in the laboratories of\u000d\u000a      its members (including all the Regional Genetic Laboratories) during that\u000d\u000a      period. The audit reported that this was an increase over previous years [e].\u000d\u000a      Humphries has continued public awareness work since the report was\u000d\u000a      published, with articles about cascade testing appearing, for example, in\u000d\u000a      the Daily Mail, on BBC News and in the Guardian [f].\u000d\u000a    In order to identify further FH patients as index cases for cascade\u000d\u000a      testing, Humphries has worked with the National Screening Committee to\u000d\u000a      include FH criteria in the NHS Vascular Checks programme [g].\u000d\u000a      Individuals with a total cholesterol level over 7.5mmol\/l who, based on\u000d\u000a      the diagnostic criteria of the Simon Broome Register, are likely to have\u000d\u000a      FH, will be flagged and referred to their local lipid clinic [h].\u000d\u000a    Information on FH has been made available to all UK GPs through a 2009\u000d\u000a      BHF factfile prepared by Humphries [i]. Our research findings are\u000d\u000a      outlined (and directly referenced) in the information given, and cascade\u000d\u000a      screening is recommended. Information based on our research is also given\u000d\u000a      to patients through articles in the HEARTUK magazine and their website [j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Basic molecular genetic research undertaken over the last 20 years by UCL\u000d\u000a      Cardiovascular Genetics has had a significant impact on the identification\u000d\u000a      and treatment of patients with familial hypercholesterolaemia (FH). We\u000d\u000a      have developed DNA testing methods in the three genes currently known to\u000d\u000a      cause FH and have established DNA diagnostic protocols which are now in\u000d\u000a      wide use throughout the UK. As a direct consequence of our work, we\u000d\u000a      estimate that up to 3,000 FH patients in the UK have had their diagnosis\u000d\u000a      of FH confirmed by a DNA test. Our work led to the National Institute of\u000d\u000a      Health and Clinical Excellence (NICE) in 2008 strongly recommending DNA\u000d\u000a      and cascade testing and early treatment with high intensity statins, and\u000d\u000a      furthermore, the inclusion of FH checks in the NHS's Vascular Checks\u000d\u000a      programme.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, Orengo\u000d\u000a      CA, Martin AC, Celli J, Humphries SE. Low-density lipoprotein receptor\u000d\u000a      gene familial hypercholesterolemia variant database: update and\u000d\u000a      pathological assessment. Ann Hum Genet. 2012 Sep;76(5):387-401.\u000d\u000a      http:\/\/dx.doi.org\/10.1111\/j.1469-1809.2012.00724.x\u000d\u000a    \u000a\u000a[2] Taylor A, Patel K, Tsedeke J, Humphries SE, Norbury G. Mutation\u000d\u000a      screening in patients for familial hypercholesterolaemia (ADH). Clin\u000d\u000a      Genet. 2010 Jan;77(1):97-9. http:\/\/doi.org\/c9799x\u000d\u000a    \u000a\u000a[3] Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA,\u000d\u000a      Harrison SC, Li K, Drenos F, Karpe F, Neil HA, Descamps OS, Langenberg C,\u000d\u000a      Lench N, Kivimaki M, Whittaker J, Hingorani AD, Kumari M, Humphries SE.\u000d\u000a      Use of low-density lipoprotein cholesterol gene score to distinguish\u000d\u000a      patients with polygenic and monogenic familial hypercholesterolaemia: a\u000d\u000a      case-control study. Lancet. 2013 Apr 13;381(9874):1293-301. http:\/\/doi.org\/f2hmx4\u000d\u000a    \u000a\u000a[4] Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil AW.\u000d\u000a      Cost effectiveness analysis of different approaches of screening for\u000d\u000a      familial hypercholesterolaemia. BMJ. 2002 Jun 1;324(7349):1303. http:\/\/dx.doi.org\/10.1136\/bmj.324.7349.1303\u000d\u000a    \u000a\u000a[5] Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D,\u000d\u000a      Cramb R, Egan S, Everdell R, Ferns G, Jones A, Marenah CB, Marples J,\u000d\u000a      Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries\u000d\u000a      SE; Steering Group for the Department of Health Familial\u000d\u000a      Hypercholesterolaemia Cascade Testing Audit Project. Family tracing to\u000d\u000a      identify patients with familial hypercholesterolaemia: the second audit of\u000d\u000a      the Department of Health Familial Hypercholesterolaemia Cascade Testing\u000d\u000a      Project. Ann Clin Biochem. 2009 Jan;46(Pt 1):24-32.\u000d\u000a      http:\/\/dx.doi.org\/10.1258\/acb.2008.008094\u000d\u000a    \u000a\u000a[6] Marteau T, Senior V, Humphries SE, Bobrow M, Cranston T, Crook MA,\u000d\u000a      Day L, Fernandez M, Horne R, Iversen A, Jackson Z, Lynas J,\u000d\u000a      Middleton-Price H, Savine R, Sikorski J, Watson M, Weinman J, Wierzbicki\u000d\u000a      AS, Wray R. Genetic Risk Assessment for FH Trial Study Group.\u000d\u000a      Psychological impact of genetic testing for familial hypercholesterolemia\u000d\u000a      within a previously aware population: a randomized controlled trial. Am J\u000d\u000a      Med Genet A. 2004 Jul 30;128A(3):285-93. http:\/\/dx.doi.org\/10.1002\/ajmg.a.30102\u000d\u000a    \u000a\u000a[7] Starr B, Hadfield SG, Hutten BA, Lansberg PJ, Leren TP, Damgaard D,\u000d\u000a      Neil HA, Humphries SE. Development of sensitive and specific age- and\u000d\u000a      gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis\u000d\u000a      of first-degree relatives with familial hypercholesterolaemia in cascade\u000d\u000a      testing. Clin Chem Lab Med. 2008;46(6):791-803. http:\/\/doi.org\/c3hpq4\u000d\u000a    \u000a\u000a[8] Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P,\u000d\u000a      Seed M, Humphries SE. Reductions in all-cause, cancer, and coronary\u000d\u000a      mortality in statin-treated patients with heterozygous familial\u000d\u000a      hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008\u000d\u000a      Nov;29(21):2625-33. http:\/\/dx.doi.org\/10.1093\/eurheartj\/ehn422\u000d\u000a    \u000aPeer-reviewed funding\u000d\u000a    Over the period 1993-2013, Humphries received peer-reviewed research\u000d\u000a      funding from the British Heart Foundation of > £6.6m, of which 25-30%\u000d\u000a      is dedicated to FH work (ie £1.6-2.0 million). He received three grants\u000d\u000a      from the Department of Health, for the London Genetic Knowledge Park of\u000d\u000a      £3.4m of which 10% was for FH, of £1.2m for the Cascade-Audit FH project\u000d\u000a      (100% FH) and for communication risk of £158,000 (50% FH). He received two\u000d\u000a      FH grants from the UCL Biomedical Research Centre, in total £185,000, a\u000d\u000a      CASE studentship from the MRC of £84,000, and peer-reviewed funding from\u000d\u000a      two small charities, in total £188,000.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    [a] UK Genetic Testing Network Gene Dossier for Familial\u000d\u000a      Hypercholesterolaemia\u000d\u000a      http:\/\/ukgtn.nhs.uk\/find-a-test\/search-by-disorder-gene\/test-service\/familial-\u000a        hypercholesterolemia-218\u000d\u000a    [b] Clinical Guidelines (CG71) — Familial hypercholesterolaemia.\u000d\u000a      http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG071\u000d\u000a      (citing ref. 2 above, and other papers by the group)\u000d\u000a    [c] National Clinical Audit of the Management of Familial\u000d\u000a      Hypercholesterolaemia 2009: Pilot FULL REPORT June 2009 http:\/\/www.rcplondon.ac.uk\/sites\/default\/files\/fh-pilot-audit-2009-report.pdf\u000d\u000a    [d] Pedersen KMV, Humphries SE, Roughton M, Besford JS. National Clinical\u000d\u000a      Audit of the Management of Familial Hypercholesterolaemia 2010: Full\u000d\u000a      Report. Clinical Standards Department, Royal College of Physicians,\u000d\u000a      December 2010\u000d\u000a      http:\/\/www.rcplondon.ac.uk\/resources\/audits\/FH\u000d\u000a    [e] Clinical Molecular Genetics Society Audit of Data for years\u000d\u000a      2011-2012:\u000d\u000a      http:\/\/www.cmgs.org\/CMGS%20audit\/2012%20audit\/CMGSAudit11_12_FINAL.pdf\u000d\u000a      (Number of tests, see p.11; increase in tests, see p.12\u000d\u000a    [f] Media articles:\u000d\u000a    \u000d\u000a      Article in the Daily Mail: http:\/\/www.dailymail.co.uk\/health\/article-2151319\/Have-YOU-\u000ainherited-heart-attack-gene-He-healthy-eater-Jonathan-needed-needed-triple-heart-\u000a          bypass.html\u000a\u000d\u000a      BBC News item: http:\/\/www.bbc.co.uk\/news\/health-12266621\u000a\u000d\u000a      Guardian article: http:\/\/www.guardian.co.uk\/society\/2013\/jan\/22\/blood-screening-heart-\u000a          attacks\u000a\u000d\u000a    \u000d\u000a    [g] Advising the Nation Screening Committee FH Policy Review 2011\u000d\u000a      http:\/\/www.screening.nhs.uk\/familialhypercholesterolaemia-adult\u000d\u000a    [h] NHS Health Check: Vascular Risk Assessment and Management Best\u000d\u000a      Practice Guidance.\u000d\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/en\/Publicatio\u000a        nsandstatistics\/Publications\/PublicationsPolicyAndGuidance\/DH_097489\u000d\u000a    [i] British Heart Foundation Fact File on FH published 2009\u000d\u000a      http:\/\/www.bhf.org.uk\/publications\/view-publication.aspx?ps=1000885\u000d\u000a    [j] HEARTUK web site on FH.\u000d\u000a      http:\/\/www.heartuk.org.uk\/images\/uploads\/beendiagnosedpdfs\/fhbooklet.pdf\u000d\u000a      Further confirmation of the contribution of the underpinning research to\u000d\u000a      the development of cascade testing is available from the Chief Executive\u000d\u000a      of HEARTUK. Contact details provided.\u000d\u000a    ","Title":"\u000d\u000a    Molecular genetic characterisation of the causes of familial\u000d\u000a      hypercholesterolaemia has led to improved diagnosis, prevention and\u000d\u000a      treatment.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The impacts reported below are the result of basic molecular genetic\u000d\u000a      research undertaken over the last 20 years that have had a significant\u000d\u000a      impact on the identification and treatment of patients with familial\u000d\u000a      hypercholesterolaemia (FH). This work led to the establishment of a DNA\u000d\u000a      diagnostic service at the Great Ormond Street Hospital in 1997 and the\u000d\u000a      establishment of the UCL LDLR mutation database, curated by the UCL\u000d\u000a      Cardiovascular Genetics Group, which is regularly updated [1].\u000d\u000a    We initially developed high-throughput screening methods — necessary\u000d\u000a      because FH is so common — which have been adapted for use in the DNA\u000d\u000a      diagnostic laboratory setting. Until recently, detecting all possible\u000d\u000a      mutations that predispose a patient to FH would be expensive, labour\u000d\u000a      intensive, and difficult to implement in clinical practice. We developed a\u000d\u000a      kit which, by examining 20 different mutations would rapidly and cheaply\u000d\u000a      identify the defect in roughly 50% of all patients where a mutation could\u000d\u000a      be identified by a complete gene screen [2]. We further reported\u000d\u000a      that c.5% of patients with FH have a large deletion\/rearrangement of the\u000d\u000a      LDLR gene and proposed a diagnostic algorithm that tests for the 20 most\u000d\u000a      common mutations, followed by sequencing of LDLR in those with no detected\u000d\u000a      mutation and finally using a commercially available MLPA kit to screen for\u000d\u000a      deletions or rearrangements [2]. Using these approaches, mutations\u000d\u000a      can be found in up to 80% of FH patients with the strongest clinical\u000d\u000a      diagnosis, but in those were no mutation can be detected we recently\u000d\u000a      demonstrated that a polygenic (not a single gene) cause is most likely [3].\u000d\u000a    In 2000 we reported on the under-diagnosis of FH patients in the\u000d\u000a      Oxfordshire area, particularly in young adults (who would benefit most\u000d\u000a      from statin treatment) and confirmed this in a UK national survey.\u000d\u000a      Together with colleagues at the LSHTM, we then carried out a modelling\u000d\u000a      exercise to determine the efficacy of cascade testing vs. other screening\u000d\u000a      approaches, and showed that cascade testing was likely to be the most cost\u000d\u000a      effective method and was within NICE costing requirements [4].\u000d\u000a    Our work in 2006-9 demonstrated the feasibility and acceptability of\u000d\u000a      cascade testing through a pilot study, in a Department of Health-funded\u000d\u000a      project involving five sites throughout the UK [5]. We also\u000d\u000a      analysed the ethical issues involved and proposed appropriate ways of\u000d\u000a      dealing with them. With colleagues at Kings College London we demonstrated\u000d\u000a      that DNA testing was not associated with significantly greater levels of\u000d\u000a      anxiety than measuring plasma cholesterol levels and that it was\u000d\u000a      associated with a number of favourable effects [6].\u000d\u000a    For patients where the causative mutation cannot be identified, we\u000d\u000a      developed age and gender specific LDL cholesterol cut-offs that would\u000d\u000a      allow a clear distinction between those with a high probability of not\u000d\u000a      having FH versus a high probability of definitely having FH. We defined\u000d\u000a      the area of uncertainty where further testing and follow up will be\u000d\u000a      required [7].\u000d\u000a    In collaboration with Andrew Neil at the University of Oxford and the\u000d\u000a      Simon Broome Register Group, we analysed data from the Simon Broome FH\u000d\u000a      register (a computerised research register of FH patients, used to track\u000d\u000a      the progression of the disease in the UK) to demonstrate a significant\u000d\u000a      increase in life expectancy in treated FH patients, firstly with the\u000d\u000a      initially available low potency statins, and subsequently with high\u000d\u000a      potency statins which have become available in the last ten years.\u000d\u000a      Although FH patients on the register who already have heart disease still\u000d\u000a      have a roughly two-fold higher future risk of a fatal CHD event even if\u000d\u000a      well treated, those who do not have evidence of heart disease can, when\u000d\u000a      treated with high intensity statins, expect to have a life expectancy\u000d\u000a      which is not significantly lower than the general population [8].\u000d\u000a    "},{"CaseStudyId":"23130","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Use of tacrolimus as the first line immunosuppression agent in liver\u000a      transplantation had begun to climb from 1999 onwards, although trials at\u000a      this stage had not demonstrated an unambiguous improvement over\u000a      ciclosporin. The research by Burroughs firmly established tacrolimus as\u000a      the optimal calcineurin inhibitor to use in immunosuppressive regimens\u000a      following liver transplantation, and has thus changed standard clinical\u000a      practice in the UK and worldwide. Tacrolimus-based immunosuppression has\u000a      become the \"gold-standard\". The results of the trial were confirmed in a\u000a      subsequent Cochrane meta-analysis of 16 trials which showed that treating\u000a      100 recipients with tacrolimus instead of ciclosporin would avoid acute\u000a      rejection and steroid-resistant rejection in nine and seven patients,\u000a      respectively, and graft loss and death in five and two patients [a].\u000a    In the US, the Organ Procurement and Transplantation Network (OPTN) and\u000a      Scientific Registry of Transplant Recipients (SRTR) Annual Data Report\u000a      2010 stated that; \"Immunosuppressive strategies based on tacrolimus and\u000a        mycophenolate continue to be the dominant early regimen. In 2009, the\u000a        alternative calcineurin inhibitor cyclosporine was used relatively\u000a        infrequently (7.3%) compared with tacrolimus (85.8%)\" [b].\u000a      In 2011, they reported that; \"Initial immunosuppression for most\u000a        recipients is tacrolimus and mycophenolate mofetil (MMF), commonly in\u000a        conjunction with steroids... By 1 year after transplant, most patients\u000a        are no longer taking steroids and are taking tacrolimus with or without\u000a        MMF. With these immunosuppressive regimens, acute rejection occurs in\u000a        less than 20% of recipients during the first year\" [c]. Of\u000a      14,658 patients transplanted between 2002 and 2010 in the US, 92% (13,515)\u000a      were on tacrolimus [d].\u000a    This landmark study therefore changed clinical practice and provided a\u000a      clear benefit to patients. A 2006 meta-analysis of 16 trials demonstrated\u000a      that tacrolimus reduced mortality by 15% and graft loss by 27% compared to\u000a      ciclosporin [e]. Assuming 550 liver transplants per year in the UK\u000a      since 2008, we can estimate that, with 90% of patients treated with\u000a      tacrolimus and 10% ciclosporin, tacrolimus-based immunosuppression has\u000a      resulted in 165 grafts and 192 lives being saved in total for the period\u000a      2008-13.\u000a    ","ImpactSummary":"\u000a    Research at UCL firmly established tacrolimus as the optimal calcineurin\u000a      inhibitor to use in immunosuppressive regimens following liver\u000a      transplantation. Compared to ciclosporin its use improved graft survival\u000a      by 6% and patient survival by 7%. Assuming 550 liver transplants per year\u000a      in the UK since 2008, we can estimate that, with 90% of patients treated\u000a      with tacrolimus and 10% ciclosporin, tacrolimus-based immunosuppression\u000a      has resulted in 165 grafts and 192 lives being saved during the period\u000a      2008-13.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] O'Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A; UK and\u000a      Republic of Ireland Liver Transplant Study Group. Tacrolimus versus\u000a      microemulsified ciclosporin in liver transplantation: the TMC randomised\u000a      controlled trial. Lancet. 2002 Oct 12;360(9340):1119-25.\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(02)11196-2\u000a    \u000a\u000a[2] O'Grady J, Hardy P, Burroughs AK, Elbourne D UK and Ireland\u000a      Transplant Study group. Randomized controlled trial of tacrolimus versus\u000a      microemulsified cyclosporine (TMC) in liver transplantation: post study\u000a      surveillance to three years. Am J Transpl 2007;7:137-41\u000a      http:\/\/dx.doi.org\/10.1111\/j.1600-6143.2006.01576.x\u000a    \u000a\u000a[3] Rolles K, Davidson BR, Burroughs AK. A pilot study of\u000a      immunosuppressive monotherapy in liver transplantation: tacrolimus versus\u000a      microemulsified cyclosporin. Transplantation 1999;68:1195-1209. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/10551650\u000a    \u000a\u000a[4] Cholongitas E, Shusang V, Germani G, Tsochatzis E, Raimondo ML,\u000a      Marelli L, Senzolo M, Davidson BR, Rolles K, Burroughs AK. Long term\u000a      follow up of immunosuppressive monotherapy in liver transplantation:\u000a      tacrolimus and microemulsified cyclosporin. Clin Transplant. 2011\u000a      Jul-Aug;25(4):614-24.\u000a      http:\/\/dx.doi.org\/10.1111\/j.1399-0012.2010.01321.x\u000a    \u000a\u000a[5] Rodriquez-Peralvares M, Germani G, Darius T, Lerut J, Tsochatzis E,\u000a      Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in\u000a      liver transplantation: a systematic review and meta-analysis. Am J\u000a      Transplantation 2012;12:2797-2814\u000a      http:\/\/dx.doi.org\/10.1111\/j.1600-6143.2012.04140.x\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    [a] Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005161. Cyclosporin\u000a      versus tacrolimus for liver transplanted patients. Haddad EM, McAlister\u000a      VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. http:\/\/dx.doi.org\/10.1002\/14651858.CD005161.pub2\u000a    [b] http:\/\/srtr.transplant.hrsa.gov\/annual_reports\/2010\/pdf\/03_liver_11.pdf\u000a    [c] http:\/\/srtr.transplant.hrsa.gov\/annual_reports\/2011\/pdf\/03_%20liver_12.pdf\u000a    [d] Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM. Sirolimus-based\u000a      immunosuppression is associated with increased survival after liver\u000a      transplantation for hepatocellular carcinoma. Hepatology 2010;51:1237-43.\u000a      http:\/\/dx.doi.org\/10.1002\/hep.23437.\u000a    [e] McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL.\u000a      Cyclosporin versus tacrolimus as primary immunosuppressant after liver\u000a      transplantation: a meta-analysis. Am J Transplant. 2006 Jul;6(7):1578-85.\u000a      http:\/\/dx.doi.org\/10.1111\/j.1600-6143.2006.01360.x\u000a    \u000a    ","Title":"\u000a    Establishment of tacrolimus as the first choice calcineurin inhibitor for\u000a      the immunosuppression regimen in liver transplant recipients\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Long-term immunosuppression with calcineurin inhibitors (ciclosporin or\u000a      tacrolimus) is essential for almost all patients undergoing liver\u000a      transplantation. However, the optimum initial immunosuppression regimen\u000a      was unknown by the late 1990s.\u000a    Previous immunosuppression trials had used rates and patterns of\u000a      rejection as measures of drug efficacy. Results from such studies had\u000a      shown lower rates of cellular rejection, steroid-resistant rejection, and\u000a      chronic rejection in tacrolimus-treated patients compared to those\u000a      receiving the old ciclosporin formulation. However this had been\u000a      superseded by the microemulsified preparation with better bioavailability.\u000a      Equally in liver transplantation the importance of acute cellular\u000a      rejection was questioned as there appeared no correlation between such\u000a      rejection and graft survival. Therefore patient and graft survival had\u000a      become regarded as the most meaningful efficacy measures of\u000a      immunosuppressive agents. At the time of the trial, results from follow-up\u000a      of the early US and European studies suggested better survival rates for\u000a      patients receiving tacrolimus than ciclosporin, although this was not a\u000a      robust finding.\u000a    Beginning in the mid-1990s, Burroughs was the instigator and chief\u000a      co-investigator of the TMC study together with O'Grady (King's College\u000a      London). The investigators undertook a trial to assess the\u000a      immunosuppressive efficacy of tacrolimus compared with micro-emulsified\u000a      ciclosporin, with their protocol standardising all aspects of drug dosing\u000a      and concomitant medication. The study showed that the clinical outcome at\u000a      one year was better with tacrolimus-based immunosuppression.\u000a    The trial's primary outcome was the combined frequency (whichever\u000a      occurred first) of death, retransplantation, or treatment failure for\u000a      immunological reasons, analysed by intention to treat This was achieved in\u000a      62 (21%) of 301 patients in the tacrolimus group versus 99 (32%) of 305\u000a      allocated microemulsified ciclosporin (p=0·001). The authors recommended\u000a      that tacrolimus should be the first choice of calcineurin inhibitor for\u000a      patients receiving their first liver graft [1]. Three-year\u000a      follow-up data confirmed the continued advantage of tacrolimus. A total of\u000a      62.1% of patients randomised to tacrolimus were alive at 3 years with\u000a      their original graft and still on their allocated study medication,\u000a      compared with only 41.6% in the ciclosporin limb [2]. A further\u000a      randomised study comparing tacrolimus and ciclosporin as monotherapy, with\u000a      no routine or maintenance steroids demonstrated that monotherapy provided\u000a      adequate immunosuppression for 87% of tacrolimus versus 64% of ciclosporin\u000a      patients [3]. Long-term follow up showed that tacrolimus\u000a      monotherapy ab initio is a viable immunosuppressive strategy in liver\u000a      transplantation and was associated with lower rejection rates and renal\u000a      complications, compared to ciclosporin [4]. Finally, a systematic\u000a      review to assess the effect of lower doses of tacrolimus on acute\u000a      rejection rates and renal impairment confirmed that these are as effective\u000a      and have fewer side effects [5].\u000a    "},{"CaseStudyId":"23143","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    Over the past 15 years, the respiratory physiology team at ICH has played\u000a      a major role, both nationally and internationally, in the development,\u000a      validation and standardisation of methods of assessing respiratory\u000a      function in infants and preschool children. As a result, standardised\u000a      equipment, software and guidelines for infant and paediatric lung function\u000a      tests are in widespread use around the world.\u000a    Impacts on development of equipment\u000a    In 2000 [ref 2], we published recommendations on equipment for assessing\u000a      infant lung function. Accordingly, such equipment has been developed in\u000a      line with our recommendations, and is now commercially available and in\u000a      use world-wide. For example, we worked with CareFusion on their BabyBody\u000a      device — they report on this collaboration as follows: \"The current 5th\u000a      generation, Jaeger MasterScreen BabyBody, resulted from collaborative\u000a      efforts of the Jaeger R&D and the Portex Respiratory Unit teams.\u000a      This collaboration ensured that the MasterScreen BabyBody was\u000a      cross-validated against existing, previously validated instruments, so\u000a      that compliance could be achieved with the ATS\/ERS guidelines \u000a\u0009  [ref 2] which represent the current standards of paediatric health\u000a      professionals in this field\". This device has been sold around the\u000a      world [a]. Similarly, since publication of our research showing\u000a      that the lung clearance index is a far more sensitive measure of early\u000a      lung disease than standard spirometry [refs 3 & 4], commercially\u000a      available multiple gas washout devices such as the ndd EasyOne ProLAB have\u000a      been developed, to enhance widespread international clinical usage [b].\u000a    All-age reference equations for lung function\u000a    During the past five years, we have published all-age reference equations\u000a      to improve accurate diagnosis of lung disease [refs 5 & 6], which have\u000a      rapidly led to changes in practice (see below) and commercial equipment\u000a      around the world. We made the GLI-2012 equations available through the\u000a      resource website (www.lungfunction.org)\u000a      which had 7,488 unique visitors in the first six months of 2013, with over\u000a      500 hits each from the USA, Canada, Japan, Germany and the Netherlands.\u000a      The GLI-2012 equations have been endorsed by all major international\u000a      respiratory societies including the European Respiratory Society, the\u000a      American Thoracic Society, the Australian and New Zealand Society of\u000a      Respiratory Science; the Asian Pacific Society for Respirology; the\u000a      Thoracic Society of Australia and New Zealand; and the American College of\u000a      Chest Physicians [c]. They have also been adopted by both national\u000a      and international professional clinical and public health organisations\u000a      such as the UK CF registry, the Health Survey for England [d] and\u000a      the US NIHR Sickle Cell Anaemia Sleep and Asthma Cohort (SAC) study [e].\u000a    These equations have also changed the way lung function is reported in\u000a      commercial equipment, due to our identification of appropriate\u000a      age-specific lower limits of normal for spirometric outcomes, rather than\u000a      dependence on fixed thresholds. Morgan Scientific, a leading manufacturer\u000a      of pulmonary function instrumentation and software, reports that: \"As\u000a        soon as we heard about the GLI initiative we eagerly accommodated the\u000a        equations, I believe we were the first manufacturer to do so. As our\u000a        customer base is heavily centred in ...pediatric hospitals in the USA,\u000a        there has been keen interest in adopting the GLI set\" [f].\u000a      Other manufacturers who have confirmed their use of our equations include:\u000a      CareFusion, Medical Graphics corporation, Cosmed, Ganshorn, Medikro,\u000a      Medisoft, Medset, MIR, Morgan, ndd Medical and nSpire [g].\u000a    Clinical benefits\u000a    One benefit of our all-age equations is that they overcome the serious\u000a      potential errors which can occur when a child is switched from paediatric\u000a      to adult equations at 18 years of age. Previously, this could result in a\u000a      sudden apparent drop in lung function by as much as 25%, simply due to the\u000a      equations selected (Kirkby et al, Eur Resp J 2011:39;1256-7). Our all-age\u000a      equations remove this sudden change, and as a result, are being adopted in\u000a      an increasing number of establishments to ensure a smooth transition\u000a      between paediatric and adult care. In 2011, Janet Stocks was awarded a\u000a      Lifetime Achievement Award by the European Respiratory Society in\u000a      recognition that her work has \"helped give paediatric medicine the\u000a        tools to better understand and treat the respiratory illnesses of\u000a        childhood\" [h]. She has also recently been awarded the\u000a      British Paediatric Respiratory Society 2013 lifetime achievement award in\u000a      recognition of her `commitment in advancing the care of children with\u000a        respiratory disease in the UK' [i].\u000a    Change in clinical practice\u000a    Our work has been widely cited in Standard Operating Procedures for\u000a      measuring lung function, demonstrating the impact our work has had on\u000a      clinical practice [j].\u000a    Great Ormond Street Hospital report that: \"the substantial clinical\u000a        impact that the work by Professor Janet Stocks and her team has made\u000a        ...[has occurred] not only at Great Ormond Street Children's Hospital,\u000a        but also in other respiratory units ...nationally and internationally...\u000a        During the past 5 years we have introduced routine lung function tests\u000a        for all clinically diagnosed infants with CF throughout infancy and the\u000a        preschool years to help guide management — whereas in the past objective\u000a        tests of lung function only commenced from 5-6 y upwards. This has led\u000a        to the description of early changes in CF hitherto unidentified and an\u000a        upscaling of our management protocols... [With the] published findings\u000a        of Prof Stocks' group on early structural and functional changes...\u000a        patient directed escalation of therapy to halt early changes during\u000a        these crucial early years is introduced — with protocols that have been\u000a        adopted by other centres in the greater London region. We are now\u000a        interpreting all clinical lung function results using the GLI 2012\u000a        equations, which has overcome problems previously faced when\u000a        interpreting results from children from Black and ethnic minorities and\u000a        when transitioning between paediatric and adult care. This seminal work\u000a        finally makes sense of the longitudinal tracking of lung function in\u000a        children through childhood, adolescence and into adulthood....we are\u000a        also now routinely using MBW as a sensitive marker of early lung disease\u000a        in clinical practice.... Of considerable clinical significance is\u000a        Professor Stocks' detailed review of outcome measures for assessing lung\u000a        function... in newborn screened CF infants. This important work led to\u000a        our clinical decision to limit CT scanning (with its inherent radiation\u000a        burden) to just those children who are showing unexplained clinical\u000a        decline and remove it from our routine surveillance programme with cost\u000a        benefits to the NHS and reduction in harm to patients [k].\u000a    In addition, Yale University report that: Our work would not have\u000a        been possible without the landmark publications by the research team at\u000a        the University College London (UCL).... It is because of the outstanding\u000a        work of the UCL team that I am better positioned to evaluate and manage\u000a        respiratory symptoms in aging populations, both as a pulmonologist and\u000a        geriatrician\" [l].\u000a    Training\u000a    Fully funded research fellows from around the world regularly apply to\u000a      undertake training in the specialised paediatric respiratory laboratories\u000a      at ICH, such that we now have collaborative satellite sites established in\u000a      Southampton, Munster, Lisbon, Barcelona, Montreal, Toronto and Australia\u000a      (Melbourne, Victoria; Perth, WA and Newcastle, NSW.\u000a    ","ImpactSummary":"\u000a    We have made substantial contributions to the diagnosis of lung disease\u000a      by providing tools to assess and interpret lung function accurately across\u000a      the entire lifespan. These contributions include: effects of lung disease\u000a      being more clearly distinguished from those of normal growth, development\u000a      and aging; increased understanding of the early determinants of adult\u000a      respiratory disease and improved diagnosis of chronic obstructive lung\u000a      disease. Commercially available equipment for assessing lung\u000a      function in infants and preschool children has been developed based on our\u000a      work and our recently developed multi-ethnic, all-age lung growth\u000a        charts have been endorsed internationally and are now in widespread\u000a      use.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6077243","Name":"Montréal"},{"GeoNamesId":"6167865","Name":"Toronto"},{"GeoNamesId":"2267057","Name":"Lisbon"},{"GeoNamesId":"2063523","Name":"Perth"},{"GeoNamesId":"2158177","Name":"Melbourne"},{"GeoNamesId":"3128760","Name":"Barcelona"},{"GeoNamesId":"7521315","Name":"Munster"}],"References":"\u000a    \u000a[1] Stocks J, Sly P, Tepper RS, Morgan WJ (eds). Infant Respiratory\u000a      Function Testing: a practical guide. New York: Wiley-Liss, John Wiley\u000a      & Sons, Inc. Publication, 1996. ISBN:0471076821. Available on request.\u000a    \u000a\u000a[2] Frey U, Stocks J, Coates A et al. Standards for infant respiratory\u000a      function testing: Specifications for equipment used for infant pulmonary\u000a      function testing. Eur Respir J 2000; 16:731-740. http:\/\/erj.ersjournals.com\/content\/16\/4\/731.full.pdf\u000a    \u000a\u000a[3] Stocks J, Lum S. Pulmonary function tests in infants and preschool\u000a      children. In: Wilmott RW, Boat TF, Bush A, Chernick V, Deterding R, Ratjen\u000a      F, eds. Kendig's disorders of the respiratory tract in children.\u000a      Philadelphia, USA: Elsevier; 2012: 169-210. ISBN:978143719840. Available\u000a      on request\u000a    \u000a\u000a[4] Aurora P, Stanojevic S, Wade A, et al. Lung Clearance Index at 4\u000a      years predicts subsequent lung function in children with Cystic Fibrosis.\u000a      Am J Respir Crit Care Med 2011; 183: 752-8.\u000a      http:\/\/dx.doi.org\/10.1164\/rccm.200911-1646OC\u000a    \u000a\u000a[5] Stanojevic S, Wade A, Stocks J et al. Reference Ranges for Spirometry\u000a      Across All Ages: A New Approach. Am J Respir Crit Care Med 2008;\u000a      177:253-260.\u000a      http:\/\/dx.doi.org\/10.1164\/rccm.200708-1248OC\u000a    \u000a\u000a[6] Quanjer PH, Stanojevic S, Cole TJ et al. Multi-ethnic reference\u000a      values for spirometry for the 3-95 year age range: the global lung\u000a      function 2012 equations. Eur Resp J 2012:40; 1324-43. http:\/\/dx.doi.org\/10.1183\/09031936.00080312\u000a    \u000aFor all-age multi-ethnic equations, see also www.lungfunction.org.\u000a    Peer-reviewed funding:\u000a    Since 1993, the research programme has been supported by peer-reviewed\u000a      grants totalling £6.8m, (JS PI: £4.7m), including £1.3m from the Wellcome\u000a      Trust, £881,700 from the MRC, £700,626 from the CF Trust and £253,559 from\u000a      Asthma UK.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    [a] Letter of testimony from CareFusion. Copy available on request\u000a      including map of international distribution.\u000a    [b] Letter of testimony from ndd. Copy available on request\u000a    [c] http:\/\/www.lungfunction.org\/faq\/87-faq\/181-have-the-gli-2012-equations-been-recommended-for-international-use.html\u000a      Endorsement by major international respiratory societies. Full list on\u000a      p.1,339 of reference 6. Copy of correspondence confirmation endorsement\u000a      from the American College of Chest Physicians, Asia Pacific Society of\u000a      Respiratory and Australian & New Zealand Society of Respiratory\u000a      Science available on request.\u000a    [d] www.ic.nhs.uk\/pubs\/hse10report;\u000a    [e] Confirmation provided by co-ordinator of this study at the Washington\u000a      University School of Medicine. Copy available on request.\u000a    [f] Email from Morgan Scientific. Copy available on request.\u000a    [g] Results of our survey available here: http:\/\/www.lungfunction.org\/manufacturers.html.\u000a      Full correspondence available on request.\u000a    [h] ERS Citation available at: http:\/\/www.ersnet.org\/ers-funding\/awards\/item\/4441-2011-ers-awardees.html\u000a    [i] Copy of BPRS Award letter available on request.\u000a    [j] Standard operating protocols\u000a    i) Primary Care Commissioning \"Guide to quality Assured Diagnostic\u000a      Spirometry\" 2013\u000a      http:\/\/www.pcc-cic.org.uk\/sites\/default\/files\/articles\/attachments\/spirometry_e-guide_1-5-13_0.pdf;\u000a    ii) Nursing times article \"How to Interpret Spirometry\" 2011,\u000a      http:\/\/www.nursingtimes.net\/nursing-practice\/clinical-zones\/respiratory\/how-to-interpret-spirometry-results\/5037130.article;\u000a    [k] Testimony from Consultant in respiratory paediatrics, Great Ormond\u000a      Street Hospital. Copy available on request.\u000a    [l] Testimony from Yale University Medical School. Copy available on\u000a      request. \u000a    ","Title":"\u000a    Elucidating the early determinants of chronic lung disease: development\u000a      of tools to enhance measurement and interpretation of lung function\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"2637487","Name":"Southampton"},{"GeoNamesId":"2645313","Name":"Kirkby"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Respiratory diseases cause around 50% of acute illness in children. Over\u000a      20 years, the Portex Respiratory Unit at the UCL Institute of Child Health\u000a      (ICH) has developed methods and equipment, enabling studies of lung growth\u000a      and development during early life. We have created sophisticated all-age,\u000a      multi-ethnic `lung growth charts' (reference equations) which have allowed\u000a      effects of disease to be identified more clearly. These tools have been\u000a      incorporated into commercially available equipment. Prior to the 1990s,\u000a      assessment of infant lung function was limited to a few specialised\u000a      physiology laboratories. Professor Janet Stocks co-founded the European\u000a      Respiratory Society\/American Thoracic Society (ERS\/ATS) Task Force on\u000a      infant lung function testing to facilitate more widespread and\u000a      standardised applications. During the 1990s, an increasing number of\u000a      infant lung function tests were developed and validated by this group,\u000a      resulting in the first textbook in the area [1] which is now used\u000a      in infant laboratories world-wide. Stocks has subsequently updated this\u000a      textbook via a series of published reports and chapters to establish\u000a      standards both for users and manufacturers [2, 3].\u000a    Having successfully established standardised methods for assessing lung\u000a      function in sleeping infants [1-3], there remained the challenge\u000a      of undertaking measurements in awake preschool children, in whom\u000a      respiratory problems are common, but complex to diagnose. Children below 5\u000a      years were hitherto considered `untestable', but the ICH team achieved a\u000a      high success rate in 3-5 year-olds, and participated in international\u000a      efforts to standardise their application [3]. Hence, for the first\u000a      time, continuous assessments of lung function became feasible from birth\u000a      to old age. Development of the multiple breath washout technique\u000a      (collaboration with P. Gustafsson, Sweden), has revolutionised the way in\u000a      which early lung disease can be detected in young children with Cystic\u000a      Fibrosis (CF) [3, 4]. Measurements during the preschool years are\u000a      predictive of lung function at school age, providing a window for earlier\u000a      therapeutic interventions [4].\u000a    These developments allowed increasing application in clinical management\u000a      and facilitated research into the early determinants of lung disease: e.g.\u000a      effects of low birth weight and maternal smoking in pregnancy on\u000a      subsequent lung health, and evolution of lung disease following extremely\u000a      preterm birth (MRC EPICure study) and in those diagnosed with CF. In 1998,\u000a      JS established the London CF collaboration (LCFC) [4], which has\u000a      demonstrated that children diagnosed through newborn screening have\u000a      significantly better growth and lung function when compared with their\u000a      clinically diagnosed counterparts, and that undertaking routine chest CTs\u000a      is not diagnostically helpful during the first year of life.\u000a    Use of lung function tests to guide clinical management of lung disease\u000a      requires appropriate reference equations with which to detect\u000a      abnormalities. These were, however, poorly developed for infants and\u000a      preschool children and for those not of white European ancestry.\u000a      Commencing in 1995 with publication of prediction equations for lung\u000a      volumes from birth to adulthood, the ICH team led numerous initiatives to\u000a      rectify this situation (in collaboration with Professor Philip Quanjer,\u000a      Netherlands), culminating in the recent publication of `All-age'\u000a      multi-ethnic equations for spirometry [5, 6]. These have improved\u000a      our interpretation of lung disease in children with CF and sickle cell\u000a      disease, especially during the transition to adult care, and also in\u000a      elderly patients with COPD.\u000a    "},{"CaseStudyId":"23454","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1668284","Name":"Taiwan"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    MCADD\u000d\u000a    Our demonstration of an automatable method for MCADD screening and the\u000d\u000a      resulting benefits to patients contributed to a decision to undertake a\u000d\u000a      pilot study of MCADD screening (UKCSNS-MCADD) which was co-ordinated by\u000d\u000a      the MRC Centre of Epidemiology for Child Health at the UCL Institute of\u000d\u000a      Child Health, London [a]. This pilot study showed good results,\u000d\u000a      and so MCADD screening was adopted in England in 2009 and Wales in 2012\u000d\u000a      using our methods [b]. Since screening began, we can estimate\u000d\u000a      (based on epidemiology in ref 2 above) that around 60 lives have been\u000d\u000a      saved and around 60 cases of long-term disability prevented. One such\u000d\u000a      example was recently highlighted on the Great Ormond Street Hospital\u000d\u000a      website — the parents of a child identified by screening could be given\u000d\u000a      specialist dietary advice and training on what to do in an emergency [c].\u000d\u000a    Fabry disease\u000d\u000a    Our CTH method has been adapted for screening programmes. For example,\u000d\u000a      screening of 172,000 newborns in Taiwan identified 89 infants with low\u000d\u000a      activity of the Fabry enzyme; these infants were further assessed using\u000d\u000a      our urine CTH method [d]. Enzyme replacement therapy (ERT) has\u000d\u000a      been approved by for the treatment of Fabry disease, and early treatment\u000d\u000a      can help to avoid complications. As well as contributing to early\u000d\u000a      diagnosis, our tests provide early evidence of the success of ERT by\u000d\u000a      falling levels of CTH in the urine. We are commissioned to test urine\u000d\u000a      samples from patients receiving enzyme replacement therapy by one of the\u000d\u000a      companies producing the enzyme (Genzyme). Between 2008 and 2013 we\u000d\u000a      analysed 760 samples per year. Income from the CTH tests (£37,000 p.a.)\u000d\u000a      and other tests undertaken in our laboratories (£41,000 p.a.) contributes\u000d\u000a      to maintenance of equipment and funds further method development [e].\u000d\u000a    Movement disorders\u000d\u000a    Our diagnostic tests and new treatments for movement disorders are now in\u000d\u000a      use in clinical practice. The treatment we devised for genetically\u000d\u000a      determined manganese build-up dramatically alleviated symptoms of\u000d\u000a      parkinsonism or dystonia in four sufferers during the period 2008-13 [f].\u000d\u000a      This work was featured on the website of the European Parkinson's Disease\u000d\u000a      Association [g].\u000d\u000a    As a result of our work on Aromatic Amino Acid Decarboxylase Deficiency\u000d\u000a      (AADC), diagnostic tests are now available [h]. Without our\u000d\u000a      research all the families on this website would have no diagnosis for\u000d\u000a      their child's extremely debilitating disorder. Now those that have not\u000d\u000a      responded to drugs are likely to be able to have gene therapy in a joint\u000d\u000a      UK\/US venture. Our work on diagnosis of AADC is featured on the AADC\u000d\u000a      Research Trust website [i].\u000d\u000a    Epilepsy\u000d\u000a    Our research on epilepsy has resulted in new diagnostic tests and better\u000d\u000a      treatment for infants and children now in use. We perform diagnostic tests\u000d\u000a      on 230 urine samples and 46 DNA samples per year, sent to us from\u000d\u000a      paediatricians looking after infants and children with severe epilepsy\u000d\u000a      around the country. Between 2008 and 2013, we identified the genetic\u000d\u000a      biochemical defect in 35 children (14 with pyridoxine 5'-phosphate oxidase\u000d\u000a      (PNPO) deficiency; 21 with antiquitin deficiency). These are potentially\u000d\u000a      fatal disorders. They respond poorly to antiepileptic drugs but respond\u000d\u000a      very well to high doses of vitamin B6 as pyridoxine or pyridoxal\u000d\u000a      phosphate. Our diagnostic test thus enables more successful treatment to\u000d\u000a      be given. [e]\u000d\u000a    Our research was quoted in a recent guideline on treatment of neonatal\u000d\u000a      seizures [j]. Referencing [5] above, along with another\u000d\u000a      publication from our group, the guidelines recommend: \"Most cases of\u000d\u000a        pyridoxine-dependent epilepsy are due to alpha-aminoadipic semialdehyde\u000d\u000a        dehydrogenase (also known as antiquitin, or ATQ) deficiency, an\u000d\u000a        autosomal recessive inborn error of metabolism caused by defects in the\u000d\u000a        ALDH7A1 gene that lead to accumulation of alpha-AASA. Mutation analysis\u000d\u000a        of the ALDH7A1 gene is recommended in patients with abnormal biochemical\u000d\u000a        screening and\/or clear evidence of pyridoxine or folinic acid\u000d\u000a        responsiveness.\"\u000d\u000a    Progressive liver disease\u000d\u000a    Our research on progressive liver disease means that children can now be\u000d\u000a      given bile acid replacement therapy for an increasing number of bile acid\u000d\u000a      synthesis disorders, preventing death from liver disease or the need for a\u000d\u000a      liver transplant [k]. We analyse samples from patients presenting\u000d\u000a      with cholestatic liver disease in the UK and overseas (280 samples, 4\u000d\u000a      treatable positives per year). For the period 2008-13, this equates to 24\u000d\u000a      lives saved \/ transplants avoided. In 2011, a bile acid preparation,\u000d\u000a      Orphacol, was licensed by the European Medicines Agency for the treatment\u000d\u000a      of inborn errors in primary bile acid synthesis. In the submission, they\u000d\u000a      state that: \"The literature provided by the applicant showed that, where\u000d\u000a      available to investigators, the clinical use of cholic acid has been\u000d\u000a      documented since at least the mid-1990s through the work primarily\u000d\u000a      conducted by the Jacquemin, Clayton and Setchell groups\". The document\u000d\u000a      references 10 of our papers [l].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Investigators at UCL have developed new diagnostic tests, new treatments\u000d\u000a      and new methods for monitoring treatment of inborn errors of metabolism.\u000d\u000a      Certain of these tests are now used to screen all newborns in the UK, all\u000d\u000a      infants with liver disease and all infants with drug-resistant epilepsy.\u000d\u000a      This is improving outcome for >120 UK children per year. For\u000d\u000a      untreatable disorders, prenatal tests prevent the birth of a second\u000d\u000a      affected child in the family.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Clayton PT, Doig M, Ghafari S, Meaney C, Taylor C, Leonard JV, Morris\u000d\u000a      M, Johnson AW. Screening for medium chain acyl-CoA dehydrogenase\u000d\u000a      deficiency using electrospray ionisation tandem mass spectrometry. Arch\u000d\u000a      Dis Child. 1998 Aug;79(2):109-15.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/adc.79.2.109\u000d\u000a    \u000a\u000a[2] Wilson CJ, Champion MP, Collins JE, Clayton PT, Leonard JV. Outcome\u000d\u000a      of medium chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch\u000d\u000a      Dis Child. 1999 May;80(5):459-62.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/adc.80.5.459\u000d\u000a    \u000a\u000a[3] Mills K, Johnson A, Winchester B. Synthesis of novel internal\u000d\u000a      standards for the quantitative determination of plasma ceramide\u000d\u000a      trihexoside in Fabry disease by tandem mass spectrometry. FEBS Lett. 2002\u000d\u000a      Mar 27;515(1-3):171-6. http:\/\/dx.doi.org\/10.1016\/S0014-5793(02)02491-2\u000d\u000a    \u000a\u000a[4] Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma\u000d\u000a      R, De Vivo DC. Aromatic L-amino acid decarboxylase deficiency: clinical\u000d\u000a      features, treatment, and prognosis. Neurology. 2004 Apr 13;62(7):1058-65.\u000d\u000a      http:\/\/dx.doi.org\/10.1212\/WNL.62.7.1058\u000d\u000a    \u000a\u000a[5] Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz\u000d\u000a      M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and\u000d\u000a      hypermanganesaemia--a new metabolic disorder. J Inherit Metab Dis. 2008\u000d\u000a      Apr;31(2):151-63. http:\/\/dx.doi.org\/10.1007\/s10545-008-0813-1\u000d\u000a    \u000a\u000a[6] Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M,\u000d\u000a      Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT.\u000d\u000a      Mutations in antiquitin in individuals with pyridoxine-dependent seizures.\u000d\u000a      Nat Med. 2006 Mar;12(3):307-9\u000d\u000a      http:\/\/dx.doi.org\/10.1038\/nm1366\u000d\u000a    \u000a\u000a[7] Clayton PT. Disorders of bile acid synthesis J Inherit Metab Dis.\u000d\u000a      2011 Jun;34(3):59 3-604.\u000d\u000a      http:\/\/dx.doi.org\/10.1007\/s10545-010-9259-3\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    [a] Oerton J, Khalid JM, Besley G et al. 2011. Newborn screening for\u000d\u000a      medium chain acyl-CoA dehydrogenase deficiency in England: prevalence,\u000d\u000a      predictive value and test validity based on 1.5 million screened babies.\u000d\u000a      Journal of Medical Screening 18:173-181\u000d\u000a      http:\/\/dx.doi.org\/10.1258\/jms.2011.011086\u000d\u000a    [b] Details of MCADD screening: http:\/\/newbornbloodspot.screening.nhs.uk\/mcadd\u000d\u000a      and see also laboratory guide referencing our publication:\u000d\u000a      http:\/\/newbornbloodspot.screening.nhs.uk\/getdata.php?id=11526\u000d\u000a    [c] http:\/\/www.gosh.org\/mgf\/events-and-appeals\/appeals\/bringing-research-to-life\/impact\/children-weve-helped-through-our-research\/harry\u000d\u000a    [d] Chien YH, Olivova P, Zhang XK, Chiang SC, Lee NC, Keutzer J, Hwu WL.\u000d\u000a      Elevation of urinary globotriaosylceramide (GL3) in infants with Fabry\u000d\u000a      disease. Mol Genet Metab. 2011 Jan;102(1):57-60. http:\/\/dx.doi.org\/10.1016\/j.ymgme.2010.08.023\u000d\u000a    [e] For confirmation please contact Biochemistry Research Group, UCL\u000d\u000a      Institute of Child Health. Contact details provided.\u000d\u000a    [f] The following three papers (two from our group, one from elsewhere)\u000d\u000a      demonstrate how this work has impacted on patients:\u000d\u000a    \u000d\u000a      Stamelou M, Tuschl K, Chong WK, Burroughs AK, Mills PB, Bhatia KP,\u000d\u000a        Clayton PT. Dystonia with brain manganese accumulation resulting\u000d\u000a          from SLC30A10 mutations: a new treatable disorder. Mov Disord.\u000d\u000a        2012 Sep 1;27(10):1317-2211\u000d\u000a\u0009\u0009http:\/\/dx.doi.org\/10.1002\/mds.25138\u000a\u000d\u000a      Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P,\u000d\u000a        Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S,\u000d\u000a        Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome\u000a          of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia\u000d\u000a          caused by mutations in SLC30A10, a manganese transporter in man.\u000d\u000a        Am J Hum Genet. 2012 Mar 9;90(3):457-66\u000d\u000a        http:\/\/dx.doi.org\/10.1016\/j.ajhg.2012.01.018\u000a\u000d\u000a      Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C,\u000d\u000a        Severijnen LA, Di Toro Mammarella L, Mignarri A, Monti L, Sanna A, Lu P,\u000d\u000a        Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP,\u000d\u000a        Bonifati V. Mutations in SLC30A10 cause parkinsonism and dystonia\u000d\u000a          with hypermanganesemia, polycythemia, and chronic liver disease.\u000d\u000a        Am J Hum Genet. 2012 Mar 9;90(3):467-77\u000d\u000a        http:\/\/dx.doi.org\/10.1016\/j.ajhg.2012.01.017\u000a\u000d\u000a    \u000d\u000a    [g] http:\/\/www.epda.eu.com\/en\/parkinsons\/in-depth\/pdsymptoms\/dystonia\/where-can-i-get-more-information\/research-papers\/?p=2\u000d\u000a    [h] http:\/\/www.aadcresearch.org\/Testing-Laboratory.html\u000d\u000a    [i] http:\/\/www.aadcresearch.org\/The-Tawara-Twins.html\u000d\u000a    [j] http:\/\/www.uptodate.com\/contents\/treatment-of-neonatal-seizures\u000d\u000a    [k] Hartley JL, Gissen P, Kelly DA. Alagille syndrome and other\u000d\u000a      hereditary causes of cholestasis. Clin Liver Dis. 2013 May;17(2):279-300.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/j.cld.2012.12.004\u000d\u000a    [l] http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Public_assessment_report\/human\/001250\/WC500131542.pdf\u000d\u000a    ","Title":"\u000d\u000a    Inborn errors of metabolism: diagnosis and treatment\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Inborn errors of metabolism are genetic disorders characterised by a\u000d\u000a      defective protein that disturbs an important metabolic pathway. Inborn\u000d\u000a      errors of metabolism are individually rare but collectively common\u000d\u000a      diseases, and can cause a very wide range of symptoms and signs from liver\u000d\u000a      disease to convulsions to movement disorders to loss of consciousness on\u000d\u000a      fasting.\u000d\u000a    MCADD\u000d\u000a      Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare genetic\u000d\u000a      condition in which a person has problems breaking down fatty acids for\u000d\u000a      energy. It affects around 1 in 10,000 babies born in the UK each year, and\u000d\u000a      is life-threatening if not discovered early, as any drop in an affected\u000d\u000a      baby's blood sugar levels can result in severe illness or death. In 1998,\u000d\u000a      working with Micromass UK Ltd, we showed that electrospray ionisation\u000d\u000a      tandem mass spectrometry could be used to measure octanoylcarnitine in\u000d\u000a      blood spots thus providing the basis for an automatable method for\u000d\u000a      screening for MCADD [1]. We showed that once MCADD had been\u000d\u000a      diagnosed and appropriately managed, the prognosis was excellent (whereas\u000d\u000a      in undiagnosed patients the mortality was 20-25% and a further 20% of\u000d\u000a      children were left disabled) [2].\u000d\u000a    Fabry disease\u000d\u000a      Fabry disease is a rare lysosomal storage disorder, affecting around 1 in\u000d\u000a      58,000 individuals. The condition has serious complications including\u000d\u000a      severe neuropathic pain, renal failure, cardiomyopathy and coronary artery\u000d\u000a      disease, and strokes. Patients often die prematurely as a result of these\u000d\u000a      complications. In 2002 we published a new method for determination of\u000d\u000a      ceramide trihexoside (CTH) in plasma and urine of patients with Fabry\u000d\u000a      disease [3]. Such measurements have proved useful in monitoring\u000d\u000a      enzyme replacement therapy. This method is now the gold standard test for\u000d\u000a      the screening and monitoring of enzyme replacement throughout the UK and\u000d\u000a      worldwide.\u000d\u000a    Movement disorders\u000d\u000a      We were the first to show, in 1993, that parkinsonism in infants can be\u000d\u000a      caused by a disorder affecting the synthesis of dopamine (aromatic amino\u000d\u000a      acid decarboxylase [AADC] deficiency); some affected patients have shown a\u000d\u000a      good response to dopamine agonists and monoamine oxidase inhibitors, and\u000d\u000a      new treatments have been developed by ourselves and others which build on\u000d\u000a      our early work [4]. We have also shown that dystonia in older\u000d\u000a      children can be caused by a disorder leading to the build-up of manganese\u000d\u000a      in the brain [5]. This disorder can be effectively treated with a\u000d\u000a      manganese chelator and iron supplementation. We developed tests for\u000d\u000a      dopamine and serotonin metabolites in cerebrospinal fluid (CSF) (for\u000d\u000a      diagnosis of AADC) and we found the gene responsible for the manganese\u000d\u000a      disorder, thereby providing a genetic test. Overall, this work has led to\u000d\u000a      the development of useful diagnostic tests and new treatments for children\u000d\u000a      and adults with movement disorders.\u000d\u000a    Epilepsy\u000d\u000a      In 2005 we identified the genetic defect responsible for a severe seizure\u000d\u000a      disorder in infancy which we had previously shown could be treated\u000d\u000a      effectively with pyridoxal phosphate (the active form of vitamin B6). In\u000d\u000a      2006 we showed that severe seizures in the newborn that respond to\u000d\u000a      treatment with pyridoxine (another form of vitamin B6) could be due to\u000d\u000a      another genetic defect (antiquitin deficiency) [6].\u000d\u000a    Progressive liver disease\u000d\u000a      We have shown that liver disease in infancy and neurological disease in\u000d\u000a      older children and adults can be caused by disorders of bile acid\u000d\u000a      synthesis and these disorders can respond extremely well to bile acid\u000d\u000a      replacement therapy. Without treatment children can progress to cirrhosis\u000d\u000a      and liver failure [7].\u000d\u000a    "},{"CaseStudyId":"23856","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3865483","Name":"Argentina"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Impact on clinical practice\u000d\u000a      When it was reported in 2005, the results of the SALTIRE trial were highly\u000d\u000a      controversial. Many commentators initially refused to accept the findings\u000d\u000a      such was the widespread belief that statin therapy would be effective in\u000d\u000a      treating aortic stenosis. However, the importance of the study was\u000d\u000a      recognised in an accompanying editorial in N Engl J Med [5.1] and it has\u000d\u000a      since been cited 336 times (Web of Knowledge; Thomson Reuters, 2013).\u000d\u000a      Importantly, two further randomised controlled trials (SEAS [2008] and\u000d\u000a      ASTRONOMER [2012]) corroborated the findings of the SALTIRE trial. The\u000d\u000a      weight of evidence, initially from SALTIRE and supported by the additional\u000d\u000a      two trials, has changed clinical practice internationally, as evidenced by\u000d\u000a      expert commentaries citing SALTIRE on international websites, for example,\u000d\u000a      UK (British Cardiovascular Society) [5.2], USA (Medscape) [5.3] and\u000d\u000a      Argentina (Sociedad Argentina de Cardiologia) [5.4]. Dr KL Chan, lead\u000d\u000a      investigator of the ASTRONOMER trial, stated on TheHeart.org \"with three\u000d\u000a      randomized trials...it really means that statins have no role per se in\u000d\u000a      the treatment of aortic stenosis\" [5.5] and a 2010 review stated \"statins\u000d\u000a      cannot be advocated to patients solely to prevent progression of aortic\u000d\u000a      stenosis\" [5.6].\u000d\u000a    Impact on public policy\u000d\u000a      The SALTIRE trial was acknowledged as being the first in the field and was\u000d\u000a      cited in 2008 American College of Cardiology\/American Heart Association\u000d\u000a      guidelines for the management of valvular heart disease as evidence\u000d\u000a      against the use of statin therapy in these patients [5.7]. Similarly, the\u000d\u000a      2012 European Society of Cardiology guidelines advise against statin usage\u000d\u000a      as a primary treatment for aortic stenosis [5.8] (SALTIRE cited in the\u000d\u000a      forerunning 2007 version).\u000d\u000a    Impact on health and welfare and the economy\u000d\u000a      Approximately 1 million people in the United Kingdom have valvular heart\u000d\u000a      disease and this is predicted by the British Cardiovascular Society\u000d\u000a      (www.statistics.gov.uk) to increase by 50% by 2025. Nearly half of these\u000d\u000a      individuals are accounted for by aortic stenosis, giving an overall\u000d\u000a      prevalence of 400-500,000 people currently in the UK. The SALTIRE findings\u000d\u000a      and their subsequent confirmation have therefore prevented the\u000d\u000a      inappropriate implementation of statin treatment as a disease-modifying\u000d\u000a      drug in the majority of patients with aortic stenosis. Furthermore,\u000d\u000a      because myalgia and major hepatic dysfunction are associated with statin\u000d\u000a      therapy in 5% and 1% of people, respectively, avoiding statin use has\u000d\u000a      prevented potentially detrimental side-effects in approximately 30,000\u000d\u000a      people.\u000d\u000a    In economic terms, based on the prescription cost of atorvastatin, this\u000d\u000a      is calculated to result in cost savings of up to £169M per annum for the\u000d\u000a      UK alone [5.9].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and welfare; a clinical trial demonstrated that\u000d\u000a      statin therapy is ineffective in aortic stenosis; this informed\u000d\u000a      international guidelines and changed clinical practice.\u000d\u000a    Significance: Unnecessary statin therapy is avoided in up to\u000d\u000a      500,000 people in the UK alone, saving the NHS £169M p.a. Known statin\u000d\u000a      side-effects of myalgia or hepatic dysfunction are avoided in 30,000\u000d\u000a      patients.\u000d\u000a    Beneficiaries: Patients with aortic stenosis; the NHS and\u000d\u000a      healthcare delivery organisations, the economy.\u000d\u000a    Attribution: Newby and Boon, UoE, undertook the first\u000d\u000a      investigator-led randomised controlled trial of statin therapy in aortic\u000d\u000a      stenosis: the SALTIRE trial.\u000d\u000a    Reach: Aortic stenosis affects 2% of people over 65. The SALTIRE\u000d\u000a      trial results informed European and N American guidelines and have\u000d\u000a      impacted the treatment of millions of people globally.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Chui M, Newby D, Panarelli M, Bloomfield P, Boon N. Association\u000d\u000a      between calcific aortic stenosis and hypercholesterolemia: is there a need\u000d\u000a      for a randomised controlled trial of cholesterol lowering therapy? Clin\u000d\u000a      Cardiol. 2001;24:52-5. DOI: 10.1002\/clc.4960240109.\u000d\u000a    \u000a\u000a3.2 Cowell S, Newby D, Prescott R,...Boon N. A randomized controlled\u000d\u000a      trial of intensive lipid lowering therapy in calcific aortic stenosis. N\u000d\u000a      Engl J Med. 2005;352:2389-97. DOI: 10.1056\/NEJMoa043876.\u000d\u000a    \u000a\u000a3.3 Cowell S, Newby D, Burton J,...Boon N, Reid J. Aortic valve\u000d\u000a      calcification on computed tomography predicts the severity of aortic\u000d\u000a      stenosis. Clin Radiol. 2003;58:712-6. DOI: 10.1016\/S0009-9260(03)00184-3.\u000d\u000a    \u000a\u000a3.4 Houslay E, Cowell S, Northridge D,...Boon N, Newby D. Progressive\u000d\u000a      coronary calcification despite intensive lipid-lowering therapy: a\u000d\u000a      randomized controlled trial. Heart. 2006;92:1207-12. DOI:\u000d\u000a      10.1136\/hrt.2005.080929.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    5.1 Rosenhek R. Statins for aortic stenosis. N Engl J Med.\u000d\u000a      2005;352:2441-3. DOI: 10.1056\/NEJMe058070.\u000d\u000a    5.2 Groves S. ASTRONOMER Trial Going where others have been before?\u000d\u000a      (2010). British Cardiovascular Society website. http:\/\/www.bcs.com\/pages\/news_full.asp?NewsID=19709572.\u000d\u000a    5.3 Intini A, Fang J. Statins for Aortic Stenosis? (2008). Medscape\u000d\u000a      website. http:\/\/www.medscape.com\/viewarticle\/583569.\u000d\u000a      [Free login required. Available on request.]\u000d\u000a    5.4 Roura P. ASTRONOMER trial. Rosuvastatin in the regression of aortic\u000d\u000a      stenosis (2010). Sociedad Argentina de Cardiologia website. http:\/\/www.sac.org.ar\/web\/es\/actualizaciones-bibliograficas-1\/astronomer-trial--rosuvastatina-en-la-regresion-de-la-estenosis-aortica-\u000d\u000a      (in Spanish).\u000d\u000a    5.5 TheHeart.org, `Heartwire' article (2010). ASTRONOMER published: No\u000d\u000a      role for statins in aortic stenosis. http:\/\/www.theheart.org\/article\/1038095.do.\u000d\u000a      [Free login required. Available on request.]\u000d\u000a    5.6 Hermans H, Herijgers P, Holvoet P, et al. Statins for calcific aortic\u000d\u000a      valve stenosis: into oblivion after SALTIRE and SEAS? An extensive review\u000d\u000a      from bench to bedside. Curr Probl Cardiol. 2010;35:284-306. DOI:\u000d\u000a      10.1016\/j.cpcardiol.2010.02.002.\u000d\u000a    5.7 2008 Focused update incorporated into the ACC\/AHA\u000a        2006 guidelines for the management of patients with valvular heart\u000d\u000a        disease: a report of the American College of Cardiology\/American Heart\u000d\u000a        Association Task Force on Practice Guidelines. Circulation.\u000d\u000a      2008;118:e523-661. DOI: 10.1161\/CIRCULATIONAHA.108.190748.\u000d\u000a    5.8 The Joint Task Force on the Management of Valvular Heart Disease of\u000d\u000a      the European Society of Cardiology (ESC) and the European Association for\u000d\u000a      Cardio-Thoracic Surgery (EACTS) Guidelines on the management of valvular\u000d\u000a      heart disease (version 2012). Eur Heart J. 2012;33:2451-96. DOI:\u000d\u000a      10.1093\/eurheartj\/ehs109.\u000d\u000a    5.9 British National Formulary. www.bnf.org.\u000d\u000a      [Calculated on the basis of atorvastatin costing £28.21 for 80 tablets;\u000d\u000a        £366.73 per patient per year.]\u000d\u000a    ","Title":"\u000d\u000a    B: Avoiding ineffective statin use in aortic stenosis\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In the late 1990s, Professor David Newby (Professor of Cardiology, UoE,\u000d\u000a      1995-present), later with Dr Nicholas Boon (Honorary Fellow, UoE,\u000d\u000a      2005-2013), began investigating the potential association between\u000d\u000a      dyslipidaemia and aortic stenosis. They published preliminary data\u000d\u000a      suggesting that patients with severe aortic stenosis had higher serum\u000d\u000a      cholesterol concentrations [3.1].\u000d\u000a    Aortic stenosis is the commonest valvular heart disease in the western\u000d\u000a      world. Approximately 2% of people over the age of 65, 3% of people over\u000d\u000a      age 75, and 4% percent of people over age 85 have the condition. Moreover,\u000d\u000a      the prevalence of aortic stenosis is rising in North America and Europe\u000d\u000a      because of aging populations. It is a potentially fatal condition for\u000d\u000a      which the only current clinical management entails surgically replacing\u000d\u000a      the valve at the end-stage of disease. It is the leading indication for\u000d\u000a      valve surgery in North America and Europe; the number of operations is\u000d\u000a      predicted to double over the next 10-20 years.\u000d\u000a    At the turn of the millennium, there was widespread support for the\u000d\u000a      concept that lipid deposition and an atherosclerosis-like process was\u000d\u000a      responsible for the initiation and progression of the aortic valve disease\u000d\u000a      process, and many observational studies indicated that statins could\u000d\u000a      reduce disease progression. With £185K British Heart Foundation (BHF)\u000d\u000a      funding (2000-2004), and with research infrastructure provided through a\u000d\u000a      £4.4M Clinical Research Infrastructure Initiative (BHF and MRC Programme\u000d\u000a      Grant) and a £7.6M BHF Research Excellence award, Newby and Boon undertook\u000d\u000a      the first investigator-led randomised controlled trial of lipid-lowering\u000d\u000a      therapy in patients with aortic stenosis: the SALTIRE trial. In SALTIRE,\u000d\u000a      155 people were assigned in 2001-2002 to atorvastatin or placebo and\u000d\u000a      clinically evaluated for up to three years. The trial demonstrated no\u000d\u000a      effect of atorvastatin on disease progression: no decrease in aortic-jet\u000d\u000a      velocity (P = 0.95) or valvular calcification (P = 0.93)\u000d\u000a      [3.2].\u000d\u000a    These findings were extremely controversial on a background of increasing\u000d\u000a      enthusiasm for statin therapy in patients with aortic stenosis and many\u000d\u000a      clinicians prescribing statins to these patients based on early\u000d\u000a      observational data. Crucially, and in part because of the contentious\u000d\u000a      nature of the findings of this investigator-led trial, two subsequent\u000d\u000a      randomised controlled trials were initiated — SEAS (2008) and ASTRONOMER\u000d\u000a      (2012) — both of which directly replicated the findings of the SALTIRE\u000d\u000a      trial.\u000d\u000a    In the early 2000s, during the conduct of the SALTIRE trial, Newby and\u000d\u000a      Boon made several important and consistent observations of relevance to\u000d\u000a      defining the underlying pathogenesis and natural history of calcified\u000d\u000a      vascular lesions. They demonstrated that the severity of aortic stenosis\u000d\u000a      and degree of valvular calcification were very closely associated and\u000d\u000a      interdependent [3.3] and demonstrated in a randomised controlled trial a\u000d\u000a      lack of effect of high-dose atorvastatin on the progression of coronary\u000d\u000a      artery calcification [3.4].\u000d\u000a    "},{"CaseStudyId":"23857","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Impact on health and welfare\u000d\u000a    An international comparison of preterm birth using the UoE data [3.3]\u000d\u000a      together with data from Europe, the USA and Canada confirmed that higher\u000d\u000a      rates of elective preterm birth are associated with lower rates of\u000d\u000a      stillbirth and neonatal death [5.1].\u000d\u000a    The work is partly responsible for the fall in stillbirth and perinatal\u000d\u000a      mortality rates in Scotland from 5.3 and 7.36 per 1000 (respectively) in\u000d\u000a      2009 to 4.9 and 6.94 per 1000 in 2010 [5.2].\u000d\u000a    Women can now make a more informed choice about the timing of birth.\u000d\u000a      Additionally, there is an emotional benefit of early induction if the\u000d\u000a      woman requests it, rather than waiting until spontaneous labour starts.\u000d\u000a    Impact on public policy\u000d\u000a    Reference [3.1] was cited in the 2013 RCOG Scientific Impact Paper, which\u000d\u000a      endorses elective induction of labour from 39 weeks' gestation in pregnant\u000d\u000a      women of 40 years of age and older [5.3]. Routine induction of labour at\u000d\u000a      39 weeks for all women is calculated to prevent the perinatal death of 500\u000d\u000a      babies per year. The RCOG guidelines suggest the strategy of elective\u000d\u000a      induction at 39 weeks should be targeted to those at highest risk (women\u000d\u000a      of 40 years or more) and calculate this will prevent the stillbirths of 17\u000d\u000a      UK babies per year.\u000d\u000a    The research led to appointment in 2012 of Jane Norman as Chair of the\u000d\u000a      Guideline Development Group [5.4] for the National Institute for Health\u000d\u000a      and Care Excellence (NICE) Guideline on Preterm Labour and Birth.\u000d\u000a    Impact on clinical practice\u000d\u000a    Despite its very recent publication (May 2012), the compelling data have\u000d\u000a      resulted in an immediate change in practice internationally, as attested\u000d\u000a      by leaders in the field from, for example, Canada [5.5]. The paper [3.1]\u000d\u000a      has been downloaded approximately 25,000 times from the BMJ website,\u000d\u000a      confirming both the interest generated among obstetric clinicians of\u000d\u000a      targeting elective induction and the early impact on management.\u000d\u000a    Impact on society\u000d\u000a    Public awareness and public involvement in research has been increased by\u000d\u000a      reference to the work in the media including Scottish Television, BBC\u000d\u000a      Scotland, BBC Radio 4's Today Programme, BBC Radio 1, BBC Radio 5 Live,\u000d\u000a      BBC Radio Scotland and Radio Forth, Daily Telegraph in September 2009; and\u000d\u000a      the Scotsman, Daily Mail, The Herald (combined circulation over 2 million)\u000d\u000a      and the BBC news website [5.6] (all on 11th May 2012).\u000d\u000a    Additionally, the data were referred to in a public lecture given by Jane\u000d\u000a      Norman \"The mysteries of birth — far from elementary my dear Watson\" in\u000d\u000a      October 2010, which has been accessed over 2,700 times on YouTube [5.7].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and welfare; healthcare guidelines on elective\u000d\u000a      induction of labour. The research showed that elective induction at time\u000d\u000a      points from 37 weeks' gestation progressively reduces perinatal mortality.\u000d\u000a      UK guidelines now recommend routine induction at 39 weeks in mothers\u000d\u000a      >40 years of age.\u000d\u000a    Significance: Implementation of the guidelines for mothers >40\u000d\u000a      years of age is estimated to prevent the stillbirth of 17 babies per year\u000d\u000a      in the UK.\u000d\u000a    Beneficiaries: Pregnant women, policy makers and healthcare\u000d\u000a      providers.\u000d\u000a    Attribution: The work was led by Jane Norman with Sarah Stock at\u000d\u000a      UoE, in collaboration with NHS Information Scotland.\u000d\u000a    Reach: UK, Europe, North America. Applies to all pregnant women,\u000d\u000a      especially those over 40 years of age.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Stock S, Ferguson E, Duffy A,...Norman J. Outcomes of elective\u000d\u000a      induction of labour compared to expectant management: a population based\u000d\u000a      study. BMJ. 2012;344:e2838. DOI: 10.1136\/bmj.e2838. [downloaded\u000d\u000a        approximately 25,000 times by census date].\u000d\u000a    \u000a\u000a3.2 Stock S, Ferguson E, Duffy A, Ford I, Chalmers J, Norman J. Outcomes\u000d\u000a      of induction of labour in women with previous caesarean delivery: a\u000d\u000a      retrospective cohort study using a population database. PLoS One.\u000d\u000a      2013;8:e60404. DOI: 10.1371\/journal.pone.0060404.\u000d\u000a    \u000a\u000a3.3 Norman J, Morris C, Chalmers J. The effect of changing patterns of\u000d\u000a      obstetric care in Scotland (1980-2004) on rates of preterm birth and its\u000d\u000a      neonatal consequences. Perinatal Database Study. PLoS Med.\u000d\u000a      2009;6:e1000153. DOI: 10.1371\/journal.pmed.1000153.\u000d\u000a    \u000aGrants\u000d\u000a    Norman J, Chalmers J, Shanks E. Temporal trends and outcomes associated\u000d\u000a      with obstetric causes of preterm birth in Scotland. Chief Scientist\u000d\u000a      Office, Scottish Executive, 2007-2008, £10,051. This grant (and the one\u000d\u000a      below) were awarded to Jane Norman shortly before she left the University\u000d\u000a      of Glasgow; the work was conducted by Jane Norman and Sarah Stock at the\u000d\u000a      University of Edinburgh in collaboration with Information Services\u000d\u000a      Division, NHS National Services Scotland.\u000d\u000a    Ferguson E, Norman J, Chalmers J, Shanks E, Finlayson A. Investigation of\u000d\u000a      the beneficial and adverse effects of induction of labour. Chief Scientist\u000d\u000a      Office, Scottish Executive, 2008-2009, CZG\/2\/292 £10,651.\u000d\u000a    Reference [3.1] informed guidelines Norman is introducing in a stepped\u000d\u000a      wedge cluster randomised trial of stillbirth prevention, AFFIRM\u000d\u000a      (£330,000), funded by the Chief Scientist Office of the Scottish\u000d\u000a      Executive, Tommy's and SANDS, which will be conducted in Scotland, Wales\u000d\u000a      and Ireland starting late 2013.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    5.1 Lisonkova S, Sabr Y, Butler B, Joseph K. International comparisons of\u000d\u000a      preterm birth: higher rates of late preterm birth are associated with\u000d\u000a      lower rates of stillbirth and neonatal death. BJOG. 2012;119:1630-9. DOI:\u000d\u000a      10.1111\/j.1471-0528.2012.03403.x.\u000d\u000a    5.2 Scottish Perinatal and Infant Mortality and Morbidity Report (2010).\u000d\u000a      Healthcare Improvement Scotland, NHS National Services Scotland.\u000d\u000a      http:\/\/www.healthcareimprovementscotland.org\/default.aspx?page=14046.\u000d\u000a    5.3 RCOG (2013). Induction of labour at term in older mothers. Scientific\u000d\u000a      Impact Paper no 34. London. http:\/\/www.rcog.org.uk\/files\/rcog-corp\/1.2.13%20SIP34%20IOL.pdf.\u000d\u000a    5.4 NICE, Preterm Labour and Birth, Guideline Development Group\u000d\u000a      Membership List.\u000d\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/14004\/64412\/64412.pdf.\u000d\u000a    5.5 Letter from Chief of Maternal-Fetal Medicine, Sunnybrook Hospital,\u000d\u000a      Toronto. [Available on request. States that the research has changed\u000d\u000a        clinical practice in Ontario, Canada, and provided the impetus for a\u000d\u000a        $12M randomised controlled trial.]\u000d\u000a    5.6 BBC News website (11 May 2012). \"Induction cuts risk of babies dying,\u000d\u000a      researchers say\".\u000d\u000a      http:\/\/www.bbc.co.uk\/news\/health-18018067.\u000d\u000a    5.7 The mysteries of birth — far from elementary my dear Watson (2010).\u000d\u000a      http:\/\/www.youtube.com\/watch?v=TC43j2UJ-GI.\u000d\u000a    ","Title":"\u000d\u000a    J: Elective delivery of pregnant women reduces perinatal mortality,\u000d\u000a        particularly in mothers over 40 years of age\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Jane Norman (Professor of Maternal and Fetal Health, UoE,\u000d\u000a      2008-present) and Dr Sarah Stock (Clinical Lecturer, UoE, 2008-present),\u000d\u000a      with colleagues from NHS Information Scotland, showed that routine\u000d\u000a      induction of labour would prevent unnecessary perinatal death,\u000d\u000a      particularly in women of >40 years of age.\u000d\u000a    Induction of labour at term is one of the most common obstetric\u000d\u000a      interventions, occurring in over 20% of pregnant women. \"Elective\"\u000d\u000a      induction of labour on \"maternal request\" and in the absence of a specific\u000d\u000a      complication is increasingly asked for by women, but the risks and\u000d\u000a      benefits are unclear. Randomised trials are unlikely to be sufficiently\u000d\u000a      large to determine the effects on perinatal mortality.\u000d\u000a    Induction of labour at term in women without a previous caesarean\u000d\u000a        section\u000d\u000a    In a retrospective cohort study of an unselected population database of\u000d\u000a      over 1.2 million pregnant women at term, conducted between 2008 and 2011,\u000d\u000a      Norman and colleagues compared the outcomes of elective induction of\u000d\u000a      labour at term (in women without caesarean section) at 37, 38, 39, 40 and\u000d\u000a      41 weeks' gestation with those of expectant management (continuation of\u000d\u000a      pregnancy to either spontaneous labour, induction of labour or caesarean\u000d\u000a      section at a later gestation). The team found that elective induction of\u000d\u000a      labour (compared with expectant management) decreased the odds of\u000d\u000a      perinatal mortality (adjusted odds ratio at 40 weeks' gestation was 0.39\u000d\u000a      [99% confidence interval (CI) 0.24-0.63]), without a reduction in the odds\u000d\u000a      of normal vaginal delivery [3.1]. Given that older women are at higher\u000d\u000a      risk of experiencing perinatal fetal death, guidelines from the Royal\u000d\u000a      College of Obstetricians and Gynaecologists (RCOG) have recommended that\u000d\u000a      induction of labour at 39 weeks should be routinely offered to older\u000d\u000a      women.\u000d\u000a    Induction of labour in women with one previous caesarean section\u000d\u000a    In a subsequent study, conducted between 2008 and 2012, Norman and\u000d\u000a      colleagues analysed the effects of induction of labour in women with one\u000d\u000a      previous caesarean section, where induction of labour is considered by\u000d\u000a      some to pose unacceptable risks to both mother and baby. In contrast to\u000d\u000a      the prevailing view, the team found that induction of labour (compared\u000d\u000a      with expectant management) was associated with a lower odds of caesarean\u000d\u000a      delivery (adjusted odds ratio at 39 weeks was 0.81 [95% CI 0.71-0.91] with\u000d\u000a      no effect on perinatal mortality [3.2]. In contrast, elective repeat\u000d\u000a      caesarean delivery was associated with lower perinatal mortality than\u000d\u000a      expectant management (adjusted odds ratio at 39 weeks was 0.23 [95% CI\u000d\u000a      0.07-0.75]). Hence, a more liberal policy of induction of labour at term\u000d\u000a      in women with previous caesarean delivery would reduce repeat caesarean\u000d\u000a      delivery; but repeat caesarean delivery is optimal in reducing perinatal\u000d\u000a      death.\u000d\u000a    Elective preterm delivery\u000d\u000a    In a parallel study of women delivering preterm in Scotland conducted\u000d\u000a      between 2007 and 2009, again using record linkage of population-based\u000d\u000a      data, Norman and team showed a progressive increase in the rate of\u000d\u000a      elective preterm birth for infants between 28 and 37 weeks' gestation\u000d\u000a      during the period 1980 to 2004. During this time, there was a reduction in\u000d\u000a      stillbirth and extended perinatal mortality rates for electively born but\u000d\u000a      not spontaneous preterm infants. These data contribute to a growing\u000d\u000a      understanding that a high rate of indicated late preterm birth is\u000d\u000a      associated with a lower rate of stillbirth and neonatal death [3.3].\u000d\u000a    "},{"CaseStudyId":"23858","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"895949","Name":"Zambia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"192950","Name":"Kenya"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"49518","Name":"Rwanda"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"226074","Name":"Uganda"}],"Funders":[],"ImpactDetails":"\u000a    Pathways to impact\u000a    Because of the \"orphan\" nature of non-cancer palliative care at the\u000a      outset of the work, the team engaged in an important drive to establish\u000a      the importance of this service and its development with professional\u000a      groups and healthcare students. To assist in this, Murray and colleagues\u000a      founded the International Primary Palliative Care Network in 2007. This\u000a      global network (committee members from UK, Australia, Canada, South\u000a      Africa, Belgium) leads its field in research, advocacy and service\u000a      innovation. It helps researchers from all continents collaborate and\u000a      advocate for palliative care in the community.\u000a    Impact on clinical practice and education\u000a    Murray's team developed the Supportive & Palliative Care Indicators\u000a      Tool (SPICT) to identify for palliative care more people dying with\u000a      conditions such as COPD and dementia [5.1]. In 2009, they introduced\u000a      routine advance care planning in all nursing homes in Midlothian,\u000a      Scotland, decreasing hospital admissions by 50%, and greatly improving the\u000a      overall quality of care as evaluated by relatives. Both of these\u000a      interventions are now being rolled out throughout the UK; the latter won a\u000a      Scottish Award for Excellence in Dementia Care and has prevented thousands\u000a      of hospital admissions and deaths, with considerable economic benefits\u000a      [5.2]. Internationally, the SPICT has been adopted in the UK, Spain,\u000a      Holland, Ireland and Uganda.\u000a    All UK hospices now have community care teams supporting patients with\u000a      non-malignant diseases. Non-cancer palliative care rose from 6% of UK\u000a      services in 2000 to 18% in 2012 (National Council for Palliative Care\u000a      [5.3]). The research has also informed quality improvement standards for\u000a      heart failure in UK and Europe [5.4].\u000a    Regarding educational practice, in 2008, the team won the BMJ's \"Making a\u000a      Difference Campaign\", so that until 2011, the BMJ prioritised publications\u000a      about non-cancer palliative care. Moreover, this opportunity was used to\u000a      advocate successfully for a new journal, BMJ Supportive & Palliative\u000a      Care, launched in 2011. Illustrations of the conceptual framework for\u000a      service are now incorporated in major undergraduate and postgraduate\u000a      medical texts [e.g., 5.5].\u000a    Impact on public policy\u000a    Through the Palliative Care Network and other channels, such as the\u000a      independent think-tank Demos, which cited the work in 2010 [5.6], Murray\u000a      and colleagues have stimulated governmental and public debate about\u000a      demographic and end-of-life challenges. The work has directly influenced\u000a      both UK Government policy and previously cancer-only-funding charities,\u000a      such as Marie Curie Cancer Care, so that they are both now investing twice\u000a      as much in palliative care for non-cancer patients than they were a decade\u000a      ago.\u000a    UK, Irish and Singaporean government policies reference the work\u000a      [5.7-5.9, respectively], calling for a re-design of services to better\u000a      meet diverse needs. In 2013, Murray, as an executive member of the\u000a      International Association of Hospice and Palliative Care, co-authored a\u000a      successful submission to the World Health Organization to list palliative\u000a      care medications in a separate section from oncology, and for morphine to\u000a      be listed as an essential medicine for palliative care for the first time.\u000a    Impact on society\u000a    Murray became a founder member of a national group to encourage a public\u000a      discourse about death and dying, and mobilise communities and individuals\u000a      to be involved in preventing and minimising distress at the end of life.\u000a      The website of this group had 1908 unique hits during a recent \"death\u000a      awareness\" week [5.10]. Similar public involvement strategies are\u000a      increasingly being integrated in other national end-of-life strategies\u000a      [e.g., 5.9].\u000a    Impact on international development\u000a    In 2011, the team was instrumental in founding an African Palliative Care\u000a      Research Network, which currently supports the first African-based BSc and\u000a      MSc in palliative care. Furthermore, the group, with Edinburgh University\u000a      Global Health Academy, was awarded a £1.5M Department for International\u000a      Development grant to integrate palliative care into the health systems of\u000a      Rwanda, Kenya, Uganda and Zambia. The team has helped develop the first\u000a      patient pathway for palliative care from a tertiary hospital down to\u000a      district and health centre levels in Africa. The Palliative Care Unit at\u000a      Makerere University, Uganda, led by Leng (Honorary Research Fellow, UoE),\u000a      trials many innovations. African Ministry of Health personnel have\u000a      attended training in Edinburgh, and the team has advised the Zambian\u000a      Ministry of Health on cervical cancer care.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; evidence-based palliative care for\u000a      patients with non-malignant disease beyond cancer patients and in\u000a      low-income countries; influencing policy; public engagement.\u000a    Significance: Care quality-standard changes and targeted\u000a      interventions: for example, up to 50% fewer unplanned hospital admissions\u000a      from nursing homes. Palliative care service development\/redesign\u000a      internationally; clinical tools deployed internationally.\u000a    Beneficiaries: Patients and their families\/carers; NHS and\u000a      healthcare providers; policymakers including UK and international\u000a      governments; medical charities.\u000a    Attribution: The work was performed by an international team led\u000a      by S. Murray at UoE.\u000a    Reach: International; policy changes and new guidelines\/service\u000a      structures in 11 countries (UK, Europe, N. America, Asia, sub-Saharan\u000a      Africa); applicable to all those at end of life.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"}],"References":"\u000a    \u000a3.1 Kendall M, Murray S, Carduff A, et al. Use of multiperspective\u000a      qualitative interviews to understand patients' and carers' beliefs,\u000a      experiences, and needs. BMJ. 2009;339:b4122. DOI: 10.1136\/bmj.b4122.\u000a    \u000a\u000a3.2 Murray S, Sheikh A. Serial interviews for patients with progressive\u000a      diseases. Lancet. 2006;368:901-2. DOI: 10.1016\/S0140-6736(06)69350-1.\u000a    \u000a\u000a3.3 Murray S, Kendall M, Boyd K, Sheikh A. Illness trajectories and\u000a      palliative care. BMJ. 2005;330:1007-11. DOI: 10.1136\/bmj.330.7498.1007.\u000a    \u000a\u000a3.4 Murray S, Boyd K, Kendall M, Worth A, Benton T, Clausen H. Dying of\u000a      lung cancer or cardiac failure: prospective qualitative interview study of\u000a      patients and their carers in the community. BMJ. 2002;325:929. DOI:\u000a      10.1136\/bmj.325.7370.929.\u000a    \u000a\u000a3.5 Murray S, Kendall M, Boyd K, Grant L, Highet G, Sheikh A. Archetypal\u000a      trajectories of social, psychological, and spiritual wellbeing and\u000a      distress in family care givers of patients with lung cancer: secondary\u000a      analysis of serial qualitative interviews. BMJ. 2010;340:c2581. DOI:\u000a      10.1136\/bmj.c2581.\u000a    \u000a\u000a3.6 Murray S, Grant E, Grant A, Kendall M. Dying from cancer in developed\u000a      and developing countries: lessons from two qualitative interview studies\u000a      of patients and their carers. BMJ. 2003;326:368. DOI:\u000a      10.1136\/bmj.326.7385.368.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"10","Subject":"Nursing"}],"Sources":"\u000a    5.1 Boyd K, Murray S. Recognising and managing key transitions in end of\u000a      life care. BMJ 2010;341:c4863. DOI: 10.1136\/bmj.c4863.\u000a    5.2 Badger F,Clifford C, Hewison A, Thomas K. An evaluation of the\u000a      implementation of a programme to improve end-of-life care in nursing\u000a      homes. Palliat Med. 2009;23:502-11. DOI: 10.1177\/0269216309105893.\u000a    5.3 National Council for Palliative Care (2013). National Survey of\u000a      patient activity data for specialist palliative care services.\u000a      http:\/\/www.ncpc.org.uk\/sites\/default\/files\/MDS%20Full%20Report%202012_1.pdf\u000a      [page 44.]\u000a    5.4 Jaarsma T, Beattie J, Ryder M, et al; Advanced Heart Failure Study\u000a      Group of the HFA of the ESC Palliative care in heart failure: a position\u000a      statement from the palliative care workshop of the Heart Failure\u000a      Association of the European Society of Cardiology. Eur J Heart Fail.\u000a      2009;11:433-43. DOI: 10.1093\/eurjhf\/hfp041.\u000a    5.5 Davidson's Principles & Practice of Medicine. 21st\u000a      Edition, London; Churchill Livingston [Available on request. See page\u000a        284].\u000a    5.6 Garber J, Leadbeater C. Dying for Change. London; DEMOS (2010).\u000a      http:\/\/www.demos.co.uk\/publications\/dyingforchange.\u000a      [Murray's work cited on p. 27 and 28.]\u000a    5.7 UK Department of Health (2008). End of life Care Strategy: promoting\u000a      high quality care for all adults at the end of life\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/en\/Publicationsandstatistics\/Publications\/PublicationsPolicyAndGuidance\/DH_086277.\u000a    5.8 The Irish Hospice Foundation (2011). Primary Palliative Care in\u000a      Ireland: Identifying improvements in primary care to support the care of\u000a      those in their last year of life\u000a      http:\/\/www.lenus.ie\/hse\/bitstream\/10147\/192381\/1\/Primary%20Palliative%20Care%20in%20Ireland.pdf.\u000a    5.9 Singaporean guidelines. Duke Nus Graduate Medical School. Report on\u000a      the National Strategy for Palliative Care. Singapore (2011). http:\/\/www.dukenus.edu.sg\/sites\/default\/files\/Report_on_National_Strategy_for_Palliative_Care%2031Jan2012_0.pdf.\u000a      [Murray and team's work referenced on pages 14, 15 & 61.]\u000a    5.10 Scottish Partnership for Palliative Care. Good Life, Good Death,\u000a      Good Grief website.\u000a      http:\/\/www.goodlifedeathgrief.org.uk\/content\/about\/.\u000a    ","Title":"\u000a    M: Defining patient needs and delivering evidence-based palliative and\u000a        end-of-life care for non-malignant disease, through services that can be\u000a        delivered in developed and low-income countries\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Using a qualitative, rigorous serial interview technique, Professor Scott\u000a      Murray (St Columba's Hospice Professor of Primary Palliative Care, UoE,\u000a      1990-present), with Dr Kirsty Boyd (Honorary Clinical Senior Lecturer,\u000a      UoE, 2000-present) and Dr Marilyn Kendall (Senior Research Fellow, UoE,\u000a      1999-present), were the first to establish the needs of patients\u000a      terminally ill with non-malignant disease, highlighting the health\u000a      inequalities affecting this group [3.1].\u000a    Prior to 2000, palliative care was largely limited to cancer patients in\u000a      the last month of life in hospices in developed countries. Since 2001,\u000a      Murray has created an internationally leading team to establish the\u000a      evidence base to inform palliative care interventions and pathways for\u000a      non-malignant disease. The breadth of this multi-disciplinary research\u000a      group has enabled construction of a wide paradigm of palliative care.\u000a      International collaborative research evolving from this activity has led\u000a      to developments in Europe, America, Africa and Australasia.\u000a    Supported by major awards (e.g., £467K from the National Institute for\u000a      Health Research), Murray generated a compelling dataset on which\u000a      innovations to redesign palliative care services could be based. Murray,\u000a      Boyd and Kendall designed multi-perspective, serial, in-depth interviews\u000a      and deployed them with patients with various progressive illnesses (lung\u000a      cancer, bowel cancer, glioma, heart failure, chronic obstructive pulmonary\u000a      disease (COPD), liver failure, frailty) and their carers. This enabled the\u000a      team to describe and explore dying experiences, and identify and map\u000a      typical patterns of physical, social, psychological and spiritual distress\u000a      at the end of life [3.1, 3.2].\u000a    The work established compelling evidence that palliative care should be\u000a      implemented:\u000a    \u000a      \u000aTo all patients with progressive life-threatening illness,\u000a        not just cancer patients as currently predominates [3.3]. Indeed, there\u000a        has been a 200% increase in non-cancer palliative care patients in the\u000a        UK since 2008. Murray established that patients with heart failure and\u000a        COPD have a similar symptom burden and indeed have this for longer than\u000a        do patients with cancer [3.4].\u000a      \u000aAt diagnosis, not just in the terminal stages. By\u000a        clearly demonstrating that patients may have greater distress at, or\u000a        even before, formal diagnosis of cancer than in the terminal stage, and\u000a        by mapping all dimensions of health (physical, social, psychological and\u000a        spiritual) in individuals with life-threatening illness and their\u000a        carers; the work established the importance and interconnectedness of\u000a        these factors [3.5].\u000a      \u000aIn low-income and transitional economies. The\u000a        team showed that palliative care can function in healthcare\u000a        resource-poor environments [3.6].\u000a    \u000a    "},{"CaseStudyId":"23859","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"390903","Name":"Greece"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"660013","Name":"Finland"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2921044","Name":"Germany"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Pathways to impact\u000a      Expert advice underpinning legislative changes in both Europe and North\u000a      America leaned\u000a      heavily on Sharpe's work. Sharpe has contributed to expert reports to\u000a      policy-makers at the\u000a      highest levels. Examples include: the Advisory Committee on Hazardous\u000a      Substances (2010);\u000a      the European Parliament Science and Technology Options Assessment (2013);\u000a      the European\u000a      Science Foundation (2010); the European Environment Agency [5.1]; the US\u000a      National\u000a      Academies Committee on Health Risks of Phthalates (2008); the US Consumer\u000a      Product Safety\u000a      Commission: US Chronic Hazard Advisory Panel on Phthalates (2011); Food\u000a      and Agriculture\u000a      Organisation\/the World Health Organization (2012) [5.2]; EC Scientific\u000a      Committee on emerging\u000a      and newly identified health risks (2013); and the US Department of Health\u000a      & Human Services\u000a      National Toxicology Program (2008). Invitations to speak at critical\u000a      European and international\u000a      conferences included: the European Chemical Industry on EDC and\u000a      phthalates, ECETOC\u000a      (2009), European (2012) and International (2013) Plasticizers conferences,\u000a      and a critical review\u000a      for the NGO ChemTrust (2009) on the role of EDC in TDS [5.3]. Sharpe has\u000a      also acted as\u000a      expert adviser to many companies, including Johnson & Johnson (2009;\u000a      safety of phthalates in\u000a      children's toys), Bayer (2013), and BASF (2011-13; scientific advisory\u000a      panel).\u000a    Impact on public policy\u000a      Sharpe's research at UoE, with others (such as Swan's group in the USA)\u000a      fundamentally altered\u000a      UK and EU and significantly influenced North American attitudes to EDC in\u000a      general, and to\u000a      phthalates specifically, their presence in the environment and their\u000a      associated potential health\u000a      effects, especially in high-risk groups where there is exposure to EDC at\u000a      critical periods in\u000a      development or susceptibility: in utero and in childhood.\u000a    Sharpe's work on the impact of environmental exposure to EDC and\u000a      phthalates alerted\u000a      legislators to the developmental dangers of EDC exposure and took a lead\u000a      role in driving a\u000a      radical reformulation of regulations for the manufacture and use of all\u000a      chemicals in Europe:\u000a      REACH (Registration, Evaluation, Authorisation & Restriction of\u000a      Chemicals) [5.4, 5.5]. REACH\u000a      represented a critical shift in liability, placing the onus on chemical\u000a      manufacturers to prove the\u000a      safety of their compounds before approval and registration. It also\u000a      encompassed retrospective\u000a      evaluation of key chemicals where manufacture and use preceded REACH\u000a      implementation (in\u000a      particular EDC), and laid the foundations for new regulation of EDC in\u000a      food by the European\u000a      Food Safety Authority [5.6].\u000a    Sharpe's work linking TDS to phthalate exposure led to certain phthalates\u000a      being banned from\u000a      use in children's toys and childcare articles [5.7-5.10], as detailed\u000a      below.\u000a    Following an EC Recommendation on the ban of phthalates in children's\u000a      toys in 1998, eight\u000a      member states (Austria, Denmark, Finland, France, Germany, Greece, Italy\u000a      and Sweden)\u000a      restricted the use of phthalates in toys and in childcare articles, with\u000a      the other member states\u000a      taking a `controlled use' approach by measuring the release of phthalates\u000a      from children's toys.\u000a      In 1999 the EC published a \"Community Strategy for Endocrine Disruptors\"\u000a      followed (to 2011)\u000a      by a series of official reports dealing with its implementation [5.1,\u000a      5.7].\u000a    Subsequently, the EU Phthalates Directive 2005\/84\/EC banned the use of\u000a      certain phthalates\u000a      (DEHP, DBP and BBP) in PVC and other plasticised materials in all toys and\u000a      childcare articles\u000a      throughout the EU from January 2007. Phthalates DINP, DIDP and DNOP were\u000a      banned for toys\u000a      and childcare articles that could be placed in the mouth of children of\u000a      all ages, even if in parts\u000a      unlikely to be mouthed [5.8]. The impact extends further than children's\u000a      articles: since 2010,\u000a      Denmark's Environmental Protection Agency has put pressure on the EU to\u000a      ban phthalates\u000a      from sex toys with new restrictions in REACH planned by the European\u000a      Chemicals Agency.\u000a    The impact of Sharpe's research on EU policy and legislation is referred\u000a      to by the primary EU\u000a      website on this area of healthcare, the Endocrine Disruptors Website\u000a      [5.7]. EU strategy for\u000a      short, medium and long-term actions on EDC management in the EU is\u000a      covered; Sharpe's\u000a      research is referenced several times in its supporting database.\u000a    In 2009, the US Congress banned six phthalates from children's toys\u000a      throughout the USA;\u000a      additional requirements added in 2011 require third-party testing and\u000a      certification for products\u000a      manufactured after 31 December 2011 [5.9]. A CBS in-depth video article\u000a      (May 2010) quoted\u000a      Sharpe and acknowledged that \"Dr. Sharpe's study led to Congress banning\u000a      the phthalates in\u000a      toys\" [5.10]. In Canada, the same six phthalates were banned from all\u000a      children's toys and\u000a      childcare articles in 2011.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; policy; the environment; fundamental\u000a      changes to phthalate use, wider\u000a      EU and US Endocrine Disrupting Chemical (EDC) regulations and chemical\u000a      bans.\u000a    Significance: Shaped policy, regulation and the potential causal\u000a      relationship of environmental\u000a      EDC on male reproductive disorders and testicular dysgenesis syndrome.\u000a    Beneficiaries: Governments; chemical and food regulatory agencies;\u000a      healthcare workers\u000a      advising and treating pregnant women; pregnant women and their fetuses;\u000a      males with\u000a      disorders of sex development; adult males; plastics manufacturers.\u000a    Attribution: EDC research was developed and shaped by Prof Richard\u000a      Sharpe and colleagues at\u000a      UoE.\u000a    Reach: International; Europe, North America.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Sharpe R, Skakkebaek N. Are oestrogens involved in falling sperm\u000a      counts and disorders of\u000a      the male reproductive tract? Lancet. 1993;341:1392-5. DOI:\u000a      10.1016\/0140-6736(93)90953-E.\u000a    \u000a\u000a3.2 Toppari J, Larsen J,...Sharpe R, et al. Male reproductive health and\u000a      environmental\u000a      xenoestrogens. Environ Health Perspect. 1996;104:741-803. DOI:\u000a      10.2307\/3432709.\u000a    \u000a\u000a3.3 Sharpe R. The 'oestrogen hypothesis'. Where do we stand now? Int J\u000a      Androl. 2003;26:2-15. DOI: 10.1046\/j.1365-2605.2003.00367.x.\u000a    \u000a\u000a3.4 Rivas A, McKinnell C, Fisher J, Atanassova N, Williams K, Sharpe R.\u000a      Neonatal co-administration of testosterone with diethylstilbestrol\u000a      prevents diethylstilbestrol induction of most\u000a      reproductive tract abnormalities in male rats. J Androl. 2003;24:557-67.\u000a      DOI: 10.1002\/j.1939-4640.2003.tb02707.x.\u000a    \u000a\u000a3.5 Fisher J, Macpherson S, Marchetti N, Sharpe R. Human 'testicular\u000a      dysgenesis syndrome': a\u000a      possible model using in-utero exposure of the rat to dibutyl phthalate.\u000a      Hum Reprod. 2003;18:1383-94. DOI: 10.1093\/humrep\/deg273.\u000a    \u000a\u000a3.6 Welsh M, Saunders P, Fisken M,...Sharpe R. Identification in rats of\u000a      a programming\u000a      window for reproductive tract masculinization, disruption of which leads\u000a      to hypospadias and\u000a      cryptorchidism. J Clin Invest. 2008;118:1479-90. DOI: 10.1172\/JCI34241.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    5.1 European Environment Agency (EEA) report: The impacts of endocrine\u000a      disrupters on\u000a      wildlife, people and their environments. 2012. EEA technical report No\u000a      2\/2012; ISSN 1725-2237.\u000a      http:\/\/www.pnrpe.fr\/IMG\/pdf\/Tech_02_2012_1_-2.pdf.\u000a    5.2 Joint FAO\/WHO Expert Meeting to Review Toxicology and Health Aspects\u000a      of Bisphenol A.\u000a      2010. ftp:\/\/ftp.fao.org\/ag\/agn\/agns\/BPA_Summary_Report.pdf.\u000a    5.3 ChemTrust Joint NGO Press Release on EFSA's Opinion on BPA (Bisphenol\u000a      A)\u000a      http:\/\/www.chemtrust.org.uk\/Press_and_Media.php.\u000a    5.4 Health and Safety Executive REACH homepage. http:\/\/www.hse.gov.uk\/reach\/.\u000a    5.5 European Chemicals Agency Regulations: REACH\u000a      http:\/\/echa.europa.eu\/web\/guest\/regulations\/reach.\u000a    5.6 EFSA Paves Way for Regulating Endocrine Disruptors in Food.2013.\u000a      http:\/\/www.euractiv.com\/health\/food-safety-agency-backs-definin-news-518638.\u000a    5.7 EC Endocrine Disruptors homepage. http:\/\/ec.europa.eu\/environment\/endocrine.\u000a    5.8 EU Phthalates Directive 2005\/84\/EC Update. 2006.\u000a      http:\/\/www.intertek.com\/uploadedFiles\/Intertek\/Divisions\/Consumer_Goods\/Media\/PDFs\/Sparkles\/2006\/sparkle250.pdf.\u000a    5.9 United States Consumer Product Safety Commission website.\u000a      http:\/\/www.cpsc.gov\/phthalates.\u000a    5.10 Phthalates are they safe? 2010. CBS 60 mins video\u000a      http:\/\/www.cbs.com\/shows\/60_minutes\/video\/1500260381\/phthalates-are-they-safe.\u000a    ","Title":"\u000a    P: Testicular Dysgenesis Syndrome is linked to endocrine-disrupting\u000a        phthalate exposure; specific phthalates are now banned from children's\u000a        mouth toys\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Led by Professor Richard Sharpe (Programme Leader and Principal\u000a      Investigator, MRC Centre for\u000a      Reproductive Health, UoE, 1974-present), UoE-based researchers played the\u000a      key role in\u000a      demonstrating that the widely used plasticiser, dibutyl phthalate (DBP)\u000a      was a cause of testicular\u000a      dysgenesis syndrome (TDS) by suppressing androgen production. This finding\u000a      had critical\u000a      implications for the framing of environmental and chemical legislation in\u000a      Europe and North\u000a      America, and for the manufacture and sales of children's toys and products\u000a      that might be\u000a      \"mouthed\".\u000a    Sharpe played the key role in generating the so-called `oestrogen\u000a      hypothesis' (1993) [3.1] (>1800\u000a      citations), [3.2] (>1300 citations). This created worldwide interest,\u000a      concern and controversy by\u000a      interlinking the high or rising incidence of human male reproductive\u000a      disorders (collectively termed\u000a      `testicular dysgenesis syndrome', TDS) with increased exposure to\u000a      environmental oestrogens via\u000a      environmental chemicals or diet [3.3]. Work at UoE between 2005 and 2008\u000a      identified that only\u000a      potent (pharmaceutical, not environmental) oestrogens induced male\u000a      reproductive disorders by\u000a      suppressing androgen production or action, reducing expression of androgen\u000a      receptor protein\u000a      [3.4]. This led to a refocusing on fetal androgens and their perturbation;\u000a      in particular, the potential\u000a      role that exposure to anti-androgenic endocrine-disrupting chemicals (EDC)\u000a      might play. Sharpe\u000a      and others identified that certain phthalate esters (widely used to\u000a      enhance the malleability of plastic\u000a      components, objects and toys), to which there is ubiquitous human\u000a      exposure, can suppress\u000a      androgen production by the fetal rat testis. The next key development in\u000a      the field was the\u000a      development and validation by Sharpe's group of animal models of TDS,\u000a      based on exposure of\u000a      pregnant rats to one of these compounds, dibutyl phthalate (DBP) [3.5].\u000a      This work has been\u000a      instrumental in validating the TDS hypothesis (which was untestable in\u000a      man), and in identifying\u000a      both the interlinking of TDS and its common mechanistic origins in fetal\u000a      life, which can then be\u000a      applied in man. The wide use of phthalates in the manufacture of plastics\u000a      encompasses a range of\u000a      products, including those to which pregnant females, neonates and babies\u000a      are frequently exposed.\u000a      Sharpe and colleagues' research has played a lead role in risk assessment\u000a      and regulation of the\u000a      relevant phthalates, and in shaping worldwide research on these compounds.\u000a    The models developed by UoE investigators for the first time allowed (a)\u000a      retrospective\u000a      determination of the origin in fetal life, and causes, of TDS in humans,\u000a      in particular those emerging\u000a      in young adulthood such as low sperm count or testis germ cell cancer, (b)\u000a      the identification of the\u000a      `masculinisation programming window' (MPW; ~8-12 weeks' gestation in\u000a      humans): the critical fetal\u000a      period when function, reproductive organ size and reproductive disorders\u000a      in newborn and adult\u000a      males are predetermined by the level of androgen exposure, and (c)\u000a      determination that anogenital\u000a      distance (AGD), which is sexually dimorphic, was also programmed by\u000a      androgen exposure in the\u000a      MPW, and could be used from birth to adulthood to determine fetal androgen\u000a      exposure in the MPW\u000a      retrospectively [3.6]. This had major consequences: (i) it identified a\u000a      critical window: EDC could\u000a      only induce TDS if maternal (fetal) exposure occurred during the MPW; (ii)\u000a      it allowed the\u000a      application of AGD measurement in humans as a means to retrospectively\u000a      determine the origin of\u000a      TDS, and\/or to forecast future reproductive function or disorders in\u000a      adults, and\/or at birth to identify\u000a      directly potential causal association between EDC exposure and\u000a      reproductive development; and\u000a      (iii) it provided a biomarker for regulatory purposes [3.6].\u000a    "},{"CaseStudyId":"23860","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Impact on public policy and services\u000a    The STOPPIT study showed that progesterone was ineffective in women with\u000a      twin pregnancy, and\u000a      has led to clear guidelines published in 2011 or 2012 from three\u000a      continents (Europe (NICE), North\u000a      America and Australasia [5.1-5.6, 5.7]) that progesterone should not be\u000a      used for this purpose.\u000a    Impact on health and welfare\u000a    The research has changed clinical practice internationally for women with\u000a      twin pregnancy (e.g. in\u000a      Canada, Australia [5.8]). In the UK alone, the research has prevented the\u000a      ineffective treatment of\u000a      11,000 women per year.\u000a    Daily administration of a vaginal gel in pregnancy (as advocated in women\u000a      with singleton\u000a      pregnancy at high risk of preterm birth) is unpleasant. The STOPPIT study\u000a      has stopped this\u000a      happening. Additionally, all drugs administered during pregnancy have the\u000a      potential for teratogenic\u000a      effects, with these effects sometimes not being immediately apparent\u000a      (e.g., stilboestrol). Although\u000a      there are no known adverse effects of progesterone at the stage of\u000a      pregnancy used for preterm\u000a      labour prevention, the STOPPIT study has prevented risk of exposure to any\u000a      covert long-term\u000a      adverse effects.\u000a    Impact on the economy\u000a    The excess cost of treating women with twin pregnancy with progesterone\u000a      was £2,334 per patient,\u000a      with no clinical benefit. On a UK population basis alone, the excess cost\u000a      of treating women with\u000a      twin pregnancy with progesterone was £25M (2008 prices). These costs are\u000a      now avoided.\u000a    Impact on society\u000a    Public awareness and public involvement in research has been increased by\u000a      reference to the work\u000a      in the media including the BBC News website on 10th June 2009\u000a      [5.9].\u000a    Additionally, the data were referred to in a public lecture given by Jane\u000a      Norman \"The mysteries of\u000a      birth — far from elementary my dear Watson\" in October 2010, which has\u000a      been accessed over\u000a      2,700 times on YouTube [5.10].\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; public policy; the work led to UK and\u000a      international guidelines advising\u000a      against progesterone use to prevent preterm birth in twin pregnancy.\u000a    Significance: Thousands of women now avoid this unpleasant\u000a      procedure annually, with a saving\u000a      to the NHS of £25M.\u000a    Beneficiaries: Pregnant women, policy-makers, the NHS and\u000a      healthcare-providers.\u000a    Attribution: The work was initiated by a five-centre UK\u000a      collaborative group including UoE. Data\u000a      analysis, interpretation and translation into practice were led by Jane\u000a      Norman, UoE.\u000a    Reach: The data are cited in guidelines and have changed clinical\u000a      practice on three continents:\u000a      Europe (NICE), North America and Australasia. Applies to 11,000 women\u000a      annually in UK alone.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Norman J, Mackenzie F, Owen P, et al. Progesterone for the prevention\u000a      of preterm birth in\u000a      twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled\u000a      study and meta-analysis.\u000a      Lancet. 2009;373:2034-40. DOI: 10.1016\/S0140-6736(09)60947-8. [cited\u000a        100 times;\u000a        Google scholar, 24 Jun 2013].\u000a    \u000a\u000a3.2 Eddama O, Petrou S, Regier D,...Norman J. Study of progesterone for\u000a      the prevention of\u000a      preterm birth in twins (STOPPIT): Findings from a trial-based\u000a      cost-effectiveness analysis. Int J\u000a      Technol Assess Health Care. 2010;26:141-8. DOI: 10.1017\/S0266462310000036.\u000a    \u000aGrant:\u000a    Norman J, Mackenzie F, Owen P, et al. Double blind randomised placebo\u000a      controlled study of\u000a      progesterone for the prevention of preterm labour in twins (STOPPIT).\u000a      Chief Scientist Office,\u000a      Scottish Executive, 2004-2008. £224,062. [This grant was awarded to a\u000a        UK collaborative group,\u000a        led by Professor Jane Norman, Edinburgh Co-Is Professor Andrew Calder\u000a        and Dr Sarah Cooper,\u000a        and managed by the University of Glasgow. Participants were recruited\u000a        when Jane Norman was at\u000a        the University of Glasgow. Data analysis and interpretation were\u000a        performed by Jane Norman,\u000a        Professor of Maternal and Fetal Health at UoE after her appointment in\u000a        2008.]\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    5.1 NICE Clinical Guideline on Multiple Pregnancy (2011). The management\u000a      of twin and triplet\u000a      pregnancies in the antenatal period. http:\/\/www.nice.org.uk\/nicemedia\/live\/13571\/56422\/56422.pdf.\u000a    5.2 Society for Maternal-Fetal Medicine Publications Committee, with\u000a      assistance of Vincenzo\u000a      Berghella. Progesterone and preterm birth prevention: translating clinical\u000a      trials data into clinical\u000a      practice. Am J Obstet Gynecol. 2012;206:376-86. DOI:\u000a      10.1016\/j.ajog.2012.03.010.\u000a    5.3 Committee on Practice Bulletins—Obstetrics, The American College of\u000a      Obstetricians and\u000a      Gynecologists. Practice bulletin no. 130: prediction and prevention of\u000a      preterm birth. Obstet\u000a      Gynecol. 2012;120:964-73. DOI: 10.1097\/AOG.0b013e3182723b1b.\u000a    5.4 Di Renzo G, Roura L, Facchinetti F, et al. Guidelines for the\u000a      management of spontaneous\u000a      preterm labor: identification of spontaneous preterm labor, diagnosis of\u000a      preterm premature rupture\u000a      of membranes, and preventive tools for preterm birth. J Matern Fetal\u000a      Neonatal Med. 2011;24:659-\u000a      67. DOI: 10.3109\/14767058.2011.553694.\u000a    5.5 The Royal Australian and New Zealand College of Obstetricians and\u000a      Gynaecologists (2010).\u000a      C-Obs 29 (b). Progesterone: Use in the second and third trimester of\u000a      pregnancy for the prevention\u000a      of preterm birth. http:\/\/www.ranzcog.edu.au\/component\/docman\/doc_view\/962-c-obs-29b-progesterone-use-in-the-second-trimester-and-third-trimester-of-pregnancy.html?Itemid=341.\u000a    5.6 González R. Prenatal administration of progesterone for preventing\u000a      preterm birth in women\u000a      considered at risk of preterm birth: RHL commentary (last revised: 1\u000a      December 2009). The WHO\u000a      Reproductive Health Library; Geneva: World Health Organization.\u000a      http:\/\/apps.who.int\/rhl\/pregnancy_childbirth\/complications\/preterm_birth\/cd004947_gonzalezr_com\/en\/.\u000a    5.7 NICE, Preterm Labour and Birth, Guideline Development Group\u000a      Membership List.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/14004\/64412\/64412.pdf.\u000a    5.8 Letter from the Head, Department of Obstetrics and Gyaecology, Monash\u000a      University,\u000a      Australia. [Available on request. Confirms that the work informed\u000a        changes to clinical practice\u000a        guidelines in Victoria, Australia, changing the recommended care for\u000a        women with twin pregnancy.]\u000a    5.9 BBC News website (10 Jun 2009). Multiple birth differences found.\u000a      http:\/\/news.bbc.co.uk\/1\/hi\/scotland\/edinburgh_and_east\/8093621.stm.\u000a    5.10 The mysteries of birth — far from elementary my dear Watson (2010).\u000a      http:\/\/www.youtube.com\/watch?v=TC43j2UJ-GI.\u000a    ","Title":"\u000a    K: Progesterone does not prevent preterm birth in twin pregnancy\u000a        (STOPPIT study)\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Jane Norman (Professor of Maternal and Fetal Health, UoE,\u000a      2008-present), with UoE\u000a      Co-Is Dr Sarah Cooper (UoE 2001-2003) and Professor Andrew Calder (UoE\u000a      1987-2009; now\u000a      Emeritus), initiated (while based in Glasgow) the STOPPIT trial. Following\u000a      relocation to Edinburgh\u000a      (2008) Norman undertook trial data analysis and showed definitively that\u000a      progesterone does not\u000a      prevent pre-term birth in twin pregnancy.\u000a    Over 22,000 twins are born in the UK each year. Babies from twin\u000a      pregnancy have a three-times\u000a      higher chance of dying during gestation or in the first week of life\u000a      (perinatal mortality), and this\u000a      excess in perinatal mortality is largely owing to increased rates of\u000a      preterm birth.\u000a    Progesterone prevents preterm birth in other scenarios where women are at\u000a      high risk. Before the\u000a      STOPPIT study, many clinicians had started to use progesterone for the\u000a      prevention of preterm\u000a      birth in twin pregnancy. This would have involved treatment of 11,000\u000a      women per year in the UK,\u000a      and many more worldwide. On the basis of this, and the fact that women\u000a      with twin pregnancy are\u000a      at especially high risk, Norman conceived the \"STOPPIT\" study to determine\u000a      whether progesterone\u000a      is effective in preventing preterm birth in twins. The project was funded\u000a      by a Chief Scientist Office\u000a      grant awarded in 2004 to a five-centre collaborative group including UoE,\u000a      and was led by Norman,\u000a      who performed the analysis after having moved to UoE in 2008.\u000a    The group conducted a double-blind, placebo-controlled trial, recruiting\u000a      500 women with twin\u000a      pregnancy from nine clinics specialising in the management of twin\u000a      pregnancy. Women were\u000a      randomised, in permuted blocks of randomly mixed sizes, either to daily\u000a      vaginal progesterone gel\u000a      90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24\u000a      weeks' gestation. All study\u000a      personnel and participants were masked to treatment assignment for the\u000a      duration of the study. The\u000a      primary outcome was delivery or intrauterine death before 34 weeks'\u000a      gestation. Analysis was by\u000a      intention to treat. Additionally the group undertook a meta-analysis of\u000a      published and unpublished\u000a      data to establish the efficacy of progesterone in the prevention of early\u000a      (<34 weeks' gestation)\u000a      preterm birth or intrauterine death in women with twin pregnancy, and an\u000a      economic evaluation.\u000a    The study found that the combined proportion of intrauterine death or\u000a      delivery before 34 weeks of\u000a      pregnancy was 24.7% (61\/247) in the progesterone group and 19.4% (48\/247)\u000a      in the placebo\u000a      group (odds ratio [OR] 1.36, 95% confidence interval [CI] 0.89-2.09; p=0.16).\u000a      The rate of adverse\u000a      events did not differ between the two groups. The meta-analysis confirmed\u000a      that progesterone does\u000a      not prevent early preterm birth in women with twin pregnancy (pooled OR\u000a      1.16, 95% CI 0.89-1.51)\u000a      [3.1].\u000a    The economic evaluation showed that giving progesterone prophylaxis to\u000a      women with twin\u000a      pregnancy is not cost-effective, with a mean excess cost in the\u000a      progesterone group of £2,059 per\u000a      woman treated [3.2].\u000a    "},{"CaseStudyId":"23861","Continent":[{"GeoNamesId":"6255146","Name":"Africa"}],"Country":[{"GeoNamesId":"203312","Name":"Democratic Republic of the Congo"},{"GeoNamesId":"2233387","Name":"Cameroon"}],"Funders":[],"ImpactDetails":"\u000a    The WHO and its subsidiary African Programme for Onchocerciasis Control\u000a      (APOC) have reduced morbidity in many parts of west Africa and eliminated\u000a      onchocerciasis from some isolated foci in South America [5.1].\u000a      Onchocerciasis is now identified as a target for elimination from Africa\u000a      by 2020.\u000a    Because ivermectin is not suitable for use in children under 5 years or\u000a      in those co-infected with L Loa, and drug resistance is emerging,\u000a      it is unsuitable for mass treatment programmes in over 8 million Africans.\u000a      The work described above in Cameroon [5.2] demonstrated that doxycycline\u000a      could overcome the problem of L loa co-infection, provided\u000a      attention is paid to ensure community involvement in drug administration.\u000a    Impact on practitioners and services\u000a      Doxycycline is now defined as one of only two treatments effective for\u000a      onchocerciasis by the CDC [5.3]. CDC also notes that the alternative\u000a      (ivermectin) may cause dangerous side effects in the presence of L Loa\u000a      co-infection.\u000a    The Cameroon Academy of Sciences has recommended the use of doxycycline\u000a      for the treatment of river blindness to the Cameroon Government (2013)\u000a      [5.4]; the Government is now revising the national onchocerciasis control\u000a      strategy in accordance with these recommendations. Furthermore, in South\u000a      America, doxycycline is being used to treat residual cases and foci where\u000a      eradication rather than control is being targeted [5.5].\u000a    Impact on public policy\u000a      The Cameroon study's very high compliance rate of over 97.5% was\u000a      attributed to detailed training of health workers recruited directly from\u000a      the study community and the involvement of social scientists to ensure\u000a      local traditions were not compromised. Since the study, WHO\/APOC has\u000a      advocated greater use of community-directed treatment programmes [5.1].\u000a      This approach is more expensive than traditional mass treatment programmes\u000a      but, as demonstrated, effective use of doxycycline would protect the\u000a      community for at least 4 years [5.2] and therefore be cost-effective.\u000a    Impact on the economy\u000a      A 2004 WHO study concluded that the disease burden of onchocerciasis was\u000a      about 884,000 disability-adjusted life years. This can be interpreted as a\u000a      loss of 15% gross national product in areas of high endemicity. Such\u000a      losses are being reduced through the adoption of doxycycline in mass\u000a      treatment campaigns.\u000a    Impact on health and welfare\u000a      The Cameroon study showed that, when empowered, community health workers\u000a      can successfully deliver doxycycline for six weeks for the treatment of\u000a      onchocerciasis. It paves the way for the initiation of control programmes\u000a      for 8 million people across Cameroon, DR Congo and the Central African\u000a      Republic.\u000a    At the end of the 6-week course of treatment with doxycycline, the\u000a      community as a whole reported both immediate and long-term benefits [3.6].\u000a      Relief from itching and the regression of nodules were indicative of\u000a      clearance of O volvulus. More rapid wound healing and reduction of\u000a      secondary bacterial infections were reported together with increased\u000a      appetite and sexual desire. The positive feedback from community members\u000a      who took part in the first phase of treatment motivated reluctant\u000a      individuals to adhere to treatment.\u000a    Resolution and prevention of skin disease is particularly important for\u000a      women as this avoids the major social stigma and societal exclusion\u000a      (including no marriage) that is associated with onchocerciasis.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare and public healthcare policy;\u000a      demonstrating that community-directed treatment of onchocerciasis with\u000a      doxycycline is effective where ivermectin is contra-indicated.\u000a    Significance: 12,936 onchocerciasis patients were treated safely\u000a      and protected for at least 4 years. The treatment regime has been adopted\u000a      by the US Centers for Disease Control and Prevention, the World Health\u000a      Organization and governments.\u000a    Beneficiaries: Patients with onchocerciasis; governments and\u000a      policy-makers.\u000a    Attribution: Studies performed by a long-standing African-European\u000a      partnership formed and led by Taylor (UoE).\u000a    Reach: International; up to 8 million people in the Congo basin;\u000a      onchocerciasis patients in Africa where ivermectin is not appropriate plus\u000a      those in South America participating in focal eradication campaigns.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Maréchal P, Le Goff L, Hoffman W,...Taylor D, et al. Immune response\u000a      to the filaria Litomosoides sigmodontis in susceptible and resistant mice.\u000a      Parasite Immunol. 1997;19:273-9. DOI: 10.1046\/j.1365-3024.1997.d01-209.x.\u000a    \u000a\u000a3.2 Le Goff L, Loke P, Ali H,... Taylor D, Allen J. Interleukin-5 is\u000a      essential for vaccine-mediated immunity but not innate resistance to a\u000a      filarial parasite. Infect Immun. 2000;68:2513-7. DOI:\u000a      10.1128\/IAI.68.5.2513-2517.2000.\u000a    \u000a\u000a3.3 van der Werf N, Redpath S, Azuma M, Yagita H, Taylor M. Th2\u000a      cell-intrinsic hypo- responsiveness determines susceptibility to helminth\u000a      infection. PLoS Pathog. 2013;9:e1003215. DOI:\u000a      10.1371\/journal.ppat.1003215.\u000a    \u000a\u000a3.4 Langworthy S, Renz A, Mackenstedt U, et al. Macrofilaricidal activity\u000a      of tetracycline against the filarial nematode, Onchocerca ochengi:\u000a      elimination of Wolbachia proceeds worm death and suggests a dependent\u000a      relationship. Proc Biol Sci. 2000;267:1063-9. DOI: 10.1098\/rspb.2000.1110.\u000a    \u000a\u000a3.5 Hoerauf A, Spechts S, Marfo-Debrekyi Y, et al. Efficacy of 5 week\u000a      doxycycline treatment on adult Onchocerca volvulus. Parasitol Res.\u000a      2009;104:437-47. DOI: 10.1007\/s00436-008-1217-8.\u000a    \u000a\u000a3.6 Wanji S, Tendongfor N, Nji T,...Taylor D. Community-directed delivery\u000a      of doxycycline for the treatment of onchocerciasis in areas of\u000a      co-endemicity with loiasis in Cameroon. Parasit Vectors. 2009;2:39. DOI:\u000a      10.1186\/1756-3305-2-39.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    5.1 World Health Organization, African Programme for Onchocerciasis\u000a      Control (APOC), 2012. Achievements of community-directed treatment with\u000a      ivermectin (CDTI).\u000a      http:\/\/www.who.int\/apoc\/cdti\/achievements\/en\/.\u000a    5.2 Tamarozzi F, Tendongfor N, Enyong P, et al. Long term impact of large\u000a      scale community-directed delivery of doxycycline for the treatment of\u000a      onchocerciasis. Parasit Vectors. 2012;5:53. DOI: 10.1186\/1756-3305-5-53.\u000a    5.3 CDC Resources for Health Professionals, Parasites — Onchocerciasis\u000a      (also known as River Blindness), 2013. http:\/\/www.cdc.gov\/parasites\/onchocerciasis\/health_professionals\/.\u000a    5.4 Cameroon Academy of Sciences, 2013. Recent advances in onchocerciasis\u000a      research and implications for control. [Available on request.]\u000a    5.5 Gustavsen K, Hopkins A, Sauerbrey M. Onchocerciasis in the Americas:\u000a      from arrival to (near) elimination. Parasit Vectors. 2011;4:205. DOI:\u000a      10.1186\/1756-3305-4-205. \u000a    ","Title":"\u000a    R: Community-directed delivery of doxycycline in Cameroon demonstrates\u000a        effectiveness as a treatment for onchocerciasis (river blindness) in\u000a        Africa that avoids adverse effects associated with ivermectin\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor David Taylor (Professor of Tropical Animal Health, UoE,\u000a      1994-present), demonstrated for the first time that doxycycline was an\u000a      effective treatment for onchocerciasis. This work led to the adoption of\u000a      the doxycycline treatment regime by the US Centers for Disease Control and\u000a      Prevention (CDC) and other international agencies, replacing ivermectin as\u000a      the first-line mass treatment.\u000a    Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca\u000a        volvulus, is the second most common infectious blinding disease of\u000a      the developing world, afflicting 31 million people, 95% of whom live in\u000a      West or Central Africa. Seventy percent of patients experience severe and\u000a      debilitating skin disease that has major economic and social consequences\u000a      including poor school performance, low productivity, low income, higher\u000a      health-related costs, and extreme social stigmatization, especially among\u000a      women.\u000a    Ivermectin has long been used in mass treatment campaigns to control\u000a      onchocerciasis. However, when these treatment programmes were extended to\u000a      Cameroon, where a proportion of the target population is co-infected with\u000a      the eye worm Loa loa, there was an unacceptable number of severe,\u000a      sometimes fatal, adverse reactions including encephalopathy. Ivermectin is\u000a      no longer considered safe for mass treatment programmes where O\u000a        volvulus and L loa are co-endemic.\u000a    Taylor has led an African-European partnership, funded by six successive\u000a      European Framework contracts, to improve treatment and control of\u000a      onchocerciasis. Human epidemiological and immunological studies in\u000a      Cameroon, Ghana and Togo were combined with immunological studies in\u000a      animal models, and with parasite proteomics and genomics. Infections with\u000a      O volvulus cannot be established in mice, but Bain (Paris) and\u000a      Taylor demonstrated that the filariae Litomosoides sigmodonitis\u000a      could produce potent infections in mice and that the parasitological\u000a      presentations replicated those of the human parasites [3.1], leading the\u000a      way for detailed immunological investigations [e.g., 3.2, 3.3]. In\u000a      parallel, the partnership developed a bovine model using O ochengi\u000a      [3.4]. Both models were pivotal to the work underpinning and leading to\u000a      the trial of doxycycline.\u000a    In 2000, it was identified that O volvulus harbours the\u000a      endosymbiotic Gram-negative bacteria Wolbachia. This opened the\u000a      possibility of therapy with antibiotics, led directly to consortium\u000a      partners demonstrating the efficacy of tetracyclines in the O ochengi\u000a      bovine model [3.4] and, crucially, human studies in the field that\u000a      demonstrated similar efficacy [3.5].\u000a    These results took on far greater significance when it was discovered\u000a      that L loa does not possess Wolbachia. This raised the\u000a      prospect of using doxycycline to selectively target O volvulus in\u000a      patients co-infected with L loa previously at risk of\u000a      ivermectin-induced side effects.\u000a    Doxycycline treatment requires administration of the drug three times a\u000a      day for 6 weeks, which is difficult to achieve conventionally in remote\u000a      regions of developing countries. To overcome this, Taylor and colleagues\u000a      conducted a community-directed treatment trial of doxycycline in five\u000a      hyper-endemic areas of Cameroon [3.6]. The study communities identified\u000a      trusted individuals whom the group subsequently trained to diagnose\u000a      infection, dispense drugs and record treatment and any side effects\u000a      (carried out under the supervision of the Ministry of Health, Cameroon).\u000a      21,000 people were recruited and 12,936 individuals were treated with\u000a      doxycycline, giving a therapeutic coverage of the eligible population of\u000a      73.8% and a compliance rate of 97.5% at the end of six weeks. No serious\u000a      side effects were registered.\u000a    "},{"CaseStudyId":"23862","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"3017382","Name":"France"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Impact on clinical practice\u000a    The first clinical application of transplanted frozen ovarian tissue was\u000a      in Edinburgh in 1993 and this led to an explosion of interest and activity\u000a      in this field around the world. The first human live birth was reported in\u000a      2004 from Belgium [5.1], using a procedure that exactly replicated the one\u000a      first validated in Edinburgh.\u000a    Since 2008, ovarian cryopreservation has become widespread in clinical\u000a      practice world-wide, and the term `oncofertility' is now in general use to\u000a      describe this developing clinical specialty, linking fertility\u000a      preservation and cancer treatment. Major centres of expertise and national\u000a      programmes operate in Europe (Denmark, Belgium, France, Spain, Israel and\u000a      Germany) and elsewhere (US, Australia). Ovarian tissue cryopreservation is\u000a      now regarded as a standard of care in the UK and elsewhere.\u000a    Clinical practice recommendations were published by the American Society\u000a      of Clinical Oncology (and updated in 2013 [5.2]) — on which guideline\u000a      group Wallace was the only UK representative — and led to the rapid\u000a      development of the field in the US. Both Anderson and Wallace have been\u000a      keynote guest speakers at the Oncofertility Consortium, founded in 2008\u000a      with funding from the National Institutes of Health to establish US\u000a      clinical care pathways and promote research in fertility preservation and\u000a      now covering 50 centres across the US.\u000a    While most of the impact has been in adult oncology, prepubertal and\u000a      adolescent girls have made up approximately one third of the patients for\u000a      whom ovarian tissue has been stored in Edinburgh and UoE remains the only\u000a      centre in the UK offering this clinical service. The UoE contribution in\u000a      paediatric oncology is widely recognised internationally with centres in\u000a      France and Denmark (and probably elsewhere) now offering this clinically\u000a      (e.g., [5.3]) with the team's approach widely adopted as indicated by 347\u000a      citations of reference [3.3].\u000a    Impact on public policy\u000a    Anderson and colleagues' pioneering contribution in this field is\u000a      recognised in Scottish (Scottish Intercollegiate Guidelines Network\u000a      (SIGN), 2013), UK (National Institute for Health and Care Excellence,\u000a      2013), Europe, and US (American Society for Reproductive Medicine, 2008)\u000a      guideline documents [5.4-5.6], all of which cite the work of the Edinburgh\u000a      group. The importance of ovarian cryopreservation in girls is recognised\u000a      in the current SIGN guidance (2013), which states: `Cryopreservation of\u000a      ovarian tissue (within the context of a clinical trial) should be\u000a      considered in girls at high risk of premature ovarian insufficiency'\u000a      [5.5].\u000a    Anderson and Wallace were instrumental in establishing, and are key\u000a      members of, the International Society for Fertility Preservation (2009)\u000a      [5.7] and a task force for fertility preservation by the European Society\u000a      for Human Reproduction and Embryology (2010) [5.8], whose aims are to\u000a      develop ovarian tissue cryopreservation for much wider access to women\u000a      across Europe and worldwide.\u000a    In the UK, ovarian tissue storage requires a license from both the Human\u000a      Tissue Authority and the Human Fertilisation and Embryology Authority\u000a      (HFEA). The Tissue and Cells Directorate of the Scottish National Blood\u000a      Transfusion Service in Edinburgh is currently the only tissue bank in the\u000a      UK with these licenses, although other centres (Oxford, Southampton) are\u000a      developing this. The UoE team's interactions with the HFEA helped develop\u000a      the latter's approach.\u000a    Impact on health and welfare\u000a    The cryopreservation of ovarian tissue has now been performed in many\u000a      hundreds of women and girls, initially in Europe and subsequently in the\u000a      USA, Australia and South Africa. Despite the time lag required to ensure\u000a      survival from their cancer, ovarian tissue has now been replaced in 60\u000a      women in three leading European centres (Denmark, Belgium and Spain) and\u000a      more elsewhere, and has resulted in a rapidly growing number of babies.\u000a      Twenty-four babies have now been born in nine countries around the world\u000a      since 2008 (Belgium, Denmark, Spain, Israel, France, Italy, Germany, USA,\u000a      Australia) [5.9, 5.10] and an increasing number of successful pregnancies\u000a      and new centres are reported every year.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; policy and guidelines. Anderson and\u000a      colleagues demonstrated that cryopreservation of ovarian tissue could be\u000a      used for preservation of fertility following cancer therapy. This\u000a      step-change has been incorporated into guideline documents internationally\u000a      and has been adopted into clinical practice world-wide.\u000a    Significance: Ovarian tissue has been preserved from many hundreds\u000a      of women; this is now translating into a growing number of babies born\u000a      worldwide (currently 24 in nine countries).\u000a    Beneficiaries: Women at risk of fertility loss including\u000a      pre-pubertal girls newly diagnosed with cancer; clinicians; the NHS and\u000a      healthcare delivery organisations.\u000a    Attribution: The underpinning research was performed entirely at\u000a      UoE.\u000a    Reach: Worldwide: UK, Europe, US, Australia.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2637487","Name":"Southampton"}],"References":"\u000a    \u000a3.1 Gosden R, Baird D, Wade J, Webb R. Restoration of fertility to\u000a      oophorectomized sheep by ovarian autografts stored at -196°C. Hum Reprod.\u000a      1994;9:597-603. URL:\u000a        http:\/\/www.humrep.oxfordjournals.org\/content\/9\/4\/597.long\u000a    \u000a\u000a3.2 Baird D, Webb R, Campbell B, Harkness L, Gosden R. Long term ovarian\u000a      function in sheep after ovariectomy and transplantation of autografts\u000a      stored at -196°C. Endocrinology. 1999;140:462-71. DOI:\u000a      10.1210\/en.140.1.462.\u000a    \u000a\u000a3.3 Wallace W, Anderson R, Irvine D. Fertility preservation for young\u000a      patients with cancer: who is at risk and what can be offered? Lancet\u000a      Oncol. 2005;6:209-18. DOI: 10.1016\/S1470-2045(05)70092-9.\u000a    \u000a\u000a3.4 Anderson R, Wallace W, Baird D. Ovarian cryopreservation for\u000a      fertility preservation: indications and outcomes. Reproduction.\u000a      2008;136:681-9. DOI: 10.1530\/REP-08-0097.\u000a    \u000a\u000a3.5 Wallace W, Critchley H, Anderson R. Optimizing reproductive outcome\u000a      in children and young people with cancer. J Clin Oncol. 2012;30:3-5. DOI:\u000a      10.1200\/JCO.2011.38.3877.\u000a    \u000a\u000a3.6 Telfer E, McLaughlin M, Ding C, Thong K. A two step serum free\u000a      culture system supports development of human oocytes form primordial\u000a      follicles in the presence of activin. Hum Reprod. 2008;23:1151-8. DOI:\u000a      10.1093\/humrep\/den070.\u000a    \u000aExample Grant:\u000a    Telfer E, Anderson R, Thong, K. Activation of human ovarian follicles and\u000a      derivation of competent oocytes. MRC grant G0901839 July 2010 to Oct 2013;\u000a      £610,000.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a      5.1 Donnez J, Dolmans M, Demylle D, et al. Livebirth after orthotopic\u000a        transplantation of cryopreserved ovarian tissue. Lancet.\u000a        2004;364:1405-10. DOI: 10.1016\/S0140-6736(12)61172-6.\u000a      5.2 Loren A, Mangu P, Beck L, et al. Fertility preservation for patients\u000a        with cancer: American Society of Clinical Oncology clinical practice\u000a        guideline update. J Clin Oncol. 2013;31:2500-10. DOI:\u000a        10.1200\/JCO.2013.49.2678.\u000a      5.3 Poirot C, Abirached F, Prades M, Coussieu C, Bernaudin F, Piver P.\u000a        Induction of puberty by autograft of cryopreserved ovarian tissue.\u000a        Lancet. 2012;379:588. DOI: 10.1016\/S0140- 6736(11)61781-9.\u000a      5.4 NICE (2013): Assessment and treatment for people with fertility\u000a        problems. http:\/\/www.nice.org.uk\/nicemedia\/live\/14078\/62769\/62769.pdf.\u000a        [Makes fertility preservation part of UK mainstream care (section\u000a          1.16).]\u000a      5.5 SIGN 132 (2013). Long term follow up of survivors of childhood cancer.\u000a        http:\/\/www.sign.ac.uk\/pdf\/sign132.pdf.\u000a        Summarised by UoE authors in: Wallace W, Thompson L, Anderson R. Long\u000a        term follow-up of survivors of childhood cancer: summary of updated SIGN\u000a        guidance. BMJ. 2013;346:f1190. DOI: 10.1136\/bmj.f1190.\u000a      5.6 American Society for Reproductive Medicine (ASRM Committee Opinion No.\u000a        405: ovarian tissue and oocyte cryopreservation; 2008). Fertil Steril.\u000a        2008;90:S241-6. DOI: 10.1016\/j.fertnstert2008.08.039.\u000a      5.7 International Society for Fertility Preservation. http:\/\/www.isfp-fertility.org\/.\u000a      5.8 ESHRE Task Force in Fertility Preservation. http:\/\/www.eshre.eu\/Specialty-Groups\/Task-forces\/TF-Fertility-preservation.aspx.\u000a      5.9 Monash IVF, Australia (November 2012). \"Monash IVF announces first\u000a        pregnancy in Australia from ovarian tissue freezing\". http:\/\/monashivf.com\/first-pregnancy-in-australia-from-ovarian-tissue-freezing\/.\u000a      5.10 Donnez J, Dolmans M, Pellicer A, et al. Restoration of ovarian\u000a        activity and pregnancy after transplantation of cryopreserved ovarian\u000a        tissue: a review of 60 cases of reimplantation. Fertil Steril.\u000a        2013;99:1503-13. DOI: 10.1016\/j.fertnstert2013.03.030.\u000a    ","Title":"\u000a    H: Ovarian cryopreservation can restore fertility in women following\u000a        cancer treatment that would otherwise irreversibly deny them children\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professors Richard Anderson (UoE, 1994-1997, Professor of Clinical\u000a      Reproductive Science, 2005-present), David Baird (Professor of\u000a      Reproductive Endocrinology, UoE, 1977-2000; now Emeritus) and W Hamish\u000a      Wallace (Honorary Professor of Paediatric Oncology, UoE, 2007-present)\u000a      were the first to show that ovarian tissue obtained laparoscopically could\u000a      be cryopreserved and used for fertility preservation in the context of\u000a      cancer therapy; leading ultimately to successful conception. This is a\u000a      step-change of profound significance to female survivors of cancer therapy\u000a      who would otherwise face a childless future.\u000a    The current use of cryopreservation of ovarian tissue to restore\u000a      fertility in women following cancer can be traced directly to the studies\u000a      carried out in Edinburgh by Dr Roger Gosden (Reader in Physiology, UoE,\u000a      1976-1994), Baird and colleagues using sheep as a model for human ovarian\u000a      function. The first publication of this approach in 1994 [3.1]\u000a      demonstrated that spontaneous ovarian cycles and fertility could be\u000a      restored by autotransplantation of ovarian cortex. Subsequent studies\u000a      (1994-1999) by Baird [3.2] investigated the long-term function of\u000a      frozen\/thawed grafts up to 2 years after auto-transplantation,\u000a      highlighting the survival of primordial oocytes as key to success. This\u000a      procedure was introduced into clinical practice in Edinburgh in\u000a      collaboration with the Tissue Services directorate of Scottish National\u000a      Blood Transfusion Service (SNBTS) in 1997: the first clinical application\u000a      of this in the world.\u000a    Anderson, Baird and Wallace first demonstrated that this procedure using\u000a      minimally invasive laparoscopic surgery is also appropriate in\u000a      pre-pubertal girls and introduced this into clinical practice in a\u000a      research-based programme approach and decade-long case experience\u000a      described in [3.3, 3.4]. Their approach and criteria for patient selection\u000a      [3.3, 3.5] set an international standard.\u000a    Restoration of fertility by replacement of cryopreserved ovarian tissue\u000a      is not always appropriate, particularly if there are safety concerns\u000a      regarding malignant contamination of the tissue. This requires the\u000a      development of techniques for in vitro growth of early human ovarian\u000a      follicles, which has been pioneered by Professor Evelyn Telfer (Professor\u000a      of Reproductive Biology, UoE, 1992-present) and colleagues since 2005\u000a      [3.6]. Recent developments have demonstrated that follicles can be grown\u000a      from primordial stages right through to large antral stages, with oocytes\u000a      then matured further in vitro to metaphase II of meiosis (i.e., to a stage\u000a      at which they can be fertilised). This multi-stage protocol is\u000a      world-leading (reflected in numerous invitations of the researchers to\u000a      international meetings) and is being developed further with £610K MRC\u000a      funding. Safety in all aspects of assisted reproduction remains a key\u000a      concern: Wallace and colleagues recently demonstrated that children born\u000a      from assisted conception are not at increased risk of childhood cancer.\u000a    "},{"CaseStudyId":"23863","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"660013","Name":"Finland"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    The work performed at the MRC Human Genetics Unit created the foundations\u000a      of OPT and\u000a      demonstrated the enormous potential of this technique in the biomedical\u000a      sciences. Huge interest\u000a      associated with the original publication (front cover of \"Science\"\u000a      magazine and over 400 citations in\u000a      the scientific literature [ISI Web of Knowledge]), together with the\u000a      patents secured, rapidly\u000a      translated into successful commercialisation and world-wide popularisation\u000a      of this new technology.\u000a    Impact on commerce\u000a      In response to the discovery of OPT, MRC Technology — the exclusive\u000a      technology transfer agent\u000a      for the UK's Medical Research Council — formed MRCT Bioptonics. MRCT\u000a      Bioptonics was\u000a      responsible for the promotion and licencing of OPT technology, the\u000a      manufacturing and distribution\u000a      of OPT equipment and the provision of OPT scanning services [5.1, 5.2].\u000a      Five people in full-time\u000a      employment managed the development and marketing of OPT between 2008 and\u000a      2012. In\u000a      addition, a significant part of the manufacturing work was outsourced to\u000a      the Belgian company\u000a      SkyScan (employment figures unavailable; SkyScan was acquired in 2012 by\u000a      Bruker Corporation\u000a      adding ~$13M to Bruker's annual revenue [5.3]). In 2006, MRCT Bioptonics\u000a      developed a\u000a      commercial OPT scanner, the OPT 3001. Since January 2008, more than 30\u000a      instruments have\u000a      been sold to multiple countries around the world including in the UK, USA,\u000a      Canada, Sweden,\u000a      Finland and Switzerland. During this period, MRCT Bioptonics staff\u000a      provided specialist training in\u000a      the use of OPT technology to approximately 50 users from multiple\u000a      countries including the UK,\u000a      USA, Spain, Singapore, Canada, and Germany. The sales figures for MRCT\u000a      Bioptonics in the\u000a      period 2008-2012 were as follows: £775,129 (financial year 2008-9),\u000a      £523,736 (financial year\u000a      2009-10), £194,977 (financial year 2010-11) and £773,054 (financial year\u000a      2011-12) [5.2].\u000a    In addition, in November 2008, the MRC licenced OPT technology to a major\u000a      international\u000a      microscopy manufacturer (name withheld because of a confidentiality\u000a      agreement). Three of the\u000a      patents are licensed to this company for further development and\u000a      manufacture [5.2].\u000a    MRC and MRC Technology have also invested in OPT's potential use in\u000a      pathology diagnostics. As\u000a      a pilot, they have developed a sponsored collaboration of £190,000 with\u000a      the University of Dundee,\u000a      NHS Tayside and Oxford University to investigate OPT use in the diagnosis\u000a      of colonic polyps [5.2].\u000a    Impact on professional services\u000a      Chapters on OPT are now a standard part of major international microscopy\u000a      textbooks [5.4] and\u000a      OPT technology was a feature at the EMBO Practical Course on 3D\u000a      developmental imaging in\u000a      2009 and 2010 [5.5]. OPT instruments are available at scientific\u000a      institutions in multiple countries\u000a      and have become a routine service offered by their imaging facilities [5.6\u000a      a-e]. It is difficult to\u000a      estimate the number of people using OPT on regular basis but it must be\u000a      substantial judged by the\u000a      number of OPT-based publications available in the public domain (over 100\u000a      papers are listed on\u000a      the MRCT Bioptonics web-site alone; two of the Wellcome Image awards in\u000a      2011 were given for\u000a      images produced using OPT [5.1]).\u000a    In April 2012, the International Mouse Phenotyping Consortium (IMPC)\u000a      workshop supported by the\u000a      European Union's InfraCoMP programme agreed on a common strategy to\u000a      undertake phenotyping\u000a      of embryonic lethal lines. The IMPC aims to create 20,000 knockout mouse\u000a      strains over the next\u000a      ten years and it is estimated that at least 30% of all these strains will\u000a      die during the embryonic or\u000a      perinatal periods. The IMPC listed OPT as one of the leading 3D imaging\u000a      techniques considered\u000a      for high-throughput screening of embryonic phenotypes in its Bloomsbury\u000a      report on mouse embryo\u000a      phenotyping [5.7]. OPT is already used in several other \"atlas-type\"\u000a      projects including EMAP - the\u000a      e-Mouse Atlas Project [5.8], the Interactive 3D Mouse Limb Anatomy Atlas\u000a      [5.9] and the e-Chick\u000a      Atlas of Gene Expression [5.10].\u000a    ","ImpactSummary":"\u000a    Impact: Commerce and professional services; the development of\u000a      Optical Projection Tomography\u000a      (OPT) — a technique for three-dimensional (3D) optical microscopy.\u000a    Significance: A step-change in scientific imaging; novel equipment\u000a      and training services for\u000a      imaging laboratories, offering a new standard in 3D microscopy. Over £2M\u000a      in sales for the MRC.\u000a    Beneficiaries: Scientific institutions and imaging facilities,\u000a      commerce.\u000a    Attribution: OPT was developed, by Sharpe, Baldock and Davidson,\u000a      and commercialised at the\u000a      MRC Human Genetics Unit, UoE.\u000a    Reach: World-wide: OPT instruments are used in Europe, America,\u000a      Asia and Australia; chapters\u000a      on OPT can be found in major microscopy textbooks.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"}],"References":"\u000a    \u000a3.1 Sharpe J, Ahlgren U, Perry P,...Davidson D. Optical projection\u000a      tomography as a tool for 3D\u000a      microscopy and gene expression studies. Science. 2002;296:541-545. DOI:\u000a      10.1126\/science.1068206.\u000a    \u000a\u000a3.2 Kerwin J, Scott M, Sharpe J, et al. 3 dimensional modelling of early\u000a      human brain\u000a      development using optical projection tomography. BMC Neurosci. 2004;5:27.\u000a      DOI: 10.1186\/1471-\u000a      2202-5-27.\u000a    \u000a\u000a3.3 McGurk L, Morrison H, Keegan L, Sharpe J, O'Connell M.\u000a      Three-dimensional imaging of\u000a      Drosophila melanogaster. PLoS One. 2007;2:e834. DOI:\u000a      10.1371\/journal.pone.0000834.\u000a    \u000a\u000a3.4 Boot M, Westerberg C, Sanz-Ezquerro J,...Sharpe J. In vitro\u000a      whole-organ imaging: 4D\u000a      quantification of growing mouse limb buds. Nat Methods. 2008;5:609-12.\u000a      DOI:\u000a      10.1038\/nmeth.1219.\u000a    \u000a3.5 Patent applications resulting from the work described, which were\u000a      filed under the Patent\u000a      Cooperation Treaty (PCT) scheme: PCT\/GB02\/02373, PCT\/03\/002570,\u000a      PCT\/03\/003726,\u000a      PCT\/GB03\/003746.\u000a    3.6 Examples of patents already granted for OPT technologies [available\u000a      on request]:\u000a       • \"Optical imaging apparatus and associated specimen support means\".\u000a        Europe, grant number\u000a        1530073, grant year 2007. USA, grant number 7,218,393, grant year 2007.\u000a        Japan, grant\u000a        number 4308535, grant year 2009. Australia, grant number 2002256798,\u000a        grant year 2002.\u000a        Canada, grant number 2,445,780, grant year 2010.\u000a      • \"Laser scanning OPT system\". China, grant number ZL03818363.3, grant\u000a        year 2009.\u000a      • \"Treatment of tissue specimens\". Europe, grant number 1516183, grant\u000a        year 2007. USA,\u000a        grant number 7677197, grant year 2010. Japan, grant number 4129456,\u000a        grant year 2008.\u000a        Australia, grant number 2003280409, grant year 2008. Formal title: \"Non\u000a        focal optics for OPT\u000a        system\". Europe, grant number 1520173, grant year 2003. USA, grant\u000a        number\u000a        US8014063B2, grant year 2011. China, grant number ZL03818574.1, grant\u000a        year 2009.\u000a    ","ResearchSubjectAreas":[{"Level1":"2","Level2":"99","Subject":"Other Physical Sciences"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"}],"Sources":"\u000a    5.1 MRCT Bioptonics web-site. http:\/\/www.bioptonics.co.uk\/.\u000a    5.2 Letter from MRC Technology. [Available on request. The letter\u000a        provides information about the\u000a        production of OPT equipment and training provided by MRCT Bioptonics. It\u000a        also confirms the\u000a        sales, employment figures and licencing of OPT technology to a major\u000a        international manufacturer.]\u000a    5.3 \"Bruker announces acquisition of SkyScan\", news release from Bruker\u000a      Corp., 2 Apr 2012.\u000a      http:\/\/ir.bruker.com\/phoenix.zhtml?c=121496&p=irol-newsArticle&ID=1678843&highlight.\u000a    5.4 Examples of international microscopy textbooks containing chapters on\u000a      OPT [available on\u000a      request]:\u000a    \u000a      Molecular Imaging: Principles and Practice. Editors: Weissleder R,\u000a        Ross B,\u000a        Rehemtulla A, Gambhir S. PMPH-USA, 2010.\u000a      Advanced Imaging in Biology and Medicine. Editors: Sensen C,\u000a        Hallgrimsson B.\u000a        Springer, 2009.\u000a    \u000a    5.5 Research Changes Lives. 2009-2014 mid-term update on progress against\u000a      objectives. Medical\u000a      Research Council report, July 2012. http:\/\/mrcblogs.helpfulclients.com\/comment\/files\/2012\/11\/Mid-term-progress-reA33730.pdf.\u000a    5.6 Examples of imaging facilities that offer OPT as a service:\u000a    a) University College London (UCL) Centre for Advanced Biomedical\u000a      Imaging, UK.\u000a      http:\/\/www.ucl.ac.uk\/cabi\/imaging\/imaging_techniques\/opt.\u000a    b) Medical Center at Erasmus University, Holland, Applied Molecular\u000a      Imaging Erasmus\u000a      MC (AMIE). http:\/\/www.erasmusmc.nl\/amie\/instrumentation\/opt\/?lang=en.\u000a    c) Institute of Translational Health Sciences, Washington State\u000a      University, USA, Small\u000a      Animal Tomographic Analysis Facility (SANTA). https:\/\/www.iths.org\/resource-centers\/small-animal-tomographic-analysis-facility-santa-0.\u000a    d) Institute of Development, Aging and Cancer, Tohoku University, Japan,\u000a      Center of\u000a      Research Instruments.\u000a      http:\/\/www.idac.tohoku.ac.jp\/en\/activities\/research\/common_ic\/.\u000a    e) Singapore Bioimaging Consortium, Singapore. http:\/\/www.sbic.a-star.edu.sg\/resources\/equipment.php#.\u000a    5.7 Adams D, Baldock R, Bhattacharya S, et al. Bloomsbury report on mouse\u000a      embryo phenotyping:\u000a      recommendations from the IMPC workshop on embryonic lethal screening. Dis\u000a      Model Mech. 2013;\u000a      6:571-579. DOI: 10.1242\/dmm.011833.\u000a    5.8 e-Mouse Atlas Project. http:\/\/www.emouseatlas.org\/emap\/home.html.\u000a    5.9 Interactive 3D Mouse Limb Anatomy Atlas. http:\/\/www.nimr.mrc.ac.uk\/3dlimb.\u000a    5.10 e-Chick Atlas of Gene Expression. http:\/\/www.echickatlas.org\/ecap\/home.html.\u000a    \u000a    ","Title":"\u000a    U: Invention, licensing and commercialisation of optical projection\u000a        tomography microscopy\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Scientists at the MRC Human Genetics Unit, UoE, (Director Professor Nick\u000a      Hastie FRS, 1994-\u000a      present) — Dr James Sharpe (Postdoctoral Fellow, 1998-2006), Professor\u000a      Richard Baldock\u000a      (Professor of Biomedical Systems Analysis, 1986-present) and Dr Duncan\u000a      Davidson (Biomedical\u000a      Systems Analyst, 1964-2010) — developed the OPT microscopy technique,\u000a      which represented a\u000a      step-change in biomedical scientific imaging.\u000a    Optical microscopy has contributed enormously to progress in science and\u000a      technology and it is fair\u000a      to say that the current state of biomedical research could never have been\u000a      achieved without the\u000a      availability of different types of microscopes. Despite more than four\u000a      hundred years of history,\u000a      optical microscopy continues to evolve. One of the clear challenges for\u000a      microscopy in the\u000a      postgenomic era is efficient mapping of gene expression patterns into 3D\u000a      tissue descriptions.\u000a    When Sharpe joined the MRC Human Genetics Unit, UoE, in 1998 to work as a\u000a      postdoctoral fellow\u000a      with Baldock and Davidson, 3D optical imaging could be achieved using\u000a      deconvolution, confocal\u000a      microscopy and optical coherence tomography. None of these techniques\u000a      allowed imaging of intact\u000a      specimens to depths greater than 1-3 mm. A non-optical technique, magnetic\u000a      resonance imaging,\u000a      allowed visualisation to greater depths, but its complexity and expense\u000a      combined with its inability\u000a      to image commonly used coloured and fluorescent dyes made it unsuitable\u000a      for general application.\u000a    With these limitations in mind, between August 1998 and November 2001,\u000a      Sharpe, Davidson and\u000a      Baldock conceived and developed a completely novel microscopy technique,\u000a      Optical Projection\u000a      Tomography (OPT) microscopy, to produce high-resolution 3D images of both\u000a      fluorescent and\u000a      non-fluorescent biological specimens with a thickness of up to 15 mm. The\u000a      technique was used to\u000a      analyse the expression of mRNA for the Sox9 gene in a whole mouse\u000a      embryo, and to identify new\u000a      phenotypic abnormalities in Bapx1 (Nkx3.2)-null mice. OPT was described\u000a      for the first time in a\u000a      seminal paper in Science in April 2002 [3.1]. Subsequently, Sharpe and\u000a      colleagues at the MRC\u000a      Human Genetics Unit have applied this technique in many other biological\u000a      settings, for example to\u000a      image the human embryo and detect structures within the nervous system\u000a      without the use of\u000a      markers (2004) [3.2], to provide 3D imaging of the fruit fly Drosophila\u000a        melanogaster (2007) [3.3]\u000a      and to perform quantitative mapping of the normal tissue dynamics of an\u000a      entire developing\u000a      mammalian organ (2008) [3.4].\u000a    In parallel to academic development, several patent applications were\u000a      filed between May 2002 and\u000a      January 2005 [3.5]. Patents for OPT and associated technologies were\u000a      granted between 2002 and\u000a      2011 in a wide range of countries (including the US, Europe, China,\u000a      Australia, Canada and Japan),\u000a      facilitating commercialization [3.6].\u000a    "},{"CaseStudyId":"23864","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Impact on health and welfare and clinical services\u000d\u000a      Below, three groups of genetic disorders identified and characterised by\u000d\u000a      UoE researchers, and their specific impact on aspects of clinical\u000d\u000a      management\/service, are described in greater detail. Although rare,\u000d\u000a      inherited developmental disorders are distributed across the world and are\u000d\u000a      devastating for patients and their families. Crucially, the identification\u000d\u000a      of causative mutations permits effective genetic counselling: a\u000d\u000a      cornerstone of the family management of each of these disorders. UoE\u000d\u000a      research findings have directly resulted in the availability of clinical\u000d\u000a      tests (including some offered in-house, see below) to clarify genetic risk\u000d\u000a      and have enabled diagnostic and\/or prenatal testing for these devastating\u000d\u000a      disorders.\u000d\u000a    Genetic testing and pre-natal screening - eye disorders:\u000d\u000a      Developmental eye disorders occur in approximately five per 10,000 live\u000d\u000a      births and are responsible for around 25% of severe visual impairments in\u000d\u000a      childhood. Diagnosis of the primary ocular disorder may be self-evident,\u000d\u000a      but >50% of cases manifest distinct systemic abnormalities, such as\u000d\u000a      developmental delay, kidney or heart defects and cleft lip or palate. A\u000d\u000a      full diagnosis including identification of causative genetic abnormalities\u000d\u000a      is essential to define the visual potential of the child, inform the\u000d\u000a      counselling of the parents and establish prospective management, including\u000d\u000a      the possible need for special educational placement, with respect to the\u000d\u000a      long-term prognosis.\u000d\u000a    Tests for mutations in the SOX2, OTX2 and PAX6\u000d\u000a      genes are now offered by multiple labs in the UK and internationally\u000d\u000a      including the USA, Germany, France, Denmark and Switzerland [5.1].\u000d\u000a      Prenatal genetic testing for anomalies in these genes (that allows\u000d\u000a      informed decision on pregnancy) is offered by some laboratories, e.g.,\u000d\u000a      GeneDx in the USA. Tests for STRA6, NF1 and SMOC1\u000d\u000a      gene abnormalities are available in the UK and internationally [5.1].\u000d\u000a    Molecular diagnosis informing effective clinical management and\u000d\u000a        counselling - childhood-onset neurological disease: CMT is one of\u000d\u000a      the most common inherited neurological disorders affecting approximately 1\u000d\u000a      in 2,500 people, equating to approximately 23,000 people in the UK and\u000d\u000a      125,000 people in the USA. While Aicardi-Goutières syndrome represents a\u000d\u000a      rarer disorder, together, these conditions demonstrate the distinct ways\u000d\u000a      in which clinical diagnosis can be facilitated by accurate genetic\u000d\u000a      testing. Both conditions are incurable and early diagnosis is instrumental\u000d\u000a      for clinical management and counselling. Genetic testing for causative\u000d\u000a      mutations is important in CMT because it does not represent a single\u000d\u000a      disorder, but a group of conditions that are superficially clinically\u000d\u000a      similar, but with widely differing modes of inheritance and penetrance.\u000d\u000a      Effective genetic counselling has only become possible with the\u000d\u000a      application of genetic testing [5.2]. In contrast, Aicardi-Goutières\u000d\u000a      syndrome poses a rather different clinical challenge, as it phenocopies\u000d\u000a      congenital viral infections such as CMV, rubella and transplacentally\u000d\u000a      acquired HIV. Given the substantial risk of recurrence in subsequent\u000d\u000a      pregnancies, molecular diagnosis of Aicardi-Goutières syndrome is\u000d\u000a      essential for counselling and also key to the provision of prenatal\u000d\u000a      diagnosis in subsequent pregnancies.\u000d\u000a    Tests for mutations in TREX1, RNASEH2A, RNASEH2B,\u000d\u000a      RNASEH2C (Aicardi-Goutières syndrome) and PRX (CMT) are\u000d\u000a      offered in several countries including the UK, USA, Germany, Spain,\u000d\u000a      Austria, France and Italy [5.1].\u000d\u000a    Genetic testing to establish effective prospective management - growth\u000d\u000a        syndromes: Primordial dwarfism is a rare disorder resulting in\u000d\u000a      extreme pre- and postnatal growth failure, such that people with this\u000d\u000a      group of conditions are often described as `the smallest people in the\u000d\u000a      world'. The identification of the genetic basis has had a significant\u000d\u000a      impact on clinical management. In particular, it has helped to define\u000d\u000a      those with resulting syndromes who are at risk of insulin-resistant\u000d\u000a      diabetes mellitus, and of neurovascular complications, enabling specific\u000d\u000a      targeting of appropriate surveillance [5.3].\u000d\u000a    Tests for mutations in primordial dwarfism genes are available in the UK,\u000d\u000a      USA and the Netherlands [5.1]. In the UK they are offered directly by\u000d\u000a      Jackson's laboratory, and since 2008 Jackson's lab has performed molecular\u000d\u000a      gene testing on over 400 patients from 35 countries worldwide.\u000d\u000a    Impact on policy and guidelines\u000d\u000a      In the report \"Genetic ophthalmology in focus: a needs assessment and\u000d\u000a      review of specialist services for genetic eye disorders\" published in\u000d\u000a      April 2008 (to which FitzPatrick and van Heyningen contributed), the\u000d\u000a      Foundation for Genomics and Population Health indicated how NHS\u000d\u000a      ophthalmology services needed to change in response to the opportunities\u000d\u000a      offered by genetic science. The foundation placed mutation detection in\u000d\u000a      severe developmental eye disorders on the list of main gaps and perceived\u000d\u000a      priorities for testing [5.4]. This report has had major impact on UK\u000d\u000a      Government policy: for example, it was analysed by the House of Lords'\u000d\u000a      Science and Technology Committee in 2008-2009 [5.5], leading to new\u000d\u000a      recommendations and improved services. Notably, van Heyningen was an\u000d\u000a      expert witness to the Committee on April 30th, 2008 [5.5].\u000d\u000a    Impact on society and public engagement\u000d\u000a      Genetic testing is recommended by diverse societies and organisations and\u000d\u000a      is promoted on their websites, e.g., the International Children's\u000d\u000a      Anophthalmia Network [5.6]. In addition, because people with primordial\u000d\u000a      dwarfism are among the shortest people in the world, this small group has\u000d\u000a      a disproportionately large impact on public engagement with developmental\u000d\u000a      disorders. Primordial dwarfism and its genetic causes have been discussed\u000d\u000a      in several high-profile television documentaries that generated huge\u000d\u000a      public interest, e.g., \"The Tiniest Boy in Britain\" (2011) and \"21 and 3ft\u000d\u000a      tall\" (2013). Notably, the latter included an interview with Jackson and\u000d\u000a      describes research in his lab [5.7].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and welfare; policy and guidelines; public\u000d\u000a      engagement. The identification of >20 genes linked to human\u000d\u000a      developmental and childhood degenerative disorders.\u000d\u000a    Significance: Definitive diagnosis is essential for genetic\u000d\u000a      counselling, prenatal screening and postnatal management.\u000d\u000a    Beneficiaries: People with developmental disorders and their\u000d\u000a      families, prospective parents, the NHS and healthcare delivery\u000d\u000a      organisations; public understanding of genetic disorders.\u000d\u000a    Attribution: Researchers from UoE identified\/characterised all the\u000d\u000a      genes described, and their mutation in disease.\u000d\u000a    Reach: Worldwide: these developmental disorders affect thousands\u000d\u000a      of people. Genetic tests established as a result of the research are\u000d\u000a      provided for people from 35 countries on all continents.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    The references below represent selected examples from the large body of\u000d\u000a      published work.\u000d\u000a    \u000a3.1 Fantes J, Ragge N, Lynch S,...van Heyningen V, FitzPatrick D.\u000d\u000a      Mutations in SOX2 cause anophthalmia. Nat Genet. 2003;33:461-3. DOI:\u000d\u000a      10.1038\/ng1120.\u000d\u000a    \u000a\u000a3.2 Ragge N, Brown A, Poloschek C,...Fitzpatrick D, van Heyningen V,\u000d\u000a      Hanson I. Heterozygous mutations of OTX2 cause severe ocular\u000d\u000a      malformations. Am J Hum Genet. 2005;76:1008-22. DOI: 10.1086\/430721.\u000d\u000a    \u000a\u000a3.3 Sisodiya S, Free S, Williamson K,...van Heyningen V. PAX6\u000d\u000a      haploinsufficiency causes cerebral malformation and olfactory dysfunction\u000d\u000a      in humans. Nat Genet. 2001;28:214-6. DOI: 10.1038\/90042.\u000d\u000a    \u000a\u000a3.4 Bicknell L, Bongers E, Leitch A,...Jackson A. Mutations in the\u000d\u000a      pre-replication complex cause Meier-Gorlin syndrome. Nat Genet.\u000d\u000a      2011;43:356-9. DOI: 10.1038\/ng.775.\u000d\u000a    \u000a\u000a3.5 Crow Y, Leitch A, Hayward B,...Jackson A. Mutations in genes encoding\u000d\u000a      ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic\u000d\u000a      congenital viral brain infection. Nat Genet. 2006;38:910-6. DOI:\u000d\u000a      10.1038\/ng1842.\u000d\u000a    \u000a\u000a3.6 Guilbot A, Williams A, Ravisé N,... Brophy P, et al. A mutation in\u000d\u000a      periaxin is responsible for CMT4F, an autosomal recessive form of\u000d\u000a      Charcot-Marie-Tooth disease. Hum Mol Genet. 2001;10:415-21. DOI:\u000d\u000a      10.1093\/hmg\/10.4.415.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    5.1 Example lists of multiple laboratories from up to 12 countries\u000d\u000a      providing genetic tests for the genes mentioned in the text. http:\/\/www.orpha.net\/consor\/cgi-bin\/index.php\u000d\u000a      (under: directory of medical laboratories providing diagnostic tests).\u000d\u000a      Further examples can be found at http:\/\/www.ncbi.nlm.nih.gov\/gtr\/tests\/.\u000d\u000a    5.2 Siskind C, Panchal S, Smith C, et al. A review of genetic counselling\u000d\u000a      for Charcot Marie Tooth disease (CMT). J Genet Couns. 2013;22:422-36. DOI:\u000d\u000a      10.1007\/s10897-013-9584-4.\u000d\u000a    5.3 Semple R, Savage D, Cochran E, et al. Genetic syndromes of severe\u000d\u000a      insulin resistance. Endocr Rev. 2011;32:498-514. DOI:\u000d\u000a      10.1210\/er.2010-0020.\u000d\u000a    5.4 Foundation for Genomics and Population Health (PHG Foundation) report\u000d\u000a      (April 2008). \"Genetic ophthalmology in focus: a needs assessment and\u000d\u000a      review of specialist services for genetic eye disorders\". http:\/\/www.phgfoundation.org\/file\/4199.\u000d\u000a    5.5 Genomic medicine: 2nd report of session 2008-2009, Volume II:\u000d\u000a      Evidence. Great Britain Parliament, House of Lords, Science and Technology\u000d\u000a      Committee. http:\/\/www.publications.parliament.uk\/pa\/ld200809\/ldselect\/ldsctech\/107\/107ii.pdf.\u000d\u000a    5.6 International Children's Anophthalmia Network website. http:\/\/www.anophthalmia.org\/diagnosis\/.\u000d\u000a    5.7 Daily Mail online (2nd July 2013). \"Aged 21 but just 35\u000d\u000a      inches tall: The man with a rare form of dwarfism which makes him the size\u000d\u000a      of a three-year-old\". http:\/\/www.dailymail.co.uk\/health\/article-2353418\/Nick-Smith-The-man-rare-form-dwarfism-makes-size-year-old.html.\u000d\u000a      [Article about the Channel 5 documentary.]\u000d\u000a    ","Title":"\u000d\u000a    G: Diagnosis from gene discovery - developmental disorders of eye,\u000d\u000a        brain, nerve and skeleton\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The development of genetic tests to underpin accurate diagnosis, genetic\u000d\u000a      counselling and prospective management in developmental disorders\u000d\u000a      represents a major translational focus for the MRC Human Genetics Unit\u000d\u000a      (HGU) within UoE.\u000d\u000a    Developmental disorders are significant clinical problems that result\u000d\u000a      from perturbation of embryogenesis or early brain development. At least 3%\u000d\u000a      of live-born babies have a developmental disorder that will have a\u000d\u000a      deleterious impact on their life. The majority of these disorders are\u000d\u000a      genetically determined. An understanding of developmental disorders, which\u000d\u000a      is critical for adequate diagnosis, prognosis and management, requires\u000d\u000a      both knowledge of the genes involved and how the gene products function as\u000d\u000a      effectors of the specific developmental processes. The identification and\u000d\u000a      characterisation of these monogenic disorders exemplifies well the wide\u000d\u000a      range of impacts that result from apparently \"basic\" research.\u000d\u000a    Scientists from the MRC HGU, including Professors David FitzPatrick\u000d\u000a      (Programme Leader, UoE, 2000-present), Veronica van Heyningen (Programme\u000d\u000a      Leader, UoE, 1977-2012; now Emeritus), Andrew Jackson (Programme Leader,\u000d\u000a      UoE, 2005-present) and Peter Brophy (Professor of Anatomy, UoE,\u000d\u000a      1995-present) have directly contributed to the identification and\u000d\u000a      functional characterisation of more than 20 genes associated with human\u000d\u000a      developmental and degenerative disorders. Key examples include:\u000d\u000a    Eye: Between 2000 and 2012, FitzPatrick and van Heyningen\u000d\u000a      identified abnormalities in the SOX2, OTX2, PAX6,\u000d\u000a      STRA6, NF1 and SMOC1 genes as the causes of serious\u000d\u000a      human eye malformations, notably anophthalmia (absent eye), microphthalmia\u000d\u000a      (small eye) and coloboma (failure of optic fissure closure) [e.g., 3.1,\u000d\u000a      3.2]. van Heyningen linked haploinsufficiency of PAX6 to cerebral\u000d\u000a      malformation and olfactory dysfunction (2001) [3.3] and FitzPatrick\u000d\u000a      identified SATB2 as the cleft palate gene (2003). FitzPatrick\u000d\u000a      undertook studies that showed the causative role of mutations in DHCR24\u000d\u000a      in desmosterolosis, an autosomal recessive disorder of cholesterol\u000d\u000a      biosynthesis (2001) and in studies that associated disruption of the ST5\u000d\u000a      gene with mental retardation and multiple congenital anomalies (2010).\u000d\u000a    Skeleton: More recently, FitzPatrick's work has led to the\u000d\u000a      identification of mutations in CEP57 that cause mosaic variegated\u000d\u000a      aneuploidy syndrome (2011), the discovery that gain-of-function mutations\u000d\u000a      in ARHGAP31, a Cdc42\/Rac1 GTPase regulator, cause syndromic cutis\u000d\u000a      aplasia and limb anomalies (2011), and that a rare intragenic deletion\u000d\u000a      within the region encoding the NIPBL protein is associated with atypical\u000d\u000a      facial appearance and growth pattern in Cornelia de Lange Syndrome (2012).\u000d\u000a    Brain: The work of Jackson since 2005 has been essential to the\u000d\u000a      identification of seven microcephalic primordial dwarfism genes (ORC1,\u000d\u000a      ORC4, ORC6, CDT1, CDC6, PCNT and CEP152)\u000d\u000a      that regulate organism size and cerebral cortex volume [e.g., 3.4].\u000d\u000a      Jackson and colleagues also showed that mutations in genes encoding the\u000d\u000a      DNA exonuclease TREX1 and ribonuclease H2 subunits (RNASEH2A, RNASEH2B,\u000d\u000a      RNASEH2C) cause Aicardi-Goutières syndrome, a congenital immune-mediated\u000d\u000a      neurodevelopmental disorder [e.g., 3.5].\u000d\u000a    Nerve: Brophy and colleagues discovered that a mutation in PRX,\u000d\u000a      encoding periaxin, is responsible for a form of Charcot-Marie-Tooth (CMT)\u000d\u000a      disease, a disorder of the peripheral nervous system characterised by\u000d\u000a      progressive loss of muscle tissue and touch sensation (2001) [3.6].\u000d\u000a    "},{"CaseStudyId":"23865","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"1227603","Name":"Sri Lanka"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Impact on public policy\u000d\u000a      Eddleston's work has had a profound impact on WHO policies regarding world\u000d\u000a      pesticide-related\u000d\u000a      poisoning avoidance and treatment. The pralidoxime study led the WHO to\u000d\u000a      exclude pralidoxime\u000d\u000a      from its Essential Drugs List in 2009; high-dose regimens of pralidoxime\u000d\u000a      are no longer\u000d\u000a      recommended [5.1, 5.2]. In addition, 2009 WHO guidance about how to\u000d\u000a      prevent deaths from\u000d\u000a      pesticide poisoning [5.3] was heavily based on Eddleston's work: all six\u000d\u000a      publications cited in its\u000d\u000a      summary were from the Eddleston group. A 2008 WHO meeting led by Eddleston\u000d\u000a      resulted in\u000d\u000a      publication of guidance for triaging and treating patients with acute\u000d\u000a      pesticide poisoning [5.4]. The\u000d\u000a      WHO Mental Health Gap Action Programme (mhGAP) thereafter in 2008\u000d\u000a      integrated pesticide\u000d\u000a      poisoning into its assessment of patients [5.5].\u000d\u000a    In addition to the changes in WHO recommendations relating to\u000d\u000a      pralidoxime, Eddleston's work led\u000d\u000a      directly to national bans in Sri Lanka of fenthion, dimethoate and\u000d\u000a      paraquat (2008) [5.6].\u000d\u000a    These interventions, and particularly the three pesticide bans, have been\u000d\u000a      estimated to save 1000\u000d\u000a      lives per year in that country alone [5.7].\u000d\u000a    Impact on clinical practice and guidelines\u000d\u000a      Guidance concerning treatment of OP-poisoned patients has now changed\u000d\u000a      across Asia (for\u000d\u000a      example, 2010 national guidelines for Indian clinicians [5.8] demonstrate\u000d\u000a      by citation the importance\u000d\u000a      of Eddleston's work).\u000d\u000a    In summary, based on 250,000 deaths from pesticide self-poisoning across\u000d\u000a      Asia per year,\u000d\u000a      Eddleston and colleagues' findings on the use of atropine, pralidoxime and\u000d\u000a      charcoal, and the bans\u000d\u000a      of three toxic pesticides in Sri Lanka, are estimated to be saving\u000d\u000a      approximately 10,000 lives per\u000d\u000a      year on this continent.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and welfare; public health studies in Sri Lanka and\u000d\u000a      clinical trials in a cohort of\u000d\u000a      35,000 pesticide self-poisoning patients have led to the withdrawal of\u000d\u000a      high-dose pralidoxime as a\u000d\u000a      WHO-recommended treatment and bans of three toxic pesticides in Sri Lanka.\u000d\u000a    Significance: Resultant changes in clinical practice and pesticide\u000d\u000a      regulation have saved 3000\u000d\u000a      lives in the last four years in Sri Lanka alone; in the rest of Asia many\u000d\u000a      times this as local guidelines\u000d\u000a      and practice have changed.\u000d\u000a    Beneficiaries: Patients and communities, healthcare providers,\u000d\u000a      policy-makers.\u000d\u000a    Attribution: Studies designed and led, with international\u000d\u000a      collaborators, by Michael Eddleston,\u000d\u000a      UoE.\u000d\u000a    Reach: International, particularly Asia, changes in WHO and\u000d\u000a      international guidelines on pesticide\u000d\u000a      use.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Eddleston M, Eyer P, Worek F, et al. Differences between\u000d\u000a      organophosphorus insecticides in\u000d\u000a      human self-poisoning — a prospective cohort study. Lancet.\u000d\u000a      2005;366:1452-9. DOI:\u000d\u000a      10.1016\/S0140-6736(05)67598-8.\u000d\u000a    \u000a\u000a3.2 Eddleston M, Juszczak E, Buckley N, et al. Multiple dose activated\u000d\u000a      charcoal in acute self-poisoning — a\u000d\u000a      randomised controlled trial. Lancet. 2008;371:579-86. DOI:\u000d\u000a      10.1016\/S0140-6736(08)60270-6.\u000d\u000a    \u000a\u000a3.3 Eddleston M, Eyer P, Worek F, et al. Pralidoxime in acute\u000d\u000a      organophosphorus insecticide\u000d\u000a      poisoning — a randomised controlled trial. PLoS Medicine. 2009;6:e1000104.\u000d\u000a      DOI:\u000d\u000a      10.1371\/journal.pmed.1000104.\u000d\u000a    \u000a\u000a3.4 Gunnell D, Fernando R, Hewagama M,...Eddleston M. The impact of\u000d\u000a      pesticide regulations\u000d\u000a      on suicide in Sri Lanka. Int J Epidemiol. 2007;36:1235-42. DOI:\u000d\u000a      10.1093\/ije\/dym164.\u000d\u000a    \u000aExample Grant:\u000d\u000a    Wellcome Trust Intermediate Fellowship to M Eddleston. Title:\u000d\u000a      Acute organophosphorus pesticide\u000d\u000a      poisoning in Sri Lanka; 2001-7. £699,801.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    5.1 Bevan M, 2009. Proposal for the inclusion of pralidoxime in the WHO\u000d\u000a      model list of essential\u000d\u000a      medicines.\u000d\u000a      http:\/\/www.who.int\/selection_medicines\/committees\/expert\/17\/application\/Pralidoxime_web.pdf.\u000d\u000a      [Systematic review produced for the WHO assessing the evidence for\u000d\u000a        effectiveness of pralidoxime\u000d\u000a        in OP poisoning. Eddleston's pre-publication RCT was presented as the\u000d\u000a        key study.]\u000d\u000a    5.2 WHO, 2009. The selection and use of essential medicines. Report of\u000d\u000a      the Expert\u000d\u000a      Committee, 2009 (including the 16th WHO Model List of Essential Medicines\u000d\u000a      and the 2nd WHO\u000d\u000a      Model List of Essential Medicines for Children).\u000d\u000a      http:\/\/whqlibdoc.who.int\/trs\/WHO_TRS_958_eng.pdf.\u000d\u000a      [Report of the Expert Committee's decision\u000d\u000a        not to make pralidoxime an Essential Drug, which cited Eddleston's RCT.]\u000d\u000a    5.3 WHO, 2009. Guns, knives, and pesticides: reducing access to lethal\u000d\u000a      means. (Series of\u000d\u000a      briefings on violence prevention: the evidence).\u000d\u000a      http:\/\/whqlibdoc.who.int\/publications\/2009\/9789241597739_eng.pdf.\u000d\u000a      [WHO discussion of restricting\u000d\u000a        access to pesticides as a method of suicide prevention, relying heavily\u000d\u000a        on Eddleston and\u000d\u000a        colleagues' work.]\u000d\u000a    5.4 WHO, 2008. Clinical management of acute pesticide intoxication:\u000d\u000a      prevention of suicidal\u000d\u000a      behaviours. http:\/\/www.who.int\/mental_health\/prevention\/suicide\/pesticides_intoxication.pdf.\u000d\u000a      [Report on WHO meeting led by Eddleston that provided advice on best\u000d\u000a        management of pesticide\u000d\u000a        poisoned patients.]\u000d\u000a    5.5 WHO, 2008. mhGAP Intervention guide for mental, neurological and\u000d\u000a      substance use\u000d\u000a      disorders in non-specialized health settings.\u000d\u000a      http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241548069_eng.pdf.\u000d\u000a      [Guide to aid implementation\u000d\u000a        of the WHO mhGAP program in resource-poor developing countries. With\u000d\u000a        Eddleston's guidance,\u000d\u000a        acute pesticide poisoning was integrated into the assessment and\u000d\u000a        management of acutely sick\u000d\u000a        patients.]\u000d\u000a    5.6 Minutes of the 44th Meeting of the Sri Lankan Pesticides\u000d\u000a      Technical Advisory Committee\u000d\u000a      held on the 9th November 2007. Point 44.2.2 Use Restriction of Dimethoate\u000d\u000a      and Fenthion in\u000d\u000a      Pollonnaruwa. [Available on request. Minutes showing discussion of\u000d\u000a        Eddleston's public health\u000d\u000a        intervention study that showed a reduction in case fatality following a\u000d\u000a        ban of fenthion and\u000d\u000a        dimethoate. As a result, the two pesticides were banned for agricultural\u000d\u000a        use in the country in 2008.\u000d\u000a        A further meeting discussed the ban of paraquat.]\u000d\u000a    5.7 Dawson A*, Eddleston M*, Senarathna L, et al. Acute human lethal\u000d\u000a      toxicity of agricultural\u000d\u000a      pesticides: a prospective cohort study. PLoS Med. 2010;7:e1000357. DOI:\u000d\u000a      10.1371\/journal.pmed.1000357. (*co-first author). [Study that\u000d\u000a        estimated the effect of the three Sri\u000d\u000a        Lankan bans based on Eddleston and colleagues' work.]\u000d\u000a    5.8 Sundaray N, Kumar R. Organophosphorus poisoning: current management\u000d\u000a      guidelines. In:\u000d\u000a      Rao M, ed. Medicine Update, 20 edn. New Delhi, Association of\u000d\u000a      Physicians of India. 2010:420-5.\u000d\u000a      [Available on request. National guidance to Indian clinicians.]\u000d\u000a    ","Title":"\u000d\u000a    D: Preventing deaths from pesticide self-poisoning in rural Asia —\u000d\u000a        pralidoxime\u000d\u000a        is hazardous and banning organophosphorus insecticides is beneficial\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Michael Eddleston (Professor of Clinical Toxicology, UoE,\u000d\u000a      2005-present) has led a\u000d\u000a      series of studies dissecting the roles of specific organophosphates,\u000d\u000a      vehicle components and\u000d\u000a      antidote regimes in deaths following self-poisoning. The work has led to\u000d\u000a      the banning of specific\u000d\u000a      pesticides and changes in World Health Organization (WHO) treatment\u000d\u000a      recommendations.\u000d\u000a    In 2002, Eddleston, with international collaborators, established in Sri\u000d\u000a      Lanka the first prospective\u000d\u000a      cohort of patients with acute self-poisoning in the developing world. The\u000d\u000a      cohort continues today\u000d\u000a      and now includes over 35,000 patients, with clinical description and, for\u000d\u000a      a sub-sample, laboratory\u000d\u000a      proof of the poison ingested. The quality of this research is evidenced by\u000d\u000a      over 60 peer-reviewed\u000d\u000a      publications by Eddleston's group and twelve peer-reviewed grants (>\u000d\u000a      £9.5M) awarded.\u000d\u000a    In early research, Eddleston used the cohort to describe, often for the\u000d\u000a      first time, the clinical\u000d\u000a      presentation and outcome of poisoning with many pesticides and the use of\u000d\u000a      the antidote atropine.\u000d\u000a      In particular, in 2005, he described the effects of poisoning with three\u000d\u000a      common organophosphorus\u000d\u000a      (OP) insecticides, dimethoate, chlorpyrifos, and fenthion, showing very\u000d\u000a      different clinical syndromes\u000d\u000a      and case fatality despite all having the same WHO toxicity classification\u000d\u000a      [3.1].\u000d\u000a    Eddleston was appointed to UoE in 2005, where he performed the research\u000d\u000a      that has led to impact.\u000d\u000a      Two randomised controlled trials (RCTs) were nested into the cohort: one\u000d\u000a      of activated charcoal for\u000d\u000a      all cases of self-poisoning and a second of the antidote pralidoxime in\u000d\u000a      symptomatic OP pesticide\u000d\u000a      poisoning. The former (4632 patients) showed no significant effect of\u000d\u000a      multiple-dose charcoal on\u000d\u000a      death [3.2]. However, it was found to be safe and reduced the need for\u000d\u000a      hazardous gastric lavage,\u000d\u000a      which itself slightly increases case fatality. The second trial, of 235\u000d\u000a      patients, found pralidoxime to\u000d\u000a      be hazardous for patients (adjusted hazard ratio for death of 1.69, 95%\u000d\u000a      confidence interval 0.88-3.26,\u000d\u000a      p = 0.12). Incorporating the baseline amount of\u000d\u000a      acetylcholinesterase and the plasma OP\u000d\u000a      concentration into the analysis increased the hazard ratio for patients\u000d\u000a      receiving pralidoxime to 3.94\u000d\u000a      (1.25-12.36, p = 0.02), decreasing the likelihood that pralidoxime\u000d\u000a      is beneficial [3.3].\u000d\u000a    Eddleston has also performed further relevant observational and\u000d\u000a      interventional public health\u000d\u000a      studies. For example, in 2007, he showed how transient bans of the most\u000d\u000a      toxic pesticides in Sri\u000d\u000a      Lanka in the 1980-90s were followed by a 50% reduction in the overall\u000d\u000a      suicide rate over 10 years\u000d\u000a      [3.4].\u000d\u000a    "},{"CaseStudyId":"23866","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The work was the first to alert UK governments, policymakers and\u000a      professional bodies to the scale of the burden of poorly treated allergic\u000a      disease and led to a range of policy and service initiatives to enhance\u000a      allergy care provision.\u000a    Impact on public policy\u000a    Since commencing this research in 2003, Sheikh and co-workers have\u000a      consistently reported their findings to professional bodies and UK\u000a      government. Sheikh led the national epidemiological research that informed\u000a      the Scottish Medical and Scientific Advisory Committee's Review Working\u000a      Group on Allergy Services in Scotland (2009) [5.1] and contributed\u000a      to the Royal College of Physicians and Royal College of Pathologists\u000a      report Allergy Services: Still not Meeting the Unmet Need (2010)\u000a      [5.2].\u000a    Sheikh and colleagues have also provided expert clinical, methodological\u000a      and leadership input in relation to national and international guidelines,\u000a      for example:\u000a    \u000a      Resuscitation Council (UK) Guidelines on Emergency Treatment of\u000a          Anaphylactic Reactions (2008) [5.3] (Sheikh was a co-author and is\u000a        co-chair for the 2013 revised guidelines).\u000a      World Allergy Organization Guidelines for the Assessment and\u000a          Management of Anaphylaxis (2013) [5.4], which are used in 89\u000a        countries (Sheikh was the sole UK and one of only three European\u000a        co-authors).\u000a      World Allergy Organization White Book on Allergy (2011 and\u000a        2012) [5.5], which provides international gold standard recommendations\u000a        for allergy care (Sheikh was a co-author).\u000a      European Academy of Allergy and Clinical Immunology's European\u000a          Declaration on Immunotherapy [5.6] (2012) (Sheikh was a co-author)\u000a        and Guidelines on Anaphylaxis (2013) (Sheikh has been a member\u000a        of the Guideline Executive, was the Methodology Lead and is senior\u000a        author on these Europe-wide clinical guidelines).\u000a    \u000a    Sheikh's involvement has harmonised the national, European and\u000a      international anaphylaxis guidelines to ensure that evidence-based and\u000a      consistent messages are being communicated to front-line clinicians\u000a      worldwide. Key amongst these is ensuring that professionals understand\u000a      that adrenaline is the first-line treatment; this has translated into more\u000a      provision of potentially life-saving adrenaline auto-injectors to\u000a      patients\/carers.\u000a    The UoE team is closely involved with UK charities: The Anaphylaxis\u000a      Campaign (Levy is Scientific Chair, Schwarze and Sheikh are members of the\u000a      Scientific Committee), Allergy UK (Sheikh has provided advice on strategic\u000a      direction) and Asthma UK (Schwarze is a Trustee). This involvement has\u000a      broadened the focus of these charities to encompass community-based\u000a      allergy care, which in turn has enhanced their capacity to fundraise. For\u000a      example, Allergy UK is running a £1M appeal to fund community-based\u000a      allergy nurses across the UK (the first appointee, in Autumn 2013, will be\u000a      based in Edinburgh). In 2013, Asthma UK awarded funding for the £2M\u000a      community-focused Centre for Applied Asthma Research to UoE.\u000a    Impact on practitioners and services\u000a    The policy impacts have led to many UK governmental and professional\u000a      service developments. Sheikh co-authored the Department of\u000a      Health-commissioned Royal College of Paediatrics and Child Health\u000a      anaphylaxis care pathway for children with allergies (2011) [5.7]. Sheikh\u000a      was the Royal College of General Practitioners joint inaugural Clinical\u000a      Champion for Allergy (2010-2012), which led to the College designating\u000a      allergy a clinical priority, and is now their Clinical Expert. The UoE\u000a      team was also instrumental in the establishment of a new Managed Clinical\u000a      Network in 2012: The Children and Young People's Allergy Network Scotland\u000a      (CYANS; chaired by Schwarze, with Sheikh and Worth on the Steering Group\u000a      and leading the National Anaphylaxis Database), which has involved over\u000a      450 healthcare professionals across Scotland [5.8]. For the National\u000a      Review of Asthma Deaths (2012-13) [5.9], Levy is the Clinical Lead and\u000a      Sheikh is a member of the External Expert Reviewer Group.\u000a    The UoE team has also been instrumental in driving service improvements\u000a      through professional training through, for example, the BMJ Masterclass on\u000a      respiratory\/allergic diseases delivered by Sheikh, Pinnock and Levy. This\u000a      has been given 2-4 times\/year since 2008, attracting ~3000 participants\u000a      from across the UK. Clinician awareness of anaphylaxis is now very high:\u000a      in a 2012 survey of 3537 US paramedics, 98.9% correctly identified a case\u000a      of classic anaphylaxis.\u000a    Impact on health and welfare\u000a    Increased awareness of allergy and anaphylaxis among clinicians and\u000a      patients\/members of the public and harmonised evidence-based guidelines\u000a      have contributed to a decline in allergy-related deaths worldwide.\u000a      Dramatic decreases have been reported in Ontario, Canada: there were 31\u000a      food-related anaphylaxis deaths from 1986 to 2000 but only 6 from 2004 to\u000a      2011 [5.10]. In the UK, Sheikh and Levy are involved with re-establishing\u000a      anaphylaxis and asthma fatality registries, which will enable accurate\u000a      data-gathering for the future.\u000a    Impact on society and public engagement\u000a    Sheikh has made numerous appearances in the mainstream media (e.g., Fox\u000a      News, Radio 4, Telegraph, The Herald and Daily Mail) and social media\u000a      discussing the changing epidemiology, risk factors, new treatments and\u000a      public health implications of allergy. This has contributed to a public\u000a      shift away from ineffective complementary and alternative treatments,\u000a      towards greater involvement with academics (UoE has a 50-strong\u000a      allergy\/respiratory patient and public involvement group), charities and\u000a      service planners\/providers (e.g., CYANS and Care Commissioning Groups) to\u000a      ensure improved, more equitable provision of evidence-based allergy care.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare, policy and services. By quantifying\u000a      the high lifetime prevalence of allergy, high costs and sub-optimal NHS\u000a      care, UoE researchers catalysed international policy change and UK service\u000a      developments.\u000a    Significance: Investment in expanded allergy services and improved\u000a      standards of care, resulting in a significant drop in global\u000a      allergy-related mortality rates.\u000a    Beneficiaries: People with allergies; GPs and emergency care\u000a      clinicians; policymakers and professional bodies.\u000a    Attribution: The work was led by Sheikh (UoE) with collaborators\u000a      for national surveys.\u000a    Reach: International. 1 in 3 people in the UK have an allergy;\u000a      World Allergy Organization anaphylaxis guidelines are used in 89\u000a      countries.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Gupta R, Sheikh A, Strachan D, Anderson H. Burden of allergic disease\u000a      in the UK: secondary analyses of national databases. Clin Exp Allergy.\u000a      2004;34:520-6. DOI: 10.1111\/j.1365-2222.2004.1935.x.\u000a    \u000a\u000a3.2 Punekar Y, Sheikh A. Establishing the incidence and prevalence of\u000a      clinician-diagnosed allergic conditions in children and adolescents using\u000a      routinely collected data from general practices. Clin Exp Allergy.\u000a      2009;39:1209-16. DOI: 10.1111\/j.1365-2222.2009.03248.x.\u000a    \u000a\u000a3.3 Netuveli G, Hurwitz B, Levy M,...Sheikh A. Ethnic variations in UK\u000a      asthma frequency, morbidity, and health-service use: a systematic review\u000a      and meta-analysis. Lancet. 2005;365:312-17. DOI:\u000a      10.1016\/S0140-6736(05)17785-X.\u000a    \u000a\u000a3.4 Rankin K, Sheikh A. Serious shortcomings in the management of\u000a      children with anaphylaxis in Scottish schools. PLoS Med. 2006;3:e326. DOI:\u000a      10.1371\/journal.pmed.0030326.\u000a    \u000a\u000a3.5 Levy M, Price D, Zheng X, Simpson C, Hannaford P, Sheikh A.\u000a      Inadequacies in UK primary care allergy services: national survey of\u000a      current provisions and perceptions of need. Clin Exp Allergy.\u000a      2004;34:518-9. DOI: 10.1111\/j.1365-2222.2004.1945.x.\u000a    \u000a\u000a3.6 Walker S, Khan-Wasti S, Fletcher M, Cullinan P, Harris J, Sheikh A.\u000a      Seasonal allergic rhinitis is associated with a detrimental effect on\u000a      examination performance in United Kingdom teenagers: case-control study. J\u000a      Allergy Clin Immunol. 2007;120:381-7. DOI: 10.1016\/j.jaci.2007.03.034.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    5.1 Scottish Medical and Scientific Advisory Committee's Review Working\u000a      Group on Allergy Services in Scotland (SMASAC) report 2009.\u000a      www.scotland.gov.uk\/Publications\/2009\/06\/17135245\/0.\u000a    5.2 Royal College of Physicians and Royal College of Pathologists (2010).\u000a      Allergy services: still not meeting the unmet need. http:\/\/www.rcplondon.ac.uk\/sites\/default\/files\/documents\/allergy-services-still-not-meeting-the-unmet-need.pdf.\u000a    5.3 Resuscitation Council (UK). Emergency Treatment of Anaphylactic\u000a      Reactions. London: Resuscitation Council (UK), 2008. [Available on\u000a        request.]\u000a    5.4 Simons F, Ardusso L, Dimov V,...Sheikh A, et al. World Allergy\u000a      Organization Anaphylaxis Guidelines: 2013 Update of the Evidence Base. Int\u000a      Arch Allergy Immunol. 2013;162:193-204. DOI: 10.1159\/000354543.\u000a    5.5 World Allergy Organization White Book on Allergy. 2011. http:\/\/www.worldallergy.org\/definingthespecialty\/white_book.php.\u000a    5.6 Calderon M, Demoly P, Gerth van Wijk R,...Sheikh A, et al. EAACI: A\u000a      European Declaration on Immunotherapy. Designing the future of allergen\u000a      specific immunotherapy. Clin Transl Allergy. 2012;2:20. DOI:\u000a      10.1186\/2045-7022-2-20.\u000a    5.7 Royal College of Paediatrics and Child Health care pathway: www.rcpch.ac.uk\/child-health\/research-projects\/care-pathways-children-allergies\/anaphylaxis\/care-pathway-anaphylaxis\u000a      and Clark A, Lloyd K, Sheikh A, et al. The RCPCH care pathway for children\u000a      at risk of anaphylaxis: an evidence and consensus based national approach\u000a      to caring for children with life-threatening allergies. Arch Dis Child.\u000a      2011;96 (Suppl 2):i6-9. DOI: 10.1136\/adc.2011.212662.\u000a    5.8 The Children and Young People's Allergy Network Scotland (CYANS).\u000a      http:\/\/www.cyans.org.uk\/.\u000a    5.9 National Review of Asthma Deaths. http:\/\/www.rcplondon.ac.uk\/projects\/national-review-asthma-deaths.\u000a    5.10 American Academy of Allergy, Asthma & Immunology (AAAAI) 2013\u000a      Annual Meeting: Abstract 511. Presented February 24, 2013. Discussed on\u000a      Medscape website, March 7th 2013: Anaphylaxis Death Rate Down,\u000a      but Epinephrine Use Poor.\u000a      http:\/\/www.medscape.com\/viewarticle\/780414\u000a      [Free login required. Document available on request.]\u000a    ","Title":"\u000a    N: Detailed epidemiological studies of people with allergy have\u000a        triggered policy developments and catalysed service innovations to\u000a        enhance care\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Epidemiological research undertaken by UoE researchers Professor Aziz\u000a      Sheikh (Professor of Primary Care Research & Development,\u000a      1993-present), Dr Colin Simpson (Reader, 2009-present), Dr Mark Levy\u000a      (Senior Lecturer, 2004-present) and Dr Chantelle Anandan (Post-Doctoral\u000a      Fellow, 2005-present) demonstrated that the UK now has the highest\u000a      prevalence of allergic disorders in the world, with 1 in 3 of the\u000a      population developing one or more allergic disorder at some point in their\u000a      lives [3.1]. Their subsequent retrospective General Practice Research\u000a      Database-derived national birth cohort study of >40,000 children found\u000a      that 1 in 2 children developed an allergic disorder within the first 18\u000a      years of life. This alerted policymakers to the fact that the overall\u000a      population prevalence is likely to climb much higher in the decades ahead\u000a      [3.3].\u000a    Importantly, this research, for the first time, reliably quantified\u000a      healthcare utilisation and healthcare costs resulting from allergic\u000a      disorders in the UK (i.e., 6% of all GP consultations; 70,000 hospital\u000a      admissions\/year; and 11% of all community prescribing (>£1B\/year) [3.2,\u000a      3.3]. The research also identified major shortcomings in allergy care\u000a      provision, highlighting the need to focus particular attention on the\u000a      needs of: the 15% of children with multiple allergic disorders [3.4];\u000a      ethnic minorities [3.3]; the ~40,000 people in the UK with a history of\u000a      anaphylaxis; and those with a history of other systemic, potentially\u000a      life-threatening allergies [3.4]. Moreover, >80% of GPs judged NHS care\u000a      to be of poor quality for the ~20 million people in the UK with allergy\u000a      problems [3.5].\u000a    Subsequent descriptive, analytical and qualitative research by Sheikh, Dr\u000a      Hilary Pinnock (Reader, UoE, 2004-present) and Dr Allison Worth (Senior\u000a      Research Fellow, 2006-present) with patients, their families and health\u000a      professionals has sought to understand the impact of living with severe\u000a      allergic problems [3.6] and has been used to inform educational, policy\u000a      and service developments led by Sheikh, Levy, and Professor Jürgen\u000a      Schwarze (Edward Clark Chair of Child Life and Health, UoE, 2007-present).\u000a    "},{"CaseStudyId":"23867","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The original description of this work [3.1] has had a major impact on the\u000d\u000a      field, even defining a new\u000d\u000a      language and terminology used to describe liver volumes in the context of\u000d\u000a      resectional surgery. Pre-operative\u000d\u000a      liver volume analysis has become the standard of care incorporated in\u000d\u000a      guidelines\u000d\u000a      internationally, and has reduced mortality related to liver surgery.\u000d\u000a    Impact on public policy\u000d\u000a      The utility of liver volume analysis, and the finding that the critical\u000d\u000a      volume of liver required for safe\u000d\u000a      liver function is around 26%, has been corroborated by others and\u000d\u000a      incorporated into guidelines\u000d\u000a      worldwide for the safety of liver surgery and its practice, for example in\u000d\u000a      the UK (2012), USA (2013),\u000d\u000a      Japan (2008) and Australia [5.1-5.4].\u000d\u000a    Impact on clinical practice\u000d\u000a      The techniques of 3D modelling and virtual hepatic resection developed in\u000d\u000a      this work have been\u000d\u000a      universally adopted in major centres performing complex liver surgery and\u000d\u000a      are now the standard of\u000d\u000a      care worldwide. Evidence of this is the use of liver volume analysis as a\u000d\u000a      baseline in initiatives to\u000d\u000a      improve surgical and oncological outcomes. For example, registries of\u000d\u000a      novel surgical techniques\u000d\u000a      that seek to extend what is achievable by liver resection require liver\u000d\u000a      volume analysis [5.5] and\u000d\u000a      randomised controlled trials of neoadjuvant chemotherapy in unresectable\u000d\u000a      secondary liver cancer\u000d\u000a      that use \"resectability\" as an outcome measure require liver volume\u000d\u000a      analysis where an extended\u000d\u000a      resection may be required [5.6]. Furthermore, the UoE team's approach to\u000d\u000a      measuring liver volume\u000d\u000a      has been adopted for a wider context than just liver resection and it is\u000d\u000a      now a particularly important\u000d\u000a      component of the assessment of living liver donors as part of the\u000d\u000a      transplant assessment process\u000d\u000a      [5.7].\u000d\u000a    The association between liver volume and functional metabolic adaptation\u000d\u000a      has been recognised\u000d\u000a      and it has been shown that functional recovery of the liver precedes\u000d\u000a      volume recovery [5.7]. This\u000d\u000a      important observation permits surgery to take place considerably earlier\u000d\u000a      after portal vein\u000d\u000a      embolisation than hitherto considered. The importance of liver volume\u000d\u000a      analysis and critical liver\u000d\u000a      volume has also been recognised in association with the small-for-size\u000d\u000a      syndrome that can occur\u000d\u000a      after liver resection or partial liver transplantation [5.7].\u000d\u000a    The use of open-source software has been important to increase the\u000d\u000a      accessibility of the techniques\u000d\u000a      to surgeons worldwide. The software developed at UoE used in study [3.6],\u000d\u000a      OsiriX, is the most\u000d\u000a      widely used healthcare image viewer with 50,000 active users and >1000\u000d\u000a      downloads\/150 000 hits\u000d\u000a      per day. These methods have subsequently been used in reporting outcomes\u000d\u000a      in clinical trials [5.8].\u000d\u000a    Impact on health and welfare\u000d\u000a      The principal beneficiaries of this work are patients undergoing liver\u000d\u000a      surgery, through gains in the\u000d\u000a      number of patients made resectable and improvements in safety, with\u000d\u000a      implications for the\u000d\u000a      treatment of 3600 patients annually in the UK alone. The safety of liver\u000d\u000a      surgery, in which liver\u000d\u000a      volume analysis has become an integral part, has improved significantly in\u000d\u000a      the past two decades.\u000d\u000a      Death from haemorrhage or liver failure is now a rare event with mortality\u000d\u000a      rates of 2-4% in most\u000d\u000a      major centres. The ability to determine the volume of the liver remnant\u000d\u000a      accurately is an essential\u000d\u000a      adjunct to treatments that render 85% of patients previously deemed\u000d\u000a      irresectable to become\u000d\u000a      resectable [5.9].\u000d\u000a    Impact on commerce\u000d\u000a      Using extensions of the techniques developed at UoE, commercial software\u000d\u000a      and hardware\u000d\u000a      companies have developed technologies for 3D reconstruction of vascular\u000d\u000a      and biliary structures\u000d\u000a      and the volumes of the territories they supply or drain [5.10]. Specific\u000d\u000a      systems for 3D liver\u000d\u000a      reconstruction currently being developed are Ova (Hitachi Medical\u000d\u000a      Corporation, Japan), Synapse\u000d\u000a      Vincent (Fujifilm, Japan), HepaVision (MeVisLab, Germany), Ziostation (Qi\u000d\u000a      Imaging, Japan),\u000d\u000a      VirtualPlace (AZE, Japan) and VR-Render (IRCAD, France). Other large\u000d\u000a      multinational companies\u000d\u000a      such as Siemens, GE Healthcare and Philips Healthcare are developing\u000d\u000a      general 3D visualisation\u000d\u000a      systems that can be applied to the liver. In 2013, Global Industry\u000d\u000a      Analysts, Inc. projected that the\u000d\u000a      global market for 3D medical imaging would reach US$2.2B by 2018.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: UoE-developed techniques to determine liver volume and\u000d\u000a      define, pre-operation, the\u000d\u000a      minimum liver remnant required have transformed the viability and success\u000d\u000a      of liver surgery and\u000d\u000a      stimulated commercial development of imaging software\/hardware.\u000d\u000a    Significance: Precise functional liver volume measurement prior to\u000d\u000a      surgery is now the standard of\u000d\u000a      care and, for example, renders 85% of patients previously deemed\u000d\u000a      irresectable to be resectable\u000d\u000a      with a perioperative mortality of 2-4%.\u000d\u000a    Beneficiaries: Patients with liver cancer; the NHS and healthcare\u000d\u000a      delivery organisations; imaging\u000d\u000a      software\/hardware companies.\u000d\u000a    Attribution: Pivotal studies were led by Wigmore and Garden at\u000d\u000a      UoE.\u000d\u000a    Reach: Worldwide; technique recommended in guidelines in Europe, N\u000d\u000a      America, Asia, Australasia;\u000d\u000a      deployed in the management of 3600 patients per annum in the UK alone; the\u000d\u000a      use of open-source\u000d\u000a      software increases accessibility in developing world.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Wigmore S, Redhead D, Yan X,...Garden OJ. Virtual hepatic resection\u000d\u000a      using three-dimensional\u000d\u000a      reconstruction of helical computed tomography angioportograms. Ann Surg.\u000d\u000a      2001;233:221-6. DOI: 10.1097\/00000658-200102000-00011.\u000d\u000a    \u000a\u000a3.2 Schindl M, Redhead D, Fearon K, Garden OJ, Wigmore S; Edinburgh Liver\u000d\u000a      Surgery and\u000d\u000a      Transplantation Experimental Research Group (eLISTER). The value of\u000d\u000a      residual liver volume as a\u000d\u000a      predictor of hepatic dysfunction and infection after major liver\u000d\u000a      resection. Gut. 2005;54:289-96.\u000d\u000a      DOI: 10.1136\/gut.2004.046524.\u000d\u000a    \u000a\u000a3.3 Schindl M, Millar A, Redhead D,...Garden OJ, Wigmore S. The adaptive\u000d\u000a      response of the\u000d\u000a      reticuloendothelial system to major liver resection in humans. Ann Surg.\u000d\u000a      2006;243:507-14. DOI:\u000d\u000a      10.1097\/01.sla.0000205826.\u000d\u000a    \u000a\u000a3.4 van de Poll M, Wigmore S, Redhead D,...Garden OJ, et al. Effect of\u000d\u000a      major liver resection on\u000d\u000a      hepatic ureagenesis in humans. Am J Physiol Gastrointest Liver Physiol.\u000d\u000a      2007;293:G956-62. DOI:\u000d\u000a      10.1152\/ajpgi.00366.2006.\u000d\u000a    \u000a\u000a3.5 Dello S, van Dam R, Slangen J,...Wigmore S, Dejong C. Liver volumetry\u000d\u000a      plug and play: do it\u000d\u000a      yourself with ImageJ. World J Surg. 2007;31:2215-21. DOI:\u000d\u000a      10.1007\/s00268-007-9197-x.\u000d\u000a    \u000a\u000a3.6 Dello S, Stoot J, van Stiphout R,...Wigmore S, et al. Prospective\u000d\u000a      volumetric assessment of\u000d\u000a      the liver on a personal computer by nonradiologists prior to partial\u000d\u000a      hepatectomy. World J Surg.\u000d\u000a      2011; 35:386-92. DOI: 10.1007\/s00268-010-0877-6.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    5.1 Khan S, Davidson B, Goldin R, et al. Guidelines for the diagnosis and\u000d\u000a      treatment of\u000d\u000a      cholangiocarcinoma: an update. Gut. 2012;61:1657-69. DOI:\u000d\u000a      10.1136\/gutjnl-2011-301748. [British\u000d\u000a        Society of Gastroenterology guidelines update.]\u000d\u000a    5.2 Adams R, Aloia T, Loyer E, et al. Selection for hepatic resection of\u000d\u000a      colorectal liver\u000d\u000a      metastases: expert consensus statement. HPB. 2013;15:91-103. DOI:\u000d\u000a      10.1111\/j.1477-\u000d\u000a      2574.2012.00557.x. [Statement from the Americas\u000d\u000a        Hepato-Pancreato-Biliary Association; Society\u000d\u000a        of Surgical Oncology; Society for Surgery of the Alimentary Tract.]\u000d\u000a    5.3 Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management\u000d\u000a      of biliary tract and\u000d\u000a      ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg.\u000d\u000a      2008;15:41-54. DOI:\u000d\u000a      10.1007\/s00534-007-1279-5.\u000d\u000a    5.4 Rahbari N, Garden OJ, Padbury R, et al. Posthepatectomy liver\u000d\u000a      failure: a definition and\u000d\u000a      grading by the International Study Group of Liver Surgery (ISGLS).\u000d\u000a      Surgery. 2011;149:713-24.\u000d\u000a      DOI: 10.1111\/j.1477-2574.2011.00319.x.\u000d\u000a    5.5 ClinicalTrials.gov. (2013). Registry of Major Liver Resections\u000d\u000a      Including ALPPS and Other\u000d\u000a      Liver Resections in Two Stages (ALLPSREG). http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01924741.\u000d\u000a    5.6 Folprecht G, Gruenberger T, Bechstein W, et al. Tumour response and\u000d\u000a      secondary\u000d\u000a      resectability of colorectal liver metastases following neoadjuvant\u000d\u000a      chemotherapy with cetuximab: the\u000d\u000a      CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38-47. DOI:\u000d\u000a      10.1016\/S1470-2045(09)70330-4.\u000d\u000a    5.7 Clavien P, Oberkofler C, Raptis D, Lehmann K, Rickenbacher A,\u000d\u000a      El-Badry AM. What is\u000d\u000a      critical for liver surgery and partial liver transplantation: Size or\u000d\u000a      quality? Hepatology.\u000d\u000a      2010;52(2):715-29. DOI: 10.1002\/hep.23713.\u000d\u000a    5.8 Millet G, Truant S, Leteurtre E, et al. Volumetric analysis of\u000d\u000a      remnant liver regeneration after\u000d\u000a      major hepatectomy in bevacizumab-treated patients: a case-matched study in\u000d\u000a      82 patients. Ann\u000d\u000a      Surg. 2012;256:755-61; Discussion 761-2. DOI:\u000d\u000a      10.1097\/SLA.0b013e31827381ca.\u000d\u000a    5.9 Abulkhir A, Limongelli P, Healey A, et al. Preoperative portal vein\u000d\u000a      embolization for major liver\u000d\u000a      resection: a meta-analysis. Ann Surg. 2008;247:49-57. DOI:\u000d\u000a      10.1097\/SLA.0b013e31815f6e5b.\u000d\u000a    5.10 Mise Y, Tani K, Aoki T, et al. Virtual liver resection:\u000d\u000a      computer-assisted operation planning\u000d\u000a      using a three-dimensional liver representation. J Hepatobiliary Pancreat\u000d\u000a      Sci. 2013;20:157-64. DOI:\u000d\u000a      10.1007\/s00534-012-0576-y.\u000d\u000a    ","Title":"\u000d\u000a    F: By defining the minimum liver remnant required, volumetric analysis\u000d\u000a        is now the pre-operative standard of care in liver cancer surgery\u000d\u000a        worldwide\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Between 1999 and 2000, a team led by Professor Stephen Wigmore (Professor\u000d\u000a      of Transplantation\u000d\u000a      Surgery, UoE, 1997-2005 and 2007-present) and Professor O James Garden\u000d\u000a      (Regius Professor\u000d\u000a      of Clinical Surgery, UoE, 1988-present) developed at UoE a new technique\u000d\u000a      in which a three-dimensional\u000d\u000a      (3D) reconstruction of the liver was created from contrast-enhanced\u000d\u000a      computed\u000d\u000a      tomography scans using volume-rendering software [3.1]. Subsequent\u000d\u000a      research has led to this\u000d\u000a      approach being adopted worldwide. This was supported by a European Society\u000d\u000a      for Organ\u000d\u000a      Transplantation Senior Fellowship and a £57K award from the Royal College\u000d\u000a      of Surgeons of\u000d\u000a      Edinburgh and Tenovus.\u000d\u000a    In 2008, an estimated 520,000 new cases of primary liver cancer and\u000d\u000a      165,000 cases of liver\u000d\u000a      metastases from colon cancer were reported worldwide. The only possibility\u000d\u000a      of cure for these\u000d\u000a      patients is surgical resection, ablation or liver transplantation. The\u000d\u000a      treatment of choice in patients\u000d\u000a      without cirrhosis is liver resection where possible. In UK terms, the 7-8%\u000d\u000a      of affected patients with\u000d\u000a      colon cancer who will either present with or develop metastatic disease\u000d\u000a      amenable to resection\u000d\u000a      equates to approximately 3600 per annum. Prior to the 1990s, liver\u000d\u000a      resectional surgery was\u000d\u000a      dangerous, with an estimated 25% mortality owing to post-operative liver\u000d\u000a      failure. The\u000d\u000a      establishment of dedicated and specialised units started to reduce this\u000d\u000a      figure, but continued to rely\u000d\u000a      on global clinical assessment to predict perioperative mortality, which\u000d\u000a      lacked rigour and was\u000d\u000a      inherently inaccurate. The key to understanding an individual's risk of\u000d\u000a      post-operative liver failure is\u000d\u000a      the ability to accurately measure liver volume. Using the virtual livers\u000d\u000a      created by 3D volume\u000d\u000a      reconstruction, a simulation of a planned liver resection could be\u000d\u000a      performed and the software used\u000d\u000a      to determine predicted residual and resected liver volumes. This approach\u000d\u000a      was validated by\u000d\u000a      comparing virtual resection volumes with actual liver volumes in patients\u000d\u000a      who underwent liver\u000d\u000a      resection. This was published in the highest-ranking surgery journal\u000d\u000a      (Annals of Surgery) and not\u000d\u000a      only established a novel technique, but defined a new language for\u000d\u000a      describing liver volumes in the\u000d\u000a      radiology and surgical communities [3.1].\u000d\u000a    Having established an accurate technique for measuring liver component\u000d\u000a      volumes in surgery, this\u000d\u000a      was applied pre-operatively to a cohort of patients undergoing liver\u000d\u000a      resection. Patients underwent\u000d\u000a      pre-operative volumetric analysis with 3D reconstruction of the liver and\u000d\u000a      virtual hepatectomy to\u000d\u000a      calculate future remnant liver volumes. This manuscript defined for the\u000d\u000a      first time the percentage\u000d\u000a      liver volume associated with resection for all common liver resectional\u000d\u000a      procedures [3.2]. More\u000d\u000a      importantly, by combining a postoperative scoring system for liver\u000d\u000a      dysfunction with the measured\u000d\u000a      future liver remnant volume, a relationship between liver volume and\u000d\u000a      function after surgery was\u000d\u000a      established. Crucially, the work demonstrated that a residual functional\u000d\u000a      liver volume of at least 26%\u000d\u000a      is required for non-cirrhotic livers to avoid serious postoperative liver\u000d\u000a      dysfunction. The team also\u000d\u000a      made an important link between liver volume and risk of postoperative\u000d\u000a      sepsis [3.2].\u000d\u000a    Having developed a new technique for accurate preoperative measurement of\u000d\u000a      liver volume, and\u000d\u000a      confirmed the clinical utility of such measurements in defining the\u000d\u000a      complications of liver surgery,\u000d\u000a      the UoE team analysed two key aspects of liver function in human subjects\u000d\u000a      undergoing liver\u000d\u000a      resection. The first, on reticuloendothelial function, identified that a\u000d\u000a      major liver resection produced\u000d\u000a      a profound reduction in reticuloendothelial clearance capacity, which was\u000d\u000a      only partially restored\u000d\u000a      one week after resection [3.3]. This may be the link between liver surgery\u000d\u000a      and postoperative\u000d\u000a      immunocompromise, leading to sepsis and multiorgan failure.\u000d\u000a    The second study investigated the impact of major liver resection on a\u000d\u000a      key liver metabolic pathway:\u000d\u000a      urea synthesis. In collaboration with the University of Maastricht, the\u000d\u000a      team demonstrated an almost\u000d\u000a      instantaneous increase in metabolic activity following major liver\u000d\u000a      resection to compensate for loss\u000d\u000a      of liver cell mass [3.4]. A linear relationship between increased\u000d\u000a      metabolic activity and resection\u000d\u000a      volume (up to approximately 26%) validated the earlier clinical study\u000d\u000a      demonstrating this as a\u000d\u000a      critical volume in non-diseased liver, beyond which the liver cannot\u000d\u000a      metabolically compensate.\u000d\u000a    Importantly, the UoE team has ensured accessibility to surgeons in\u000d\u000a      resource-poor countries, by\u000d\u000a      publishing the techniques using open source software [3.5, 3.6].\u000d\u000a    "},{"CaseStudyId":"23868","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Impact on health and welfare\u000a    Implementation of both anti-platelet and coronary interventional\u000a      therapies in ACS has led to major improvements in mortality rates. Fox\u000a      demonstrated a marked improvement in performance measures for reperfusion\u000a      in ST-elevation myocardial infarction in 2008, across 21 countries in\u000a      Europe, compared with data from 2006: the number of eligible patients\u000a      receiving reperfusion therapy in a timely manner increased from 53.1% to\u000a      63.5% (P < 0.0001). In parallel, over the 2-year period,\u000a      in-hospital mortality decreased from 8.1 to 6.6% (P = 0.047) [5.1].\u000a    Furthermore, the UK Myocardial Ischaemia National Audit Project public\u000a      report demonstrated a decline in 30-day mortality for non-ST-elevation\u000a      myocardial infarction from 12.5% in 2003 to 7% in 2012 [5.2]. The\u000a      improvements in case fatality and acute outcomes have been independently\u000a      attributed to the innovations in care following the adoption of guideline\u000a      recommendations.\u000a    The data were corroborated by 2012 British Heart Foundation Coronary\u000a      Heart Disease statistics [5.3]. For instance most European countries\u000a      witnessed a 10% to 50% decrease in death from coronary heart disease from\u000a      1998 to 2008 (45% decrease in UK).\u000a    Impact on public policy\u000a    Clopidogrel was the first anti-platelet agent to demonstrate major\u000a      improvements in clinical outcome when added to aspirin. Fox and\u000a      colleagues' landmark study [3.2] changed guidelines in the UK (National\u000a      Institute for Health and Care Excellence [5.4]), Europe (European Society\u000a      of Cardiology [5.5]; 55 countries have pledged to implement these\u000a      guidelines) and North America (American College of Cardiology\u000a      Foundation\/American Heart Association [5.6]). Further to Fox's\u000a      demonstration of the effect of genetic polymorphisms on the variable\u000a      clopidogrel metabolism among individuals, the US Food and Drug\u000a      Administration has, since 2010, recommended consideration of genetic\u000a      testing for clopidogrel [5.7].\u000a    Impact on clinical practice\u000a    Dual anti-platelet therapy and coronary revascularisation with PCI has\u000a      become the standard of care worldwide for all patients presenting with\u000a      ACS. In 2010, there had been an almost 1000% increase in the number of\u000a      PCIs in the UK per annum since 1991 [5.3]. This was mirrored by a steady\u000a      rise in prescription of anti-platelet drugs since their introduction in\u000a      the late 1980s, up to 40,000 prescriptions in England in 2011 [5.3].\u000a    A collaborative meta-analysis led by Fox (2010) confirmed the long-term\u000a      beneficial impact of interventional revascularisation, demonstrating\u000a      2.0-3.8% absolute reductions in cardiovascular death or myocardial\u000a      infarction in the low- and intermediate-risk groups and an 11.1% absolute\u000a      risk reduction in the highest-risk patients [5.8].\u000a    Impact on commerce\u000a    Clopidogrel (marketed as Plavix®) was described as a \"blockbuster\" drug\u000a      for its manufacturers Bristol Myers Squibb and Sanofi, generating US$6.5B\u000a      in sales in the USA in 2011, where it was the second best-selling drug\u000a      [5.9]. This ranking reduced when the US Food and Drug Administration\u000a      approved generic versions in 2012, but the drug now generates revenues for\u000a      multiple manufacturers worldwide (USA, Canada, Europe, India, Australia).\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare, policy and clinical practice;\u000a      randomised trial evidence has changed the management and outcome of acute\u000a      coronary syndromes (ACS) globally.\u000a    Significance: Advanced anti-platelet and revascularisation\u000a      therapies have become standards of care worldwide. There have been large\u000a      (10-50%) reductions in the death rate from coronary heart disease across\u000a      Europe. Clopidogrel was the second best-selling drug in the USA in 2011.\u000a    Beneficiaries: Patients with ACS, clinical practitioners, NHS and\u000a      healthcare delivery organisations, policy-makers, pharmaceutical\u000a      companies.\u000a    Attribution: Building on prior studies, Fox (UoE) and colleagues\u000a      led multicentre randomised controlled trials; international trials were\u000a      co-chaired by Fox with international investigators.\u000a    Reach: Global; guideline changes in Europe and USA; applies to the\u000a      up to 5% of the population who have ACS.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Fox K, Anderson F Jr, Goodman S, et al; GRACE Investigators. Time\u000a      course of events in acute coronary syndromes: implications for clinical\u000a      practice from the GRACE registry. Nat Clin Pract Cardiovasc Med.\u000a      2008;5:580-9. DOI: 10.1038\/ncpcardio1302.\u000a    \u000a\u000a3.2 Yusuf S, Zhao F, Mehta S,...Fox K; Clopidogrel in Unstable Angina to\u000a      Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in\u000a      addition to aspirin in patients with acute coronary syndromes without\u000a      ST-segment elevation. N\u000a      Engl J Med. 2001;345:494-502. DOI: 10.1056\/NEJMoa010746.\u000a    \u000a\u000a3.3 Bhatt D, Fox K, Hacke W, et al; CHARISMA Investigators. Clopidogrel\u000a      and aspirin versus aspirin alone for the prevention of atherothrombotic\u000a      events. N Engl J Med. 2006;354:1706-17. DOI: 10.1056\/NEJMoa060989.\u000a    \u000a\u000a3.4 Roe M, Armstrong P, Fox K, et al; TRILOGY ACS Investigators.\u000a      Prasugrel versus clopidogrel for acute coronary syndromes without\u000a      revascularization. N Engl J Med. 2012:367:1297-309. DOI:\u000a      10.1056\/NEJMoa1205512.\u000a    \u000a\u000a3.5 Mega J, Braunwald E, Wiviott S,...Fox K; ATLAS ACS 2-TIMI 51\u000a      Investigators. Rivaroxaban in patients with a recent acute coronary\u000a      syndrome. N Engl J Med. 2012;366:9-19. DOI: 10.1056\/NEJMoa1112277.\u000a    \u000a\u000a3.6 Fox K, Poole-Wilson P, Clayton T, et al. 5-year outcome of an\u000a      interventional strategy in non-ST-elevation acute coronary syndrome: the\u000a      British Heart Foundation RITA 3 randomised trial. Lancet. 2005;366:914-20.\u000a      DOI: 10.1016\/S0140-6736(05)67222-4.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    5.1 Schiele F, Hochadel M, Tubaro M...Fox K, Gitt A. Reperfusion strategy\u000a      in Europe: temporal trends in performance measures for reperfusion therapy\u000a      in ST-elevation myocardial infarction. Eur Heart J. 2010;31:2614-24. DOI:\u000a      10.1093\/eurheartj\/ehq305.\u000a    5.2 Myocardial Ischaemia National Audit Report (2012).\u000a      http:\/\/www.ucl.ac.uk\/nicor\/audits\/minap\/publicreports\/pdfs\/minap2012publicreportlowres.\u000a    5.3 British Heart Foundation (2012). Coronary Heart Disease Statistics\u000a      2012.\u000a      http:\/\/www.bhf.org.uk\/publications\/view-publication.aspx?ps=1002097.\u000a    5.4 National Institute for Health and Care Excellence (March 2010).\u000a      Unstable angina and NSTEMI The early management of unstable angina and\u000a      non-ST-segment- elevation myocardial infarction. http:\/\/www.nice.org.uk\/nicemedia\/live\/12949\/47921\/47921.pdf.\u000a    5.5 Hamm C, Bassand J, Agewall S, et al; ESC Committee for Practice\u000a      Guidelines. ESC Guidelines for the management of acute coronary syndromes\u000a      in patients presenting without persistent ST-segment elevation: The Task\u000a      Force for the management of acute coronary syndromes (ACS) in patients\u000a      presenting without persistent ST-segment elevation of the European Society\u000a      of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054. DOI:\u000a      10.1093\/eurheartj\/ehr236.\u000a    5.6 Jneid H, Anderson J, Wright R, et al; American College of Cardiology\u000a      Foundation; American Heart Association Task Force on Practice Guidelines.\u000a      2012 ACCF\/AHA focused update of the guideline for the management of\u000a      patients with unstable angina\/non-ST-elevation myocardial infarction: a\u000a      report of the American College of Cardiology Foundation\/American Heart\u000a      Association Task Force on Practice Guidelines. Circulation,\u000a      2012;126:875-910. DOI: 10.1161\/CIR.0b013e318256f1e0.\u000a    5.7 US Food and Drug Administration (2010). FDA Drug Safety\u000a      Communication: Reduced effectiveness of Plavix (clopidogrel) in patients\u000a      who are poor metabolizers of the drug.\u000a      http:\/\/www.fda.gov\/drugs\/drugsafety\/postmarketdrugsafetyinformationforpatientsandproviders\/ucm\u000a        203888.htm.\u000a    5.8 Fox K, Clayton T, Damman P, et al; FIR Collaboration. Long-term\u000a      outcome of a routine versus selective invasive strategy in patients with\u000a      non-ST-segment elevation acute coronary syndrome: a meta-analysis of\u000a      individual patient data. J Am Coll Cardiol. 2010;55:2435-45. DOI:\u000a      10.1016\/j.jacc.2010.03.007.\u000a    5.9 Drugs.com (2013). Plavix sales data. http:\/\/www.drugs.com\/stats\/plavix.\u000a    ","Title":"\u000a    L: Pharmacological and interventional therapies for acute coronary\u000a        syndromes improve patient outcome\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Keith Fox (Professor of Cardiology, UoE, 1999-present) and\u000a      colleagues have defined the evidence base for anti-platelet therapies and\u000a      coronary revascularisation strategies in acute coronary syndromes (ACS);\u000a      their implementation as the standard of care worldwide has reduced\u000a      mortality from coronary heart disease.\u000a    ACS refers to any group of symptoms attributed to obstruction of the\u000a      coronary arteries. It usually occurs as a result of myocardial infarction\u000a      or unstable angina. ACS affects approximately 5% of men and 3% of women\u000a      [5.3]. In the UK, about 114,000 patients with ACS are admitted to hospital\u000a      each year; in the USA, more than 5.5 million patients a year present to an\u000a      emergency department with chest pain and other symptoms related to ACS.\u000a      Patients with ACS are at risk of death and re-infarction. In 2008, Fox and\u000a      colleagues defined the characteristics of patients with ST- and non ST-\u000a      elevation ACS and their early and late complications [3.1], demonstrating\u000a      that such complications follow erosion or fissuring of an atheromatous\u000a      plaque, triggering contact activation of coagulation, platelet aggregation\u000a      and amplification of the coagulation cascade. Since then, Fox's team has\u000a      taken an integrated approach to clinical research into pharmacological and\u000a      interventional methods to inhibit coronary thrombosis in ACS.\u000a    Pharmacological strategies: innovations in anti-platelet therapy\u000a    In the first ever investigator-led study to test the role of dual\u000a      anti-platelet therapy (aspirin plus the thienopyridine clopidogrel), Fox,\u000a      as co-chair with Salim Yusuf (McMaster University, Canada) led the\u000a      international CURE trial, enrolling 12,562 patients from 28 countries from\u000a      1998-2000, and demonstrated a highly significant (21% risk reduction) and\u000a      sustained improvement in outcome (principally myocardial infarction)\u000a      [3.2]. However, the clinical responses were not uniform. In later landmark\u000a      studies in stratified medicine, Fox and colleagues evaluated the impact of\u000a      the CYP2C19 genotype on outcomes following clopidogrel treatment\u000a      and identified the relationship between CYP2C19 polymorphisms and\u000a      ischaemic and bleeding outcomes.\u000a    In subsequent research, Fox and colleagues have extended their findings\u000a      in international clinical trials of secondary prevention in stable\u000a      cardiovascular disease, notably CHARISMA (2002-2003; 15,603 patients)\u000a      [3.3], and more potent platelet inhibitors in ACS, namely prasugrel in\u000a      TRILOGY (2008-2011; 9326 patients from 52 countries) [3.4].\u000a    Interventional strategies: coronary revascularisation\u000a    Revascularisation procedures (percutaneous coronary intervention [PCI;\u000a      also known as angioplasty] and coronary artery bypass graft surgery\u000a      [CABG]) involve physically opening, with a balloon and stent, or\u000a      surgically bypassing blocked or narrowed arteries. Although\u000a      revascularisation had been proven to reduce myocardial ischaemia, the\u000a      long-term effect on recurrent myocardial infarction and mortality was\u000a      unknown, and practice was highly variable. In a British Heart\u000a      Foundation-funded study of 1810 UK non-ST-elevation ACS patients (the RITA\u000a      3 trial, 1997-2001; Fox Principal Investigator), the team compared an\u000a      interventional strategy (early coronary angiography followed by\u000a      revascularisation) with a strategy of conservative management. At 1-year\u000a      follow-up, rates of death or non-fatal myocardial infarction were similar.\u000a      However, at 5 years' follow-up, there were fewer deaths or recurrent\u000a      myocardial infarctions in the intervention group (P = 0.044). The\u000a      benefits of an intervention strategy were mainly seen in patients at high\u000a      risk of death or myocardial infarction (P = 0·004), and for the\u000a      highest risk group, the odds ratio of death or non-fatal myocardial\u000a      infarction was 0·44 (0·25-0·76) [3.6].\u000a    "},{"CaseStudyId":"23869","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2264397","Name":"Portugal"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"3469034","Name":"Brazil"}],"Funders":[],"ImpactDetails":"\u000a    Impact on public policy\u000a    The National Institute for Health and Care Excellence (NICE) tested all\u000a      of the published risk scores for ACS using an unselected population of\u000a      approximately 70,000 patients from the United Kingdom. NICE guideline 94\u000a      [5.1], published in 2010, European Society of Cardiology (ESC; 2011)\u000a      [5.2], American Heart Association and American College of Cardiology\u000a      (2012) [5.3] guidelines now recommend that the GRACE risk score should be\u000a      used because of its superior performance when compared to the other\u000a      published risk-scoring tools. Fifty-five countries have pledged to\u000a      implement the ESC cardiovascular guidelines.\u000a    Impact on clinical practice\u000a    Recent publications from others have extended the role of the GRACE risk\u000a      score to other indications including pulmonary embolism [5.4] and contrast\u000a      renal nephropathy. In addition, an independent study demonstrated that the\u000a      score predicts outcome (whereas stress imaging does not) in follow-up\u000a      patients after chest pain [5.5]. Similarly, the GRACE risk score remains\u000a      accurate at predicting hospital and long-term fatality in ACS patients in\u000a      the era of high-sensitivity troponin and B-type natriuretic peptide [5.6].\u000a      The GRACE risk score has been extensively tested, and implemented\u000a      internationally: PubMed (May 2013) retrieved 291 published manuscripts and\u000a      4034 citations involving the GRACE risk score, and on Google there are 46\u000a      pages of citations using the term \"GRACE risk score\". Examples [5.4-5.8]\u000a      include studies from clinical settings as diverse as Brazil, Portugal and\u000a      China that demonstrate the superiority of the GRACE score.\u000a    The GRACE Steering Committee (Chair, K Fox) made the GRACE risk score\u000a      freely available to download to a mobile device (2011; more than 10,000\u000a      downloads from Google Play alone). In addition, a simplified version of\u000a      the GRACE risk score was developed in 2012, externally validated in the\u000a      French Acute MI FAST registry; the updated version is now implemented and\u000a      freely available (July 2013). The GRACE risk score app provides a\u000a      user-friendly interface of the variables that convey 90% of the risk of\u000a      the full multivariable GRACE risk model. The clinician uses this\u000a      information alongside his or her clinical evaluation to guide management\u000a      of the patient. The app received coverage in UK and international media\u000a      (The Times [5.9], The Times of India and many others) and has been\u000a      requested by NHS England's Pan-London Clinical Leadership Advisory Group\u000a      for Cardiology for use in its inter-hospital transfer system [5.10]. The\u000a      GRACE score will also be incorporated into a \"pocket guidelines\" app\u000a      developed by the ESC for distribution to clinicians in the 55 affiliated\u000a      countries.\u000a    Impact on health and welfare\u000a    The GRACE programme identified that survivors of non-ST elevation ACS\u000a      (previously perceived as minor or threatened heart attacks) had higher\u000a      long-term risks of death and recurrent myocardial infarction and\u000a      ST-elevation myocardial infarction [3.1, 3.2]. In consequence, a series of\u000a      international randomised trials has focussed on improving outcomes in\u000a      non-ST elevation ACS, including Fox's British Heart Foundation-funded RITA\u000a      3 trial. By facilitating appropriate treatment, the GRACE risk score has\u000a      contributed to a change in practice and improved outcomes [3.5]. Fox and\u000a      colleagues demonstrated temporal changes in outcomes, improved use of\u000a      evidence-based therapies, a decline in deaths and myocardial infarction\u000a      and approximately a halving of new heart failure [3.5]. These findings for\u000a      international GRACE sites are corroborated by British Heart Foundation\u000a      statistics. Modelling by the UoE team suggests that implementation of the\u000a      GRACE score results in a saving of 30-80 lives for every 10,000 patients\u000a      presenting with non-ST elevation ACS.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; the GRACE risk score (derived using\u000a      data from 102,000 patients with acute coronary syndrome (ACS) in 30\u000a      countries) identifies high-risk ACS patients more effectively than do\u000a      alternative methods.\u000a    Significance: GRACE is now a reference standard and has resulted\u000a      in international guideline changes. It is estimated to save 30-80 lives\u000a      for every 10,000 patients presenting with non-ST elevation ACS.\u000a    Beneficiaries: Patients with ACS; the NHS and healthcare delivery\u000a      organisations.\u000a    Attribution: All work was led by Fox (UoE) with co-chair Gore\u000a      (University of Massachusetts) and was developed from Edinburgh-based\u000a      studies.\u000a    Reach: Worldwide: guidelines adopted in more than 55 countries;\u000a      >10,000 downloads of app.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6254926","Name":"Massachusetts"}],"References":"\u000a    \u000a3.1 Fox K, Eagle K, Gore J, Steg P, Anderson F; GRACE and GRACE2\u000a      Investigators. The Global Registry of Acute Coronary Events, 1999 to 2009\u000a      — GRACE. Heart. 2010;96:1095-101. DOI: 10.1136\/hrt2009.190827.\u000a    \u000a\u000a3.2 Fox K, Carruthers K, Dunbar D, et al. Underestimated and\u000a      under-recognized: the late consequences of acute coronary syndrome (GRACE\u000a      UK-Belgian Study). Eur Heart J. 2010;31:2755-64. DOI:\u000a      10.1093\/eurheartj\/ehq326.\u000a    \u000a\u000a3.3 Fox K, Anderson F Jr, Goodman S, et al; GRACE Investigators. Time\u000a      course of events in acute coronary syndromes: implications for clinical\u000a      practice from the GRACE registry. Nat Clin Pract Cardiovasc Med.\u000a      2008;5580-9. DOI: 10.1038\/ncpcardio1302.\u000a    \u000a\u000a3.4 Fox K, Dabbous O, Goldberg R, et al. Prediction of risk of death and\u000a      myocardial infarction in the six months after presentation with acute\u000a      coronary syndrome: prospective multinational observational study (GRACE).\u000a      BMJ. 2006;333:1091. DOI: 10.1136\/bmj.38985.646481.55.\u000a    \u000a\u000a3.5 Fox K, Steg P, Eagle K, et al; GRACE Investigators. Decline in rates\u000a      of death and heart failure in acute coronary syndromes, 1999-2006. JAMA.\u000a      2007;297:1892-900. DOI: 10.1001\/jama.297.17.1892.\u000a    \u000a\u000a3.6 Budaj A, Flasinska K, Gore J,...Fox K; GRACE Investigators. Magnitude\u000a      of and risk factors for in-hospital and post discharge stroke in patients\u000a      with acute coronary syndromes: findings from a Global Registry of Acute\u000a      Coronary Events. Circulation. 2005;111:3242-7. DOI:\u000a      10.1161\/CIRCULATIONAHA.104.512806.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    5.1 NICE guideline 94 (March 2010). Unstable angina and NSTEMI The early\u000a      management of unstable angina and non-ST-segment-elevation myocardial\u000a      infarction.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/12949\/47921\/47921.pdf.\u000a    5.2 Hamm C, Bassand J, Agewall S, et al; ESC Committee for Practice\u000a      Guidelines. ESC Guidelines for the management of acute coronary syndromes\u000a      in patients presenting without persistent ST-segment elevation: The Task\u000a      Force for the management of acute coronary syndromes (ACS) in patients\u000a      presenting without persistent ST-segment elevation of the European Society\u000a      of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054. DOI:\u000a      10.1093\/eurheartj\/ehr236.\u000a    5.3 Jneid H, Anderson J, Wright R, et al; American College of Cardiology\u000a      Foundation; American Heart Association Task Force on Practice Guidelines.\u000a      2012 ACCF\/AHA focused update of the guideline for the management of\u000a      patients with unstable angina\/non-ST-elevation myocardial infarction: a\u000a      report of the American College of Cardiology Foundation\/American Heart\u000a      Association Task Force on Practice Guidelines. Circulation,\u000a      2012;126:875-910. DOI: 10.1161\/CIR.0b013e318256f1e0.\u000a    5.4 Paiva L, Providencia R, Barra S, Faustino A, Botelho A, Marques A.\u000a      Cardiovascular risk assessment of pulmonary embolism with the GRACE risk\u000a      score. Am J Cardiol. 2013;111: 425-31. DOI: 10.1016\/j.amjcard.2012.10.020.\u000a    5.5 van der Zee P, Verberne H, Cornel J, et al. GRACE and TIMI risk\u000a      scores but not stress imaging predict long-term cardiovascular follow-up\u000a      in patients with chest pain after a rule-out protocol. Neth Heart J.\u000a      2011;19: 324-30. DOI: 10.1007\/s12471-011-0154-9.\u000a    5.6 Meune C, Drexler B, Haaf P, et al. The GRACE score's performance in\u000a      predicting in-hospital and 1-year outcome in the era of high-sensitivity\u000a      cardiac troponin assays and B-type natriuretic peptide. Heart.\u000a      2011;97:1479-83. DOI: 10.1136\/hrt2010.220988.\u000a    5.7 D'Ascenzo F, Biondi-Zoccai G, Moretti C, et al. TIMI, GRACE and\u000a      alternative risk scores in acute coronary syndromes: a meta-analysis of 40\u000a      derivation studies on 216,552 patients and of 42 validation studies on\u000a      31,625 patients. Contemp Clin Trials. 2012;33:507-14. DOI:\u000a      10.1016\/j.cct2012.01.001.\u000a    5.8 Abu-Assi E, Garciá Acuña J, Peña-Gil C, González-Juanatey J.\u000a      Validation of the GRACE risk score for predicting death within 6 months of\u000a      follow-up in a contemporary cohort of patients with acute coronary\u000a      syndrome. Rec Esp Cardiol 2010; 63(6):640-8. DOI:\u000a      10.1016\/S1885-5857(10)70138-9.\u000a    5.9 The Times (3rd Sep 2013). Scots university app aids\u000a      cardiac diagnosis.\u000a      http:\/\/www.thetimes.co.uk\/tto\/news\/uk\/scotland\/article3859051.ece.\u000a    5.10 Letter from the Pan-London Clinical Leadership Advisory Group for\u000a      Cardiology (August 2013), requesting use of the GRACE risk score app for\u000a      the inter-hospital transfer system. [Available on request.]\u000a    ","Title":"\u000a    A: The GRACE risk score: a reference standard for the management of\u000a        acute coronary syndrome\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Prior to 2000, it was well recognised that acute coronary syndrome (ACS)\u000a      constituted a leading cause of death, but the management and outcome of\u000a      patients with ACS was poorly defined. Trial populations do not reflect the\u000a      full spectrum of patients with ACS and hence do not reflect the diversity\u000a      of clinical practice. Professor Keith Fox (Professor of Cardiology, UoE,\u000a      1989-present; Chair) and co-chair, Joel Gore (University of Massachusetts)\u000a      designed a 10-year programme of research and established the largest\u000a      multi-national study of acute coronary artery disease [3.1]. This built on\u000a      underpinning research in Edinburgh [3.2, 3.3 and the British Heart\u000a      Foundation Randomised Intervention Trials in Angina (RITA) and earlier\u000a      registry programmes]. GRACE (Global Registry of Acute Coronary Events)\u000a      involved more than 102,000 patients in 30 countries [3.1]. This has become\u000a      an international reference standard for the management and outcome of ACS\u000a      and the data are used as the basis for designing large-scale clinical\u000a      trials. The GRACE programme was launched in 1999; since then, the group\u000a      has published 132 manuscripts and presented 119 abstracts at major\u000a      congresses.\u000a    This study, and others, identified the \"risk-treatment paradox\"\u000a      applicable irrespective of geographic region and healthcare system. The\u000a      paradox demonstrates that, in contrast to the evidence, lower-risk rather\u000a      than higher-risk patients receive more intensive medical treatment and\u000a      interventional treatment. The GRACE risk score was designed to address\u000a      this problem by providing clinicians with a powerful yet user-friendly\u000a      means of identifying higher-risk patients at the time of their first\u000a      presentation. Previously used clinical parameters are inadequate to define\u000a      risk; neither is using single biomarkers adequate. To develop the GRACE\u000a      score, Fox and colleagues derived the independent predictors of outcome in\u000a      21,688 patients presenting with ACS and validated the predictions\u000a      prospectively in a further 22,122 patients, with the aim of predicting\u000a      both in-hospital and 6-month risk of death, and death or myocardial\u000a      infarction [3.4]. Moreover, external validation was completed in an\u000a      independent dataset [3.4]. Nine factors independently predicted both death\u000a      and the combination of death or myocardial infarction and conveyed more\u000a      than 90% of the risk. The simplified model was robust with good fit and\u000a      prospectively validated, with C statistics of 0.81 for predicting death\u000a      and 0.74 for predicting death or myocardial infarction. The score has been\u000a      extensively tested by the GRACE team [e.g., 3.5, 3.6] and in many diverse\u000a      healthcare systems, internationally and on all continents.\u000a    By characterising the ACS population, the team was able to define the\u000a      deficiencies in management and outcome and to provide a key resource for\u000a      raising hypotheses for subsequent testing in randomised trials\u000a      (anti-platelet therapy, anti-thrombin therapy and interventional\u000a      strategies). A number of independent international trials have now used\u000a      the GRACE score to define populations at particular risk, and populations\u000a      with the potential for benefit.\u000a    "},{"CaseStudyId":"23870","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"719819","Name":"Hungary"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Pathways to impact\u000a    Improvements made to SCNT and the successful cloning of Dolly the sheep\u000a      challenged the dogma that the genetic material of specialised cells is no\u000a      longer capable of driving the development of a complete animal. This\u000a      momentous achievement opened new frontiers in science, technology and\u000a      medicine. It also inspired heated debate on the essence of humanity among\u000a      scientists, philosophers, religious leaders, politicians and the public.\u000a      Dolly the sheep found her place among major scientific achievements and\u000a      her legacy continues to have enormous impact. Wilmut has played a key role\u000a      in the public engagement surrounding mammalian stem cell cloning,\u000a      delivering 49 public lectures since 2008.\u000a    Impact on society, public scientific and ethical policy\u000a    The realisation that it is possible to clone adult mammals had profound\u000a      implications for religious organisations and led to the introduction of\u000a      new laws and ethical guidelines. Although many were instituted prior to\u000a      2008, the \"legacy of Dolly\" continues to impact on ethical debate in the\u000a      religious, secular and legislative arenas. For example, the cloning of\u000a      Dolly is specifically referred to in a recent church position statement:\u000a      \"A statement of the United States Conference of Catholic Bishops on\u000a      embryonic stem cell research\" published for the first time in June 2008\u000a      [5.1], and in numerous recently published books on ethics [5.2]. \"Dolly\"\u000a      continues to inform governmental thinking and policy: for example, in\u000a      2008, the European Group on Ethics of Science and New Technologies (EGE),\u000a      in response to a request from the European Commission, issued an opinion\u000a      on the ethical implications of cloning animals for food supply [5.3]; and\u000a      the Australian government requested a review of its Prohibition of Human\u000a      Cloning for Reproduction and Research Involving Human Embryos Acts in\u000a      December 2010 [5.4].\u000a    Impact on society, public engagement, arts and culture\u000a    The life and death of Dolly continues to have a significant impact on art\u000a      and culture. For example, a mask taken from Dolly the sheep was one of the\u000a      highlights at the Scottish National Portrait Gallery at its reopening\u000a      after major renovation in 2011 (11,186 visitors within the first four days\u000a      after reopening alone) [5.5], and Krystelle Bamford, a winner of the 2010\u000a      New Writers Award, wrote a poem entitled \"On the Death Mask of Dolly the\u000a      Sheep\" that was published in the November 2012 issue of the American\u000a      Poetry Review, a major international poetry magazine based in the USA\u000a      [5.6]. Dolly and the scientists who created her were also featured in the\u000a      exhibition \"Cells - the smallest of all portraits\", an experimental\u000a      learning project involving pupils from Scottish schools (October 29th\u000a      2012 - February 3rd 2013, Scottish National Portrait Gallery).\u000a    The manner in which Dolly as a scientific icon has caught the public\u000a      imagination is unlike few scientific discoveries of the last decades.\u000a      Starting with extensive broadsheet coverage, including the cover of Time\u000a      magazine (Fig. 1 in section 2), the media interest in and reach of Dolly\u000a      has demonstrated extraordinary breadth and durability. Since 2008,\u000a      reference to Dolly and cloning have appeared in numerous media relevant to\u000a      a wide range of age groups ranging from the \"Itchy & Scratchy\" cartoon\u000a      and \"The Simpsons Comic\" to the recently completed \"Great Tapestry of\u000a      Scotland\", in which a whole panel is devoted to Dolly to represent\u000a      Scottish scientific discovery (Fig. 2).\u000a    \u000a   Fig. 2 The Great Tapestry of Scotland\u000a   \u000a   \u000a  The Simpsons Comic\u000a   \u000a    Impact on society, public engagement and education\u000a    Dolly herself has become a \"scientific icon\" of UK biomedical science and\u000a      is displayed in the National Museum of Scotland in Edinburgh (1.9M\u000a      visitors annually). The National Museum of Scotland website lists Dolly as\u000a      a highlight, and states that \"Dolly has been enormously popular, with\u000a      visitors coming from all over the world to see her. She has even travelled\u000a      to Hungary to open a new science museum in Budapest!\" [5.7].\u000a    The principles of SCNT are now part of the science curriculum at high\u000a      school level in the UK and other countries. Notably, they have been\u000a      integrated into the International Baccalaureate (IB) Diploma curriculum\u000a      [5.8], a two-year educational programme primarily aimed at students aged\u000a      16-19 that provides an internationally accepted qualification for entry\u000a      into higher education, and is recognised by many universities worldwide.\u000a      IB courses are available in 3628 schools in Europe, North America, South\u000a      America, Asia and Africa [5.9].\u000a    Impact on society, public science policy\u000a    Dolly played a major role in clarifying the value of stem cell and\u000a      regenerative medicine research to Government, contributing to the\u000a      establishment of several high-profile initiatives including the UK Stem\u000a      Cell Initiative chaired by Sir John Pattison. More recently, in autumn\u000a      2012, the Chancellor of the Exchequer identified Eight Great Technologies\u000a      of strategic importance to the UK and announced an additional funding of\u000a      £600M to help support their development. Regenerative medicine is placed\u000a      among these great technologies and the influence of Dolly the Sheep and\u000a      Edinburgh's research was highlighted in a speech by the Minister for\u000a      Universities and Science (the Rt Hon David Willetts MP) delivered on\u000a      January 24, 2013 at the Policy Exchange [5.10].\u000a    ","ImpactSummary":"\u000a    Impact: Public engagement and education, influence on public\u000a      ethical and scientific policy.\u000a    Significance: The first demonstration of cloning from an adult\u000a      mammalian somatic cell has stimulated rolling religious, ethical,\u000a      cultural, political and scientific debates. Dolly has become a scientific\u000a      icon entering the public and educational lexicons in addition to\u000a      scientific ones.\u000a    Beneficiaries: Human society, culture, education.\u000a    Attribution: Wilmut and colleagues (Roslin Institute, UoE),\u000a      undertook somatic cell nuclear transfer and used it to perform the first\u000a      successful cloning of an adult mammal.\u000a    Reach: Worldwide: Dolly became a scientific icon that is\u000a      recognisable all around the world, representing a major public engagement\u000a      with bioscience. For example; cloning principles are part of high school\u000a      education including the International Baccalaureate (implemented in\u000a      >3600 schools on five continents).\u000a    ","ImpactType":"Societal","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3054643","Name":"Budapest"}],"References":"\u000a    \u000a3.1 Campbell K, Loi P, Cappai P, Wilmut I. Improved development to\u000a      blastocyst of ovine nuclear transfer embryos reconstructed during the\u000a      presumptive S-phase of enucleated activated oocytes. Biol Reprod.\u000a      1994;50:1385-93. DOI: 10.1095\/biolreprod50.6.1385.\u000a    \u000a\u000a3.2 Otaegui P, O'Neill G, Campbell K, Wilmut I. Transfer of nuclei from\u000a      8-cell stage mouse embryos following use of nocodazole to control the cell\u000a      cycle. Mol Reprod Dev. 1994;39:147-52. DOI: 10.1002\/mrd.1080390205.\u000a    \u000a\u000a3.3 Otaegui P, Waddington D, Wilmut I. Nuclear transfer of 4-cell mouse\u000a      embryos: synchronisation with cytoplast partially overcomes nuclear donor\u000a      cell-cycle effect. J Reprod Fertil Abstr Ser 13. 1994;Abstract 24.\u000a    \u000a\u000a3.4 Campbell K, McWhir J, Ritchie W, Wilmut I. Sheep cloned by nuclear\u000a      transfer from a cultured cell line. Nature. 1996;380:64-6. DOI:\u000a      10.1038\/380064a0.\u000a    \u000a\u000a3.5 Wilmut I, Schnieke A, McWhir J, Kind A, Campbell K. Viable offspring\u000a      derived from fetal and adult mammalian cells. Nature. 1997;385:810-813.\u000a      DOI: 10.1038\/385810a0.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    5.1 A statement of the United States Conference of Catholic Bishops on\u000a      embryonic stem cell research. USCCB Publishing, Washington, D.C., 2008.\u000a      http:\/\/old.usccb.org\/prolife\/issues\/bioethic\/bishopsESCRstmt.pdf.\u000a    5.2 Examples of major books on ethics that specifically mention the\u000a      cloning of Dolly the sheep [available on request]:\u000a    \u000a      Ravitsky V, Fiester A, Caplan A. The Penn Center Guide to Bioethics.\u000a        Springer Publishing Company, New York, USA, 2009.\u000a      Morrison E. Health Care Ethics: Critical Issues for the 21st Century,\u000a        second edition. Jones and Bartlett Publishers, London, UK, 2008.\u000a    \u000a    5.3 The European Group on Ethics in Science and New Technologies to the\u000a      European Commission Opinion 23 - Ethical aspects of animal cloning for\u000a      food supply, 2008.\u000a      http:\/\/ec.europa.eu\/bepa\/european-group-ethics\/docs\/publications\/opinion23_en.pdf.\u000a    5.4 Report of the Independent Review of the Prohibition of Human Cloning\u000a      for Reproduction Act 2002 and Research Involving Human Embryos Act 2002 -\u000a      A Report to the Parliament and the Council of Australian Governments,\u000a      2011.\u000a      https:\/\/legislationreview.nhmrc.gov.au\/files\/legislation_review_reports.pdf.\u000a    5.5 Record number of visitors to Scottish National Portrait Gallery, STV\u000a      news, 6 December 2011 by Clare Carswell. http:\/\/news.stv.tv\/east-central\/285503-scottish-national-portrait-gallery-announces-record-number-of-visitors\/.\u000a      [Corroborates number of visitors to gallery.]\u000a    5.6 Bamford K. On the Death Mask of Dolly the sheep. American Poetry\u000a      Review. Nov\/Dec 2012;41:46. [Available on request.]\u000a    5.7 National Museum of Scotland website.\u000a      http:\/\/www.nms.ac.uk\/our_collections\/highlights\/dolly_the_sheep.aspx.\u000a    5.8 Walpole B, Merson-Davis A, Dann L. Biology for the IB Diploma.\u000a      Cambridge University Press 2011. [Available on request. International\u000a        Baccalaureate diploma programme textbook; Dolly mentioned on page 94].\u000a    5.9 Statistics available from the website of the International\u000a      Baccalaureate Organisation.\u000a      http:\/\/www.ibo.org\/facts\/schoolstats\/progcombinationsbyregion.cfm.\u000a    5.10 Policy: Investing in research,development and innovation; Speech:\u000a      Eight Great Technologies, Minister: The Rt Hon David Willetts MP; Date: 24\u000a      Jan 2013; Place: Policy Exchange; Transcript: https:\/\/www.gov.uk\/government\/speeches\/eight-great-technologies.\u000a    ","Title":"\u000a    V: Dolly the sheep - the first cloned mammal and a public icon for\u000a        regenerative medicine\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Sir Ian Wilmut (Chair of Reproductive Biology, UoE, 1973-2011;\u000a      now Emeritus) led the team that used somatic cell nuclear transfer (SCNT)\u000a      to create Dolly. This scientific breakthrough is widely recognised as the\u000a      key stepping stone between the earlier amphibian-based work of Gurdon and\u000a      the reprogramming of adult human somatic cells to a stem cell state\u000a      (induced pluripotent stem cells) by Yamanaka.\u000a    Wilmut, with colleagues from the Roslin Institute (now UoE), focused\u000a      their scientific efforts on the manipulation of eggs (female reproductive\u000a      cells), oocytes (egg precursor cells) and stem cells (cells that can\u000a      divide and self-renew, but also differentiate into diverse specialised\u000a      cell types). They were particularly interested in utilising SCNT to\u000a      produce viable embryos. This technique involves transfer of the nucleus\u000a      from a somatic cell (any cell that is not a reproductive or stem cell)\u000a      into an oocyte or egg deprived of its own nucleus (cytoplast).\u000a    In 1994, Wilmut and colleagues discovered that the development of embryos\u000a      reconstructed by nuclear transfer is related to interactions between the\u000a      donor nucleus and the recipient cytoplasm at the time of fusion and during\u000a      the first cell cycle after reconstruction [3.1]. This led to the proposal\u000a      of two distinct protocols for embryo reconstruction by nuclear transfer\u000a      when using MII oocytes (oocytes at the metaphase II stage of cell\u000a      division) as cytoplasts: (i) transfer of nuclei in G1 phase of the cell\u000a      cycle into MII cytoplasts containing a high activity of the so-called\u000a      maturation-promoting factor (MPF), and (ii) transfer of nuclei in G1, S or\u000a      G2 phase into enucleated oocytes after the disappearance of MPF activity\u000a      (in the so-called \"universal recipient\" stage). The group also showed that\u000a      it was possible to use microtubule inhibitors such as nocodazole to hold\u000a      cells in mitosis before releasing them and using them as nuclear donors as\u000a      they passed through G1 phase [3.2, 3.3]. Unfortunately, although this\u000a      synchronisation method worked in mice, it proved to be unreliable in\u000a      embryos of livestock species. Consequently, Wilmut and colleagues\u000a      developed a different approach for the synchronisation of donor nuclei.\u000a      The approach was based on serum-starvation of donor cells, which forced\u000a      them to arrest in the G0\/G1 phase of the cell cycle (the so-called state\u000a      of quiescence). This enabled the successful cloning of sheep from cultured\u000a      cells derived from sheep embryos. This study was published in early 1996\u000a      [3.4]. The same procedure allowed the group to clone a sheep using a\u000a      nucleus derived from an adult mammary gland cell. Dolly — the first cloned\u000a      adult mammal — was born on July 5, 1996, providing the first evidence that\u000a      adult specialised cells are capable of driving the development of a\u000a      complete and fertile animal. This first successful cloning of an adult\u000a      mammal was reported in Nature in 1997 [3.5] and met with huge and\u000a      sustained public and media interest (Fig. 1).\u000a\u0009  \u000a      Fig. 1\u000a\u0009  \u000a    "},{"CaseStudyId":"23871","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2658434","Name":"Switzerland"}],"Funders":[],"ImpactDetails":"\u000a    Although Campbell and Rudan's work with CHERG showed that pneumonia was\u000a      the largest single\u000a      cause of global child mortality in 2008 [3.1], it was receiving\u000a      considerably less global investment\u000a      and attention than other conditions such HIV and malaria. Clearly,\u000a      effective action on global child\u000a      pneumonia mortality was an essential part of reaching the United Nations\u000a      Millennium Development\u000a      Goal 4 set in 2005 by 170 Heads of State to reduce global child mortality\u000a      by two thirds from 1990-2015.\u000a      This has been triggered as a direct consequence of Campbell and Rudan's\u000a      work\u000a    The CHERG committee, including Campbell and Rudan as pneumonia technical\u000a      advisers [5.1] met\u000a      every 6 months from 2000-2013. WHO and UNICEF attended all meetings; other\u000a      international\u000a      agencies (e.g., Save the Children Fund, Global Alliance on Vaccines and\u000a      Immunisations (GAVI),\u000a      US Agency for International Development (USAID), Bill and Melinda Gates\u000a      Foundation) attended\u000a      when appropriate.\u000a    Impact on public policy\u000a    Campbell and Rudan have regularly acted as advisers \/ working group\u000a      chairs on child pneumonia\u000a      to WHO (30 occasions since 1993) [5.2], the UK government (All-Party\u000a      Parliamentary Group for\u000a      Global Action Against Childhood Pneumonia), UNICEF [5.3] and other\u000a      international agencies.\u000a    CHERG's pneumonia disease estimates were adopted not only by WHO and\u000a      UNICEF [5.2-5.5] but\u000a      also by major international agencies (including GAVI, Save the Children\u000a      Fund and the Bill and\u000a      Melinda Gates Foundation). Lancet editor Richard Horton (#richardhorton1)\u000a      tweeted on 24\/5\/2013\u000a      \"CHERG has made stellar contributions to our understanding of child\u000a      health.\" This recognition has\u000a      led directly to increased emphasis and priority given by international\u000a      agencies and national health\u000a      systems to tackling this problem. Examples include:\u000a    \u000a      Impact on WHO and UNICEF policy, leading to the establishment in 2009\u000a        of a Global Action\u000a        Plan on Pneumonia (GAPP). Campbell and Rudan led the pneumonia overview,\u000a        published in a\u000a        Bulletin WHO supplement, which assisted in preparation of the GAPP\u000a        document [5.6]. This\u000a        ongoing action plan gives renewed emphasis to pneumonia control. It has\u000a        led to increased\u000a        coverage of effective pneumonia interventions, for example through the\u000a        initiation of community\u000a        case-management programmes (by community health workers) and the\u000a        investment in new\u000a        pneumonia vaccines (see point 2 and [5.7]).\u000a      Impact on GAVI to give priority to the accelerated global\u000a        implementation of pneumonia vaccines\u000a        (Hib and pneumococcal conjugate vaccines). There was a steep\u000a        acceleration in uptake of Hib\u000a        conjugate vaccine by low- and middle-income countries from 2007\/8 with\u000a        50 countries introducing\u000a        Hib conjugate vaccine into their national vaccination schedules over the\u000a        period 2008-13. Similarly,\u000a        the uptake of pneumococcal conjugate vaccine, from its introduction in\u000a        2004, accelerated from\u000a        2007\/8, with more than 50 countries introducing this vaccine from 2008\u000a        onwards.\u000a      Impact on the >190 member states of the World Health Assembly (WHA)\u000a        (2010). Campbell\u000a        initiated a UK action to lead a WHA pneumonia resolution (WHA63.24 -\u000a        Accelerated progress\u000a        towards achievement of MDG4 to reduce child mortality: prevention and\u000a        treatment of pneumonia).\u000a        Campbell met Chief Medical Officer (CMO) Sir Liam Donaldson to propose\u000a        and help draft the\u000a        resolution, and was technical consultant to the UK delegation in Geneva\u000a        in 2010. Ministers of\u000a        Health, CMOs and other senior health officials from the 170 Member\u000a        States constituting the WHA\u000a        endorsed the resolution on the Control of Pneumonia, committing them to\u000a        adoption of pneumonia\u000a        control policies and actions and to giving increased priority to this\u000a        problem [5.8].\u000a    \u000a    Impact on health and welfare\u000a    One of the major success stories in international health has been the\u000a      substantial progress made\u000a      since 2000 in the reduction of global child mortality. This has fallen\u000a      from 11 million deaths per year\u000a      in 2000 to 6.9 million per year in 2012. The largest single cause of death\u000a      over this period, and the\u000a      disease showing the largest relative and absolute rate of mortality\u000a      reduction over the period of\u000a      REF2014, is child pneumonia [3.1]. There have been approximately 1M fewer\u000a      child pneumonia\u000a      deaths over the period 2008-12 than if 2008 mortality levels has\u000a      persisted. These falls in mortality\u000a      have occurred in >170 countries, with the main impact in low- and\u000a      middle-income countries. These\u000a      estimates have been endorsed in WHO and UNICEF documents [5.4 a & b,\u000a      5.5]. WHO and\u000a      UNICEF consider that the direct action to prevent and treat child\u000a      pneumonia that has been taken\u000a      by national governments and international agencies, driven by the clear\u000a      need and imperative\u000a      demonstrated by the work of Campbell, Rudan and CHERG, is the major cause\u000a      of the mortality\u000a      reduction.\u000a    Impact on society\u000a    Campbell spoke at the global launch (in New York) of the World Pneumonia\u000a      Day movement in\u000a      2007, which has since grown worldwide [5.9]. In 2011, it included\u000a      activities in 25 countries\u000a      worldwide to support pneumonia control efforts. This led to the creation\u000a      of a Global Coalition\u000a      Against Child Pneumonia in 2009 comprising over 140 non-governmental\u000a      organisations, civil\u000a      society organisations, academic institutions (including UoE) and\u000a      government agencies [5.9].\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; raised awareness of childhood\u000a      pneumonia as the largest single cause\u000a      of global childhood mortality, which has led to increased investment and\u000a      action. Global deaths\u000a      have reduced from 2.01M (in 2002) to 1.58M (2008) and 1.26M (2011).\u000a    Significance: Global child pneumonia mortality (2008-2013) showed\u000a      about 1M deaths fewer than\u000a      if 2008 levels had persisted throughout this period.\u000a    Attribution: Campbell and Rudan (UoE) derived global pneumonia\u000a      incidence and mortality\u000a      estimates as the pneumonia technical experts for the WHO \/ UNICEF Child\u000a      Health Epidemiology\u000a      Reference Group.\u000a    Beneficiaries: Young children and families, international\u000a      agencies, Ministries of Health.\u000a    Reach: Global (>170 countries on all continents, especially\u000a      low- and middle-income countries).\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5128638","Name":"New York"},{"GeoNamesId":"2660646","Name":"Genève"}],"References":"\u000a    \u000a3.1 Liu L, Johnson H, Cousens S,...Rudan I, Campbell H, et al; Child\u000a      Health Epidemiology\u000a      Reference Group of WHO and UNICEF. Global, regional, and national causes\u000a      of child mortality: an\u000a      updated systematic analysis for 2010 with time trends since 2000. Lancet.\u000a      2012;379:2151-61.\u000a      DOI: 10.1016\/S0140-6736(12)60560-1.\u000a    \u000a\u000a3.2 Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H; WHO Child Health\u000a      Epidemiology\u000a      Reference Group. Global estimate of the incidence of clinical pneumonia\u000a      among children under\u000a      five years of age. Bull World Health Organ. 2004;82:895-903. DOI:\u000a      10.1590\/S0042-96862004001200005.\u000a    \u000a\u000a3.3 Black R, Cousens S, Johnson H,...Rudan I,...Campbell H, et al; Child\u000a      Health Epidemiology\u000a      Reference Group of WHO and UNICEF. Global, regional, and national causes\u000a      of child mortality in\u000a      2008: a systematic analysis. Lancet. 2010;375:1969-87. DOI:\u000a      10.1016\/S0140-6736(10)60549-1.\u000a    \u000a\u000a3.4 Bryce J, Boschi-Pinto C, Shibuya K, Black R; WHO Child Health\u000a      Epidemiology Reference\u000a      Group (including Campbell as pneumonia technical expert). WHO estimates of\u000a      the causes of death\u000a      in children. Lancet. 2005;365:1147-52. DOI: 10.1016\/S0140-6736(05)71877-8.\u000a    \u000a\u000a3.5 Theodoratou E, Zhang J, Kolcic I,...Rudan I, Campbell H. Estimating\u000a      pneumonia deaths of\u000a      post-neonatal children in countries of low or no death certification in\u000a      2008. PLoS One.\u000a      2011;6:e25095. DOI: 10.1371\/journal.pone.0025095.\u000a    \u000a\u000a3.6 Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H.\u000a      Epidemiology and etiology of\u000a      childhood pneumonia. Bull World Health Organ. 2008;86:408-16. DOI:\u000a      10.2471\/BLT.07.048769.\u000a    \u000aKey Grants:\u000a    Bill and Melinda Gates Foundation (US$1.8M) Modelling the impact of\u000a      emerging interventions\u000a      against pneumonia. (Rudan and Campbell co-PIs.)\u000a    Bill and Melinda Gates Foundation (US$10M) Child Health Epidemiology\u000a      Reference Group. (Black,\u000a      Johns Hopkins University PI; Campbell and Rudan sub-grantees to support\u000a      their CHERG\u000a      research.)\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    5.1 Letter from Chair of International Health, Johns Hopkins University\u000a      and chair of CHERG.\u000a      [Available on request. Confirms Campbell and Rudan's role in CHERG as\u000a        technical experts on\u000a        pneumonia and from 2011 Campbell's role as co-chair of CHERG].\u000a    5.2 Letter from Director of WHO Maternal and Child Health Programme,\u000a      Geneva. [Available on\u000a        request. Confirms Campbell and Rudan's role in CHERG and its influence\u000a        on WHO global child\u000a        health policy; role of Campbell and Rudan in Global Action Plans on\u000a        pneumonia control.]\u000a    5.3 Letter from Head of Health, UNICEF, New York [Available on\u000a        request. Confirms Campbell\u000a        and Rudan's role in CHERG and its influence on global health\u000a        priority-setting by UNICEF.]\u000a    5.4 (a) WHO (2009). Global Action Plan for the Prevention and Control of\u000a      Pneumonia 2009.\u000a      http:\/\/www.unicef.org\/media\/files\/GAPP3_web.pdf;\u000a    (b) WHO \/ UNICEF, 2013, Integrated Global Action Plan for the Prevention\u000a      and Control of\u000a      Pneumonia and Diarrhoea.\u000a      http:\/\/apps.who.int\/iris\/bitstream\/10665\/79200\/1\/9789241505239_eng.pdf\u000a      [These documents cite\u000a        and show official endorsement of CHERG estimates.]\u000a    5.5 UNICEF (2006). Pneumonia: the forgotten killer of children.\u000a      http:\/\/www.childinfo.org\/files\/Pneumonia_The_Forgotten_Killer_of_Children.pdf\u000a      [This UNICEF\u000a        policy document acknowledges the contribution of Campbell and Rudan and\u000a        show official\u000a        endorsement of CHERG estimates; this pre-2008 policy fed into REF-period\u000a        impact on mortality.]\u000a    5.6 Letter from the Coordinator of the Expanded Programme on\u000a      Immunization, WHO Department\u000a      of Immunization, Vaccines and Biologicals, Geneva. [Available on\u000a        request. Confirms Campbell and\u000a        Rudan's role in the establishment of the Global Action Plan on\u000a        Pneumonia.]\u000a    5.7 International Vaccine Access Centre (2012). IVAC Vaccine Information\u000a      Management System\u000a      report 2012 poster.\u000ahttp:\/\/www.jhsph.edu\/research\/centers-and-institutes\/ivac\/vims\/IVAC-VIMS_Report-2012-03.pdf.\u000a      [Hib vaccine introduction in 22 countries in 2007, 65 countries in 2011\u000a        and >70 (projected) in 2013 - page 7; PCV vaccine introduction in 0\u000a        countries in 2007, 18\u000a        countries in 2011 and >50 (projected) in 2013 - page 11.]\u000a    5.8 WHO (2010). Sixty-third World Health Assembly, Resolutions and\u000a      Decisions.\u000a      http:\/\/apps.who.int\/gb\/ebwha\/pdf_files\/WHA63-REC1\/WHA63_REC1-en.pdf.\u000a      [Endorsement of the\u000a        resolution on the control of pneumonia, led by Campbell.]\u000a    5.9 World Pneumonia Day (2011). World Pneumonia Day global report 2011\u000a      http:\/\/worldpneumoniaday.org\/wp-content\/uploads\/2012\/04\/World-Pneumonia-Day-2011-online.pdf.\u000a      [Details achievements including 62 events in 29 countries across 6\u000a        continents (including\u000a        thousands of children receiving free healthcare); 24 local organisations\u000a        in 14 countries receiving\u000a        grants; direct targeting of 11 governments; 240 unique news stories in\u000a        52 countries.]\u000a    \u000a    ","Title":"\u000a    Q: Accurate epidemiological pneumonia incidence and mortality\u000a        estimates have influenced child health policy to reduce global child\u000a        pneumonia mortality\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Harry Campbell (Director, Centre for Population Health\u000a      Sciences, UoE, 1995-present)\u000a      and Professor Igor Rudan (Research Director, Centre for Population Health\u000a      Sciences, UoE, 2001-present)\u000a      have conducted epidemiological research on child pneumonia, publishing\u000a      over 50 papers.\u000a      These include estimates of disease burden, pneumonia vaccine\u000a      immunogenicity, prevalence of risk\u000a      factors, estimates of effectiveness of interventions, and the WHO\u000a      pocketbook of Hospital Care for\u000a      Children (Campbell was overall editor and author of pneumonia chapter).\u000a    Campbell and Rudan were founding members and the pneumonia technical\u000a      experts from 2001\u000a      (with Campbell acting as deputy chair 2011-) of the Child Health\u000a      Epidemiology Reference Group\u000a      (CHERG), which was established by WHO \/ UNICEF to conduct research to\u000a      prepare global child\u000a      disease burden estimates and advise international agencies and national\u000a      governments. Campbell\u000a      and Rudan's subsequent research on pneumonia mortality, under the auspices\u000a      of CHERG,\u000a      involved extensive systematic literature review (including in Chinese\u000a      language databases) and\u000a      identification of unpublished data sources coupled to interpretation and\u000a      assembly of routine death\u000a      certification (vital registration) from every country, and verbal autopsy\u000a      data from large international\u000a      surveys. The analysis involved complex statistical modelling of data [3.1,\u000a      3.2]. The resultant child\u000a      pneumonia mortality estimates were published in several Lancet [3.1, 3.3,\u000a      3.4] and other [3.5]\u000a      papers. (Reference 3.3 was the most highly cited paper published in Lancet\u000a      2010-12: source\u000a      Lancet). Thus, CHERG (with pneumonia technical leadership by Campbell and\u000a      Rudan) detailed the\u000a      major causes of child death and estimated the magnitude of this burden for\u000a      > 170 countries over\u000a      the period 2000 to date.\u000a    Using similar methods, Campbell and Rudan also published the first global\u000a      incidence estimates for\u000a      childhood pneumonia in 2004 and 2008 [3.3, 3.6].\u000a    The high international quality of this research is indicated by Campbell\u000a      and Rudan publishing 10\u000a      Lancet original papers and two commentaries on child pneumonia over the\u000a      last 10 years.\u000a    Most recently, Campbell and Rudan were invited by WHO and UNICEF (as part\u000a      of their Global\u000a      Action Plan for the control of Pneumonia and Diarrhoea) to review progress\u000a      in pneumonia control\u000a      (2000 to 2013), which was published as a \"Lancet series\" in 2013. Campbell\u000a      and Rudan spoke at\u000a      the global launch of the series in London and Washington DC.\u000a    "},{"CaseStudyId":"23872","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Pathways to impact\u000d\u000a      The founding by Ghazal of a cross-disciplinary research Centre (ScGTI) to\u000d\u000a      facilitate and foster multidisciplinary interactions within and between\u000d\u000a      academia and industry was essential to generate innovation within a\u000d\u000a      rapidly emerging yet poorly served field. Ghazal identified the biological\u000d\u000a      applications and, with the founding team, enabled determination of the\u000d\u000a      essential set of materials and processes needed to convert this early\u000d\u000a      technology (developed with UoE) into a working commercial product. Using\u000d\u000a      experience gained from founding an earlier microarray-based company in\u000d\u000a      Scotland, Ghazal with the founding team secured initial first-round\u000d\u000a      funding to form a spin-out company to attract private investment and to\u000d\u000a      develop the technology. The company, Lab901, was formed in 2002 with\u000d\u000a      initial investment contacts provided by Ghazal and commercialisation led\u000d\u000a      by Fearnley and Polwart. From the outset Lab901 established research\u000d\u000a      facilities and a development team at an industrial park.\u000d\u000a    The founding patent for the company was granted in full in 2012. Lab901\u000d\u000a      initially secured £0.23M funding in 2002 with further rounds in 2003\u000d\u000a      (£0.56M), 2004 (£0.34M), 2006 (£1.34M and £1.5M), 2008 (£3.6M) and 2009\u000d\u000a      (£2.4M). Lab901 worked collaboratively with UoE, especially in the early\u000d\u000a      phases of its development, but this reduced as the business started to\u000d\u000a      develop and market its products. From 2007, Lab901 employed between 40 and\u000d\u000a      50 people and this employment has been maintained since its acquisition.\u000d\u000a      Currently there are approximately 160 employees at the Edinburgh facility;\u000d\u000a      this includes all of the original employees of Lab901.\u000d\u000a    Impact on commerce and the economy\u000d\u000a      The first product sales of ScreenTape™ were in 2008. From 2008-2013,\u000d\u000a      product sales reached over £[text removed for publication]. In February\u000d\u000a      2011, Lab901 was acquired by the US multinational company, Agilent: the\u000d\u000a      world's premier measurement company and a technology leader in chemical\u000d\u000a      analysis, life sciences, diagnostics, electronics and communications\u000d\u000a      [5.1-5.3]. The acquisition price was £[text removed for publication].\u000d\u000a      Agilent's 20,000 employees serve customers in more than 100 countries, and\u000d\u000a      it had revenues of US$6.9B in fiscal 2012. The acquisition resulted in\u000d\u000a      UoE-generated IP being preserved and maintained, 50 employees from Lab901\u000d\u000a      securing continued employment with Agilent, a further 110 jobs being\u000d\u000a      created, considerable inward investment and wealth creation in the UK and\u000d\u000a      beyond, and global market opportunities for the product [5.4].\u000d\u000a    Impact on practitioners and services\u000d\u000a      The product, ScreenTape™, has been bought and used by a wide range of\u000d\u000a      practitioners, including research and diagnostic laboratories.\u000d\u000a      Applications of the microfluidic ScreenTape™ tool were developed by Lab901\u000d\u000a      for DNA and genomics analysis [5.5], including workflows for next-\u000d\u000a      generation sequencing, for rapid high-sensitivity quality-control analysis\u000d\u000a      for RNA, and for proteins and antibodies.\u000d\u000a    Impact on health and welfare\u000d\u000a      ScreenTape™ has been used by both academic and diagnostic laboratories\u000d\u000a      around the world, and has recently secured a global market presence\u000d\u000a      through the acquisition of Lab901 and sales by Agilent [5.4, 5.5].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: New business, technology, intellectual property and\u000d\u000a      employment resulting from the invention and exploitation of a micro-scale\u000d\u000a      laboratory device (ScreenTapeTM).\u000d\u000a    Significance: New business and technology commercialised resulting\u000d\u000a      in sales of novel products worldwide, acquisition by Agilent Technologies\u000d\u000a      Limited (Agilent) for £[text removed for publication] in 2011, product\u000d\u000a      sales of over £[text removed for publication] to August 2013, generation\u000d\u000a      of sustained employment for 50-160 people, major inward investment (£6M)\u000d\u000a      by local investors followed by a US multinational.\u000d\u000a    Beneficiaries: The economy, commerce, employment, research and\u000d\u000a      diagnostic laboratories, Agilent Technologies Inc. (Agilent).\u000d\u000a    Attribution: UoE Prof Peter Ghazal and Dr Douglas Roy inventors on\u000d\u000a      granted patent, establishment of multi-disciplinary research in biochip\u000d\u000a      medicine, collaborators with ex-Motorola engineers, co-founders of\u000d\u000a      spin-out company for commercialisation of intellectual property.\u000d\u000a    Reach: Worldwide, including employment and product sales. Inward\u000d\u000a      investment to UK.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Publication was restricted for commercialisation reasons.\u000d\u000a    \u000a3.1 Polwart, Fearnley, Roy and Ghazal. US patent granted 28 February\u000d\u000a      2012: \"Apparatus and methods for microfluidic applications\", US8124029B2.\u000d\u000a      This patent describes a non-rigid tape apparatus and fabrication methods\u000d\u000a      for microfluidic processing applications such as gel electrophoresis are\u000d\u000a      provided, where microfluidic processing is performed on selected areas.\u000d\u000a      Foreign patent documents: 0 976 453; 1388369; WO 94 26414; WO 97 47967;\u000d\u000a      WO9919717; WO 99 03584; WO 99 19717; WO 99 43432; WO 99\/65664; WO 01\u000d\u000a      07892; WO 01 26812; WO 01 30490; WO 01 54814; WO 02\/081934; WO 03\/045557;\u000d\u000a      WO 2004\/071660; WO 2004\/080597(http:\/\/www.google.com\/patents\/US6863878).\u000d\u000a    \u000a\u000a3.2 Edinburgh Research and Innovation (ERI) licence\/revenue-sharing\u000d\u000a      agreement ref: LIC2200065. ERI tech ID: TECH1100400. [Available on\u000d\u000a        request. Provides details of inventive contributions.]\u000d\u000a    \u000a\u000a3.3 Laghaee A, Malcolm C, Hallam J, Ghazal P. Artificial intelligence and\u000d\u000a      robotics in high-throughput post-genomics. Drug Discov Today.\u000d\u000a      2005;10:1253-9. DOI: 10.1016\/S1359-6446(05)03581-6.\u000d\u000a    \u000a\u000a3.4 Livingston A, Campbell C, Wagner E, Ghazal P. Biochip sensors for the\u000d\u000a      rapid and sensitive detection of viral disease. Genome Biol. 2005;6:112.\u000d\u000a      DOI: 10.1186\/gb-2005-6-6-112.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"8","Level2":"1","Subject":"Artificial Intelligence and Image Processing"},{"Level1":"1","Level2":"2","Subject":"Applied Mathematics"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    5.1 Agilent Technologies Inc. acquisition (Feb 2011):\u000d\u000a\u0009http:\/\/www.agilent.com\/about\/newsroom\/presrel\/2011\/28feb-gp11006.html.\u000d\u000a    5.2 Scottish Investment Bank Annual Review 2010-2011. http:\/\/www.scottish-enterprise.com\/~\/media\/SE\/Resources\/Documents\/STUV\/Scottish-Investment-Bank-Annual-Review-2010-2011.ashx.\u000d\u000a    5.3 Investors press release at acquisition by Agilent (Mar 2011):\u000d\u000a\u0009http:\/\/www.tricapital.co.uk\/content\/news\/LAB901Exit.php.\u000d\u000a    5.4 Agilent Technologies Inc. global launch of product (Nov 2011):\u000d\u000a\u0009http:\/\/www.agilent.com\/about\/newsroom\/presrel\/2011\/07nov-ca11075.html.\u000d\u000a    5.5 Agilent Technologies Inc. launches genomic DNA ScreenTape (Feb 2013).\u000d\u000a      http:\/\/www.agilent.co.uk\/about\/newsroom\/presrel\/2013\/20feb-ca13014.html.\u000d\u000a    ","Title":"\u000d\u000a    T: Commercialisation of ScreenTape™ — a microfluidic tool for\u000d\u000a        genomics, next-generation sequencing and proteomic analysis\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Peter Ghazal (Professor of Molecular Genetics and Biomedicine,\u000d\u000a      UoE, 2000-present) and Dr Douglas Roy (Senior Lecturer, UoE,\u000d\u000a      1983-present), working with colleagues in Motorola, developed and patented\u000d\u000a      a means to separate DNA in meso-scale on a tape. This led directly to the\u000d\u000a      development of a product: ScreenTapeTM, now established as a\u000d\u000a      micro-scale laboratory design for analytical and high throughput\u000d\u000a      automation in genomics and proteomics.\u000d\u000a    New microfluidic tools for genomics, proteomics, metabolomics research\u000d\u000a      and medicine are rapidly progressing in research, with potential\u000d\u000a      applications in diagnostics and point-of-care devices. Performing\u000d\u000a      laboratory operations at micro\/meso-scales enables the use of small\u000d\u000a      quantities of samples and reagents, the ability to carry out ultrafast\u000d\u000a      separations and detections with high sensitivity and resolution, and\u000d\u000a      massively reduces costs. The design and fabrication of such systems is\u000d\u000a      extremely challenging.\u000d\u000a    Prof Peter Ghazal was founding Principal Investigator (PI) and Director\u000d\u000a      of the Scottish Centre for Genomic Technology and Informatics (ScGTI) in\u000d\u000a      2001, a multidisciplinary academic model to foster an engineering link\u000d\u000a      with genomics. As PI, he raised £10.4M in grant funds from European and UK\u000d\u000a      sources between 2003 and 2007, followed by a further £2.3M in 2010,\u000d\u000a      establishing a vibrant inter- and multi-disciplinary Centre incorporating:\u000d\u000a    \u000d\u000a      application and development of custom and high-density\u000d\u000a        bioarray\/microarray platforms for gene expression and proteomic studies;\u000d\u000a      utilisation of high-throughput approaches in biomedical and clinical\u000d\u000a        research;\u000d\u000a      computational and systems biology; and\u000d\u000a      an environment for translational research and the development of\u000d\u000a        commercial enterprises based on innovation, intellectual property and\u000d\u000a        technology development,\u000d\u000a    \u000d\u000a    From ScGTI\/DPM's inception, industry and the private sector were engaged\u000d\u000a      through outreach programmes including collaborations with ex-Motorola\u000d\u000a      engineers Stuart Polwart and Joel Fearnley, which culminated in the\u000d\u000a      generation of novel IP [3.1] (granted in 2012) for the development and\u000d\u000a      commercialisation of the product \"ScreenTape™\". Named inventors included\u000d\u000a      Ghazal and Roy. Ghazal and Polwart made the principal inventive\u000d\u000a      contributions in concept and design [3.2], conceived, designed and\u000d\u000a      performed the first proof-of-concept experiments, involving separation of\u000d\u000a      DNA in a meso-scale channel on a tape. This successful collaboration\u000d\u000a      between UoE and industry was secured by the biological know-how of Ghazal\u000d\u000a      and Roy with the engineering know-how of Polwart and Fearnley. With an\u000d\u000a      initial investment of £230K from Angel Investors, in 2002 the team\u000d\u000a      launched a spin-out company for product development and further enablement\u000d\u000a      of patent claims. Ghazal and Roy were non-executive scientific advisors,\u000d\u000a      Fearnley was CEO and Polwart CTO. The product, ScreenTape™, took over 6\u000d\u000a      years to develop from a simple concept to the first point-of-sale; the\u000d\u000a      first main customer was in 2008, a Korean Diagnostic firm using\u000d\u000a      ScreenTape™ for multiple pathogen screening in hospitals and airports.\u000d\u000a      After multiple rounds of funding, the company was acquired by the US\u000d\u000a      multinational Agilent.\u000d\u000a    ScreenTape™ is based on a micro-scale laboratory fabricated in a plastic\u000d\u000a      substrate (Lab-on-a-Tape) for analytical and high-throughput laboratory\u000d\u000a      automation in genomics and proteomics research [3.3, 3.4]. It comprises a\u000d\u000a      unique \"credit card\" size, automated laboratory that is easy to use and,\u000d\u000a      with scalable throughput, ideally suited for rapid (under 10 minutes)\u000d\u000a      sample quality control in (a) next-generation sequencing and gene\u000d\u000a      expression monitoring work flows, (b) protein electrophoresis and DNA\u000d\u000a      fragment separation, and (c) RNA separation and quality control using\u000d\u000a      proprietary software. Because it is a closed system, it is suited to\u000d\u000a      diagnostics. For a video of the product see: http:\/\/www.youtube.com\/watch?v=N2DU_Udvvts.\u000d\u000a\u000d\u000a\u000d\u000a\u000d\u000a    The picture above shows the first ScreenTape™ product (P200) for the\u000d\u000a      rapid separation of DNA fragments, in particular PCR fragments less than\u000d\u000a      200 base-pairs. It has overall dimensions that are similar to those of an\u000d\u000a      old 35-mm film. Fabricated in the device is a series of columns that are\u000d\u000a      pre-packed with running gel and reagents. Integrated at the ends of the\u000d\u000a      column are electrode contact points. The ScreenTape™ is loaded and samples\u000d\u000a      run in an automated sample loader machine.\u000d\u000a    "},{"CaseStudyId":"23873","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"290557","Name":"United Arab Emirates"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000a    Approximately 50% of hysterectomies performed worldwide are for the\u000a      treatment of symptomatic\u000a      uterine fibroids (12,000 per year in the UK). Fibroids thus constitute a\u000a      major public health problem\u000a      and it was crucial to know whether UAE is a useful alternative. Murray's\u000a      work has clarified that\u000a      UAE is superior to surgery in the short term.\u000a    Impact on public policy\u000a      The REST trial has informed key clinical guidelines. The 2010 NICE\u000a      guidance on UAE for fibroids\u000a      [5.1] was informed by Murray and colleagues' publication [3.1] together\u000a      with a pre-publication\u000a      version of the follow-up paper [3.2]. The fact that NICE sought this\u000a      pre-publication version reflects\u000a      the lack of robust long-term evidence prior to the REST trial being\u000a      conducted. The REST results\u000a      also formed a key part of the evidence base for the 2009 report by a joint\u000a      working party of the\u000a      Royal College of Obstetricians and Gynaecologists and the Royal College of\u000a      Radiologists on the\u000a      use of UAE in the management of fibroids [5.2]. The REST study is also\u000a      cited in NICE guidelines\u000a      on heavy menstrual bleeding [5.3], which endorse the use of UAE for\u000a      treatment of fibroids.\u000a    Internationally, REST is cited by the American College of Radiology\u000a      Appropriateness Criteria®\u000a      Expert Panel on Interventional Radiology [5.4] and in a review published\u000a      in the Australian and New\u000a      Zealand Journal of Obstetrics and Gynaecology [5.5], both of which endorse\u000a      the use of UAE,\u000a      based on the REST data.\u000a    The relevant Cochrane systematic review was updated in 2012 [5.6]. There\u000a      are still only six\u000a      randomised trials published in the area, only two of which (including\u000a      REST) report follow-up data to\u000a      5 years. Notably, REST has the greatest number of UAE procedures to be\u000a      evaluated within any\u000a      single randomised trial.\u000a    In addition, the primary publication [3.1] has affected professional\u000a      standards for reporting trial\u000a      results, with the paper being flagged in the British Medical Journal [5.7]\u000a      as a model for good\u000a      reporting of patient flow through a trial.\u000a    Impact on clinical practice\u000a      Although the numbers of UAE procedures are not readily available, a 2011\u000a      survey by the Medical\u000a      Technology Group [5.8] showed that 90% of primary care trusts in England\u000a      now routinely\u000a      commission UAE, with UAE accounting for 10% of all in-patient treatments\u000a      for women with fibroids.\u000a      Across Europe, a 2009 survey of members of the Cardiovascular and\u000a      Interventional Radiological\u000a      society of Europe [5.9] showed widespread access to UAE, with the UK\u000a      containing the greatest\u000a      number of providing centres. The REST trial was again cited in this survey\u000a      as providing clinical\u000a      rationale for the procedure.\u000a    Impact on health and wellfare\u000a      Women considering UAE rather than hysterectomy as a treatment for their\u000a      symptomatic fibroids\u000a      are now able to make an informed choice comparing the immediate benefits\u000a      (including faster\u000a      recovery time) of the less-invasive UAE against the greater 5-year risk\u000a      (32% with UAE compared\u000a      with 4% with surgery) of the need for subsequent re-intervention to\u000a      control emergent symptoms.\u000a    Impact on the economy\u000a      The Royal College of Obstetricians and Gynaecologists working party report\u000a      [5.2] highlights the\u000a      finding that although UAE is cost-effective relative to surgery when\u000a      evaluated at 12-months follow-up, the economic benefit in favour of UAE\u000a      diminishes over time with the increased need for re-interventions, and is\u000a      negated after five years.\u000a    ","ImpactSummary":"\u000a    Impact: Health and welfare; a UK clinical trial of uterine artery\u000a      embolisation (UAE), with five-year\u000a      follow-up, defined the risk- and cost-benefit of UAE versus surgery.\u000a    Significance: The trial informed guidelines\/recommendations\u000a      internationally and changed clinical\u000a      practice. Women worldwide can now make an informed choice about their\u000a      treatment; economic\u000a      factors have been quantitated.\u000a    Beneficiaries: Uterine fibroid patients, the NHS, healthcare\u000a      providers.\u000a    Attribution: G. Murray, UoE, developed and delivered innovative\u000a      trial methodology; clinical\u000a      aspects led by University of Glasgow.\u000a    Reach: UK guidelines; worldwide (Australia, USA, Europe) effect on\u000a      clinical practice that will\u000a      impact up to 25% of women.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Edinburgh\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a3.1 Edwards R, Moss J, Lumsden M,...Murray G; REST Investigators.\u000a      Uterine-artery\u000a      embolisation versus surgery for symptomatic uterine fibroids. N Engl J\u000a      Med. 2007;356:360-70.\u000a      DOI: 10.1056\/NEJMoa062003. [Cited 211 times as of 12-Aug 2013.]\u000a    \u000a\u000a3.2 Moss J, Cooper K, Khaund A,...Murray G, et al. Randomised comparison\u000a      of uterine artery\u000a      embolisation (UAE) with surgical treatment in patients with symptomatic\u000a      uterine fibroids (REST\u000a      trial): 5-year results. BJOG. 2011;118:936-44. DOI:\u000a      10.1111\/j.1471-0528.2011.02952.x.\u000a    \u000a\u000a3.3 Rashid S, Khaund A, Murray L,...Murray G, Lumsden M. The effects of\u000a      uterine artery\u000a      embolisation and surgical treatment on ovarian function in women with\u000a      uterine fibroids. BJOG.\u000a      2010;117:985-9. DOI: 10.1111\/j.1471-0528.2010.02579.x.\u000a    \u000a\u000a3.4 Ananthakrishnan G, Murray L, Ritchie M, Murray G, et al. Randomized\u000a      comparison of uterine\u000a      artery embolization (UAE) with surgical treatment in patients with\u000a      symptomatic uterine fibroids\u000a      (REST Trial): subanalysis of 5-year MRI findings. Cardiovasc Intervent\u000a      Radiol. 2013;36:676-81.\u000a      DOI: 10.1007\/s00270-012-0485-y.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    5.1 NICE guidelines (2010) Uterine artery embolisation for fibroids.\u000a      Interventional procedures\u000a      guidance IPG367. http:\/\/guidance.nice.org.uk\/IPG367.\u000a    5.2 Royal College of Obstetricians and Gynaecologists and the Royal\u000a      College of Radiologists\u000a      (2009). Clinical recommendations on the use of uterine artery embolisation\u000a      in the management of\u000a      fibroids. Second edition. http:\/\/www.rcog.org.uk\/files\/rcog-corp\/uploaded-files\/WPRUterineArteryEmbolisation2009.pdf.\u000a    5.3 NICE guidelines (2007). Heavy menstrual bleeding. Clinical guideline\u000a      no. 44.\u000a      http:\/\/www.nice.org.uk\/cg44. NB.\u000a        [This remains the current guideline for the period 2008-13.]\u000a    5.4 USA recommendations. Burke C, Funaki\u000a        B, Ray\u000a        C Jr, et al. ACR Appropriateness Criteria®\u000a      on treatment of uterine leiomyomas. J Am Coll Radiol. 2011;8:228-34. DOI:\u000a      10.1016\/j.jacr.2010.12.020.\u000a    5.5 Australasia recommendations. Hickey M, Hammond I. What\u000a        is the place of uterine arteryembolisation in the management of\u000a        symptomatic uterine fibroids? Aust N Z J Obstet Gynaecol.\u000a      2008;48:360-8. DOI: 10.1111\/j.1479-828X.2008.00886.x.\u000a    5.6 Gupta JK, Sinha A, Lumsden M, Hickey M. Uterine artery embolization\u000a      for symptomatic\u000a      uterine fibroids. Cochrane Database Syste Rev. 2012; 5:CD005073. DOI:\u000a      10.1002\/14651858.CD005073.pub3.\u000a    5.7 Pocock S, Travison T, Wruck L. How to interpret figures in reports of\u000a      clinical trials. BMJ.\u000a      2008;336:1166-9. DOI: 10.1136\/bmj.39561.548924.94.\u000a    5.8 Medical Technology Group (2011). \"Your first choice — the provision\u000a      of and access to UFE\".\u000a      http:\/\/www.mtg.org.uk\/index.php\/policy-initiatives\/mtg-campaigns\/8-a-review-of-the-provision-of-and-access-to-uterine-arteryfibroid-embolisation-a-treatment-for-fibroids-for-women-in-england.\u000a    5.9 Voogt M, Arntz M, Lohle P, Mali W, Lampmann LE. Uterine\u000a        fibroid embolisation forsymptomatic uterine fibroids: a survey of\u000a        clinical practice in Europe. Cardiovasc Intervent Radiol.\u000a      2011;34:765-73. DOI: 10.1007\/s00270-010-9978-8.\u000a    ","Title":"\u000a    E: Uterine artery embolisation is superior to surgery in the short\u000a        term,\u000a        for the treatment of symptomatic uterine fibroids\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Gordon Murray (Professor of Medical Statistics, UoE,\u000a      1996-present) led the\u000a      methodological work underpinning the first definitive trial (the REST\u000a      trial) [3.1] to define the benefits\u000a      and disadvantages of UAE — an intervention that had been adopted into\u000a      clinical practice without\u000a      evidence.\u000a    The introduction of interventional procedures into clinical practice is\u000a      far less regulated than the\u000a      introduction of new drugs. Surgical and other interventional procedures\u000a      tend to evolve over time\u000a      and are introduced into practice on the basis of being \"obviously\" more\u000a      effective and\/or less\u000a      invasive than alternative procedures. Robust evaluation of the\u000a      effectiveness and safety of new\u000a      interventional procedures is the exception rather than the norm.\u000a    One example of an innovative procedure is uterine artery embolisation\u000a      (UAE) for the treatment of\u000a      symptomatic uterine fibroids. 25% of women worldwide will at some point\u000a      experience these benign\u000a      gynaecological tumours. UAE was introduced in 1995 and quickly became\u000a      accepted as a minimally\u000a      invasive alternative to hysterectomy, or, for women wishing to maintain\u000a      their fertility, myomectomy.\u000a      In the decade following the introduction of UAE, over 100,000 procedures\u000a      were performed\u000a      worldwide, without any robust evaluation of the procedure. In the UK, the\u000a      National Institute for\u000a      Health and Care Excellence (NICE) issued guidance in October 2004 stating\u000a      that the procedure\u000a      appeared to be safe for routine use and that the majority of patients\u000a      gained short-term symptomatic\u000a      relief. At the time, there was no robust evidence about the long-term\u000a      effectiveness of the\u000a      procedure.\u000a    The REST Trial (Randomised trial of Embolisation versus Surgical\u000a      Treatment for Fibroids; 2000 to\u000a      2005) was a multi-centre randomised trial funded by a £280K grant from the\u000a      Chief Scientist Office.\u000a      The clinical aspects were led by Professor Jon Moss (University of\u000a      Glasgow) and the\u000a      methodological aspects (trial design, conduct, analysis, reporting and\u000a      interpretation) were led by\u000a      Murray. The trial recruited 157 women over 27 hospitals and was the first\u000a      in this area that was both\u000a      adequately powered and had long-term follow-up. The one-year follow-up\u000a      data were published in\u000a      the New England Journal of Medicine [3.1]. A five-year follow-up was\u000a      published subsequently [3.2],\u000a      as were data relating to mechanistic endpoints [3.3, 3.4].\u000a    The trial showed that UAE is indeed associated with less short-term\u000a      morbidity than surgery, with,\u000a      for example, a median hospital stay of one day following UAE compared with\u000a      a median stay of five\u000a      days following surgery. However, this must be balanced against the\u000a      increased risk of minor\u000a      adverse events that occur in 34% of the UAE cases (compared with 20% in\u000a      the surgery group, p =\u000a      0.047), including the post-embolisation syndrome of pyrexia, pain and\u000a      elevated inflammatory\u000a      markers. In the UAE group, one third of women required re-intervention to\u000a      control recurrent\u000a      symptoms. In terms of health economics, the early savings of an average of\u000a      almost £1000 per\u000a      woman associated with the less invasive procedure were negated after 5\u000a      years by the need for re-intervention\u000a      to control recurrent symptoms [3.2]. Thus Murray and colleagues showed\u000a      that UAE\u000a      and surgery had equivalent efficacy at 5 years in terms of quality of life\u000a      and cost.\u000a    "},{"CaseStudyId":"23874","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"798544","Name":"Poland"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Pathways to impact\u000d\u000a      It was clear that the linkage of a new widely-used material to a mechanism\u000d\u000a      of toxicity might spark\u000d\u000a      an unbalanced response and result in damage to UK and worldwide industry\u000d\u000a      and wealth creation.\u000d\u000a      Therefore, Donaldson took a considered and multi-faceted approach to\u000d\u000a      dissemination of the\u000d\u000a      findings to government, industry and the public. He and colleagues\u000d\u000a      informed and presented the\u000d\u000a      findings to the UK Health and Safety Executive (HSE), the UK Department\u000d\u000a      for Environment, Food\u000d\u000a      and Rural Affairs and the Nanotechnology Industry Association (NIA) prior\u000d\u000a      to publication of the\u000d\u000a      Nature Nanotechnology paper [3.1]; consequently the NIA informed its\u000d\u000a      members and developed a\u000d\u000a      proportionate public response.\u000d\u000a    In collaboration with the Science Media Centre (London), Donaldson gave a\u000d\u000a      press conference in\u000d\u000a      May 2008 that was attended by top UK and international science journalists\u000d\u000a      (including the BBC,\u000d\u000a      Times and Guardian). Accompanying statements were provided by the British\u000d\u000a      Lung Foundation\u000d\u000a      and UK academic leaders in the field [5.1]. Craig Poland (technician then\u000d\u000a      PhD candidate, UoE,\u000d\u000a      2004-2009) presented the findings as an invited speaker at the American\u000d\u000a      Thoracic Society\u000d\u000a      Annual meeting in Toronto (2008).\u000d\u000a    Impact on society: public engagement and awareness\u000d\u000a      Donaldson's study achieved widespread global coverage in multiple media\u000d\u000a      forms: newspapers\u000d\u000a      (e.g., Financial Times, New York Times, Agence France Press and Indo-Asian\u000d\u000a      News Service),\u000d\u000a      magazines (e.g., Scientific American), television and internet forums\u000d\u000a      (e.g. BBC News, CBC News\u000d\u000a      Canada, NHS Choices). These increased public awareness and stimulated\u000d\u000a      debate on the risks of\u000d\u000a      CNT, as evidenced by news interest and by prominent citations of the work\u000d\u000a      in high-impact\u000d\u000a      documents discussing the human health risks of CNT, such as those produced\u000d\u000a      by the US National\u000d\u000a      Institute for Occupational Safety and Health (NIOSH) [5.2] and by Safe\u000d\u000a      Work Australia [5.3].The\u000d\u000a      practical impact of the work is illustrated by the HSE Nanosafety\u000d\u000a      Partnership Group's health and\u000d\u000a      safety guidance document [5.4].\u000d\u000a    Impact on public policy\u000d\u000a      In September 2008, an HSE guidance document entitled \"Risk Management of\u000d\u000a      Carbon\u000d\u000a      Nanotubes\" [5.5], which specifically and solely cited Donaldson's study,\u000d\u000a      was provided to all UK\u000d\u000a      nanotube-related researchers and industries. Later that year, the US\u000d\u000a      Environmental Protection\u000d\u000a      Agency (EPA) formally put manufacturers on notice that it considered CNT\u000d\u000a      to be chemically\u000d\u000a      different from conventional carbon compounds, and potentially subject to\u000d\u000a      regulation as \"new\"\u000d\u000a      chemicals under the Toxic Substances Control Act [5.6]. Donaldson has\u000d\u000a      frequently been, and\u000d\u000a      continues to be, consulted as an expert in the field of toxicity of\u000d\u000a      nanoparticles: for example, in\u000d\u000a      2010 to the Science and Technology Committee of the House of Lords [5.7].\u000d\u000a    Impact on industry\/commerce\u000d\u000a      The results of Donaldson's research were noted by industry with interests\u000d\u000a      in CNT (see NIA\u000d\u000a      response noted above): for example, specifically addressed in a statement\u000d\u000a      submitted to the US\u000d\u000a      Technology Sciences Group by Bayer Material Science AG [5.8]. There have\u000d\u000a      been at least two\u000d\u000a      publications from the legal profession considering the ramifications of\u000d\u000a      the Donaldson study alone\u000d\u000a      [5.9], and its importance was recognised by the insurance company Lloyds\u000d\u000a        of London, which\u000d\u000a      awarded Poland a \"Science of Risk\" prize in November 2010. Concerns within\u000d\u000a      the key insurance\u000d\u000a      industry on the risks of nanotechnology are reflected in the impact of\u000d\u000a      Donaldson's work; the work\u000d\u000a      assisted with actuarial decisions that resulted in the withdrawal of\u000d\u000a      insurance provision for CNT from\u000d\u000a      November 2008 by Continental Western Insurance Group [5.10].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Influencing industry, governmental policy, insurance\u000d\u000a      industry policy and public\u000d\u000a      awareness\/engagement.\u000d\u000a    Significance: By establishing the actual risks posed by specific\u000d\u000a      carbon nanotubes (CNT), UK\u000d\u000a      Health and Safety Executive (HSE) guidance and workplace guidance and\u000d\u000a      industry was\u000d\u000a      influenced internationally.\u000d\u000a    Beneficiaries: CNT industry and users, governments and\u000d\u000a      policy-makers, the HSE and its\u000d\u000a      international equivalents, the public.\u000d\u000a    Attribution: Donaldson and colleagues (UoE) published the first\u000d\u000a      demonstrations of potential CNT\u000d\u000a      toxicity.\u000d\u000a    Reach: Global media coverage, encompassing UK, Europe, USA and\u000d\u000a      India. Results considered by\u000d\u000a      national and international policy-making bodies, for example, House of\u000d\u000a      Lords Science and\u000d\u000a      Technology committee, US National Institute for Occupational Safety and\u000d\u000a      Health.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6167865","Name":"Toronto"}],"References":"\u000d\u000a    \u000a3.1 Poland C, Duffin R, Kinloch I,...Donaldson K. Carbon nanotubes\u000d\u000a      introduced into the\u000d\u000a      abdominal cavity of mice show asbestos-like pathogenicity in a pilot\u000d\u000a      study. Nat Nanotechnol.\u000d\u000a      2008;3:423-8. DOI: 10.1038\/nnano.2008.111.\u000d\u000a    \u000a\u000a3.2 Poland C, Byrne F, Cho W,...Donaldson K. Length dependent\u000d\u000a      pathogenic effects of nickel\u000d\u000a      oxide nanowires in the lungs and the peritoneal cavity. Nanotoxicology.\u000d\u000a      2012;6:899-911. DOI:\u000d\u000a      10.3109\/17435390.2011.626535.\u000d\u000a    \u000a\u000a3.3 Murphy F, Poland C, Duffin R,...Donaldson K. Length-dependent\u000d\u000a      retention of carbon\u000d\u000a      nanotubes in the pleural space of mice initiates sustained inflammation\u000d\u000a      and progressive fibrosis\u000d\u000a      on the parietal pleura. Am J Pathol. 2011;178:2587-600. DOI:\u000d\u000a      10.1016\/j.ajpath.2011.02.040.\u000d\u000a    \u000a\u000a3.4 Murphy F, Poland C, Duffin R, Donaldson K. Length-dependent pleural\u000d\u000a      inflammation and\u000d\u000a      parietal pleural responses after deposition of carbon nanotubes in the\u000d\u000a      pulmonary airspaces of\u000d\u000a      mice. Nanotoxicology. 2013;7:1157-67. DOI: 10.3109\/17435390.2012.713527.\u000d\u000a    \u000a\u000a3.5 Donaldson K, Murphy F, Duffin R, Poland C. Asbestos, carbon nanotubes\u000d\u000a      and the pleural\u000d\u000a      mesothelium: a review and the hypothesis regarding the role of long fibre\u000d\u000a      retention in the parietal\u000d\u000a      pleura, inflammation and mesothelioma. Part Fibre Toxicol. 2010;7:5. DOI:\u000d\u000a      10.1186\/1743-8977-7-\u000d\u000a      5.\u000d\u000a    \u000a\u000a3.6 Schinwald A, Murphy F, Prina-Mello A,...Donaldson K. The threshold\u000d\u000a      length for fiber-induced\u000d\u000a      acute pleural inflammation: shedding light on the early events in\u000d\u000a      asbestos-induced mesothelioma.\u000d\u000a      Toxicol Sci. 2012;128:461-70. DOI: 10.1093\/toxsci\/kfs171.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"99","Subject":"Other Medical and Health Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    5.1 NIA news item \"Carbon Nanotube News Travels Fast\" (2008)\u000d\u000a      http:\/\/www.sciencemediacentre.org\/scientists-comment-on-research-into-carbon-nanotubes-as-published-in-nature-nanotechnology-2-2\/.\u000d\u000a    5.2 US National Institute for Occupational Safety and Health,\u000d\u000a      \"Occupational Exposure to Carbon\u000d\u000a      Nanotubes and Nanofibers\" Publication No. 2013-145 Current Intelligence\u000d\u000a      Bulletin 65 (2013).\u000d\u000a      www.cdc.gov\/niosh\/docs\/2013-145\/pdfs\/2013-145.pdf.\u000d\u000a    5.3 Australian Government Department of Health and Ageing.\u000d\u000a      SafeWorkAustralia: \"Human\u000d\u000a      Health Hazard Assessment and Classification of Carbon Nanotubes\" (2012). [Available\u000d\u000a        on\u000d\u000a        request.]\u000d\u000a    5.4 The UK NanoSafety Partnership Group. \"Working Safely with\u000d\u000a      Nanomaterials in Research\u000d\u000a      and Development\" (2012). [Available on request.]\u000d\u000a    5.5 HSE \"Risk management of carbon nanotubes\" (2009). [Available on\u000d\u000a        request.] This was\u000d\u000a      reported by The Scotsman on 13 Mar 2009 under the headline \"Safety body\u000d\u000a      acts on city experts'\u000d\u000a      work\". http:\/\/www.scotsman.com\/news\/safety-body-acts-on-city-experts-work-1-1195142.\u000d\u000a    5.6 Goodwin Proctor Client Alert \"EPA Takes First-Ever Regulatory Actions\u000d\u000a      Aimed at Potential\u000d\u000a      Nanomaterial Risks\" (2008).\u000d\u000a      http:\/\/www.goodwinprocter.com\/~\/media\/Files\/Publications\/Newsletters\/Client%20Alert\/2008\/EPA_Takes_First_Ever_Regulatory_Actions_Aimed_at_Potential_Nanomaterial_Risks.ashx.\u000d\u000a    5.7 House of Lords Science and Technology Committee Minutes of Evidence\u000d\u000a      (2009).\u000d\u000a      http:\/\/www.publications.parliament.uk\/pa\/ld200910\/ldselect\/ldsctech\/22\/9050502.htm.\u000d\u000a      [Memorandum by Donaldson to the Science and Technology Committee\u000d\u000a        Nanotechnologies and\u000d\u000a        Food inquiry.]\u000d\u000a    5.8 Technology Science Group Inc. \"Multiwalled Carbon Nanotube Toxicity\u000d\u000a      Information\" (2008).\u000d\u000a      http:\/\/www.epa.gov\/oppt\/tsca8e\/pubs\/8ehq\/2008\/jul08\/fyi_0708_01611a.pdf.\u000d\u000a    5.9 (a) Stimers P. The implications of recent nanomaterials toxicity\u000d\u000a      studies for the nanotech\u000d\u000a      community\"; Nanotechnology Law and Business. 2008;5(3):313-8.\u000d\u000a      http:\/\/www.klgates.com\/files\/Publication\/2b1f4c2a-298b-4948-9ce7-69f1396b61ac\/Presentation\/PublicationAttachment\/bbdf8cdc-be42-4fa6-b942-7263b449d0b3\/Article_Stimers_Nanotech.pdf.\u000d\u000a   (b) Monica J Jnr and Monica J. A Nano-Mesothelioma False Alarm.\u000d\u000a      Nanotechnology Law and\u000d\u000a      Business. 2008;5(3):319-33. http:\/\/www.nanolawreport.com\/5_3_Policy_Ethics_254_1__pdf.pdf.\u000d\u000a    5.10 Cozzens S and Wetmore J (eds). Nanotechnology and the Challenges of\u000d\u000a      Equity, Equality\u000d\u000a      and Development. Springer London Limited, 2011.\u000d\u000a      http:\/\/www.springer.com\/social+sciences\/book\/978-90-481-9614-2.\u000d\u000a        [Available on request.]\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    O: Making technological advancement safer by defining the specific\u000d\u000a        attributes of carbon nanofibres that are detrimental to human health\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Over the last decade, there has been a great deal of investment in\u000d\u000a      R&D and increasing production\u000d\u000a      of nanoparticles including nanofibres; however, despite concerns over\u000d\u000a      health effects, relatively\u000d\u000a      little effort or funding had been directed towards assessing their safety.\u000d\u000a      Responding to this deficit,\u000d\u000a      and based on his experience with asbestos and coalmine dust, Professor Ken\u000d\u000a      Donaldson\u000d\u000a      (Professor of Respiratory Toxicology, UoE, 2002-2013; now Emeritus)\u000d\u000a      established a programme\u000d\u000a      in 2006 to address the possible dangers of these new materials.\u000d\u000a    Donaldson's intention was to relate structure to toxicity, and was\u000d\u000a      therefore relevant to both known\u000d\u000a      and untested nanofibres. Drawing on the comparison with asbestos, the\u000d\u000a      focus was on pleural\u000d\u000a      effects because mesothelioma, a pleural cancer, is uniquely associated\u000d\u000a      with asbestos exposure.\u000d\u000a      Fibre length plays a crucial role in the harmfulness of a fibre so, to\u000d\u000a      investigate whether length was\u000d\u000a      related to toxicity, Donaldson compared different lengths of carbon\u000d\u000a      nanotubes (CNT) in a mouse\u000d\u000a      peritoneal model. Only those CNT that comprised long (>~10 µm)\u000d\u000a      individual fibres were\u000d\u000a      pathogenic, whilst those that were compact (agglomerated) and short were\u000d\u000a      rapidly cleared and did\u000d\u000a      not cause appreciable inflammation or fibrosis. At the same mass dose, the\u000d\u000a      effects seen were\u000d\u000a      significantly greater that those observed with long asbestos fibres; thus,\u000d\u000a      long-fibre CNT could\u000d\u000a      cause mesothelioma. With internal and external collaborators, Donaldson\u000d\u000a      published the findings in\u000d\u000a      Nature Nanotechnology (impact factor 31.17) in 2008 [3.1].\u000d\u000a    In subsequent studies, Donaldson demonstrated the same length dependence\u000d\u000a      for inflammation\u000d\u000a      and fibrosis for nickel nanowires [3.2], and also, following direct\u000d\u000a      delivery of CNT into the pleural\u000d\u000a      cavity of mice, the most common site of mesothelioma development [3.3].\u000d\u000a      Long, but not short CNT\u000d\u000a      introduced into the airways caused pleural inflammation; thus, the same\u000d\u000a      effects were seen using a\u000d\u000a      physiological route of delivery [3.4].\u000d\u000a    These early results led to the publication by Donaldson of a highly\u000d\u000a      accessed article (15,775 times)\u000d\u000a      outlining the potential risks of fibrous nanomaterials and routes of\u000d\u000a      safe-by-design particles [3.5].\u000d\u000a    By fully exploiting nanomaterials' variety and ability to generate\u000d\u000a      materials to exacting\u000d\u000a      specifications, Donaldson investigated a large panel of different fibres,\u000d\u000a      demonstrating that the\u000d\u000a      length-dependent effect was not material-specific. Silver nanowires in\u000d\u000a      well-defined length classes,\u000d\u000a      plus a wide range of nanofibres, were used to show that the threshold\u000d\u000a      length for retention and\u000d\u000a      pathogenesis in the pleural space was 5 µm [3.6]. This has great\u000d\u000a      significance for understanding\u000d\u000a      and controlling the risk from asbestos and other existing fibres, and for\u000d\u000a      the safe-by-design\u000d\u000a      development of new nanofibres.\u000d\u000a    "},{"CaseStudyId":"23875","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"298795","Name":"Turkey"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2017370","Name":"Russia"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The widespread adoption of lapatinib as a combination agent for advanced\u000d\u000a      breast cancer hinged\u000d\u000a      on the detailed analysis of sub-groups led by Cameron (3.2-3.4). The\u000d\u000a      results of the phase III trial\u000d\u000a      with lapatinib confirmed the clinical efficacy of a small molecular\u000d\u000a      tyrosine kinase inhibitor in patients\u000d\u000a      with HER2+ breast cancer for which trastuzumab was no longer effective.\u000d\u000a      Lapatinib was the first\u000d\u000a      agent to be approved for use in HER2+ breast cancer after trastuzumab.\u000d\u000a    Impact on health and welfare\u000d\u000a    There are no robust data available on the number of patients treated with\u000d\u000a      lapatinib, but it is likely to\u000d\u000a      be around 10 000 or more each year, based on the drug costs and average\u000d\u000a      duration of therapy.\u000d\u000a      For women with advanced HER2+ breast cancer, who without effective therapy\u000d\u000a      have a poor\u000d\u000a      prognosis, the use of lapatinib plus capecitabine offers an entirely oral,\u000d\u000a      effective therapy once the\u000d\u000a      disease has become resistant to trastuzumab, which is the first-line\u000d\u000a      therapy. The treatment is not\u000d\u000a      curative — cures are rare in metastatic breast cancer — but it delivers\u000d\u000a      clear clinical benefits for\u000d\u000a      patients. Also, because of the availability of lapatinib, a phase II study\u000d\u000a      compared radiotherapy with\u000d\u000a      capecitabine plus lapatinib, and confirmed that this combination was an\u000d\u000a      equally effective\u000d\u000a      alternative to conventional radiotherapy for treating patients with HER2+\u000d\u000a      breast cancer metastatic\u000d\u000a      to the brain [5.1].\u000d\u000a    Impact on commerce and the economy\u000d\u000a    Lapatinib generated sales for the UK-based company (GSK) of £227M in\u000d\u000a      2010, £231M in 2011 and\u000d\u000a      £239M in 2012 [5.2]. In addition, but hard to quantify, there are economic\u000d\u000a      benefits of an effective\u000d\u000a      therapy for patients with advanced breast cancer — some are able to\u000d\u000a      continue working because\u000d\u000a      their disease is being better controlled.\u000d\u000a    Impact on public policy\u000d\u000a    The positive results of this pivotal, registration phase III trial led to\u000d\u000a      marketing authorisations in 107\u000d\u000a      countries including the USA, Europe, Australia, India, Brazil, Russia,\u000d\u000a      Turkey, South Korea and\u000d\u000a      other countries around the world [5.3]. The majority of these\u000d\u000a      authorisations have occurred after 1st\u000d\u000a      Jan 2008; for example, the European Commission granted a conditional\u000d\u000a      marketing authorisation\u000d\u000a      for lapatinib in all 27 European Union (EU) member states on June 10, 2008\u000d\u000a      [5.4]. The option of\u000d\u000a      using lapatinib in combination with capecitabine is recommended within a\u000d\u000a      number of guidelines\u000d\u000a      (e.g., European School of Oncology, German Gynecological Oncology Group\u000d\u000a      (Arbeitsgemeinschaft\u000d\u000a      Gynaekologische Oncologie, AGO), National Comprehensive Cancer Network\u000d\u000a      (NCCN) guidelines\u000d\u000a      in the USA and European Society for Medical Oncology (ESMO) guidelines\u000d\u000a      [5.5, 5.6, 5.7]).\u000d\u000a      Although it is licensed in the UK, the regimen was not approved by either\u000d\u000a      the National Institute for\u000d\u000a      Health and Care Excellence (NICE) or the Scottish Medicines Consortium\u000d\u000a      (SMC), as it was felt to\u000d\u000a      be insufficiently cost-effective. Denial to fund this treatment led to\u000d\u000a      intensive patient-led\u000d\u000a      campaigning, and the lapatinib-treatment-seeking patient Nikki Blunden,\u000d\u000a      whose case was\u000d\u000a      highlighted in the House of Commons (June 16, 2010), became \"the face\" of\u000d\u000a      the Government's\u000d\u000a      £50M emergency fund to pay for new cancer drugs for those with\u000d\u000a      life-shortening cancer [5.8]. From\u000d\u000a      October 2010 until February 2011, 195 patients obtained lapatinib\u000d\u000a      treatment due to the interim\u000d\u000a      cancer drugs funding, and from April until September 2011 more than 350\u000d\u000a      patients received the\u000d\u000a      drug with support from the Cancer Drugs Fund [5.9]. Lapatinib used in this\u000d\u000a      indication is one of the\u000d\u000a      top ten drugs within the English Cancer Drugs' fund with an approval rate\u000d\u000a      of 94% (June 2011)\u000d\u000a      [5.10], reflecting strong UK clinician support for the treatment whose\u000d\u000a      efficacy was confirmed by the\u000d\u000a      phase III trial.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and welfare; additional effective therapy for women\u000d\u000a      with advanced, HER2+ breast\u000d\u000a      cancer.\u000d\u000a    Significance: Allows approximately 10,000 patients a year, whose\u000d\u000a      disease is no longer being\u000d\u000a      controlled by trastuzumab, to receive a more effective therapy than\u000d\u000a      chemotherapy with\u000d\u000a      capecitabine alone.\u000d\u000a    Beneficiaries: Patients with incurable metastatic HER2+ subtype\u000d\u000a      breast cancer; policy-makers;\u000d\u000a      commerce.\u000d\u000a    Attribution: Cameron (UoE) was joint chief-investigator on the\u000d\u000a      global pivotal registration trial that\u000d\u000a      led to the marketing authorisation of the drug lapatinib in combination\u000d\u000a      with capecitabine.\u000d\u000a    Reach: World-wide: the drug is approved in >100 countries and\u000d\u000a      generated >£650M in sales for\u000d\u000a      manufacturer GlaxoSmithKline.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Geyer C, Forster J, Lindquist D,...Cameron D. Lapatinib plus\u000d\u000a      capecitabine compared with\u000d\u000a      capecitabine alone for HER2-positive advanced breast cancer. New Eng J\u000d\u000a      Med. 2006;355:2733-43.\u000d\u000a      DOI: 10.1056\/NEJMoa064320.\u000d\u000a    \u000a\u000a3.2 Cameron D, Casey M, Press M, et al. A phase III randomized comparison\u000d\u000a      of lapatinib plus\u000d\u000a      capecitabine versus capecitabine alone in women with advanced breast\u000d\u000a      cancer that has\u000d\u000a      progressed on trastuzumab: updated efficacy and biomarker analyses. Breast\u000d\u000a      Cancer Res Treat.\u000d\u000a      2008;112:533-43. DOI: 10.1007\/s10549-007-9885-0.\u000d\u000a    \u000a\u000a3.3 Press M, Finn R, Cameron D, et al. HER-2 gene amplification, HER-2\u000d\u000a      and epidermal growth\u000d\u000a      factor receptor mRNA and protein expression, and lapatinib efficacy in\u000d\u000a      women with metastatic\u000d\u000a      breast cancer. Clin Cancer Res. 2008;14:7861-70. DOI:\u000d\u000a      10.1158\/1078-0432.CCR-08-1056.\u000d\u000a    \u000a\u000a3.4 Scaltriti M, Chandarlapaty S, Prudkin L,...Cameron D, et al. Clinical\u000d\u000a      benefit of lapatinib-based\u000d\u000a      therapy in patients with human epidermal growth factor receptor 2-positive\u000d\u000a      breast tumors\u000d\u000a      coexpressing the truncated p95HER2 receptor. Clin Cancer Res.\u000d\u000a      2010;16:2688-95. DOI:\u000d\u000a      10.1158\/1078-0432.CCR-09-3407.\u000d\u000a    \u000a\u000a3.5 Zhou X, Cella D, Cameron D, et al. Lapatinib plus capecitabine versus\u000d\u000a      capecitabine alone for\u000d\u000a      HER2+ (ErbB2+) metastatic breast cancer: quality-of-life assessment.\u000d\u000a      Breast Cancer Res Treat.\u000d\u000a      2009;117:577-89. DOI: 10.1007\/s10549-009-0310-8.\u000d\u000a    \u000a\u000a3.6 Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in\u000d\u000a      women with HER-2-positive\u000d\u000a      advanced breast cancer: final survival analysis of a phase III randomized\u000d\u000a      trial. Oncologist.\u000d\u000a      2010;15:924-34. DOI: 10.1634\/theoncologist.2009-0181.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    5.1 Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine\u000d\u000a      in patients with\u000d\u000a      previously untreated brain metastases from HER-2 positive metastatic\u000d\u000a      breast cancer\u000d\u000a      (LANDSCAPE): a single group phase 2 study. Lancet Oncol. 2013;14:64-71.\u000d\u000a      DOI: 10.1016\/S1470-2045(12)70432-1.\u000d\u000a    5.2 GSK Annual Report 2012. http:\/\/www.gsk.com\/investors\/annual-reports\/annual-report.html.\u000d\u000a    5.3 Lapatinib clinical trial update, GSK press release issued on 9 Sep\u000d\u000a      2011.\u000d\u000a      http:\/\/us.gsk.com\/html\/media-news\/pressreleases\/2011\/2011-pressrelease-614856.htm.\u000d\u000a    5.4 European Medicines Agency (EMA) marketing authorisation for European\u000d\u000a      Union.\u000d\u000a      http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/000795\/humanmed_001120.jsp&mid=WC0b01ac058001d124.\u000d\u000a    5.5 Cardoso F, Costa A, Norton L, et al. 1st international consensus\u000d\u000a      guidelines for advanced\u000d\u000a      breast cancer (ABC1). Breast. 2012;21:245-52. DOI:\u000d\u000a      10.1016\/j.breast.2012.03.003.\u000d\u000a    5.6 USA NCCN guidelines. http:\/\/www.nccn.org\/patients\/guidelines\/breast\/index.html#\/93\/zoomed.\u000d\u000a    5.7 ESMO guidelines. http:\/\/www.esmo.org\/Oncology-News\/The-European-Medicines-Agency-Extends-Indications-for-Lapatinib.\u000d\u000a    5.8 Daily Mail, April 12, 2011. \"Cancer mother who fulfilled wish to see\u000d\u000a      her son start school loses\u000d\u000a      fight for life\". http:\/\/www.dailymail.co.uk\/health\/article-1376007\/Lapatinib-drug-campaigner-Cancer-\u000d\u000amother-campaigned-fund-donor-paid-drug-help-son-school-loses-fight-life.html.\u000d\u000a    5.9 Breast Cancer Campaign report (November 2011). \"The cancer drugs\u000d\u000a      fund: a breast cancer\u000d\u000a      perspective\". http:\/\/www.breastcancercampaign.org\/documents\/policy\/cancer-drugs-fund-a-breast-cancer-perspective.pdf.\u000d\u000a    5.10 Macmillan Cancer Support report (December 2011). \"Improving Access?\u000d\u000a      Report on the\u000d\u000a      implementation of the Cancer Drugs Fund and the development of a\u000d\u000a      value-based pricing system\".\u000d\u000a      http:\/\/www.macmillan.org.uk\/Documents\/GetInvolved\/Campaigns\/Campaigns\/CancerDrugFund\/Im\u000d\u000a        provingAccess.pdf.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    C: Detailed analysis of trial of lapatinib in combination with\u000d\u000a        capecitabine\u000d\u000a        in advanced, HER2+ breast cancer leads to marketing authorisation\u000d\u000a        worldwide\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor David Cameron (part-time Honorary Senior Lecturer in Oncology,\u000d\u000a      UoE, since 2003;\u000d\u000a      appointed to Professor of Oncology, 2009), as joint global Chief\u000d\u000a      Investigator, undertook the\u000d\u000a      detailed analysis of sub-group outcomes that identified cohort benefit in\u000d\u000a      advanced metastatic\u000d\u000a      breast cancer in the capecitabine and lapatinib HER2+ metastatic breast\u000d\u000a      cancer trial [3.1].\u000d\u000a      Crucially, further analyses of the trial data by Cameron and colleagues\u000d\u000a      identified evidence that\u000d\u000a      there might be a subgroup of patients who particularly benefited from the\u000d\u000a      addition of lapatinib.\u000d\u000a      Circulating serum markers and tumour characteristics failed to identify\u000d\u000a      patients who did not benefit\u000d\u000a      from the use of lapatinib [3.2-3.4], other than those whose tumours were\u000d\u000a      not centrally confirmed to\u000d\u000a      be HER2-over-expressing.\u000d\u000a    The chance of a woman having invasive breast cancer some time during her\u000d\u000a      life is about one in\u000d\u000a      eight. Around 12-15% of all breast cancers over-express the cell surface\u000d\u000a      tyrosine kinase receptor\u000d\u000a      human epidermal growth factor receptor 2 (HER2+). These patients have more\u000d\u000a      aggressive disease\u000d\u000a      than those who are HER2-negative, and a higher chance of developing\u000d\u000a      incurable, life-threatening\u000d\u000a      metastatic disease. The drug trastuzumab (Herceptin) is used to treat such\u000d\u000a      cases, but in most\u000d\u000a      patients, resistance develops and alternative therapies are needed. No\u000d\u000a      such therapies were\u000d\u000a      available before the development of lapatinib.\u000d\u000a    After preliminary pre-clinical, phase I and phase II studies that\u000d\u000a      confirmed the efficacy of lapatinib in\u000d\u000a      previously treated HER2+ metastatic breast cancer, and demonstration of an\u000d\u000a      acceptable\u000d\u000a      tolerability profile when combined with the chemotherapy agent\u000d\u000a      capecitabine, it was clear that\u000d\u000a      there was real potential for this combination to be effective in treating\u000d\u000a      metastatic breast cancer that\u000d\u000a      overexpressed HER2 and was no longer responding to trastuzumab\u000d\u000a      (Herceptin). In liaison with\u000d\u000a      colleagues at GlaxoSmithKline (GSK), Cameron (who assumed the role of\u000d\u000a      joint global chief\u000d\u000a      investigator for the work while Honorary Senior Lecturer at UoE) led a\u000d\u000a      multinational, multicentre\u000d\u000a      randomised phase III trial to test the hypothesis that the combination of\u000d\u000a      lapatinib and the cytotoxic\u000d\u000a      drug capecitabine would be superior to capecitabine alone in patients with\u000d\u000a      HER2+ metastatic\u000d\u000a      breast cancer that had progressed despite trastuzumab treatment. Trial\u000d\u000a      design and execution was\u000d\u000a      closely aligned to FDA requirements to maximise the opportunity to bring a\u000d\u000a      new treatment to the\u000d\u000a      clinic rapidly. Patients were recruited in 2004-2006 and the Independent\u000d\u000a      Data Monitoring\u000d\u000a      Committee (IDMC) reviewed an interim analysis of the study in March 2006,\u000d\u000a      and recommended\u000d\u000a      that the trial be stopped and patients allowed to cross over to the\u000d\u000a      research arm. The interim\u000d\u000a      analysis data were published in late 2006 [3.1]. The data-set that was\u000d\u000a      used for the European (and\u000d\u000a      many other countries') application for marketing authorisation was the\u000d\u000a      analysis of all enrolled\u000d\u000a      patients that was published in 2008 [3.2].\u000d\u000a    The trial showed that the time to disease progression (worsening of the\u000d\u000a      cancer) almost doubled in\u000d\u000a      patients with HER2+ advanced breast cancer treated with lapatinib in\u000d\u000a      combination with\u000d\u000a      capecitabine compared with the use of capecitabine alone, with median\u000d\u000a      times to progression\u000d\u000a      significantly better in the combination arm (8.4 months) compared with the\u000d\u000a      single arm (4.4 months)\u000d\u000a      (p < 0.001, hazard ratio = 0.47). In addition there was evidence\u000d\u000a      of a higher rate of tumour\u000d\u000a      shrinkage (objective response rate) on the combination therapy with a 22%\u000d\u000a      response rate, while\u000d\u000a      the response to capecitabine alone was 14% (p = 0.09).\u000d\u000a    Data on quality of life for patients on this therapy [3.5], and a final\u000d\u000a      survival analysis [3.6] have also\u000d\u000a      been published. These report that there are quality of life benefits,\u000d\u000a      despite the modest toxicity, as\u000d\u000a      well as some evidence of a survival benefit for those patients being\u000d\u000a      offered this combination after\u000d\u000a      only one trastuzumab-containing regimen for metastatic breast cancer.\u000d\u000a    "},{"CaseStudyId":"23876","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Pathways to impact\u000d\u000a      The UoE team has disseminated the output of research endeavours\u000d\u000a      extensively. Critchley, Baird, Glasier and Williams have made major\u000d\u000a      contributions and provided expert consultancy to the National Institutes\u000d\u000a      of Health and major Pharma: Jenapharm, TAP Pharmaceutical Products Inc,\u000d\u000a      Schering, Repros Therapeutics Inc., Bayer Pharma AG, HRA Pharma, PregLem\u000d\u000a      and Gedeon Richter. Glasier has engaged public opinion and lobbied\u000d\u000a      government to ensure OTC availability of emergency contraception.\u000d\u000a    Impact on health and welfare, policy and the economy\u000d\u000a      Contraception: Emergency contraception is used by over 4 million\u000d\u000a      women per year in the USA and 20% of women aged 18-35 per year in the UK.\u000d\u000a      The UoE data on the safety and utility of PR ligands as emergency\u000d\u000a      contraceptives persuaded the Scottish Government to make levonorgestrel\u000d\u000a      available OTC for this purpose for free from 2008. This resulted in a 10%\u000d\u000a      drop in medical abortion rates in Scotland (13,904 to 12,447) between 2008\u000d\u000a      and 2012 [5.1].\u000d\u000a    Later, the team's demonstration of the superiority of ulipristal acetate\u000d\u000a      over levonorgestrel was used to support the decision in 2010 by the US\u000d\u000a      Food and Drug Administration (FDA) to license the former as an emergency\u000d\u000a      contraceptive [5.2]. The data are also cited in guidelines in the UK and\u000d\u000a      US: the UK National Institute for Health and Care Excellence (2011)\u000d\u000a      \"Clinical Knowledge Summary\", endorsing the use of ulipristal acetate as\u000d\u000a      an emergency contraceptive; guidelines from the UK Faculty of Sexual and\u000d\u000a      Reproductive Health (updated January 2012); the Centers for Disease\u000d\u000a      Control and Prevention \"US Selected Practice Recommendations for\u000d\u000a      Contraceptive Use, 2013\" [5.3]; and the American College of Obstetricians\u000d\u000a      and Gynaecologists Practice Bulletin on Emergency Contraception (November\u000d\u000a      2012). In March 2013, the WHO Family Planning steering group, chaired by\u000d\u000a      Williams, agreed that ulipristal acetate should be added to the \"Medical\u000d\u000a      Eligibility Criteria for Contraceptive Use\" when it is updated in 2014.\u000d\u000a    An independent cost-effectiveness analysis that cites ref. [3.2]\u000d\u000a      suggested that the use of ulipristal acetate as an emergency contraceptive\u000d\u000a      instead of the alternative levonorgestrel would result in 37,589 fewer\u000d\u000a      unintended pregnancies and resultant societal savings of $116.3M in the\u000d\u000a      USA each year [5.4]. This study concludes by stating that \"Efforts should\u000d\u000a      be promoted to increase access to [ulipristal acetate]\".\u000d\u000a    Treatment of fibroids: Annual estimated direct costs of managing\u000d\u000a      uterine fibroids in the USA alone are $4.1-9.4B and lost work-hours cost\u000d\u000a      $1.55-17.2B. UoE work on the mechanism of action and predicted efficacy of\u000d\u000a      PRMs was instrumental in the first PRM being approved for the treatment of\u000d\u000a      symptomatic fibroids. Ulipristal acetate (marketed as Esmya®) received a\u000d\u000a      European Medicines Agency & Medicines and Healthcare Products\u000d\u000a      Regulatory Agency license in Spring 2012 for use in women for 3 months\u000d\u000a      pre-hysterectomy, offering women a convenient oral treatment option to\u000d\u000a      reduce heavy bleeding and fibroid size prior to surgery. The Scottish\u000d\u000a      Medicines Consortium approved ulipristal acetate as a pre-operative\u000d\u000a      treatment for uterine fibroids (up to 3 months) in January 2013. Drugs\u000d\u000a      targeting the PR are now licensed for use in 67 countries.\u000d\u000a    Treatment of HMB: UoE researchers have formed the lead UK team\u000d\u000a      deriving data on the mechanism of action of LNG-IUS and thus contributed\u000d\u000a      to the development of management strategies with use of this slow-released\u000d\u000a      PR agonist for the 1 million women in the UK who annually seek help for\u000d\u000a      HMB. International guidance documents in the UK and USA recommend LNG-IUS\u000d\u000a      for the treatment of women with HMB and state that it should be offered\u000d\u000a      before invasive procedures (UK National Institute for Health and Care\u000d\u000a      Excellence Clinical Guideline on Heavy Menstrual Bleeding, published in\u000d\u000a      2007 and remaining the current guideline; Institute for Quality and\u000d\u000a      Efficiency in Health Care \"Treatment Options for Heavy Periods\", published\u000d\u000a      in 2009 and updated in 2013 [5.5]).\u000d\u000a    Impact on practitioners\u000d\u000a      To provide meaningful quantitation in the studies of uterine architecture\u000d\u000a      and HMB necessary to define the positive or negative effects of\u000d\u000a      therapeutic PRM intervention, and critically to stratify patients with\u000d\u000a      abnormal uterine bleeding for both research and therapeutic purposes,\u000d\u000a      Critchley, as co-chair of the FIGO Working Group on Menstrual Disorders,\u000d\u000a      with colleagues defined the PALM-COEIN classification system for abnormal\u000d\u000a      uterine bleeding (2011). This is now entering clinical use worldwide (for\u000d\u000a      example in North America [5.6, 5.7]), and is being adopted as the industry\u000d\u000a      standard.\u000d\u000a    Impact on commerce\u000d\u000a      The UoE work on PRMs, both directly and via Baird and colleagues' input to\u000d\u000a      the World Health Organization and other bodies, indirectly influenced the\u000d\u000a      drug development programme of Pharma to identify PRMs, define the biology\u000d\u000a      of PRMs and, crucially, to explore the potential indications of PRMs\u000d\u000a      [5.8]. The expertise of the Edinburgh team continues to be sought by\u000d\u000a      international pharmaceutical companies (Bayer Healthcare AG; HRA Pharma;\u000d\u000a      Gedeon-Richter; TAP Pharmaceuticals Inc.). This input has been essential\u000d\u000a      to inform therapeutic developments, for example through the review and\u000d\u000a      classification of histological slides etc., and to conduct\u000d\u000a      Pharma-supported multi-centre clinical trials [5.9, 5.10] to progress the\u000d\u000a      clinical utility of PRMs in the field of benign gynaecological complaints\u000d\u000a      (including HMB and fibroids).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and wellbeing; commerce; studies and clinical\u000d\u000a      trials of the effects of progesterone receptor modulators (PRMs)\u000d\u000a      underpinned their application for the benefit of women of childbearing\u000d\u000a      age.\u000d\u000a    Significance: UoE studies underpinned the application of PRMs as\u000d\u000a      emergency contraception including over-the-counter availability and the\u000d\u000a      treatment of heavy menstrual bleeding (HMB); changed clinical guidelines;\u000d\u000a      influenced Pharma R&D.\u000d\u000a    Beneficiaries: Women of reproductive age; the NHS and healthcare\u000d\u000a      delivery organisations; pharmaceutical companies.\u000d\u000a    Attribution: Studies were conducted by Critchley, Baird and\u000d\u000a      colleagues (UoE).\u000d\u000a    Reach: Worldwide; annually 4M women seek emergency contraception\u000d\u000a      in the USA, and in the UK 1M women seek help for HMB. Drugs targeting the\u000d\u000a      PR are licenced in 67 countries. Multiple global Pharma are active in the\u000d\u000a      field of PRM biology.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Glasier A, Baird D. The\u000a        effects of self-administering emergency contraception. N Engl J Med.\u000d\u000a      1998;339:1-4. DOI: 10.1056\/NEJM199807023390101.\u000d\u000a    \u000a\u000a3.2 Glasier A, Cameron S, Fine P, et al. (2010). Ulipristal acetate\u000d\u000a      versus levonorgestrel for emergency contraception: a randomised\u000d\u000a      non-inferiority trial and meta-analysis. Lancet. 2010;375:555-62. DOI:\u000d\u000a      10.1016\/S0140-6736(10)60101-8.\u000d\u000a    \u000a\u000a3.3 Critchley H, Wang H, Kelly R, Gebbie A, Glasier A. Progestin receptor\u000d\u000a      isoforms and prostaglandin dehydrogenase in the endometrium of women using\u000d\u000a      a levonorgestrel-releasing intrauterine system. Hum Reprod.\u000d\u000a      1998;13:1210-7. DOI: 10.1093\/humrep\/13.5.1210.\u000d\u000a    \u000a\u000a3.4 Critchley H, Jones R, Lea R, et al. Role of inflammatory mediators in\u000d\u000a      human endometrium during progesterone withdrawal and early pregnancy. J\u000d\u000a      Clin Endocrinol Metab. 1999;84:240-8. DOI: 10.1210\/jc.84.1.240.\u000d\u000a    \u000a\u000a3.5 Williams A, Critchley H, Osei J, et al. The effects of the selective\u000d\u000a      progesterone receptor modulator asoprisnil on the morphology of uterine\u000d\u000a      tissues after 3 months treatment in patients with symptomatic uterine\u000d\u000a      leiomyomata. Hum Reprod. 2007;22:1696-704. DOI: 10.1093\/humrep\/dem026.\u000d\u000a    \u000a\u000a3.6 Baird D, Brown A, Critchley H, Williams A, Lin S, Cheng L. Effect of\u000d\u000a      long-term treatment with low-dose mifepristone on the endometrium. Hum\u000d\u000a      Reprod. 2003;18:61-8. DOI: 10.1093\/humrep\/deg022.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000d\u000a    5.1 NHS National Services Scotland (2013). Abortion Statistics.\u000d\u000a      http:\/\/www.isdscotland.org\/Health-Topics\/Sexual-Health\/Publications\/2013-05-28\/2013-05-28-Abortions-Summary.pdf.\u000d\u000a    5.2 FDA Reproductive Health Drugs Advisory Committee (2010). ella®,\u000d\u000a      ulipristal acetate.\u000d\u000a      http:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/Drugs\/ReproductiveHealthDrugsAdvisoryCommittee\/UCM217418.pdf.\u000d\u000a      [FDA licensing of ulipristal acetate; cites UoE research.]\u000d\u000a    5.3 Centers for Disease Prevention and Control, Morbidity and Mortality\u000d\u000a      Weekly Report (2013). U.S. Selected Practice Recommendations for\u000d\u000a      Contraceptive Use, 2013.\u000d\u000a      http:\/\/www.cdc.gov\/mmwr\/pdf\/rr\/rr6205.pdf.\u000d\u000a    5.4 Bayer L, Edelman A, Caughey A, Rodriguez M. The price of emergency\u000d\u000a      contraception in the United States: what is the cost-effectiveness of\u000d\u000a      ulipristal acetate versus single-dose levonorgestrel? Contraception.\u000d\u000a      2013;87: 385-90. DOI: 10.1016\/j.contraception.2012.08.034.\u000d\u000a    5.5 Institute for Quality and Efficiency in Health Care (2009; updated in\u000d\u000a      2013). \"Treatment Options for Heavy Periods\". PubMed Health.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pubmedhealth\/PMH0005201\/.\u000d\u000a    5.6 The Agency for Healthcare Research and Quality. Research Protocol,\u000d\u000a      November 21st 2011. Primary Care Management of Abonormal\u000d\u000a      Uterine Bleeding.\u000d\u000a      http:\/\/effectivehealthcare.ahrq.gov\/index.cfm\/search-for-guides-reviews-and-reports\/?productid=850&pageaction=displayproduct.\u000d\u000a    5.7 Society of Obstetricians and Gynaecologists of Canada Clinical\u000d\u000a      Practice Guidelines (2013). Abnormal Uterine Bleeding in Pre-Menopausal\u000d\u000a      Women. http:\/\/sogc.org\/guidelines\/abnormal-uterine-bleeding-in-pre-menopausal-women\/.\u000d\u000a    5.8 Letter from the Senior Medical Director of Women's Health, AbbVie\u000d\u000a      Inc., in support of the contributions made by UoE researchers in the field\u000d\u000a      of reproductive health, particularly basic and clinical research with\u000d\u000a      PRMs. [Available on request.]\u000d\u000a    5.9 Mutter G, Bergeron C, Deligdisch L,...Williams A, Blithe D. The\u000d\u000a      spectrum of endometrial pathology induced by progesterone receptor\u000d\u000a      modulators. Mod Pathol. 2008;21:591-8. DOI: 10.1038\/modpathol.2008.19.\u000d\u000a    5.10 Wilkens J, Chwalisz K, Han C,...Williams A, Critchley H. Effects of\u000d\u000a      the selective progesterone receptor modulator asoprisnil on uterine artery\u000d\u000a      blood flow, ovarian activity, and clinical symptoms in patients with\u000d\u000a      uterine leiomyomata scheduled for hysterectomy. J Clin Endocrinol Metab.\u000d\u000a      2008;93:4664-71. DOI: 10.1210\/jc.2008-1104. \u000d\u000a    ","Title":"\u000d\u000a    S: Progesterone receptor modulators are effective in emergency\u000d\u000a        contraception and therapy of heavy menstrual bleeding\/fibroids\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    A 20-year continuous programme of studies at UoE by Professor Hilary\u000d\u000a      Critchley (Professor of Reproductive Medicine, UoE, 1993-present), Dr\u000d\u000a      Alistair Williams (Reader in Pathology, UoE, 1998-present), Professor\u000d\u000a      David Baird (Professor of Reproductive Endocrinology, UoE, 1977-2000; now\u000d\u000a      Emeritus), Dr Pamela Warner (Reader in Medical Statistics, UoE,\u000d\u000a      1994-present), Dr Sharon Cameron (Consultant in Gynaecology and\u000d\u000a      Reproductive Health, Honorary Senior Lecturer, UoE) and Professor Anna\u000d\u000a      Glasier (Honorary Professor, 2004-present) has provided pivotal data for\u000d\u000a      the development of progesterone receptor modulators (PRMs), most\u000d\u000a      importantly as contraceptives, but also with other important clinical\u000d\u000a      utilities in women's health.\u000d\u000a    Effective and safe contraception remains a major issue in women's health\u000d\u000a      worldwide. Between 2000 and 2007, Baird (with Critchley, Glasier and\u000d\u000a      Cameron) pioneered research in the use of PRMs for contraception by\u000d\u000a      demonstrating that PRM exposure prevents the establishment of pregnancy.\u000d\u000a      Glasier established that the PRM mifepristone was effective as emergency\u000d\u000a      contraception, and that emergency contraception could be safely given\u000d\u000a      over-the-counter (OTC; without prescription) [3.1]. These data led to UK\u000d\u000a      government approval of alternative emergency contraception available OTC\u000d\u000a      in 2001. A subsequent multicentre randomised trial and meta-analysis of\u000d\u000a      2221 women, led by Glasier and Cameron, showed that the PRM ulipristal\u000d\u000a      acetate is the most safe and effective form of emergency contraception\u000d\u000a      [3.2].\u000d\u000a    A second focus of the team's research has been menstrual complaints,\u000d\u000a      specifically heavy menstrual bleeding (HMB) and uterine fibroids, which\u000d\u000a      often co-occur (fibroids are present in up to 80% of women of reproductive\u000d\u000a      age). HMB can cause anaemia, have a negative impact on quality of life and\u000d\u000a      productivity, and cause significant morbidity in women: 1 in 3 women will\u000d\u000a      complain of HMB during their reproductive years. Critchley established\u000d\u000a      (1996 onwards) that progesterone receptors A and B and progesterone\u000d\u000a      withdrawal play a pivotal role in regulating the cyclical remodelling\u000d\u000a      occurring within the endometrium during the menstrual cycle [3.3, 3.4].\u000d\u000a      Critchley, Baird and Williams undertook formative \"in human\" studies of\u000d\u000a      the actions of PRMs (mifepristone, asoprisnil) on uterine\/endometrial\u000d\u000a      tissue [3.5, 3.6], demonstrating a unique histological effect on the\u000d\u000a      endometrium [3.5]. Furthermore, they reported the anti-proliferative\u000d\u000a      effects on the endometrium of low-dose continuous administration of\u000d\u000a      mifepristone, when women took this class of drug for 6 months [3.6]. This\u000d\u000a      highlighted the potential of this drug class to achieve morphological and\u000d\u000a      functional effects that reduce menstrual bleeding.\u000d\u000a    UoE studies from 1995 onwards have also provided unique insights into the\u000d\u000a      local endometrial effects of intrauterine use (i.e., slow release) of the\u000d\u000a      PR agonist levonorgestrel. Levonorgestrel delivered by an intrauterine\u000d\u000a      system (LNG-IUS) is currently a first-line management for HMB. Crucial\u000d\u000a      data were also derived from ensuing detailed studies of uterine morphology\u000d\u000a      following exposure to selected PRMs, which showed the marked\u000d\u000a      anti-proliferative effects of this class of compound, along with the added\u000d\u000a      health benefit of amenorrhoea, and in turn directly informed the\u000d\u000a      development and refinement of the drug class, i.e., PRMs, for the\u000d\u000a      treatment of fibroids and HMB [3.6].\u000d\u000a    "},{"CaseStudyId":"23877","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Pathways to impact\u000d\u000a      Walsh lead-authored a high-impact open-access clinical review (BMJ\u000d\u000a      341:doi:10.1136\/bmj.c4408) authored\/co-authored eight chapters\/book\u000d\u000a      contributions from 2001-12 and has spoken on this topic at >30 national\u000d\u000a      and international meetings from 2003-12. He organised and hosted national\u000d\u000a      educational meetings on blood transfusion in 2004 and 2009.\u000d\u000a    Impact on public policy\u000d\u000a      Walsh has worked closely with the Scottish National Blood Transfusion\u000d\u000a      Service [5.1, 5.2] and Better Blood Transfusion Programmes (acting as\u000d\u000a      expert advisor from 2003, a member of the National Transfusion Committee\u000d\u000a      from 2005-12, and acting as Lothian Regional Lead 2004-8). He played key\u000d\u000a      advisory roles (2005-10) in the development and implementation of the\u000d\u000a      Scottish Transfusion Epidemiology Project that links national databases to\u000d\u000a      report on blood use at regional, hospital and individual clinician level,\u000d\u000a      and in national audit initiatives around major haemorrhage management\u000d\u000a      (2008-9).\u000d\u000a    Walsh chaired a British Committee for Safety in Haematology\/UK Intensive\u000d\u000a      Care Society evidence- based guideline group (2011-12), which completed\u000d\u000a      the first evidence-based UK guideline for RBC transfusion practice in\u000d\u000a      critical care [5.3]. Moreover, six of Walsh's papers are cited as part of\u000d\u000a      the underpinning evidence for US\/international guidelines on transfusion\u000d\u000a      in critical care [5.4]. Walsh co-initiated the development of a National\u000d\u000a      Institute for Health and Care Excellence Guideline for Transfusion and was\u000d\u000a      selected as the UK critical care representative (first meeting 2013).\u000d\u000a    Impact on clinical practice and the economy\u000d\u000a      Impact on UK critical care: Walsh showed in 2001 that 40% of ICU\u000d\u000a      patients were transfused, each receiving on average 1.9 RBC units. In\u000d\u000a      comparison, his 2010 analysis [5.5] of 2006 data from 29 ICUs showed that\u000d\u000a      transfusion rates had decreased to 33% of ICU admissions. Data calculated\u000d\u000a      on the reduction in transfusion per admission over this period indicate\u000d\u000a      that of the >100,000 patients treated annually in UK general ICUs,\u000d\u000a      around 7000 fewer patients receive RBCs compared with in 2001, saving\u000d\u000a      >40,000 RBCs\/year. There have been substantial changes in practice\u000d\u000a      among clinicians, and a major saving in precious blood supplies as donor\u000d\u000a      numbers fall and production costs rise.\u000d\u000a    Impact on surgical practice: Evidence from critical care has been\u000d\u000a      widely implemented in surgical and perioperative practice. The recognition\u000d\u000a      that RBC transfusions should be avoided wherever possible has led to an\u000d\u000a      increase in the use of blood conservation technologies, especially\u000d\u000a      perioperative cell salvage. Walsh's study of cell salvage in orthopaedic\u000d\u000a      surgery supported the widespread introduction of this technology, and\u000d\u000a      Walsh initiated the Scotland-wide cell salvage programme, wrote the model\u000d\u000a      business cases, and secured ongoing funding from 2005 for a Scottish\u000d\u000a      coordinator to lead education, safety, and data management. Red cell\u000d\u000a      salvage use has increased from 90 cases\/million population (2005) to 650\u000d\u000a      cases\/million population (2010), and the technology has been adopted\u000d\u000a      across all health boards in Scotland undertaking major surgery.\u000d\u000a    Overall and economic impact: Data from the Scottish Transfusion\u000d\u000a      Epidemiology Project indicate a reduction in annual RBC transfusions from\u000d\u000a      45.9 to 34.0 per 1000 population (2001 to 2012). Trends in England\u000d\u000a      indicate similar reductions [5.6]. In Scotland, this represents a 50,000\u000d\u000a      units\/year (22%) reduction in RBC use, at a cost reduction of\u000d\u000a      approximately £6.5M\/year (extrapolated to approximately £100M annually\u000d\u000a      across the UK). In intensive care, around 7000 fewer patients are exposed\u000d\u000a      to RBCs annually, saving 40,000 RBCs\/year (annual cost saving\u000d\u000a      approximately £5M).\u000d\u000a    Impact on health and welfare\u000d\u000a      Existing evidence suggests that restricting exposure to RBC transfusions\u000d\u000a      improves patient outcome, so practice change is likely to have directly\u000d\u000a      translated into saving lives. In critical care, reducing RBC use is\u000d\u000a      associated with improved outcomes in many patient sub-groups [3.5]. A\u000d\u000a      reasonable but conservative estimate of 1-2% mortality reduction in the UK\u000d\u000a      over 10 years would indicate approximately 500 lives saved per year.\u000d\u000a      Although attribution of direct causality is difficult in critical care\u000d\u000a      populations, these changes are consistent with the progressive improvement\u000d\u000a      in Standardised Mortality Ratios in Scottish ICUs over the past decade\u000d\u000a      from 1.06 (2001) to 0.86 (2010) [5.7].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Impact: Health and wellbeing; translation of a clear evidence base\u000d\u000a      for reducing red blood cell use in intensive care and surgery into\u000d\u000a      guidelines and changed clinical practice.\u000d\u000a    Significance: A 20% reduction in overall UK red blood cell usage\u000d\u000a      between 2002-2012, saving the NHS approximately £100M annually; 7000 fewer\u000d\u000a      patients are exposed to red cell transfusion annually, saving 500 lives.\u000d\u000a    Beneficiaries: Patients in intensive care units; the NHS and\u000d\u000a      healthcare delivery agencies.\u000d\u000a    Attribution: Studies were led by Walsh at UoE with NHS and\u000d\u000a      Canadian collaborators.\u000d\u000a    Reach: 7000 patients per year, UK-wide; incorporation into\u000d\u000a      international guidelines.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Edinburgh\u000d\u000a    ","Institutions":[{"AlternativeName":"Edinburgh (University of)","InstitutionName":"University of Edinburgh","PeerGroup":"A","Region":"Scotland","UKPRN":10007790}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a3.1 Chohan S, McArdle F, McClelland D, Mackenzie S, Walsh T. Red cell\u000d\u000a      transfusion practice following the transfusion requirements in critical\u000d\u000a      care (TRICC) study: prospective observational cohort study in a large UK\u000d\u000a      intensive care unit. Vox Sang. 2003;84:211-8. DOI: 10.1046\/j.1423-\u000d\u000a      0410.2003.00284.x.\u000d\u000a    \u000a\u000a3.2 Walsh T, Garrioch M, Maciver C, et al.; Audit of Transfusion in\u000d\u000a      Intensive Care in Scotland (ATICS) study group. Red cell requirements for\u000d\u000a      intensive care units adhering to evidence-based transfusion guidelines.\u000d\u000a      Transfusion. 2004:44:1405-11. DOI: 10.1111\/j.1537-2995.2004.04085.x.\u000d\u000a    \u000a\u000a3.3 Walsh T, McClelland D, Lee R, et al.; ATICS Study Group. Prevalence\u000d\u000a      of ischaemic heart disease at admission to intensive care and its\u000d\u000a      influence on red cell transfusion thresholds: multicentre Scottish Study.\u000d\u000a      Br J Anaesth. 2005;94:445-52. DOI: 10.1093\/bja\/aei073.\u000d\u000a    \u000a\u000a3.4 Walsh T, McIver C; Scottish Critical Care Trials Group and Scottish\u000d\u000a      National Blood Transfusion Service Clinical Effectiveness Group. A\u000d\u000a      clinical scenario-based survey of transfusion decisions for intensive care\u000d\u000a      patients with delayed weaning from mechanical ventilation. Transfusion.\u000d\u000a      2009;49:2661-7. DOI: 10.1111\/j.1537-2995.2009.02336.x.\u000d\u000a    \u000a\u000a3.5 Walsh T, Boyd J, Watson D, et al. Restrictive versus liberal\u000d\u000a      transfusion strategies for older mechanically ventilated critically ill\u000d\u000a      patients: a randomized pilot trial. Crit Care Med. 2013;41:2354- 63. DOI:\u000d\u000a      10.1097\/CCM.0b013e318291cce4.\u000d\u000a    \u000a\u000a3.6 Bateman A, McArdle F, Walsh T. Time course of anemia during six\u000d\u000a      months follow up following intensive care discharge and factors associated\u000d\u000a      with impaired recovery of erythropoiesis. Crit Care Med. 2009;37:1906-12.\u000d\u000a      DOI: 10.1097\/CCM.0b013e3181a000cf.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    5.1 Letter from the Medical Director of the Scottish National Blood\u000d\u000a      Transfusion Service. [Available on request. Confirms the impact of the\u000d\u000a        Walsh group's research].\u000d\u000a    5.2 Letter from the Professor of Blood Transfusion Medicine, University\u000d\u000a      of Oxford [Available on request. Confirms the impact of the Walsh\u000d\u000a        group's research].\u000d\u000a    5.3 Retter A, Wyncoll D, Pearse R,...Walsh T. Guidelines on the\u000d\u000a      management of anaemia and red cell transfusion in adult critically ill\u000d\u000a      patients. Br J Haematol. 2013;160:445-64. DOI: 10.1111\/bjh.12143. [The\u000d\u000a        first UK evidence-based guideline.]\u000d\u000a    5.4 Napolitano L, Kurek S, Luchette F, et al.; American College of\u000d\u000a      Critical Care Medicine of the Society of Critical Care Medicine; Eastern\u000d\u000a      Association for the Surgery of Trauma Practice Management Workgroup.\u000d\u000a      Clinical practice guideline: Red blood cell transfusion in adult trauma\u000d\u000a      and critical care. Crit Care Med. 2009;37:3124-57. DOI:\u000d\u000a      10.1097\/CCM.0b013e3181b39f1b. [International guidelines citing Walsh's\u000d\u000a        work.]\u000d\u000a    5.5 Seretny M. Red Blood Cell Transfusion in Intensive Care: A review of\u000d\u000a      the Intensive Care Study of Coagulopathy (ISOC) dataset. Masters thesis,\u000d\u000a      University of Edinburgh, 2010. [Available on request. Provides\u000d\u000a        evidence for decreased transfusion rates in UK critical care.]\u000d\u000a    5.6 Tinegate H, Chattree S, Iqbal A, Plews D, Whitehead J, Wallis J;\u000d\u000a      Northern Regional Transfusion Committee. Ten-year pattern of red blood\u000d\u000a      cell use in the North of England. Transfusion. 2013;53:483-9. DOI:\u000d\u000a      10.1111\/j.1537-2995.2012.03782.x. [Provides evidence for decreased\u000d\u000a        overall RBC use.]\u000d\u000a    5.7 Audit of Critical Care in Scotland. Scottish Intensive Care Society\u000d\u000a      Audit Group (2012). www.sicsag.scot.nhs.uk\/Publications\/web-SICSAG-report-2012-Final.pdf.\u000d\u000a      [Corroborates decrease in ICU mortality rates.] \u000d\u000a    ","Title":"\u000d\u000a    I: Reducing blood transfusions in intensive care and surgery saves\u000d\u000a        precious blood, reduces costs and decreases patient risk\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Tim Walsh (Senior Lecturer; now Professor of Critical Care,\u000d\u000a      UoE, 1999-present) established a research programme to define the\u000d\u000a      relevance of Canadian pilot studies of transfusion in intensive care units\u000d\u000a      (ICU) to UK practice. He established clear evidence for restricted\u000d\u000a      transfusion use and, going further than other investigators, showed\u000d\u000a      definitively that not only are outcomes not affected by restrictive\u000d\u000a      transfusion practice, but also that mortality rates are almost certainly\u000d\u000a      reduced.\u000d\u000a    During the late 1990s there was increasing interest in defining the risk\u000d\u000a      (as opposed to assumed benefit) of red blood cell (RBC) transfusion in\u000d\u000a      anaemic critically ill patients. Supported by awards from the National\u000d\u000a      Institute for Health Research (£1.4M) and Chief Scientist Office (£182K),\u000d\u000a      Walsh began to define current UK practice, explore persisting\u000d\u000a      uncertainties among clinicians, quantify the risk of RBC transfusion and\u000d\u000a      implement an evidence-based approach. Collaborations with the Scottish and\u000d\u000a      English National Blood Transfusion Service and Canadian transfusion\u000d\u000a      researchers aimed to quantify risk and reduce unnecessary patient exposure\u000d\u000a      to blood transfusions, thereby conserving blood supplies.\u000d\u000a    Walsh developed methodology to describe ICU transfusion practice at\u000d\u000a      Edinburgh Royal Infirmary in 1999-2000 [3.1]. He led a programme of\u000d\u000a      education across all 25 Scottish ICUs, and completed a national cohort\u000d\u000a      study of >1000 ICU patients in 2001; this was the first national\u000d\u000a      benchmarking study of blood use in UK critical care [3.2] and highlighted\u000d\u000a      areas where better evidence to define the risk of RBC transfusion was\u000d\u000a      needed.\u000d\u000a    Severely unwell critically ill patients with heart disease.\u000d\u000a      Walsh's observational studies of practice and national surveys (2001-8)\u000d\u000a      demonstrated that existing evidence was insufficient to define best\u000d\u000a      practice for patients with prolonged critical illness or heart disease\u000d\u000a      [3.3, 3.4]. With funding from the Chief Scientist Office, Walsh and\u000d\u000a      colleagues completed a multicentre feasibility trial (2009-11). This trial\u000d\u000a      showed signals for harm from liberal use of RBCs even in the sickest ICU\u000d\u000a      patients with multiple co-morbidities (absolute mortality difference over\u000d\u000a      6 months 18%; hazard ratio 0.54 (P = 0.061)), providing further\u000d\u000a      evidence to support restricting RBC transfusion [3.5].\u000d\u000a    Storage age of the blood. The Edinburgh group associated the\u000d\u000a      changes that occur during red cell storage with the evidence that RBC\u000d\u000a      transfusions could have adverse effects (Br J Anaesth. 2002;89:537). Walsh\u000d\u000a      is the UK lead on a large international randomised controlled trial, the\u000d\u000a      Age of Blood Evaluation study, which will report in 2014-15.\u000d\u000a    Persisting anaemia following critical illness. In a series of cohort\u000d\u000a    studies (2005-8), Walsh and colleagues explored clinician concern that\u000d\u000a    restrictive transfusion management and resultant ongoing anaemia might\u000d\u000a    affect long-term health-related quality of life (HRQoL) among ICU survivors.\u000d\u000a    These studies confirmed that anaemia was often prevalent for many months\u000d\u000a    after ICU discharge and was associated with poor HRQoL, but that it could be\u000d\u000a    an epiphenomenon [3.6]. The Walsh group's recent feasibility trial indicated\u000d\u000a    no associations between restrictive RBC use and reduced patient survival,\u000d\u000a    HRQoL, or disability over 6 months follow up [3.5]. Thus, Walsh and\u000d\u000a    colleagues have demonstrated that restrictive transfusion practice should be\u000d\u000a    used even among the sickest critically ill patients and will not result in\u000d\u000a    adverse outcomes.\u000d\u000a    Cell salvage during surgery. Walsh, collaborating with the\u000d\u000a      National Blood Transfusion Service, led a multicentre cohort study in 11\u000d\u000a      hospitals (210 cases), which indicated that cell salvage reduced RBC use\u000d\u000a      in high-risk orthopaedic surgery (Br J Anaesth. 2012;108:63).\u000d\u000a    "},{"CaseStudyId":"26451","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Our research into FAF imaging has transformed clinical practice in\u000d\u000a      retinal disease. The 2010 text\u000d\u000a      book Medical Retina: Focus on Retinal Imaging describes how \"the\u000d\u000a        era of FAF imaging as applied\u000d\u000a        today has begun in 1995. Von Ruckmann, Fitzke and Bird described in\u000d\u000a        their landmark paper the\u000d\u000a        use of a confocal scanning laser ophthalmoscope for FAF imaging in a\u000d\u000a        large number of patients\"\u000d\u000a      [a]. The subsequent widespread adoption of this technique has led\u000d\u000a      to patient benefits in terms of\u000d\u000a      earlier detection and monitoring of disease. The technique has also\u000d\u000a      impacted on the development\u000d\u000a      of new therapies, as efficacy can be better assessed. The economic impacts\u000d\u000a      on commercial\u000d\u000a      companies who produce equipment have also been substantial.\u000d\u000a    FAF imaging is now a widely used technique in the assessment of retinal\u000d\u000a      disease, and is available\u000d\u000a      nationwide as part of NHS services. At Moorfields Eye Hospital alone,\u000d\u000a      between 300 and 500\u000d\u000a      patients per week are imaged by FAF (c.20,000 per year) [b]. In\u000d\u000a      the Department of Health's 2007\u000d\u000a      document, What is Physiological Measurement? A guide to\u000d\u000a        the tests and procedures conducted by\u000d\u000a        Physiological Measurement diagnostic services, FAF is listed as a\u000d\u000a      standard technique, as follows:\u000d\u000a    \"Test: Fundus autofluorescence (AF) with confocal\u000d\u000a        scanning laser ophthalmoscope\u000d\u000a        (Heidelberg Retina Angiograph HRA). Function: To\u000d\u000a        image the lipofuscin pigment in the\u000d\u000a        retinal pigment epithelium for diagnosis and monitoring of retinal\u000d\u000a        dystrophies and\u000d\u000a        degenerations. Indication: Retinal dystrophies;\u000d\u000a        Age-related macular degeneration\" [c]\u000d\u000a    2009 guidelines from the Royal College of Ophthalmologists described FAF\u000d\u000a      as a \"commonly used\u000d\u000a        retinal imaging technique\" and recommended it in the diagnosis of\u000d\u000a      Age Related Macular\u000d\u000a      Degeneration as follows: \"The use of scanning laser ophthalmoscopy to\u000d\u000a        generate fundus\u000d\u000a        autofluorescence images and the use of en-face imaging using spectral\u000d\u000a        domain OCT have made it\u000d\u000a        easier to diagnose GA [geography atrophy] as these can reveal areas of\u000d\u000a        GA which may not be\u000d\u000a        clinically visible on biomicroscopy\" and \"[Autofluorescence] can\u000d\u000a        give an indication of the health of\u000d\u000a        the RPE.\" The 2013 update to these guidelines further emphasised the\u000d\u000a      utility of FAF, saying:\u000d\u000a      \"Several imaging modalities may be useful, in particular\u000d\u000a          fundus autofluorescence, in the evaluation\u000d\u000a        of GA\" (emphasis added) and \"Fundus autofluorescence imaging\u000d\u000a        especially when combined with\u000d\u000a        optical coherence tomography is helpful in distinguishing PD from AMD\"\u000d\u000a      [d].\u000d\u000a    That the impact of this technique on clinical practice has spread beyond\u000d\u000a      the UK is demonstrated by\u000d\u000a      a 2010 review article in Eye Net magazine (produced by the American\u000d\u000a      Academy of\u000d\u000a      Ophthalmology) which described how \"Fundus autofluorescence (FAF) has\u000d\u000a        recently pole-vaulted\u000d\u000a        from a research tool to a real clinical application\" [e].\u000d\u000a    The application of FAF imaging in the clinic has considerable benefits\u000d\u000a      for patients. As described in\u000d\u000a      a recent review, which described FAF imaging as \"a valuable asset in\u000d\u000a        diagnosing retinal disease\",\u000d\u000a      the technique may allow for earlier identification of retinal diseases\u000d\u000a      which are not otherwise evident\u000d\u000a      [f]. This allows earlier treatment, and better monitoring of the\u000d\u000a      efficacy of this treatment.\u000d\u000a    Development of new therapies\u000d\u000a    New forms of interventions such as gene therapy and stem cell therapy\u000d\u000a      increasingly rely on FAF\u000d\u000a      and related novel forms of imaging to determine potentially beneficial\u000d\u000a      effects of treatment. Clinical\u000d\u000a      trials use FAF and other new forms of imaging in addition to conventional\u000d\u000a      endpoints such as visual\u000d\u000a      function (visual acuity or visual fields) and electrophysiological\u000d\u000a      measures. For example, a recent\u000d\u000a      trial of intravitreal injections of ranibizumab for pigment epithelial\u000d\u000a      detachment (PED) secondary to\u000d\u000a      AMD used FAF as one of its methods of assessment, as did another study of\u000d\u000a      subconjunctival\u000d\u000a      sirolimus for the treatment of geographic atrophy [g]. One trial\u000d\u000a      investigator reported that \"In\u000d\u000a        designing clinical trials that test new pharmacologic interventions,\u000d\u000a        [fundus autofluorescence] is\u000d\u000a        helpful in distinguishing progressers from slow progressers\" [h].\u000d\u000a    In the US, the FDA recently advised that: \"FDA's Center for Drug\u000d\u000a        Evaluation and Research\u000d\u000a        (CDER) has accepted as an anatomic endpoint a decrease in the rate of\u000d\u000a        growth of an area of\u000d\u000a        retina that no longer has any photoreceptors. This can be measured in\u000d\u000a        one of several ways... The\u000d\u000a        hallmark of dry AMD is geographic atrophy in the macula. Geographic\u000d\u000a        atrophy is a breakdown in\u000d\u000a        the retinal pigment epithelium (RPE) and subsequent overlying retinal\u000d\u000a        tissue. There is not a\u000d\u000a        uniform destruction of the retina, and photoreceptors are often spared\u000d\u000a        at the periphery of the\u000d\u000a        lesions. These \"fuzzy borders,\" when viewed by fundus photography or\u000d\u000a        autofluorescence, often\u000d\u000a        surround an area where there is complete destruction of the\u000d\u000a        photoreceptors. Reduction in the rate\u000d\u000a        of progression of these areas of complete destruction of the\u000d\u000a        photoreceptors can sometimes be\u000d\u000a        measured indirectly by fundus photography or autofluorescence. When the\u000d\u000a        area of complete\u000d\u000a        destruction of the photoreceptors in dry AMD can be measured, it is an\u000d\u000a        acceptable endpoint. A\u000d\u000a        change in the area of non-seeing retina has been used as a clinical\u000d\u000a        endpoint to support New Drug\u000d\u000a        Applications (NDAs) such as ganciclovir and foscarnet in the treatment\u000d\u000a        of cytomegalovirus (CMV)\u000d\u000a        retinitis\" [i].\u000d\u000a    Economic impacts\u000d\u000a    Since our first demonstration of FAF in the eyes of patients using the\u000d\u000a      SLO, numerous other\u000d\u000a      research centres throughout the world have taken up the technique and many\u000d\u000a      thousands of\u000d\u000a      instruments have been deployed clinically worldwide. Several major\u000d\u000a      companies now manufacture\u000d\u000a      these devices, including Canon, Heidelberg Engineering and Optos [j].\u000d\u000a      Large numbers are sold\u000d\u000a      every year. [text removed for publication] [k]. Globally,\u000d\u000a      it has been estimated that c.10,000 of\u000d\u000a      these instruments have been sold. Thus the economic impacts of this\u000d\u000a      industry are considerable:\u000d\u000a      with instruments costing about $200,000, this implies spending of c.$2bn\u000d\u000a      for the instruments alone.\u000d\u000a      In addition to this sum, there has been worldwide investment in clinical\u000d\u000a      staff, infrastructure and\u000d\u000a      medical resources to provide FAF imaging for patients. This is a clear\u000d\u000a      indicator of the impact FAF\u000d\u000a      has on clinical practice and perceived benefit to patients.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Fundus autofluorescence imaging has transformed understanding of retinal\u000d\u000a      disease and brought\u000d\u000a      enormous benefit to millions of patients world-wide. By visualising what\u000d\u000a      is predominantly a\u000d\u000a      lipofuscin signal from the retinal pigment epithelium, retinal diagnosis\u000d\u000a      is now much more\u000d\u000a      sophisticated, therapy can be better targeted to an individual patient's\u000d\u000a      needs and clinical trials can\u000d\u000a      use area of loss of autofluorescence as an outcome measure. Certain\u000d\u000a      inherited retinal disorders\u000d\u000a      have distinctive patterns of altered fluorescence and ageing changes can\u000d\u000a      be followed with much\u000d\u000a      greater precision. A global industry has built up around the devices\u000d\u000a      required to image retinal\u000d\u000a      autofluorescence safely.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] von Rückmann A, Fitzke FW, Bird AC. Distribution of fundus\u000d\u000a      autofluorescence with a scanning\u000d\u000a      laser ophthalmoscope. Br J Ophthalmol. 1995 May;79(5):407-12. http:\/\/doi.org\/bmc975\u000d\u000a    \u000a\u000a[2] von Rückmann A, Fitzke FW, Bird AC. Fundus autofluorescence in\u000d\u000a      age-related macular\u000d\u000a      disease imaged with a laser scanning ophthalmoscope. Invest Ophthalmol Vis\u000d\u000a      Sci. 1997\u000d\u000a      Feb;38(2):478-86. http:\/\/www.iovs.org\/content\/38\/2\/478.long\u000d\u000a    \u000a\u000a[3] von Rückmann A, Fitzke FW, Bird AC. In vivo fundus autofluorescence\u000d\u000a      in macular dystrophies.\u000d\u000a      Arch Ophthalmol. 1997 May;115(5):609-15. http:\/\/doi.org\/c2h4j2\u000d\u000a    \u000a\u000a[4] Robson AG, Moreland JD, Pauleikhoff D, Morrissey T, Holder GE, Fitzke\u000d\u000a      FW, Bird AC, van\u000d\u000a      Kuijk FJ. Macular pigment density and distribution: comparison of fundus\u000d\u000a      autofluorescence with\u000d\u000a      minimum motion photometry. Vision Res. 2003 Jul;43(16):1765-75. http:\/\/doi.org\/b2m932\u000d\u000a    \u000a\u000a[5] Robson AG, Egan CA, Luong VA, Bird AC, Holder GE, Fitzke FW.\u000d\u000a      Comparison of fundus\u000d\u000a      autofluorescence with photopic and scotopic fine-matrix mapping in\u000d\u000a      patients with retinitis\u000d\u000a      pigmentosa and normal visual acuity. Invest Ophthalmol Vis Sci. 2004\u000d\u000a      Nov;45(11):4119-25.\u000d\u000a      http:\/\/dx.doi.org\/10.1167\/iovs.04-0211\u000d\u000a    \u000a\u000a[6] Scholl HP, Bellmann C, Dandekar SS, Bird AC, Fitzke FW. Photopic and\u000d\u000a      scotopic fine matrix\u000d\u000a      mapping of retinal areas of increased fundus autofluorescence in patients\u000d\u000a      with age-related\u000d\u000a      maculopathy. Invest Ophthalmol Vis Sci. 2004 Feb;45(2):574-83. http:\/\/doi.org\/fh9qxv\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    [a] Holz FG, Spaide RF. (Eds.) Medical Retina: Focus on Retinal Imaging.\u000d\u000a      New York: Springer;\u000d\u000a      2010. (Essentials in Ophthalmology). ISBN 978-3-540-85540-8. Chapter 5 is\u000d\u000a      on FAF and\u000d\u000a      references the underpinning research. Copy of relevant section available\u000d\u000a      on request.\u000d\u000a    [b] Patient numbers can be corroborated by Moorfields Eye Hospital.\u000d\u000a      Contact details provided. As\u000d\u000a      well as Moorfields, examples include:\u000d\u000a    \u000d\u000a      Gloucestershire Eye Unit (http:\/\/www.ophthalmology.severndeanery.nhs.uk\/about-us\/hospitals\/gloucestershire-eye-unit\/)\u000d\u000a      Southampton Eye Unit\u000d\u000a        http:\/\/jobs.uhs.nhs.uk\/job\/UK\/Hampshire\/Southampton\/University_Hospital_Southampton_NHS_Foundation_Trust\/The_Eye_Unit\/The_Eye_Unit-v289350?ss=2&nc=80841382794467\u000d\u000a        (Copy available on request)\u000d\u000a      Great Ormond Street: http:\/\/www.gosh.nhs.uk\/health-professionals\/clinical-specialties\/ophthalmology-information-for-health-professionals\/refer-a-patient\/\u000a\u000d\u000a    \u000d\u000a    [c] Department of Health. What is Physiological Measurement? A guide to\u000d\u000a      the tests and\u000d\u000a      procedures conducted by Physiological Measurement diagnostic services. May\u000d\u000a      2007. (Copy\u000d\u000a      available upon request.)\u000d\u000a    [d] 2009 guidelines are available here: http:\/\/www.heartofengland.nhs.uk\/wp-content\/uploads\/FOI1808Attachment1.pdf (And copy available on\u000d\u000a      request.) The current (2013)\u000d\u000a      guidelines are available from the RCOpth website:\u000d\u000a      http:\/\/www.rcophth.ac.uk\/core\/core_picker\/download.asp?id=1851&filetitle=Age%2DRelated+Macular+Degeneration%3A+Guidelines+for+Management+2013\u000d\u000a    [e] http:\/\/www.aao.org\/publications\/eyenet\/201006\/feature.cfm\u000d\u000a    [f] http:\/\/www.revophth.com\/content\/d\/imaging_and_diagnostic_instruments\/c\/22655\/\u000d\u000a    [g] Examples include:\u000d\u000a    \u000d\u000a      Clemens CR, Alten F, Milojcic C, Nicole E. Morphologic Changes In\u000d\u000a        Pigment Epithelial\u000d\u000a        Detachment After Ranibizumab Treatment Assessed By Spectral Domain Oct,\u000d\u000a        Fundus\u000d\u000a        Autofluorescence, Fluorescein And Icg Angiography: Six-month Results Of\u000d\u000a        A Prospective\u000d\u000a        Randomized Study. ARVO 2011 Abstract no 1658\/A53 http:\/\/tinyurl.com\/ox2bbh3\u000a\u000d\u000a      Wong WT, Dresner S, Forooghian F, Glaser T, Doss L, Zhou M, Cunningham\u000d\u000a        D, Shimel K,\u000d\u000a        Harrington M, Hammel K, Cukras CA, Ferris FL, Chew EY. Treatment of\u000d\u000a        geographic\u000d\u000a        atrophy with subconjunctival sirolimus: results of a phase I\/II clinical\u000d\u000a        trial. Invest Ophthalmol\u000d\u000a        Vis Sci. 2013 Apr 26;54(4):2941-50. http:\/\/dx.doi.org\/10.1167\/iovs.13-11650.\u000d\u000a    \u000d\u000a    [h] Frank Holz, University of Bonn, quoted in a 2008 article in Healio,\u000d\u000a      Ocular Surgery News:\u000d\u000a      http:\/\/www.healio.com\/ophthalmology\/retina-vitreous\/news\/print\/ocular-surgery-news\/%7B1a16733d-8f99-4f6b-bfec-2da309dc675f%7D\/fundus-autofluorescence-imaging-may-help-predict-amd-progression\u000d\u000a    [i] Briefing Document FDA Cellular, Tissue, and Gene Therapies Advisory\u000d\u000a      Committee CTGTAC\u000d\u000a      Meeting #522028Cellular and Gene Therapies for Retinal Disorders June 29,\u000d\u000a      2011.\u000d\u000a      http:\/\/www.fda.gov\/downloads\/advisorycommittees\/committeesmeetingmaterials\/bloodvaccinesandotherbiologics\/cellulartissueandgenetherapiesadvisorycommittee\/ucm259087.pdf\u000d\u000a    [j] At least 5 companies, selling 14 different products reported here:\u000d\u000a      http:\/\/www.medicalexpo.com\/medical-manufacturer\/slo-ophthalmoscope-887.html.\u000d\u000a      These\u000d\u000a      include:\u000d\u000a      Canon http:\/\/www.canon-europe.com\/Medical\/Eye_Care\/FAF\/Index.aspx\u000d\u000a      Heidelberg Engineering http:\/\/www.heidelbergengineering.com\/us\/products\/spectralis-models\/imaging-modes\/autofluorescence\/\u000d\u000a      Optos http:\/\/www.optos.com\/en\/Products\/Retinal-imaging-products\/Ultra-widefield-imaging\/Fundus-Autofluorescence\/\u000d\u000a    [k] Correspondence from Vice President of Medical Affairs & Quality,\u000d\u000a      Optos. Copy available on\u000d\u000a      request and contact details provided.\u000d\u000a    ","Title":"\u000d\u000a    Fundus autofluorescence imaging transforms understanding of retinal\u000d\u000a      disease\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Age-related macular degeneration (AMD) is the leading cause of visual\u000d\u000a      impairment in the UK,\u000d\u000a      affecting 462,000 people to some degree. For many years it was known that\u000d\u000a      the so-called \"age\u000d\u000a      pigment\", lipofuscin, accumulates in the cells of the eye and is\u000d\u000a      critically implicated in the\u000d\u000a      pathogenesis of AMD and other forms of retinal disease. However until the\u000d\u000a      early 1990s, all that\u000d\u000a      was known about the accumulation of lipofuscin in AMD was obtained from\u000d\u000a      post-mortem studies; it\u000d\u000a      was not possible to view it in the living eye. Research at the UCL\u000d\u000a      Institute of Ophthalmology, led by\u000d\u000a      Fred Fitzke and Alan Bird, pioneered the technique of Fundus\u000d\u000a      Autofluorescence (FAF) Imaging to\u000d\u000a      allow visualisation of lipofuscin. Our work in optics and imaging of the\u000d\u000a      eye led to the first images of\u000d\u000a      Fundus Autofluorescence using the Scanning Laser Ophthalmoscope (SLO),\u000d\u000a      which were published\u000d\u000a      in 1995 [1]. These provided high resolution imaging of the\u000d\u000a      distribution and levels of FAF\u000d\u000a      attributable to specific molecular species which are fundamentally\u000d\u000a      involved in the pathogenic\u000d\u000a      mechanisms of AMD, hereditary retinal degenerations such as retinitis\u000d\u000a      pigmentosa and other\u000d\u000a      blinding diseases [2].\u000d\u000a    Over the following years, we, with colleagues at Moorfields Eye Hospital,\u000d\u000a      pioneered use of the\u000d\u000a      technique, remaining from some time the only centre publishing in this\u000d\u000a      area. Our research efforts\u000d\u000a      measuring visual function in spatially contiguous locations of the retina\u000d\u000a      in the same eyes of\u000d\u000a      patients showed that FAF is of great value in the diagnosis of many\u000d\u000a      retinal disorders including\u000d\u000a      inherited macular dystrophies [3]. We showed that it provides\u000d\u000a      insights into the distribution of\u000d\u000a      macular pigment [4] and importantly demonstrated key linkages\u000d\u000a      between FAF and retinal function\u000d\u000a      in inherited retinal degenerations [5] and age-related macular\u000d\u000a      degeneration [6].\u000d\u000a    Since then a world-wide intensive research effort has been underway to\u000d\u000a      study FAF and understand\u000d\u000a      the fundamental pathophysiological processes leading to loss of vision.\u000d\u000a      Building on our research, it\u000d\u000a      is now understood that a key molecule (A2E) contributes to the FAF. This\u000d\u000a      molecule accumulates in\u000d\u000a      the cell layer underlying the photoreceptor layer (the Retinal Pigment\u000d\u000a      Epithelial cells), on which the\u000d\u000a      photoreceptors depend for their metabolic support and which is centrally\u000d\u000a      implicated in the\u000d\u000a      abnormalities of AMD. With the advent of \"molecular imaging\" it has been\u000d\u000a      recognised that FAF\u000d\u000a      allows characterisation of the role of key molecules by imaging the living\u000d\u000a      eyes of patients using\u000d\u000a      these non-invasive techniques based on confocal scanning laser\u000d\u000a      ophthalmoscopy. The optical\u000d\u000a      properties of the eye allow unprecedented resolution using this form of\u000d\u000a      molecular imaging and\u000d\u000a      enables measurement of the effects on visual function during the course of\u000d\u000a      the abnormality. FAF\u000d\u000a      provides a measure of the abnormal processes which would otherwise not be\u000d\u000a      detectable nor\u000d\u000a      visible using previous methods.\u000d\u000a    Our investigations have shown that photoreceptors can retain their\u000d\u000a      function in the early stages of\u000d\u000a      disease, diagnosed by an abnormal increase of FAF. This provides a window\u000d\u000a      of opportunity for\u000d\u000a      novel interventions before the patient experiences loss of vision. By\u000d\u000a      providing earlier indications of\u000d\u000a      abnormality in cellular function, FAF provides novel measures of clinical\u000d\u000a      endpoints which are\u000d\u000a      closely linked to visual function and reflect fundamentally important\u000d\u000a      aspects of metabolic function.\u000d\u000a    "},{"CaseStudyId":"26479","Continent":[{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1269750","Name":"India"}],"Funders":[],"ImpactDetails":"\u000a    Our research over the last 15 years has developed new local and systemic\u000a      treatments for uveitis, and these have become standard practice. Our work\u000a      has introduced new treatments where none existed, specifically patients\u000a      with uveitis that is not responsive to steroid therapy or in which steroid\u000a      therapy is contraindicated because of adverse effects. For these patients,\u000a      treatment with mycophenolate or intraocular methotrexate may be\u000a      sight-saving. In other patients, as a result of these treatments, vision\u000a      has been restored and the dose of systemic steroids reduced or stopped\u000a      completely. MMF is now the major second-line drug used in management of\u000a      uveitis. Our demonstration of its effectiveness in 1999 was key in\u000a      bringing the potential of this drug to the attention of the inflammatory\u000a      eye disease community. Our study was also quoted in US guidelines in 2000\u000a      [a] and provided the impetus for several additional studies over\u000a      the years (e.g. Teoh et al 2008 [b]). A recent review of the\u000a      management of uveitis demonstrates that the use of MMF is established\u000a      practice [c].\u000a    A further recent article states: \"Antimetabolites now enjoy favor as a\u000a        first choice of treatment with IMT [immunomodulatory therapy] in most\u000a        cases of posterior uveitis.\" Two of the key drugs used are MMF and\u000a      MTX [d]. The importance of MMF and MTX as treatments for uveitis\u000a      is further emphasised by a recently commenced clinical trial that compares\u000a      the two agents as first line therapy for steroid unresponsive uveitis [e].\u000a    Robust data concerning the numbers of patients affected globally by\u000a      uveitis where steroids are either ineffective or toxic are not available.\u000a      However, from our own institution MMF is the major drug used with steroids\u000a      in about 80% of these patients [f].\u000a    Cystoid macular oedema is a particularly challenging complication of\u000a      uveitis and is the most common cause of blindness and visual impairment in\u000a      chronic uveitis patients occurring in up to one third. Our studies have\u000a      contributed greatly to the present best practice in the management of this\u000a      condition. We demonstrated that vision could be improved by injecting TA\u000a      into the eye where systemic and periocular medication had failed. This led\u000a      to a profusion of papers on TA and then to the longer acting intraocular\u000a      steroids being developed. Our research also introduced intraocular\u000a      methotrexate as a successful treatment option for macular oedema in\u000a      patients who cannot have intraocular steroids. A recent review notes the\u000a      use of both intraocular TA and methotrexate in the management of uveitic\u000a      cystoid macular oedema. Regarding the former, it notes that \"intravitreal\u000a        triamcinolone (various formulations) is commonly used for CME\" [g].\u000a      A number of studies are cited, of which ours was notably the first and\u000a      largest. Our paper on intraocular methotrexate is also cited in both this\u000a      review, and another from India in 2013 [h].\u000a    A further complication of uveitis is glaucoma, which developes in up to\u000a      20% of patients. Prior to our research, ocular hypotensive prostaglandin\u000a        analogues had been used successfully in primary open angle glaucoma\u000a      but there was major concern about their use in uveitis patients. Our study\u000a      allowed these very effective drops to be brought into the management of\u000a      uveitic glaucoma and reduced the need for surgery [i].\u000a    Our demonstration in 2011 that anti-TNF drugs can reduce the risk\u000a      of visual loss in patients with Behcet's disease, who have the worst\u000a      visual prognosis of all patients with uveitis, is now being quoted\u000a      worldwide in support of this treatment [j].\u000a    ","ImpactSummary":"\u000a    Research at the UCL Institute of Ophthalmology over the last 15 years has\u000a      developed new treatments for management of uveitis and its\u000a      sight-threatening complications, which have subsequently become standard\u000a      practice. Our work, in previously untreatable disease, has allowed\u000a      restoration of vision in many patients and prevention of further visual\u000a      loss in others. Many patients have been able to reduce systemic\u000a      medication, limiting adverse effects of treatment.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Larkin G, Lightman S. Mycophenolate mofetil. A useful\u000a      immunosuppressive in inflammatory eye disease. Ophthalmology. 1999\u000a      Feb;106(2):370-4. http:\/\/dx.doi.org\/10.1016\/S0161-6420(99)90078-7\u000a    \u000a\u000a[2] Young S, Larkin G, Branley M, Lightman S. Safety and efficacy of\u000a      intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin\u000a      Experiment Ophthalmol. 2001 Feb;29(1):2-6.\u000a      http:\/\/dx.doi.org\/10.1046\/j.1442-9071.2001.00360.x\u000a    \u000a\u000a[3] Kok H, Lau C, Maycock N, McCluskey P, Lightman S. Outcome of\u000a      intravitreal triamcinolone in uveitis. Ophthalmology. 2005\u000a      Nov;112(11):1916.e1-7.\u000a      http:\/\/dx.doi.org\/10.1016\/j.ophtha.2005.06.009\u000a    \u000a\u000a[4] Chang JH, McCluskey P, Missotten T, Ferrante P, Jalaludin B, Lightman\u000a      S. Use of ocular hypotensive prostaglandin analogues in patients with\u000a      uveitis: does their use increase anterior uveitis and cystoid macular\u000a      oedema? Br J Ophthalmol. 2008 Jul;92(7):916-21.\u000a      http:\/\/dx.doi.org\/10.1136\/bjo.2007.131037\u000a    \u000a\u000a[5] Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular\u000a      methotrexate in the treatment of uveitis and uveitic cystoid macular\u000a      edema. Ophthalmology. 2009 Apr;116(4):797-801.\u000a      http:\/\/dx.doi.org\/10.1016\/j.ophtha.2008.10.033\u000a    \u000a\u000a[6] Taylor SR, Singh J, Menezo V, Wakefield D, McCluskey P, Lightman S.\u000a      Behçet disease: visual prognosis and factors influencing the development\u000a      of visual loss. Am J Ophthalmol. 2011 Dec;152(6):1059-66. http:\/\/dx.doi.org\/10.1016\/j.ajo.2011.05.032\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    [a] Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS,\u000a      Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D.\u000a      Guidelines for the use of immunosuppressive drugs in patients with ocular\u000a      inflammatory disorders: recommendations of an expert panel. Am J\u000a      Ophthalmol. 2000 Oct;130(4):492-513.\u000a      http:\/\/www.sciencedirect.com\/science\/article\/pii\/S0002939400006590\u000a    [b] Teoh SC, Hogan AC, Dick AD, Lee RW. Mycophenolate mofetil for the\u000a      treatment of uveitis. Am J Ophthalmol. 2008 Nov;146(5):752-60, 760.e1-3.\u000a      doi: 10.1016\/j.ajo.2008.03.004. Epub 2008 May 2. http:\/\/dx.doi.org\/10.1016\/j.ajo.2008.03.004\u000a      Cites two of our papers - see references 11 and 14.\u000a    [c] Gallego-Pinazo R, Dolz-Marco R, Martínez-Castillo S, Arévalo JF,\u000a      Díaz-Llopis M. Update on the principles and novel local and systemic\u000a      therapies for the treatment of non-infectious uveitis. Inflamm Allergy\u000a      Drug Targets. 2013 Feb;12(1):38-45.\u000a      http:\/\/dx.doi.org\/10.2174\/1871528111312010006\u000a    [d] http:\/\/www.retinalphysician.com\/articleviewer.aspx?articleID=107380\u000a    [e] http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01829295\u000a    [f] Moorfields pharmacy data provided by Chief Pharmacist. Copy available\u000a      on request.\u000a    [g] http:\/\/www.jhasio.com\/files\/articlefiles\/pdf\/ASIO_7_2p60_67.pdf\u000a    [h] http:\/\/www.ijo.in\/article.asp?issn=0301-4738;year=2013;volume=61;issue=6;spage=277;epage=283;aulast=Babu\u000a    [i] Horsley MB, Chen TC. The use of prostaglandin analogs in the uveitic\u000a      patient. Semin Ophthalmol. 2011 Jul-Sep;26(4-5):285-9. http:\/\/dx.doi.org\/10.3109\/08820538.2011.588650\u000a    [j] Pato E, Muñoz-Fernández S, Francisco F, Abad MA, Maese J, Ortiz A,\u000a      Carmona L; Uveitis Working Group from Spanish Society of Rheumatology.\u000a      Systematic review on the effectiveness of immunosuppressants and\u000a      biological therapies in the treatment of autoimmune posterior uveitis.\u000a      Semin Arthritis Rheum. 2011 Feb;40(4):314-23.\u000a      http:\/\/dx.doi.org\/10.1016\/j.semarthrit.2010.05.008\u000a    ","Title":"\u000a    Development of new treatments for uveitis\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Uveitis is an uncommon eye condition, which affects two to five in every\u000a      10,000 people in the UK every year. Although rare, it is a leading cause\u000a      of visual impairment in patients of working age. Chronic uveitis is\u000a      associated with a high incidence of vision-threatening complications such\u000a      as cataract, macular oedema, and, most importantly, glaucoma, which may\u000a      cause irreversible visual loss. Research at UCL, over the last 15 years,\u000a      has developed new treatments for uveitis and its complications.\u000a    In 1999 we assessed the usefulness of mycophenolate mofetil (MMF), an\u000a      immunosuppressant used extensively in transplant medicine, but not\u000a      previously used in uveitis. Our findings indicated that MMF was a useful\u000a      immunosuppressive drug for controlling ocular inflammation [1]; it\u000a      proved to be more effective with fewer adverse effects than other drugs\u000a      used to treat uveitis (ciclosporin and methotrexate).\u000a    Further to this, in 2001 we undertook a pilot study in six patients with\u000a      idiopathic uveitis complicated by visually significant cystoid macular\u000a      oedema (CMO) that was resistant to periocular and\/or systemic\u000a      corticosteroid treatment. We demonstrated that one injection into the eye\u000a      of the steroid triamcinolone (TA) was an effective short-term treatment\u000a      for resistant CMO in uveitis [2]. This paper changed the way that\u000a      refractory macular oedema was considered in uveitis. Previously it was\u000a      thought that oedema was refractory because permanent blood-retinal barrier\u000a      breakdown had occurred. By demonstrating that vision could be improved by\u000a      injecting TA into the eye where previous systemic and periocular\u000a      medication had failed, the research had shown that oedema was reversible\u000a      using this method of steroid delivery. A larger study in 2005 confirmed\u000a      these findings, showing that in patients with uveitic CMO, intravitreal TA\u000a      can effectively reduce CMO and improve visual acuity. In some patients it\u000a      allows the cessation and\/or major reduction of systemic immunosuppressive\u000a      therapy [3]. For the first time, previously incurable visual loss\u000a      could now be treated, resulting in vision gain and subsequent improvement\u000a      in the quality of life for patients. This led to a profusion of papers on\u000a      TA and then to the licensing of longer acting intraocular steroids, now a\u000a      NICE-approved therapy.\u000a    In 2009 we undertook a study to determine whether the use of topical\u000a      prostaglandin (PG) analogues to treat raised intraocular pressure (IOP) in\u000a      patients with uveitis resulted in an increase in uveitis reactivation or\u000a      CMO. This was thought likely and these drops were then contraindicated in\u000a      uveitis. We demonstrated that PG analogues are potent topical medications\u000a      for lowering raised IOP in patients with uveitis and are not associated\u000a      with an increased risk of CMO or uveitis reactivation [4]. The\u000a      study allowed these very effective drops to be brought into the management\u000a      of uveitic glaucoma and reduced the need for surgery to prevent visual\u000a      loss.\u000a    In the same year we undertook a pilot study in 15 patients to evaluate\u000a      the use of intravitreal methotrexate (MTX) for the treatment of uveitis\u000a      and uveitic CMO as an alternative to intravital steroids. We showed that\u000a      in these patients, intravitreal MTX can improve visual acuity and reduce\u000a      CMO and, in some patients, allows the reduction of immunosuppressive\u000a      therapy [5]. This study introduced intraocular methotrexate as a\u000a      successful treatment option for macular oedema in patients who cannot have\u000a      intraocular steroids — this led to an international series and widespread\u000a      use and for the first time offered a non-steroid intraocular treatment\u000a      regime for those in whom periocular\/intraocular steroids are\u000a      contraindicated. Many of these patients were able to come off systemic\u000a      therapy as a result with good vision maintained.\u000a    Most recently, we assessed the visual prognosis of patients with ocular\u000a      Behçet disease, who have the worst visual prognosis of all patients with\u000a      uveitis, to determine factors predictive of visual loss and severe visual\u000a      loss. These patients are all young and both eyes are usually affected. We\u000a      showed that the use of anti-TNF-α drugs was associated with a\u000a      statistically significant reduction in the rate of severe visual loss,\u000a      with a greatly reduced risk of visual loss at 5 and 10 years [6].\u000a      This has led to the early introduction of biologics for treatment in these\u000a      patients.\u000a    "},{"CaseStudyId":"26519","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    Haemophilia B patients have a defective factor IX gene and cannot make\u000a      the protein factor IX, which is essential for normal blood clot formation.\u000a      They suffer from frequent, often life-threatening, bleeding episodes that\u000a      occur without any apparent injury. Current treatment involves injection of\u000a      factor IX protein concentrates every two to three days for the life-time\u000a      of the patient. This treatment is invasive, extremely expensive (£150,000\u000a      per year) and only available to 20% of the world's haemophilia patients\u000a      who live in high income countries. Importantly, this treatment is not\u000a      curative and patients continue to bleed despite prophylactic factor IX\u000a      treatment which by necessity is administered intermittently, resulting in\u000a      significant periods when the plasma level is below 1% of normal.\u000a    Gene therapy overcomes these limitations by replacing the damaged factor\u000a      IX gene with a normal copy, thus allowing the patient to make factor IX\u000a      protein continuously without the need for regular injections. Our recent\u000a      study showed that a single injection of our novel AAV vector into six\u000a      patients with severe haemophilia B resulted in an increase in blood FIX\u000a      levels from undetectable levels before gene therapy to between 1-6% of\u000a      normal in all participants for a period that now extends to over three\u000a      years.\u000a    Four of the six patients have been able to stop regular injections with\u000a      FIX protein and still remain free of spontaneous bleeding episodes. This\u000a      is despite engaging in activities such as playing football and running a\u000a      marathon that had previously been associated with bleeding. The first\u000a      patient commented \"This type of solution is something permanent and can\u000a        make a lot of difference\". The sixth patient said \"I have not\u000a        needed any of my normal treatment, either preventative or on-demand as a\u000a        result of an injury. Previously, I used to infuse at home three times a\u000a        week .... I play football, run and take part in triathlons — and\u000a        previously I might have had to infuse both before I took part and\u000a        possibly after as well. Not having to do that has been absolutely\u000a        brilliant\" [a].\u000a    This, the first gene therapy success for haemophilia in the world, has\u000a      been lauded by experts in the field [b]. The results have been\u000a      widely covered by the media, including the BBC and the New York Times\u000a      amongst other news outlets across the world [c]. It has also been\u000a      covered on patient-facing websites [c].\u000a    There has been a significant saving to the NHS just from the first six\u000a      patients treated through reduction or elimination of the need for FIX\u000a      protein concentrates, amounting to more than £1.5m, a figure which\u000a      increases with each month that passes. This approach has recently been\u000a      extended to four more patients who were all treated at the high dose level\u000a      and are expressing factor IX at 5-8% level over a follow-up period of 9-18\u000a      months.\u000a    Indeed, the same approach is now being developed by Nathwani and\u000a      Tuddenham for haemophilia A, the most common severe inherited bleeding\u000a      disorder affecting approximately 1 in 5,000 males. Patents for the novel\u000a      factor VIII expression cassette has been filed [e] and recently\u000a      licensed to BioMarin for [text removed for publication] [f].\u000a      This development is prompting increased investment in research, and is\u000a      accelerating clinical trials for gene therapy of haemophilia A. [text\u000a        removed for publication].\u000a    ","ImpactSummary":"\u000a    Haemophilia, an inherited bleeding disease, is treated by frequent and\u000a      extremely expensive infusions of recombinant versions of the missing\u000a      factors. Advances in gene therapy have now been achieved at UCL, with\u000a      successful treatment of Haemophilia B in 10 severely affected patients.\u000a      The novel factor IX expression cassette has been patented and licensed to\u000a      an industrial partner (UniQure). Savings to the NHS in excess of £1.5m\u000a      have already been made and increase every month. Pre-clinical advances\u000a      have also been made in Haemophilia A, and the factor VIII expression\u000a      cassette has been patented and licensed to an industrial partner\u000a      (BioMarin).\u000a    ","ImpactType":"Technological","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN,\u000a      Tuddenham EG, Kemball-Cook G, McIntosh J, Boon-Spijker M, Mertens K,\u000a      Davidoff AM. Self-complementary adeno-associated virus vectors containing\u000a      a novel liver-specific human factor IX expression cassette enable highly\u000a      efficient transduction of murine and nonhuman primate liver. Blood. 2006\u000a      Apr 1;107(7):2653-61. http:\/\/dx.doi.org\/10.1182\/blood-2005-10-4035\u000a    \u000a\u000a[2] Nathwani AC, Gray JT, McIntosh J, Ng CY, Zhou J, Spence Y, Cochrane\u000a      M, Gray E, Tuddenham EG, Davidoff AM. Safe and efficient transduction of\u000a      the liver after peripheral vein infusion of self-complementary AAV vector\u000a      results in stable therapeutic expression of human FIX in nonhuman\u000a      primates. Blood. 2007 Feb 15;109(4):1414-21. http:\/\/dx.doi.org\/10.1182\/blood-2006-03-010181\u000a    \u000a\u000a[3] Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch\u000a      DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O'Beirne J, Smith K, Pasi\u000a      J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay\u000a      J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E,\u000a      Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM (2011).\u000a      Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.\u000a      N Engl J Med. 2011 Dec 22;365(25):2357-65. http:\/\/dx.doi.org\/10.1056\/NEJMoa1108046\u000a    \u000a\u000a[4] McIntosh J, Lenting PJ, Rosales C, Lee D, Rabbanian S, Raj D, Patel\u000a      N, Tuddenham EG, Christophe OD, McVey JH, Waddington S, Nienhuis AW, Gray\u000a      JT, Fagone P, Mingozzi F, Zhou SZ, High KA, Cancio M, Ng CY, Zhou J,\u000a      Morton CL, Davidoff AM, Nathwani AC. Therapeutic levels of FVIII following\u000a      a single peripheral vein administration of rAAV vector encoding a novel\u000a      human factor VIII variant. Blood. 2013 Apr 25;121(17):3335-44. http:\/\/dx.doi.org\/10.1182\/blood-2012-10-462200\u000a    \u000a\u000a[5] Ward NJ, Buckley SM, Waddington SN, Vandendriessche T, Chuah MK,\u000a      Nathwani AC, McIntosh J, Tuddenham EG, Kinnon C, Thrasher AJ, McVey JH.\u000a      Codon optimization of human factor VIII cDNAs leads to high-level\u000a      expression. Blood. 2011 Jan 20;117(3):798-807.\u000a      http:\/\/dx.doi.org\/10.1182\/blood-2010-05-282707\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    [a] Statements provided by patients to UCL's News Editor. Contact details\u000a      provided.\u000a    [b] Our findings have been widely discussed in the scientific literature:\u000a    \u000a      Ponder KP. Merry christmas for patients with hemophilia B. N Engl J\u000a        Med. 2011;365:2424-2425. http:\/\/doi.org\/10.1056\/NEJMe1111138\u000a\u000a      Vandendriessche T, Chuah MK. Clinical progress in gene therapy:\u000a        sustained partial correction of the bleeding disorder in patients\u000a        suffering from severe hemophilia B. Hum Gene Ther. 2012;23:4-6. http:\/\/dx.doi.org\/10.1089\/hum.2011.221\u000a\u000a      Landis MW, Quong JN. A major advance in gene therapy for hemophilia.\u000a        Cancer Discovery 2011;2:11. http:\/\/dx.doi.org\/10.1158\/2159-8290.CD-RW2011-61\u000a\u000a      Evans-Molina C. A New FIX for Hemophilia B. Science Translational\u000a        Medicine 2012;4:5.\u000a        http:\/\/doi.org\/10.1126\/scitranslmed.3003668\u000a\u000a      Ponder KP. Hemophilia Gene Therapy: A Holy Grail Found. Molecular\u000a        Therapy 2011;19 3:427 http:\/\/doi.org\/10.1038\/mt.2011.13\u000a\u000a    \u000a    [c] Media coverage of our work:\u000a    \u000a      BBC News. `Haemophilia gene therapy shows early success.'\u000a        http:\/\/www.bbc.co.uk\/news\/health-16107411\u000a\u000a      New York Times. `Treatment for Blood Disease Is Gene Therapy\u000a        Landmark.'\u000a\u0009\u0009http:\/\/www.nytimes.com\/2011\/12\/11\/health\/research\/hemophilia-b-gene-therapy-breakthrough.html?_r=0\u000a\u000a    \u000a    [d] News of our research was reported on NHS Choices:\u000a\u0009http:\/\/www.nhs.uk\/news\/2011\/12December\/Pages\/haemophilia-b-christmas-disease-gene-therapy.aspx\u000a    [e] Patents:\u000a    \u000a      Patent no: US8030065. IMPROVED EXPRESSION OF FACTOR IX IN GENE THERAPY\u000a        VECTORS\u000a      Patent no: 0911870.4. Optimised Coding Sequence and Promoter\u000a      Patent no: 1210357.8. Codon Optimised Factor VIII V3\u000a    \u000a    [f] BioMarin press release: http:\/\/investors.bmrn.com\/releasedetail.cfm?ReleaseID=742285\u000a      Licensing details can be corroborated by Director BioPharm, UCL Business.\u000a      Contact details provided.\u000a    [g] [text removed for publication].\u000a    ","Title":"\u000a    Advances in gene therapy lead to successful treatment of haemophilia\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Haemophilia is an inherited deficiency of one of the clotting factors\u000a      that achieve haemostasis and prevent uncontrolled bleeding. Since the\u000a      cloning of the factor VIII gene, which involved a seminal contribution\u000a      from Professor Edward Tuddenham at the UCL Cancer Institute, and the later\u000a      cloning of other clotting factor genes, the standard treatment for\u000a      haemophilia has been with the infusion of recombinant versions of the\u000a      missing factor. This approach is very expensive to the NHS (£400m per\u000a      annum) and beyond the means of 80% of patients living in the developing\u000a      world.\u000a    In 1999, Tuddenham began a collaboration with Dr Amit Nathwani (also UCL\u000a      Cancer Institute) to develop gene therapy for Haemophilia A and B with the\u000a      intention of overcoming this problem and providing improved disease\u000a      control. The initial studies focussed on Haemophilia B (factor IX\u000a      deficiency) because the factor IX gene is smaller than the factor VIII\u000a      gene and is easier to package. Extensive iterative preclinical studies\u000a      performed in collaboration with St Jude Children's Research Hospital, in\u000a      Memphis, TN, USA led to highly improved in vivo delivery and expression of\u000a      the factor IX gene in mice and then in primates. This was achieved by\u000a      incremental technical modifications including codon optimisation of the\u000a      factor IX gene, the development of a self-complementary gene construct\u000a      and design of a small tissue specific promoter [1, 2].\u000a    Good Manufacturing Practice protocols for vector purification were\u000a      developed and in 2010 studies in patients commenced [3]. In the\u000a      initial report, the vector was infused at one of 3 doses into the\u000a      peripheral vein of six severely affected haemophilia B patients with\u000a      baseline factor IX activity <1% of normal. Stable adeno-associated\u000a      virus (AAV)-mediated endogenous expression of factor IX at 2-6% of normal\u000a      levels was observed in all participants for a period of at least three\u000a      years (follow-up still on-going). Four additional subjects were recruited\u000a      in 2012 at the high dose level and they have stable expression of factor\u000a      IX at 5% of normal.\u000a    Building on the expertise developed during the haemophilia B work, a new\u000a      expression cassette for factor VIII has been designed that overcomes the\u000a      size barrier to incorporation in AAV and also allows highly efficient\u000a      synthesis compared to all previous expression vectors [4, 5].\u000a      Final pre-clinical toxicology studies are now ongoing to support a Phase\u000a      I\/II trial of factor VIII gene transfer for Haemophilia A.\u000a    "},{"CaseStudyId":"26546","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    As a result of the research described above, rituximab is now in\u000d\u000a      widespread use as a treatment for RA, with usage rising every year [a].\u000d\u000a      By the end of July 2013, Roche estimated that 228,801 patients have been\u000d\u000a      treated with rituximab for RA [b].\u000d\u000a    In March 2006, the FDA approved rituximab for use in combination with\u000d\u000a      methotrexate in adult patients with moderately to severely active RA who\u000d\u000a      have had an inadequate response to anti-TNFα therapy. Approval by the\u000d\u000a      European Medicines Agency (EMA) came in July of the same year. Towards the\u000d\u000a      end of 2006, a consensus statement and guidance document on the use of\u000d\u000a      rituximab for routine care of patients with RA was issued by the European\u000d\u000a      League Against Rheumatism (EULAR), describing the treatment as \"a major\u000d\u000a      advance in the therapeutic armamentarium for patients with rheumatoid\u000d\u000a      arthritis\" [c].\u000d\u000a    In 2007, NICE issued guidance (updated in 2011) recommending rituximab as\u000d\u000a      follows:\u000d\u000a    Rituximab in combination with methotrexate is recommended as an option\u000d\u000a        for the treatment of adults with severe active rheumatoid arthritis who\u000d\u000a        have had an inadequate response to, or have an intolerance of, other\u000d\u000a        disease-modifying anti-rheumatic drugs (DMARDs), including at least one\u000d\u000a        tumour necrosis factor (TNF) inhibitor [d].\u000d\u000a    British Society for Rheumatology (BSR) and British Health Professionals\u000d\u000a      in Rheumatology (BHPR) issued further guidelines on the use of rituximab\u000d\u000a      in 2010 [e]. Rituximab was also recommended in guidelines issued\u000d\u000a      by the American College of Rheumatology (ACR) in 2008, updated in 2012 [f].\u000d\u000a    Benefits to patients\u000d\u000a    The use of rituximab extends treatment to those patients who cannot have\u000d\u000a      anti-TNFα drugs because of contra-indications (a history of cancer or\u000d\u000a      pre-malignant conditions and patients with history of recurrent and\/or\u000d\u000a      serious infections or considered to be at a high risk of infection). Data\u000d\u000a      from a collaboration of different European registries shows that 36% of\u000d\u000a      patients received rituximab as first-line biologic [g].\u000d\u000a    Rituximab is also indicated as a second line treatment for patients where\u000d\u000a      anti-TNFα drugs failed, and this amounts to between 30 and 40% of patients\u000d\u000a      that are considered for biologic therapy. One patient, for whom three\u000d\u000a      anti-TNFα drugs had failed, described the impact of rituximab as follows:\u000d\u000a    \"Blood tests showed that my levels of inflammation were the lowest\u000d\u000a        that they'd been for years. I was less tired and had more mental and\u000d\u000a        physical energy. I resumed several of my hobbies... Mabthera transformed\u000d\u000a        my life... the effects have been radical. I can truthfully say that I\u000d\u000a        haven't experienced this level of wellbeing for many years\" [h].\u000d\u000a    A major advantage of rituximab is that it can be given as two infusions\u000d\u000a      two weeks apart (or four smaller weekly injections), with effects\u000d\u000a      persisting for 6-12 months thereafter. From the patient's perspective,\u000d\u000a      this is a more convenient schedule of administration than other biologics\u000d\u000a      (typically administered 12-24 times per year). Furthermore, as the UCL\u000d\u000a      team and others have demonstrated, rituximab infusions can be repeated on\u000d\u000a      an annual basis for several years. Loss of response to rituximab in\u000d\u000a      patients with RA that have previously responded well is rare, and it is\u000d\u000a      well tolerated with excellent safety profiles in RA and in patients with\u000d\u000a      many other conditions [i].\u000d\u000a    Economic impacts\u000d\u000a    Rituximab costs £5,000 per annum less than other biologics. In the UK it\u000d\u000a      is generally the next choice before other more expensive alternatives such\u000d\u000a      as tocilizumab, abatacept or belimumab. Use in patients in this setting\u000d\u000a      has already generated considerable savings to the NHS. The economic impact\u000d\u000a      of rituximab has been greater in low and middle income countries (for\u000d\u000a      example, Brazil) where the lower cost of rituximab makes it the first-line\u000d\u000a      biologic for RA [j].\u000d\u000a    Use of rituximab in other conditions\u000d\u000a    The success of B cell depletion therapy in RA has led directly to it\u000d\u000a      being used for autoimmune rheumatic diseases (such as systemic lupus\u000d\u000a      erythematosus, ANCA associated vasculitis, Behcets syndrome, myositis,\u000d\u000a      anti-phospholipid syndrome, Sjogren's syndrome, neuromyelitis optica).\u000d\u000a      Rituximab is licensed for ANCA-associated vasculitis [k], is\u000d\u000a      approved for funding by NHS England for SLE [l], and has been\u000d\u000a      nationally commissioned for the treatment of Behcets disease [m]\u000d\u000a      and neuromyelitis optica [n].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research at UCL pioneered B cell depletion to treat rheumatoid arthritis\u000d\u000a      (RA) and also stimulated the development of B-cell-directed therapies for\u000d\u000a      other autoimmune rheumatic, haematological and neurological diseases. Now\u000d\u000a      NICE approved, B cell depletion (based on rituximab) in RA is as effective\u000d\u000a      as the alternative (anti-TNFα drugs) and an option for patients unable to\u000d\u000a      gain benefit from anti-TNFα drugs. Rituximab offers drug-cost savings of\u000d\u000a      up to £5,000\/annum\/patient and for many is a more convenient therapy,\u000d\u000a      being given as an infusion only every five months apart, or more. B cell\u000d\u000a      depletion has also proved to have an excellent safety profile, with many\u000d\u000a      receiving repeated courses of treatment. As a consequence of UCL research,\u000d\u000a      rituximab has brought substantial benefit to patients with many autoimmune\u000d\u000a      diseases, including over 200,000 who have been treated with rituximab for\u000d\u000a      RA so far.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Edwards JCW, Cambridge G. B-cell targeting in rheumatoid arthritis\u000d\u000a      and other autoimmune diseases. Nat Rev Immunol. 2006 6(5):394-403. http:\/\/dx.doi.org\/10.1038\/nri1838\u000d\u000a    \u000a\u000a[2] Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B\u000d\u000a      lymphocytes drive human autoimmune disease? Immunology. 1999\u000d\u000a      Jun;97(2):188-96. http:\/\/dx.doi.org\/10.1046\/j.1365-2567.1999.00772.x\u000d\u000a    \u000a\u000a[3] Edwards JC, Cambridge G. Sustained improvement in rheumatoid\u000d\u000a      arthritis following a protocol designed to deplete B lymphocytes.\u000d\u000a      Rheumatology (Oxford). 2001 Feb;40(2):205-11.\u000d\u000a      http:\/\/dx.doi.org\/10.1093\/rheumatology\/40.2.205\u000d\u000a    \u000a\u000a[4] Leandro MJ, Edwards JC, Cambridge G. Clinical outcome in 22 patients\u000d\u000a      with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum\u000d\u000a      Dis. 2002 Oct;61(10):883-8.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/ard.61.10.883\u000d\u000a    \u000a\u000a[5] Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A,\u000d\u000a      Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy\u000d\u000a      with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004\u000d\u000a      Jun 17;350(25):2572-81.\u000d\u000a      http:\/\/dx.doi.org\/10.1056\/NEJMoa032534\u000d\u000a    \u000a\u000a[6] Leandro MJ, Edwards JCW, Cambridge G, Ehrenstein MR, Isenberg DA. An\u000d\u000a      open study of B lymphocyte depletion in systemic lupus erythematosus.\u000d\u000a      Arthritis Rheum. 2002 Oct;46(10):2673-7. http:\/\/dx.doi.org\/10.1002\/art.10541\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    [a] As reported by Roche (the drug's manufacturers) in their 2013 Half\u000d\u000a      Year Report.\u000d\u000a      http:\/\/www.roche.com\/hy13e.pdf\u000d\u000a      See p.22.\u000d\u000a    [b] Email correspondence from Roche. Available on request.\u000d\u000a    [c] Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N,\u000d\u000a      Burmester GR, Dougados M, Ferraccioli G, Jaeger U, Klareskog L, Kvien TK,\u000d\u000a      Martin-Mola E, Pavelka K; Working Group on the Rituximab Consensus\u000d\u000a      Statement. Consensus statement on the use of rituximab in patients with\u000d\u000a      rheumatoid arthritis. Ann Rheum Dis. 2007 Feb;66(2):143-50. Epub 2006 Oct\u000d\u000a      26.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/ard.2006.061002\u000d\u000a    [d] NICE technology appraisal guidance 195. Adalimumab, etanercept,\u000d\u000a      infliximab, rituximab and abatacept for the treatment of rheumatoid\u000d\u000a      arthritis after the failure of a TNF inhibitor.\u000d\u000a      http:\/\/publications.nice.org.uk\/adalimumab-etanercept-infliximab-rituximab-and-abatacept-for-the-treatment-of-rheumatoid-ta195\/evidence-and-interpretation\u000d\u000a    [e] Bukhari M, Abernethy R, Deighton C, Ding T, Hyrich K, Lunt M, Luqmani\u000d\u000a      R, Kiely P, Bosworth A, Ledingham J, Ostör A, Gadsby K, McKenna F, Finney\u000d\u000a      D, Dixey J; BSR and BHPR Standards, Guidelines and Audit Working Group.\u000d\u000a      BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis.\u000d\u000a      Rheumatology (Oxford). 2011 Dec;50(12):2311-3.\u000d\u000a      http:\/\/dx.doi.org\/10.1093\/rheumatology\/ker106a\u000d\u000a    [f] Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM,\u000d\u000a      Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham\u000d\u000a      WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King\u000d\u000a      CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A,\u000d\u000a      Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update\u000d\u000a      of the 2008 American College of Rheumatology recommendations for the use\u000d\u000a      of disease-modifying antirheumatic drugs and biologic agents in the\u000d\u000a      treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012\u000d\u000a      May;64(5):625-39.\u000d\u000a      http:\/\/dx.doi.org\/10.1002\/acr.21641\u000d\u000a    [g] Chatzidionysiou K, Lie E, Nasonov E, Lukina G, Hetland ML, Tarp U,\u000d\u000a      Gabay C, van Riel PL, Nordström DC, Gomez-Reino J, Pavelka K, Tomsic M,\u000d\u000a      Kvien TK, van Vollenhoven RF. Highest clinical effectiveness of rituximab\u000d\u000a      in autoantibody-positive patients with rheumatoid arthritis and in those\u000d\u000a      for whom no more than one previous TNF antagonist has failed: pooled data\u000d\u000a      from 10 European registries. Ann Rheum Dis. 2011 Sep;70(9):1575-80.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/ard.2010.148759\u000d\u000a    [h] Jean Bailey-Dering. My experience of rituximab (Mabthera) infusions.\u000d\u000a      03\/12\/08. Case study on website of the National Rheumatoid Arthritis\u000d\u000a      Society.\u000d\u000a      http:\/\/www.nras.org.uk\/about_rheumatoid_arthritis\/living_with_rheumatoid_arthritis\/case_studies\/female\/my_experience_of_rituximab_mabthera_infusions.aspx\u000d\u000a    [i] Tony HP, Burmester G, Schulze-Koops H, Grunke M, Henes J, Kötter I,\u000d\u000a      Haas J, Unger L, Lovric S, Haubitz M, Fischer-Betz R, Chehab G,\u000d\u000a      Rubbert-Roth A, Specker C, Weinerth J, Holle J, Müller-Ladner U, König R,\u000d\u000a      Fiehn C, Burgwinkel P, Budde K, Sörensen H, Meurer M, Aringer M, Kieseier\u000d\u000a      B, Erfurt-Berge C, Sticherling M, Veelken R, Ziemann U, Strutz F, von\u000d\u000a      Wussow P, Meier FM, Hunzelmann N, Schmidt E, Bergner R, Schwarting A,\u000d\u000a      Eming R, Hertl M, Stadler R, Schwarz-Eywill M, Wassenberg S, Fleck M,\u000d\u000a      Metzler C, Zettl U, Westphal J, Heitmann S, Herzog AL, Wiendl H, Jakob W,\u000d\u000a      Schmidt E, Freivogel K, Dörner T; GRAID investigators. Safety and clinical\u000d\u000a      outcomes of rituximab therapy in patients with different autoimmune\u000d\u000a      diseases: experience from a national registry (GRAID). Arthritis Res Ther.\u000d\u000a      2011 May 13;13(3):R75.\u000d\u000a      http:\/\/dx.doi.org\/10.1186\/ar3337.\u000d\u000a    [j] Data on prescribing costs in Brazil. Copy of files available on\u000d\u000a      request.\u000d\u000a    [k] SPC for rituximab; http:\/\/www.medicines.org.uk\/emc\/medicine\/2570#POSOLOGY\u000d\u000a    [l] Interim Clinical Commissioning Policy Statement: Rituximab for the\u000d\u000a      treatment of Systemic Lupus Erythematosus in adults. September 2013.\u000d\u000a      Reference: NHS ENGLAND A13\/PS\/a2. Copy available on request.\u000d\u000a    [m] National Specialised Commissioning Team. Behçet's Syndrome Service\u000d\u000a      Specification. April 2012. Copy available on request.\u000d\u000a    [n] National Specialist Commissioning Team. Neuromyelitis Optica Service\u000d\u000a      Specification. 2012-3. Copy available on request.\u000d\u000a    ","Title":"\u000d\u000a    B cell depletion: an effective therapy in rheumatoid arthritis\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    In the 1980s and early 1990s it was a general view that rheumatoid\u000d\u000a      arthritis (RA) was caused by T cells that attacked specific targets in\u000d\u000a      joints. The consequent release of toxic cytokines by joint macrophages was\u000d\u000a      generally agreed to be responsible for inflammation. Yet, despite more\u000d\u000a      than 20 years of research, no consistently autoreactive T cell had been\u000d\u000a      identified. Research at UCL conducted by Jonathan Edwards and Geraldine\u000d\u000a      Cambridge led to the hypothesis that B cells played an essential role in\u000d\u000a      the pathogenesis of RA [1].\u000d\u000a    Following anatomical and immunohistochemical studies of normal and\u000d\u000a      diseased human synovium they found that a receptor (CD16) was\u000d\u000a      constitutively expressed on macrophages in synovial lining and to a lesser\u000d\u000a      extent in other sites affected in the disease. The consequence of CD16\u000d\u000a      activation was to stimulate macrophages to generate TNFα, a powerful\u000d\u000a      pro-inflammatory cytokine known to be involved in joint inflammation. CD16\u000d\u000a      appeared to be activated by soluble complexes of particular\u000d\u000a      autoantibodies, previously described in RA patients. They suggested that\u000d\u000a      the constant supply of autoantibodies capable of forming these small\u000d\u000a      `activating' complexes was due to expansion of B cells (responsible for\u000d\u000a      autoantibody generation) in a manner that avoided usual pathways to\u000d\u000a      control their number [2]. This led to the hypothesis that removing\u000d\u000a      B cells would reduce the inflammatory stimulus and also break the vicious\u000d\u000a      cycle of autoreactive B cell expansion.\u000d\u000a    Towards the end of the 1990s, Roche developed a drug, rituximab (which\u000d\u000a      binds the CD20 marker on all mature B cells), for the treatment of B-cell\u000d\u000a      cancers notably lymphomas. Edwards and Cambridge were quick to recognise\u000d\u000a      that since both B-cell lymphoma and RA involved uncontrolled proliferation\u000d\u000a      of B cell clones, rituximab might well be what they had been waiting for\u000d\u000a      to treat patients with RA. Proof of concept followed with the clinical\u000d\u000a      success of a small trial of the B-cell-depleting agent, rituximab, in 5\u000d\u000a      patients with intractable RA in 1998\/9 by the UCL team, and confirmed by\u000d\u000a      them in a larger cohort [3, 4].\u000d\u000a    The first randomised trial started in 2002 and was published in NEJM in\u000d\u000a      2004 [5]. The results indicated that rituximab produced results in\u000d\u000a      patients with RA that at least matched those of patients treated with TNFα\u000d\u000a      blockade. Successful treatment of patients with systemic lupus\u000d\u000a      erythematosus by the group followed [6]. Rituximab was licensed\u000d\u000a      for the treatment of patients with RA in 2006.\u000d\u000a    "},{"CaseStudyId":"26549","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The last 20 years has seen a significant improvement in outcome for\u000d\u000a      patients with scleroderma, and specifically an increase in survival, much\u000d\u000a      of it attributable to research from our centre. We have more than 2,000\u000d\u000a      cases, seen over the past 20 years, where we have explored the change in\u000d\u000a      outcome over time and also used the uniquely well-characterised patient\u000d\u000a      cohort to define timing and frequency of each of the major\u000d\u000a      life-threatening complications of the disease. Our SSc cohort saw\u000d\u000a      approximately 20 fewer deaths in 2010 compared to 1994. In addition, by\u000d\u000a      avoiding unnecessary high dose immunosuppression there were 10% fewer\u000d\u000a      hospital admissions for infection 2005-10 compared with 1990) [a].\u000d\u000a    Defining subsets of SSc to improve treatment\u000d\u000a    The biomarkers we have described have enabled better prediction of\u000d\u000a      complications such as scleroderma renal crisis and lung fibrosis, and\u000d\u000a      identified subsets that benefit from more aggressive treatment. As a\u000d\u000a      result of our definition of hallmark SSc antibodies associated with lung\u000d\u000a      fibrosis and scleroderma renal disease, these tests are now routinely used\u000d\u000a      in risk assessment of SSc worldwide. They have been incorporated into new\u000d\u000a      classification criteria for SSc issued by the American College of\u000d\u000a      Rheumatology (ACR) the European League Against Rheumatism (EULAR) in 2013,\u000d\u000a      to which we contributed [b]. This permits more effective patient\u000d\u000a      education and earlier engagement with other specialised hospital services.\u000d\u000a    Defining the use of immunosuppression\u000d\u000a    We have defined the cases of lung fibrosis in scleroderma that are most\u000d\u000a      likely to benefit from immunosuppression and developed a simple staging\u000d\u000a      system for lung fibrosis that is now used in most centres in UK and abroad\u000d\u000a      and has been validated in two independent studies in the USA [c]\u000d\u000a      and Australia. This helps to avoid use of toxic immunosuppression in cases\u000d\u000a      of SSc where this is unnecessary and enables us to target\u000d\u000a      immunosuppressive therapy to more severe cases who gain the most benefit.\u000d\u000a      This is a result of our definition of \"good prognosis\" cases of SSc. A\u000d\u000a      logical extension of this work is more effective enrichment of clinical\u000d\u000a      trial cohorts to allow smaller sample size and improved study design. Our\u000d\u000a      approach using cyclophosphamide is incorporated into the European\u000d\u000a      recommendations for treatment of SSc [d] and is now effectively\u000d\u000a      standard of care for SSc cases worldwide [e].\u000d\u000a    Defining the importance of regular proactive screening of cases\u000d\u000a    As a result of our research, regular screening for pulmonary\u000d\u000a      complications (lung fibrosis and pulmonary hypertension) has become\u000d\u000a      standard in the management of SSc. This is now adopted in all European\u000d\u000a      scleroderma centres and incorporated in recommendations for international\u000d\u000a      societies including the European Society of Cardiology (ESC) and European\u000d\u000a      Respiratory Society (ERS) [f] and the Expert Panel on Outcomes\u000d\u000a      Measures in PAH related to Systemic Sclerosis (EPOSS) [g]. As a\u000d\u000a      result, historically poor outcomes have been positively impacted [h].\u000d\u000a    In conclusion, our work has impacted on overall outcome in SSc,\u000d\u000a      appropriate follow up and screening of cases and use of broad-spectrum\u000d\u000a      immunosuppression in appropriate cases and has helped to define current\u000d\u000a      standards of care for a disease with high medical burden and the highest\u000d\u000a      case-specific mortality of any rheumatic condition.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Systemic sclerosis (SSc) is an important, but uncommon, connective tissue\u000d\u000a      disease with high mortality and has a major non-lethal morbidity. Research\u000d\u000a      at UCL has been instrumental in defining modern management of SSc and has\u000d\u000a      contributed in three main ways. First we have defined the importance of\u000d\u000a      regular proactive screening of cases, secondly we have defined the use of\u000d\u000a      immunosuppression and thirdly we have delineated important clinical and\u000d\u000a      laboratory subsets of SSc that underpin an individualised (or\u000d\u000a      personalised) approach to assessment and treatment. These topics exemplify\u000d\u000a      stepwise progress in management of SSc that also has direct relevance to\u000d\u000a      other more common medical conditions.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Denton CP, Abraham DJ. Transforming growth factor-beta and connective\u000d\u000a      tissue growth factor: key cytokines in scleroderma pathogenesis. Curr Opin\u000d\u000a      Rheumatol. 2001 Nov;13(6):505-11. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11698729\u000d\u000a    \u000a\u000a[2] Shand L, Lunt M, Nihtyanova S, Hoseini M, Silman A, Black CM, Denton\u000d\u000a      CP. Relationship between change in skin score and disease outcome in\u000d\u000a      diffuse cutaneous systemic sclerosis: application of a latent linear\u000d\u000a      trajectory model. Arthritis Rheum. 2007 Jul;56(7):2422-31.\u000d\u000a      http:\/\/dx.doi.org\/10.1002\/art.22721\u000d\u000a    \u000a\u000a[3] Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP.\u000d\u000a      Improved survival in systemic sclerosis is associated with better\u000d\u000a      ascertainment of internal organ disease: a retrospective cohort study.\u000d\u000a      QJM. 2010 Feb;103(2):109-15. http:\/\/dx.doi.org\/10.1093\/qjmed\/hcp174.\u000d\u000a    \u000a\u000a[4] Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM, Burns\u000d\u000a      A, Denton CP. Scleroderma renal crisis: patient characteristics and\u000d\u000a      long-term outcomes. QJM. 2007 Aug;100(8):485-94. http:\/\/dx.doi.org\/10.1093\/qjmed\/hcm052\u000d\u000a    \u000a\u000a[5] Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts\u000d\u000a      C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale\u000d\u000a      DJ, Denton CP, Wells AU, Black CM, du Bois RM. A multicenter, prospective,\u000d\u000a      randomized, double-blind, placebo-controlled trial of corticosteroids and\u000d\u000a      intravenous cyclophosphamide followed by oral azathioprine for the\u000d\u000a      treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006\u000d\u000a      Dec;54(12):3962-70. http:\/\/dx.doi.org\/10.1002\/art.22204\u000d\u000a    \u000a\u000a[6] Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM,\u000d\u000a      Corte TJ, Sander CR, Ratoff J, Devaraj A, Bozovic G, Denton CP, Black CM,\u000d\u000a      du Bois RM, Wells AU. Interstitial lung disease in systemic sclerosis: a\u000d\u000a      simple staging system. Am J Respir Crit Care Med. 2008 Jun\u000d\u000a      1;177(11):1248-54. http:\/\/dx.doi.org\/10.1164\/rccm.200706-877OC\u000d\u000a    \u000a\u000a[7] Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, Silliman\u000d\u000a      N, Streisand J, Powell J, Akesson A, Coppock J, Hoogen F, Herrick A, Mayes\u000d\u000a      MD, Veale D, Haas J, Ledbetter S, Korn JH, Black CM, Seibold JR; Cat-192\u000d\u000a      Study Group; Scleroderma Clinical Trials Consortium. Recombinant human\u000d\u000a      anti-transforming growth factor beta1 antibody therapy in systemic\u000d\u000a      sclerosis: a multicenter, randomized, placebo-controlled phase I\/II trial\u000d\u000a      of CAT-192. Arthritis Rheum. 2007 Jan;56(1):323-33. http:\/\/dx.doi.org\/10.1002\/art.22289\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    [a] Patient details can be verified from local audit and through the\u000d\u000a      hospital activity figures. Contact details for clinical audit lead for\u000d\u000a      Rheumatology provided.\u000d\u000a    [b] http:\/\/www.rheumatology.org\/Practice\/Clinical\/Classification\/Classification_Criteria_for_Rheumatic_Diseases\u000d\u000a    [c] This was independently validated by data from a large North American\u000d\u000a      trial, the scleroderma lung study: Tashkin DP, Elashoff R, Clements PJ,\u000d\u000a      Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M,\u000d\u000a      Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms\u000d\u000a      R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak\u000d\u000a      K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M;\u000d\u000a      Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in\u000d\u000a      scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655-66.\u000d\u000a      PubMed PMID: 16790698. http:\/\/doi.org\/10.1056\/NEJMoa055120\u000d\u000a    [d] Kowal-Bielecka O, Landewe R, Avouac J, et al.; EUSTAR Co-Authors.\u000d\u000a      EULAR recommendations for the treatment of systemic sclerosis: a report\u000d\u000a      from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum\u000d\u000a      Dis. 2009 May;68(5):620-8. http:\/\/dx.doi.org\/10.1136\/ard.2008.096677\u000d\u000a      References Hoyles et al. 2006 in the recommendation \"In view of the\u000d\u000a        results from two high-quality RCT and despite its known toxicity,\u000d\u000a        cyclophosphamide should be considered for the treatment of SSc-related\u000d\u000a        interstitial lung disease (SSc-ILD)\" (see ref. 63)\u000d\u000a    [e] For example, in Canada: Walker KM, Pope J; Scleroderma Clinical\u000d\u000a      Trials Consortium; Canadian Scleroderma Research Group. Expert agreement\u000d\u000a      on EULAR\/EUSTAR recommendations for the management of systemic sclerosis.\u000d\u000a      J Rheumatol. 2011 Jul;38(7):1326-8. http:\/\/dx.doi.org\/10.3899\/jrheum.101262\u000d\u000a      This paper reports a survey of members of the Scleroderma Clinical\u000d\u000a        Trials Consortium and the Canadian Scleroderma Research Group as to\u000d\u000a        their level of agreement with the European guidelines (above). It\u000d\u000a        concludes that \"the EULAR\/EUSTAR recommendations for the treatment of\u000d\u000a        SSc are relatively well accepted among the world's SSc experts.\" The\u000d\u000a        survey used a 1-9 ranking, and 85% of respondents put the recommendation\u000d\u000a        on cyclophosphamide in the top three categories.\u000d\u000a    [f] Galiè N, Hoeper MM, Humbert M, et al.; ESC Committee for Practice\u000d\u000a      Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary\u000d\u000a      hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary\u000d\u000a      Hypertension of the European Society of Cardiology (ESC) and the European\u000d\u000a      Respiratory Society (ERS), endorsed by the International Society of Heart\u000d\u000a      and Lung Transplantation (ISHLT). Eur Heart J. 2009 Oct;30(20):2493-537. \u000d\u000a\u0009  http:\/\/dx.doi.org\/10.1093\/eurheartj\/ehp297\u000d\u000a      These guidelines reference three of our papers (ref 1: Simonneau et al\u000d\u000a        2009; ref 88: Williams et al 2006; ref 114: Mukerjee et al 2003).\u000d\u000a    [g] Avouac J, Huscher D, Furst DE, Opitz CF, Distler O, Allanore Y; for\u000d\u000a      the EPOSS group. Expert consensus for performing right heart\u000d\u000a      catheterisation for suspected pulmonary arterial hypertension in systemic\u000d\u000a      sclerosis: a Delphi consensus study with cluster analysis. Ann Rheum Dis.\u000d\u000a      2013 Feb 20 http:\/\/dx.doi.org\/10.1136\/annrheumdis-2012-202567\u000d\u000a    [h] Following paper showed that in the 1990s: \"the lung (both pulmonary\u000d\u000a      hypertension and PF) is the primary cause of scleroderma-related deaths\":\u000d\u000a      Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis,\u000d\u000a      1972-2002. Ann Rheum Dis. 2007 Jul;66(7):940-4. http:\/\/doi.org\/10.1136\/ard.2006.066068\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Management of systemic sclerosis - better follow up, risk stratification\u000d\u000a      and use of immunosuppression\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    From 1993, under the direction of Carol Black, then from 2006 under Chris\u000d\u000a      Denton and David Abraham, the Centre for Rheumatology and Connective\u000d\u000a      Tissue Diseases at UCL pioneered translational research in scleroderma. We\u000d\u000a      recognised the value of systematic collection of bio-samples and careful\u000d\u000a      cataloguing of longitudinal clinical data related to a unique cohort of\u000d\u000a      patients. Thus we have data spanning 20 years on more than 2,000 cases —\u000d\u000a      the largest single centre cohort in Europe and equal to any in the world.\u000d\u000a      This resource has been used to identify key targets for therapy and define\u000d\u000a      novel pathogenic mechanisms. We were the first to describe altered\u000d\u000a      chemokine expression in SSc and these observations delineated key\u000d\u000a      mechanisms of immunopathogenesis [1].\u000d\u000a    In addition we have discovered factors that predict future deterioration\u000d\u000a      of skin, lung or other organ-based complications of SSc. These are\u000d\u000a      landmark studies that have been adopted as standard of care across many\u000d\u000a      centres internationally. We have pioneered the use of skin score\u000d\u000a      trajectory as a way of stratifying SSc cases [2]. Work led by\u000d\u000a      Denton has enabled more informative recruitment into clinical trials, to\u000d\u000a      make these studies more robust and also to help focus resources and\u000d\u000a      therapies appropriately. In a landmark study we showed that regular\u000d\u000a      screening and a proactive strategy significantly improved survival in\u000d\u000a      diffuse SSc [3]. Our work on SSc-specific autoantibodies has used\u000d\u000a      the unique resource of our large cohort of cases to define associations\u000d\u000a      that are durable through the course of disease and permit more\u000d\u000a      individualised risk stratification of SSc cases at diagnosis so that\u000d\u000a      treatment and investigation is targeted more effectively. Our research\u000d\u000a      defined hallmark SSc antibodies associated with lung fibrosis\u000d\u000a      (anti-topoisomerase-1; ATA) and scleroderma renal disease (anti-RNA\u000d\u000a      polymerase-III; ARA) [4].\u000d\u000a    Our centre conducted the first major prospective controlled study\u000d\u000a      comparing intravenous cyclophosphamide with placebo for lung fibrosis\u000d\u000a      complicating SSc [5]. As a result of this research, our treatment\u000d\u000a      protocol using intravenous cyclophosphamide has been adopted by most\u000d\u000a      centres in USA and Europe. Together with the Royal Brompton Hospital, we\u000d\u000a      have helped to define those cases that are at risk of progression and\u000d\u000a      developed and validated a simple data-driven staging system of disease\u000d\u000a      severity [6]. This was independently validated by data from a\u000d\u000a      large North American trial, the scleroderma lung study. In a related study\u000d\u000a      we used an observational design to complete one of the largest prospective\u000d\u000a      evaluations of immunosuppression in SSc skin disease, focusing on the more\u000d\u000a      severe diffuse subset of the disease [7]. This UK observational\u000d\u000a      study recruited nearly 150 cases of dcSSc, more than half from our centre,\u000d\u000a      and evaluated immunosuppressive therapies including mycophenolate mofetil,\u000d\u000a      cyclophosphamide, methotrexate and anti-thymocyte globulin. This study was\u000d\u000a      a landmark initiative as it demonstrated that protocolised approaches with\u000d\u000a      standardised observation, analogous to oncology strategies, could be used\u000d\u000a      to explore best therapies for SSc, a condition with outcome worse than\u000d\u000a      many malignancies.\u000d\u000a    "},{"CaseStudyId":"27416","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000a    Leeds research has led to the introduction of a highly effective drug,\u000a      eculizumab, for PNH which has transformed patients lives, returned their\u000a      survival to normal, radically reconfigured care services and generated a\u000a      huge new pharmaceutical activity. Eculizumab is the only approved agent\u000a      for PNH in Europe, US, Canada, Japan and over 40 other countries and\u000a      research in Leeds played a critical role leading to these approvals [A].\u000a      Eculizumab was awarded the 2008 Prix Galien USA Award for Best\u000a      Biotechnology Product with broad implications for future biomedical\u000a      research and the 2009 Prix Galien France Award for Drugs for Rare\u000a      Diseases. Research led by Hillmen from Leeds has reached all patients with\u000a      this condition in the developed world and has demonstrated normalization\u000a      of overall survival for patients with PNH [A]. The impact on patients'\u000a      lives is highly significant and impacts the areas of (i) health and\u000a      welfare, (ii) commerce changing PNH from a disease that destroyed the\u000a      quality of life of patients, often young adults, leading to the death of\u000a      half of patients to one that is effectively managed with most patients\u000a      returning to a normal life.\u000a    Health outcomes\u000a    PNH is a serious blood disorder found in 5 per million population with a\u000a      huge impact on quality of life with severe disabling lethargy, severe\u000a      intermittent abdominal pain, difficulty swallowing, erectile failure and\u000a      life-threatening thrombosis with half dying due to PNH. 3 per million are\u000a      severely affected requiring regular transfusions and usually being unable\u000a      to work and\/or are dependent. Eculizumab immediately reverses the symptoms\u000a      and complications of PNH meaning that patients are able to return to work\u000a      and stop supportive therapies, such as transfusions and pain-killers.\u000a      Pregnancy is associated with very high maternal mortality (10% to 20%)\u000a      meaning that many patients wouldn't risk pregnancy. We have demonstrated\u000a      that eculizumab is safe in pregnancy and markedly reduces the risks with\u000a      many women having now had successful pregnancies. Eculizumab prevents the\u000a      complications of PNH meaning that patients can lead near normal lives\u000a      including working and contributing to society (6) [B, C, D, E]. This was\u000a      demonstrated in 195 patients from the clinical trials, 153 UK patients\u000a      managed by Hillmen and colleagues and through the Global PNH Registry\u000a      (currently over 2000 patients) and is Chaired by Peter Hillmen.\u000a      Approximately 3000 patients have received eculizumab since its initial\u000a      approval in 2007 including all eligible patients in the UK and global\u000a      sales suggest that this pattern is similar in all developed healthcare\u000a      systems.\u000a    Eculizumab has a clear, well-documented impact on survival in PNH as\u000a      demonstrated by Hillmen's group (Kelly et al., 20126).\u000a      Previously half of patients with PNH died within 10 years of diagnosis\u000a      with only 25% of patients surviving 25 years which, given the disease is\u000a      often diagnosed in early adulthood, has a profound impact. However\u000a      eculizumab normalizes survival in PNH (PNH registry data [F]) compared to\u000a      a 5 year mortality of approximately 35%.6 The spectre of PNH\u000a      for patients with virtually no quality of life and a high risk of early\u000a      death has now been lifted by the use of eculizumab [B-E] which has a high\u000a      public profile [G].\u000a    Guidelines and Governmental Approvals\u000a    PNH has now been nationally funded in many countries worldwide including\u000a      the Netherlands, France, Australia, Canada, and Japan as well as being\u000a      available in the US, Germany, etc. Since 2011 eculizumab has been approved\u000a      in the US, Europe and Canada for atypical Haemolytic Uraemic Syndrome\u000a      (aHUS), previously an untreatable condition leading to renal failure and\u000a      premature death. This approval would not have happened without the PNH\u000a      trials [A, B, C].\u000a    Changes in service configurations and disease regulation\u000a    As a result of our research PNH is designated as a highly specialised\u000a      service in England and funded as a National Service through the Advisory\u000a      Group for National Specialised Services (AGNSS) [H]. This covers the cost\u000a      of the Service (in excess of £1million\/year) and the cost of eculizumab\u000a      for PNH (approximately £25million\/year). The National PNH Service employs\u000a      15 people and contracts homecare nurses to deliver 4000 doses of\u000a      eculizumab by intravenous infusion in patients' homes each year.\u000a    The approval of eculizumab led to the establishment of the PNH Global\u000a      Registry (http:\/\/www.pnhsource.com\/pnh-registry)\u000a      which has enrolled over 2000 patients with PNH. Hillmen chairs the\u000a      Executive Committee of the PNH Registry and Leeds has recruited over 250\u000a      patients being the largest Centre globally.\u000a    Commercial impacts\u000a    The approval of eculizumab for PNH has been an economic success for\u000a      Alexion Pharmaceuticals as their only approved drug [I]. The sales of\u000a      eculizumab in 2012 were $1.134 billion. This was highlighted in the\u000a      September 2012 edition of Forbes magazine in an article entitled: \"How A\u000a      $440,000 Drug Is Turning Alexion Into Biotech's New Innovation Powerhouse\"\u000a      [G]. The current estimated market capitalisation for Alexion is $19billion\u000a      making Alexion and the development of eculizumab one of the most\u000a      impressive economic successes in the last 10 years [J].\u000a    ","ImpactSummary":"\u000a    Eculizumab has transformed quality of life and life expectancy for\u000a      patients with PNH and led to major economic impacts with global drug sales\u000a      of $1,134 million in 2012 and to Alexion Pharmaceuticals being worth over\u000a      $19 billion. PNH is a disabling blood disorder that was previously fatal\u000a      in 50% of patients but with eculizumab survival is comparable to the\u000a      normal population as well as returning patients to having a normal quality\u000a      of life. Research in Leeds led to the introduction of eculizumab in 2007.\u000a      Eculizumab is now approved for clinical use in over 40 countries and for\u000a      another life threatening disease, atypical haemolytic uraemic syndrome.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Hillmen P, Lewis SM, Bessler M, Luzzatto L and Dacie JV.\u000a      Natural history of paroxysmal nocturnal hemoglobinuria. (1995) New\u000a        England Journal of Medicine, 333, 1253-1258. 343 citations\u000a      Defined for the first time the dismal outcome for patients with PNH\u000a    \u000a\u000a[2] Hillmen P, Hall C, Marsh JCW, Elebute M, Bombara MP, Petro\u000a      BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF and Rother RP. Effect of\u000a      eculizumab on hemolysis and transfusion requirements in paroxysmal\u000a      nocturnal hemoglobinuria. (2004) New England Journal of Medicine,\u000a      350, 552-559. 176 citations\u000a      First description that targeted therapy with eculizumab was extremely\u000a        effective in PNH\u000a    \u000a\u000a[3] Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P,\u000a      Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A,\u000a      Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP\u000a      and Luzzatto L. The Complement Inhibitor eculizumab in paroxysmal\u000a      nocturnal hemoglobinuria. (2006) New England Journal of Medicine,\u000a      355, 1233-1243. 234 citations\u000a      Randomised trial proving that eculizumab is highly effective in PNH.\u000a        Ensured the drug was accepted and funded in many countries\u000a    \u000a\u000a[4] Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J,\u000a      Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler\u000a      M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement\u000a      inhibitor eculizumab on thromboembolism in patients with paroxysmal\u000a      nocturnal hemoglobinuria. (2007) Blood, 110, 4123-4128. 107\u000a      citations\u000a      First demonstration that the main cause of death and a major cause of\u000a        illness in PNH, namely thrombosis, was effectively prevented and treated\u000a        with eculizumab\u000a    \u000a\u000a[5] Risitano AM, Notaro R, Luzzatto L, Hill A, Kelly R, Hillmen P.\u000a      Paroxysmal nocturnal hemoglobinuria--hemolysis before and after\u000a      eculizumab. (2010) New England Journal of Medicine, 363,\u000a      2270-2272. 7 citations\u000a      Explanation for the continued transfusions for a minority of patient on\u000a        eculizumab\u000a    \u000a\u000a[6] Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M,\u000a      Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment\u000a      with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy\u000a      and improved survival. (2011) Blood, 117, 6786-6792. 29 citations\u000a      First convincing evidence that survival in PNH was normalized by\u000a        eculizumab. This led to it's approval and funding in many countries\u000a        worldwide\u000a    \u000aResults of the eculizumab trials have been published in very high impact\u000a      journals and presented at numerous International Conferences including the\u000a      American Society of Hematology 2002 to 2012, the European Haematology\u000a      Association 2004 to 2011 and other conferences such as the Japanese\u000a      Society of Hematology, Brazilian Society of Hematology and the British\u000a      Society of Haematology by Hillmen.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    A) Regulatory approval of eculizumab for the treatment of PNH in the U.S,\u000a      E.U., Japan and other countries.\u000a    B) Australian Government Department of Health and Aging report entitled:\u000a      \"Guidelines for the treatment of Paroxysmal Noctunrnal Haemoglobinuria\u000a      (PNH) through the Life Saving Drugs Program\" published in December 2010\u000a      recommending the funding of eculizumab for PNH Nationally in Australia and\u000a      widely referencing researchers from Leeds including Hillmen, Hill and\u000a        Kelly.\u000a    C) All Wales Medicines Strategy Group Final Appraisal Report entitled:\u000a      \"Eculizumab (Soliris) for the treatment of paroxysmal nocturnal\u000a      haemoglobinuria\" was published in April 2009 with extensive references to\u000a      the work of Leeds researchers (Hillmen, Hill, Kelly). It\u000a      recommended that: \"Eculizumab (Soliris®) is recommended for restricted use\u000a      within NHS Wales according to agreed guidelines for the treatment of\u000a      paroxysmal nocturnal haemoglobinuria.\"\u000a    D) Letters of support from leading international PNH clinicians\u000a      confirming the impact the research on PNH in Leeds led by Hillmen\u000a      has had on the lives of patients with PNH globally.\u000a    E) Letter of support from patients with PNH (one from UK and one from\u000a      Canada) confirming the dramatic impact eculizumab has had on their lives.\u000a    F) Changes in outcome in national figures for PNH documented from the\u000a      National Registry. Currently over 150 patients with PNH are on treatment\u000a      with eculizumab in the United Kingdom.\u000a    G) Extensive coverage in the national and international media (print,\u000a      electronic, radio and television; file available) involving Hillmen. This\u000a      includes the recent article in the Forbes magazine describes the impact of\u000a      eculizumab and Alexion Pharmaceuticals which extensively acknowledges the\u000a      central role of Hillmen. (http:\/\/www.forbes.com\/sites\/matthewherper\/2012\/09\/05\/how-a-\u000a440000-drug-is-turning-alexion-into-biotechs-new-innovation-powerhouse\/3\/).\u000a    H) Service Specification and Standards 2012\/13 - Paroxysmal Nocturnal\u000a      Haemoglobinuria Service. National Specialised Commissioning Team (NSCT).\u000a      http:\/\/www.specialisedservices.nhs.uk\/document\/10383\u000a    I) Sales figures for eculizumab are available online\u000a      (http:\/\/www.cnbc.com\/id\/49531010\/Alexion_Reports_Third_Quarter_2012_Results_Soliris_R_eculi\u000a        zumab_Net_Product_Sales_Increased_44_to_294_1_Million)\u000a    J) Letter of support from Dr Leonard Bell, Chief Executive Officer,\u000a      Alexion Pharmaceuticals Inc. confirming the central role Hillmen\u000a      played in the development of eculizumab for PNH.\u000a    (http:\/\/www.specialisedservices.nhs.uk\/service\/paroxysmal-noctural-haemoglobunuria\/)\u000a    ","Title":"\u000a    Case Study 10. Improving lives and transforming services for Paroxysmal\u000a      Nocturnal Haemoglobinuria (PNH), a life-threatening, disabling blood\u000a      disorder.\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired\u000a      haemolytic anaemia affecting approximately 5 people per million\u000a      population, most frequently occurring in early adulthood, is associated\u000a      with severe life-long symptoms and results in death in half of patients.\u000a      Peter Hillmen qualified in Medicine from the University of Leeds in 1985\u000a      and was awarded a PhD for his research into PNH in 1995. Hillmen\u000a      was appointed as a Consultant Haematologist in Leeds and Honorary Senior\u000a      Lecturer with the University of Leeds in 1996. He became Honorary\u000a      Professor in 2008 and the Chair of Experimental Haematology in 2013. In\u000a      1995 Hillmen published the \"Natural History of PNH\" demonstrating\u000a      that approximately 50% of patients died of PNH.1 In 1997\u000a      Alexion Pharmaceuticals developed eculizumab, an inhibitor of the\u000a      complement component C5, and commenced trials in autoimmune disorders.\u000a    In the early 1990's Hillmen had confirmed the importance of\u000a      complement, a system of proteins that form part of innate immunity, in the\u000a      destruction of PNH blood cells leading to the features, complications and\u000a      deaths in PNH. This made Hillmen realize that anti-complement\u000a      therapy, such as eculizumab, should be extremely effective in PNH. Hillmen\u000a      had continued PNH research after returning to Leeds in 1994, published\u000a      several papers and developed a PNH clinic. In 1999 Hillmen\u000a      approached Alexion to request eculizumab to perform a clinical trial in\u000a      PNH. The initial approach to Alexion to run a clinical trial was rejected\u000a      due to concern over patient numbers for this rare disease. However Hillmen\u000a      continued persuading Alexion to permit him to perform the trial and\u000a      towards the end of 2001 the initial Pilot study was approved.\u000a    Since 2002 Hillmen has supervised Leeds PhD students working on\u000a      PNH and including Dr Anita Hill from 2003 to 2006 (awarded a PhD in 2009)\u000a      and Dr Richard Kelly from 2007 to 2011 (PhD to be submitted 2013). Drs\u000a      Hill and Kelly were important in the clinical trials of eculizumab in PNH\u000a      and now both work within the PNH National Service led by Hillmen\u000a      and based in Leeds.\u000a    In May 2002 the Pilot study of eculizumab in 11 patients with PNH (9 in\u000a      Leeds) commenced with Hillmen as the Chief Investigator. The\u000a      results were dramatic leading to publication in the New England Journal of\u000a      Medicine in 2004.2 There were two subsequent Registration\u000a      trials of eculizumab in PNH (the TRIUMPH3 and SHEPHERD trials)\u000a      which Hillmen helped design, was the Chief Investigator for both\u000a      and recruited the largest number of patients. In total 195 patients were\u000a      recruited into the three Pivotal studies of eculizumab in PNH from 43\u000a      Centres worldwide and the Leeds contribution was 34 of these patients\u000a      (over double the next largest Centre). These trials confirmed the\u000a      impressive responses to eculizumab seen in the Pilot study leading to the\u000a      approval of eculizumab for clinical use in 2007 by the Food and Drug\u000a      Administration in the USA and the European Medicines Agency in Europe.\u000a      Subsequently eculizumab has been approved in over 40 countries for PNH and\u000a      was approved for atypical haemolytic uraemic syndrome (aHUS) by the FDA\u000a      and EMA in 2011. Eculizumab stopped the intravascular haemolysis in all\u000a      PNH patients and Hillmen subsequently demonstrated that the\u000a      complications of PNH, including thrombosis, renal failure and pulmonary\u000a      hypertension, were successfully treated. Subsequent publications from the\u000a      Leeds PNH group (Kelly, Hill, Hillmen) have demonstrated that the\u000a      survival of patients with PNH is normalised by eculizumab and that\u000a      patients can lead relatively normal lives.6\u000a    "},{"CaseStudyId":"27417","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2750405","Name":"Netherlands"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    This strategic programme of clinical and translational research into\u000a      colorectal cancer led from\u000a      Leeds has changed clinical guidelines and practice in this common cancer,\u000a      nationally and\u000a      internationally, benefitting thousands of patients.\u000a    Impacts on health and welfare\u000a      The MRC CRO7 trial (1) of preoperative radiotherapy, analysed together\u000a      with a similar trial from\u000a      The Netherlands, has changed clinical practice in the UK and across Europe\u000a      by recommending its\u000a      use in resectable rectal cancer [A, B]. Nationally this has resulted in an\u000a      increase in the overall use\u000a      of radiotherapy, and specifically in the one-week regimen used in CR07.\u000a      Data from the National\u000a      Bowel Cancer Audit for England & Wales [C] show that preoperative\u000a      radiotherapy increased by\u000a      76% from 1022 patients in 2007\/8 to 1803 patients in 2011. Over the same\u000a      period, the use of the\u000a      one-week radiotherapy regimen increased by 65% from 416 to 690 patients.\u000a      In North America,\u000a      where short-course radiotherapy was initially met with resistance, the\u000a      2013 National\u000a      Comprehensive Cancer Network guidance now states: \"Short course RT\u000a        gives effective local\u000a        control and the same overall survival as more conventional RT schedules\u000a        and may therefore be an\u000a        appropriate choice\" [D]. Patient information from Cancer Research UK\u000a      states: \"If your tumour can\u000a        be operated on, you are likely to have a short course of five\u000a        radiotherapy treatments in the week\u000a        before surgery.\"\u000a    Trials led by Seymour (2-4) established the \"MdG\" regimens for aCRC with\u000a      high activity, good\u000a      tolerability and reduced drug costs that are delivered on an outpatient\u000a      basis. These regimens have\u000a      been adopted in national guidelines [E] and, as well as being received by\u000a      over 5,000 patients in\u000a      trials, they underpin the non-trial management of aCRC in most NHS Units\u000a      in England & Wales.\u000a      Figures from the national Systemic Anti-cancer Therapy Audit (which\u000a      captured around one-half of\u000a      all chemotherapy prescribing over 1 year) suggest that around 40,000\u000a      cycles of MdG-based\u000a      regimens are received by 7,000 patients each year in England & Wales\u000a      [F].\u000a    Although aCRC is moderately chemo-sensitive, eradication or permanent\u000a      control of disease by\u000a      drugs alone is rare. Because of the unwanted effects of drug therapy, and\u000a      the development of drug\u000a      resistance, oncologists and patients need to make informed choices of\u000a      strategy, including the\u000a      integration of drug and surgical therapy, the sequencing of available\u000a      drugs and the option of drug-free\u000a      treatment breaks. The series of national trials led and co-led by Seymour\u000a      has made many\u000a      contributions to the evidence-base to guide these decisions. Complex\u000a      decision-making involves\u000a      synthesis of data from many sources, but the contribution of his work is\u000a      highlighted by the 16\u000a      references to FOCUS (2) alone in the current NICE colorectal guidance\u000a      evidence review [E].\u000a      Similarly, the data from these trials is cited extensively in guidance\u000a      documents outside the UK, in\u000a      Europe, North America and elsewhere [G, H].\u000a    Survival for patients with metastatic colorectal cancer has improved from\u000a      median of under a year in\u000a      the 1990s to over 2 years today. Many factors have contributed to this,\u000a      including the safe and\u000a      practicable regimens and patient-centred management strategies developed\u000a      and promulgated\u000a      through Seymour's research [I].\u000a    The median age at death from colorectal cancer in the UK is 75 years, and\u000a      median age at\u000a      diagnosis of aCRC is around 73 years. However, the median age of\u000a      participants in most RCTs in\u000a      aCRC, even those without formal age restrictions, is 60-65 years. A UK\u000a      survey in 2002 established\u000a      that in research-active units around 50% of aCRC patients were being\u000a      treated off-trial with lower-intensity\u000a      schedules than those used in trials because of concerns from oncologists\u000a      or patients\u000a      themselves that full-intensity regimens would be unsuitable for them.\u000a      FOCUS2, with a median age\u000a      of 75, was the first RCT to target this population, using adapted\u000a      lower-intensity regimens. It\u000a      provides a unique data source and is used by many oncologists to guide\u000a      treatment choices.\u000a      Evidence from FOCUS2 is included in international colorectal guidance\u000a      documents, including in the\u000a      USA and Europe [G, J].\u000a    Seymour and Quirke initiated predictive biomarker studies from 1997, and\u000a      in 2000 pioneered the\u000a      inclusion of prospective consent for future translational research within\u000a      a trial, FOCUS. This\u000a      practice is now standard in cancer trials. The translational outputs from\u000a      FOCUS led to the design of\u000a      two pioneering prospective stratified medicine trials, FOCUS3 and FOCUS4.\u000a      In PICCOLO we\u000a      identified, within the KRAS-wt population, 30% patients with mutations\u000a      predicting non-response or\u000a      harm with anti-EGFR antibody therapy — a finding with important\u000a      consequences for influencing\u000a      future practice. Commercial laboratories worldwide, responding to these\u000a      and other corroborating\u000a      data, have expanded their mutation panels for molecular stratification of\u000a      colorectal cancer patients\u000a      [K].\u000a    Impacts on practitioners and services\u000a      Sebag-Montefiore and Quirke are members of the Steering Committee and\u000a      Teaching Faculty for\u000a      the national programme for low rectal cancer (LOREC) in England. Between\u000a      2010 and 2012 it\u000a      trained 147\/164 multidisciplinary rectal cancer teams in England in\u000a      improved surgical techniques\u000a      and selection of patients for preoperative radiotherapy.\u000a    ","ImpactSummary":"\u000a    Colorectal cancer is a common disease, which frequently causes death or\u000a      morbidity, either\u000a      because of failure to control the primary tumour or failure to prevent\u000a      distant metastases. Leeds\u000a      researchers have devised new treatment approaches using chemotherapy and\u000a      radiotherapy and\u000a      tested them in large randomised controlled trials which have led to major\u000a      changes in clinical\u000a      practice in the management of rectal cancer and advanced colorectal cancer\u000a      (aCRC), driving\u000a      clinical decision-making and improving outcomes for patients. This\u000a      includes better-evidenced\u000a      treatment for elderly patients and patient stratification on the basis of\u000a      molecular biomarkers.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leeds\u000a    ","Institutions":[{"AlternativeName":"Leeds (University of)","InstitutionName":"University of Leeds","PeerGroup":"A","Region":"Yorkshire And Humberside","UKPRN":10007795}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Sebag-Montefiore D, Stephens R, Steele R, Monson J, Grieve B, Khanna\u000a      S, Quirke P, Couture\u000a      J, de Metz C, Myint S, Bessell E, Griffiths G, Thompson L, Parmar M. A\u000a      randomised trial\u000a      comparing pre-operative radiotherapy and selective post-operative\u000a      chemo-radiotherapy in rectal\u000a      cancer. Results from the Medical Research Council CR07 and National Cancer\u000a      Institute of Canada\u000a      Clinical Trials Group C016 trial. Lancet 2009; 373: 811-20.\u000a      The definitive trial showing benefits to patients with primary rectal\u000a        cancer from modern\u000a        radiotherapy and surgery combined\u000a    \u000a\u000a2) Seymour MT, Maughan TS, Ledermann JA, et al, for the FOCUS Trial\u000a      Investigators and the\u000a      National Cancer Research Institute Colorectal Clinical Studies Group.\u000a      Different strategies of\u000a      sequential and combination chemotherapy for patients with poor- prognosis\u000a      advanced colorectal\u000a      cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370:\u000a      143-52.\u000a      This was at the time of publication the largest-ever trial in aCRC.\u000a        Multiple references in\u000a        NICE guidance, reviews and meta-analyses.\u000a    \u000a\u000a3) Seymour MT, Thompson LC, Wasan H, et al, on behalf of the FOCUS2\u000a      Investigators and the\u000a      National Cancer Research Institute Colorectal Cancer Clinical Studies\u000a      Group. Chemotherapy\u000a      options in elderly and frail patients with metastatic colorectal cancer\u000a      (MRC FOCUS2): an open-label\u000a      randomised factorial trial. Lancet 2011; 377: 1749-59.\u000a      The largest ever RCT focusing specifically on frail and elderly aCRC\u000a        patients, who\u000a        constitute around 40% of the aCRC population; extensively cited in SIOG\u000a        guidance (the\u000a        international society for geriatric oncology).\u000a    \u000a\u000a4) Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, et al, for the\u000a      MRC COIN Trial\u000a      Investigators. Addition of cetuximab to oxaliplatin-based first-line\u000a      combination chemotherapy for\u000a      treatment of advanced colorectal cancer: results of the randomised phase 3\u000a      MRC COIN trial.\u000a      Lancet 2011; 377: 2103-14.\u000a      This and a sister publication in Lancet Oncol (2011;12:642-53) together\u000a        report COIN, which\u000a        succeeded FOCUS as the largest-ever RCT in aCRC, and included two\u000a        separate trial\u000a        questions.\u000a    \u000a\u000a5) Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, Barrett\u000a      JH, Selby P, Meade AM,\u000a      Stephens RJ, Parmar MK, Seymour MT. Predictive biomarkers of chemotherapy\u000a      efficacy in\u000a      colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008;\u000a      26: 2690-98.\u000a      Using samples collected in the FOCUS trial, we detected molecular\u000a        correlates of treatment\u000a        benefit which were then used to select stratification factors for the\u000a        FOCUS3 trial.\u000a    \u000a\u000a6) Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S,\u000a      Lowe C, Seligmann\u000a      JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A,\u000a      Benstead K,\u000a      Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and\u000a      irinotecan versus\u000a      irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant\u000a      advanced colorectal cancer\u000a      (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 2013;\u000a      14(8):749-59. doi\u000a      10.1016\/S1470-2045(13)70163-3.\u000a      This was the first RCT in the world to use prospective molecular\u000a        selection in advanced\u000a        colorectal cancer. This publication reports the evaluation of anti-EGFR\u000a        targeted therapy in\u000a        patients with KRAS-unmutated tumours.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    A) Scottish Intercollegiate Guidelines Network (SIGN) 126, 2011:\u000a      Diagnosis and Management\u000a      of colorectal cancer. (www.sign.ac.uk\/guidelines\/fulltext\/126\/index.html)\u000a    B) ESMO Clinical Practice Guidelines — Rectal cancer; diagnosis treatment\u000a      and follow-up,\u000a      2013. (http:\/\/www.esmo.org\/Guidelines-Practice\/Clinical-Practice-Guidelines\/Gastrointestinal-Cancers\/Rectal-Cancer)\u000a    C) National Bowel Cancer Audit (please compare data for successive years\u000a      from 2007).\u000a      (http:\/\/www.hscic.gov.uk\/searchcatalogue?q=title%3A%22bowel+cancer%22&area=&size=10&sort=Relevance)\u000a    D) National Comprehensive Cancer Network (NCCN) Clinical practice\u000a      guidelines in Rectal\u000a      Cancer, V.1.2014, MS-16 (http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/rectal.pdf)\u000a    E) NICE review of colorectal cancer management\u000a      (http:\/\/www.nice.org.uk\/nicemedia\/live\/13597\/57047\/57047.pdf)\u000a    F) Systemic Anti-cancer Therapy Audit. Go to http:\/\/www.chemodataset.nhs.uk\/home\u000a      and\u000a      select \"Top Regimens\" then \"Lower GI\" and \"colorectal\" to show data.\u000a    G) European Society for Medical Oncology (ESMO) Consensus Guidelines:\u000a      management of\u000a      patients with colon and rectal cancer — a personalised approach to\u000a      clinical decision making.\u000a      doi: 10.1093\/annonc\/mds236 (http:\/\/annonc.oxfordjournals.org\/content\/23\/10\/2479.long)\u000a    H) National Comprehensive Cancer Network (NCCN) Clinical Practice\u000a      guidelines in Colon\u000a      Cancer, Version 1.2014. (http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/colon.pdf)\u000a    I) Letter from National Cancer Director to corroborate contributions in\u000a      colorectal cancer and\u000a      attribute improved outcomes to a significant degree to Leeds-led research.\u000a    J) National Comprehensive Cancer Network (NCCN) Clinical practice\u000a      guidelines in Senior\u000a      Adult Oncology, version 2.2014, SAO.B-9 & MS-26 (available at http:\/\/www.nccn.org).\u000a    K) Recommendations of the Evaluation of Genomic Applications in Practice\u000a      and Prevention\u000a      (EGAPP) Working Group.\u000a      (http:\/\/www.nature.com\/gim\/journal\/v15\/n7\/full\/gim2012184a.html)\u000a    \u000a    ","Title":"\u000a    Case Study 4. Improving chemotherapy, radiotherapy and patient outcomes\u000a      for colorectal cancer\u000a      through patient-focused integrated clinical trials.\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Colorectal cancer afflicts 40,000 people per year in the UK and this\u000a      number is rising by 5,000 per\u000a      decade. However the rates of cure and disease control are improving, with\u000a      significant contributions\u000a      from Leeds researchers.\u000a    Rectal cancer affects 14,000 patients in the UK a year. Local recurrence\u000a      after surgical resection of\u000a      rectal cancer is frequently incurable and leads to major debilitating\u000a      symptoms. Strategies to reduce\u000a      the risk of local recurrence included improved surgical technique and the\u000a      use of adjuvant\u000a      radiotherapy. Yet there had been uncertainty over whether the benefits\u000a      from preoperative\u000a      radiotherapy remained when it was combined with modern surgical technique.\u000a      Between 1997 and\u000a      2005 David Sebag-Montefiore (Professor of Clinical Oncology, Leeds 1997-)\u000a      led an international\u000a      trial (CR07) of 1350 patients from 80 centres in four countries showing a\u000a      one-week course of\u000a      preoperative radiotherapy prior to surgery halved the risk of local\u000a      recurrence and improved\u000a      disease-free survival (1).\u000a    For all patients with colorectal cancer, even if the primary local\u000a      disease is controlled, the risk of\u000a      distant metastatic spread remains high, resulting in serious morbidity and\u000a      15,000 deaths per year\u000a      in the UK. The mainstay of treatment for the large majority of patients\u000a      with advanced colorectal\u000a      cancer (aCRC) is chemotherapy. Between 1995 and 1999 Matthew Seymour\u000a      (Professor of\u000a      Gastrointestinal Cancer Medicine, Leeds 1995-), who was a co-investigator\u000a      in trials which\u000a      established two new drugs — irinotecan and oxaliplatin — in the treatment\u000a      of aCRC, identified the\u000a      need to develop better schedules combining these agents with established\u000a      drugs to maximise\u000a      effectiveness, reduce toxicity and allow their practicable and\u000a      cost-effective use throughout the\u000a      NHS. Between 2000 and 2008, in collaboration with the Colorectal Cancer\u000a      Clinical Studies Group\u000a      of the National Cancer Research Institute (NCRI) and the NIHR Cancer\u000a      Research Network\u000a      (NCRN), Seymour led or co-led a series of large national phase III\u000a      randomised controlled trials\u000a      (RCTs) to address the optimum sequencing of available drugs (2-4). The\u000a      schedules he developed\u000a      (MdG, OxMdG and IrMdG) have since become UK standards.\u000a    FOCUS (2) — with 2135 patients at 61 UK centres and at the time the\u000a      largest ever trial of patients\u000a      with aCRC — tested three strategies of sequential and combination\u000a      chemotherapy. This was\u000a      followed by FOCUS2 (3) assessing the adaptation of treatment for frail,\u000a      elderly patients — a fast-growing\u000a      population. The merits of intermittent or continuous therapy were studied\u000a      in COIN (4) — the\u000a      largest RCT in aCRC — which along with FOCUS2 also assessed the\u000a      introduction of oral therapy.\u000a      Together, these trials included 5000 patients and provided firm evidence\u000a      to guide many aspects of\u000a      day-to-day management and subsequent international meta-analyses.\u000a    Throughout this period, particularly from 2008 onwards, Seymour and Phil\u000a      Quirke (Professor of\u000a      Pathology 1982- ), worked to identify molecular predictive biomarkers and\u000a      introduce prospective\u000a      molecular stratification, especially in relation to novel targeted\u000a      therapies. In FOCUS (2) we\u000a      introduced, for the first time in aCRC, prospective consent for use of\u000a      surplus tumour material,\u000a      enabling the subsequent identification of potential predictors of\u000a      treatment benefit (5). We then led\u000a      PICCOLO, the first phase III trial internationally to introduce\u000a      prospective genotyping with different\u000a      randomisations based on KRAS mutation status. This identified a\u000a      subpopulation of patients with\u000a      KRAS-unmutated tumours who receive increased benefit from the\u000a      addition of the anti-EGFR\u000a      therapeutic antibody panitumumab, while around 30% of patients, with\u000a      tumours unmutated for\u000a      KRAS but having a mutation in a related gene, gain no benefit or\u000a      are harmed (6).\u000a    "},{"CaseStudyId":"28031","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S9.\u000d\u000a    Context\u000d\u000a    Over 70 lysosomal diseases exist with an incidence of 1\/7000. They are\u000d\u000a      progressive, multisystem diseases, usually affecting children, with\u000d\u000a      severely shortened life expectancy. In 1993 there was one treatment for\u000d\u000a      LSDs: haematopoietic stem cell transplant. This was only effective in\u000d\u000a      severe MPSI and had a high procedure-related mortality rate of ~45%. Drug\u000d\u000a      treatments were slow to appear and individually had limited impact; the\u000d\u000a      first drug in 1994 for Gaucher disease was cerezyme (imiglucerase), used\u000d\u000a      for around 80 patients in the UK. In the early 1990s, LSDs were often\u000d\u000a      diagnosed very late or misdiagnosed and palliative management was\u000d\u000a      dispersed throughout the UK.\u000d\u000a    Reach and significance of the impact\u000d\u000a    Improved clinical management of LSDs\u000d\u000a    \u000d\u000a      Several multinational collaborative natural history studies in\u000d\u000a        Manchester, most of which are still ongoing, resulted in\u000d\u000a        improved\/earlier LSD diagnosis and disease management (S1).\u000d\u000a      \u000aWraith wrote NHS clinical management guidelines for 6 LSDs\u000d\u000a        which helped to reduce age of diagnosis in several LSDs including MPSI,\u000d\u000a        from an average range of 2-10 years of age (2000) to 3 months-4 years of\u000d\u000a        age (2013), depending on severity (S2). This improvement is important as\u000d\u000a        early treatment has increased clinical benefit.\u000d\u000a      2005: Manchester was made one of eight National Specialist\u000d\u000a        Commissioned Centres in England for management and treatment of LSDs\u000d\u000a        with Wraith (now Jones) as director due to Wraith's\u000d\u000a        natural history trial background (S3-S6).\u000d\u000a      2010-11 Manchester's recognition as a worldwide centre for LSDs\u000d\u000a        resulted in Manchester and Wraith handling 15,500 diagnoses per\u000d\u000a        annum for paediatric inherited metabolic diseases from over 20\u000d\u000a        countries, of which ~30% are LSDs.\u000d\u000a      2010-11: 1983 LSD patients were managed at 8 NCG centres — 350 in\u000d\u000a        Manchester (S5).\u000d\u000a    \u000d\u000a    Enzyme replacement and substrate reduction therapies\u000d\u000a    Enzyme replacement therapy trials with Wraith\/Jones as CI\u000d\u000a      in Manchester were conducted for the LSDs MPSI, MPSII, MPSVI, Fabry,\u000d\u000a      and Pompe disease, and the substrate reduction therapy drug miglustat for\u000d\u000a      Niemann pick C, in collaboration with Biomarin, Shire, TKT, Genzyme,\u000d\u000a      Actelion and Synageva.\u000d\u000a    \u000d\u000a      2003-13: 6 drugs licensed from these trials in >20 countries\u000d\u000a        including US, Europe, Canada, Latin America, Japan and Australia (S7).\u000d\u000a      2011-12: 9 licensed drugs for 7 LSDs provided in 8 English NCG centres\u000d\u000a        for 801 patients with a drug budget of £124 million, 6 of which (~2\/3 of\u000d\u000a        worldwide LSD drug market) were trialled in Manchester by Wraith\/Jones\u000d\u000a        (S3).\u000d\u000a      2013 >3000 LSD patients in >20 countries worldwide benefited\u000d\u000a        from drug treatment, ~2\/3 from the 6 drugs trialled by Wraith\/Jones\u000d\u000a        (S7, S8).\u000d\u000a      2013 GALNS for MPSIVA trialled in Manchester (Jones) awaiting\u000d\u000a        FDA and EMA approval (S7).\u000d\u000a      \u000aWraith and colleagues have delivered significant quality of\u000d\u000a        life improvements in patients with these 7 LSDs as a result of their\u000d\u000a        research, with improvements in cognitive function, muscular, and\u000d\u000a        skeletal function as well as significantly improved life expectancy of\u000d\u000a        on average around 10 years or more depending on disease severity.\u000d\u000a      Previous life expectancies of a few months in MPSI Hurler disease, is\u000d\u000a        now considerably extended lifespans of decades, as well as improved\u000d\u000a        cognitive and\/or skeletal outcomes.\u000d\u000a    \u000d\u000a    Improved haematopoietic stem cell transplantation outcomes\u000d\u000a    To improve HSCT outcomes, Fairbairn and Wraith developed\u000d\u000a      retroviral gene therapy in HSCT as a safer and more efficacious\u000d\u000a      alternative with the world's first LSD gene therapy clinical trial for\u000d\u000a      MPSIH in Manchester in 1997.\u000d\u000a    \u000d\u000a      This trial allowed a more efficacious approach developed by Bigger\u000d\u000a        and colleagues using a lentiviral vector for MPSIIIA between 2007-13,\u000d\u000a        expected in clinical trial in 2015.\u000d\u000a      \u000aWynn and colleagues developed safer HSCT for LSDs. Prior to\u000d\u000a        1995, 1-2 patients pa were transplanted for MPSIH in Manchester. By\u000d\u000a        2010, this rose to 7 pa and transplant expanded to other LSDs, including\u000d\u000a        Niemann Pick CII, resulting in ~10-15 patients transplanted pa (S8, S9).\u000d\u000a      Engrafted survival improved from 57% in 1994-2007 to 94% post-2007 and\u000d\u000a        a demonstration by Wynn, Bigger that HSCT is more effective than\u000d\u000a        ERT in MPSI disease, with some patients' cognitive development in the\u000d\u000a        normal range.\u000d\u000a      \u000aWynn and colleagues wrote metabolic transplant guidelines for\u000d\u000a        The European Group for Blood and Marrow Transplantation haematopoietic\u000d\u000a        stem cell transplant handbook 2008 which include expansion to other\u000d\u000a        lysosomal diseases (S9).\u000d\u000a      Novel biomarkers for LSDs were developed or validated in Manchester\u000d\u000a        including heparan cofactor II thrombin complex and dermatan sulphate\u000d\u000a        chondroitin sulphate ratio, both of which correlate with clinical\u000d\u000a        outcomes in treated patients with MPSI, II and VI.\u000d\u000a      Dermatan sulphate chondroitin sulphate ratio has been adopted into\u000d\u000a        standard clinical disease management in Manchester.\u000d\u000a\u0009\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Researchers at the University of Manchester (UoM) characterised fatal\u000d\u000a      childhood lysosomal storage diseases (LSDs) and developed new treatments.\u000d\u000a      The research has led to the licensing of 6 drugs worldwide (of a total of\u000d\u000a      9 available) for LSDs including mucopolysaccharide disease I, II, IIIA,\u000d\u000a      IVA, VI, Fabry, Pompe and Niemann Pick C. As a result, longevity and\u000d\u000a      quality of life have improved for more than 800 LSD patients in England\u000d\u000a      and more than 3000 worldwide. Home enzyme treatment has improved quality\u000d\u000a      of life for the majority of LSD patients in the UK (>400). The research\u000d\u000a      has broadened the scope of haematopoietic stem cell transplantation for\u000d\u000a      LSDs and reduced mortality, benefiting more than 100 LSD patients\u000d\u000a      worldwide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    The research was published in the top metabolic journals of the field.\u000d\u000a      Key references:\u000d\u000a    \u000a1. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer\u000d\u000a      J, Rapoport DM, Berger KI, Swiedler SJ, Kakkis ED, Braakman T, Chadbourne\u000d\u000a      E, Walton-Bowen K, Cox GF. Enzyme replacement therapy for\u000d\u000a      mucopolysaccharidosis I: a randomized, double-blinded, placebo-\u000d\u000a      controlled, multinational study of recombinant human α-L-iduronidase\u000d\u000a      (laronidase). The Journal of Pediatrics. 2004;144(5):581-8. DOI:\u000d\u000a      10.1016\/j.jpeds.2004.01.046\u000d\u000a    \u000a\u000a2. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, Leslie N,\u000d\u000a      Levine J, Spencer C, McDonald M, Li J, Dumontier J, Halberthal M, Chien\u000d\u000a      YH, Hopkin R, Vijayaraghavan S, Gruskin D, Bartholomew D, van der Ploeg A,\u000d\u000a      Clancy JP, Parini R, Morin G, Beck M, De la Gastine GS, Jokic M, Thurberg\u000d\u000a      B, Richards S, Bali D, Davison M, Worden MA, Chen YT, Wraith JE.\u000d\u000a      Recombinant human acid α-glucosidase: Major clinical benefits in\u000d\u000a      infantile-onset Pompe disease. Neurology. 2007;68(2):99-109. DOI:\u000d\u000a      10.1212\/01.wnl.0000251268.41188.04\u000d\u000a    \u000a\u000a3. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat\u000d\u000a      for treatment of Niemann-Pick C disease: a randomised controlled study. The\u000d\u000a        Lancet Neurology. 2007;6(9):765-72. DOI:\u000d\u000a      10.1016\/S1474-4422(07)70194-1\u000d\u000a    \u000a\u000a4. Pastores GM, Arn P, Beck M, Clarke JTR, Guffon N, Kaplan P, Muenzer J,\u000d\u000a      Norato DYJ, Shapiro E, Thomas J, Viskochil D, Wraith JE. The MPS I\u000d\u000a      registry: Design, methodology, and early findings of a global disease\u000d\u000a      registry for monitoring patients with Mucopolysaccharidosis Type I. Molecular\u000d\u000a        Genetics and Metabolism. 2007;91(1):37-47. DOI:\u000d\u000a      10.1016\/j.ymgme.2007.01.011\u000d\u000a    \u000a\u000a5. Wynn RF, Wraith JE, Mercer J, O'Meara A, Tylee K, Thornley M,\u000d\u000a      Church HJ, Bigger BW. Improved Metabolic Correction in Patients\u000d\u000a      with Lysosomal Storage Disease Treated with Hematopoietic Stem Cell\u000d\u000a      Transplant Compared with Enzyme Replacement Therapy. The Journal of\u000d\u000a        Pediatrics. 2009;154(4):609-11. DOI: 10.1016\/j.jpeds.2008.11.005\u000d\u000a    \u000a\u000a6. Malinowska M, Wilkinson FL, Langford-Smith KJ, Langford-Smith A, Brown\u000d\u000a      JR, Crawford BE, Vanier MT, Grynkiewicz G, Wynn RF, Wraith JE,\u000d\u000a      Wegrzyn G, Bigger BW. Genistein improves neuropathology and\u000d\u000a      corrects behaviour in a mouse model of neurodegenerative metabolic\u000d\u000a      disease. PLoS One. 2010;5(12):e14192. DOI:\u000d\u000a      10.1371\/journal.pone.0014192\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    S1. Natural history studies: The MPSI registry (Natural history registry)\u000d\u000a      https:\/\/www.lsdregistry.net\/mpsiregistry\/\u000d\u000a      ; The MPSII Hunter outcome survey (Natural history registry) http:\/\/www.globaloutcomesurveys.com\/overview.aspx;\u000d\u000a      Alpha mannosidosis FP7 natural history study http:\/\/www.alpha-man.eu\/index.htm\u000d\u000a    S2. Department of Health, National Guidelines for treatment of lysosomal\u000d\u000a      diseases:\u000d\u000a      http:\/\/www.specialisedservices.nhs.uk\/documents\/index\/document_category_id:23\u000d\u000a    S3. Advisory Group for National Specialised Services Annual Report,\u000d\u000a      2011-12 (LSD statistics, p. 82; ERT drug budget, table 10, p. 104; ERT by\u000d\u000a      disease and drug with patient numbers, England, table 11, p. 105).\u000d\u000a    S4. Advisory Group for National Specialised Services Annual Report\u000d\u000a      2010-11 (ERT by disease and drug with patient numbers, England, p. 62; p.\u000d\u000a      79).\u000d\u000a    S5. National Specialised Commissioning Priorities 2011-12 (Total LSD\u000d\u000a      patient numbers in England, p. 45). http:\/\/www.specialisedservices.nhs.uk\/library\/21\/National_Specialised_Commissioning_Priorities_201112.pdf\u000d\u000a    S6. Changes to National Commissioning Group services and NCG\u000d\u000a      Commissioning intentions 2008-9 (p. 7). http:\/\/www.specialisedservices.nhs.uk\/library\/24\/Changes_to_Nationally_Commissioned_S\u000d\u000aervices_from_April_2008_and_the_National_Commissioning_Group_Commissioning_Intentions_for_200809.pdf\u000d\u000a    S7. Companies benefiting directly from the research: Genzyme http:\/\/www.genzyme.co.uk\/products.aspx;\u000d\u000a      Shire Human Genetic Therapies www.shire.com\/shireplc\/en\/products\/list;\u000d\u000a      Actelion http:\/\/www.actelion.co.uk\/uk\/healthcare-professionals\/products\/index.page;\u000d\u000a      Biomarin\u000d\u000a      http:\/\/www.bmrn.com\/products\/aldurazyme.php\u000d\u000a    S8. Organisations directly benefiting from the research: UK MPS society\u000d\u000a      research page\u000d\u000a      http:\/\/www.mpssociety.org.uk\/research\/\u000d\u000a      ; National MPS Society USA\u000d\u000a      http:\/\/www.mpssociety.org\/clinical-trials\/\u000d\u000a      ; Canadian MPS society:\u000d\u000a      http:\/\/www.mpssociety.ca\/page\/announcements.aspx\u000d\u000a    S9. Boelens JJ, Wynn RF, Bierings M. HSCT for inborn errors of\u000d\u000a      metabolism. In: Apperley J et al., editors. The EBMT-ESH Handbook.\u000d\u000a      2008. pp. 544-553.\u000d\u000a      http:\/\/www.ebmt.org\/Contents\/Resources\/Library\/EBMTESHhandbook\/Pages\/EBMT-ESH-handbook.aspx\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved clinical management of lysosomal disorders\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    UoM researchers are given in bold.\u000d\u000a    The aims of the research carried out at UoM were to improve the\u000d\u000a      diagnosis, treatment and management of LSDs. The research was carried out\u000d\u000a      between 1993 and 2013, with the majority of the work taking place 2005-13.\u000d\u000a    Key UoM researchers:\u000d\u000a    \u000d\u000a      \u000aEd Wraith (Honorary Senior Lecturer, 1993-2008; Honorary\u000d\u000a        Professor, 2008-2013)\u000d\u000a      \u000aLez Fairbairn (Professor, 1993-2005)\u000d\u000a      \u000aRobert Wynn (Honorary Lecturer, 1998-2007; Honorary Senior\u000d\u000a        Lecturer, 2007-date)\u000d\u000a      \u000aBrian Bigger (Research Fellow, 2006-2008; Senior Research\u000d\u000a        Fellow, 2008-2013; Reader, 2013-date)\u000d\u000a      \u000aSimon Jones (Honorary Lecturer, 2009-date)\u000d\u000a    \u000d\u000a    Genetic characterisation of LSDs\u000d\u000a    \u000d\u000a      \u000aWraith and colleagues have identified several major genetic\u000d\u000a        mutations in LSDs including mucopolysaccharidosis type II, IV, VI,\u000d\u000a        Gaucher and Fabry since 1993.\u000d\u000a      \u000aWraith recognised a poor genotype-phenotype correlation, but as\u000d\u000a        many patients are from consanguineous backgrounds, Wraith\u000d\u000a        identified that common mutations followed similar clinical courses,\u000d\u000a        allowing improved clinical classification of MPS diseases.\u000d\u000a    \u000d\u000a    Bone marrow transplantation and gene therapy development for MPSI\u000d\u000a    \u000d\u000a      \u000aWraith, Fairbairn and colleagues characterised outcomes after\u000d\u000a        haematopoietic stem cell transplantation (HSCT) in MPS I, II and III.\u000d\u000a        This is the only treatment for some LSDs and led to adoption of HSCT for\u000d\u000a        MPSI Hurler and discontinuation for MPSII and III.\u000d\u000a      A retroviral HSCT gene therapy approach was adopted for MPSI Hurler\u000d\u000a        which resulted in an unsuccessful clinical trial in Manchester in 1997.\u000d\u000a    \u000d\u000a    Natural history studies on LSDs\u000d\u000a    \u000d\u000a      Several natural history studies on MPSI (MPSI Registry), MPSII (Hunter\u000d\u000a        outcome survey), MPSIII, MPSIVA (MOR001), MPSVI (Clinical Surveillance\u000d\u000a        Program), alpha mannosidosis (Alpha-man), were led in Manchester or with\u000d\u000a        significant contributions from Wraith, Jones and\u000d\u000a        colleagues.\u000d\u000a      \u000aWraith, Bigger, Jones and colleagues validated\u000d\u000a        biomarkers of lysosomal diseases including dermatan sulphate chondroitin\u000d\u000a        sulphate ratio and HCIIT against clinical outcomes in\u000d\u000a        mucopolysaccharidosis diseases.\u000d\u000a    \u000d\u000a    Treatment development for LSDs\u000d\u000a    \u000d\u000a      \u000aWraith and Jones were co-investigators on clinical\u000d\u000a        trials evaluating enzyme replacement therapy for MPSI, MPSII, MPSVI,\u000d\u000a        Fabry, and Pompe disease, and the substrate reduction therapy drug\u000d\u000a        miglustat for Niemann Pick C.\u000d\u000a      \u000aJones is co-investigator in ongoing enzyme replacement therapy\u000d\u000a        trials for MPSIIIA, MPSIIIA-C, MPS IVA and Wolman.\u000d\u000a      6 licensed drugs resulted from this work and Wraith and\u000d\u000a        colleagues demonstrated that enzyme replacement therapy for MPSII and VI\u000d\u000a        could be given safely at home.\u000d\u000a      \u000aWraith, Bigger, Jones, Wynn developed\u000d\u000a        the substrate reduction therapy drug genistein for MPSIII (trial\u000d\u000a        starting January 2014) and HSCT gene therapy for MPSIIIA (trial starting\u000d\u000a        2015).\u000d\u000a      \u000aWraith, Wynn, Bigger and colleagues showed HSCT\u000d\u000a        to be more effective than enzyme replacement therapy in MPSI, which has\u000d\u000a        significantly improved transplantation mortality in MPSIH and in a\u000d\u000a        pan-European HSCT policy, and broadened the indication of HSCT to\u000d\u000a        include more LSDs.\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"28032","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S6.\u000d\u000a    Context\u000d\u000a      Non-steroidal AIs are now the standard of care for hormone\u000d\u000a      receptor-positive breast cancers in post-menopausal women, nationally and\u000d\u000a      internationally (S1). Our research established that AIs are, however,\u000d\u000a      associated with increases in osteoporotic fractures and increased bone\u000d\u000a      mineral density loss (1, 2). Almost 30,000 post-menopausal women in the UK\u000d\u000a      develop breast cancer annually, 50% of whom already have significant bone\u000d\u000a      mineral density loss before starting treatment. Prior to the research\u000d\u000a      carried out at UoM, 2.3% of those treated with AIs annually developed bone\u000d\u000a      fragility fractures.\u000d\u000a    Pathways to impact\u000d\u000a      UoM research has led to the following standards of care now adopted\u000d\u000a      internationally:\u000d\u000a    \u000d\u000a      Routine assessment of BMD using a DEXA scan prior to AI therapy in\u000d\u000a        post-menopausal women with hormone receptor positive breast cancer;\u000d\u000a      Bisphosphonate therapy for all women with a T score < -2;\u000d\u000a      Discontinuation of HRT as a therapeutic intervention after breast\u000d\u000a        cancer diagnosis;\u000d\u000a      Contraindication of HRT in breast cancer patients with menopausal\u000d\u000a        symptoms\/bone loss.\u000d\u000a    \u000d\u000a    Reach and significance of the impact\u000d\u000a      The research has had a substantial influence on clinical guidelines\u000d\u000a      governing the treatment of breast cancer in the UK and internationally.\u000d\u000a    Use of DEXA scan and bisphosphonates\u000d\u000a      As a result of the research, national and international consensus\u000d\u000a      guidelines were issued which indicate the need for pre-adjuvant therapy\u000d\u000a      bone mineral density DEXA scanning to identify patients already\u000d\u000a      osteoporotic or at risk of bone loss (S1-S4). The guidelines ensure\u000d\u000a      commencement of intravenous or oral bisphosphonates where bone loss has\u000d\u000a      been identified or patients have had previous osteoporotic fractures.\u000d\u000a    The research was cited and adopted in NICE CG80, Early and locally\u000d\u000a        advanced breast cancer: Diagnosis and treatment (2009). One of the\u000d\u000a      key priorities identified in these guidelines is that: `Patients with\u000d\u000a      early invasive breast cancer should have a baseline dual energy X-ray\u000d\u000a      absorptiometry (DEXA) scan to assess bone mineral density if they are\u000d\u000a      starting adjuvant aromatase inhibitor treatment\/have treatment-induced\u000d\u000a      menopause\/are starting ovarian ablation\/suppression therapy' (S1, p. vi).\u000d\u000a      The guidance in the NICE document on treatment with bisphosphonates cites\u000d\u000a      our research, stating: `Evidence from RCTs (Brufsky, 2006 [S5 below] and Bundred\u000d\u000a      et al., 2008 [reference 2 above]) have indicated that in women who were\u000d\u000a      receiving adjuvant letrozole, immediate treatment with zoledronate\u000d\u000a      compared to delayed may prevent loss of BMD at both lumbar spine and total\u000d\u000a      hip. There is evidence that immediate treatment with zoledronic acid\u000d\u000a      maintains the baseline osteopenia status of patients compared with delayed\u000d\u000a      treatment at 12 months [S6 below]. Furthermore, Bundred et al.\u000d\u000a      (2008) showed no evidence to suggest a difference in the occurrence of\u000d\u000a      fractures in immediate versus delayed treatment with zoledronate and that\u000d\u000a      there was no difference in breast cancer recurrence when comparing\u000d\u000a      immediate and delayed treatment with zoledronate. There are no significant\u000d\u000a      acute adverse effects with zoledronate.' (S1, p. 68)\u000d\u000a    The US guidelines (ASCO, S3; NCCN US Task Force Report on Bone Health in\u000d\u000a      Cancer Care, S4) cite our research and advise the use of DEXA scanning and\u000d\u000a      bisphosphonates in patients on aromatase inhibitor therapy after breast\u000d\u000a      cancer treatment.\u000d\u000a    The guidelines ensure that assessment of BMD using DEXA scan prior to AI\u000d\u000a      therapy is now routine for women with hormone receptor positive breast\u000d\u000a      cancer. Bisphosphonate therapy is now offered to all women with a T score\u000d\u000a      of < -2.\u000d\u000a    The addition of bisphosphonates has led to a 5-fold reduction in fracture\u000d\u000a      rate to 0.5% annually in patients being treated with AIs. This change in\u000d\u000a      practice, adapted worldwide, has significantly decreased the morbidity and\u000d\u000a      suffering associated with the use of AIs in breast cancer.\u000d\u000a    HRT use after breast cancer treatment now contraindicated\u000d\u000a      The NICE guidelines recognise that Tibolone and HRT should not be\u000d\u000a      indicated for the vasomotor symptoms of women with breast cancer and,\u000d\u000a      importantly, that HRT is a less effective treatment than bisphosphonates\u000d\u000a      for women on AIs with breast cancer (S1).\u000d\u000a    The research has contributed to the discontinuation of HRT as a\u000d\u000a      therapeutic intervention after breast cancer diagnosis. HRT is\u000d\u000a      contraindicated for breast cancer patients with menopausal symptoms or\u000d\u000a      bone loss.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Aromatase inhibitors (AIs) significantly improve survival from breast\u000d\u000a      cancer but are associated with increases in osteoporotic fractures and\u000d\u000a      bone mineral density loss. Research at the University of Manchester (UoM)\u000d\u000a      has provided key evidence that has contributed to preventing debilitating\u000d\u000a      bone demineralisation safely in breast cancer patients undergoing adjuvant\u000d\u000a      therapy with AIs. UoM findings have led to an international consensus on\u000d\u000a      guidelines recommending Dual-energy X-ray Absorptiometry (DEXA) scanning\u000d\u000a      to identify patients at risk of bone loss as well as the use of\u000d\u000a      bisphosphonates where bone loss has been identified. Further guidelines\u000d\u000a      advise against the use of HRT to treat bone loss as a result of its\u000d\u000a      association with breast cancer recurrence.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF,\u000d\u000a      Hoctin-Boes G, Houghton J, Locker GY, Tobias JS. Results of the ATAC\u000d\u000a      (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5\u000d\u000a      years' adjuvant treatment for breast cancer. The Lancet.\u000d\u000a      2005;365(9453):60-2. DOI: 10.1016\/S0140-6736(04)17666-6\u000d\u000a    \u000a\u000a2. Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H,\u000d\u000a      Monnier A, Neven P, von Minckwitz G, Miller JC, Schenk NL, Coleman RE.\u000d\u000a      Effective inhibition of aromatase inhibitor-associated bone loss by\u000d\u000a      zoledronic acid in postmenopausal women with early breast cancer receiving\u000d\u000a      adjuvant letrozole: ZO-FAST study results. Cancer.\u000d\u000a      2008;112(5):1001-10. DOI: 10.1002\/cncr.23259\u000d\u000a    \u000a\u000a3. Kenemans P, Bundred NJ, Foidart J-M, Kubista E, von Schoultz\u000d\u000a      B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M,\u000d\u000a      Mulder R, van Os S, Beckmann MW. Safety and efficacy of tibolone in\u000d\u000a      breast-cancer patients with vasomotor symptoms: a double-blind,\u000d\u000a      randomised, non-inferiority trial. The Lancet Oncology.\u000d\u000a      2009;10(2):135-46. DOI: 10.1016\/S1470-2045(08)70341-3\u000d\u000a    \u000a\u000a4. Bundred NJ, Kenemans P, Yip CH, Beckmann MW, Foidart JM,\u000d\u000a      Sismondi P, Schoultz B, Vassilopoulou-Sellin R, Galta RE, Lieshout EV,\u000d\u000a      Mol-Arts M, Planellas J, Kubista E. Tibolone increases bone mineral\u000d\u000a      density but also relapse in breast cancer survivors: LIBERATE trial bone\u000d\u000a      substudy. Breast Cancer Research. 2012;14(1):R13. DOI:\u000d\u000a      10.1186\/bcr3097\u000d\u000a    \u000a\u000a5. Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson\u000d\u000a      N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R. Efficacy of\u000d\u000a      zoledronic acid in postmenopausal women with early breast cancer receiving\u000d\u000a      adjuvant letrozole: 36-month results of the ZO-FAST Study. Annals of\u000d\u000a        Oncology. 2010;21(11):2188-94. DOI: 10.1093\/annonc\/mdq217\u000d\u000a    \u000a\u000a6. Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J,\u000d\u000a      Beckmann MW, Coleman RE. Long-term effects of anastrozole on bone mineral\u000d\u000a      density: 7-year results from the ATAC trial. Annals of Oncology.\u000d\u000a      2011;22(4):857-62. DOI: 10.1093\/annonc\/mdq541\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    S1.NICE\/National Collaborating Centre for Cancer. Early and locally\u000d\u000a        advanced breast cancer: Diagnosis and treatment. CG80. London: NICE;\u000d\u000a      2009.\u000d\u000a    S2.Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey\u000d\u000a      EV, Powles T, Selby P, Coleman RE. Guidance for the management of breast\u000d\u000a      cancer treatment-induced bone loss: A consensus position statement from a\u000d\u000a      UK Expert Group. Cancer Treatment Reviews. 2008;34, Supplement\u000d\u000a      1(0):S3-S18.\u000d\u000a    S3.Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS,\u000d\u000a      Bosserman LD, Geoghegan C, Hillner BE, Theriault RL, Zuckerman DS, Von\u000d\u000a      Roenn JH. American Society of Clinical Oncology Executive Summary of the\u000d\u000a      Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in\u000d\u000a      Metastatic Breast Cancer. Journal of Clinical Oncology.\u000d\u000a      2011;29(9):1221-7.\u000d\u000a    S4.Gralow JR, Biermann JS, Farooki A, Fornier MN, Gagel RF, Kumar RN,\u000d\u000a      Shapiro CL, Shields A, Smith MR, Srinivas S, Van Poznak CH. NCCN Task\u000d\u000a      Force Report: Bone Health in Cancer Care. Journal of the National\u000d\u000a        Comprehensive Cancer Network. 2009;7(Suppl 3):S1-32.\u000d\u000a    S5.Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, et\u000d\u000a      al. Zoledronic Acid Inhibits Adjuvant Letrozole-Induced Bone Loss in\u000d\u000a      Postmenopausal Women With Early Breast Cancer. Journal of Clinical\u000d\u000a        Oncology. 2007 March 1, 2007;25(7):829-36.\u000d\u000a    S6.Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kässmann\u000d\u000a      H, Piswanger-Sölkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal\u000d\u000a      F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H,\u000d\u000a      Wohlmuth P, Mittlböck M, Jakesz R. Adjuvant endocrine therapy plus\u000d\u000a      zoledronic acid in premenopausal women with early-stage breast cancer:\u000d\u000a      5-year follow-up of the ABCSG-12 bone-mineral density substudy. The\u000d\u000a        Lancet Oncology. 2008;9(9):840-9. \u000d\u000a    ","Title":"\u000d\u000a    Preventing bone loss in patients treated for breast cancer\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000a    Background\u000d\u000a      Two large International trials, Arimidex Tamoxifen Adjuvant Combination\u000d\u000a      (ATAC) (1) and the Breast International Group (BIG) 1-98 Study (New\u000d\u000a        England Journal of Medicine, 353:2747-2757), confirmed the\u000d\u000a      superiority of non-steroidal aromatase inhibitors (AIs) used for five\u000d\u000a      years after surgery, compared with Tamoxifen, in preventing breast cancer\u000d\u000a      recurrence. The findings led to the widespread use of AIs internationally\u000d\u000a      and AIs are now the standard NICE approved treatment for breast cancer in\u000d\u000a      oestrogen receptor positive post-menopausal breast cancer cases (NICE, Early\u000a        and locally advanced breast cancer: Diagnosis and treatment, 2009).\u000d\u000a    Research on AIs, bone loss and osteoporotic fractures\u000d\u000a      Key UoM researchers:\u000d\u000a    \u000d\u000a      \u000aNigel Bundred (Senior Lecturer, 1991-1996; Reader, 1996-2001;\u000d\u000a        Professor, 2001-date)\u000d\u000a      \u000aAnthony Howell (Senior Lecturer, 1980-1997; Professor,\u000d\u000a        1997-date)\u000d\u000a    \u000d\u000a    Researchers at UoM led three studies (ATAC, ZO-FAST, LIBERATE) that\u000d\u000a      generated important insights around the association between AIs, bone loss\u000d\u000a      and osteoporotic fractures as well as evidence for optimal interventions\u000d\u000a      to prevent bone loss in those treated for breast cancer. Key findings:\u000d\u000a    \u000d\u000a      \u000aHowell (UK lead, ATAC) and Bundred (lead author, chief\u000d\u000a        investigator, ZO-FAST) demonstrated that the complications of using AIs\u000d\u000a        were increased bone loss and subsequent osteoporotic fractures on\u000d\u000a        treatment (1, 2).\u000d\u000a      \u000aBundred (lead author, chief investigator) led LIBERATE, the\u000d\u000a        largest international randomised controlled trial of HRT to prevent\u000d\u000a        menopausal symptoms and bone loss in breast cancer patients. Over 3000\u000d\u000a        women in 31 countries were recruited to LIBERATE. In the bone\u000d\u000a        mineralisation study within LIBERATE, 50% of post-menopausal women with\u000d\u000a        breast cancer were found to be osteopaenic or osteoporotic at diagnosis\u000d\u000a        (3, 4). HRT increased bone mineral density by 3% but also breast cancer\u000d\u000a        recurrence (3), mostly in patients with normal bone mineral density\u000d\u000a        (BMD). There was also a significant increase in breast tumour recurrence\u000d\u000a        in patients randomised to HRT, especially for patients on AIs.\u000d\u000a      Bisphosphonates had been shown to prevent bone loss in osteoporosis. Bundred\u000d\u000a        led research to study the effect of bisphosphonates in the setting of\u000d\u000a        hormone receptor positive patients with early breast cancer commencing\u000d\u000a        adjuvant AI therapy with Letrozole. The use of intravenous\u000d\u000a        bisphosphonates prevented bone loss and increased bone density (2).\u000d\u000a        Additionally, irrespective of BMD, there was a survival advantage for\u000d\u000a        those patients who commenced bisphosphonates from the start of\u000d\u000a        treatment, at analysis 60 months later (5, 6).\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"28033","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000aSee section 5 for corroborating sources S1-S7.\u000d\u000aContext\u000d\u000aDysphagia after stroke affects at least 40,000 patients annually in the UK alone, increases\u000d\u000amortality (x2.7 relative risk of death) and prolongs hospital bed stay by 10 days. The consequence\u000d\u000ais that dysphagia in stroke has an estimated £400m cost burden to the NHS each year. Despite\u000d\u000athis, the treatment of swallowing problems remains difficult, with very few treatments being shown\u000d\u000ato have any major effect on swallowing disability (S1).\u000d\u000aThe general goals in dysphagia therapy are to reduce the morbidity and mortality associated with\u000d\u000aaspiration and chest infections (6% of all strokes), improve nutritional status and return patients to\u000d\u000aa normal diet with resultant reductions in complications and improvement of quality of life. This is\u000d\u000arecognised in the UK National Stroke Strategy (2007), in which the aim of `the life after stroke'\u000d\u000astrategy section is for patients to `achieve a good quality of life and maximise independence, well-being and choices' (S2). The report goes on to identify seven target outcomes that contribute to\u000d\u000aachieving this goal. Restoration of swallowing function has the highest impact in almost all of the\u000d\u000aseven outcomes identified.\u000d\u000aPathways to impact\u000d\u000aFrom these observations, the innovation was created and has progressed to an automated\u000d\u000abedside, patient-friendly, battery operated intra-luminal throat (pharyngeal) stimulator for use in\u000d\u000apatients.\u000d\u000aTwo patent applications for the UK and Europe have been approved. Through a spin out company\u000d\u000a(Phagenesis Ltd — see below), the innovation has started to lead to improved patient outcome,\u000d\u000ashorter hospital stays, and significant financial savings for the NHS. An analysis of phase 2 study\u000d\u000adata shows that pharyngeal stimulation produces a 25% reduction in aspiration compared with\u000d\u000astandard therapy and that catheters are well tolerated by patients and are easily operated by\u000d\u000acarers.\u000d\u000aReach and significance of the impact\u000d\u000aResearch at UoM funded by MRC and then NIHR RfPB has led to new evidence that pharyngeal\u000d\u000astimulation is an effective treatment in stroke. Over the last 7 years, in collaboration with the\u000d\u000aUniversity of Manchester Intellectual Property Ltd, Hamdy has become the clinical scientific officer\u000d\u000aof a UMIP spin out company, Phagenesis Ltd (S3).\u000d\u000aFunded initially by £220,000 of pump priming venture capital money from UMIP and The Liverpool\u000d\u000aSeed Fund, Merseyside Investment Group, Phagenesis Limited is now managing and leading the\u000d\u000aprogramme of work in the area. As industry lead, Phagenesis is now managing and delivering the\u000d\u000acommercial business based on the technology. Indeed, the company entered into an exclusive\u000d\u000afunding round arrangement with Angloscientific in 2010, a technology based investment company,\u000d\u000aand has secured 2 tranches of finance.\u000d\u000aPhagenesis Ltd, having successfully raised ~£10m in VC funding, has now commenced\u000d\u000aimplementation of the technology (PhagenyxTM), gained CE marking in 2012 (S4), has been\u000d\u000aawarded the BioNow healthcare product of the year 2012 and is achieving sales in the UK, Europe\u000d\u000aand the Middle East. The medical technologies panel of NICE and Health Horizons are currently\u000d\u000alooking at the product with a view to providing the NHS with clinical recommendations (S5-7). Over\u000d\u000a100 patients have now been treated. Sales are now estimated at £2m with orders from the Middle\u000d\u000aEast (£1.5m), UK Hospitals (£0.25m), RoI (£0.3m) and Germany (£0.1m).\u000d\u000a","ImpactSummary":"\u000d\u000aDysphagia affects >50% of stroke patients with increased risk of aspiration and pneumonia,\u000d\u000acosting the NHS approximately £400m pa. Until recently there has been no effective treatment.\u000d\u000aOver the last 15 years, Hamdy has identified the mechanisms underlying dysphagia after stroke\u000d\u000aand demonstrated that electrostimulation delivered to the pharynx dramatically alters brain regions\u000d\u000acontrolling swallowing beneficially. This work has gone through extensive clinical evaluation and\u000d\u000aforms the basis of a company, Phagenesis Ltd (~£10m VC funding), which has now commenced\u000d\u000aimplementation of the technology (PhagenyxTM), gained CE marking and has sold >£2.0m of\u000d\u000aproduct in the UK, Europe and the Middle East.\u000d\u000a","ImpactType":"Health","Institution":"\u000d\u000aThe University of Manchester\u000d\u000a","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000aBelow is a list in sequence of the 6 key references that have led to the implementation of\u000d\u000apharyngeal stimulation in stroke patients.\u000d\u000a\u000a1. Hamdy S, Aziz Q, Rothwell JC, Singh K, Barlow J, Hughes DG, Tallis RC, Thompson DG.\u000d\u000aThe Cortical Topography of Human Swallowing Musculature in Health and Disease. Nature\u000d\u000aMedicine. 1996;2(11):1217-1224. DOI: 10.1038\/nm1196-1217\u000d\u000a\u000a\u000a2. Hamdy S, Aziz Q, Rothwell JC, Crone R, Hughes DG, Tallis RC, Thompson DG. Explaining\u000d\u000aOro-pharyngeal Dysphagia after Unilateral Hemispheric Stroke. Lancet. 1997;350:686-692.\u000d\u000aDOI: 10.1016\/S0140-6736(97)02068-0\u000d\u000a\u000a\u000a3. Hamdy S, Aziz Q, Rothwell JC, Power M, Singh K, Nicholson DA, Tallis RC, Thompson DG.\u000d\u000aRecovery of Swallowing after Dysphagic Stroke Relates to Functional Reorganisation in Intact\u000d\u000aMotor Cortex. Gastroenterology. 1998;115:1104-1112. DOI: 10.1016\/S0016-5085(98)70081-2\u000d\u000a\u000a\u000a4. Hamdy S, Rothwell JC, Aziz Q, Singh K, Thompson DG. Long-Term Reorganisation of\u000d\u000aHuman Motor Cortex Driven by Short-Term Sensory Stimulation. Nature Neuroscience\u000d\u000a1998;1(1):64-68. DOI: 10.1038\/264\u000d\u000a\u000a\u000a5. Fraser C, Hamdy S, Power M, Rothwell JC, Tyrell P, Hollander I, Hobday D, Williams S,\u000d\u000aJackson A, Thompson DG. Driving Plasticity in Adult Human Motor Cortex Improves\u000d\u000aFunctional Performance after Cerebral Injury. Neuron. 2002;34:831-840. DOI: 10.1016\/S0896-6273(02)00705-5\u000d\u000a\u000a\u000a6. Jayasekeran V, Singh S, Rothwell JC, Tyrrell P, Mistry S, Jefferson S, Michou E, Gamble\u000d\u000aE, Thompson DG, Hamdy S. Adjunctive functional pharyngeal electrical stimulation reverses\u000d\u000aswallowing disability following brain lesions. Gastroenterology. 2010;138:1737-1746. DOI:\u000d\u000a10.1053\/j.gastro.2010.01.052\u000d\u000a\u000aKey Grants\u000d\u000a1. Studies of dysphagia following hemispheric stroke using transcranial magnetic stimulation:\u000d\u000aassessment of pathophysiology, mechanisms of recovery and outcome. Stroke Association.\u000d\u000a1994-1996. £150k. Awarded to David Thompson, UoM.\u000d\u000a2. Exploring mechanisms of dysphagia in brain injury. MRC. 1996-1999. £280k. Awarded to\u000d\u000aDavid Thompson, UoM.\u000d\u000a3. Characterisation, modulation and therapeutic application of neuroplasticity within human\u000d\u000acerebral cortex in health and after brain injury. MRC Clinician Scientist Fellowship. 2000-2004. £600k. Awarded to Shaheen Hamdy, UoM.\u000d\u000a4. Exploring the functional, behavioural and neurochemical correlates of stimulus-induced\u000d\u000acortical plasticity in health and stroke. MRC. 2004-2006. £220k. Awarded to Shaheen\u000d\u000aHamdy, UoM.\u000d\u000a5. Imaging the neuroanatomical, functional and behavioural substrates of cortical swallowing\u000d\u000aorganization. Wellcome Trust. 2007-2010.£260k. Awarded to Shaheen Hamdy, UoM.\u000d\u000a6. A randomised controlled trial of pharyngeal electrical stimulation in the treatment of dysphagia\u000d\u000aafter brain injury. NIHR Research for Patient Benefit Scheme. 2009-2013. £265k. Awarded to\u000d\u000aShaheen Hamdy, UoM.\u000d\u000a7. Design and implementation of electrical pharyngeal stimulation in chronic dysphagic stroke.\u000d\u000aWellcome Trust. 2011-2014. £990k. Awarded to Daniel Green, CEO of Phagenesis.\u000d\u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000aS1.Geeganage C, Beavan J, Ellender S, Bath Philip MW. Interventions for dysphagia and\u000d\u000anutritional support in acute and subacute stroke. Cochrane Database of Systematic Reviews.\u000d\u000a2012; (10). DOI: 10.1002\/14651858.CD000323.pub2\u000d\u000aS2.Department of Health. National Stroke Strategy. 2007 (p. 34) Available from:\u000d\u000ahttp:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consu\u000d\u000am_dh\/groups\/dh_digitalassets\/documents\/digitalasset\/dh_081059.pdf\u000d\u000aS3.http:\/\/www.phagenesis.com\/\u000d\u000aS4.CE marking certificate, awarded July 2012.\u000d\u000aS5.Reuters, Electric stimulation may help stroke victims swallow, 24 Feb 2010\u000d\u000ahttp:\/\/www.reuters.com\/article\/2010\/02\/24\/us-electric-stimulation-idUSTRE61N5X320100224?feedType=RSS&feedName=healthNews&utm_source=twitterfeed&ut\u000d\u000am_medium=twitter&utm_campaign=Feed%3A+reuters%2FhealthNews+%28News+%2F+US+%2F\u000d\u000a+Health+News%29amp;utm_content=Twitter\u000d\u000aS6.Letter from Professor of Stroke Medicine, King's College London.\u000d\u000aS7.Letter from Professor of Stroke Medicine, University of Edinburgh.\u000d\u000a\u000d\u000a","Title":"\u000d\u000aDesign and implementation of a new treatment for dysphagia after stroke\u000d\u000a","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aSee section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000aResearch activity was carried out from 1996 to the present. Key researchers at UoM:\u000d\u000a\u000d\u000a\u000aDavid Thompson (Professor of Gastroenterology, 1996-date)\u000d\u000a\u000aShaheen Hamdy (MRC Clinician Scientist, 2000-2005; Professor of\u000d\u000aNeurogastroenterology, 2010-date)\u000d\u000a\u000aQasim Aziz (Clinical Research Fellow, 1991-1994; Clinical Lecturer, 1994-1998; Clinical\u000d\u000aResearch Fellow, 2000-2002; Senior Lecturer, 2002-2006; Honorary Professor, 2006-2009)\u000d\u000a\u000d\u000aDetails of the research innovation\u000d\u000aSwallowing problems (dysphagia) after stroke result in major morbidity and mortality yet the\u000d\u000atreatments available are both disappointing in terms of efficacy and lacking in terms of scientific\u000d\u000aevidence. The research was developed to revolutionise the management of swallowing after\u000d\u000adysphagic stroke. The initial phases of the research are described below:\u000d\u000a\u000d\u000a The cortical organisation of swallowing in health\u000d\u000aThis research demonstrated that the swallowing muscles are arranged in separate areas on\u000d\u000athe motor strip, with the oral muscles most lateral and the pharynx and oesophagus more\u000d\u000amedial. However, the most important finding was that in the majority of individuals, one or other\u000d\u000ahemispheres tended have dominant swallowing representation, independent of handedness\u000d\u000a(1).\u000d\u000a Mechanisms for dysphagia after stroke\u000d\u000aThis research showed that although activity in the stroke damaged hemisphere was reduced or\u000d\u000aabsent in most stroke victims, activity in the undamaged hemisphere was greater in the non-dysphagic\u000d\u000athan in the dysphagic patients. Thus, the size of the hemispheric projection to\u000d\u000aswallowing muscles could determine the presence or absence of dysphagia, supporting the\u000d\u000aconcept of cerebral dominance for swallowing (2).\u000d\u000a Mechanisms for swallowing recovery after brain injury\u000d\u000aThis research explored the mechanisms of recovery from dysphagia by mapping changes in\u000d\u000aswallowing representation in a large series of dysphagic stroke patients over several months.\u000d\u000aIn those who recovered swallowing, the area of pharyngeal representation on the unaffected\u000d\u000ahemisphere increased markedly, suggesting that the recovery depends on the increasing\u000d\u000aactivity in intact pathways in undamaged hemisphere (i.e. compensatory reorganisation) (3).\u000d\u000a Inducing reorganisation in swallowing motor cortex\u000d\u000aThis research examined the role of peripheral pharyngeal stimulation as a means of\u000d\u000aaccelerating swallowing reorganisation and recovery. The work was able to show that\u000d\u000aprolonged electrical stimulation of the pharynx can induce immediate and sustained changes in\u000d\u000acortical swallowing excitability (4).\u000d\u000a Peripheral stimulation and plasticity associated with changes in swallowing behaviour\u000d\u000aThis research identified the parameters for optimal excitation of the cortical swallowing\u000d\u000apathways (i.e. 10 minutes of 5Hz of pharyngeal electrical stimulation at 75% of that maximally\u000d\u000atolerated). Critically, when applied to stroke patients, this was associated with an improvement\u000d\u000ain swallowing using objective measures. The implication from these results was that input to\u000d\u000athe human adult brain can be programmed to promote beneficial changes in plasticity that\u000d\u000aresult in an improvement of function after stroke (5, 6).\u000d\u000a\u000d\u000a"},{"CaseStudyId":"28034","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S10.\u000d\u000a    Context and pathways to impact\u000d\u000a    Statistics published by DUK show that CVD is the cause of death in 52% of\u000d\u000a      people with type 2 diabetes and 44% with type 1. Within 5 years of its\u000d\u000a      onset (and many people are not diagnosed until then) CVD risk in type 2\u000d\u000a      diabetes is the same as in non-diabetic people who have already had a\u000d\u000a      myocardial infarction. The additional risk is higher still in diabetic\u000d\u000a      compared with non-diabetic women. Within 5 years of diagnosis stroke risk\u000d\u000a      is doubled. The publication of CARDS in 2004 (1) therefore attracted great\u000d\u000a      interest both in scientific journals and lay press. The initial Lancet\u000d\u000a      report has over 2500 citations, and DUK set new target levels of LDL\u000d\u000a      cholesterol of <2mmol\/l, to be achieved with statins if necessary,\u000d\u000a      which were widely broadcast.\u000d\u000a    Reach and significance of the impact\u000d\u000a    Impact on national and international clinical guidelines\u000d\u000a    Following publication of the findings, DUK rapidly ensured that new\u000d\u000a      guidelines for statin use in diabetes were incorporated in the Joint\u000d\u000a      British Societies second recommendations (JBS2, 2005) (S1). The\u000d\u000a      recommendations state that all type 2 diabetic patients aged ≥40 years\u000d\u000a      (and also some younger patients with particularly adverse risk factors)\u000d\u000a      should receive statin treatment to achieve an LDL cholesterol <2mmo\/l.\u000d\u000a      The DUK recommendations were further extrapolated to include type 1\u000d\u000a      diabetes, but this was on the basis of their CVD risk and the practicality\u000d\u000a      of implementation when the distinction between the two types was often\u000d\u000a      blurred in general practice.\u000d\u000a    The British Heart Foundation endorsed the JBS2 recommendation (S2), but\u000d\u000a      the Association of British Clinical Diabetologists (ABCD) was one of a\u000d\u000a      number of groups to challenge the CARDS conclusions. The arguments were\u000d\u000a      that the patients randomised in CARDS were atypical, particularly in their\u000d\u000a      high CVD risk. In fact, they were subsequently shown to be at high risk,\u000d\u000a      but no more than typical diabetic patients. There was initial reluctance\u000d\u000a      to accept that an apparently low LDL cholesterol target for statin\u000d\u000a      treatment was justified by CARDS. In fact, in CARDS the mean LDL\u000d\u000a      cholesterol had been decreased from around 3mmol\/l (the average in\u000d\u000a      middle-aged Britons is 3.7mmol\/l) to under 2mmol\/l.\u000d\u000a    These arguments were overcome and the guidance issued by ABCD, NICE and\u000d\u000a      SIGN (2007-2010) (S3, S4) is essentially the same as JBS2\u000d\u000a      (S1). The guidance was strengthened by a meta-analysis by Kearney and\u000d\u000a      colleagues largely drawing on data from CARDS and the Heart Protection\u000d\u000a      Study, which was a mixed primary and secondary trial of the less effective\u000d\u000a      simvastatin, and which included a diabetic cohort (S5).\u000d\u000a    North American guidelines were modified to take account of the new\u000d\u000a      evidence provided by CARDS (S6) and European recommendations rapidly\u000d\u000a      followed (S7, S8).\u000d\u000a    Improved management of diabetes\u000d\u000a    The acceptance of the CARDS findings is now universal and statins are an\u000d\u000a      essential part of diabetic management. Indeed statin targets are generally\u000d\u000a      easier to achieve than recommended goals for glycaemia or blood pressure.\u000d\u000a      Proof of benefit and evidence of cost-effectiveness is stronger for statin\u000d\u000a      therapy than any other aspect of type 2 diabetes management (S9).\u000d\u000a    The full impact of CARDS on global health is difficult to evaluate\u000d\u000a      precisely, but it is likely to be vast. Many of the 400 million people\u000d\u000a      with diabetes globally inhabit countries that are not affluent. However,\u000d\u000a      now that both simvastatin and atorvastatin are out of patent, many more of\u000d\u000a      the 2 million CVD deaths occurring annually in diabetes worldwide should\u000d\u000a      be preventable (S10).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The Collaborative Atorvastatin Diabetes Study (2004), led by researchers\u000d\u000a      at the University of Manchester (UoM), established the efficacy of statin\u000d\u000a      therapy in the prevention of atherosclerotic cardiovascular disease (CVD)\u000d\u000a      among patients with diabetes. The research challenged the previously held\u000d\u000a      view that, since CVD risk is markedly raised in people with diabetes even\u000d\u000a      when blood cholesterol levels are normal, statins were unlikely to be\u000d\u000a      beneficial for this group. These key findings have informed clinical\u000d\u000a      guidelines governing the use of statin therapy in the UK (NICE, SIGN) and\u000d\u000a      internationally (American Heart Association and the American Diabetes\u000d\u000a      Association, ESC, EAS), ensuring that statins are now considered for all\u000d\u000a      diabetic patients.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,\u000d\u000a      Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V,\u000d\u000a      Fuller JH on behalf of the CARDS Investigators. Primary prevention of\u000d\u000a      cardiovascular disease with atorvastatin in Type 2 diabetes in the\u000d\u000a      Collaborative Atorvastatin Diabetes Study (CARDS); a multicentre\u000d\u000a      randomised placebo controlled trial. Lancet. 2004; 364: 685-96.\u000d\u000a      DOI: 10.1016\/S0140-6736(04)16895-5\u000d\u000a    \u000a\u000a2. Colhoun H, Betteridge DJ, Durrington PN et al. Rapid emergence\u000d\u000a      of effect of atorvastatin on cardiovascular outcomes in the Collaborative\u000d\u000a      Atorvastatin Diabetes Study (CARDS). Diabetologia. 2005; 48:\u000d\u000a      2482-2485. DOI: 10.1007\/s00125-005-0029-y\u000d\u000a    \u000a\u000a3. Raikou M., McGuire A., Colhoun HM, Betteridge DJ, Durrington PN,\u000d\u000a      Hitman GA, Neil HAW, Livingstone SJ, Charlton-Menys V, Fuller JH.\u000d\u000a      Cost effectiveness of primary prevention of CVD with atorvastatin in type\u000d\u000a      2 diabetes: results from the Collaborative Atorvastatin Diabetes, Study\u000d\u000a      (CARDS). Diabetologia. 2007; 50: 733-740. DOI:\u000d\u000a      10.1007\/s00125-006-0561-4\u000d\u000a    \u000a\u000a4. Charlton-Menys\u000a          V, Betteridge DJ, Colhoun H, Fuller J, France M, Hitman\u000d\u000a        GA, Livingstone SJ, Neil HA, Newman CB, Szarek M, Demicco DA, Durrington\u000a          PN. Apolipoproteins, cardiovascular risk and statin response\u000d\u000a      in type 2 diabetes: the Collaborative Atorvastatin Diabetes Study (CARDS).\u000d\u000a      Diabetologia. 2009; 52: 218-225. DOI: 10.1007\/s00125-008-1176-8\u000d\u000a    \u000a\u000a5. Charlton-Menys V, Betteridge DJ, Colhoun H, Fuller J, France\u000a        M, Hitman GA, Livingstone SJ, Neil HA, Newman CB, Szarek M, DeMicco\u000d\u000a      DA, Durrington PN. Targets\u000a        of statin therapy: LDL cholesterol, non-HDL cholesterol, and\u000d\u000a        apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin\u000d\u000a        Diabetes Study (CARDS). Clinical Chemistry. 2009;55:473-80.\u000d\u000a      DOI: 10.1373\/clinchem.2008.111401\u000d\u000a    \u000a\u000a6. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,\u000d\u000a      Livingstone SJ, Charlton- Menys V, Demicco DA, Fuller JH; CARDS\u000d\u000a      Investigators. Effects\u000a        of Atorvastatin on Kidney Outcomes and Cardiovascular Disease in\u000d\u000a        Patients with Diabetes: An Analysis from the Collaborative Atorvastatin\u000d\u000a        Diabetes Study (CARDS). American Journal of Kidney Diseases.\u000d\u000a      2009; 54: 810-819. DOI: 10.1053\/j.ajkd.2009.03.022\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    S1.Joint British Societies' Guidelines on Prevention of Cardiovascular\u000d\u000a      Disease in Clinical Practice (JBS2). Heart. 2005; 91 Suppl V: 1-52\u000d\u000a      DOI: 10.1136\/hrt.2005.079988\u000d\u000a    S2.British Heart Foundation Factfile Jan 2006: Joint British Societies'\u000d\u000a      Guidelines on Prevention of Cardiovascular Disease in Clinical Practice:\u000d\u000a      Risk Assessment. http:\/\/www.bhsoc.org\/files\/5013\/3363\/9191\/Factfile_2006_JBS2_Guidelines_on_the_Prevention_of_Cardiovascular_Disease_in_Clinical_Practice.pdf\u000d\u000a    S3.Feher MD, Winocour PH. On behalf of the Association of British\u000d\u000a      Clinical Diabetologists (ABCD). ABCD position statement on lipid modifying\u000d\u000a      drug therapy in diabetes. Practical Diabetes International. 2007;\u000d\u000a      24: 458-462 (published jointly with Scottish Intercollegiate Guidelines\u000d\u000a      Network). See SIGN 116 Management of diabetes. Summary of recommendations.\u000d\u000a      http:\/\/www.sign.ac.uk\/guidelines\/fulltext\/116\/index.html).\u000d\u000a    S4.National Institute for Health and Clinical Excellence (NICE) clinical\u000d\u000a      guideline 67. Lipid modification. Cardiovascular risk assessment and the\u000d\u000a      modification of blood lipids for the primary and secondary prevention of\u000d\u000a      cardiovascular disease. Developed by the National Collaborating Centre for\u000d\u000a      Primary Care. Issue date: May 2008 (reissued March 2010) http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG67NICEguideline.pdf\u000d\u000a    S5.Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Baigent C,\u000d\u000a      Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of\u000d\u000a      cholesterol-lowering therapy in 18,686 people with diabetes in 14\u000d\u000a      randomised trials of statins: a meta-analysis. Lancet. 2008; 371:\u000d\u000a      117-25. DOI: 10.1016\/S0140-6736(08)60104-X\u000d\u000a    S6.Buse JB., Ginsberg HN., Bakris GL et al. Primary prevention of\u000d\u000a      cardiovascular disease in people with diabetes mellitus: a scientific\u000d\u000a      statement from the American Heart Association and the American Diabetes\u000d\u000a      Association. Circulation. 2007; 115: 114-126 DOI: 10.1161\/\u000d\u000a      CIRCULATIONAHA.106.179294\u000d\u000a    S7.Graham\u000a        I Atar D, Borch-Johnsen K et al. European guidelines on\u000d\u000a      cardiovascular disease prevention in clinical practice: executive summary.\u000d\u000a      Fourth\u000d\u000a        Joint Task Force of the European Society of Cardiology and Other\u000d\u000a        Societies on Cardiovascular Disease Prevention in Clinical Practice. European\u000d\u000a          Heart Journal. 2007;28: 2375-2414. DOI:\u000d\u000a      10.1093\/eurheartj\/ehm316\u000d\u000a    S8.Catapano AL et al. ESC\/EAS Guidelines for the management of\u000d\u000a      dyslipidaemias, The Task Force for the management of dyslipidaemias of the\u000d\u000a      European Society of Cardiology (ESC) and the European Atherosclerosis\u000d\u000a      Society (EAS). European Heart Journal. 2011; 32: 1769-818 DOI:\u000d\u000a      10.1093\/eurheartj\/ehr158 and Atherosclerosis. 2011; 217: 3-46.\u000d\u000a    S9.Annemanns L, Marbaix S, Webb K et al. Cost effectiveness of\u000d\u000a      atorvastatin in patients with type 2 diabetes mellitus: a pharmacoeconomic\u000d\u000a      analysis of the collaborative atorvastatin diabetes study in the Belgian\u000d\u000a      population. Clinical Drug Investigation. 2010; 30: 133-42. DOI:\u000d\u000a      10.2165\/11531910-000000000-00000\u000d\u000a    S10.International Diabetes Federation. Global Guideline for Type 2\u000d\u000a      Diabetes (2012). www.idf.org\/sites\/default\/files\/IDF-Guideline-for-Type-2-Diabetes.pdf\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved management of population cardiovascular risk in diabetic\u000d\u000a      patients\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000a    Background\u000d\u000a    A number of trials (e.g., Scandinavian Simvastatin Survival Study, Lancet\u000d\u000a      1994) established the value of statins in preventing CVD in non-diabetic\u000d\u000a      patients. However, diabetologists were reluctant to extrapolate this\u000d\u000a      evidence to diabetic patients because diabetes does not typically cause\u000d\u000a      raised cholesterol. In addition there were earlier adverse experiences\u000d\u000a      with less effective and possibly harmful lipid-lowering medication and a\u000d\u000a      disinclination to add to complex treatment regimens for glycaemia and\u000d\u000a      blood pressure control.\u000d\u000a    Collaborative Atorvastatin Diabetes Study (CARDS)\u000d\u000a    Key researchers at UoM:\u000d\u000a    \u000d\u000a      \u000aPaul Durrington (Professor of Medicine, 1995-2009; Honorary\u000d\u000a        Professor of Medicine, 2009-date)\u000d\u000a      \u000aMichael Mackness (Research Fellow, 1998-1999; Lecturer,\u000d\u000a        1999-2002; Senior Research Fellow, 2002-2003; Reader, 2003-2008)\u000d\u000a      \u000aValentine Charlton-Menys (Research Associate, 1999-2010)\u000d\u000a      \u000aMichael France (Honorary Lecturer, 2007-date)\u000d\u000a    \u000d\u000a    Durrington and Fuller (University of London) raised funding from\u000d\u000a      Diabetes UK (DUK) to convene a committee to design a trial of lipid\u000d\u000a      lowering specifically in type 2 diabetes. The committee comprised the\u000d\u000a      Director of R and D from DUK, a representative of the Department of Health\u000d\u000a      (DH), Neil (Oxford), Hitman (London) and Betteridge (London). A large,\u000d\u000a      scientifically rigorous trial was designed, with substantial funding\u000d\u000a      provided by industry as well as DH and DUK. Parke Davies provided funding,\u000d\u000a      atorvastatin and placebo. Durrington led the central laboratory,\u000d\u000a      which was managed initially by Mackness and later by Charlton-Menys.\u000d\u000a      Durrington also joined the Steering Committee.\u000d\u000a    After a pilot investigation in secondary prevention, the key trial to\u000d\u000a      test the hypothesis that in primary prevention a statin could decrease CVD\u000d\u000a      risk began in 1998. By then, it was becoming obvious from transnational\u000d\u000a      epidemiology that there was no lower threshold below which low-density\u000d\u000a      lipoprotein (LDL) ceased to be a risk factor for CVD. Therefore the target\u000d\u000a      of the new primary prevention study was aimed at patients with lower LDL\u000d\u000a      levels. The participants were 2838 type 2 diabetic patients with LDL\u000d\u000a      cholesterol ≤4.14mmol\/l and no clinical evidence of CVD, attending 132\u000d\u000a      centres in the UK and Ireland. They had at least one risk factor for CVD\u000d\u000a      besides diabetes, most commonly mild hypertension.\u000d\u000a    Key findings:\u000d\u000a    \u000d\u000a      The trial was terminated in 2003 after 3.9 years (2 years early) by\u000d\u000a        the Safety Monitoring Committee because of a substantial highly\u000d\u000a        significant lower CVD event rate on the active treatment.\u000d\u000a      The mean pre-treatment LDL cholesterol was 3mmol\/l and the average\u000d\u000a        decrease on atorvastatin was 1.2mmol\/l (1). This produced a 37% decrease\u000d\u000a        in CVD incidence (P<0.001) due to reductions of 36% in acute coronary\u000d\u000a        events, 31% in coronary revascularisation and 48% in stroke (2-5).\u000d\u000a      All-cause mortality declined by 27%, which just failed to reach\u000d\u000a        statistical significance (P=0.059) for the whole trial, but was highly\u000d\u000a        significant in its final year (2).\u000d\u000a      Adverse active treatment effects were no more frequent than on placebo\u000d\u000a        (for example, albuminuria incidence was not increased, 6).\u000d\u000a    \u000d\u000a    The CARDS database and biobank (created in Manchester), which includes DNA,\u000d\u000a    serum and urine, continues to generate significant scientific findings about\u000d\u000a    aspects of atherosclerosis and metabolic responses to statin treatment.\u000d\u000a    "},{"CaseStudyId":"28035","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S4.\u000d\u000a    Context\u000d\u000a      Cervical screening has been based on cytology (`cervical smear') for over\u000d\u000a      50 years. Its principal\u000d\u000a      strength is its specificity in detecting precancerous cells, but its\u000d\u000a      sensitivity is thought to be in the\u000d\u000a      range of 50-80%. Testing for human papillomavirus, the cause of cervical\u000d\u000a      cancer, is more sensitive\u000d\u000a      whether in population screening or testing for residual disease following\u000d\u000a      treatment. The hypothesis\u000d\u000a      behind these studies was that HPV negative women are at very low risk,\u000d\u000a      whereas further\u000d\u000a      investigation can be concentrated on HPV positive women who are at risk of\u000d\u000a      developing cervical\u000d\u000a      neoplasia.\u000d\u000a    Pathway to Impact\u000d\u000a      The robustness of the findings of these studies was critical to the\u000d\u000a      decisions made by the Advisory\u000d\u000a      Committee for Cervical Screening who make recommendations to Ministers on\u000d\u000a      changes to the\u000d\u000a      Cervical Screening Programme.\u000d\u000a    Reach and Significance of the Impact\u000d\u000a      The results of these studies have fed directly into NHS policy in the\u000d\u000a      following ways:\u000d\u000a    \u000d\u000a      The ARTISTIC Trial directly influenced the decision to establish a\u000d\u000a        large HPV primary screening\u000d\u000a        pilot study which began in the second quarter of 2013. The notes of the\u000d\u000a        UK National Screening\u000d\u000a        Committee (UK NSC) meeting held on 25 April 2012 demonstrate that\u000d\u000a        ARTISTIC informed the\u000d\u000a        Committee's decision-making: `Members were asked about the\u000d\u000a        cost-effectiveness of HPV\u000d\u000a        TaPS [Testing as Primary Screening]. [Committee member] said the\u000d\u000a        ARTISTIC trial had looked\u000d\u000a        at both clinical and cost effectiveness but further modelling would be\u000d\u000a        needed as part of the\u000d\u000a        feasibility study. The UK NSC agreed that there is enough evidence to\u000d\u000a        suggest that HPV TaPS\u000d\u000a        would be cost and clinically effective. It was agreed that the UK NSC\u000d\u000a        should consult on a\u000d\u000a        recommendation to approve HPV as a primary screen for cervical cancer\u000d\u000a        and that the\u000d\u000a        feasibility study should explore implementation issues including length\u000d\u000a        of time before a re-screen\u000d\u000a        following a HPV negative result.' (S1, p. 7)\u000d\u000a      The MAVARIC Trial directly influenced the decision not to adopt\u000d\u000a        automated reading of cervical\u000d\u000a        cytology in England, because it was less sensitive than manual reading\u000d\u000a        (S2). The `No further\u000d\u000a        review' facility of the BD Systems was shown to be reliable and its use\u000d\u000a        endorsed by the\u000d\u000a        Advisory Committee for Cervical Screening (S3). The international reach\u000d\u000a        of this study is\u000d\u000a        exemplified by the findings having been accepted by the Health Council\u000d\u000a        of the Netherlands,\u000d\u000a        who have rejected automated screening (S4).\u000d\u000a      The favourable results of the test of cure study (6) directly\u000d\u000a        influenced the decision to initiate\u000d\u000a        HPV test of cure as standard in the cervical screening programme in\u000d\u000a        England.\u000d\u000a    \u000d\u000a    Kitchener has contributed significantly to the Cervical Screening\u000d\u000a      Programme in other ways. He\u000d\u000a      chairs the Department of Health Advisory Committee for Cervical Screening,\u000d\u000a      which advises\u000d\u000a      Government on the direction of the Programme. He also chaired the Steering\u000d\u000a      Group of the pilot\u000d\u000a      studies of HPV triage and test of cure, both of which are being rolled out\u000d\u000a      nationally in 2011\/12. He\u000d\u000a      now chairs the Steering Group for the HPV primary screening pilot studies,\u000d\u000a      which have received\u000d\u000a      National Screening Committee and Ministerial approval and commenced in the\u000d\u000a      English Screening\u000d\u000a      Programme in the second quarter of 2013.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The results of two major randomised trials and a cohort study based at\u000d\u000a      the University of\u000d\u000a      Manchester (UoM) have had a major impact on cervical screening in the UK\u000d\u000a      and influenced\u000d\u000a      thinking internationally. These trials evaluated two technologies which\u000d\u000a      had the potential to improve\u000d\u000a      cervical screening. As a result HPV primary screening has moved to a large\u000d\u000a      national pilot study.\u000d\u000a      HPV as a test of cure following treatment of cervical precancerous lesions\u000d\u000a      has now been adopted\u000d\u000a      as standard across the National Screening Programme. Automation assisted\u000d\u000a      technology, which\u000d\u000a      was shown to be inferior to manually read cytology, will not be adopted.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A,\u000d\u000a      Stoykova B, Gilham C,\u000d\u000a      Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner\u000d\u000a      A, Moss S, Peto J.\u000d\u000a      HPV testing in combination with liquid-based cytology in primary cervical\u000d\u000a      screening\u000d\u000a      (ARTISTIC): a randomised controlled trial. Lancet Oncology.\u000d\u000a      2009;10(7):672-82.\u000d\u000a      DOI: 10.1016\/S1470-2045(09)70156-1\u000d\u000a    \u000a\u000a2. HTA Monograph:\u000d\u000a      Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B. ARTISTIC: a\u000d\u000a      randomised trial\u000d\u000a      of human papillomavirus (HPV) testing in primary cervical screening. Health\u000d\u000a        Technology\u000d\u000a        Assessment. 2009;13(51):150.\u000d\u000a      DOI: 10.3310\/hta13510\u000d\u000a    \u000a\u000a3. Kitchener HC, Gilham C, Sargent A, Bailey A, Albrow R, Roberts\u000d\u000a        C, Desai M, Mather J,\u000d\u000a      Turner A, Moss S, Peto J. A comparison of HPV DNA testing and liquid based\u000d\u000a      cytology\u000d\u000a      over three rounds of primary cervical screening: Extended follow up in the\u000d\u000a      ARTISTIC trial.\u000d\u000a      European Journal of Cancer. 2011;47(6):864-71.\u000d\u000a      DOI: 10.1016\/j.ejca.2011.01.008\u000d\u000a    \u000a\u000a4. Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener\u000d\u000a        H, Segnan N,\u000d\u000a      Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ; the International\u000d\u000a      HPV screening\u000d\u000a      working group. Efficacy of HPV-based screening for prevention of invasive\u000d\u000a      cervical cancer:\u000d\u000a      follow-up of four European randomised controlled trials. Lancet. 2013 Nov\u000d\u000a      1. pii: S0140-6736(13)62218-7.\u000d\u000a      doi: 10.1016\/S0140-6736(13)62218-7. [Epub ahead of print]\u000d\u000a    \u000a\u000a5. MAVARIC:\u000d\u000a      Kitchener HC, Blanks R, Dunn G, Gunn L, Desai M, Albrow R,\u000d\u000a      Mather J, Rana DN, Cubie\u000d\u000a      H, Moore C, Legood R, Gray A, Moss S. Automation-assisted versus manual\u000d\u000a      reading of\u000d\u000a      cervical cytology (MAVARIC): a randomised controlled trial. Lancet\u000d\u000a        Oncology.\u000d\u000a      2011;12(1):56-64.\u000d\u000a      DOI: 10.1016\/S1470-2045(10)70264-3\u000d\u000a    \u000a\u000a6. Kitchener HC, Walker PG, Nelson L, Hadwin R, Patnick J,\u000d\u000a      Anthony GB, Sargent A, Wood\u000d\u000a      J, Moore C, Cruickshank ME. HPV testing as an adjunct to cytology in the\u000d\u000a      follow up of\u000d\u000a      women treated for cervical intraepithelial neoplasia. BJOG.\u000d\u000a      2008;115(8):1001-7.\u000d\u000a      DOI: 10.1111\/j.1471-0528.2008.01748.x\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    S1. ARTISTIC:\u000d\u000a      UK National Screening Committee Minutes from 25 April 2012 meeting (items\u000d\u000a      4.15 and 4.16, p. 7).\u000d\u000a      http:\/\/www.screening.nhs.uk\/meetings\u000d\u000a    S2. MAVARIC:\u000d\u000a      Summary note of the meeting of the Advisory Committee on Cervical\u000d\u000a      Screening, 22 June 2011\u000d\u000a      (Item 11.1). Available from:\u000d\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/documents\/digitalasset\/dh_131296.pdf\u000d\u000a    S3.MAVARIC:\u000d\u000a      Summary note of the meeting of the Advisory Committee on Cervical\u000d\u000a      Screening, 2 December 2010\u000d\u000a      (Item 6.1). Available from:\u000d\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_d\u000d\u000a        h\/groups\/dh_digitalassets\/documents\/digitalasset\/dh_126029.pdf\u000d\u000a    S4. MAVARIC:\u000d\u000a      Health Council of the Netherlands, Population screening for cervical\u000d\u000a      cancer\u000d\u000a      http:\/\/www.gezondheidsraad.nl\/en\/publications\/population-screening-cervical-cancer\u000d\u000a      (p. 51)\u000d\u000a    ","Title":"\u000d\u000a    Developing the evidence base for a changing cervical screening programme\u000d\u000a      in England\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000a    Key UoM researchers:\u000d\u000a    \u000d\u000a      \u000aHenry Kitchener (Professor of Gynaecological Oncology,\u000d\u000a        1996-date)\u000d\u000a      \u000aGraham Dunn (Professor of Biostatistics,1996-date)\u000d\u000a      \u000aChris Roberts (Senior Research Fellow, 1997; Senior Lecturer,\u000d\u000a        1997-2004; Professor of\u000d\u000a        Biostatistics, 2004-date)\u000d\u000a    \u000d\u000a    Two trials led by Kitchener, together with Dunn and Roberts,\u000d\u000a      formed the basis of this research.\u000d\u000a      Both trials were funded by the NIHR Health Technology Assessment (HTA)\u000d\u000a      Programme (2001-\u000d\u000a      2009).\u000d\u000a    ARTISTIC: HPV Testing\u000d\u000a      The first was a primary cervical screening trial (ARTISTIC) involving\u000d\u000a      24,000 women, which\u000d\u000a      compared cytology alone with cytology combined with HPV testing. HPV\u000d\u000a      testing was performed on\u000d\u000a      the cytology-only arm but the results were concealed and did not influence\u000d\u000a      management. This\u000d\u000a      study produced a large powerful dataset of cytology and HPV (including\u000d\u000a      comprehensive\u000d\u000a      genotyping) and histopathology outcomes, which informed not only a robust\u000d\u000a      trial result, but also\u000d\u000a      important data which allowed comparison of the performance of cytology and\u000d\u000a      HPV testing over the\u000d\u000a      six years of three screening rounds (2001-9).\u000d\u000a    The results of the trial (1) and an NIHR HTA Monograph (2) showed that\u000d\u000a      combining HPV and liquid\u000d\u000a      based cytology did not detect more high grade cervical intraepithelial\u000d\u000a      neoplasia than liquid based\u000d\u000a      cytology over two rounds but it did result in a reduction in high grade\u000d\u000a      CIN in the second round.\u000d\u000a      This trial is only one of the several major RCTs internationally which\u000d\u000a      involved liquid-based cytology\u000d\u000a      and is the only one to be extended to three rounds. Following completion\u000d\u000a      of the third round, we\u000d\u000a      showed very convincingly that HPV baseline screening is as protective over\u000d\u000a      six years as cytology\u000d\u000a      was over three years (3). ARTISTIC has now been included in a pooled\u000d\u000a      analysis of four European\u000d\u000a      trials which has shown a reduction in the incidence of cervical cancer\u000d\u000a      following HPV screening (4).\u000d\u000a    MAVARIC: Automated Assisted Reading\u000d\u000a      The second study, also funded by the NIHR HTA programme, was a randomised\u000d\u000a      trial led from\u000d\u000a      Manchester, which compared conventionally read slides with automated\u000d\u000a      assisted reading and\u000d\u000a      involved 75,000 randomised samples from women in Greater Manchester\u000d\u000a      undergoing primary\u000d\u000a      cervical screening between 2006 and 2009. It was the most robustly\u000d\u000a      designed study to date, using\u000d\u000a      histopathology rather than cytology outcomes as the primary endpoint. It\u000d\u000a      produced a clear cut\u000d\u000a      result showing that automated reading was 8% less sensitive, relative to\u000d\u000a      manual reading and was\u000d\u000a      thus considered inferior. One of the two commercial systems has the\u000d\u000a      ability to file around one\u000d\u000a      quarter of slides as normal, requiring no human reading (5). This `No\u000d\u000a      further review' facility was\u000d\u000a      found to be very reliable and could be recommended for use in the NHS\u000d\u000a      based on its ability to\u000d\u000a      reduce staff time and costs.\u000d\u000a    In addition to ARTISTIC and MAVARIC, a prospective study on the use of\u000d\u000a      HPV testing to\u000d\u000a      determine cure after treatment for cervical pre-cancer led by Kitchener's\u000d\u000a      team has also had\u000d\u000a      significant impact. The study, funded by the NHS Cervical Screening\u000d\u000a      Programme between 2004\u000d\u000a      and 2007, showed that the cumulative incidence of failed treatment in\u000d\u000a      women who were cytology-negative\/HPV-positive\u000d\u000a      6 months after treatment was low, such that treated women could be\u000d\u000a      returned to 3-year recall instead of annual cervical cytology for 10\u000d\u000a      years. This system was adopted\u000d\u000a      by the National Cervical Screening Programme in September 2012 (6).\u000d\u000a    "},{"CaseStudyId":"28036","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S6.\u000a    Context\u000a      Children with ALL in the UK (~450 pa) now benefit from one of the highest\u000a      cure rates in the world.\u000a      During 1980-2000, however, UK success rates fell below other international\u000a      groups. At that time it\u000a      was unclear as to why this was the case and both Eden and Saha\u000a      were instrumental in initiating\u000a      changes that have turned this around, so that our clinical outcomes in\u000a      2013 are among the best in\u000a      the world. The changes included the introduction of risk stratification\u000a      using MRD, optimising drug\u000a      schedules and the testing of drugs hitherto not used widely in children\u000a      with ALL.\u000a    Pathways to impact\u000a      Eden's national leadership has been pivotal to the improvement in\u000a      outcome in children with ALL in\u000a      UK. In 1999, he introduced risk stratification (2), incorporated modern\u000a      therapeutic blocks, the use\u000a      of dexamethasone and PEG-Asparaginase (ALL99) (1), which evolved into the\u000a      ALL2003 trial.\u000a      Similarly, between 1990 and 2003, there had been little improvement in\u000a      outcome in relapsed\u000a      childhood ALL worldwide. Saha used a novel design for a relapse\u000a      trial in childhood ALL (3) and\u000a      developed strategies for high risk ALL in collaboration with international\u000a      groups (5, 6). Based on\u000a      the observations made in the clinical trials, Saha designed\u000a      translational research to understand the\u000a      biological mechanisms for the variations in therapeutic response (4)\u000a      leading to further refinements\u000a      in therapy now being tested in frontline ALL trials in UK.\u000a    Reach and significance of the impact\u000a      These clinical trials in childhood ALL have led to an improvement of\u000a      outcome in children with ALL\u000a      in the 2008-2013 period in the UK and shaped treatment strategies\u000a      worldwide. As a result of the\u000a      changes initiated by Eden, in the period of 2008-2013, the\u000a      survival rates in newly diagnosed\u000a      childhood ALL in UK are now over 85%, among the best in the world (2).\u000a    ALLR3, the trial designed by Saha has improved by 10% the outcome\u000a      for children with relapsed\u000a      ALL in the UK, Netherlands, Australia and New Zealand and identified a\u000a      role for the drug\u000a      Mitoxantrone in childhood ALL (3) (S1-S3). The Vice-Chair for Relapse, ALL\u000a      Committee, Children's\u000a      Oncology Group and Professor of Paediatrics at The University of Toronto\u000a      underlines the\u000a      importance of these findings: `the outcomes achieved with the mitoxantrone\u000a      arm of the R3\u000a      regimen, as published in the Lancet Oncology by Parker et al [reference 3\u000a      above], represent the\u000a      best published results to date for the first relapse of childhood ALL. The\u000a      R3 regimen thus\u000a      represents a new standard of care for children with first relapse of\u000a      childhood ALL, and has been\u000a      adopted as such at a number of leading institutions around the world for\u000a      children with first relapse\u000a      of ALL, including my own institution, the Hospital for Sick Children.'\u000a      (S4, S5) Mitoxantrone\u000a      improves the outcome of all categories of relapses, compared to the\u000a      traditionally used Idarubicin.\u000a      However MRD levels in both arms of the trial were identical, suggesting\u000a      that the effect of\u000a      Mitoxantrone is not explained by direct cytotoxicity. Thus MRD cannot be\u000a      used reliably as a\u000a      surrogate marker for outcome. The trial shows that MRD levels can be used\u000a      to identify patients\u000a      with relapsed ALL who do not need an allogeneic transplant.\u000a    The ALLR3 trial design underpins the current international trial in\u000a      relapsed disease funded by the\u000a      European Union FP7 programme. This is the largest study of its kind in the\u000a      world running across\u000a      20 different countries (IntReALL, http:\/\/www.intreall-fp7.eu\/)\u000a      and incorporates the MRD\u000a      stratification for transplantation. As chair of the International study\u000a      group on Relapsed and\u000a      Resistant Disease in Childhood ALL (I-BFM-SG), Co-Chief Investigator for\u000a      IntReALL and an\u000a      advisor to the European Medicines Agency, Saha has been able to\u000a      initiate studies utilising new\u000a      agents in relapsed childhood ALL by collaborating with industry e.g.\u000a      IntReALL will use the drug\u000a      Epratuzamab (ImmunoMedics). The standards of procedures developed for the\u000a      ALLR3 cell bank\u000a      now form the basis of an IntReALL cell bank. The ALLR3 cell bank also led\u000a      to the centralisation of\u000a      the UK childhood leukaemia cell bank to Manchester Biobank (funded by\u000a      LLR).\u000a    The EsPhALL study has shown the benefit of a targeted drug (imatinib) in\u000a      conjunction with\u000a      conventional chemotherapy, in this high-risk population (5). Moreover the\u000a      use of imatinib has\u000a      resulted in a dramatic decrease in MRD levels, and we now only transplant\u000a      those with high MRD\u000a      levels. Thus currently imatinib is given to all children with Ph+ ALL in\u000a      Europe and other countries.\u000a      Less than half of the children previously transplanted now require one,\u000a      considerably reducing the\u000a      burden of therapy. The trial has led to the further development of this\u000a      group with the inclusion of\u000a      the Children's Oncology Group (USA). A current collaborative study,\u000a      between USA, Italy and UK is\u000a      investigating the role of Dasatinib on the EsPhALL chemotherapy backbone\u000a      (NCRN 350) (S6).\u000a      This study is being replaced by a 20-country collaborative effort in 2015.\u000a    In the era 1993-2013, Manchester investigators have led the way in\u000a      setting standards for the\u000a      improvement of outcome in childhood ALL. During the period 2008-2013, the\u000a      ensuing research of\u000a      that period has led to a greater than 10% improvement in the cure of both\u000a      de novo and relapsed\u000a      ALL. Prompt dissemination of our results has enabled international\u000a      colleagues to rapidly\u000a      incorporate the knowledge gained from our trials thus benefitting patients\u000a      worldwide.\u000a    ","ImpactSummary":"\u000a    Researchers at the University of Manchester (UoM) have made a significant\u000a      impact nationally and\u000a      internationally on improving the outcome for children with acute\u000a      lymphoblastic leukaemia (ALL)\u000a      (~450 pa in the UK). The changes in clinical practice based on our\u000a      research are now national\u000a      standards of care for children with de novo and relapsed ALL in\u000a      the UK and Ireland. Other\u000a      international groups have adopted key findings from the results of our\u000a      frontline trials. Our relapse\u000a      protocol for childhood ALL underpins European and North American strategy\u000a      for the management\u000a      of relapsed disease.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6167865","Name":"Toronto"}],"References":"\u000a    \u000a1. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden T.\u000a      Benefit of\u000a      dexamethasone compared with prednisolone for childhood acute lymphoblastic\u000a      leukaemia:\u000a      results of the UK Medical Research Council ALL97 randomized trial. British\u000a        Journal of\u000a        Haematology. 2005;129:734-745. DOI: 10.1111\/j.1365-2141.2005.05509.x\u000a    \u000a\u000a2. Mitchell C, Payne J, Wade R, Vora A, Kinsey S, Richards S, Eden T.\u000a      The impact of risk\u000a      stratification by early bone-marrow response in childhood lymphoblastic\u000a      leukaemia: results from\u000a      the United Kingdom Medical Research Council trial ALL97 and ALL97\/99. British\u000a        Journal of\u000a        Haematology. 2009;46:424-36. DOI: 10.1111\/j.1365-2141.2009.07769.x\u000a    \u000a\u000a3. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV,\u000a      Ancliff P, Morgan M,\u000a      Masurekar A, Goulden N, Green N, Revesz T, Darbyshire P, Love S, Saha\u000a        V. Effect of\u000a      mitoxantrone on outcome of children with first relapse of acute\u000a      lymphoblastic leukaemia (ALL\u000a      R3): an open-label randomised trial. Lancet. 2010;376:2009-17.\u000a      DOI: 10.1016\/S0140-\u000a      6736(10)62002-8\u000a    \u000a\u000a4. Patel N, Krishnan S, Offman MN, Krol M, Moss CX, Leighton C, van Delft\u000a      FW, Holland M,\u000a      Liu J, Alexander S, Dempsey C, Ariffin H, Essink M, Eden TO, Watts\u000a      C, Bates PA, Saha V. A\u000a      dyad of lymphoblastic lysosomal cysteine proteases degrades the\u000a      antileukemic drug L-\u000a      asparaginase. The Journal of Clinical Investigation.\u000a      2009;119:1964-73. DOI: 10.1172\/JCI37977\u000a    \u000a\u000a5. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V,\u000a      Pieters R, Stary\u000a      J, Escherich G, Campbell M, Li CK, Vora A, Arico M, Rottgers S, Saha V,\u000a      Valsecchi MG.\u000a      Imatinib after induction for treatment of children and adolescents with\u000a      Philadelphia-\u000a      chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised,\u000a      open-label,\u000a      intergroup study. Lancet Oncology. 2012;13:936-45. DOI:\u000a      10.1016\/S1470-2045(12)70377-7\u000a    \u000a\u000a6. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A,\u000a      Conter V, Otten J,\u000a      Ohara A, Versluys AB, Escherich G, Heyman M, Silverman LB, Horibe K, Mann\u000a      G, Camitta BM,\u000a      Harbott J, Riehm H, Richards S, Devidas M, Zimmermann M. Outcomes after\u000a      Induction Failure\u000a      in Childhood Acute Lymphoblastic Leukemia. The New England Journal of\u000a        Medicine. 2012;\u000a      366:1371-81. DOI: 10.1056\/NEJMoa1110169\u000a    \u000aKey funding underpinning the research\u000a      Cancer Research UK: Clinical and Biological Studies in Acute\u000a      Leukaemias of Childhood.\u000a      01\/10\/2006 - 30\/09\/2013, Total Award: £2,855,485 to Saha.\u000a    Teenage Cancer Trust: Chair of Teenage Cancer Trust. 01\/10\/2005 -\u000a      30\/09\/2015, Total Award:\u000a      £2,500,000 to Eden.\u000a    Cancer Research UK: Professor Vaskar Saha Personal Support\u000a      01\/09\/2006 - 31\/08\/2009\u000a      Total Award: £405,936 to Saha.\u000a    Leukaemia & Lymphoma Research: Molecular Pharmacology of\u000a      Imatinib in Patients with\u000a      Philadelphia Positive ALL. 01\/10\/2006 - 28\/02\/2011. Total Award: £170,215\u000a      to Saha.\u000a    Leukaemia & Lymphoma Research: Correlation of AEP expression\u000a      with Asparaginase activity,\u000a      hypersensitivity and antibody formation in acute lymphoblastic leukaemia\u000a      (ALL) of childhood.\u000a      01\/12\/2008 - 22\/03\/2013.Total Award: £265,800 to Saha.\u000a    European Commission (FP7): International study for treatment of\u000a      childhood relapsed ALL 2010\u000a      with standard therapy, systematic integration of new agents, and\u000a      establishment of standardized\u000a      diagnostic and research. 01\/10\/2011 - 30\/09\/2016. Total Award: £430,724.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    S1. The ALLR3 protocol is now the standard of care for children with\u000a      relapsed ALL in UK,\u000a      Netherlands, Australia and New Zealand and all patients receive the drug\u000a      Mitoxantrone. This is\u000a      also being evaluated by the Children's Oncology Group in the USA\u000a      (http:\/\/www.cancer.gov\/cancertopics\/pdq\/treatment\/childALL\/HealthProfessional\/Page8#Section_1401)\u000a    S2. Letter from Senior Paediatric Haematologist-Oncologist, Women's and\u000a      Children's Hospital,\u000a      North Adelaide, Australia.\u000a    S3. The COG are now using the ALLR3 protocol as a strategy.\u000a      (http:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.24420\/full)\u000a    S4. Letter from Vice-Chair for Relapse, ALL Committee, Children's\u000a      Oncology Group, Director,\u000a      Garron Family Cancer Centre, The Hospital for Sick Children and Professor\u000a      of Paediatrics, The\u000a      University of Toronto, Canada.\u000a    S5. Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M,\u000a      Raetz EA, Committee\u000a      COGALL. Children's Oncology Group's 2013 blueprint for research: acute\u000a      lymphoblastic\u000a      leukemia. Pediatric Blood Cancer. 2013;60(6):957-63. DOI:\u000a      10.1002\/pbc.24420\u000a    S6. NCRN 350 (http:\/\/public.ukcrn.org.uk\/Search\/StudyDetail.aspx?StudyID=11289)\u000a    \u000a    ","Title":"\u000a    Improving outcomes for children with leukaemia internationally: the\u000a      results of scientifically designed\u000a      clinical trials and translational research\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    Key UoM researchers:\u000a    \u000a      \u000aTim Eden (Professor of Paediatric Oncology, 1994-2007; Honorary\u000a        Professor 2007- date)\u000a      \u000aVaskar Saha (Professor of Paediatric Oncology, 2006 - date)\u000a    \u000a    UoM is recognised both nationally and internationally as a centre for\u000a      expertise in Teenage and\u000a      Young Adult Cancers and nationally as a centre for clinical studies in\u000a      childhood leukaemia. The UK\u000a      chair in Teenage and Young Adult Cancer (funded by the Teenage Cancer\u000a      Trust) is based here\u000a      (Eden, 2005-2011; Radford, 2010-date) and Manchester is the\u000a      sponsor and clinical trial centre for\u000a      two national phase III clinical trials in childhood ALL.\u000a    Eden was chief investigator for the two main path-changing\u000a      protocols in childhood ALL in the UK,\u000a      namely UKALL VIII and ALL97\/99 (1). The latter trial was the first to\u000a      stratify patients for risk in the\u000a      UK based on the early response to therapy (2), leading to an improvement\u000a      in outcome of high-risk\u000a      patients. His work in the period 1993-2003 led to the routine use of\u000a      dexamethasone (instead of\u000a      prednisolone), mercaptopurine (instead of thioguanine) and pegylated\u000a      L-Asparaginase (PEG-\u000a      Asnase) instead of native asparaginase in childhood ALL in the UK and\u000a      elsewhere. These drugs\u000a      are now the mainstay in the therapy of childhood ALL in UK and Ireland.\u000a    Incorporating the three drugs identified by Eden's work, Saha\u000a      developed a new concept for the\u000a      treatment of relapsed ALL for all patients being treated in UK and Ireland\u000a      (3). The trial introduced\u000a      minimal residual disease (MRD) based risk stratification to select for\u000a      patients to either receive\u000a      chemotherapy or an allogeneic transplantation and was the first randomised\u000a      international trial for\u000a      relapsed ALL. A bespoke remote entry clinical trial management system was\u000a      constructed\u000a      indigenously. This system permitted remote registration and data entry,\u000a      provided decision support\u000a      and standardised the reporting of MRD across all recruiting centres. This\u000a      approach allowed\u000a      countries including the Netherlands, Australia and New Zealand to adapt\u000a      the study rapidly for their\u000a      patients at all centres. This clinical study, the ALLR3 trial (2003-2013),\u000a      forms the basis of relapse\u000a      strategies in childhood ALL worldwide. A centralised cell bank for the UK\u000a      was developed in\u000a      Manchester for this trial. Building translational research into clinical\u000a      trials has also allowed the\u000a      identification of previously unidentified mechanisms of therapeutic\u000a      failure paving the way for novel\u000a      therapeutic strategies (4).\u000a    Eden and Saha participated in and led international\u000a      initiatives in childhood ALL. They represent\u000a      the UK on the influential international think-tank (the Ponte de Ligno\u000a      group). As ALL is a rare\u000a      disease and associated with a high cure rate, the numbers of patients at a\u000a      risk of relapse (or\u000a      relapsing) are small in any study group. Thus international collaborative\u000a      studies are key to\u000a      identifying optimal strategies for these sub-groups.\u000a    An example is EsPhALL, the only randomised study of tyrosine kinase\u000a      inhibitors in Philadelphia-\u000a      positive (Ph+) ALL (2004-to date) (5), which is a European collaborative\u000a      study. Ph+ ALL is a high-\u000a      risk group of childhood ALL and almost all patients are transplanted in\u000a      first remission. Saha helped\u000a      design the study and analyse the randomised data, with the UK contributing\u000a      the maximum number\u000a      of randomised patients. Another large international study to which Saha\u000a      contributed to design and\u000a      writing identified a therapeutic strategy for patients who fail initial\u000a      therapy (6).\u000a    "},{"CaseStudyId":"28037","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S9.\u000d\u000a    Research outputs from the BSRBR study have refined the way anti-TNF\u000d\u000a      therapies are prescribed\u000d\u000a      in RA with a goal of maximising patient benefit and minimising patient\u000d\u000a      risk.\u000d\u000a    Pathways to impact have included:\u000d\u000a    \u000d\u000a      Membership of UoM key researchers on national and international\u000d\u000a        rheumatoid arthritis\u000d\u000a        guideline working parties;\u000d\u000a      Submission of data to National Institute for Health and Clinical\u000d\u000a        Excellence (NICE) to support\u000d\u000a        technology appraisal;\u000d\u000a      Collaboration with national arthritis charities including Arthritis\u000d\u000a        Research UK and the National\u000d\u000a        Rheumatoid Arthritis Society.\u000d\u000a    \u000d\u000a    Reach and significance of the impact\u000d\u000a    \u000d\u000a      NICE guidance is the most important factor in determining which new\u000d\u000a        therapies can be\u000d\u000a        prescribed to patients in the UK. If guidance does not exist for a new\u000d\u000a        technology or if guidance\u000d\u000a        does not allow a technology, funding is likely to be denied. This study\u000d\u000a        has contributed to one\u000d\u000a        recent NICE technology appraisal (TA) and several previous appraisals\u000d\u000a        now superseded.\u000d\u000a      (a) Impact: Improved treatment outcomes for patients\u000d\u000a        By demonstrating the benefits of combining anti-TNF treatments with\u000d\u000a        continued background MTX\u000d\u000a        (unless contra-indicated) the study has contributed directly to NICE\u000d\u000a        TA195 (published 2010 and\u000d\u000a        still in effect in 2013). The previous guidelines did not specify that\u000d\u000a        MTX treatment should be\u000d\u000a        continued (TA36). However, we demonstrated that, year on year from\u000d\u000a        2001-8, the proportion of\u000d\u000a        patients continuing MTX with anti-TNF increased in the UK, with\u000d\u000a        subsequent improvements in\u000d\u000a        treatment responses (S1,S2).\u000d\u000a      (b) Impact: Improved access to controlled treatments for UK patients\u000d\u000a        By demonstrating the benefits of switching between anti-TNF agents when\u000d\u000a        a first has been\u000d\u000a        ineffective, the study contributed to NICE TA195. This new guidance\u000d\u000a        allows sequential anti-TNF\u000d\u000a        use if rituximab is contraindicated — an approach that was not\u000d\u000a        previously allowed under NICE\u000d\u000a        guidance (TA36) (S1).\u000d\u000a      Output from the BSRBR has also contributed to new national\u000d\u000a        guidelines outlining eligibility\u000d\u000a        criteria for anti-TNF. The study indicated that the drugs should no\u000d\u000a        longer be reserved for patients\u000d\u000a        with high disease activity, but should instead be used in all patients\u000d\u000a        with ongoing disease activity\u000d\u000a        resistant to standard treatments (S3). This has improved choice and\u000d\u000a        access for patients within this\u000d\u000a        subgroup.\u000d\u000a      Our research into the risk of intracellular infections such as\u000d\u000a        listeria and salmonella has led to\u000d\u000a        new information being incorporated into Arthritis Research UK Drug\u000d\u000a        Information Leaflets (provided\u000d\u000a        to every patient in the UK considering anti-TNF therapies). It has also\u000d\u000a        prompted the FDA to update\u000d\u000a        product labelling. Specifically, the new information warns of the risk\u000d\u000a        of consuming undercooked or\u000d\u000a        unpasteurised foods, similar to the advice provided to pregnant women.\u000d\u000a        Our research has shown\u000d\u000a        that updating the Arthritis Research UK Drug Information Leaflets in\u000d\u000a        2006 led to a 73% decrease in\u000d\u000a        new cases of intracellular infection in RA patients exposed to anti-TNF\u000d\u000a        in the UK from 2007-12 (S4,\u000d\u000a        S5). This leaflet remains in print today.\u000d\u000a      Our publications on outcomes among women exposed to anti-TNF\u000d\u000a        therapy during pregnancy\u000d\u000a        have contributed to a significant change in product labelling. It is now\u000d\u000a        indicated that women can\u000d\u000a        continue anti-TNF therapies into pregnancy if clearly needed, as opposed\u000d\u000a        to previous labelling that\u000d\u000a        treatment should be discontinued in the months leading up to conception\u000d\u000a        (which often resulted in a\u000d\u000a        disease flare). This is a major change within rheumatology, as other\u000d\u000a        non-biologic DMARDs are\u000d\u000a        contra-indicated in pregnancy, many with the risk of teratogenicity. Our\u000d\u000a        research offers a safer\u000d\u000a        option for disease control in the months leading up to conception.\u000d\u000a      Our research data are contributing to the training of new doctors,\u000d\u000a        as well as to the maintenance\u000d\u000a        of certification among established physicians, with data featuring in\u000d\u000a        `Up-to-Date', an evidence-based\u000d\u000a        online guide for physicians on current best practice. In particular, we\u000d\u000a        are the only group to\u000d\u000a        have published a differential risk of tuberculosis across anti-TNF\u000d\u000a        therapies, which may direct\u000d\u000a        choice of treatment in high-risk cases (S6).\u000d\u000a      Finally, the BSRBR is proving to be an invaluable resource for\u000d\u000a        patients and physicians across\u000d\u000a        the UK and internationally, for pharmaceutical companies who manufacture\u000d\u000a        the drugs and for\u000d\u000a        international drug regulators (e.g. MHRA, FDA, EMA) (S7-S9). With data\u000d\u000a        on over 20,000 patients\u000d\u000a        and >80000 adverse events, it has become a vital and accessible\u000d\u000a        resource for up-to-date and\u000d\u000a        unpublished safety information. Physicians can access information\u000d\u000a        directly from the investigators,\u000d\u000a        and pharmaceutical companies and regulators are provided with detailed\u000d\u000a        serious adverse event\u000d\u000a        information and publications to ensure effective risk management of\u000d\u000a        these new therapies.\u000d\u000a    \u000d\u000a    The Director of Vigilance and Risk Management of Medicines at the MHRA\u000d\u000a      states: `The greatest\u000d\u000a      regulatory impact of the BSRBR has been in helping to define the clinical\u000d\u000a      safety profile of biological\u000d\u000a      agents in the treatment of rheumatoid arthritis, particularly over the\u000d\u000a      long term. The unique scale of\u000d\u000a      the register provides the opportunity to study the risks of rare serious\u000d\u000a      safety concerns with unusual\u000d\u000a      precision.' (S7)\u000d\u000a    The Chief Executive of the National Rheumatoid Arthritis Society\u000d\u000a      underlines the significance of the\u000d\u000a      BSRBR research for those living with RA: `This information has supported\u000d\u000a      our campaign for\u000d\u000a      widening access to anti-TNF therapies, especially in patients who do not\u000d\u000a      respond to their first\u000d\u000a      biologic. The study has also been an invaluable source of information\u000d\u000a      about the safety of these\u000d\u000a      treatments.' (S9)\u000d\u000a    The manufacturers of newer agents continue to approach UoM for\u000d\u000a      information on how to join this\u000d\u000a      important study, thereby ensuring the long-term observation of patients\u000d\u000a      starting new therapies for\u000d\u000a      arthritis.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    When anti-TNF therapies (which block tumour necrosis factor) were first\u000d\u000a      licensed in 1999 only a\u000d\u000a      few hundred patients with rheumatoid arthritis had received them, most for\u000d\u000a      relatively short periods\u000d\u000a      of time. Although the drugs represented a major breakthrough, `real-world'\u000d\u000a      effectiveness and safety\u000d\u000a      were unproven. Research at the University of Manchester (UoM) has\u000d\u000a      addressed this knowledge\u000d\u000a      gap and has successfully refined the ways in which anti-TNF drugs are used\u000d\u000a      around the world,\u000d\u000a      leading directly to more effective prescribing and improved patient\u000d\u000a      outcomes. The research has\u000d\u000a      also provided strong evidence that women do not need to discontinue\u000d\u000a      anti-TNF treatment prior to\u000d\u000a      conception.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Hyrich KL, Watson KD, Silman AJ, Symmons DP; British\u000d\u000a      Society for Rheumatology Biologics\u000d\u000a      Register. Predictors of response to anti-TNF-alpha therapy among patients\u000d\u000a      with rheumatoid\u000d\u000a      arthritis: results from the British Society for Rheumatology Biologics\u000d\u000a      Register. Rheumatology\u000d\u000a      (Oxford). 2006; 45:1558-65. DOI: 10.1093\/rheumatology\/kel149\u000d\u000a    \u000a\u000a2. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ;\u000d\u000a      British Society for Rheumatology\u000d\u000a      Biologics Register. Outcomes after switching from one anti-tumor necrosis\u000d\u000a      factor alpha agent to a\u000d\u000a      second anti-tumor necrosis factor alpha agent in patients with rheumatoid\u000d\u000a      arthritis: results from a\u000d\u000a      large UK national cohort study. Arthritis & Rheumatism.\u000d\u000a      2007;56:13-20. DOI: 10.1002\/art.22331\u000d\u000a    \u000a\u000a3. Hyrich KL, Deighton C, Watson KD; BSRBR Control Centre\u000d\u000a      Consortium, Symmons DP, Lunt\u000d\u000a        M; British Society for Rheumatology Biologics Register. Benefit of\u000d\u000a      anti-TNF therapy in rheumatoid\u000d\u000a      arthritis patients with moderate disease activity. Rheumatology\u000d\u000a      (Oxford). 2009;48:1323-7. DOI:\u000d\u000a      10.1093\/rheumatology\/kep242\u000d\u000a    \u000a\u000a4. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J,\u000d\u000a      Ustianowski A; BSRBR Control Centre\u000d\u000a      Consortium, Symmons DP; BSR Biologics Register. Drug-specific risk of\u000d\u000a      tuberculosis in patients\u000d\u000a      with rheumatoid arthritis treated with anti-TNF therapy: results from the\u000d\u000a      British Society for\u000d\u000a      Rheumatology Biologics Register (BSRBR). Annals of the Rheumatic\u000d\u000a        Diseases. 2010;69:522-8.DOI: 10.1136\/ard.2009.118935\u000d\u000a    \u000a\u000a5. Dixon WG, Watson K, Lunt M, Hyrich KL, Silman\u000d\u000a        AJ, Symmons DP; British Society for\u000d\u000a      Rheumatology Biologics Register. Rates of serious infection, including\u000d\u000a      site-specific and bacterial\u000d\u000a      intracellular infection, in rheumatoid arthritis patients receiving\u000d\u000a      anti-tumor necrosis factor therapy:\u000d\u000a      results from the British Society for Rheumatology Biologics Register. Arthritis\u000d\u000a        & Rheumatism.\u000d\u000a      2006;54(8):2368-76. DOI: 10.1002\/art.21978\u000d\u000a    \u000a\u000a6. Verstappen, S, King, Y, Watson, K, Symmons, D, Hyrich, K.\u000d\u000a      Anti-TNF therapies and\u000d\u000a      pregnancy: outcome of 130 pregnancies in the British Society for\u000d\u000a      Rheumatology Biologics\u000d\u000a      Register. Annals of the Rheumatic Diseases. 2011;70(5): 823-826.\u000d\u000a      DOI: 10.1136\/ard.2010.140822\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    S1. National Institute for Health and Care Excellence. Adalimumab,\u000d\u000a      etanercept, infliximab,\u000d\u000a      rituximab and abatacept for the treatment of rheumatoid arthritis after\u000d\u000a      the failure of a TNF inhibitor.\u000d\u000a      TA195. London: National Institute for Health and Care Excellence, 2010.\u000d\u000a      Available from:\u000d\u000a      www.nice.org.uk\/guidance\/TA195\u000d\u000a      NICE TA 195 specifies a treatment algorithm in patients who fail a first\u000d\u000a      anti-TNF therapy, including\u000d\u000a      choice in patients intolerant of MTX, with data or analyses from the BSRBR\u000d\u000a      referenced on pp 18-49.\u000d\u000a    S2. Hyrich KL, Watson KD, Lunt M, Symmons DP; British Society for\u000d\u000a      Rheumatology Biologics\u000d\u000a      Register (BSRBR). Changes in disease characteristics and response rates\u000d\u000a      among patients in the\u000d\u000a      United Kingdom starting anti-tumour necrosis factor therapy for rheumatoid\u000d\u000a      arthritis between 2001\u000d\u000a      and 2008. Rheumatology (Oxford). 2011; 50:117-23. DOI:\u000d\u000a      10.1093\/rheumatology\/keq209\u000d\u000a    S3. BSR\/BHPR rheumatoid arthritis guidelines on eligibility criteria for\u000d\u000a      the first biologic therapy\u000d\u000a      (http:\/\/www.rheumatology.org.uk\/includes\/documents\/cm_docs\/2010\/r\/2_ra_guidelines_on_eligibilit\u000d\u000a      y_criteria_for_the_first_biological_therapy.pdf\u000d\u000a      ; DOI: 10.1093\/rheumatology\/keq006b) state that\u000d\u000a      biologic therapies should be offered to RA patients with a DAS28 >3.2\u000d\u000a      and at least three tender\u000d\u000a      and three swollen joints.\u000d\u000a    S4. Arthritis Research UK Drug Information Leaflets e.g.\u000d\u000a      http:\/\/www.arthritisresearchuk.org\/arthritis-information\/drugs\/etanercept.aspx\u000d\u000a      and http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm270849.htm\u000d\u000a      warn patients on anti-TNF therapy that\u000d\u000a      they should avoid foods such as unpasteurised cheeses and undercooked\u000d\u000a      meats.\u000d\u000a    S5. Davies R, Dixon WG, Watson KD, Lunt M; BSRBR Control Centre\u000d\u000a      Consortium, Symmons\u000d\u000a        DP, Hyrich KL; BSRBR. Influence of anti-TNF patient warning\u000d\u000a      regarding avoidance of high risk\u000d\u000a      foods on rates of listeria and salmonella infections in the UK. Annals\u000d\u000a        of the Rheumatic Diseases.\u000d\u000a      2013 ;72:461-2. DOI: 10.1136\/annrheumdis-2012-202228\u000d\u000a    S6. www.uptodate.com cites data\u000d\u000a      from the BSRBR as the only source of information on the\u000d\u000a      differential risk of TB across anti-TNF agents. See uptodate.com topics\u000d\u000a      `Tumor necrosis factor-alpha\u000d\u000a      inhibitors: Risk of bacterial, viral, and fungal infections' (updated\u000d\u000a      2013) and `Tumor necrosis\u000d\u000a      factor-alpha inhibitors and mycobacterial infections' (updated 2013).\u000d\u000a    S7. Letter from Director of Vigilance and Risk Management of Medicines,\u000d\u000a      MHRA.\u000d\u000a    S8. Survey of BSR Membership, 2012.\u000d\u000a    S9. Letter from Chief Executive, National Rheumatoid Arthritis Society.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving treatment outcomes for patients with rheumatoid arthritis\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000a    Rheumatoid arthritis (RA) is a common condition, affecting 1% of adults\u000d\u000a      and causing chronic pain,\u000d\u000a      disability, loss of work and early mortality. Standard treatments (e.g.\u000d\u000a      methotrexate (MTX)) are not\u000d\u000a      effective in all patients and have a range of undesirable side-effects,\u000d\u000a      including nausea and\u000d\u000a      headaches.\u000d\u000a    UoM launched The British Society for Rheumatology Biologics Register\u000d\u000a      (BSRBR) in 2001 and it is\u000d\u000a      now the world's largest prospective cohort study of anti-TNF treated RA\u000d\u000a      patients. This ongoing\u000d\u000a      study, funded by the British Society for Rheumatology (BSR), has recruited\u000d\u000a      and continues to follow\u000d\u000a      over 16,000 patients starting anti-TNF and related therapies alongside a\u000d\u000a      control group of patients\u000d\u000a      receiving standard therapy. The research focuses on measuring `real-world'\u000d\u000a      effectiveness in terms\u000d\u000a      of: reducing disease activity (painful and swollen joints) and disability;\u000d\u000a      quantifying the risk of\u000d\u000a      adverse events. The project's first major publication was in 2005.\u000d\u000a    Key researchers:\u000d\u000a    \u000d\u000a      \u000aDeborah Symmons (Clinical Epidemiologist 1991-2004; Professor\u000d\u000a        of Rheumatology 2004-date)\u000d\u000a      \u000aAlan Silman (Professor of Rheumatology 1992-2011)\u000d\u000a      \u000aKimme Hyrich (Research Fellow 2001-2005; Clinical Senior\u000d\u000a        Lecturer 2006-2012; Reader\u000d\u000a        2012-date)\u000d\u000a      \u000aMark Lunt (Research Fellow 1999-2001 ; Lecturer 2001-2004 ;\u000d\u000a        Senior Lecturer 2004 ;\u000d\u000a        Reader 2004-date)\u000d\u000a      \u000aWilliam Dixon (Clinical Research Fellow 2004-2008; Lecturer\u000d\u000a        2009-2010; Clinical Senior\u000d\u000a        Lecturer 2010-date)\u000d\u000a      \u000aSuzanne Verstappen (Drug Studies Coordinator 2007-2009;\u000d\u000a        Research Associate 2009;\u000d\u000a        Senior Research Fellow 2010-date)\u000d\u000a    \u000d\u000a    The key research outputs of this study include the following:\u000d\u000a    \u000d\u000a      We were the first to demonstrate a clear benefit, in terms of\u000d\u000a        greater reduction in disease\u000d\u000a        activity, among patients continuing their background MTX therapy,\u000d\u000a        despite being resistant to\u000d\u000a        MTX when taken without anti-TNF(1).\u000d\u000a      We were the first to quantify the response to a second anti-TNF\u000d\u000a        agent in patients who either\u000d\u000a        failed to respond or experienced an adverse reaction to their first\u000d\u000a        anti-TNF agent (2).\u000d\u000a      We were the first to demonstrate that the benefits of anti-TNF\u000d\u000a        therapy, in terms of\u000d\u000a        improvements in disability, are independent of the severity of the\u000d\u000a        inflammation present at the\u000d\u000a        start of therapy (3).\u000d\u000a      The large size of the study has enabled us to quantify the risk of\u000d\u000a        tuberculosis and establish a\u000d\u000a        differential risk between anti-TNF therapies. We have demonstrated that\u000d\u000a        the risk is\u000d\u000a        substantially higher with anti-TNF monoclonal antibodies (adalimumab,\u000d\u000a        infliximab) than with\u000d\u000a        recombinant receptor proteins (etanercept) (4).\u000d\u000a      We identified a previously unknown increased risk of bacterial\u000d\u000a        intracellular infections (e.g.\u000d\u000a        salmonella and listeria) (5).\u000d\u000a      We have published the largest collection of robust prospectively\u000d\u000a        collected pregnancy outcome\u000d\u000a        data in women with RA who were inadvertently exposed to biologic\u000d\u000a        treatment at conception.\u000d\u000a        This found no increase in pregnancy complications or congenital\u000d\u000a        abnormalities (6).\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"28098","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    See section 5 for corroborating sources S1-S7.\u000d\u000a    Context\u000d\u000a    Lung cancer is the commonest cause of cancer-related morbidity and\u000d\u000a      mortality worldwide. 30,000\u000d\u000a      cases are diagnosed annually in the UK. The majority of patients have\u000d\u000a      metastatic disease for\u000d\u000a      which there is no curative treatment. Historically lung cancer is\u000d\u000a      classified into small cell (SCLC) or\u000d\u000a      non-small cell (NSCLC) subtypes according to microscopic appearances. In\u000d\u000a      the 1990s it was\u000d\u000a      believed that chemotherapy for NSCLC was ineffective. The UoM Lung Cancer\u000d\u000a      Group led in\u000d\u000a      research to identify effective chemotherapy treatments for patients with\u000d\u000a      NSCLC and to address the\u000d\u000a      `therapeutic nihilism' surrounding NSCLC.\u000d\u000a    Reach and significance of the impact\u000d\u000a    Effective treatments for non-small cell lung cancer (NSCLC)\u000d\u000a    a) UoM research contributed significantly to establishing the evidence\u000d\u000a      base and the role for\u000d\u000a      chemotherapy compared with best supportive care and for gemcitabine and\u000d\u000a      platinum (GP) based\u000d\u000a      chemotherapy in the first line treatment for advanced NSCLC (2, S1). Key\u000d\u000a      outcomes demonstrated\u000d\u000a      were a relative increase in survival of 23% for chemotherapy and better\u000d\u000a      quality of life, less toxicity\u000d\u000a      and fewer hospital admissions for GP compared with older chemotherapy\u000d\u000a      regimens (2). As a result\u000d\u000a      of our research, chemotherapy, including the GP regimen, is now a\u000d\u000a      universal standard of care for\u000d\u000a      patients with metastatic NSCLC, as evidenced in the UK guidelines (S2),\u000d\u000a      European guidelines (S3)\u000d\u000a      and the US guidelines (S4).\u000d\u000a    b) Gefitinib is the first targeted treatment for lung cancer to be\u000d\u000a      licensed (in 2009) for patients with\u000d\u000a      NSCLC bearing epidermal growth factor receptor (EGFR) gene mutations. This\u000d\u000a      treatment\u000d\u000a      represents a landmark for personalised medicine in lung cancer. The first\u000d\u000a      patient worldwide to\u000d\u000a      receive gefitinib was in Manchester (1) and the group have continued to\u000d\u000a      play a major role in the\u000d\u000a      clinical development of this drug (1, 3), notably identifying patient\u000d\u000a      populations with increased\u000d\u000a      chance of benefit. This latter observation led to other researchers\u000d\u000a      identifying the mutation to predict\u000d\u000a      for benefit. The treatment is available worldwide and at least 1 million\u000d\u000a      (likely more) patients have\u000d\u000a      received it (S5, S6).\u000d\u000a    Optimising treatment for small cell lung cancer (SCLC)\u000d\u000a    a) UoM research has contributed to the evidence base for platinum\u000d\u000a      etoposide as the standard first\u000d\u000a      line chemotherapy for SCLC (5, 6). Platinum etoposide was standard in the\u000d\u000a      US but not in Europe.\u000d\u000a      UoM researchers demonstrated grade 3 and 4 neutropenia rates of 90% versus\u000d\u000a      57% and grade 3\u000d\u000a      and 4 infection rates of 73 vs 29% with anthracycline versus platinum\u000d\u000a      based regimens respectively.\u000d\u000a      UoM researchers have also demonstrated lack of benefit of `newer'\u000d\u000a      chemotherapy agents with a\u000d\u000a      20% lower response rate and worse survival for pemetrexed based treatment.\u000d\u000a      These studies have\u000d\u000a      contributed to a shift from using more toxic anthracycline based regimens\u000d\u000a      in Europe and platinum — etoposide\u000d\u000a      as the mainstay of standard treatment worldwide (S2, S7).\u000d\u000a    b) UoM research has significantly contributed to the evidence base that\u000d\u000a      prophylactic cranial\u000d\u000a      irradiation reduces the incidence of symptomatic brain metastases by 25%\u000d\u000a      and doubles one year\u000d\u000a      survival from 13% to 27% in patients with incurable, extensive stage SCLC\u000d\u000a      without adverse impact\u000d\u000a      on quality of life (4) (S2, S4).\u000d\u000a    Significance of changes to guidelines\u000d\u000a    The guidelines ensure that optimal treatment regimens are administered\u000d\u000a      worldwide such that\u000d\u000a      patients can expect the same clinical outcomes regardless of where they\u000d\u000a      live and are treated. In\u000d\u000a      the early 1990s, fewer than 10% of patients with lung cancer survived for\u000d\u000a      one year from diagnosis.\u000d\u000a      While there is still much progress to be made, today, with treatment such\u000d\u000a      as gemcitabine-based\u000d\u000a      chemotherapy, survival of around one year is achieved for most patients\u000d\u000a      with advanced lung\u000d\u000a      cancer, and around 25% of patients can now expect to survive for two years\u000d\u000a      or more. With respect\u000d\u000a      to targeted therapy with gefitinib, average survival is ~20 months\u000d\u000a      compared with less than 4\u000d\u000a      months with no treatment and 9 months with chemotherapy alone.\u000d\u000a    The UK NICE guidelines for lung cancer treatment also inform the\u000d\u000a      treatments that are reimbursed\u000d\u000a      by National Health Service Funding. UoM research contributed to the\u000d\u000a      evidence for licensing and\u000d\u000a      funding for gemcitabine, gefitinib and erlotinib. The compliance with NICE\u000d\u000a      guidance is audited\u000d\u000a      nationally to ensure patients are benefiting from evidence based practice.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Lung cancer is the commonest cause of cancer-related mortality worldwide.\u000d\u000a      The University of\u000d\u000a      Manchester (UoM) Lung Cancer Group has generated insights that underpin\u000d\u000a      new standards of\u000d\u000a      care in the treatment of advanced, metastatic small cell (SCLC) and\u000d\u000a      non-small cell lung cancer\u000d\u000a      (NSCLC), contributed to the results required for licensing of new drugs\u000d\u000a      and secured approval for\u000d\u000a      new treatment regimens now in routine clinical use internationally. Key\u000d\u000a      contributions include an\u000d\u000a      increase in survival of 23% in advanced NSCLC with the use of chemotherapy\u000d\u000a      and doubling one-year\u000d\u000a      survival from 13% to 27% in patients with incurable, extensive stage SCLC\u000d\u000a      by the use of\u000d\u000a      prophylactic cranial irradiation. The Group's research has impacted on\u000d\u000a      outcomes for thousands of\u000d\u000a      patients worldwide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    The University of Manchester\u000d\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Key publications:\u000d\u000a    \u000a1. Ranson M, Hammond LA, Ferry D, Kris M, Tullo A, Murray PI,\u000d\u000a      Miller V, Averbuch S, Ochs J,\u000d\u000a      Morris C, Feyereislova A, Swaisland H, Rowinsky EK. ZD1839, a selective\u000d\u000a      oral epidermal growth\u000d\u000a      factor receptor-tyrosine kinase inhibitor, is well tolerated and active in\u000d\u000a      patients with solid, malignant\u000d\u000a      tumors: results of a phase I trial. Journal of Clinical Oncology.\u000d\u000a      2002;20(9):2240-50. DOI:\u000d\u000a      10.1200\/JCO.2002.10.112\u000d\u000a    \u000a\u000a2. Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M,\u000d\u000a      Hassan J, Anderson H, Burt PA,\u000d\u000a      Faivre-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher\u000d\u000a        N. Phase III trial of\u000d\u000a      gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or\u000d\u000a      mitomycin, vinblastine,\u000d\u000a      and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer.\u000d\u000a      2003;98(3):542-53.\u000d\u000a      DOI: 10.1002\/cncr.11535\u000d\u000a    \u000a\u000a3. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu\u000d\u000a      T, von Pawel J, Thongprasert\u000d\u000a      S, Tan EH, Pemberton K, Archer V, Carroll K. Gefitinib plus best\u000d\u000a      supportive care in previously\u000d\u000a      treated patients with refractory advanced non-small-cell lung cancer:\u000d\u000a      results from a randomised,\u000d\u000a      placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung\u000d\u000a      Cancer). The Lancet.\u000d\u000a      2005;366(9496):1527-37. DOI: 10.1016\/S0140-6736(05)67625-8\u000d\u000a    \u000a\u000a4. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton\u000d\u000a      M, Postmus P, Collette L,\u000d\u000a      Musat E, Senan S, Group ERO, Lung Cancer G. Prophylactic cranial\u000d\u000a      irradiation in extensive small-cell\u000d\u000a      lung cancer. The New England Journal of Medicine.\u000d\u000a      2007;357(7):664-72.\u000d\u000a      DOI: 10.1056\/NEJMoa071780\u000d\u000a    \u000a\u000a5. Baka S, Califano R, Ferraldeschi R, Aschroft L, Thatcher N,\u000d\u000a      Taylor P, Faivre-Finn C,\u000d\u000a        Blackhall F, Lorigan P. Phase III randomised trial of\u000d\u000a      doxorubicin-based chemotherapy compared\u000d\u000a      with platinum-based chemotherapy in small-cell lung cancer. British\u000d\u000a        Journal of Cancer.\u000d\u000a      2008;99(3):442-7. DOI: 10.1038\/sj.bjc.6604480\u000d\u000a    \u000a\u000a6. Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna\u000d\u000a      A, Blakely J, Serwatowski P,\u000d\u000a      Karaseva NA, Ciuleanu T, Jassem J, Dediu M, Hong S, Visseren-Grul C,\u000d\u000a      Hanauske AR, Obasaju\u000d\u000a      CK, Guba SC, Thatcher N. Phase III study of pemetrexed plus\u000d\u000a      carboplatin compared with\u000d\u000a      etoposide plus carboplatin in chemotherapy-naive patients with\u000d\u000a      extensive-stage small-cell lung\u000d\u000a      cancer. Journal of Clinical Oncology. 2009;27(28):4787-92. DOI:\u000d\u000a      10.1200\/JCO.2009.23.1548\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    S1. NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to\u000d\u000a      supportive care\u000d\u000a      improves survival in advanced non-small-cell lung cancer: a systematic\u000d\u000a      review and meta-analysis\u000d\u000a      of individual patient data from 16 randomized controlled trials. Journal\u000d\u000a        of Clinical Oncology.\u000d\u000a      2008;26(28):4617-25. DOI: 10.1200\/JCO.2008.17.7162\u000d\u000a    S2. National Institute for Health and Care Excellence. The diagnosis and\u000d\u000a      treatment of lung cancer.\u000d\u000a      CG121. London: National Institute for Health and Care Excellence, 2011.\u000d\u000a      Available from:\u000d\u000a      http:\/\/guidance.nice.org.uk\/cg121\u000d\u000a    S3. Felip E, Gridelli C, Baas P, Rosell R, Stahel R, Panel Members.\u000d\u000a      Metastatic non-small-cell lung\u000d\u000a      cancer: consensus on pathology and molecular tests, first-line,\u000d\u000a      second-line, and third-line therapy:\u000d\u000a      1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Annals of\u000d\u000a        Oncology.\u000d\u000a      2011;22(7):1507-19. DOI: 10.1093\/annonc\/mdr150.\u000d\u000a    S4. NCCN guidelines (US clinical guidelines for lung cancer treatment)\u000d\u000a      for SCLC and NSCLC.\u000d\u000a      Available from: http:\/\/www.nccn.org\/professionals\/physician_gls\/f_guidelines.asp.\u000d\u000a    S5. Campbell L, Blackhall F, Thatcher N. Gefitinib for the\u000d\u000a      treatment of non-small-cell lung\u000d\u000a      cancer. Expert Opinion on Pharmacotherapy. 2010;11(8):1343-57.\u000d\u000a      DOI: 10.1517\/14656566.2010.481283.\u000d\u000a    S6. Blackhall F, Ranson M, Thatcher N. Where next for gefitinib\u000d\u000a      in patients with lung cancer?\u000d\u000a      The Lancet Oncology. 2006;7(6):499-507.DOI:\u000d\u000a      10.1016\/S1470-2045(06)70725-2\u000d\u000a    S7. Stahel R, Thatcher N, Früh M, Le Péchoux C, Postmus PE,\u000d\u000a      Sorensen JB, Felip E, Panel\u000d\u000a      Members. 1st ESMO Consensus Conference in lung cancer; Lugano 2010:\u000d\u000a      Small-cell lung cancer.\u000d\u000a      Annals of Oncology. 2011;22(9):1973-80. DOI: 10.1093\/annonc\/mdr313\u000d\u000a    ","Title":"\u000d\u000a    Establishing the evidence for treatment to improve outcomes in patients\u000d\u000a      with lung cancer\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000d\u000a    The impact is based on research that took place at UoM from 1993 to 2013.\u000d\u000a      Key researchers:\u000d\u000a    \u000d\u000a      \u000aFiona Blackhall (NHS Consultant, 2005; Honorary Senior Clinical\u000d\u000a        Lecturer, 2007-2012;\u000d\u000a        Senior Clinical Lecturer in Oncology, 2012-date)\u000d\u000a      \u000aCorinne Faivre-Finn (NHS Consultant, 2003; Honorary Senior\u000d\u000a        Clinical Lecturer, 2007-2013;\u000d\u000a        Reader, 2013-date)\u000d\u000a      \u000aPaul Lorigan (Senior Lecturer, 2002-2004; Reader, 2004-date)\u000d\u000a      \u000aMalcolm Ranson (Senior Lecturer, 1995-2004; Professor of\u000d\u000a        Medical Oncology, 2004-date)\u000d\u000a      \u000aNicholas Thatcher (Professor of Oncology, 1996-2010)\u000d\u000a    \u000d\u000a    The research established an evidence base for treatments that have\u000d\u000a      improved outcomes for\u000d\u000a      patients with lung cancer.\u000d\u000a    1. Effective treatments for non-small cell lung cancer (NSCLC)\u000d\u000a    The Group designed and conducted ~30 early phase I\/II trials of new\u000d\u000a      agents and regimens to\u000d\u000a      establish dosing schedules, side effect profiles and efficacy in NSCLC.\u000d\u000a      This research has led to the\u000d\u000a      design and conduct of randomised phase III trials that have defined new\u000d\u000a      standards of care. UoM\u000d\u000a      researchers performed the first studies of paclitaxel, gemcitabine and\u000d\u000a      gefitinib, all now routinely\u000d\u000a      used for the first line treatment of metastatic lung cancer (1-3).\u000d\u000a    2. Optimising treatment for small cell lung cancer (SCLC)\u000d\u000a    The Group's phase I-III clinical trials have provided evidence for\u000d\u000a      platinum and etoposide\u000d\u000a      chemotherapy, thoracic and prophylactic cranial irradiation in small cell\u000d\u000a      lung cancer, and important\u000d\u000a      evidence against dose intense chemotherapy regimens and newer chemotherapy\u000d\u000a      drugs such as\u000d\u000a      pemetrexed (4-6).\u000d\u000a    The Group has designed, conducted, analysed and published results from 77\u000d\u000a      clinical trials of new\u000d\u000a      treatments or regimens in patients with lung cancer since 1993, 28 of\u000d\u000a      which were published from\u000d\u000a      2008 to present.\u000d\u000a    "},{"CaseStudyId":"28099","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000a    (See section 5 for corroborating sources S1-S10.)\u000a    Context\u000a      Clayton's research group has demonstrated, using a very rare\u000a      population in Brazil as an exemplar, the effect of severe growth hormone\u000a      deficiency on hormone profiles and phenotype and, using discovery science,\u000a      how new molecular aetiologies for growth disorders can be found. The\u000a      impact of this in clinical practice is that standards have been set\u000a      against which milder forms of GH deficiency commonly treated in first\u000a      world countries should be compared. The research has brought about\u000a      improvements in the management of growth disorders and has paved the way\u000a      for new diagnostic tests.\u000a    Pathways to impact\u000a      Clayton's research provided important insights to inform the\u000a      construction of consensus guidelines for less severe growth disorders — in\u000a      particular which tests should be carried out and in which circumstances.\u000a      He was selected by International Societies to chair and\/or sit on the\u000a      steering\/organising committees of five growth-related workshops (S1-S5).\u000a      These meetings brought together experts representing the global\u000a      paediatric endocrine community (with European, North American, Canadian,\u000a      South American and Asia-Pacific Societies invited), the Pharma Industry\u000a      and Regulatory Bodies (US FDA) to generate guideline publications for\u000a      clinical use.\u000a    Reach and significance of the impact\u000a      Improved management of growth disorders\u000a      The consensus guidelines (S1-S5) have been cited ~700 times, have been\u000a      used internationally to guide clinicians in pragmatic management, to\u000a      support licensing applications (e.g. recombinant human (r-h)GH licence for\u000a      treating short small for gestational age children in Japan), to guide\u000a      Medical Insurance Company funding for r-hGH treatment and have been\u000a      scrutinised extensively by Pharma. Estimates of the worldwide spend on\u000a      r-hGH are difficult to make, but it is known that r-hGH prescriptions in\u000a      the UK total ~£30m per year (5000 children on treatment) and in the US\u000a      (for paediatric indications) ~$1bn (~50,000 on treatment).\u000a    Clayton's work in severe growth hormone deficiency provided him\u000a      with the appropriate expertise to write (with Patel) evidence for\u000a      NICE technology appraisal guidance 188, Human growth hormone\u000a        (somatropin) for the treatment of growth failure in children (2010;\u000a      review of NICE TA42, 2002) (S6). Clayton's evidence for TA188, a\u000a      review on treating a child with GHD, was prepared on behalf of the British\u000a      Society for Paediatric Endocrinology and Diabetes (BSPED) and informed the\u000a      NICE guidance (S6, TA188, p. 45; BSPED submission acknowledged; source\u000a      authors not directly credited in the NICE TA process). Clayton\u000a      also produced evidence on behalf of BSPED for the NICE TA42 process in\u000a      2002 (S6, TA42). The NICE guidance determines the criteria for children\u000a      who should receive r-hGH, how much benefit should be derived from the\u000a      treatment and guidelines on how the treatment should be monitored. This\u000a      relates to ~5,000 children treated with r-hGH in the UK, including ~800\u000a      new prescriptions each year (S7).\u000a    The international paediatric endocrine community has always considered\u000a      evaluation of the long-term safety of recombinant human GH as a major\u000a      priority (considering issues such as the potential link between use of\u000a      rhGH and cancer and the occurrence of Creutzfeldt-Jacob disease associated\u000a      with the use of pituitary-derived GH), and thus safety has always been a\u000a      part of Consensus guidelines (in particular S2). Long-term (post-GH)\u000a      pharmacovigilance had not been directly addressed; a consortium from 8\u000a      European countries were awarded an EU grant (2009-2011) to focus on this\u000a      issue (S8). A cohort of ~25,000 r-hGH users, now adults, are under\u000a      surveillance, including ~4,000 in the UK.\u000a    R-hGH is a `high-cost' drug: ensuring r-hGH is used as effectively as\u000a      possible is a priority. One approach is to predict response at initiation\u000a      of treatment. It is recognised that pharmacogenomics can be used in the\u000a      management of growth disorders treated with GH (see, e.g., Clayton P\u000a      et al., Eur J Endocrinol. 2013 Jul 29;169(3):277-89). MerckSerono\u000a      has invested an estimated €15m in PREDICT (S9), an international (14\u000a      countries) research programme to investigate further the role of\u000a      pharmacogenomics in managing growth disorders. Clayton is Co-Chief\u000a      Investigator with Chatelain from Lyon, France. PREDICT is relevant to all\u000a      children worldwide treated with r-hGH, and aims to identify the ~10% of\u000a      children in whom r-hGH is ineffective and should be stopped, thereby\u000a      significantly enhancing the cost-benefit ratio. (The estimated incremental\u000a      cost per quality adjusted life-year (QALY) for r-hGH treatment in the UK\u000a      is currently £23k for GHD and £33k for the short SGA child).\u000a    Making molecular diagnoses in primordial growth disorders\u000a      Following its identification of genes associated with 3-M, Manchester has\u000a      become a recognised centre for referral of potential 3-M cases both for a\u000a      clinical opinion and a molecular diagnosis (from the UK and ~10 countries\u000a      worldwide). Manchester receives requests at ~1 per month, has assessed\u000a      ~100 families, and has now developed new techniques (Haloplex Next Gen\u000a      Exome Sequencing on targeted genes) for routine clinical use. The\u000a      commercial sector has recognised the need for molecular testing in 3-M,\u000a      and companies in the US are now offering to sequence 3-M genes (www.ctgt.net\/\u000a      Sequencing Costs: CUL7 $1830, OBSL1 $1680, CCDC8 $595).\u000a    A 3-M website has been established to provide information on UoM work on\u000a      3-M (http:\/\/3msyndrome.com\/), and\u000a      over the 8 months during which detailed visit statistics have been\u000a      collated, there has been a total of 1,896 views from 40 countries, with\u000a      30-40 visits per month and 70-160 page views. Contact from parents also\u000a      led to the genesis of grouped growth data on their 3-M children.\u000a    The interest in making specific genetic diagnoses has led Pharma\u000a      companies that market r-hGH to develop programmes that evaluate genetic\u000a      contributions to short stature of as yet undefined aetiology (ISS). One\u000a      example is Ipsen's EPIGROW, a pharmacoepidemiological study across 8\u000a      European countries to identify genes related to ISS. Clayton was\u000a      invited to be the Chief Investigator and at completion of the study (S10)\u000a      has received all the data from the study for further data mining under a\u000a      Material Transfer Agreement between Ipsen and UoM.\u000a    ","ImpactSummary":"\u000a    One in ~1,000 children has significant short stature that needs medical\u000a      evaluation, one in ~4,000 has growth hormone deficiency and one in\u000a      ~≥10,000 has a genetic growth disorder. Research at the University of\u000a      Manchester (UoM) has impacted on clinicians worldwide who manage growth\u000a      disorders. UoM researchers have: characterised growth disorder phenotypes\u000a      to ensure the right tests are used for the right child and verified the\u000a      accuracy of diagnostic biochemical tests; discovered new genes associated\u000a      with a primordial growth disorder and introduced new molecular diagnostic\u000a      tests for international use; and generated clinical practice guidelines\u000a      adopted by the worldwide paediatric endocrine community.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2996944","Name":"Lyon"}],"References":"\u000a    \u000a1. Aguiar-Oliveira MH, Gill MS, de ES, Barretto A, Alcântara MRS,\u000a      Miraki-Moud F, Menezes CA, Souza AHO, Martinelli CE, Pereira FA, Salvatori\u000a      R, Levine MA, Shalet SM, Camacho-Hubner C, Clayton PE. Effect of\u000a      Severe Growth Hormone (GH) Deficiency due to a Mutation in the\u000a      GH-Releasing Hormone Receptor on Insulin-Like Growth Factors (IGFs),\u000a      IGF-Binding Proteins, and Ternary Complex Formation Throughout Life. Journal\u000a        of Clinical Endocrinology & Metabolism. 1999;84(11):4118-26.\u000a      DOI: 10.1210\/jc.84.11.4118\u000a      Provided evidence in an `exemplar' cohort of the impact of severe GH\u000a        deficiency on serum biomarkers, providing evidence of which marker was\u000a        the most useful in clinical practice.\u000a    \u000a\u000a2. Gleeson HK, Souza AHO, Gill MS, Wieringa GE, De A. Barretto ES,\u000a      Barretto-Filho JAS, Shalet SM, Aguiar-Oliveira MH, Clayton PE.\u000a      Lipid profiles in untreated severe congenital isolated growth hormone\u000a      deficiency through the lifespan. Clinical Endocrinology.\u000a      2002;57(1):89-95. DOI: 10.1046\/j.1365-2265.2002.01568.x\u000a      Provided evidence in an `exemplar' cohort of the impact of severe GH\u000a        deficiency on serum lipid profiles in both adults and children as a\u000a        potential marker of cardiovascular risk.\u000a    \u000a\u000a3.Huber C, Dias-Santagata D, Glaser A, O'Sullivan J, Brauner R, Wu K, Xu\u000a      X, Pearce K, Wang R, Uzielli MLG, Dagoneau N, Chemaitilly W, Superti-Furga\u000a      A, Santos HD, Megarbane A, Morin G, Gillessen-Kaesbach G, Hennekam R,\u000a      Burgt IVd, Black GCM, Clayton PE, Read A, Merrer ML,\u000a      Scambler PJ, Munnich A, Pan Z-Q, Winter R, Cormier-Daire V. Identification\u000a      of mutations in CUL7 in 3-M syndrome. Nature Genetics.\u000a      2005;37(10):1119-24. DOI: 10.1038\/ng1628\u000a      The first description of a gene causing the 3-M syndrome in patients\u000a        for all over the world. This also demonstrated that 3-M and Gloomy Face\u000a        syndromes were in fact the same condition.\u000a    \u000a\u000a4.Hanson D, Murray PG, Sud A, Temtamy SA, Aglan M, Superti-Furga\u000a      A, Holder SE, Urquhart J, Hilton E, Manson FDC, Scambler P, Black\u000a        GCM, Clayton PE. The Primordial Growth Disorder 3- M Syndrome\u000a      Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1. The\u000a        American Journal of Human Genetics. 2009;84(6):801-6. DOI:\u000a      10.1016\/j.ajhg.2009.04.021\u000a      The first description of the second gene causing 3-M syndrome.\u000a        2007-2010 Medical Research Council  —\u000a        Clinical Training Fellowship for Dr P Murray — The Role of Disordered\u000a        Ubiquitination in Pre — and Post-natal Growth Restriction. Clayton\u000a        & Black. Award £157,482.\u000a    \u000a\u000a5.Hanson D, Murray PG, O'Sullivan J, Urquhart J, Daly S,\u000a      Bhaskar Sanjeev S, Biesecker Leslie G, Skae M, Smith C, Cole T, Kirk J,\u000a      Chandler K, Kingston H, Donnai D, Clayton PE, Black GCM. Exome\u000a      Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that\u000a      CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human\u000a      Growth. The American Journal of Human Genetics. 2011;89(1):148-53.\u000a      DOI: 10.1016\/j.ajhg.2011.05.028\u000a      The first description of the third gene causing 3-M syndrome, including\u000a        functional data on the physical relationships between the three proteins\u000a        and the recognition of a new growth pathway.\u000a    \u000a\u000a6.Hanson D, Murray PG, Coulson T, Sud A, Omokanye A,\u000a      Stratta E, Sakhinia F, Bonshek C, Wilson LC, Wakeling E, Temtamy SA, Aglan\u000a      M, Rosser EM, Mansour S, Carcavilla A, Nampoothiri S, Khan WI, Banerjee I,\u000a      Chandler KE, Black GCM, Clayton PE. Mutations in CUL7, OBSL1 and\u000a      CCDC8 in 3-M syndrome lead to disordered growth factor signalling. Journal\u000a        of Molecular Endocrinology. 2012;49(3):267-75. DOI:\u000a      10.1530\/JME-12-0034\u000a      Phenotypic detail on 3-M patients with different mutations, including\u000a        in vitro cellular responses to the growth factors GH and IGF-I.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    S1. Consensus Guidelines for the Diagnosis and Treatment of Growth\u000a      Hormone (GH) Deficiency in Childhood and Adolescence: Summary Statement of\u000a      the GH Research Society. Journal of Clinical Endocrinology &\u000a        Metabolism. 2000;85(11):3990-3. Report of a Workshop ( Clayton\u000a      a principal author) (2000)\u000a    S2. Critical Evaluation of the Safety of Recombinant Human Growth Hormone\u000a      Administration: Statement from the Growth Hormone Research Society. Journal\u000a        of Clinical Endocrinology & Metabolism. 2001;86(5):1868-70. Report\u000a        of a Workshop ( Clayton on the writing panel)\u000a        (2001).\u000a    S3. Clayton PE, Cuneo RC, Juul A, Monson JP, Shalet SM, Tauber M.\u000a      Consensus statement on the management of the GH-treated adolescent in the\u000a      transition to adult care. European Journal of Endocrinology.\u000a      2005;152(2):165-70.\u000a    S4. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R,\u000a      Rogol A. Management of the Child Born Small for Gestational Age through to\u000a      Adulthood: A Consensus Statement of the International Societies of\u000a      Pediatric Endocrinology and the Growth Hormone Research Society. Journal\u000a        of Clinical Endocrinology & Metabolism. 2007;92(3):804-10.\u000a    S5. Ho KKY. Consensus guidelines for the diagnosis and treatment of\u000a      adults with GH deficiency II: a statement of the GH Research Society in\u000a      association with the European Society for Pediatric Endocrinology, Lawson\u000a      Wilkins Society, European Society of Endocrinology, Japan Endocrine\u000a      Society, and Endocrine Society of Australia. European Journal of\u000a        Endocrinology. 2007;157(6):695-700. Clayton on\u000a        writing committee.\u000a    S6. Human Growth Hormone (somatropin) for the treatment of growth failure\u000a      in children NICE Technology appraisal guidance 42, 2002.\u000a      Human Growth Hormone (somatropin) for the treatment of growth failure in\u000a      children. Review of NICE Technology appraisal guidance 42, Guidance 188,\u000a      2010.NICE guidelines for the use of r-hGH in children, to which Clayton\u000a      contributed.\u000a    S7. Kirk J. Indications for growth hormone therapy in children. Archives\u000a        of Disease in Childhood. 2012;97(1):63-8. This is an article on\u000a        the current use of r-hGH in the UK, giving an indication of the number\u000a        of children in one European country for which clinical guidelines are\u000a        relevant to their management.\u000a    S8. 2009-2011 FP7 European Union — Safety and Appropriateness of Growth\u000a      hormone treatments in Europe — Award €2,989,154 (UK share €519,882, of\u000a      which €134,792 to UoM)) with UK investigators including Clayton\u000a      (UoM), Butler (University College London), Swerdlow (Institute of Cancer\u000a      Research, London).\u000a    S9. Clinical Trials references for the 1 month initial PREDICT study, the\u000a      long-term follow-up phase and the validation study (available from UoM on\u000a      request).\u000a    S10. Clayton P, Bonnemaire M, Dutailly P, Maisonobe P, Naudin L,\u000a      Pham E, Zhang Z, Grupe A, Thiagalingam A, Denèfle P, Group tES.\u000a      Characterizing Short Stature by Insulin-like Growth Factor Axis Status and\u000a      Genetic Associations: Results From the Prospective, Cross-sectional,\u000a      Epidemiogenetic EPIGROW Study. Journal of Clinical Endocrinology &\u000a        Metabolism. 2013;98(6):E1122-E30.\u000a    ","Title":"\u000a    Defining the phenotype of severe growth disorders, discovering new genes\u000a      that control human growth and enhancing clinical practice\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    (See section 3 for references 1-6; UoM researchers are given in bold.)\u000a    Key UoM researchers:\u000a    \u000a      \u000aPeter Clayton (Lecturer, 1992-1994; Senior Lecturer, 1994-2001;\u000a        Professor, 2001-date)\u000a      \u000aGraeme Black (Lecturer, 1995-1997; Senior Lecturer, 1997-2003;\u000a        Professor, 2003-date)\u000a      \u000aAndrew Read (Reader in Medical Genetics, 1992-1995; Professor\u000a        of Human Genetics 1995-2004; Honorary Professor of Human Genetics\u000a        2004-date)\u000a      \u000aForbes Manson (Lecturer, 2002-2005; Senior Lecturer, 2005-date)\u000a      \u000aDan Hanson (Research Associate, 2008-date)\u000a      \u000aLeena Patel (Lecturer, 1992-1994; Clinical Lecturer, 1994-1995;\u000a        Senior Lecturer, 1995- 1998; Clinical Senior Lecturer, 1998-date)\u000a    \u000a    This work was initiated at UoM in 1997 as a collaboration between Clayton\u000a      and Oliveira (Brazil) to work on a cohort of highly consanguineous very\u000a      short people. UoM's collaborators in the US (Salvatore, John Hopkins, USA)\u000a      had identified that this cohort had an autosomal recessive form of severe\u000a      isolated growth hormone deficiency (GHD) due to an inactivating mutation\u000a      in the GH releasing hormone receptor gene (GHRH-R).\u000a    The research characterised the effects of untreated severe GHD on\u000a      phenotype, biomarkers of GH action for diagnostic purposes (1) and\u000a      metabolic consequences (2), based on field-work in Brazil and analysis of\u000a      anthropometric data and samples brought to Manchester.\u000a    While working with this cohort in the field in Brazil, Clayton\u000a      recognised that some adults and children (clustered in one section of the\u000a      pedigree of the whole cohort) did not have GHD but were still very short.\u000a      Clayton identified the features of another growth disorder — the\u000a      3-M syndrome — a primordial growth disorder characterised by small size at\u000a      birth followed by poor post-natal growth resulting in a height in\u000a      childhood similar to untreated GHD, but in this case with intact GH\u000a      secretion. The 3-M syndrome was known to be an autosomal recessive\u000a      disorder but in the early 2000s no gene had been identified.\u000a    Clayton and UoM colleagues went on to find the first gene (CUL7)\u000a      associated with 3-M in 2005 at a similar time to Cormier-Daire's group in\u000a      Paris; the work was published by all who had contributed to finding this\u000a      first gene (3). UoM researchers started to build a cohort of patients with\u000a      3-M syndrome in Manchester from the local population and from regional,\u000a      national and international referrals. However no mutations in CUL7 were\u000a      found in these patients. This outcome led to a new round of autozygosity\u000a      mapping, leading to the discovery of the second gene (OBSL1) (4)\u000a      in 2008 and the third gene (CCDC8) (5) in 2010 (the latter\u000a      using the new technique of exome sequencing). As a result a new pathway\u000a      controlling growth has been defined. The 3-M syndrome is a `pure' growth\u000a      disorder without other major system disorders (unlike many other\u000a      primordial growth disorders), and is therefore an excellent model to\u000a      define growth mechanisms. Skin fibroblast cell lines from patients with\u000a      each of the mutations have been used to define their impact on cell\u000a      growth, growth factor signalling, gene expression, and metabolomic\u000a      profiles, all leading to a systems approach to identify the 3-M\u000a      interactome, and hence new candidates for primordial growth disorders (6).\u000a    "},{"CaseStudyId":"28100","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S9.\u000a    Context\u000a    While individually uncommon, rare diseases as a group represent a major\u000a      public health issue. By\u000a      definition each individual rare disease affects fewer than five in 10,000\u000a      people, but taken together\u000a      they are common, with one in 17 people affected in the UK by a rare\u000a      disease (S1, p. 7). Although\u000a      there are many thousands of different rare diseases, they frequently share\u000a      a number of\u000a      characteristics. These include a severe, chronic, often degenerative and\u000a      sometimes life-threatening\u000a      course. Most rare diseases are incurable and lack effective treatment.\u000a    Pathways to impact\u000a    The identification of the genetic basis of a rare disease by UoM\u000a      immediately allows for\u000a      diagnostic\/confirmatory testing in suspected cases, as well as carrier and\u000a      prenatal diagnostic\u000a      testing for individuals and couples worldwide.\u000a    Reach and significance of the impact\u000a    Since 1993, researchers at UoM have identified the molecular basis of 29\u000a      genetic diseases.\u000a      Testing for these conditions is now offered in more than 140 laboratories\u000a      in more than 30 countries\u000a      worldwide.\u000a    As specific examples, testing of PAX3, TCOF1, IRF6\u000a      and C9ORF72 is offered in, respectively, 42,\u000a      28, 39 and 36 laboratories officially registered in Europe and the USA\u000a      (S2, S3).\u000a    Considering individual tests in the UK only, for which numbers are most\u000a      easily collated, screening\u000a      for mutations in TCOF1 has been undertaken in more than 500\u000a      patients in the Manchester and\u000a      Oxford NHS diagnostic laboratories since 1997 (S4, S5), for mutations in BEST1\u000a      in more than 250\u000a      patients in the Manchester NHS diagnostic laboratory since 2008 (S4), for\u000a      mutations in IRF6 in\u000a      more than 170 patients at Great Ormond Street Hospital since 2005 (S6),\u000a      for mutations in\u000a      SAMHD1 in more than 80 patients in the Leeds NHS diagnostic\u000a      laboratory since 2009 (S7), and for\u000a      mutations in C9ORF72 in more than 170 patients in the UCL and\u000a      Cardiff NHS laboratories since\u000a      2011 (S8).\u000a    The availability of a genetic test can obviate the need for other more\u000a      invasive, expensive, and time-consuming\u000a      investigations. Thus, in a recent report from Rare Disease UK (S9, p. 9),\u000a      of 597\u000a      patients affected by a rare disease, one in five (20%) waited over five\u000a      years, and over one in 10\u000a      (12%) waited over 10 years for a diagnosis. Related to this delay in\u000a      diagnosis, over two thirds\u000a      (68%) of patients saw three or more doctors before their final diagnosis\u000a      was made, and over one in\u000a      five (22%) saw six or more doctors. Of extra significance, close to half\u000a      (46%) of patients were given\u000a      incorrect diagnoses before receiving their final diagnosis, and almost one\u000a      third (30%) had received\u000a      three or more misdiagnoses. These delays and misdiagnoses can be prevented\u000a      for the 29 genetic\u000a      diseases which UoM researchers have identified on a molecular basis.\u000a    Delays in diagnosis and multiple visits to doctors are a drain on\u000a      health-care resources, which can\u000a      be more efficiently used where the genetic basis of a disease is known,\u000a      and a gene test is\u000a      available. It is obvious, but worth stating, that the tortuous pathway to\u000a      diagnosis described above\u000a      can be tremendously stressful for patients and families.\u000a    Not only does the identification of the genetic basis of a disease allow\u000a      for diagnostic testing, it also\u000a      enables appropriate counselling of parents and other relatives and the\u000a      provision of prenatal testing\u000a      where that is considered relevant and appropriate. The importance of\u000a      offering choice to families\u000a      and couples in this situation is not easily measured, but must be\u000a      understood and emphasised.\u000a      Consider a couple with a child affected by a severe neurological condition\u000a      (e.g. Aicardi-Goutières\u000a      syndrome now known to be due to mutations in SAMHD1). Prior to\u000a      2009, the parents would have\u000a      been told that there was a 1 in 4 chance of having another similarly\u000a      affected child in a future\u000a      pregnancy, but that no testing was available. They could either decide to\u000a      have no further children,\u000a      adopt, or `take their chance' — a terrifying possibility for many couples.\u000a      The advent of a genetic test\u000a      allows couples in this situation to make informed choices — an advance the\u000a      benefits of which are\u000a      difficult to quantify but of undoubted importance.\u000a    ","ImpactSummary":"\u000a    Although, by definition, individually rare, the cumulative burden of\u000a      `rare disease' is significant, with\u000a      as many as 3m affected individuals in the UK. The University of Manchester\u000a      (UoM) has an\u000a      exceptional record in rare disease gene identification, with 29 such genes\u000a      defined since 1993. This\u000a      research paved the way for clinical diagnostic testing for patients and\u000a      their families, demonstrating\u000a      the immediate translational impact of gene discovery. The research has\u000a      resulted in a reduced\u000a      diagnostic burden for patients and health services and has enabled the\u000a      provision of more effective\u000a      counselling. Testing for genes identified at UoM is now offered in more\u000a      than 140 laboratories in\u000a      more than 30 countries worldwide. More than 1,100 patients have been\u000a      tested for mutations in\u000a      TCOF1, BEST1, IRF6, SAMHD1 and C9ORF72 in UK NHS\u000a      laboratories alone.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000a    The following six references are key examples from a much larger body of\u000a      research produced at\u000a      UoM since 1993:\u000a    \u000a1. Tassabehji M, Read AP, Newton VE, Patton M, Gruss P, Harris R,\u000a      Strachan T. Mutations in the\u000a      PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nature\u000a        Genetics. 1993;3(1):26-30.\u000a      DOI: 10.1038\/ng0193-26\u000a    \u000a\u000a2. Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y,\u000a      Howard E, Ferreira de\u000a      Lima RLL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer\u000a      EJ, Aylsworth\u000a      AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia\u000a      C, Houdayer C,\u000a      Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ*, Murray\u000a      JC. Mutations in IRF6 cause\u000a      Van der Woude and popliteal pterygium syndromes. Nature Genetics.\u000a      2002;32(2):285-9. DOI:\u000a      10.1038\/ng985\u000a    \u000a\u000a3. Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley\u000a      DW, Tifft C, Zhang\u000a      L, Wilkie AOM, van der Smagt JJ, Gorlin RJ, Burgess SM, Bardwell VJ, Black\u000a        GCM*, Biesecker\u000a      LG. Oculofaciocardiodental and Lenz microphthalmia syndromes result from\u000a      distinct classes of\u000a      mutations in BCOR. Nature Genetics. 2004;36(4):411-6. DOI:\u000a      10.1038\/ng1321\u000a    \u000a\u000a4. Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller\u000a      JC, Jackson RM, Lamb T,\u000a      Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP,\u000a      Bertini E, Bodemer C,\u000a      Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener\u000a      B, Hamel BCJ,\u000a      Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG,\u000a      Lourenco CM, Marom\u000a      D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M,\u000a      Shalev SA, Soler\u000a      DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E,\u000a      Whittaker E, Lebon P,\u000a      Stetson DB, Bonthron DT, Crow YJ. Mutations involved in\u000a      Aicardi-Goutieres syndrome implicate\u000a      SAMHD1 as regulator of the innate immune response. Nature Genetics.\u000a      2009;41(7):829-32. DOI:\u000a      10.1038\/ng.373\u000a    \u000a\u000a5. Renton Alan E, Majounie E, Waite A, Simón-Sánchez J, Rollinson S,\u000a      Gibbs JR, Schymick\u000a      Jennifer C, Laaksovirta H, van Swieten John C, Myllykangas L, Kalimo H,\u000a      Paetau A, Abramzon Y,\u000a      Remes Anne M, Kaganovich A, Scholz Sonja W, Duckworth J, Ding J, Harmer\u000a      Daniel W,\u000a      Hernandez Dena G, Johnson Janel O, Mok K, Ryten M, Trabzuni D, Guerreiro\u000a      Rita J, Orrell\u000a      Richard W, Neal J, Murray A, Pearson J, Jansen Iris E, Sondervan D,\u000a      Seelaar H, Blake D, Young\u000a      K, Halliwell N, Callister Janis B, Toulson G, Richardson A, Gerhard A,\u000a      Snowden J, Mann D, Neary\u000a      D, Nalls Michael A, Peuralinna T, Jansson L, Isoviita V-M, Kaivorinne A-L,\u000a      Hölttä-Vuori M, Ikonen\u000a      E, Sulkava R, Benatar M, Wuu J, Chiò A, Restagno G, Borghero G, Sabatelli\u000a      M, Heckerman D,\u000a      Rogaeva E, Zinman L, Rothstein Jeffrey D, Sendtner M, Drepper C, Eichler\u000a      Evan E, Alkan C,\u000a      Abdullaev Z, Pack Svetlana D, Dutra A, Pak E, Hardy J, Singleton A,\u000a      Williams Nigel M, Heutink P,\u000a      Pickering-Brown S*, Morris Huw R, Tienari Pentti J, Traynor Bryan\u000a      J. A Hexanucleotide Repeat\u000a      Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron.\u000a      2011;72(2):257-68. DOI: 10.1016\/j.neuron.2011.09.010\u000a    \u000a\u000a6. Rice GI, Kasher PR, Forte GMA, Mannion NM, Greenwood SM, Szynkiewicz\u000a      M, Dickerson JE,\u000a      Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM, Bacino CA, Battini R,\u000a      Bertini E, Brogan PA,\u000a      Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I,\u000a      Fazzi E, Garcia-Cazorla\u000a      A, Heiberg A, Kawaguchi M, Kumar R, Lin J-PSM, Lourenco CM, Male AM,\u000a      Marques W,\u000a      Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M, Robinson RA,\u000a      Rozenberg F, Schmidt\u000a      JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling\u000a      EL, Wassmer E,\u000a      Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP,\u000a      O'Connell MA, Lovell\u000a      SC, Crow YJ. Mutations in ADAR1 cause Aicardi-Goutieres syndrome\u000a      associated with a type I\u000a      interferon signature. Nature Genetics. 2012;44(11):1243-8. DOI:\u000a      10.1038\/ng.2414\u000a      *Joint corresponding author\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    S1. Department of Health. 2009 Annual Report of the Chief Medical\u000a      Officer. London: Department\u000a      of Health, 2010. Available from:\u000a      http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/en\/Publicatio\u000a        nsandstatistics\/Publications\/AnnualReports\/DH_113912\u000a      Detailing the importance of rare diseases to public health.\u000a    S2. http:\/\/www.orpha.net\/consor\/cgi-bin\/ClinicalLabs_Search_Simple.php?lng=EN\u000a      Search engine of laboratories offering genetic testing (by gene \/\u000a        disease) across Europe.\u000a    S3. http:\/\/www.ncbi.nlm.nih.gov\/sites\/GeneTests\/lab?db=GeneTests\u000a      Search engine of laboratories offering genetic testing (by gene \/\u000a        disease) accredited in the\u000a        USA.\u000a    S4. Corroborating email from Consultant Clinical Scientist, Manchester\u000a      Centre for Genomic\u000a      Medicine, Central Manchester University Hospitals NHS Foundation Trust.\u000a    S5. Corroborating email from Principal Clinical Scientist, Oxford Medical\u000a      Genetics Laboratories,\u000a      Oxford University Hospitals NHS Trust.\u000a    S6. Corroborating email and data from Head of Molecular Genetics, NE\u000a      Thames Regional Genetics\u000a      Service, Great Ormond Street Hospital for Children NHS Foundation Trust.\u000a    S7. Corroborating email from Research Scientist, Yorkshire Regional DNA\u000a      Laboratory, Clinical\u000a      Genetics Service, St James's University Hospital, Leeds.\u000a    S8. Corroborating email from Clinical Scientist, Institute of Medical\u000a      Genetics, University Hospital of\u000a      Wales. Corroborating email from UCL also available.\u000a    S9. Limb L, Nutt S, Sen A. Experience of Rare Diseases: An Insight from\u000a      Patients and Families.\u000a      London: Rare Disease UK, 2010. Available from:\u000a      http:\/\/www.raredisease.org.uk\/documents\/RDUK-Family-Report.pdf\u000a      Detailed survey of the experiences of patients and families affected by\u000a        rare diseases.\u000a    ","Title":"\u000a    The global impact of gene identification at the University of Manchester\u000a    ","UKLocation":[{"GeoNamesId":"2644688","Name":"Leeds"},{"GeoNamesId":"2643123","Name":"Manchester"},{"GeoNamesId":"2653822","Name":"Cardiff"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a      Research activity was carried out between 1993 and the present. The\u000a      following researchers were\u000a      all working at UoM at the time of the stated outputs:\u000a    \u000a      \u000aAndrew Read (Reader, 1992-1995; Professor, 1995-2004; Honorary\u000a        Professor, 2004-date)\u000a      \u000aMay Tassabehji (Wellcome Senior Fellow, 1996-2007; Senior\u000a        Research Fellow, 2007;\u000a        Reader, 2007-date)\u000a      \u000aMike Dixon (Professor, 1996-date)\u000a      \u000aGraeme Black (Lecturer, 1995-1997; Senior Lecturer, 1997-2003;\u000a        Professor, 2003-date)\u000a      \u000aJill Clayton-Smith (Honorary Senior Lecturer, 1998-2006;\u000a        Honorary Professor, 2006-date)\u000a      \u000aWilliam Newman (Research Training Fellow, 1997-2000; Clinical\u000a        Senior Lecturer, 2004-date)\u000a      \u000aYanick Crow (Professor, 2008-date)\u000a      \u000aNalin Thakkar (Lecturer, 1992-1996; Senior Lecturer, 1996-2003;\u000a        Professor, 2003-date)\u000a      \u000aMichael Briggs (Postdoctoral Fellow, 1996-2000; Research\u000a        Fellow, 2001-2005; Reader,\u000a        2005-2012)\u000a      \u000aStuart Pickering-Brown (Professor, 2005-date)\u000a    \u000a    Outputs are only considered where:\u000a    \u000a      At least one of the above UoM members of staff was the Corresponding\u000a          Author (Principal\u000a          Investigator) on the study;\u000a      Where the publication represents the first reporting of the disease\u000a        gene, i.e. before the\u000a        publication, the genetic basis of the study disease was unknown.\u000a    \u000a    The discoveries linked to impact relate to the following genes and their\u000a      associated phenotype\u000a      (investigator and year of discovery in parenthesis):\u000a    \u000a      \u000aPAX3: Waardenburg syndrome type 1 and 2 (Read, Tassabehji:\u000a        1993) (1)\u000a\u000a      \u000aMITF: Waardenburg syndrome (Read; Tassabehji:\u000a        1994)\u000a      \u000aTCOF1: Treacher Collins syndrome (Dixon: 1997)\u000a      \u000aCathepsin C: Papillon-Lefèvre syndrome (Thakkar: 1999)\u000a      \u000aENAM: Amelogenesis imperfecta (Dixon: 2001)\u000a      \u000aMatrilin-3: Multiple epiphyseal dysplasia (Briggs: 2001)\u000a      \u000aMAF: Congenital cataract, anterior segment dysgenesis and\u000a        coloboma (Black: 2002)\u000a      \u000aIRF6: Van der Woude syndrome (Dixon: 2002) (2)\u000a\u000a      \u000aBCOR: Oculofaciocardiodental and Lenz syndromes (Black:\u000a        2004) (3)\u000a\u000a      \u000aBEST1: Autosomal recessive `Bestrophinopathy' (Black:\u000a        2008)\u000a      \u000aOBSL1: 3M syndrome (Black: 2009)\u000a      \u000aSAMHD1: Aicardi-Goutières syndrome (Crow: 2009) (4)\u000a\u000a      \u000aC2ORF71: Retinitis pigmentosa (Black: 2010)\u000a      \u000aHPSE2: Urofacial syndrome (Newman: 2010)\u000a      \u000aOCLN: Band-like calcification with polymicrogyria (Crow:\u000a        2010)\u000a      \u000aACP5: Spondyloenchondrodysplasia (Crow: 2011)\u000a      \u000aDHFR: Dihydrofolate reductase deficiency syndrome (Newman:\u000a        2011)\u000a      \u000aFAM20A: Amelogenesis imperfecta (Dixon: 2011)\u000a      \u000aPRDM5: Brittle cornea syndrome (Black: 2011)\u000a      \u000aCCDC8: 3M syndrome (Black: 2011)\u000a      \u000aC9ORF72: Motor neurone disease (Pickering-Brown: 2011) (5)\u000a\u000a      \u000aKAT6B: Ohdo syndrome (Clayton-Smith: 2011)\u000a      \u000aRIPK4: Bartsocas-Papas syndrome (Dixon: 2012)\u000a      \u000aCTC1: Coats plus syndrome (Crow: 2012)\u000a      \u000aADAR1: Aicardi-Goutières syndrome (Crow: 2012) (6)\u000a\u000a      \u000aCLPP: Perrault syndrome (Newman: 2013)\u000a      \u000aSMARCE1: Multiple spinal meningioma (Newman: 2013)\u000a      \u000aLRIG2: Urofacial syndrome (Newman: 2013)\u000a      \u000aPRKCD: Systemic lupus erythematosus (Crow: 2013)\u000a    \u000a    Disease genes were identified through a combination of patient\u000a      recruitment, expert clinical\u000a      selection and detailed phenotyping, allied to state-of-the-art genetic\u000a      techniques including linkage\u000a      analysis, homozygosity mapping, candidate gene sequencing and, most\u000a      recently, next-generation\u000a      technologies. The advent of new technologies has been mirrored by an\u000a      increased rate of gene\u000a      identification since 2010.\u000a    "},{"CaseStudyId":"28101","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S10.\u000a    Pathway to impact\u000a    The epidemiological work on NF1 and NF2 at UoM in the 1990s (Evans\u000a      and colleagues) and\u000a      consensus guidelines on NF1 (6) and NF2 (4) in 2007 and 2005 respectively\u000a      led to the\u000a      development of national services.\u000a    Evans wrote the application for the national services, holding\u000a      meeting with stakeholders over a 6-month\u000a      period to secure support from colleagues in neurosurgery and ENT\u000a      nationally, as well as\u000a      liaising with the National Commissioning Group. The epidemiology and\u000a      mortality data published by\u000a      Evans, in particular the statistically significant improved\u000a      survival in specialist centres, was pivotal\u000a      to the success of the application. Work on ABI led by Ramsden was\u000a      also critical to this success.\u000a    Reach and significance of the impact\u000a    The national NF1 service (annual funding £2.5m) was commissioned in 2009;\u000a      the NF2 service\u000a      (annual funding £7.5m) followed in 2010.\u000a    Manchester is the lead centre of 4 UK centres for NF2 (S1), and is led by\u000a      Evans. Huson (with\u000a      Evans) runs the English complex NF1 service (S2), which is one of\u000a      just two centres. Since the\u000a      inception of these services, epidemiological mortality predictions have\u000a      been confirmed (S3, S4),\u000a      with evidence of an improvement in survival from NF1\/NF2 from specialist\u000a      management in\u000a      Manchester from 1990 (S4).\u000a    All 850 patients with NF2 in England and the ~800 complex NF1 patients\u000a      are managed through the\u000a      national services. The Neuro Foundation, which provides support nationally\u000a      in England for NF\u000a      patients, has confirmed that it is `fully supportive of the work being\u000a      undertaken by the team in\u000a      Manchester' (S5).\u000a    UoM through Ramsden developed both Cochlear and Brain Stem\u000a      Implants (ABI) and pioneered\u000a      this service in NF2. Manchester is only one of two centres providing this\u000a      service in the UK. The\u000a      Managing Director of the principal provider of implants, MED-EL, has\u000a      confirmed the expertise and\u000a      leadership in Manchester: `MED-EL hearing implants have been implanted by\u000a      the Manchester\u000a      Cochlear Implant Programme since the late 1990s and as such we have been\u000a      privileged to be\u000a      involved with one of the world's leading centres as both Cochlear\u000a      implantation as well as Auditory\u000a      Brain Stem implantation have moved from pioneering treatments to\u000a      established medical\u000a      techniques.' (S6) The impact of the UoM research on treatment and services\u000a      in the UK and\u000a      internationally is also noted: `the University research base into NF2 is\u000a      equally acknowledged to be\u000a      world class. This research base underpins the appropriate provision of\u000a      treatment as well as\u000a      driv[ing] advances for the UK's national ABI service. Indeed, I may also\u000a      comment [that]\u000a      Manchester's ABI specific research expertise has been drawn upon in\u000a      respect of [the]\u000a      establishment of the South African National ABI Programme' (S6).\u000a    The UK model for management of NF is highly regarded in Europe and North\u000a      America. The French\u000a      network is in the process of trying to establish a similar initiative in\u000a      France. The director of the\u000a      French NF2 centre acknowledges the improved prognosis associated with\u000a      specialist management\u000a      of NF2 and affirms that he is working with Evans in order to\u000a      `convince the French medical\u000a      community [...] to try to develop the same organization' (S7).\u000a    The impact arising from this work is continuing, with Manchester\u000a      centrally involved in taking\u000a      forward new initiatives on medical treatment of NF. Evans\u000a      co-chaired the first international initiative\u000a      and authored the publication on developing clinical trials (S8) and also\u000a      co-chaired the second\u000a      initiative (S9). An international state-of-the-art conference was held in\u000a      Manchester in 2012 and the\u000a      Manchester group continues to lead translational collaborative research.\u000a      The US-based Childrens'\u000a      Tumor Foundation sponsored these meetings and the Chief Scientific Officer\u000a      of the Foundation\u000a      confirmed that: `Dr Evans has been an opinion leader on behalf of\u000a      CTF, leading Consensus\u000a      conferences on schwannomatosis and NF2. The members of Manchester's team\u000a      are considered to\u000a      be key opinion leaders in Europe for NF: Dr Evans for NF2 and\u000a      Schwannomatosis, and Dr Huson\u000a      for NF1' (S10). Since the original 2008 meeting, when there were virtually\u000a      no clinical drug trials in\u000a      NF, there are now over 20 in progress or closed to recruitment.\u000a    ","ImpactSummary":"\u000a    Research conducted at the University of Manchester (UoM) has brought\u000a      about significantly\u000a      improved management of neurofibromatosis type 2 (NF2) and\u000a      neurofibromatosis type 1 (NF1). The\u000a      demonstration of a survival advantage in NF2 from specialist management\u000a      centres by Evans and\u000a      the pioneering work on brain stem\/cochlear implants by Ramsden and\u000a      team were deciding factors\u000a      for the creation of nationally commissioned services for NF1 and NF2 in\u000a      2009 and 2010. All 850\u000a      patients with NF2 in England and ~800 complex NF1 patients are now managed\u000a      through the\u000a      national services. This specialist management of neurofibromatoses leads\u000a      to improved life\u000a      expectancy.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Evans DG, Trueman L, Wallace A, Collins S, Strachan T.\u000a      Genotype\/phenotype correlations in\u000a      type 2 neurofibromatosis (NF2): evidence for more severe disease\u000a      associated with truncating\u000a      mutations. Journal of Medical Genetics. 1998;35(6):450-5. DOI:\u000a      10.1136\/jmg.35.6.450\u000a    \u000a\u000a2. Evans DGR, Wallace AJ, Wu CL, Trueman L, Ramsden RT,\u000a      Strachan T. Somatic Mosaicism:\u000a      A Common Cause of Classic Disease in Tumor-Prone Syndromes? Lessons from\u000a      Type 2\u000a      Neurofibromatosis. The American Journal of Human Genetics.\u000a      1998;63(3):727-36. DOI:\u000a      10.1086\/512074\u000a    \u000a\u000a3. Baser ME, Friedman JM, Aeschliman D, Joe H, Wallace AJ, Ramsden\u000a        RT, Evans DGR.\u000a      Predictors of the Risk of Mortality in Neurofibromatosis 2. The\u000a        American Journal of Human\u000a        Genetics. 2002;71(4):715-23. DOI: 10.1086\/342716\u000a    \u000a\u000a4. Evans DG, Baser ME, O'Reilly B, Rowe J, Gleeson M, Saeed S,\u000a      King A, Huson SM, Kerr R,\u000a      Thomas N, Irving R, MacFarlane R, Ferner R, McLeod R, Moffat D, Ramsden\u000a        R. Management\u000a      of the patient and family with neurofibromatosis 2: a consensus conference\u000a      statement. British\u000a        Journal of Neurosurgery. 2005;19(1):5-12. DOI:\u000a      10.1080\/02688690500081206 First major\u000a        consensus statement on management of NF2; led to the National bid.\u000a    5. Evans DGR, Baser ME, McGaughran J, Sharif S, Howard E, Moran\u000a      A. Malignant peripheral\u000a      nerve sheath tumours in neurofibromatosis 1. Journal of Medical\u000a        Genetics. 2002;39(5):311-4.\u000a      DOI: 10.1136\/jmg.39.5.311. Highly cited article on MPNST in NF1\u000a        pivotal to need for specialist\u000a        team involvement.\u000a    \u000a\u000a6. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans\u000a        DG, Upadhyaya M, Towers R,\u000a      Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management\u000a      of individuals\u000a      with neurofibromatosis 1. Journal of Medical Genetics.\u000a      2007;44(2):81-8. DOI:\u000a      10.1136\/jmg.2006.045906 First major consensus statement on management\u000a        of NF1.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    S1. http:\/\/www.specialisedservices.nhs.uk\/service\/neurofibromatosis-type-2-nf2\/search:true\u000a      AGNSS website for the national NF2 service led by Evans.\u000a    S2. http:\/\/www.specialisedservices.nhs.uk\/service\/complex-neurofibromatosis-type-1\u000a      AGNSS website for the national NF1 service.\u000a    S3. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson\u000a        SM, Lalloo F. Birth incidence and\u000a      prevalence of tumor-prone syndromes: Estimates from a UK family genetic\u000a      register service.\u000a      American Journal of Medical Genetics Part A. 2010;152A(2):327-32.\u000a      DOI:\u000a      10.1002\/ajmg.a.33139\u000a    S4. Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A,\u000a      Evans DG. Life expectancy in\u000a      hereditary cancer predisposing diseases: an observational study. Journal\u000a        of Medical Genetics.\u000a      2012;49(4):264-9. DOI: 10.1136\/jmedgenet-2011-100562\u000a    S5. Letter from Charity Manager, The Neuro Foundation.\u000a    S6. Letter from Managing Director, MED-EL UK Ltd.\u000a    S7. Letter from Coordinateur (Neurochirurgie), Site Neurofibromatose 2,\u000a      Centre Neurofibromatoses,\u000a      France.\u000a    S8. Evans DG, Kalamarides M, Hunter-Schaedle K, Blakeley J, Allen\u000a      J, Babovic-Vuskanovic D,\u000a      Belzberg A, Bollag G, Chen R, DiTomaso E, Golfinos J, Harris G, Jacob A,\u000a      Kalpana G,\u000a      Karajannis M, Korf B, Kurzrock R, Law M, McClatchey A, Packer R, Roehm P,\u000a      Rubenstein A,\u000a      Slattery W, Tonsgard JH, Welling DB, Widemann B, Yohay K, Giovannini M.\u000a      Consensus\u000a      Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type\u000a      2. Clinical Cancer\u000a        Research. 2009;15(16):5032-9.DOI: 10.1158\/1078-0432.CCR-08-3011\u000a    S9. Blakeley JO, Evans DG, Adler J, Brackmann D, Chen R, Ferner\u000a      RE, Hanemann CO, Harris G,\u000a      Huson SM, Jacob A, Kalamarides M, Karajannis MA, Korf BR, Mautner V-F,\u000a      McClatchey AI,\u000a      Miao H, Plotkin SR, Slattery W, Stemmer-Rachamimov AO, Welling DB, Wen PY,\u000a      Widemann\u000a      B, Hunter-Schaedle K, Giovannini M. Consensus recommendations for current\u000a      treatments and\u000a      accelerating clinical trials for patients with neurofibromatosis type 2. American\u000a        Journal of\u000a        Medical Genetics Part A. 2012;158A(1):24-41. DOI:\u000a      10.1002\/ajmg.a.34359.\u000a    S10. Letter from Chief Scientific Officer, Childrens' Tumor Foundation,\u000a      USA.\u000a    ","Title":"\u000a    The University of Manchester's role in establishing nationally funded\u000a      forefront services for\u000a      neurofibromatoses\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    Key researchers:\u000a    \u000a      \u000aGareth Evans (Honorary Senior Lecturer in Medical Genetics and\u000a        Cancer Epidemiology,\u000a        1995-2001; Honorary Professor 2001-2013; Professor, 2013-date)\u000a      \u000aRichard Ramsden (Honorary Lecturer, 1977-2007; Honorary\u000a        Professor, 2007-date)\u000a      \u000aSusan Huson (Honorary Senior Lecturer, 2005-date)\u000a    \u000a    Neurofibromatosis type 2 (NF2)\u000a    NF2 is an autosomal dominant inherited condition predisposing to benign\u000a      nerve sheath tumours\u000a      called schwannomas that particularly affect the vestibulocochlear nerves\u000a      (vestibular\u000a      schwannomas). Schwannomas can occur on nerve roots throughout the body\u000a      leading to muscular\u000a      weakness and paralysis. Meningiomas and ependymomas add to the disease\u000a      burden. NF2 affects\u000a      around 1 in 30,000 live births.\u000a    Over 40 epidemiological and genetic studies led by Evans since\u000a      1993 have mapped the disease\u000a      and its associated effects on life expectancy (1-3). These\u000a      publications have shown that NF2 is best\u000a      managed by an experienced team as this prolongs life expectancy (3,\u000a      4). Manchester has the sole\u000a      UK genetics laboratory carrying out NF2 mutation testing and tests samples\u000a      from all over Europe\u000a      and Australasia. Evans has published 145 articles on\u000a      neurofibromatosis (142 since 1993).\u000a    Work with auditory rehabilitation led by Ramsden was important in\u000a      developing NF2 expertise and\u000a      service innovation. Ramsden has published 61 articles on NF2 and\u000a      30 on cochlear and brain stem\u000a      implantation. He was an early pioneer of both procedures and was pivotal\u000a      in ensuring that cochlear\u000a      implantation received NHS funding in the 1990s. Development of the brain\u000a      stem implant (ABI)\u000a      meant that NF2 patients who had lost their cochlear nerve were able to be\u000a      rehabilitated. He carried\u000a      out the first ABI in the UK in 1999 and has carried out 70% of ABIs in the\u000a      UK thus far. The long\u000a      learning curve, cost and expertise necessary to carry out ABI was vital in\u000a      making a successful bid\u000a      to the Advisory Group for National Specialised Services (AGNSS).\u000a    Neurofibromatosis type 1 (NF1)\u000a    NF1 is an autosomal dominant inherited condition predisposing to benign\u000a      nerve sheath tumours\u000a      called neurofibromas as well as gliomas and developmental abnormalities.\u000a      NF1 affects around 1 in\u000a      2,500 live births.\u000a    Epidemiological research in Manchester led by Evans drove the\u000a      development of a national service\u000a      and the dissemination of good practice internationally. Of particular\u000a      importance was the work\u000a      showing loss in life expectancy due to malignant peripheral nerve sheath\u000a      tumours (MPNST) (5).\u000a      Huson has also published extensively on NF1 management (93 papers\u000a      since 1993) and both\u000a      Evans and Huson were involved in consensus management\u000a      recommendations on NF1 (6).\u000a    "},{"CaseStudyId":"28102","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":["Economic and Social Research Council"],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S9.\u000a    Context\u000a    Approximately 70% of breast cancers express oestrogen receptors (ER).\u000a      Endocrine response is\u000a      obtained by blocking the ER and\/or by reducing exposure of the tumour to\u000a      oestrogen. Endocrine\u000a      therapy increases survival by reducing the growth of advanced metastatic\u000a      breast cancer. It also\u000a      cures approximately one third of women after surgery for breast cancer by\u000a      eliminating occult\u000a      metastatic disease. In the early 1990s, tamoxifen (developed in the early\u000a      1970s by Cole and Todd\u000a      at the Christie Hospital in Manchester) was used to block the ER.\u000a      Oestrogen was lowered by\u000a      blocking adrenal steroid biosynthesis with the relatively toxic agents\u000a      amonoglutethimide and\u000a      megestrol acetate. With colleagues at AstraZeneca UoM researchers have\u000a      successfully improved\u000a      on these treatments so that more women presenting with early breast cancer\u000a      are cured, remissions\u000a      in advanced disease last longer and survival is prolonged. Furthermore, we\u000a      have demonstrated\u000a      that approximately half of breast cancer is preventable.\u000a    Pathways to impact\u000a    Howell devised the laboratory and translational research strategy\u000a      to bring fulvestrant to the clinic in\u000a      collaboration with Bundred (Surgeon) and DeFriend (Research\u000a      Fellow). Laboratory work on\u000a      tumours was followed by a phase I preoperative study (1), followed by a\u000a      phase II trial (2) and an\u000a      international phase III study also led by Howell.\u000a    After phase III trials in advanced breast cancer, anastrozole was\u000a      introduced into adjuvant therapy\u000a      in a multicentre international study with Howell as one-time\u000a      chairman of the trial steering\u000a      committee (4). In order to establish tamoxifen and, later, anastrozole for\u000a      prevention, two\u000a      international randomised controlled trials were performed with Cuzick and\u000a      Howell as joint principle\u000a      investigators (5, 6).\u000a    Reach and significance of the impact\u000a    The studies outlined above have been instrumental in changing the\u000a      endocrine treatment and\u000a      prevention of breast cancer to the benefit of the more than 1.5 million\u000a      women annually who\u000a      develop breast cancer worldwide.\u000a    As a result of these studies, anastrozole was approved by the FDA for the\u000a      first line treatment of\u000a      advanced breast cancer in 2000 and for the adjuvant treatment of breast\u000a      cancer in 2005 (S1).\u000a      These approvals have been followed by anastrozole becoming the first line\u000a      treatment for both early\u000a      and advanced breast cancer. The presentation of the comparison of\u000a      anastrozole with tamoxifen in\u000a      2005 (4) as adjuvant therapy caused considerable impact worldwide. It\u000a      resulted in a steep increase\u000a      in anastrozole use. Called a `blockbuster' by AZ, it has grossed over $1\u000a      billion per year, indicating\u000a      the extent of its use and replacement of tamoxifen as the major endocrine\u000a      therapy (S2). The chief\u000a      of the Division of Medical Oncology and Hematology at the Harbor-UCLA\u000a      Medical Center\u000a      emphasises the importance of Howell's work on the ATAC trial for\u000a      breast cancer patients: `In the 8\u000a      years since that initial Lancet report, anastrozole has maintained\u000a      its leadership position as the\u000a      most commonly prescribed adjuvant breast cancer therapy for postmenopausal\u000a      women with\u000a      hormone receptor positive disease in Europe and United States. The\u000a      development and\u000a      implementation of this new hormone therapy intervention has resulted in\u000a      tens of thousands of\u000a      women with early stage breast cancer remaining free of breast cancer\u000a      recurrence' (S3).\u000a    UoM studies led to the approval of fulvestrant by the FDA for the\u000a      treatment of advanced breast\u000a      cancer in 2002 and the new dosing was approved in 2010 (S4). The early\u000a      studies indicated that\u000a      500mg of fulvestrant was the dose which maximally down-regulated the\u000a      oestrogen receptor.\u000a      However because of perceived problems of administration of 500mg (it\u000a      requires two intramuscular\u000a      injections), the 250mg dose was used which was shown to be equivalent to\u000a      other endocrine\u000a      therapies such as tamoxifen and the aromatase inhibitor, exemestane.\u000a      However the 500mg has\u000a      now been introduced clinically and recent studies (conducted outside UoM)\u000a      indicate that, at this\u000a      dose, it is the most active endocrine therapy for breast cancer (S5, S6).\u000a    As a result of prevention trials with tamoxifen, NICE (June 2013) has now\u000a      indicated that this drug\u000a      and a similar selective oestrogen receptor modulator (raloxifene) can be\u000a      prescribed for prevention\u000a      of breast cancer in women at increased risk of the disease (S7, S8). Howell\u000a      presented the\u000a      background on BBC Breakfast Television on the day of the guideline launch\u000a      (21st June 2013). The\u000a      Director of Research for the Australia and New Zealand Breast Cancer\u000a      Trials Group affirms the\u000a      importance of Howell's contribution to the research (6) driving\u000a      the new recommendations. He\u000a      writes that Howell was `heavily involved in the trial of tamoxifen\u000a      for prevention (IBIS I). The recent\u000a      recommendation by [NICE] for tamoxifen to be offered as a standard of care\u000a      to women at\u000a      increased risk of breast cancer was substantially influenced by the IBIS I\u000a      trial results.' (S9). We\u000a      now have the results of effectiveness of anastrozole as a preventive agent\u000a      indicating its superiority\u000a      to tamoxifen (6).\u000a    ","ImpactSummary":"\u000a    Researchers at the University of Manchester (UoM) have made a significant\u000a      impact internationally\u000a      on improving outcomes for women diagnosed with breast cancer (>49,000\u000a      pa in the UK) and on\u000a      preventing the disease. The changes in clinical practice based on our\u000a      research are now national\u000a      guidelines and have helped set international treatment standards. These\u000a      new approaches have:\u000a      increased the duration of survival of women with advanced breast cancer;\u000a      reduced relapse rates\u000a      and improved survival after surgery for early breast cancer; and prevented\u000a      disease in women at\u000a      high risk. The revised treatment has benefited >1.5m women worldwide\u000a      annually who develop\u000a      breast cancer and sales of anastrozole, which has replaced tamoxifen as\u000a      the major endocrine\u000a      therapy, have grossed over $1bn p.a.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. DeFriend DJ, Howell A, Nicholson RI, Anderson E, Dowsett M,\u000a      Mansel RE, Blamey RW,\u000a      Bundred NJ, Robertson JF, Saunders C, Baum M, Walton P, Sutcliffe\u000a      F, Wakeling AE.\u000a      Investigation of a New Pure Antiestrogen (ICI 182780) in Women with\u000a      Primary Breast Cancer.\u000a      Cancer Research. 1994;54(2):408-14. Available from UoM on\u000a        request.\u000a    \u000a\u000a2. Howell A, DeFriend DJ, Blamey RW, Robertson JF, Walton P.\u000a      Response to a specific\u000a      antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet.\u000a      1995;345(8941):29-30.\u000a      DOI: 10.1016\/S0140-6736(95)91156-1\u000a    \u000a\u000a3. Howell A, Robertson JFR, Abram P, Lichinitser MR, Elledge R,\u000a      Bajetta E, Watanabe T, Morris\u000a      C, Webster A, Dimery I, Osborne CK. Comparison of Fulvestrant Versus\u000a      Tamoxifen for the\u000a      Treatment of Advanced Breast Cancer in Postmenopausal Women Previously\u000a      Untreated With\u000a      Endocrine Therapy: A Multinational, Double-Blind, Randomized Trial. Journal\u000a        of Clinical\u000a        Oncology. 2004;22(9):1605-13. DOI: 10.1200\/JCO.2004.02.112\u000a    \u000a\u000a4. Howell A, Cuzick J, Baum M, Buzdar, Dowsett M, Forbes, JF,\u000a      Hoctin-Boes G, Houghton J,\u000a      Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC\u000a      (Arimidex, Tamoxifen,\u000a      Alone or in Combination) trial after completion of 5 years' adjuvant\u000a      treatment for breast cancer.\u000a      Lancet. 2005;365(9453):60-2. DOI: 10.1016\/S0140-6736(04)17666-6\u000a    \u000a\u000a5. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, Howell\u000a        A. Long-Term Results of\u000a      Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the\u000a      Randomized IBIS-I Trial.\u000a      Journal of the National Cancer Institute. 2007;99(4):272-82. DOI:\u000a      10.1093\/jnci\/djk049\u000a    \u000a\u000a6. Cuzick J, Sestak I, Forbes JF, Cawthorn S, N. Roche, R.E. Mansel, G.\u000a      von Minckwitz, B.\u000a      Bonanni, T. Palva, A Howell A. First results of the International\u000a      Breast cancer Intervention\u000a      Study II: a multicentre prevention trial of anastrozole versus placebo in\u000a      postmenopausal\u000a      women at increased risk of developing breast cancer. Lancet.\u000a      December 2013, in press.\u000a      Available from UoM upon request.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    S1. Drugs@FDA: FDA Approved Drug Products. Record for Arimidex. Available\u000a      from:\u000a      http:\/\/www.accessdata.fda.gov\/scripts\/cder\/drugsatfda\/index.cfm\u000a    Arimidex Gains Full FDA Approval for Adjuvant Treatment of Hormone\u000a      Receptor-positive Early\u000a      Breast Cancer in Postmenopausal Women. Medical News Today. 21\u000a      September 2005.\u000a      http:\/\/www.medicalnewstoday.com\/releases\/30932.php\u000a    S2. GenericsWeb, Drug\u000a        In Focus August 2010 : Anastrozole\u000a      For the year 2009 Arimidex sales generated approximately US$1.9\u000a      billion worldwide.\u000a      www.genericsweb.com\/druginfocus\/Anastrozole\u000a    S3. Letter from Professor of Medicine, David Geffen School of Medicine at\u000a      UCLA and Chief,\u000a      Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center,\u000a      USA.\u000a    S4.Drugs@FDA: FDA Approved Drug Products. Record for Faslodex. Available\u000a      from:\u000a      http:\/\/www.accessdata.fda.gov\/scripts\/cder\/drugsatfda\/index.cfm\u000a    S5. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN,\u000a      Khasanov R, Verhoeven D,\u000a      Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S,\u000a      Lindemann JPO, Sapunar F,\u000a      Martin M. Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250\u000a      mg With\u000a      Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor-Positive\u000a      Advanced\u000a      Breast Cancer. Journal of Clinical Oncology. 2010;28(30):4594-600.\u000a      DOI:\u000a      10.1200\/JCO.2010.28.8415\u000a    S6. Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D,\u000a      Dewar J, Emerson L, Dean\u000a      A, Ellis MJ. Fulvestrant\u000a        500 mg versus anastrozole 1 mg for the first-line treatment of advanced\u000a        breast cancer: follow-up analysis from the randomized 'FIRST' study.\u000a      Breast Cancer Research\u000a        and Treatment. 2012;136(2):503-11. DOI: 10.1007\/s10549-012-2192-4.\u000a    S7. NICE. Clinical Guideline 164: Familial breast cancer: Classification\u000a      and care of people at risk of\u000a      familial breast cancer and management of breast cancer and related risks\u000a      in people with a\u000a      family history of breast cancer. (2013).\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/14188\/64204\/64204.pdf\u000a    S8. Howell A, Evans DG. Breast cancer prevention: SERMs come of age. Lancet.\u000a      2013;381(9880):1795-7. DOI: 10.1016\/S0140-6736(13)60443-2\u000a    S9. Letter from Professor of Surgical Oncology, University of Newcastle\u000a      (Australia) and Director of\u000a      Research, Australia and New Zealand Breast Cancer Trials Group.\u000a    ","Title":"\u000a    Improving outcomes of women diagnosed with and at increased risk of\u000a      breast cancer: the results of\u000a      translational research and national and international clinical trials\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    Key UoM researchers:\u000a    \u000a      \u000aAnthony Howell (Senior Lecturer, 1980-1997; Professor of\u000a        Medical Oncology, 1997-2007;\u000a        Professor of Breast Oncology, 2007-date)\u000a      \u000aNigel Bundred (Senior Lecturer, 1991-1996; Reader, 1996-2001;\u000a        Professor of Surgical\u000a        Oncology, 2001 — date)\u000a    \u000a    Breast cancer is the commonest tumour in women and the leading cause of\u000a      death in middle-aged\u000a      women. Survival is improved by early detection and the use of systemic\u000a      therapy given after\u000a      surgery. Both endocrine therapy (e.g. tamoxifen, developed in Manchester\u000a      in the 1970s) and\u000a      chemotherapy prevent relapse and improve survival. These treatments are\u000a      also used to extend the\u000a      duration of survival after systemic relapse.\u000a    The key contribution of the UoM group has been the development of new\u000a      approaches to endocrine\u000a      therapy. We led the translational development of the so-called `pure\u000a      anti-oestrogen' fulvestrant\u000a      (ICI182780), which blocks oestrogen. We conducted clinical trials of this\u000a      drug and the aromatase\u000a      inhibitor anastrozole, which lowers oestrogen concentrations in\u000a      postmenopausal women.\u000a    Key findings:\u000a    \u000a      1. We demonstrated that, in vitro, fulvestrant was a more\u000a        effective endocrine therapy than\u000a        tamoxifen. Preoperative studies demonstrated that fulvestrant completely\u000a        downregulated the\u000a        oestrogen receptor (1) and, in a trial in women with advanced breast\u000a        cancer, was active after\u000a        women became resistant to treatment with tamoxifen (2). Later we led\u000a        randomised trials in\u000a        advanced disease which indicated that fulvestrant was equivalent to\u000a        anastrozole and tamoxifen\u000a        (3). More recent studies (performed by others) at higher doses of\u000a        fulvestrant indicate that it is\u000a        the most active endocrine therapy for breast cancer.\u000a      2. In collaboration with colleagues at AstraZeneca, we improved on the\u000a        reduction of oestrogen\u000a        caused by the old drugs aminoglutethimide and megestrol acetate. We used\u000a        anastrozole, a\u000a        newly synthesised inhibitor of the enzyme aromatase (which converts the\u000a        adrenal oestrogen\u000a        precursor, androstenedione, to oestrogen in peripheral tissues). In a\u000a        randomised trial,\u000a        anastrozole gave a longer duration of remission than megestrol acetate\u000a        in women with\u000a        advanced breast cancer. At that time the standard treatment after\u000a        surgery for breast cancer\u000a        was `adjuvant' tamoxifen. In a trial of tamoxifen versus anastrozole in\u000a        over 6,000 women\u000a        worldwide, it was shown that anastrozole prevented relapse of breast\u000a        cancer to a greater\u000a        degree than tamoxifen (4).\u000a      3. UoM researchers demonstrated that treatment for five years with\u000a        tamoxifen prevents about\u000a        40% of breast cancers in women at high risk of developing breast cancer\u000a        (5). In a second\u000a        international randomised trial we demonstrated that anastrozole prevents\u000a        50-60% of breast\u000a        cancers (6).\u000a    "},{"CaseStudyId":"28134","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S10.\u000a    Reach and significance of the impact\u000a    Clinical development of voriconazole and echinocandins: saving lives\u000a        from invasive aspergillosis\u000a    The development and subsequent worldwide registration of voriconazole as\u000a      the most effective first line therapy for invasive aspergillosis has been\u000a      a critically important development with a 13% absolute survival benefit.\u000a      All international guidelines now place voriconazole as first line therapy\u000a      (S1) and numerous post-registration studies show ~15-20% better\u000a        survival with voriconazole therapy compared with all other\u000a      therapies. Likewise introduction of the very low toxicity echinocandin\u000a      antifungals has been pivotal in improved survival with minimal adverse\u000a      events from life-threatening fungal infections. In 2011, the global\u000a      antifungals market was ~ $10.7bn, with an annual growth rate of 2.9%\u000a      during 2002 and 2010. Voriconazole sales were >$750m worldwide in 2012\u000a      (S2, p. 12). Caspofungin and micafungin echinocandin sales are over $500m\u000a      each per year. Denning profiled the echinocandins as a new drug\u000a      class in The Lancet in 2003 (S3).\u000a    Resistance in Aspergillus\u000a    Without validated resistance detection in Aspergillus (S4), we\u000a      would not know that clinical failures are due to resistance (as opposed to\u000a      inactive drug, immunological failure etc.) or that azole fungicide use in\u000a      agriculture is leading to an increasing problem (since 2003) in\u000a      environmental resistance in Aspergillus (European Centres for Disease\u000a      Control report, 2013) (S5).\u000a    Validated susceptibility testing and genome sequencing as a\u000a        springboard for antifungal drug discovery: F2G Ltd\u000a    Validated susceptibility testing of Aspergillus provides an\u000a      antifungal drug discovery tool. This methodology, combined with UoM animal\u000a      modelling know-how, patented gene knockout techniques and clinical\u000a      profiling, was used as the foundation of F2G Ltd, a UoM spin out (S6).\u000a      Genome sequencing of Aspergillus greatly accelerated the finding\u000a      of novel antifungal targets for F2G (and other antifungal discovery\u000a      units). A total of ~£35m from venture capital funds has been invested in\u000a      F2G since 2001, employing up to 22 people. F2G's lead compound (F3\u000a      analogue) has a novel mode of action and chemical structure and is\u000a      therefore a new antifungal class, primarily with anti-Aspergillus\u000a      activity. It has no discernable toxicity in small animals. It is\u000a      formulated for intravenous and oral usage. Phase 1 is anticipated in Q4\u000a      2013.\u000a    The world's first commercialised molecular diagnostics for Aspergillus\u000a      (respiratory) and Pneumocystis\u000a    The major limitation to better clinical outcomes of invasive fungal\u000a      infections remains insensitive and slow diagnosis. To address this issue,\u000a      Denning founded Myconostica to develop and commercialise real-time\u000a      PCR diagnostics for fungal disease. The MycAssay® Aspergillus and\u000a      MycAssay® Pneumocystis assays are the world's first commercial real-time\u000a      quantitative PCR assays for pulmonary fungal infections and both were\u000a      developed with £10m external funding (S7). Quantitation was possible in Aspergillus\u000a      because the number of ribosomal RNA copies in the A. fumigatus\u000a      genome strain was precisely determined in the sequencing project. CE\u000a      marking throughout Europe and Canada was achieved after the international\u000a      clinical trials programme that Denning managed. Sales have been\u000a      made to 16 countries and licensing deals with Becton Dickinson (S8) and\u000a      BioRad will result in OEM developments on new platforms such as the new\u000a      fully automated BD MAX™ system, a coming revolution in microbiology.\u000a    Redefining chronic pulmonary aspergillosis (CPA) and its global impact\u000a    The National Aspergillosis Centre at the University Hospital of South\u000a      Manchester (S9) was the first nationally commissioned infectious disease\u000a      service in the UK and the world's first national clinical centre for a\u000a      fungal disease. The basis of national commissioning was Denning's\u000a      clinical expertise, the small national caseload of CPA (<1,000 UK\u000a      cases), clinical care complexity, need for specialised investigations and\u000a      antifungal drug cost. In 2013, the centre has about 270 CPA (and over 500\u000a      allergic aspergillosis) cases under its care with >250 new referrals\u000a      annually.\u000a    CPA is commonly preceded by pulmonary tuberculosis and an estimate of the\u000a      global prevalence of cases (assuming ~15% annual mortality) is 1.2m, most\u000a      in countries without access to any diagnostics for fungal disease and\u000a      unaffordable antifungal therapy. This is being addressed with the WHO STOP\u000a      TB programme. The National Aspergillosis Centre designation directly\u000a      facilitated this global health development, with multiple burden of\u000a      disease estimates emerging (S10).\u000a    Role of fungal allergy in asthma\u000a    The placebo-controlled RCT of antifungal therapy in those with SAFS has\u000a      been pivotal in altering thinking about the pathogenesis of severe asthma.\u000a      Major quality of life benefits for 60-80% of such patients were found. The\u000a      global burden of SAFS is estimated at 6-13m adults, with ~100,000 deaths\u000a      annually, but needs further epidemiological study. Very large numbers of\u000a      patients are benefitting from generic antifungal therapy for severe\u000a      asthma, including some children.\u000a    ","ImpactSummary":"\u000a    Research at the University of Manchester (UoM) has changed the landscape\u000a      of medical care and research in fungal infections internationally. The\u000a      impacts include: the world's first commercialised molecular diagnostic\u000a      products for aspergillosis and Pneumocystis pneumonia (£10m\u000a      investment); pivotal contributions to the preclinical development (£35m\u000a      investment), clinical developments and registrations of 3 new antifungals\u000a      with combined market share of ~$2 billion; one (voriconazole, 2012 sales\u000a      >$750m worldwide) now first line therapy for invasive aspergillosis\u000a      with improved survival of 15-20%; and internationally validated methods to\u000a      detect azole resistance in Aspergillus (an emerging problem partly\u000a      related to environmental spraying of azole fungicides for crop\u000a      protection).\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Azole resistance\u000a    \u000a1. Howard SJ, Cesar D, Anderson MJ, Albarrag AM, Fisher\u000a      M, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW.\u000a      Frequency and evolution of azole resistance in Aspergillus fumigatus\u000a      associated with treatment failure. Emerging Infectious Diseases.\u000a      2009;15:1068-76. DOI: 10.3201\/eid1507.090043\u000a    \u000a\u000a2. Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore\u000a      R, Smith J, Bueid A, Bowyer P, Perlin DS. High frequency triazole\u000a      resistance found in non-culturable Aspergillus fumigatus from\u000a      lungs of patients with chronic fungal disease. Clinical Infectious\u000a        Diseases. 2011;52:1123-9. DOI: 10.1093\/cid\/cir179\u000a    \u000aGenome sequencing\u000a    \u000a3. Nierman W, Pain A, Anderson MJ, Wortman J, Kim HS, Arroya J,\u000a      Berriman B, Abe K, Archer DB, Bermejo C, Bennett J, Bowyer P, Chen\u000a      D, Collins M, Coulsen R, Davies R, Dyer PS, Farman M, Federova N,\u000a      Feldblyum TV, Fisher R, Fosker N, Fraser A, García JL, García MJ,\u000a      Goble A, Goldman GH, Gomi K, Griffith-Jones S, Gwilliam R, Haas B, Harris\u000a      D, Horiuchi H, Huang J, Humphrey S, Jiménez J, Keller N, Khouri H,\u000a      Kitamoto K, Kobayashi T, Konzack S, Kulkarni R, Kumagai T, Lafton A, Latgé\u000a      JP, Lord A, Lu C, Majoros WH, May GS, Miller BL, Mohamoud Y, Molina M,\u000a      Monod M, Mouyna I, Mulligan S, Murphy L, O'Neil S, Paulsen I, Penalva MA,\u000a      Pertea M, Price C, Pritchard BL, Quail MA, Rabbinowitsch E, Rawlins N,\u000a      Rajandream M-A, Reichard U, Renauld H, Robson GD, de Córdoba SR,\u000a      Rodríguez-Peña JM, Ronning CM, Rutter S, Salzberg SL, Sanchez S,\u000a      Sánchez-Ferrero JC, Saunders D, Seeger K, Squares R, Squares S, Takeuchi\u000a      T, Tekaia F, Turner G, Vazquez de Aldana CR, Weidman J, White O, Woodward\u000a      J, Yu J-H, Fraser C, Galagan JE, Asai K, Machida M, Hall N, Barrell B, Denning\u000a        DW. Genomic sequence of the pathogenic and allergenic filamentous\u000a      fungus Aspergillus fumigatus. Nature. 2005;438:1151-6. DOI:\u000a      10.1038\/nature04332\u000a    \u000a(Two related papers in same issue of Nature reporting sequencing\u000a      of A. nidulans and A. oryzae.)\u000a    Antifungal drug development\u000a    \u000a4. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE,\u000a      Oestmann J-W, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin\u000a      RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH,\u000a      Hodges MR, Schlamm HT, Troke PF, de Pauw B. Voriconazole versus\u000a      Amphotericin B for Primary Therapy of Invasive Aspergillosis. The New\u000a        England Journal of Medicine. 2002;347(6):408-15. DOI:\u000a      10.1056\/NEJMoa020191\u000a      (Several other papers reporting clinical results of antifungal trials\u000a      published.)\u000a    \u000aChronic pulmonary aspergillosis and Severe Asthma with Fungal\u000a        Sensitisation (SAFS)\u000a    \u000a5. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic\u000a      cavitary and fibrosing pulmonary and pleural aspergillosis: Case series,\u000a      proposed nomenclature and review. Clinical Infectious Diseases.\u000a      2003;37 (Suppl 3):S265-80. DOI: 10.1086\/376526\u000a    \u000a\u000a6. Denning DW, O'Driscoll BR, Powell G, Chew F, Atherton G, Vyas\u000a      A, Miles J, Morris J, Niven RM. Randomized controlled trial of\u000a      oral antifungal treatment for severe asthma with fungal sensitisation\u000a      (SAFS), the FAST study. American Journal of Respiratory and Critical\u000a        Care Medicine. 2009;179:11-8. DOI: 10.1164\/rccm.200805-737OC\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    S1. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of\u000a      Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases\u000a      Society of America (IDSA). Clinical Infectious Diseases. 2008; 46:\u000a      327-60.\u000a    S2. Zacks Brokerage Research Digest: Pfizer, Inc., 1Q13 Results\u000a      (p. 12).\u000a    S3. Denning DW. Echinocandin antifungal drugs. The Lancet.\u000a      2003;362:1142-51.\u000a    S4. European Committee on Antimicrobial Susceptibility Testing. Rationale\u000a      documents for antifungal agents:\u000a      http:\/\/www.eucast.org\/antifungal_susceptibility_testing_afst\/rationale_documents_for_antifungals\/\u000a    S5. European Centre for Disease Prevention and Control. Risk Assessment\u000a      on the Impact of Environmental Usage of Triazoles on the Development and\u000a      Spread of Resistance to Medical Triazoles in Aspergillus Species.\u000a      Stockholm: ECDC; 2013. Available from:\u000a      http:\/\/ecdc.europa.eu\/en\/publications\/Publications\/risk-assessment-impact-environmental-usage-of-triazoles-on-Aspergillus-spp-resistance-to-medical-triazoles.pdf\u000a    S6. F2G Ltd Completes $30 Million Financing Round to Fund Pre-clinical\u000a      and Clinical Development of Novel Anti-fungal Compounds: http:\/\/www.f2g.com\/05_Sep_2012.htm\u000a    S7.\u000a        www.myconostica.co.uk\/latest-news\/y2011\u000a    S8. BD and Lab21 Collaborate to Develop Aspergillus Assay for New\u000a      BD MAX™ Molecular Testing System:\u000a      www.bd.com\/contentmanager\/b_article.asp?Item_ID=26368&ContentType_ID=1&BusinessCode=20001&d=BD+Worldwide&s=&dTitle=&dc=&dcTitle=\u000a    S9. National Aspergillosis Centre: www.nationalaspergillosiscentre.org.uk\u000a    S10. Multi-country burden of fungal disease presented at ECCMID\u000a      conference, 2013:\u000a      http:\/\/www.life-worldwide.org\/media-centre\/article\/multi-country-burden-of-fungal-disease-presented-at-eccmid-conference\/\u000a    ","Title":"\u000a    Diagnostics and novel life-saving therapies for aspergillosis\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    Key UoM researchers:\u000a    \u000a      \u000aDavid Denning (Senior Lecturer, 1990-1993; Professor,\u000a        1993-date)\u000a      \u000aMichael J Anderson (Research Associate, 1993-1998; Research\u000a        Fellow, 1998-2006; Scientific Project Manager, 2011-date)\u000a      \u000aCaroline Moore (Honorary Research Associate, 2008-date)\u000a      \u000aPeter Warn (Research Associate, 1997-2005; Senior Scientist,\u000a        2005-2007; Senior Lecturer, 2007-date)\u000a      \u000aPaul Bowyer (Senior Lecturer, 2005-date)\u000a      \u000aMike Bromley (Research Fellow, 2008-2013; Lecturer, 2013-date)\u000a      \u000aNicola Smith (Research Associate, 2011-date)\u000a      \u000aSusan Howard (Research Associate, 2008-2012)\u000a      \u000aRobert Niven (Senior Clinical Research Fellow, 1997-2002;\u000a        Senior Lecturer, 2002-date)\u000a    \u000a    Clinical and laboratory research led by Denning has resulted in\u000a      the following discoveries:\u000a    \u000a      Means of detecting azole resistance in A. fumigatus (Moore),\u000a        validated in animal models (Warn), and two mechanisms of\u000a        resistance (target site mutation and efflux). Azole resistance\u000a        methodology development was followed up by documentation of the clinical\u000a        impact of resistance in Manchester (Denning) (1) and lately by\u000a        detection of resistance using molecular methods (Bowyer, Smith,\u000a          Denning), in the absence of a positive culture, never before done\u000a        for a human pathogenic fungus (2).\u000a      Genome sequencing of A. fumigatus strain AF293 (29,000 Mb, ~9,700\u000a        genes) was published in 2005 (3). Denning led the genome\u000a        sequencing of A. fumigatus with seed funding from the Wellcome Trust,\u000a        followed up by a further Wellcome Trust grant (to Sanger) and a $3m NIH\u000a        grant (to UoM, partly subcontracted to The Institute for Genomic\u000a        Research, now J Craig Venter Institute, Rockville, MD). The strain\u000a        sequenced derived from Denning's clinical collection. In\u000a        parallel A. nidulans and A. oryzae were sequenced elsewhere with Denning\u000a        co-ordinating the analysis and publication outputs in multiple meetings\u000a        until publication. All subsequent genomic studies of filamentous studies\u000a        use AF293 as the reference Aspergillus strain.\u000a      \u000aDenning led the development of the antifungal drug voriconazole\u000a        and made a major contribution to the development of caspofungin and\u000a        micafungin. The first patients in the world were treated in Manchester\u000a        with voriconazole in 1993. Denning analysed the clinical and\u000a        radiological outcomes for the phase 2 aspergillosis studies (published\u000a        2002). He led the protocol development for the randomised registration\u000a        studies, facilitating co-working of Pfizer and the European Organisation\u000a        for the Research and Treatment of Cancer (EORTC), designing data\u000a        collection processes and training for the data analysis teams (one US\u000a        and one European). He led the European data analysis team over 3 years.\u000a        Denning wrote the first protocol draft in 1997 and the combined\u000a        studies were successfully completed in 2001 and published in 2002 (4).\u000a        Denning was one of 3 adjudicators of eligibility and outcome of invasive\u000a        aspergillosis cases recruited into the caspofungin study and\u000a        international studies of micafungin, a novel class of echinocandin\u000a        antifungal drug.\u000a      Denning and colleagues have redefined certain clinical manifestations\u000a        of aspergillosis using clinical observation and both old and new\u000a        diagnostic tools. Chronic cavitary pulmonary aspergillosis was\u000a        introduced in 2003 (5) and antifungal benefit documented for the first\u000a        time. Azole resistance is a particular problem in this group, because of\u000a        long term antifungal therapy (1) (Howard). The link between\u000a        severe asthma and fungal sensitisation (SAFS), a term coined by Denning,\u000a        Niven and colleagues, and its responsiveness to oral antifungal\u000a        therapy was exemplified in a double blind, placebo-controlled RCT\u000a        published in 2009 (6). For responsive patients, the quality of life\u000a        impact is as large as prednisolone and larger than Omalizumab.\u000a    \u000a    "},{"CaseStudyId":"28135","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S10.\u000a    Context\u000a    In the 1980s, most asthma patients took short-acting beta agonists, but\u000a      by the 1990s treatment of asthma with inhaled corticosteroids and\u000a      bronchodilators was fairly well established. However, little was known\u000a      about dosing of inhaled corticosteroids or combining inhaled\u000a      corticosteroids with novel long-acting 03b22-agonists. The\u000a      impact of allergen avoidance on allergic diseases was poorly understood.\u000a      In COPD, even less was known and no long-term intervention trials with\u000a      inhaled therapy had been carried out.\u000a    UoM researchers have safely carried out >250 clinical studies. They\u000a      have: played a key role in bringing 15 different inhaled formulations to\u000a      the market; managed the switch to CFC-free inhalers for many millions of\u000a      patients; and led guidelines that have been very influential for both\u000a      physicians and patients (e.g. Global Initiative for Asthma website had\u000a      12,586,493 hits in 2012). The first Charity-owned 36-bed dedicated\u000a      asthma\/COPD clinical trial unit, the Medicines Evaluation Unit (MEU,\u000a      Director Singh) (S1) is located in Manchester and employs over 80\u000a      people. Discussing the importance of the work carried out at UoM, the\u000a      Chief Executive Officer of GlaxoSmithKline (GSK) comments: `it is obvious\u000a      that a significant contribution to human health has been delivered.\u000a      Importantly this contribution has benefited patients in the UK and\u000a      globally' (S2). The key impacts are detailed below.\u000a    Reach and significance of the impact\u000a    Treating asthma\u000a    There are an estimated 300m individuals with asthma worldwide. The trial\u000a      work on inhaled therapies by Woodcock and Singh, as well\u000a      as the work on allergen avoidance by Woodcock (with Custovic),\u000a      has had significant impact on both the latest revision of the asthma\u000a      guidelines from the Global Initiative for Asthma (GINA), published in 2012\u000a      (S3) as well other national and international guidelines, including those\u000a      of the British Thoracic Society, also published in 2012 (S4).\u000a    Woodcock leads the Salford Lung study, the world's first pragmatic\u000a      double-blind randomised controlled trial (DBRCT) targeting ~7,000\u000a      asthma\/COPD patients, to provide data on overall health benefits of\u000a      inhaled therapy. Woodcock with Custovic led the only large\u000a      DBRCT on house dust mite avoidance in asthma (2). This single study\u000a      convincingly showed no benefit, and prevented patients and health services\u000a      worldwide from wasting £billions on measures (covers ~£200\/set; 2m\u000a      mite-sensitive asthmatics; 25% uptake; estimated saving £100m\/annum in UK\u000a      alone, for last 10 years).\u000a    Understanding and treating COPD\u000a    WHO estimates that there are 210m individuals with COPD worldwide. The\u000a      number is increasing as smoking rates rise in developing countries. Large\u000a      pivotal trials in COPD, many of them led\/co-authored by Vestbo,\u000a      form the basis for modern management of COPD as reflected in the Global\u000a      Initiative for Obstructive Lung Diseases (GOLD) Strategy Document, revised\u000a      in 2011 (S5) and the current NICE guidelines for diagnosis and management\u000a      of COPD, published in 2010 (S6).\u000a    The GOLD guidelines website had over 13m hits in 2012 alone. Traditional\u000a      guidelines focussed on measurements of lung function but current\u000a      documents, influenced by Vestbo's research, reflect today's view\u000a      of COPD. Vestbo was appointed head of the Science Committee for\u000a      the 2011 revision of the GOLD Strategy document. This document is changing\u000a      the way COPD patients are managed worldwide with a focus on risk\u000a      reduction, detection, symptom relief, and management of comorbidities.\u000a      This document has inspired numerous national COPD guidelines worldwide\u000a      with implications for millions of patients. The Executive Director of GOLD\u000a      underlines the importance of Vestbo's work for patient\u000a      care: `[Vestbo's] work has stimulated research scientists and benefitted\u000a      patients around the world, including many in the United States. It has\u000a      been a privilege for me [...] to be associated with Dr Vestbo in the GOLD\u000a      program where I find his knowledge of airway biology to be outstanding but\u000a      perhaps even more important his commitment to take findings from research\u000a      to impact on improved care of patients with these chronic lung diseases\u000a      sets an example for other clinical scientists.' (S7)\u000a    UoM studies exploring and characterising airways diseases have impacted\u000a      on current management of COPD. Early work from Singh and Vestbo\u000a      led a stratified medicine approach to `phenotyping' COPD in 2009-11. This\u000a      change from a `one size fits all' strategy has changed the way the\u000a      pharmaceutical industry designs randomised clinical trials in COPD. For\u000a      example, they defined an `exacerbator' phenotype, leading to targeted\u000a      preventive strategies with macrolides and novel anti-inflammatories.\u000a      Recent COPD guidelines reflect this stratified approach, with treatments\u000a      tailored to the patient's clinical phenotype. In this growing disease\u000a      area, these changes are impacting the treatment of millions of patients.\u000a    Drug development\u000a    Singh's work has directly influenced the drug discovery processes\u000a      of many pharmaceutical companies. For example, his work on p38 MAPK\u000a      inhibitors in 2009-12 (S8), in collaboration with industrial partners, has\u000a      been pivotal in refocusing the development of these drugs on COPD rather\u000a      than other inflammatory diseases; these drugs have progressed to phase 3\u000a      studies. This basic science research, coupled with scientific and\u000a      leadership skills in early and late phase clinical trials, has increased\u000a      the number of clinical trials performed by the spin-out Medicines\u000a      Evaluation Unit (S1), with annual turnover increased from <£2m in 2007\u000a      to >£7m in 2012 and staff employment rising from 35 to >80 in 2013.\u000a      Notable successes include conduct of the first ever study of inhaled\u000a      glycopyrrolate as a bronchodilator (for a UK biotech company) in 2005,\u000a      with close involvement in subsequent full development by a major pharma\u000a      (2009-2012). Senior representatives of the pharmaceutical company Almirall\u000a      comment that: `the Medicines Evaluation Unit has rapidly become a centre\u000a      of reference for early studies with new compounds and mechanisms, and is\u000a      highly regarded for its focus on timely delivery and doing good science.'\u000a      (S9)\u000a    Singh has also been pivotally involved as an investigator and advisor\u000a    regarding clinical development and regulatory issues for the bronchodilator\u000a    aclidinium in 2007-12. Both of these medicines are being licensed worldwide\u000a    for COPD, and are already impacting on the lives of many millions of\u000a    patients. UoM research and leadership has led to 15 different inhaled drug\u000a    formulations getting to market; these treatments are used by most of the\u000a    >500m asthma and COPD patients worldwide.\u000a    Ensuring safe inhaled medications and protecting the environment\u000a    Woodcock's leadership of the Medical Technical Options Committee\u000a      to the UNEP Montreal Protocol since 1995 has had a huge impact globally,\u000a      with 2015 projected to be the last year of CFC use in inhalers worldwide.\u000a      With a final global ban on CFCs, ozone recovery will occur by 2060 and the\u000a      worst effects of this chemical on the climate will be prevented. For these\u000a      efforts, Woodcock, as a member of the International Panel for\u000a      Climate Change (IPCC), shared the Nobel Peace Prize in 2007. The Executive\u000a      Secretary of the Ozone Secretariat at the United Nations Environment\u000a      Programme underlines the importance of this work: `[Woodcock] has\u000a      helped the efforts of the international community to promoting effective\u000a      cooperation between science, politics, environment and human health. Prof\u000a      Woodcock's contributions to such cooperation has [sic] also helped\u000a      the Vienna Convention for the Protection of the Ozone Layer and the\u000a      Montreal Protocol on Substances that Deplete the Ozone Layer, to promote\u000a      sustainable development and protect the global environment. These\u000a      contributions have indeed salient benefits for the present and future\u000a      generations.' (S10)\u000a    This major step in environmental protection and recovery has taken place\u000a      without any harm to the users of inhaled medications. Indeed, as a result\u000a      of the underlying research, ~200m patients with chronic airway disease\u000a      have been safely transferred to CFC-free inhalers and can receive even\u000a      better inhaled therapy today.\u000a    ","ImpactSummary":"\u000a    Research at the University of Manchester (UoM) has led a step-change in\u000a      respiratory care for airway disease from oral to novel inhaled therapies\u000a      targeted at asthma and chronic obstructive pulmonary disease (COPD)\u000a      patients worldwide. UoM researchers carried out >250 studies, partnered\u000a      industry to deliver >15 new inhaled drug formulations to market and\u000a      were the first to test novel CFC-free inhalers. UoM led the development of\u000a      global guidelines that influence better diagnosis and management of\u000a      airways diseases. Through leadership within the Montreal Protocol since\u000a      1995, UoM researchers coordinated the safe global transition to CFC-free\u000a      inhalers for ~200m patients with asthma and COPD, whilst protecting the\u000a      ozone layer and climate.\u000a    ","ImpactType":"Health","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2761369","Name":"Vienna"}],"References":"\u000a    \u000a1. O'Driscoll BR, Kalra S, Wilson M, Pickering CAC, Woodcock A.\u000a      Double-blind trial of steroid tapering in acute asthma. The Lancet.\u000a      1993; 341:324-7. DOI: 10.1016\/0140-6736(93)90134-3\u000a    \u000a\u000a2. Woodcock A, Forster L, Matthews E, Martin J, Letley L, Vickers\u000a      M, Britton J, Strachan D, Howarth P, Altmann D, Frost C, Custovic A.\u000a      Control of exposure to mite allergen by the use of allergen permeable bed\u000a      covers for adults with asthma. The New England Journal of Medicine.\u000a      2003; 349:221-32. DOI: 10.1056\/NEJMoa023175\u000a    \u000a\u000a3. Singh SD, Richards D, Knowles RG, Schwartz S, Woodcock AA,\u000a      Langley SJ, O'Connor BJ. Selective inducible nitric oxide synthase\u000a      inhibition has no effect on allergen challenge in asthma. American\u000a        Journal of Respiratory and Critical Care Medicine. 2007:176; 988-93.\u000a      DOI: 10.1164\/rccm.200704-588OC\u000a    \u000a\u000a4. Singh D, Brooks J, Hagan G, Cahn A, O'Connor BJ. Superiority\u000a      of \"triple\" therapy with salmeterol\/fluticasone propionate and tiotropium\u000a      bromide versus individual components in moderate to severe COPD. Thorax.\u000a      2008; 63; 592-8. DOI: 10.1136\/thx.2007.087213\u000a    \u000a\u000a5. Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW,\u000a      Yates JC, Vestbo J, on behalf of the TORCH investigators.\u000a      Salmeterol and fluticasone propionate and survival in chronic obstructive\u000a      pulmonary disease. The New England Journal of Medicine. 2007;\u000a      356:775-89. DOI: 10.1056\/NEJMoa063070\u000a    \u000a\u000a6. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H,\u000a      Tal-Singer R, Miller B, Lomas DA, Agusti A, MacNee W, Calverley P, Rennard\u000a      S, Wouters EFM, Wedzicha JA. Susceptibility to Exacerbation in Chronic\u000a      Obstructive Pulmonary Disease. The New England Journal of Medicine.\u000a      2010; 363(12):1128-38. DOI: 10.1056\/NEJMoa0909883\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    S1.Medicines Evaluation Unit: http:\/\/www.meu.org.uk\/\u000a    S2.Letter from Chief Executive Officer, GSK.\u000a    S3.Global Initiative for Asthma. Global Strategy for Asthma Management\u000a      and Prevention. 2012. http:\/\/www.ginasthma.org\/local\/uploads\/files\/GINA_Report_March13.pdf\u000a    S4.British Thoracic Society\/Scottish Intercollegiate Guidelines Network.\u000a      British Guideline on the Management of Asthma: A National Clinical\u000a      Guideline. 2008, revised 2012. http:\/\/www.brit-thoracic.org.uk\/Portals\/0\/Guidelines\/AsthmaGuidelines\/sign101%20Jan%202012.pdf\u000a    S5.Global Initiative for Chronic Obstructive Lung Disease. Global\u000a      Strategy for the Diagnosis, Management, and Prevention of Chronic\u000a      Obstructive Pulmonary Disease. Updated 2013. http:\/\/www.goldcopd.org\/uploads\/users\/files\/GOLD_Report_2013_Feb20.pdf\u000a      (see p. 51; p. 56; p. 61; pp. 73-74; p. 76)\u000a    S6.NICE. CG101 Chronic Obstructive Pulmonary Disease: Management of\u000a      chronic obstructive pulmonary disease in adults in primary and secondary\u000a      care. 2004, updated 2010. http:\/\/guidance.nice.org.uk\/CG101\/Guidance\/pdf\/English(see p. 167)\u000a    S7.Letter from Executive Director, GOLD.\u000a    S8.Letter from VP, Clinical Discovery, GSK.\u000a    S9.Letter from Senior Director, Discovery and Chief Scientific Officer\u000a      & Executive Director of R&D, Almirall, Spain.\u000a    S10.Letter from Executive Secretary, Secretariat for the Vienna\u000a      Convention and its Montreal Protocol — The Ozone Secretariat, United\u000a      Nations Environment Programme.\u000a    ","Title":"\u000a    Development and application of inhaled therapies in airway diseases\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    Asthma and COPD together affect >10% of the world's population. COPD\u000a      is the third commonest cause of death worldwide. The aim of the research\u000a      at UoM since 1993 has been to provide better disease understanding, with a\u000a      focus on safer and more effective treatments targeted to the right\u000a      patients. This research has spanned the pre-clinical research essential to\u000a      select effective drugs for clinical development, early phase clinical\u000a      trials of these drugs in healthy subjects and patients and leadership of\u000a      large clinical trials needed for drug registration.\u000a    Key UoM researchers:\u000a    \u000a      \u000aAshley Woodcock (Professor, 1993-date)\u000a      \u000aJorgen Vestbo (Professor, 2003-date)\u000a      \u000aDave Singh (Senior Lecturer, 2003-2013; Professor, 2013-date)\u000a      \u000aAdnan Custovic (Senior Clinical Research Fellow, 2000-2002;\u000a        Professor, 2002-date)\u000a    \u000a    Woodcock has conducted asthma clinical trials since 1993 that have\u000a      formed the basis for the modern management of asthma, e.g. inhaled\u000a      corticosteroids and long-acting beta2-agonists, oral steroid\u000a      tapering in acute asthma, and with Custovic allergen avoidance in\u000a      allergic asthma (1, 2). Woodcock and Custovic established\u000a      the Manchester Asthma and Allergy Cohort, which has explored the\u000a      gene-environment interactions underlying allergic disease. Woodcock\u000a      led the research for the safe phase-out of CFCs in inhalers. He developed\u000a      new methods for assessing equivalence of HFC inhalers as safe alternatives\u000a      to CFC inhalers (3, 4). He used his research experience as Co-chair of the\u000a      Medical Technical Options Committee to the UNEP Montreal Protocol since\u000a      1995, leading negotiations on the reduction of CFC use in inhalers from\u000a      15,000 tonnes per year in 1996 towards complete phase-out in 2015.\u000a    Singh focuses on translating the basic pharmacological properties\u000a      of known and novel drugs for treatment of asthma and COPD, using human\u000a      tissue models, leading to the selection of candidate molecules that have\u000a      entered early phase clinical trials. He tested novel and existing drugs by\u000a      optimising methodologies which have led to effective and early\u000a      decision-making on the clinical potential of these drugs (e.g. failed\u000a      nitric oxide synthase inhibitor, successful development to market of novel\u000a      antichoinergics) in rapid proof of concept studies (5, 6).\u000a    Vestbo has, since his appointment at UoM in 2003, led seminal\u000a      trials in COPD that have ensured a step-change in treatment via the\u000a      introduction of inhaled long-acting bronchodilators, inhaled\u000a      corticosteroids and combination therapy. Vestbo has utilised\u000a      large population-based cohorts to explore the natural history and risk\u000a      factors for airways diseases as well as conducting work on biomarkers.\u000a    Vestbo and Singh have together led research into the\u000a      definition of COPD subgroups that have a different prognosis and\/or\u000a      response to therapy. They led one of the world's largest observational\u000a      COPD studies (the ECLIPSE study, 2164 patients followed for 3 years), Vestbo\u000a      as Chair of the Steering Committee and Singh as PI in blood and\u000a      sputum biomarkers. This study documented the heterogeneity of COPD, the\u000a      variable course of the disease, and for the first time identified a\u000a      subgroup of COPD patients characterised by frequent exacerbations\u000a      requiring a novel treatment strategy (6).\u000a    "},{"CaseStudyId":"28158","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    See section 5 for corroborating sources S1-S5.\u000a    Context\u000a      Prior to the research at UoM, it was known that wrinkling associated with\u000a      chronically sun-exposed skin (photoageing) was linked to loss of collagen\u000a      and that collagen could be restored in part by the use of the prescription\u000a      drug RA. UoM researchers generated new insights about the role of\u000a      fibrillin-rich microfibrils in the pathogenesis and clinical appearance\u000a      of photoaged skin and the effects of RA on the skin's microfibril network.\u000a      These insights led to the development of the `Manchester Patch Test\u000a      Assay', which is now widely used by the personal care industry. Before the\u000a      UoM research, many product claims for over-the-counter anti-ageing\u000a      products were not verified by an external, scientific source.\u000a    Pathways to impact\u000a      The research was presented at leading conferences (British Society for\u000a      Investigative Dermatology, European Society for Dermatological Research,\u000a      International Investigative Dermatology, American Aging Association,\u000a      Gordon Conferences) and published in leading scientific journals (see\u000a      above). This exposure has led to significant interest from the\u000a      biogerontological and personal care communities, both academic and\u000a      commercial.\u000a    In 2007, the underpinning research was showcased by the BBC2 science\u000a      documentary series Horizon. The programme highlighted the assay\u000a      and described how it had been used to demonstrate that a Boots Healthcare\u000a      over-the-counter anti-ageing product, No7 `Protect & Perfect Beauty\u000a      Serum', restored the microfibril network, implying potential to rejuvenate\u000a      aged skin. There was very significant public interest. This interest\u000a      resulted in a sell-out of the 'Protect & Perfect' product and the\u000a      retooling of the Boots manufacturing plant to meet demand. [text removed\u000a      for publication.] Following the showcasing of our in vivo system\u000a      by the BBC on Horizon there was a sea-change in the public's\u000a      perception of the science underpinning product claims. This has resulted\u000a      in a consumer-driven requirement by personal care companies to support\u000a      product claims with rigorous scientific data and controlled trials of\u000a      efficacy.\u000a    Reach and significance of the impact\u000a    Commercial impact on Boots\u000a      Following the broadcast of the BBC Horizon programme at the end of\u000a      March 2007, sales of Boots No7 `Protect & Perfect Beauty Serum' rose\u000a      dramatically. [text removed for publication.]\u000a    [text removed for publication.]\u000a    In 2012-2013, Alliance Boots Ltd Health and Beauty operation (including\u000a      the No7 range) posted the highest profit growth of all Boots divisions,\u000a      with the trading profits at the arm growing 6.8% (S4). Trading profits of\u000a      the Health & Beauty operation have shown an annual increase from £667m\u000a      in 2008\/09 to £865m in 2012\/13, amounting to a 30% increase (S4).\u000a    In 2012, the American pharmaceutical company Walgreens invested £4.4bn in\u000a      an agreement with Alliance Boots Ltd to create the largest global\u000a      pharmaceutical wholesale and distribution network (S3). The No7 `Protect\u000a      & Perfect' brand was reported as a `star beauty product from Boots at\u000a      its US partner' (S3).\u000a    Impact on the personal care industry\u000a      The impact of the UoM research extends beyond Boots, influencing the\u000a      product development strategies of other key players in the personal care\u000a      industry. Several major national and international personal care companies\u000a      (as listed below) have made use of the `Manchester Patch Test Assay' to\u000a      provide confidence in product efficacy prior to product launch. This\u000a      facilitates more cohesive development strategies, leading to significant\u000a      savings for R&D departments.\u000a    The importance of the research to the industry is evidenced by\u000a      significant and sustained investment in research on both basic science and\u000a      translational studies using the `Manchester Patch Test Assay'. The\u000a      following research contracts awarded to UoM indicate the scale of this\u000a      investment.\u000a    [text removed for publication.]\u000a    ","ImpactSummary":"\u000a    Extensible fibrillin-rich microfibrils are the template for elastic\u000a      fibres that endow dynamic tissues with elastic recoil. Researchers at the\u000a      University of Manchester (UoM) showed that microfibrils are degraded in\u000a      photoaged skin. We developed a rapid in vivo assay, `The\u000a      Manchester Patch Test Assay', which predicts the potential of anti-ageing\u000a      products to restore microfibrils in photoaged skin. The assay was used to\u000a      demonstrate the efficacy of a Boots Healthcare anti-ageing product and was\u000a      showcased on the BBC's Horizon in 2007. Impacts include:\u000a      dramatically increased sales for Boots, investment and changes to the\u000a      product development strategies of more than 10 international personal care\u000a      companies, which have used our assay to support product claims.\u000a    ","ImpactType":"Technological","Institution":"\u000a    The University of Manchester\u000a    ","Institutions":[{"AlternativeName":"Manchester (University of)","InstitutionName":"University of Manchester","PeerGroup":"A","Region":"North West","UKPRN":10007798}],"Panel":"A         ","PlaceName":[],"References":"\u000a    The research has been published in leading Dermatology and Pathology\u000a      journals (Journal of Investigative Dermatology, British Journal of\u000a        Dermatology and Journal of Pathology). Additionally,\u000a      reference 4 was the most downloaded British Journal of Dermatology\u000a      manuscript in both 2009 and 2010.\u000a    Key Publications\u000a    \u000a1. Watson REB, Griffiths CEM, Craven NM, Shuttleworth CA,\u000a        Kielty CM. Fibrillin-rich microfibrils are reduced in photoaged\u000a      skin. Distribution at the dermal-epidermal junction. Journal of\u000a        Investigative Dermatology.1999; 112(5):782-7.\u000a      DOI: 10.1046\/j.1523-1747.1999.00562.x\u000a    \u000a\u000a2. Watson REB, Craven NM, Kang S, Jones CJP, Kielty CM,\u000a        Griffiths CEM. A short-term screening protocol, using fibrillin-1 as\u000a      a reporter molecule, for photoaging repair agents. Journal of\u000a        Investigative Dermatology. 2001; 116(5):672-8.\u000a      DOI: 10.1046\/j.1523-1747.2001.01322.x\u000a    \u000a\u000a3. Watson REB, Long SP, Bowden JJ, Bastrilles JY, Barton SP, Griffiths\u000a        CEM. Repair of photoaged dermal matrix by topical application of a\u000a      cosmetic `antiageing' product. British Journal of Dermatology.\u000a      2008; 158(3):472-7.\u000a      DOI: 10.1111\/j.1365-2133.2007.08364.x\u000a    \u000a\u000a4. Watson REB, Ogden S, Cotterell LF, Bowden JJ, Bastrilles JY,\u000a      Long SP, Griffiths CEM. Effects of a cosmetic `anti-ageing'\u000a      product on photoaged skin. British Journal of Dermatology. 2009;\u000a      161(2):419-26.\u000a      DOI: 10.1111\/j.1365-2133.2009.09216.x\u000a    \u000aOther Relevant Publications\u000a    \u000a5. Farwick M, Watson REB, Rawlings AV, Wollenweber U, Lersch P,\u000a      Bowden JJ, Bastrilles JY, Griffiths CEM.\u000a      Salicyloyl-phytosphingosine: a novel agent for the repair of photoaged\u000a      skin. International Journal of Cosmetic Science. 2007;\u000a      29(4):319-29.\u000a      DOI: 10.1111\/j.1467-2494.2007.00394.\u000a    \u000a\u000a6. Tran C, Michelet JF, Simonetti L, Fiat F, Garrigues A, Potter A, Segot\u000a      E, Watson REB, Griffiths CEM, de Lacharrière O. In vitro\u000a      and in vivo studies with tetra-hydro-jasmonic acid (LR2412) reveal\u000a      its potential to correct signs of skin ageing. Journal of the European\u000a        Academy of Dermatology and Venereology. 2013 (in press).\u000a      DOI: 10.1111\/jdv.12113\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    S1. Ranking of UK anti-ageing serums from IRI data and NPD data, 52-week\u000a      period 2012-2013. (Confidential)\u000a    S2. Sales data 2007-2008 provided by Alliance Boots. (Confidential)\u000a    S3. The Telegraph, 15 May 2013. `US greets Boots with anti-ageing\u000a      serums'. Online version:\u000a      http:\/\/www.telegraph.co.uk\/finance\/newsbysector\/retailandconsumer\/10060043\/US-greets-\u000a        Boots-anti-ageing-serums.html\u000a    S4. Alliance Boots Ltd Annual Report, 2012\/13: http:\/\/annualreport2012-13.allianceboots.com\/Assets\/PDFs\/overview.pdf\u000a    S5. UoM awards data, 2008-2013.\u000a    ","Title":"\u000a    Fibrillin-rich microfibrils and efficacy of anti-ageing cosmetics\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    See section 3 for references 1-6. UoM researchers are given in bold.\u000a    The impact case is based on research that took place at UoM from\u000a      1994-date, with the first major publication in 1999 (1). The key\u000a      researchers were:\u000a    \u000a      \u000aChris Griffiths (Foundation Professor of Dermatology,\u000a        1993-date)\u000a      \u000aRachel Watson (RA, 1994-1997; PDRA, 1997-2000; Clinical\u000a        Scientist and Honorary Lecturer, 2001-2008; Clinical Scientist and\u000a        Honorary Senior Lecturer, 2008-2009; Senior Lecturer, 2009-date)\u000a      \u000aCay Kielty (Wellcome Trust Postdoctoral Research Fellow,\u000a        1993-1999; MRC Senior Research Fellow, 1993-2003; Professor of Medical\u000a        Biochemistry, 1999-date)\u000a      \u000aAdrian Shuttleworth (Reader in Biochemistry, 1968-2012)\u000a    \u000a    The aim of the research was to understand the effects of chronic solar\u000a      irradiation on the structure and function of human skin. It was known that\u000a      wrinkling associated with chronically sun-exposed skin (photoageing) was\u000a      linked to loss of collagen and that this could be restored in part by the\u000a      use of the prescription drug topical all-trans retinoic acid (RA).\u000a      We investigated the role of a key component of the skin's elastic fibre\u000a      network, fibrillin-rich microfibrils, in the pathogenesis and clinical\u000a      appearance of photoaged skin. We showed that microfibrils are central to\u000a      skin elasticity and their loss contributes to the clinical manifestations\u000a      of photoaged skin. We demonstrated that loss of microfibrils occurs early\u000a      in chronically sun-exposed, photoaged skin. We showed that clinical\u000a      improvement of photoaged skin by use of topical RA is accompanied by\u000a      restoration of the microfibril network in the papillary dermis. These\u000a      observations led to the development of a controlled, short-term in\u000a        vivo assay — `The Manchester Patch Test Assay' — which allowed\u000a      assessment of efficacy of over-the-counter topical anti-ageing products.\u000a    The key steps were as follows:\u000a    \u000a      In photoaged skin, the microfibril network — historically known as\u000a        cutaneous oxytalan fibres - was incomplete and in severe cases lost (1);\u000a      The gold-standard clinical treatment for photoageing, RA, resulted in\u000a        the deposition of new microfibrils in the papillary dermis of photoaged\u000a        skin (2);\u000a      We were able to recapitulate the ability of topical RA to deposit\u000a        microfibrils in vivo by application under occlusion to photoaged\u000a        extensor forearm for 12 days. Three mm diameter skin microbiopsies were\u000a        used to provide histological confirmation of responses (2);\u000a      We showed that this novel assay system, `The Manchester Patch Test\u000a        Assay', could be used by the personal skincare industry to screen\u000a        putative ingredients or finished formulations for anti-ageing properties\u000a        (3-6).\u000a    \u000a    The work is ongoing and many commercial products have been and are being\u000a      assessed using the assay system. For example, we are using novel\u000a      bioinformatic approaches in combination with biochemistry to test\u000a      hypotheses on the molecular mechanisms of irradiation-induced microfibril\u000a      remodelling and\/or degradation (See Sherratt MJ et al. Journal of\u000a        Pathology. 2010; 222(1):32-40).\u000a    "},{"CaseStudyId":"28751","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    The impacts in this section have all occurred in 2008 or later and have\u000a      occurred as a direct result of the UoL research.\u000a    As already mentioned, sepsis is a major cause of mortality and morbidity.\u000a      In England, Wales and Northern Ireland, 27% of adult admissions to\u000a      critical care in the period December 1995 to January 2005 were found to\u000a      progress to severe sepsis within the first 24 hours. Hospital mortality in\u000a      2004 in this geography was estimated to be 44.7% for those with severe\u000a      sepsis or 14,000 cases. Other estimates are higher. Prompt diagnosis and\u000a      treatment is essential with one study reporting a 7.6% increase in\u000a      mortality for each hour that antibiotic treatment was delayed in patients\u000a      with septic shock [18,19].\u000a    Following publication of the UoL research, there was recognition that the\u000a      aPTT biphasic waveform measurements could be important through enabling\u000a      earlier diagnosis to lead onto clinical benefits for patients and economic\u000a      benefits for health system providers. Several influential journal\u000a      editorials drew international attention to the research outputs [14-17].\u000a      This led to demonstration of the benefits in two disease areas where\u000a      infection is a common and important complication, namely heart bypass\u000a      surgery and the treatment of cancer [8,9]. The superiority of the aPTT\u000a      biphasic waveform over the leading sepsis biomarker, procalcitonin, in\u000a      clinical settings has also been investigated and confirmed [10].\u000a    This work led the British Committee for Standards in Haematology, a\u000a      leading professional body in the UK, to invite Toh and others to specify\u000a      laboratory standards for diagnosing the sepsis-related complication of\u000a      disseminated intravascular coagulation (DIC). These were published in 2009\u000a      [11] and included the aPTT waveform. These measurements are being promoted\u000a      by laboratories among their clinical customers and also by haematologists\u000a      requiring these measurements to improve clinical outcomes. Whilst\u000a      initially focussed on patients in intensive care settings, the rapid,\u000a      reliable and low cost measurement is leading to the test being used in\u000a      emergency rooms, post-surgical wards and oncology. This increase in\u000a      testing for sepsis is leading to earlier diagnosis and appropriate\u000a      treatment. Through improved diagnosis, it is also reducing the use of\u000a      antibiotics through an accurate distinction between bacterial and viral\u000a      disease [16]. The research is therefore clearly and directly impacting\u000a      upon clinical and laboratory medicine practitioners in the UK and also\u000a      specialists, including haematologists, emergency and critical care\u000a      physicians and paediatricians. Patients are benefiting through improved\u000a      treatment and reduction in the burden of sepsis on the NHS.\u000a    In a similar way, Toh was asked to contribute to the International\u000a      Society on Thrombosis Haemostasis's work to establish standards\u000a      internationally for diagnosing DIC and for laboratories offering the aPTT\u000a      biphasic waveform test to ensure that there is international consistency\u000a      in its application. Guidelines were published in Feb 2013 and work on\u000a      standardising the use of aPTT biphasic waveform measurements throughout\u000a      the world is ongoing [12]. They are impacting upon laboratories,\u000a      clinicians and patients in a similar way to the UK.\u000a    These advances have also been integrated into UK and international\u000a      training in haematology [13].\u000a    A new spinout company, Sepsis Ltd, was formed in 2010 and has acquired\u000a      the four patents arising from the UoL research. Its objective is to\u000a      develop devices incorporating aPTT biphasic waveform technology that can\u000a      be used at points of care for the routine testing of sepsis, from GP\u000a      surgeries to emergency rooms. The company has secured £250k of investment\u000a      funding and £1.2m from the Technology Strategy Board. It has already\u000a      developed a prototype device and by the end of 2013 will employ 3 people.\u000a    ","ImpactSummary":"\u000a    Research at the University of Liverpool (UoL) has developed and proven a\u000a      straightforward diagnostic test method for bacterial blood infections.\u000a      This was urgently needed as sepsis is a medical emergency that lacks\u000a      adequate and rapid diagnostic tests particularly for low cost early\u000a      detection. UoL's research has demonstrated that a simple optical test that\u000a      can be conducted during routine testing of coagulation is an effective\u000a      diagnostic, prognostic and monitoring marker for sepsis that can be\u000a      routinely applied in clinical settings. There are now established UK and\u000a      international laboratory standards in place. In 2010 a spinout company was\u000a      formed to exploit four patents and incorporate the technology into a\u000a      point-of-care device suitable for all clinical settings. The company,\u000a      Sepsis Ltd, has attracted £1.45m of investment.\u000a    ","ImpactType":"Technological","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Key Publications\u000a    \u000a1. Downey C, Kazmi R, Toh CH. Novel and diagnostically applicable\u000a      information from optical waveform analysis of blood coagulation in\u000a      disseminated intravascular coagulation. B J Haem 1997; 98: 68-73.\u000a      Citations: 47 Impact Factor: 4.942\u000a    \u000a\u000a2. Toh CH, Samis J, Downey C, Walker J, Becker L, Bruffato N,\u000a      Tejidor L, Jones G, Houdijk W, Giles AR, Koschinsky M, Ticknor L, Paton\u000a        R, Wenstone R, Nesheim ME. Biphasic transmittance waveform\u000a      in the APTT coagulation assay is due to the formation of a calcium\u000a      dependant complex of C-reactive protein with very-low-density-lipoprotein\u000a      and is a novel marker of impending disseminated intravascular coagulation.\u000a      Blood 2002, 100, 2522-2529. Citations: 70 Impact Factor: 9.060\u000a    \u000a\u000a3. Toh CH, Ticknor LO, Downey C, Giles AR, Paton R, Wenstone\u000a        R. Early identification of sepsis and mortality risks through\u000a      simple, rapid clot-waveform analysis. Intensive Care Medicine 2003, 29,\u000a      55-61. Citations: 46 Impact Factor: 5.258\u000a    \u000aPatents arising directly from the research.\u000a    4. WO00046603A1 (2000) describes \"A method and apparatus for predicting\u000a      the presence of haemostatic dysfunction in a patient sample.\"\u000a      http:\/\/www.wipo.int\/pctdb\/en\/wo.jsp?WO=2000046603\u000a    5. WO01013125A1 (2000) describes \"A Method for predicting the presence of\u000a      haemostatic dysfunction in a patient sample.\" http:\/\/www.wipo.int\/pctdb\/en\/wo.jsp?WO=2001013125\u000a    6. WO01096864A2 (2001) describes \"A method for detecting a\u000a      lipoprotein-acute phase protein complex and predicting an increased risk\u000a      of system failure of mortality.\"\u000a      http:\/\/www.wipo.int\/pctdb\/en\/wo.jsp?WO=2001096864\u000a    7. WO03073099A1 (2003) describes \"A Method for diagnosing and monitoring\u000a      haemostatic dysfunction, severe infection and systemic inflammatory\u000a      response syndrome.\"\u000a      http:\/\/www.wipo.int\/pctdb\/en\/wo.jsp?WO=2003073099\u000a    Key grants\u000a    2005-2007. MRC (G0400488). The role of very low density\u000a      lipoprotein in enhancing thrombin generation in sepsis. £89,408, Toh\u000a        CH, N Rhodes, M Leuwer.\u000a    2007-2010. NIHR Biomedical Research Centre Project 3515, A\u000a      Prospective Study of the aPTT Waveform and Lipoprotein-Complexed C\u000a      Reactive Protein Assays in the Early Diagnosis and Prognosis of Sepsis.\u000a      £330,820, Toh CH, Welters I, Williamson PR\u000a    2010. NIHR Innovation for Invention Future Product Development Stage\u000a        1: (II-FS-0509-12093). A Point-of-Care Test for Sepsis based on\u000a      Calcium-induced Turbidity in Blood, £100k, Toh CH, Myers P.\u000a    2010-2012. Technology Strategy Board. Rapid point-of-care\u000a      detection of bacterial sepsis. £160k, Toh CH\u000a    2011-2014. NIHR Innovation for Invention Late Stage Development:\u000a      ((II-LS-1010-10045). A Point-of-Care Test for Sepsis based on\u000a      Calcium-induced Turbidity in Blood, £300k, Toh CH, Myers P.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact). \u000a    \u000a      Delannoy, et al. Effect of cardiopulmonary bypass on aPTT waveform\u000a        analysis, serum procalcitonin and CRP concentrations. Crit Care 2009;\u000a        12: R180.\u000a      Hussain, et al. The biphasic transmittance waveform: an early marker\u000a        of sepsis in patients with neutropenia. Thromb Haemost 2008; 100: 146-8.\u000a      Zakariah A, et al. Combination of biphasic transmittance waveform with\u000a        blood PCT levels for diagnosis of sepsis in acutely ill patients. Crit\u000a        Care Med 2008; 36: 1507-12.\u000a      Clinical guidelines: Guidelines for the diagnosis and management of\u000a        disseminated intravascular coagulation. Br J Haematol 2009; 94: 387-94.\u000a      Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK,\u000a        Nielsen JD, Dempfle CE, Levi M, Toh CH; Guidance for diagnosis and\u000a        treatment of DIC from harmonization of the recommendations from three\u000a        guidelines. (2013) The Scientific Standardization Committee on DIC of\u000a        the International Society on Thrombosis Haemostasis. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23379279\u000a          \u000a\u000a      Postgraduate Haematology (Wiley-Blackwell) 6th Edition (2010), edited\u000a        by Victor Hoffbrand, Daniel Catovsky, Edward GD Tuddenham and Tony\u000a        Green. Chapter on Acquired Coagulation Disorders features the aPTT\u000a        biphasic waveform.\u000a    \u000a    Journal editorials on the aPTT biphasic waveform in sepsis \u000a    \u000a      ten Cate H. The biphasic waveform in plasma: identifying the\u000a        sepsis-coagulation crossroad. J Thromb Haemost 2004; 2: 1534-5.\u000a      Thomas K. Transmitting and absorbing new information on the early\u000a        identification of sepsis patients: aPTT waveform. Crit Care Med 2006;\u000a        34: 1829-31.\u000a      Dempfle CE, Borggrefe M. The hidden sepsis marker: aPTT waveform\u000a        analysis. Thromb Haemost 2008; 100: 9-10.\u000a      Schneider CP, Angele MK, Hartl WH. aPTT waveform analysis as specific\u000a        sepsis marker in cardiopulmonary bypass surgery. Crit Care 2010; 14:\u000a        104.\u000a    \u000a    Evidence of the serious nature of septic shock \u000a    \u000a      Harrison DA, et al. The epidemiology of severe sepsis in England,\u000a        Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high\u000a        quality clinical database, the ICNARC Case Mix Programme Database.\u000a        Critical Care 2006, 10:R42 doi:10.1186\/cc4854 http:\/\/ccforum.com\/content\/10\/2\/R42\u000a\u000a      Gaieski D, et al. Impact of time to antibiotics on survival in\u000a        patients with severe sepsis or septic shock in whom early goal-directed\u000a        therapy was initiated in the emergency department. Crit Care Med 2010;\u000a        38; 3. DOI: 10.1097\/CCM.0b013e3181cc4824\u000a    \u000a    ","Title":"\u000a    Sepsis diagnostic & Company spin-out\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Sepsis is a bacterial infection of the blood that causes whole body\u000a      inflammation and is the leading cause of death worldwide. It affects 18\u000a      million people and 30% of cases die from it. In addition, sepsis is\u000a      increasing by 1.5% each year. This is because of an ageing population and\u000a      antibiotic-resistant bacteria. A major problem is that prompt diagnosis of\u000a      sepsis is difficult. Early diagnosis is crucial to avoid complications,\u000a      secure appropriate antibiotic treatment and can be life-saving. There is a\u000a      pressing need for rapid detection systems that can indicate bacterial\u000a      infection at the patient bedside because conventional blood cultures take\u000a      over 24 hours to produce a result.\u000a    The pioneering research, led by Prof Cheng Hok Toh at the UoL, was first\u000a      published in 1997 following investigations into the routine coagulation\u000a      test for sepsis used in intensive care setting [1]. It was found that\u000a      during this course of this measurement of the activated partial\u000a      thromboplastin time (aPTT), optical measurements could distinguish between\u000a      samples where sepsis was present and not. This optical measurement was\u000a      called the aPTT biphasic waveform and is straightforward to generate.\u000a    The next step in the UoL research was to investigate the potential of the\u000a      aPTT biphasic waveform as a diagnostic, prognostic and monitoring marker\u000a      for sepsis and sepsis related complications. There were two threads to\u000a      this research. The first was based on further prospective and large\u000a      clinical cohort studies to ascertain the sensitivity and specificity of\u000a      the aPTT biphasic waveform measurements for this application. It was found\u000a      that this new measurement was sensitive, rapid and selective. Of\u000a      particular importance was the finding that it was more sensitive than the\u000a      established aPTT coagulation test; it could detect sepsis at an earlier\u000a      stage which enables earlier diagnosis and treatment. It was found to be at\u000a      least as sensitive as the two existing sepsis biomarker measurements —\u000a      procalcitonin and C reactive protein, which are expensive and take hours\u000a      for a result and therefore, not routinely used in the UK. This is the\u000a      first significant research output, that aPTT biphasic waveform\u000a      measurements have been found to be a superior indicator in clinical sample\u000a      for the presence of sepsis [3].\u000a    The second thread to the UoL research was to investigate the underlying\u000a      molecular mechanism and establish its function. It was found to involve a\u000a      calcium-dependent complex between C reactive protein and very low density\u000a      lipoprotein, which can slow down normal bacterial clearance by the body.\u000a      It is the knowledge of this molecular mechanism that has enabled the\u000a      development of new assays for sepsis [2]. These assays form the key\u000a      technology platform for routine point-of-care use of the laboratory-based\u000a      aPTT waveform directly into clinical settings. Four patents have also\u000a      arisen from this research [4-7].\u000a    "},{"CaseStudyId":"28860","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The research attracted much international interest (e.g. it was presented\u000d\u000a      internationally (e.g.\u000d\u000a      one of 11 highlighted plenary papers at the 2006 American Gastroenterology\u000d\u000a      Association;\u000d\u000a      15,000 delegates). Influenced by this research and anticipating probable\u000d\u000a      variations in quality\u000d\u000a      of care for patients with IBD, the British Society of Gastroenterology\u000d\u000a      (BSG) asked Rhodes to\u000d\u000a      initiate a national IBD audit. The first round of this UK IBD audit, led\u000d\u000a      in 2006 by Dr Keith\u000d\u000a      Leiper (Hon Senr Lecturer UoL) and funded by the Health Foundation,\u000d\u000a      revealed widespread\u000d\u000a      variation in quality of care, including inappropriate use of long term\u000d\u000a      corticosteroid therapy in\u000d\u000a      Crohn's disease [13]. This, along with other aspects of unacceptable care,\u000d\u000a      is shown in\u000d\u000a      Figure 1.\u000d\u000a\u0009  \u000d\u000a\u0009  Figure 1: Extract from the Executive Summary of the IBD Standards [3;\u000d\u000a      page 5]\u000d\u000a\u0009  \u000d\u000a    The 2006 audit identified that the annual cost to the NHS for IBD\u000d\u000a      including ulcerative colitis\u000d\u000a      and Crohn's disease was £720m based on an annual cost of £3,000 per\u000d\u000a      patient. As the\u000d\u000a      incidence rate continues to rise with an estimated one person in 200\u000d\u000a      affected, this presents a\u000d\u000a      significant and growing disease burden.\u000d\u000a    The audits were conducted with the engagement of the BSG, Royal College\u000d\u000a      of Physicians,\u000d\u000a      Association for Coloproctology, British Society for Paediatric\u000d\u000a      Gastroenterology and\u000d\u000a      Hepatology and the patient organisation Crohn's and Colitis UK. These key\u000d\u000a      partnerships led\u000d\u000a      to voluntary hospital participation in the first audit round of 75% and\u000d\u000a      included 2,353 Crohn's\u000d\u000a      disease patients, by the third round this had risen to 3,122 Crohn's\u000d\u000a      disease patients. These\u000d\u000a      engagement mechanisms have provided a pathway for the influence of the\u000d\u000a      clinical and\u000d\u000a      policy making community leading to significant improvements in clinical\u000d\u000a      practice in the UK for\u000d\u000a      the benefit of patients.\u000d\u000a    The UoL research led to the recognition of \"steroid usage for more than 3\u000d\u000a      consecutive\u000d\u000a      months\" as a key indicator of poor practice in Crohn's disease management\u000d\u000a      in the UK IBD\u000d\u000a      Audit. The UoL led UK IBD Audit in turn led to the publication (launched\u000d\u000a      at House of Lords)\u000d\u000a      in 2009 of National Standards of Care for Patients with Inflammatory Bowel\u000d\u000a      Disease agreed\u000d\u000a      jointly by the Association of Coloproctology of Great Britain and Ireland,\u000d\u000a      the British Dietetic\u000d\u000a      Association, British Society of Gastroenterology, British Society of\u000d\u000a      Paediatric\u000d\u000a      Gastroentrology, Hepatology and Nutrition, National Association for\u000d\u000a      Colitis and Crohn's\u000d\u000a      disease (now Crohn's and Colitis UK), Primary Care Society for\u000d\u000a      Gastroenterology, Royal\u000d\u000a      College of Nursing [3].\u000d\u000a    The national standards were adopted by the Healthcare Commission in\u000d\u000a      England as part of\u000d\u000a      the Annual Health Check to identify risk. The importance of the work on\u000d\u000a      corticosteroids is\u000d\u000a      demonstrated by it being one of only two indicators for Crohn's disease\u000d\u000a      outpatient treatment\u000d\u000a      ([12] page 21).\u000d\u000a    These national standards together with the programme of audits have had\u000d\u000a      considerable\u000d\u000a      impact. The proportion of patients with Crohn's disease in the UK-wide IBD\u000d\u000a      audit who had\u000d\u000a      received corticosteroids inappropriately for more than 3 consecutive\u000d\u000a      months has fallen from\u000d\u000a      46% to 38% to 21% in the three consecutive rounds of the IBD audit to date\u000d\u000a      (2006, 2008,\u000d\u000a      2010 [4]). The three audit rounds to date have been accompanied by\u000d\u000a      substantial\u000d\u000a      improvements in outcomes as highlighted in a Lancet Editorial as: \"For\u000d\u000a      adults with ulcerative\u000d\u000a      colitis, significant improvements in the third audit included reductions\u000d\u000a      in the rate of deaths\u000d\u000a      (0.8% in 2010 vs 1.7% in 2006) and readmissions (33.6% vs 51.1%\u000d\u000a      respectively). For adults\u000d\u000a      with Crohn's disease, improvements included a non-significant reduction in\u000d\u000a      the rate of\u000d\u000a      deaths (0.8% in 2010 vs 1.3% in 2006)\" [11]. There are also financial\u000d\u000a      savings arising from\u000d\u000a      the reduced rate of sepsis and hospital admissions.\u000d\u000a    The 2010 audit further showed that, 12 out of 15 key indicators of adult\u000d\u000a      IBD care showed\u000d\u000a      statistically significant improvement over the period 2006-2012, as did 10\u000d\u000a      out of 12 indicators\u000d\u000a      of Crohn's disease care.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The University of Liverpool (UoL) research identified corticosteroid\u000d\u000a      treatment for more than 3\u000d\u000a      consecutive months as a risk for serious sepsis in Crohn's disease and an\u000d\u000a      indicator of poor\u000d\u000a      practice; there are 115,000 Crohn's disease patients in the UK. Following\u000d\u000a      this, national audits of\u000d\u000a      Inflammatory Bowel Disease (IBD), also under UoL leadership, showed\u000d\u000a      reduction in inappropriate\u000d\u000a      long term steroid from 46% of Crohn's disease patients in 2006 to 21% in\u000d\u000a      2010. These audits led\u000d\u000a      to widespread adoption of National Service Standards for the Care of\u000d\u000a      Patients with IBD. Death and\u000d\u000a      hospital readmission rates for IBD patients were subsequently\u000d\u000a      significantly reduced.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Agrawal A, Durrani S, Leiper K, Ellis A, Morris AI,\u000d\u000a        Rhodes JM. Systemic corticosteroid\u000d\u000a      therapy increases risk for intra-abdominal or pelvic abscess in\u000d\u000a      non-operated Crohn's\u000d\u000a      disease. Clinical Gastroenterology and Hepatology. 2005;3:1215-1220. PMID:\u000d\u000a      17229216.\u000d\u000a      Citations: 31 Impact Factor: 6.648\u000d\u000a    \u000a\u000a2. Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R,\u000d\u000a      Englyst H, Williams HF,\u000d\u000a      Rhodes JM. Enhanced Escherichia coli adherence and invasion in\u000d\u000a      Crohn's disease and\u000d\u000a      colon cancer. Gastroenterology 2004;127:80-93. Citations: 229 Impact\u000d\u000a      Factor: 6.648\u000d\u000a    \u000a\u000a3. Mpofu CM, Campbell BJ, Subramanian S, Marshall-Clarke S, Hart CA,\u000d\u000a        Cross A,\u000d\u000a        Roberts CL, McGoldrick A, Edwards SW, Rhodes JM. Microbial mannan\u000d\u000a      inhibits\u000d\u000a      bacteria killing by macrophages: a possible pathogenic mechanism for\u000d\u000a      Crohn's disease.\u000d\u000a      Gastroenterology 2007;133:1487-98. Citations: 30 Impact Factor: 12.821\u000d\u000a    \u000a\u000a4. Subramanian S, Roberts CL, Hart CA, Martin HM, Edwards SW, Rhodes\u000d\u000a        JM, Campbell\u000d\u000a        BJ. Replication of Colonic Crohn's Disease Mucosal Escherichia coli\u000d\u000a      Isolates within\u000d\u000a      Macrophages and Their Susceptibility to Antibiotics. Antimicrob Agents\u000d\u000a      Chemother.\u000d\u000a      2008;52:427-34. Citations: 30 Impact Factor: 4.565\u000d\u000a    \u000a\u000a5. Roberts CL, Keita AV, Duncan SH, O'Kennedy N, Söderholm JD, Rhodes\u000d\u000a        JM,\u000d\u000a        Campbell BJ. Translocation of Crohn's disease E. coli across\u000d\u000a      M-cells: contrasting effects\u000d\u000a      of soluble plant fibres and emulsifiers. Gut 2010;59:1331-9. Citations: 20\u000d\u000a      Impact Factor:\u000d\u000a      10.732\u000d\u000a    \u000a\u000a6. Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan\u000d\u000a      TJ, Campbell\u000d\u000a        BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A,\u000d\u000a      Simpson KW, Hansen JJ,\u000d\u000a      Keku TO, Fodor AA, Jobin C. Intestinal Inflammation Targets\u000d\u000a      Cancer-Inducing Activity of\u000d\u000a      the Microbiota. Science. 2012;338:120-3. Citations: 65 Impact Factor:\u000d\u000a      31.027\u000d\u000a    \u000a\u000a7. Prorok-Hamon M, Friswell MK, Alswied A, Roberts CL, Song F,\u000d\u000a        Flanagan PK, Knight\u000d\u000a        P, Codling C, Marchesi JR, Winstanley C, Hall N, Rhodes JM,\u000d\u000a        Campbell BJ. Colonic\u000d\u000a      mucosa-associated diffusely adherent afaC+ Escherichia coli expressing\u000d\u000a      lpfA and pks are\u000d\u000a      increased in inflammatory bowel disease and colon cancer. Gut. 2013 Jul\u000d\u000a      11. [Epub ahead\u000d\u000a      of print]. Citations: 1 Impact Factor: 10.732\u000d\u000a    \u000a\u000a8. Leiper K, Woolner J, Mullan MMC, Parker T, van der Vliet\u000d\u000a        M, Fear S, Rhodes JM, Hunter\u000d\u000a      JO. A randomised controlled trial of high versus low long chain\u000d\u000a      triglyceride whole protein\u000d\u000a      feed in active Crohn's disease. Gut 2001;49:790-794. Citations: 37 Impact\u000d\u000a      Factor:\u000d\u000a      10.732\u000d\u000a    \u000a\u000a9. Leiper K, Martin K, Ellis A, Watson AJ, Morris AI, Rhodes JM.\u000d\u000a      Clinical trial: randomised\u000d\u000a      placebo-controlled study of clarithromycin in active Crohn's disease.\u000d\u000a      Aliment Pharmacol\u000d\u000a      Ther. 2008;27:1233-9. Impact Factor: 4.548\u000d\u000a    \u000a\u000a10. Leiper K, Martin K, Ellis A, Subramanian S, Watson A J, Christmas\u000d\u000a        SE, Howarth D,\u000d\u000a        Campbell F, Rhodes JM. Randomised placebo-controlled trial of\u000d\u000a      rituximab (anti-CD20) in\u000d\u000a      active ulcerative colitis. Gut 2011;60:1520-6. Citations: 17 Impact\u000d\u000a      Factor: 10.732\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section\u000d\u000a      4 (details of the impact).\u000d\u000a    \u000d\u000a    \u000d\u000a      Lancet editorial. Inflammatory bowel disease audited. Lancet\u000d\u000a        2012;379:868\u000d\u000a        http:\/\/download.thelancet.com\/pdfs\/journals\/lancet\/PIIS0140673612603766.pdf\u000a\u000d\u000a      IBD standards document. (2009)\u000d\u000a        http:\/\/www.ibdstandards.org.uk\/uploaded_files\/IBDstandards.pdf\u000a\u000d\u000a      IBD UK Audit 1st, 2nd and 3rd round results via RCP website:\u000d\u000a        http:\/\/www.rcplondon.ac.uk\/projects\/ibdaudit.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved Inflammatory Bowel Disease Treatment by Reducing Unsafe\u000d\u000a      Corticosteroid Use\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Corticosteroids have for >50 years been the initial therapy in most\u000d\u000a      patients with Crohn's disease\u000d\u000a      yet they have been shown to have no useful maintenance effect (Benchimol\u000d\u000a      EL et al Cochrane\u000d\u000a      Database Syst Rev 2009 CD002913) and do not induce mucosal healing or\u000d\u000a      improve the long-term\u000d\u000a      natural history of the disease (Vermeire S et al Aliment Pharmacol Therap\u000d\u000a      2007;25:3-12). They do\u000d\u000a      however provide rapid symptomatic relief. The Liverpool researchers have\u000d\u000a      for over ten years been\u000d\u000a      at the forefront of research demonstrating a likely pathogenic role for\u000d\u000a      bacteria in Crohn's disease\u000d\u000a      pathogenesis [2-7] and had therefore been concerned that steroids were\u000d\u000a      often used inappropriately\u000d\u000a      at too high a dose and for too long and that patients were coming to harm\u000d\u000a      as a result. Several\u000d\u000a      clinical trials have been initiated from Liverpool to assess alternative\u000d\u000a      treatments such as enteral\u000d\u000a      nutrition and antibiotics [8-10 plus 2 investigator-led trials ongoing].\u000d\u000a      At the time the Liverpool study\u000d\u000a      of steroid use and sepsis in Crohn's disease was undertaken (2002) there\u000d\u000a      had been little\u000d\u000a      quantification of the safety of corticosteroid usage in this group of\u000d\u000a      patients. The study was\u000d\u000a      designed to assess possible associations between corticosteroid usage and\u000d\u000a      serious sepsis\u000d\u000a      occurring in non-operated patients with Crohn's disease (separate research\u000d\u000a      elsewhere had\u000d\u000a      identified corticosteroid usage as a risk for post-operative sepsis in\u000d\u000a      abdominal surgery).\u000d\u000a    A retrospective case-control study was performed in 432 patients\u000d\u000a      attending the Royal Liverpool\u000d\u000a      University Hospital with Crohn's disease (the 94% of the IBD database for\u000d\u000a      whom adequate\u000d\u000a      documentation could be retrieved) to compare possible risk factors with\u000d\u000a      incidence of serious intra-abdominal\u000d\u000a      sepsis occurring in non-operated patients [1]. This study was performed\u000d\u000a      between 2002\u000d\u000a      and 2004. The study was led by Prof Jonathan Rhodes (UoL throughout) with\u000d\u000a      NHS Consultant\u000d\u000a      colleagues Drs Keith Leiper and Anthony Ellis (both Hon Senior Lecturers)\u000d\u000a      and Professor Anthony\u000d\u000a      Morris (Honorary Professor) together with NHS clinical trainees Drs Anurag\u000d\u000a      Agrawal and Shireen\u000d\u000a      Durrani. It showed that systematic corticosteroid use was associated with\u000d\u000a      increased rates of intra-\u000d\u000a      abdominal or pelvic sepsis in patients with perforating Crohn's disease\u000d\u000a      (odds ratio 9.03; 95% CI\u000d\u000a      2.40-33.98) and patients with relapsed active disease (unadjusted odds\u000d\u000a      ratio 9.31; 95% CI 1.03-\u000d\u000a      83.91). Further, patients receiving higher corticosteroid doses (i.e.\u000d\u000a      20mg\/day or more of\u000d\u000a      prednisolone) or receiving steroids for more than three months experienced\u000d\u000a      higher rates of sepsis\u000d\u000a      compared to those receiving lower and\/or shorter duration therapy (odds\u000d\u000a      ratio 5.41; 95% CI 1.02-\u000d\u000a      28.79). This is important because abdominal and pelvic sepsis are\u000d\u000a      potentially life-threatening\u000d\u000a      conditions.\u000d\u000a    "},{"CaseStudyId":"28863","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"366755","Name":"Sudan"},{"GeoNamesId":"895949","Name":"Zambia"},{"GeoNamesId":"927384","Name":"Malawi"},{"GeoNamesId":"933860","Name":"Botswana"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2542007","Name":"Morocco"},{"GeoNamesId":"2300660","Name":"Ghana"},{"GeoNamesId":"49518","Name":"Rwanda"},{"GeoNamesId":"953987","Name":"South Africa"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    All impacts generated from the UoL research have occurred since 2008.\u000a    The long-term detailed descriptions of rotavirus gastroenteritis in\u000a      Malawian children helped to progress the assessment and introduction of\u000a      rotavirus vaccines in Africa by (i) demonstrating the need for rotavirus\u000a      vaccines to be effective against a wide range of rotavirus strain types;\u000a      (ii) demonstrating the need for rotavirus vaccines to protect very young\u000a      infants, since a high burden of rotavirus disease occurred in the first\u000a      year of life; and (iii) providing an ideal trial site with a wealth of\u000a      underpinning data where the pivotal rotavirus vaccine trial could be\u000a      undertaken. These data were generated in collaboration with the College of\u000a      Medicine, University of Malawi (Dr Bagrey Ngwira). The data were\u000a      disseminated through publication in peer-reviewed journals [1-3].\u000a    Based in large part upon the results of the clinical trial in Malawi,\u000a      where vaccination was shown to reduce severe rotavirus disease by 50%, a\u000a      global recommendation for rotavirus vaccine use was issued in 2009 by the\u000a      World Health Organisation. In countries where diarrhoeal deaths account\u000a      for ≥10% of mortality among children aged <5 years, the introduction of\u000a      the vaccine was strongly recommended. Effectively, this recommendation\u000a      amounted to an extension of an existing recommendation from continents\u000a      where vaccine efficacy had been demonstrated (Europe and the Americas) to\u000a      also include developing countries in Africa and Asia (where the greatest\u000a      disease burden lies but where vaccine efficacy was unknown). The clinical\u000a      trial was undertaken in partnership with the Program In Appropriate\u000a      Technology for Health, GlaxoSmithKline Biologicals, The University of\u000a      Malawi College of Medicine, and the University of Witwatersrand. The data\u000a      were presented to a WHO Strategic Advisory Group of Experts vaccine\u000a      meeting and disseminated through publication in peer-reviewed journals.\u000a      The results were made available to the Malawi Ministry of Health [15].\u000a    Following this global recommendation, African countries are introducing\u000a      rotavirus vaccines into their childhood immunisation schedules with Malawi\u000a      having introduced in November 2012. This followed the introduction of\u000a      rotavirus vaccines in Botswana, Ghana, Morocco, Rwanda, South Africa,\u000a      Sudan and Zambia. Early data are emerging from South Africa (where vaccine\u000a      was introduced in 2009) of an effect on child health in respect of reduced\u000a      hospitalisations due to rotavirus infection. For example, a recent\u000a      assessment of the impact in South Africa states that \"we estimate that at\u000a      least 13,000 to 20,000 hospitalizations in children <2 years were\u000a      prevented in the two years following rotavirus vaccine introduction\" [14].\u000a      Rotavirus diarrhoea accounts for 6.5% of global deaths of children under\u000a      five. Complete implementation in all GAVI eligible countries will prevent\u000a      180,000 deaths per year and avert 6 million clinic and hospital visits\u000a      each year, thereby saving US $68 million annually in treatment costs [9].\u000a    In order to assess vaccine effectiveness and impact on rotavirus disease\u000a      burden in Malawi (including deaths due to diarrhoea), the UoL (PI,\u000a      Cunliffe) has been awarded a 5-year Programme Grant by the Wellcome Trust\u000a      (2010-2015, listed in section 3 above).\u000a    A Cochrane review has highlighted the benefits of rotavirus vaccinations\u000a      in all populations [13] and the UK introduced rotavirus vaccine into its\u000a      childhood immunization programme in July 2013.\u000a    ","ImpactSummary":"\u000a    Rotavirus is the leading cause of acute gastroenteritis in infants and\u000a      young children worldwide, causing 500,000 deaths annually. Prof Cunliffe\u000a      at the University of Liverpool (UoL) has conducted rotavirus studies in\u000a      Malawi since 1997, including descriptive epidemiology and the first\u000a      clinical trial of a human rotavirus vaccine in Africa. Based upon the\u000a      results of this clinical trial in Malawi, where vaccination was shown to\u000a      reduce severe rotavirus disease caused by diverse strains by 50%, a global\u000a      recommendation for rotavirus vaccine use was issued by WHO in 2009.\u000a      African countries are now introducing rotavirus vaccines into their\u000a      childhood immunization schedules with introduction in Malawi in 2012.\u000a    ","ImpactType":"Health","Institution":"\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Peer-reviewed publications\u000a    \u000a1. Cunliffe NA, Gondwe JS, Kirkwood CD, Graham SM, Nhlane N,\u000a      Thindwa BDM, Dove W, Broadhead RL, Molyneux ME, Hart CA. Effect of\u000a      concomitant HIV infection on presentation and outcome of rotavirus\u000a      gastroenteritis in Malawian children. Lancet 2001;358:550-555. Citations:\u000a      52 Impact Factor: 39.060\u000a    \u000a\u000a2. Cunliffe NA, Ngwira BM, Dove W, Thindwa BDM, Turner AM,\u000a      Broadhead RL, Molyneux ME, Hart CA. Epidemiology of rotavirus infections\u000a      in children in Blantyre, Malawi, 1997-2007. Journal of Infectious Diseases\u000a      2010;202:S168-174. Citations: 16 Impact Factor: 5.848\u000a    \u000a\u000a3. Cunliffe NA, Gondwe JS, Graham SM, Thindwa BDM, Dove W,\u000a      Broadhead RL, Molyneux ME, Hart CA. Rotavirus strain diversity in\u000a      Blantyre, Malawi, from 1997 to 1999. Journal of Clinical Microbiology\u000a      2001;39:836-843. Citations: 111 Impact Factor: 4.068\u000a    \u000a\u000a4. Madhi SA*, Cunliffe NA*, Steele AD, Witte D, Kirsten M, Louw\u000a      C, Ngwira B, Victor JC, Gillard PH, Cheuvart BB, Han HH, Neuzil KM. Effect\u000a      of human rotavirus vaccine on severe gastroenteritis in African infants.\u000a      New England Journal of Medicine 2010;362:289-98. *Co-primary authors.\u000a      Citations: 211 Impact Factor: 51.658\u000a    \u000a\u000a5. Cunliffe NA, Witte D, Ngwira BM, Todd S, Bostock NJ, Turner\u000a      AM, Chimpeni P, Victor JC, Steele AD, Bouckenooghe A, Neuzil KM. Efficacy\u000a      of human rotavirus vaccine against severe gastroenteritis in Malawian\u000a      children in the first two years of life. Vaccine 2012; 30:A36-43.\u000a      Citations: 8 Impact Factor: 3.492\u000a    \u000a\u000a6. Nakagomi T, Nakagomi O, Dove W, Doan YH, Witte D, Ngwira B, Todd S,\u000a      Steele AD, Neuzil KM, Cunliffe NA. Molecular characterization of\u000a      rotavirus strains detected during a clinical trial of a human rotavirus\u000a      vaccine in Blantyre, Malawi. Vaccine 2012; 30: A140-151. Citations: 1\u000a      Impact Factor: 3.492\u000a    \u000aResearch Grants\u000a    2010-2015. Wellcome Trust. New childhood vaccines for Malawi:\u000a      Impact of a national pneumococcal and rotavirus vaccine roll-out on child\u000a      mortality and disease burden, in a region of sub-optimal strain coverage,\u000a      £2.3m Programme Grant PI NA Cunliffe with Neil French and\u000a      Robert Heyderman\u000a    2006-2011. Programme in Appropriate Technology in Health (PATH) to\u000a        University of Liverpool. A phase III, double-blind, randomised,\u000a      placebo-controlled, multi-center study to assess the efficacy, safety and\u000a      immunogenicity of two or three doses of GlaxoSmithKline (GSK) Biologicals'\u000a      oral live attenuated human rotavirus (HRV) vaccine given concomitantly\u000a      with routine Expanded Program of Immunisation (EPI) vaccinations in\u000a      healthy Malawian infants, £2m\u000a    1996-2001. Wellcome Trust. Clinical features and molecular\u000a      epidemiology of rotavirus diarrhoea in Malawian children with and without\u000a      HIV infection. Wellcome Research Training Fellowship for NA Cunliffe,\u000a      £330k\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    Each source listed below provides evidence for the corresponding numbered\u000a      claim made in section 4 (details of the impact). \u000a    \u000a      Weekly Epidemiological Record 2009; 84: 213-236. The global vaccine\u000a        recommendation and direct link to the clinical trial of rotavirus\u000a        vaccine in Malawi and South Africa\u000a      Rotavirus vaccines. WHO Position paper - January 2013. Wkly Epidemiol\u000a        Rec 2013;88: 49-64. Current WHO position paper with review of rotavirus\u000a        vaccine introduction and impact\u000a      \u000ahttp:\/\/www.path.org\/news\/press-room\/159\/\u000a        Rollout of rotavirus vaccine in Malawi (PATH)\u000a      \u000a\u000ahttp:\/\/www.gavialliance.org\/library\/news\/press-releases\/2012\/malawi-protect-thousands-childrens-lives-rotavirus-vaccines\/\u000a        Rollout of rotavirus vaccine in Malawi (GAVI)\u000a      \u000a\u000ahttp:\/\/www.afro.who.int\/en\/malawi\/press-materials\/item\/5152-malawi-introduces-the-rotavirus-vaccine-to-reduce-diarrhea-illnesses-and-deaths-among-children.html\u000a        Rollout of rotavirus vaccine in Malawi (WHO)\u000a      Msimang VM, Page N, Groome MJ, Moyes J, Cortese M, Seheri M, Kahn K,\u000a        Chagan M, Madhi SA, Cohen C. Impact of Rotavirus Vaccine on Childhood\u000a        Diarrheal Hospitalization Following Introduction into the South African\u000a        Public Immunization Program. Pediatr Infect Dis J 2013. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23934208\u000a\u000a      Soares-Weiser K, MacLehose H, Bergman H, Ben-Aharon I, Nagpal S,\u000a        Goldberg E, Pitan F, Cunliffe N \"Vaccines for preventing rotavirus\u000a        diarrhoea: Vaccines in use. Cochrane Review. 2012. http:\/\/summaries.cochrane.org\/CD008521\/vaccines-for-preventing-rotavirus-diarrhoea-vaccines-in-use#sthash.toQh67x0.dpuf\u000a\u000a      Contact: Program in Appropriate Technology for Health, Seattle, USA\u000a      Contact: Department of Health, Malawi\u000a    \u000a    ","Title":"\u000a    Rotavirus Vaccine Evaluation and Introduction in Africa\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The UoL research was designed to facilitate and accelerate the\u000a      introduction of rotavirus vaccines into childhood immunisation programmes\u000a      in Africa. Rotavirus is responsible for approximately half a million\u000a      childhood deaths from acute gastroenteritis each year, with the majority\u000a      of deaths occurring in infants in Africa and Asia. Prior to the completion\u000a      of this research, the ability of current rotavirus vaccines to protect\u000a      children in the world's poorest countries was unknown and therefore WHO\u000a      did not recommend their use in such populations.\u000a    \u000a      Through a competitive Wellcome Trust Research Training Fellowship\u000a        (1996-2001), to NA Cunliffe [UoL, supervisor CA Hart - now deceased]),\u000a        the first detailed investigation of rotavirus infections in HIV-infected\u000a        children was undertaken. The findings were published in several leading\u000a        journals including the Lancet [1] and AIDS. The seminal\u000a        observation of natural rotavirus infections being of similar severity in\u000a        HIV-infected and HIV-uninfected children encouraged the subsequent\u000a        evaluation of live, oral rotavirus vaccines in HIV-exposed and HIV-\u000a        infected infants.\u000a      In ongoing studies since 1997 to the present, funded by the Wellcome\u000a        Trust, WHO and GSK Biologicals, NA Cunliffe and CA Hart (UoL) have\u000a        described the disease burden and epidemiological features of rotavirus\u000a        infections in Malawian children, published in Journal of Infectious\u000a          Diseases [2], Journal of Clinical Microbiology [3], Virology,\u000a        Emerging Infectious Diseases and Journal of General Virology.\u000a        These studies have highlighted the high burden of rotavirus disease\u000a        amongst impoverished populations and have described particular\u000a        epidemiological features relevant to rotavirus vaccine programmes. For\u000a        example, the rotavirus disease burden in early infancy is very high — so\u000a        effective vaccines need to provide early protection in this and similar\u000a        settings. The description of a wide diversity of rotavirus strains,\u000a        including novel serotype G8 strains, has highlighted the requirement for\u000a        effective rotavirus vaccines to provide cross-serotype protection in\u000a        African countries.\u000a      Consequent to the above studies, and in partnership with the Program\u000a        in Appropriate Technology for Health (PATH), USA and GlaxoSmithKline\u000a        Biologicals (GSK), Belgium, NA Cunliffe (UoL) and SA Madhi (University\u000a        of Witwatersrand, South Africa) led as Chief Principal Investigators a\u000a        Phase III, placebo-controlled clinical trial of a human rotavirus\u000a        vaccine in Malawian and South African children (2006-2009). This first\u000a        clinical trial of a human rotavirus vaccine in Africa, including infants\u000a        exposed to HIV infection, reduced severe rotavirus disease in Malawian\u000a        children by 50% [4, 5]. Vaccine efficacy was lower than documented in\u000a        industrialised countries; however given the substantially higher burden\u000a        of disease, public health impact of rotavirus vaccination would be\u000a        greater. Protection against a wide range of rotavirus strains was\u000a        observed, including the prevalent G8 serotype [6].\u000a    \u000a    "},{"CaseStudyId":"28874","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2963597","Name":"Ireland"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The research on the meningococcal PCR was done in conjunction with the\u000d\u000a      Meningococcal\u000d\u000a      Reference Unit at the Health Protection Agency (HPA), now Health\u000d\u000a      Protection England. The HPA's\u000d\u000a      advice, information and services are underpinned by evidence-based\u000d\u000a      research. The UoL research\u000d\u000a      provided evidence that PCR offered advantages over blood culture in real\u000d\u000a      life settings and was\u000d\u000a      directly used to improve diagnosis nationally, thereby ensuring that\u000d\u000a      patients received more\u000d\u000a      appropriate and earlier treatment than they would otherwise have done. The\u000d\u000a      assay and primer\u000d\u000a      sequences used by HPA are published in journals with a wide circulation,\u000d\u000a      allowing others to\u000d\u000a      develop their own in-house PCR assays, thereby increasing global impact;\u000d\u000a      the partnership with\u000d\u000a      HPA increased the reach and impact of the research. Meningococcal PCR is\u000d\u000a      recommended as the\u000d\u000a      gold standard in the 2010 NICE Clinical Guideline CG102 [5]. The research\u000d\u000a      is also influencing the\u000d\u000a      formulation of child specific NICE guidelines through work started in 2010\u000d\u000a      [6].\u000d\u000a    These organisations fund research to prevent meningitis and septicaemia,\u000d\u000a      and improve survival\u000d\u000a      rates and outcomes. They also promote education and awareness to reduce\u000d\u000a      death and disability,\u000d\u000a      and give support to people affected. As a result of the close\u000d\u000a      collaboration between Professor Hart's\u000d\u000a      group and these patient organisations (Meningitis Merseyside, Meningitis\u000d\u000a      UK, Meningitis Research\u000d\u000a      Foundation), results from the programme were disseminated directly to\u000d\u000a      patient organisations and\u000d\u000a      through conferences and literature to scientists and clinicians. The close\u000d\u000a      links with patient groups\u000d\u000a      provided societal benefit by contributing to increased knowledge of the\u000d\u000a      disease being shared with\u000d\u000a      members of the public. Key findings from research funded by Meningitis\u000d\u000a      Research Foundation are\u000d\u000a      published on their website. Publications in medium to high impact\u000d\u000a      publications also helped to give\u000d\u000a      international recognition to this work.\u000d\u000a    The guidelines derived from the UoL research are being implemented and\u000d\u000a      are impacting patients.\u000d\u000a      For example, an HPA population-level assessment published in 2013 of the\u000d\u000a      added value of PCR\u000d\u000a      testing for MCD to augment traditional culture confirmation concluded that\u000d\u000a      PCR-testing has a\u000d\u000a      crucial role in the confirmation of MCD in England [7]. A total of 57% of\u000d\u000a      all confirmed MCD cases\u000d\u000a      were confirmed by PCR only, indicating high case ascertainment for\u000d\u000a      national surveillance. The\u000d\u000a      sensitivity of PCR in the recent HPA study is 97-99% [7].\u000d\u000a    The beneficiaries are 1) patients and patient groups through faster and\u000d\u000a      more accurate diagnosis\u000d\u000a      and therefore more effective treatment, and 2) healthcare providers who\u000d\u000a      can more effectively use\u000d\u000a      their resources. In England, in 2009 and 2010 there were 1924 reported MCD\u000d\u000a      cases, 1099 (57.1%)\u000d\u000a      were confirmed by PCR only, 432 (22.5%) by culture only and 393 (20.4%) by\u000d\u000a      both tests. This\u000d\u000a      means that, on average about 500 additional patients per year\u000d\u000a      receive an accurate diagnosis and\u000d\u000a      appropriate therapy as a result of this test.\u000d\u000a    The researchers have also engaged patient groups, the Meningitis Research\u000d\u000a      Foundation and\u000d\u000a      Meningitis UK. The beneficiaries are the public through increased\u000d\u000a      awareness and access to\u000d\u000a      knowledge.\u000d\u000a    The research has achieved international prominence and is now being\u000d\u000a      applied in Europe. For\u000d\u000a      example, in Barcelona 39% of 118 MCD were only detected by PCR [8]. MenB\u000d\u000a      is the leading\u000d\u000a      cause of meningitis and septicaemia in Ireland, with an average of 170\u000d\u000a      average cases per year.\u000d\u000a      The study by Drew [9] reports that 63% of cases were diagnosed by PCR\u000d\u000a      alone, which equates to\u000d\u000a      about 107 extra cases \/year in Ireland.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Meningococcal disease (MCD) is a major cause of morbidity and mortality\u000d\u000a      worldwide.\u000d\u000a      Underpinning research by Dr Carrol and colleagues at the University of\u000d\u000a      Liverpool (1997-1999), has\u000d\u000a      led to improved diagnosis and case confirmation, establishing Polymerase\u000d\u000a      Chain Reaction (PCR)\u000d\u000a      of meningococcal DNA as a gold standard test for diagnosis. The result is\u000d\u000a      better management and\u000d\u000a      therefore, impact on health and welfare of patients, and on practitioners.\u000d\u000a      The work was conducted\u000d\u000a      in collaboration with the Meningococcal Reference Unit, which provides a\u000d\u000a      national diagnosis and\u000d\u000a      surveillance service. The test was recommended in NICE guidelines in 2010,\u000d\u000a      thereby impacting\u000d\u000a      public policy.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3128760","Name":"Barcelona"}],"References":"\u000d\u000a    \u000a1. Carrol ED, Thomson AP, Shears P, Gray SJ, Kaczmarski EB, Hart\u000d\u000a        CA: Performance\u000d\u000a      characteristics of the polymerase chain reaction assay to confirm clinical\u000d\u000a      meningococcal\u000d\u000a      disease. Arch Dis Child 2000, 83(3):271-273. Citations: 36 Impact Factor:\u000d\u000a      3.051\u000d\u000a    \u000a\u000a2. Hackett SJ, Carrol ED, Guiver M, Marsh J, Sills JA, Thomson\u000d\u000a        AP, Kaczmarski EB, Hart\u000d\u000a        CA: Improved case confirmation in meningococcal disease with whole\u000d\u000a      blood Taqman PCR.\u000d\u000a      Arch Dis Child 2002, 86(6):449-452. Citations: 22 Impact Factor: 3.051\u000d\u000a    \u000a\u000a3. Stanton MC, Taylor-Robinson D, Harris D, Paize F, Makwana N,\u000d\u000a        Hackett SJ, Baines\u000d\u000a        PB, Riordan FA, Marzouk O, Thomson AP et al: Meningococcal disease\u000d\u000a      in children in\u000d\u000a      Merseyside, England: a 31 year descriptive study. PLoS One 2011,\u000d\u000a      6(10):e25957.\u000d\u000a      Citations: 2 Impact Factor: 3.730\u000d\u000a    \u000a\u000a4. Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, Inwald D,\u000d\u000a      Nadel S, Betts H,\u000d\u000a      Carrol ED et al: Genome-wide association study identifies variants\u000d\u000a      in the CFH region\u000d\u000a      associated with host susceptibility to meningococcal disease. Nat Genet\u000d\u000a      2010, 42(9):772-776.\u000d\u000a      Citations: 80 Impact Factor: 35.209\u000d\u000a    \u000aKey Research Grants\u000d\u000a    2004-2006. Johanne Holly Meningitis Fund, RLCH NHS Trust. The\u000d\u000a      role of\u000d\u000a      neuropeptides in the pathophysiology of meningococcal disease, £80,480, ED\u000d\u000a        Carrol, N\u000d\u000a      Makwana, APJ Thomson, PB Baines, B Flanagan, CA Hart (PI).\u000d\u000a    2004-2006. Meningitis Merseyside. The role of neuropeptides in\u000d\u000a      the pathophysiology of\u000d\u000a      meningococcal disease. £36,080, ED Carrol (PI), N Makwana, APJ\u000d\u000a      Thomson, PB Baines,\u000d\u000a      B Flanagan, CA Hart.\u000d\u000a    2006-2009. Meningitis Research Foundation. The Role Of The\u000d\u000a      Microcirculation in the\u000d\u000a      Pathophysiology of Meningococcal Disease, £154,561, N Makwana, APJ\u000d\u000a      Thomson, ED\u000d\u000a        Carrol, PB Baines, R Sarginson, CA Hart (PI).\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section\u000d\u000a      4 (details of the impact).\u000d\u000a    \u000d\u000a      National Institute for Health and Clinical Excellence. Clinical\u000d\u000a        guideline no. 102: Bacterial\u000d\u000a        meningitis and meningococcal septicaemia (CG102). 2010.\u000d\u000a        http:\/\/guidance.nice.org.uk\/CG102\u000a\u000d\u000a      Bacterial meningitis and meningococcal septicaemia in children.\u000d\u000a        (2010).\u000d\u000a        http:\/\/guidance.nice.org.uk\/CG\/Wave11\/3\u000a\u000d\u000a      Heinsbroek E, Ladhani S, Gray S, Guiver M, Kaczmarski E, Borrow R,\u000d\u000a        Ramsay M: Added\u000d\u000a          value of PCR-testing for confirmation of invasive meningococcal\u000d\u000a          disease in England.\u000d\u000a        J Infect 2013, 67(5):385-390.\u000d\u000a      Munoz-Almagro C, Rodriguez-Plata MT, Marin S, Esteva C, Esteban E,\u000d\u000a        Gene A, Gelabert\u000d\u000a        G, Jordan I. Polymerase chain reaction for diagnosis and serogrouping of\u000d\u000a        meningococcal\u000d\u000a        disease in children. Diagn Microbiol Infect Dis. 2009 Feb;63(2):148-54\u000d\u000a      Drew RJ, Ó Maoldomhnaigh C, Gavin PJ, O' Sullivan N, Butler KM,\u000d\u000a        Cafferkey M. The\u000d\u000a        impact of meningococcal polymerase chain reaction testing on laboratory\u000d\u000a        confirmation of\u000d\u000a        invasive meningococcal disease. Pediatr Infect Dis J. 2012\u000d\u000a        Mar;31(3):316-8.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving Meningococcal Disease Diagnosis\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The University of Liverpool (UoL) research group led by Professor Hart\u000d\u000a      between 1977 and 2007\u000d\u000a      was one of only two groups in the UK and one of four worldwide conducting\u000d\u000a      research into MCD in\u000d\u000a      children. Between 1997-1999, Dr Enitan Carrol (then Clinical research\u000d\u000a      fellow at the UoL) in\u000d\u000a      collaboration with the Meningococcal Reference Unit, which provides a\u000d\u000a      national diagnosis and\u000d\u000a      surveillance service, evaluated the impact of meningococcal DNA detection\u000d\u000a      in blood or\u000d\u000a      cerebrospinal fluid by PCR.\u000d\u000a    The research achieved three things:\u000d\u000a    \u000d\u000a      Demonstrated the feasibility of whole blood PCR testing for MCD\u000d\u000a        diagnosis, a significant step\u000d\u000a        forward. The research showed that meningococcal DNA detection in blood\u000d\u000a        or cerebrospinal\u000d\u000a        fluid by PCR is a useful method of diagnosis of MCD, and improves case\u000d\u000a        confirmation.\u000d\u000a      Developed a test method or assay that could be used in clinical\u000d\u000a        settings and laboratories that\u000d\u000a        significantly increased the diagnostic confirmation rate. This was done\u000d\u000a        by modifying the above\u000d\u000a        test using whole blood which significantly improved the diagnostic\u000d\u000a        confirmation rate from 31%\u000d\u000a        (before introduction of meningococcal PCR into routine testing) to 88%\u000d\u000a        in 2002, establishing\u000d\u000a        this test as the gold standard for confirming cases of MCD [1,2].\u000d\u000a      The utility of this test in clinical settings, with its superior\u000d\u000a        diagnostic confirmation rates and\u000d\u000a        sufficiently rapidity to be clinically useful, was demonstrated in a\u000d\u000a        real-life clinical setting. It\u000d\u000a        showed a dramatic fall in serogroup C cases following introduction of\u000d\u000a        the meningococcal C\u000d\u000a        vaccine in 1999. Improved case confirmation allows better public health\u000d\u000a        surveillance and\u000d\u000a        assessment of the impact of introducing new vaccines.\u000d\u000a    \u000d\u000a    Dr Enitan Carrol collated all the data collected from the Hart group\u000d\u000a      between 1977 and 2007, which\u000d\u000a      comprised 1157 children with MCD, 730 of these were recruited between 1993\u000d\u000a      and 2007. The\u000d\u000a      analysis described the impact of introduction of the meningococcal C\u000d\u000a      vaccine, and examined the\u000d\u000a      association with social deprivation. This is one of the largest\u000d\u000a      single-centre studies of MCD (from\u000d\u000a      1997 to 2007) and also supports the association between social deprivation\u000d\u000a      and MCD [3]\u000d\u000a    The patients recruited by Dr Enitan Carrol between 1997 and 1999 were\u000d\u000a      included in a multi-centre\u000d\u000a      study which conducted the first whole genome screening of confirmed MCD.\u000d\u000a      Liverpool contributed\u000d\u000a      25% of the patients in the initial Genome Wide Association study (GWAS)\u000d\u000a      [4]. This study\u000d\u000a      demonstrated the importance of host genetic variation in the regulation of\u000d\u000a      complement activation.\u000d\u000a      Genetic variation in complement factor H (CFH) and CFH-related protein 3\u000d\u000a      (CFHR3) play a role in\u000d\u000a      determining the occurrence of invasive disease versus asymptomatic\u000d\u000a      colonization by Neisseria\u000d\u000a        meningitidis.\u000d\u000a    "},{"CaseStudyId":"29077","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The research described above has resulted in a paradigm shift in the\u000d\u000a      treatment of valvular heart\u000d\u000a      disease. The wealth of data and experience generated through research at\u000d\u000a      UCL was used for\u000d\u000a      regulatory approval of the Melody™ device in Europe and Canada in 2006.\u000d\u000a      The safety and\u000d\u000a      effectiveness of PPVI have since been demonstrated in several additional\u000d\u000a      studies performed by\u000d\u000a      other investigators, including an FDA-sponsored trial in the US [a].\u000d\u000a      Importantly, the FDA trials were\u000d\u000a      designed using our PPVI protocols and our imaging and clinical pre- and\u000d\u000a      post-PPVI assessments.\u000d\u000a      In 2007, NICE interventional procedure guidance (IPG 237) approved the use\u000d\u000a      of the PPVI, with\u000d\u000a      subsequent update in 2013 (IPG 436) [b]. FDA approval was obtained\u000d\u000a      in the USA in 2010 for both\u000d\u000a      the device and procedure [c]. Our data and subsequent protocol for\u000d\u000a      monitoring valve fracture were\u000d\u000a      instrumental in FDA approval.\u000d\u000a    Following approval, we were responsible for training practitioners from\u000d\u000a      the first 30 centres to\u000d\u000a      implement the procedure. All sites planning to implant the Melody™ device\u000d\u000a      had to visit UCL\/\u000d\u000a      GOSH prior to becoming and approved implantation site, and for many sites,\u000d\u000a      members of the UCL\/\u000d\u000a      GOSH team visited the site at the time of their first implantation [d].\u000d\u000a    As a result of our invention, optimisation of implantation and\u000d\u000a      monitoring, and training of\u000d\u000a      cardiologists, the device and procedure is now used routinely in cardiac\u000d\u000a      centres worldwide to treat\u000d\u000a      patients with either narrowed or leaky pulmonary valves [e]. By\u000d\u000a      July 2013, over 5,000 valves had\u000d\u000a      been implanted in 35 countries worldwide [f]. Patients have\u000d\u000a      therefore avoided open-heart surgery\u000d\u000a      with its greater risk of mortality and morbidity, its longer stay in\u000d\u000a      hospital and its prolonged\u000d\u000a      recuperation time. In 2012, the Melody device was awarded the Prix Galien\u000d\u000a      USA 2012 award for\u000d\u000a      Best Medical Technology [g].\u000d\u000a    The Melody device has also had significant commercial and economic\u000d\u000a      impacts. With each device\u000d\u000a      costing £17,000, total sales to date have been around £85m. There are also\u000d\u000a      wider economic\u000d\u000a      benefits due to the avoidance of open-heart surgery. A recent cost\u000d\u000a      evaluation conducted in the US\u000d\u000a      found that PPVI holds a significant cost advantage over the surgical\u000d\u000a      approach for both health\u000d\u000a      services and patients, since it requires fewer hospital days, and incurs\u000d\u000a      less patient wage loss [h].\u000d\u000a    Moreover the introduction of cardiac valves that can be implanted without\u000d\u000a      the need for open-heart\u000d\u000a      surgery has transformed the landscape of the management of valvular heart\u000d\u000a      disease throughout\u000d\u000a      the world, and is a paradigm shift in this field of cardiovascular\u000d\u000a      medicine. Our work on the PPVI\u000d\u000a      device has been at the forefront of this new wave of treatments. Although\u000d\u000a      developed for the\u000d\u000a      relatively small population of congenital heart disease, PPVI has\u000d\u000a      established the way forward for\u000d\u000a      much more common valve diseases in adults (transcatheter aortic valve and\u000d\u000a      mitral clip). We have\u000d\u000a      also influenced the way devices are designed, how they are introduced into\u000d\u000a      man (`first-in-man'\u000d\u000a      implantations), how patients are investigated prior to implantation and\u000d\u000a      how they are followed up.\u000d\u000a      The PPVI programme has gone hand-in-hand with the development of\u000d\u000a      transcatheter aortic valve\u000d\u000a      implantation (TAVI). Indeed, without the success of the PPVI programme,\u000d\u000a      TAVI may not have\u000d\u000a      developed as quickly, because in its early stage of development, TAVI\u000d\u000a      mortality rates were very\u000d\u000a      high (>60%), and the whole TAVI programme underwent ethical review in\u000d\u000a      France. Our successful\u000d\u000a      PPVI programme at UCL, with very low complication rates, permitted the\u000d\u000a      TAVI programme to\u000d\u000a      continue [i].\u000d\u000a    The new device we have developed with Medtronic (Native Outflow Tract\u000d\u000a      Transcatheter Pulmonary\u000d\u000a      Valve (TPV) — shared IP with UCL\/ GOSH) is in the process of being\u000d\u000a      commercialised by Medtronic,\u000d\u000a      and is currently in early phase clinical testing, with three patients\u000d\u000a      implanted so far [j]. This new\u000d\u000a      device can be used for many of the patients with right ventricular outflow\u000d\u000a      tract disease (~1 in every\u000d\u000a      1,000 live births [f]) who are not suitable for Melody™, replacing\u000d\u000a      open-heart surgery in these\u000d\u000a      patients.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Percutaneous heart valve implantation is an innovative, minimally\u000d\u000a      invasive alternative to open-heart\u000d\u000a      surgery for treating valvular heart disease. Over the last 10 years,\u000d\u000a      research at UCL has\u000d\u000a      advanced the original method of minimally invasive valve implantation in\u000d\u000a      the pulmonary position.\u000d\u000a      Over 5,000 patients have now benefitted from this procedure and have\u000d\u000a      therefore avoided open-heart\u000d\u000a      surgery. The research has been used for regulatory approval of the Melody™\u000d\u000a      device in\u000d\u000a      Europe and Canada (CE marking) and has led to FDA approval in the USA for\u000d\u000a      both the device and\u000d\u000a      procedure and NICE approval in the UK.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Khambadkone S, Coats L, Taylor AM, Boudjemline Y, Derrick G, Tsang V,\u000d\u000a      Cooper J,\u000d\u000a      Muthurangu V, Hegde SR, Razavi RS, Pellerin D, Deanfield JE, Bonhoeffer P.\u000d\u000a      Percutaneous pulmonary valve implantation in humans &mdah; Results in\u000d\u000a      59 consecutive patients.\u000d\u000a      Circulation. 2005 Aug;112(8):1189-1197. http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.104.523266\u000d\u000a    \u000a\u000a[2] Coats L, Khambadkone S, Derrick G, Sridharan S, Schievano S, Mist B,\u000d\u000a      Jones R, Deanfield\u000d\u000a      JE, Pellerin D, Bonhoeffer P, Taylor AM. Physiological and clinical\u000d\u000a      consequences of relief of\u000d\u000a      right ventricular outflow tract obstruction late after repair of\u000d\u000a      congenital heart defects.\u000d\u000a      Circulation. 2006 May 2;113(17):2037-2044. http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.105.591438\u000d\u000a    \u000a\u000a[3] Nordmeyer J, Khambadkone S, Coats L, Schievano S, Lurz P, Parenzan G,\u000d\u000a      Taylor AM, Lock\u000d\u000a      JE, Bonhoeffer P. Risk stratification, systematic classification and\u000d\u000a      anticipatory management\u000d\u000a      strategies for stent fracture after percutaneous pulmonary valve\u000d\u000a      implantation. Circulation. 2007\u000d\u000a      Mar 20;115(11):1392-1397. http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.106.674259\u000d\u000a    \u000a\u000a[4] Lurz P, Coats L, Khambadkone K, Nordmeyer J, Boudjemline Y, Schievano\u000d\u000a      S, Muthurangu V,\u000d\u000a      Yen Lee T, Parenzan G, Derrick G, Cullen S, Walker F, Tsang V, Deanfield\u000d\u000a      J, Taylor AM,\u000d\u000a      Bonhoeffer P. Percutaneous pulmonary valve implantation: impact of\u000d\u000a      evolving technology and\u000d\u000a      learning curve on clinical outcome. Circulation. 2008 Apr\u000d\u000a      15;117(15):1964-72.\u000d\u000a      http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.107.735779\u000d\u000a    \u000a\u000a[5] Lurz P, Nordmeyer J, Muthurangu V, Khambadkone S, Derrick G, Yates R,\u000d\u000a      Sury M, Bonhoeffer\u000d\u000a      P, Taylor AM. Comparison of bare metal stenting and PPVI for treatment of\u000d\u000a      RVOT obstruction:\u000d\u000a      Utilization of an X-ray\/MR hybrid lab for acute physiological comparison.\u000d\u000a      Circulation.\u000d\u000a      2009;119(23):2995-3001. http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.108.836312\u000d\u000a    \u000a\u000a[6] Schievano S, Taylor AM, Capelli C, Coats L, Walker F, Lurz P,\u000d\u000a      Nordmeyer J, Wright S,\u000d\u000a      Khambadkone S, Tsang V, Carminati M, Bonhoeffer P. First-in-man\u000d\u000a      implantation of a novel\u000d\u000a      percutaneous valve — A new approach to medical device development.\u000d\u000a      EuroIntervention. 2010\u000d\u000a      Jan;5:745-750. http:\/\/dx.doi.org\/10.4244\/EIJV5I6A122\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    [a] Results from FDA-sponsored clinical trial:\u000d\u000a    \u000d\u000a      Zahn EM, Hellenbrand WE, Lock JE, McElhinney DB. Implantation of the\u000d\u000a        melody\u000d\u000a        transcatheter pulmonary valve in patients with a dysfunctional right\u000d\u000a        ventricular outflow tract\u000d\u000a        conduit early results from the U.S. Clinical trial. J Am Coll Cardiol\u000d\u000a        2009; 54(18):1722-1729\u000d\u000a        http:\/\/dx.doi.org\/10.1016\/j.jacc.2009.06.034\u000a\u000d\u000a      McElhinney DB, Hellenbrand WE, Zahn EM et al. Short- and medium-term\u000d\u000a        outcomes after\u000d\u000a        transcatheter pulmonary valve placement in the expanded multicenter US\u000d\u000a        melody valve\u000d\u000a        trial. Circulation 2010; 122(5):507-516\u000d\u000a        http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.109.921692\u000a\u000d\u000a    \u000d\u000a    [b] IPG436 Percutaneous pulmonary valve implantation for right\u000d\u000a      ventricular outflow tract\u000d\u000a      dysfunction: guidance. http:\/\/guidance.nice.org.uk\/IPG436\/Guidance\/pdf\/English\u000d\u000a    [c] http:\/\/www.fda.gov\/MedicalDevices\/ProductsandMedicalProcedures\/DeviceApprovalsandClear\u000d\u000a        ances\/Recently-ApprovedDevices\/ucm199258.htm\u000d\u000a    [d] Example of training at one centre:\u000d\u000a      http:\/\/www.dhzb.de\/patients_visitors\/dhzb_news\/detail\/ansicht\/pressedetail\/258\/\u000d\u000a    [e] http:\/\/www.medtronic.com\/melody\/melody-system.html\u000d\u000a    [f] Email from Medtronic reporting that over 5,000 valves had been\u000d\u000a      implanted by July 2013. Copy\u000d\u000a      available on request.\u000d\u000a      Article reporting valves implanted in 35 countries by end of 2012:\u000d\u000a      McElhinney DB, Hennesen\u000d\u000a      JT. The Melody® valve and Ensemble® delivery system for transcatheter\u000d\u000a      pulmonary valve\u000d\u000a      replacement. Ann N Y Acad Sci. 2013 Jul; 1291:77-85. http:\/\/dx.doi.org\/10.1111\/nyas.12194.\u000d\u000a    [g] http:\/\/www.galienfoundation.org\/hall-of-fame\/pgu.php\u000d\u000a    [h] Vergales JE, Wanchek T, Novicoff W, Kron IL, Lim DS. Cost-analysis of\u000d\u000a      percutaneous\u000d\u000a      pulmonary valve implantation compared to surgical pulmonary valve\u000d\u000a      replacement. Catheter\u000d\u000a      Cardiovasc Interv. 2013 Jul 15. doi: http:\/\/dx.doi.org\/10.1002\/ccd.25128.\u000d\u000a    [i] 'Innovation and Fragility.' Somerville lecture, Capetown 2013.\u000d\u000a      Phillip Bonhoeffer explains the\u000d\u000a      history of the two programmes (see minutes 26-30) https:\/\/vimeo.com\/76872760\u000d\u000a    [j] http:\/\/clinicaltrials.gov\/show\/NCT01762124\u000d\u000a    ","Title":"\u000d\u000a    Introduction of percutaneous pulmonary valve implantation into clinical\u000d\u000a      practice\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Dysfunction of the right ventricular outflow tract (RVOT) with pulmonary\u000d\u000a      stenosis and\/or\u000d\u000a      regurgitation is a common and challenging condition in children and adults\u000d\u000a      with congenital heart\u000d\u000a      defects — of the 8 in every 1,000 live births that have congenital heart\u000d\u000a      disease, 20% will have an\u000d\u000a      RVOT problem. Surgical RVOT revision can be performed with a very low\u000d\u000a      mortality, but valve\u000d\u000a      conduits that are inserted to connect the right ventricle to the pulmonary\u000d\u000a      artery have a limited\u000d\u000a      lifespan, often less than 10 years, and as a result, the majority of\u000d\u000a      patients with such conduits\u000d\u000a      undergo multiple open-heart operations. The development of new, less\u000d\u000a      invasive percutaneous\u000d\u000a      methods to insert a heart valve without the need for open-heart surgery,\u000d\u000a      with its potential\u000d\u000a      complications, long hospital stay and long time off work\/school, has the\u000d\u000a      potential to significantly\u000d\u000a      alter the life-long treatment of these patients. Research at UCL has\u000d\u000a      advanced percutaneous\u000d\u000a      pulmonary valve implantation (PPVI) through meticulous patient follow-up,\u000d\u000a      computer modelling to\u000d\u000a      identify procedural complications, technical improvements to the implanted\u000d\u000a      device and definition of\u000d\u000a      outcomes of success.\u000d\u000a    The first PPVI was performed in 2000 in a pilot case (one child) in\u000d\u000a      Paris, France. In 2002,\u000d\u000a      Professor Bonhoeffer moved to UCL to assess if implantation of the device\u000d\u000a      could reduce the need\u000d\u000a      for open-heart surgery in a broader patient group, taking advantage of UCL\u000d\u000a      collaborators and the\u000d\u000a      patient population at Great Ormond Street Hospital (GOSH). The next 220\u000d\u000a      patients who were\u000d\u000a      recruited to studies of this valve implant were patients at GOSH\/UCL. The\u000d\u000a      first series was\u000d\u000a      published in 2006 [1] establishing the feasibility and safety of\u000d\u000a      the procedure, and detailed the\u000d\u000a      haemodynamic consequences [2, 3]. Importantly, we determined that\u000d\u000a      mechanical failure of one\u000d\u000a      part of the stent occurred in 25% of cases, but that it was possible to\u000d\u000a      detect this, monitor it and\u000d\u000a      intervene in time to prevent adverse consequences [3].\u000d\u000a      Subsequently we established the optimal\u000d\u000a      valve design, device implantation technique and patient selection for this\u000d\u000a      procedure and monitoring\u000d\u000a      schedule [4, 5]. This device was commercialised by Medtronic\u000d\u000a      (MelodyTM), with CE marking\u000d\u000a      obtained in 2006. Our research was the basis for the protocols for\u000d\u000a      implantation of the valve, and\u000d\u000a      training of the first 30 centres to use this technique was undertaken at\u000d\u000a      UCL between 2005 and\u000d\u000a      2008.\u000d\u000a    Melody™ is only suitable for implantation into 15% of patients\u000d\u000a      with pulmonary valve disease,\u000d\u000a      because in the majority of patients the main pulmonary artery is too\u000d\u000a      dilated for the procedure and\u000d\u000a      such patients therefore still require open-heart surgery. We have used\u000d\u000a      integrated computer-modelling\u000d\u000a      techniques that utilise patient-specific data to design a new device that\u000d\u000a      is suitable for a\u000d\u000a      greater proportion of patients [6]. This new device — Native\u000d\u000a      Outflow Tract Transcatheter Pulmonary\u000d\u000a      Valve (TPV) — is in the process of being commercialised with Medtronic,\u000d\u000a      and is currently in early\u000d\u000a      phase clinical testing (three patients implanted so far).\u000d\u000a    "},{"CaseStudyId":"29098","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    The overall impact of this work has been to avoid the unnecessary use of\u000d\u000a      stem cell transplantation\u000d\u000a      in adults with acute leukaemia by identifying those who are most likely to\u000d\u000a      benefit from this\u000d\u000a      procedure.\u000d\u000a    Impact on guidelines and clinical practice\u000d\u000a    Following the publication of the results of the AML 10 and 12 trials,\u000d\u000a      jointly devised by researchers\u000d\u000a      at UCL and Glasgow (subsequently Cardiff), the consolidation of first\u000d\u000a      remission AML with an\u000d\u000a      autologous stem cell transplant has ceased in the UK and most other parts\u000d\u000a      of the world. An\u000d\u000a      allogeneic transplant from a matched sibling had been the treatment of\u000d\u000a      choice for consolidation in\u000d\u000a      first complete remission, but we were able to show that this should not be\u000d\u000a      carried out in patients\u000d\u000a      with good risk cytogenetics, classified according to a system developed at\u000d\u000a      UCL and known as the\u000d\u000a      MRC classification. By a series of sequential biomarker studies carried\u000d\u000a      out at UCL, we have been\u000d\u000a      able to further subdivide patients into specific prognostic categories\u000d\u000a      according to the presence and\u000d\u000a      level of specific mutations. This allows low risk patients to be spared an\u000d\u000a      allogeneic transplant and\u000d\u000a      this risk classification has been incorporated into treatment algorithms\u000d\u000a      throughout the world. Such\u000d\u000a      use of molecular biomarkers is now standard of care in the UK and is used\u000d\u000a      to stratify patients in the\u000d\u000a      current UK AML17 trial [a].\u000d\u000a    The results of our research underpin European guidance on AML produced by\u000d\u000a      the European\u000d\u000a      Leukaemia Network [b]. These guidelines are signposted by the\u000d\u000a      British Committee for Standards\u000d\u000a      in Haematology [c]. US National Comprehensive Cancer Network\u000d\u000a      guidelines for the treatment of\u000d\u000a      AML also cite our work [d].\u000d\u000a    In ALL, the demonstration that autologous transplantation has no role in\u000d\u000a      the management of this\u000d\u000a      disease means that this treatment is no longer used in the UK and further\u000d\u000a      afield. The results of\u000d\u000a      ALL12 are widely cited in justifying treatment recommendations for adult\u000d\u000a      ALL in the US (NCCN)\u000d\u000a      and European (ELNET) guidelines [e, f].\u000d\u000a    Impact on the health of individuals\u000d\u000a    By defining the patients most likely to benefit from HSCT, this research\u000d\u000a      has had a significant\u000d\u000a      impact on individual health. For AML, these results have influenced\u000d\u000a      clinical practice in the\u000d\u000a      developed world since approximately 1999 and for ALL since 2004.\u000d\u000a      Importantly, patients unlikely to\u000d\u000a      benefit from HSCT can be identified — in adult AML, using the combination\u000d\u000a      of cytogenetic and\u000d\u000a      molecular markers, about 400 patients per year in the UK can be spared\u000d\u000a      consideration of an\u000d\u000a      allogeneic HSCT in first remission (based on UK AML incidence data in\u000d\u000a      under 65 year olds who\u000d\u000a      would be transplant-eligible [g] and breakdown of AML into\u000d\u000a      prognostic categories [h].) The\u000d\u000a      equivalent figures per annum for the USA and the European Union (excluding\u000d\u000a      the UK) are 2,000\u000d\u000a      and 3,000 respectively [i]. Avoidance of HSCT reduces the\u000d\u000a      significant risks of treatment-induced\u000d\u000a      toxicity and mortality and improves the quality of life for patients being\u000d\u000a      treated for acute leukaemia.\u000d\u000a    Economic benefits\u000d\u000a    An allogeneic transplant from a matched sibling currently costs\u000d\u000a      approximately £70,000 to the NHS\u000d\u000a      and the cost of an autologous transplant is approximately £35,000. In AML,\u000d\u000a      the avoidance of 400\u000d\u000a      allogeneic HSCT by risk stratification is a potential saving of £28m per\u000d\u000a      annum. Although harder to\u000d\u000a      quantify, avoiding HSCT may have a significant positive impact on the\u000d\u000a      economy more widely, as\u000d\u000a      patients avoid treatment-related mortality and chronic disability which\u000d\u000a      may be associated with\u000d\u000a      HSCT. In ALL, approximately 100 adult patients per year could be treated\u000d\u000a      with an autologous\u000d\u000a      HSCT and the demonstration that this is not necessary by the ALL12 study\u000d\u000a      is a potential saving of\u000d\u000a      £3.5 million per year [j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research conducted at UCL\/UCLH over the last 20 years has enabled the\u000d\u000a      identification of adults\u000d\u000a      with acute leukaemia who are most likely to benefit from the use of stem\u000d\u000a      cell transplantation, i.e.\u000d\u000a      those with acute leukaemia in first remission. The treatment is highly\u000d\u000a      intensive, potentially toxic and\u000d\u000a      expensive high-dose chemotherapy followed by haemopoietic stem cell\u000d\u000a      transplantation, and is\u000d\u000a      inappropriate for some patients. The work has made a major contribution to\u000d\u000a      the development of\u000d\u000a      guidelines worldwide for the treatment of this disease. Improved patient\u000d\u000a      selection for\u000d\u000a      transplantation results in improved survival, less toxicity with improved\u000d\u000a      overall quality of life, and a\u000d\u000a      more appropriate use of NHS resources.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG,\u000d\u000a      Wheatley K.\u000d\u000a      Randomised comparison of addition of autologous bone-marrow\u000d\u000a      transplantation to intensive\u000d\u000a      chemotherapy for acute myeloid leukaemia in first remission: results of\u000d\u000a      MRC AML 10 trial. UK\u000d\u000a      Medical Research Council Adult and Children's Leukaemia Working Parties.\u000d\u000a      Lancet. 1998 Mar\u000d\u000a      7;351(9104):700-8. http:\/\/dx.doi.org\/10.1016\/S0140-6736(97)09214-3\u000d\u000a    \u000a\u000a[2] Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G,\u000d\u000a      Rees J, Hann I,\u000d\u000a      Stevens R, Burnett A, Goldstone A. The importance of diagnostic\u000d\u000a      cytogenetics on outcome in\u000d\u000a      AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood.\u000d\u000a      1998 Oct\u000d\u000a      1;92(7):2322-33. http:\/\/bloodjournal.hematologylibrary.org\/content\/92\/7\/2322.full.pdf\u000d\u000a    \u000a\u000a[3] Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA,\u000d\u000a      Walker H, Wheatley\u000d\u000a      K, Bowen DT, Burnett AK, Goldstone AH, Linch DC. The presence of a FLT3\u000d\u000a      internal tandem\u000d\u000a      duplication in patients with acute myeloid leukemia (AML) adds important\u000d\u000a      prognostic\u000d\u000a      information to cytogenetic risk group and response to the first cycle of\u000d\u000a      chemotherapy: analysis\u000d\u000a      of 854 patients from the United Kingdom Medical Research Council AML 10\u000d\u000a      and 12 trials.\u000d\u000a      Blood. 2001 Sep 15;98(6):1752-9. http:\/\/dx.doi.org\/10.1182\/blood.V98.6.1752\u000d\u000a    \u000a\u000a[4] Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, Linch DC;\u000d\u000a      The impact of FLT3\u000d\u000a      internal tandem duplication mutant level, number, size, and interaction\u000d\u000a      with NPM1 mutations in\u000d\u000a      a large cohort of young adult patients with acute myeloid leukemia. Blood.\u000d\u000a      2008 Mar\u000d\u000a      1;111(5):2776-84. http:\/\/dx.doi.org\/10.1182\/blood-2007-08-109090\u000d\u000a    \u000a\u000a[5] Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic\u000d\u000a      significance of\u000d\u000a      CEBPA mutations in a large cohort of younger adult patients with acute\u000d\u000a      myeloid leukemia:\u000d\u000a      impact of double CEBPA mutations and the interaction with FLT3 and NPM1\u000d\u000a      mutations. J Clin\u000d\u000a      Oncol. 2010 Jun 1;28(16):2739-47. http:\/\/dx.doi.org\/10.1200\/JCO.2009.26.2501\u000d\u000a    \u000a\u000a[6] Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding\u000d\u000a      AK,Burnett AK,\u000d\u000a      Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J,\u000d\u000a      McMillan A,\u000d\u000a      Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk\u000d\u000a      acute lymphoblastic\u000d\u000a      leukemia, the greatest benefit is achieved from a matched sibling\u000d\u000a      allogeneic transplantation in\u000d\u000a      first complete remission, and an autologous transplantation is less\u000d\u000a      effective than conventional\u000d\u000a      consolidation\/maintenance chemotherapy in all patients: final results of\u000d\u000a      the International ALL\u000d\u000a      Trial (MRC UKALL XII\/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33.\u000d\u000a      http:\/\/dx.doi.org\/10.1182\/blood-2007-10-116582\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    [a] Documentation regarding the Acute Myeloid Leukaemia clinical trial 17\u000d\u000a      is available to\u000d\u000a      download from: http:\/\/aml17.cardiff.ac.uk\/files\/files.htm.\u000d\u000a      Including the AML17\u000d\u000a        Protocol version\u000d\u000a        8.0 (October 2012), see page 61.\u000d\u000a      http:\/\/aml17.cardiff.ac.uk\/files\/new5\/AML%2017%20Protocol%20V8.0%20October%202012.pdf\u000d\u000a    [b] http:\/\/www.leukemia-net.org\/content\/physicians\/recommendations\/index_eng.html\u000d\u000a      Döhner H, Estey EH , Amadori S, Appelbaum FR, Büchner T, Burnett AK,\u000d\u000a      Dombret H, Fenaux\u000d\u000a      P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele\u000d\u000a      GJ , Sanz\u000d\u000a      MA, Sierra J, Tallman MS, Löwenberg B and Bloomfield C D. Diagnosis and\u000d\u000a      management of\u000d\u000a      Acute Myeloid Leukemia in adults. Recommendations from an international\u000d\u000a      expert panel, on\u000d\u000a      behalf of European LeukemiaNet. Blood 2010 Jan 21;115(3):453-74.\u000d\u000a      http:\/\/dx.doi.org\/10.1182\/blood-2009-07-235358.\u000d\u000a      Reference 1 is cited on page 461. Five other\u000d\u000a      papers to which the group have contributed are also referenced.\u000d\u000a    [c] This is linked to from the British Committee for Standards in\u000d\u000a      Haematology (BCSH) website at:\u000d\u000a      http:\/\/www.bcshguidelines.com\/353_NON-BCSH_GUIDELINES.html\u000d\u000a      Although not endorsed by the BCSH, they state that \"These Guidelines have\u000d\u000a      not been\u000d\u000a      prepared by BCSH. However, they have been reviewed by the relevant Task\u000d\u000a      Force and\u000d\u000a      deemed appropriate that they are sign posted. The BCSH will not be\u000d\u000a      producing guidelines in\u000d\u000a      these areas.\"\u000d\u000a    [d] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Acute\u000d\u000a      Myeloid Leukemia,\u000d\u000a      Version 2.2013, January 2013. http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/aml.pdf\u000d\u000a      (login required — copy available on request). The AML 10 trial is cited on\u000d\u000a      page MS-27.\u000d\u000a    [e] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Acute\u000d\u000a      Lymphoblastic\u000d\u000a      Leukemia, Version 1.2013, March 2013.\u000d\u000a      http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/all.pdf\u000d\u000a      (login required — copy available on\u000d\u000a      request). Reference 6 is cited on page MS-25.\u000d\u000a    [f] Gökbuget et al. Recommendations of the European Working Group for\u000d\u000a      Adult ALL. UNI-MED\u000d\u000a      Verlag AG, 2011. Abstract available at http:\/\/www.leukemia-\u000d\u000a        net.org\/content\/leukemias\/all\/standards_and_sop\/index_eng.html\u000d\u000a    [g] Data on the incidence of leukaemia in the UK can be found at:\u000d\u000a      http:\/\/www.cancerresearchuk.org\/cancer-info\/cancerstats\/types\/leukaemia\/incidence\/\u000d\u000a    [h] Breakdown of AML into prognostic categories: Patel JP, Levine RL. How\u000d\u000a      do novel molecular\u000d\u000a      genetic markers influence treatment decisions in acute myeloid leukemia?\u000d\u000a      Hematology Am\u000d\u000a      Soc Hematol Educ Program. 2012;2012:28-34.\u000d\u000a      http:\/\/asheducationbook.hematologylibrary.org\/content\/2012\/1\/28.long\u000d\u000a    [i] Data on the incidence of leukaemia in the US and EU were obtained\u000d\u000a      from\u000d\u000a      http:\/\/seer.cancer.gov\/faststats\/index.php\u000d\u000a    [j] Based on 2013\/14 tariff for Adult Bone Marrow Transplantation.\u000d\u000a      Corroboration available from\u000d\u000a      Head of Contracts (Acute), University College London Hospitals NHS\u000d\u000a      Foundation Trust.\u000d\u000a      Contact details provided.\u000d\u000a    ","Title":"\u000d\u000a    Stratification of treatment for adult patients with acute leukaemia\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2653822","Name":"Cardiff"},{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Around 2,500 adults in the UK are diagnosed with acute myeloid and\u000d\u000a      lymphoid leukaemias (AML\u000d\u000a      and ALL) each year. Their treatment includes intensive courses of\u000d\u000a      cytotoxic chemotherapy and\u000d\u000a      consideration of additional high dose cytotoxic therapy and haemopoietic\u000d\u000a      stem cell transplantation\u000d\u000a      (HSCT). Work from UCL has defined those patients with acute leukaemia most\u000d\u000a      appropriately\u000d\u000a      treated with high dose cytotoxic therapy and HSCT.\u000d\u000a    Acute Myeloid Leukaemia (AML)\u000d\u000a    Professors Goldstone (UCL) and Burnett (Glasgow, later Cardiff) were\u000d\u000a      asked by the MRC to\u000d\u000a      design and set up national randomised trials addressing the value of both\u000d\u000a      autologous and\u000d\u000a      allogeneic stem cell transplantation in AML. The AML10 trial (1988-1995)\u000d\u000a      recruited 1,571 adult\u000d\u000a      patients and confirmed that high dose therapy and an autologous HSCT\u000d\u000a      resulted in a reduced\u000d\u000a      relapse rate, but no overall reduction in death rate, due to unexpectedly\u000d\u000a      high procedure-related\u000d\u000a      mortality [1]. Allogeneic transplantation was shown to be\u000d\u000a      beneficial only in a subset of patients.\u000d\u000a      Further analysis of this latter question in the subsequent MRC AML12 trial\u000d\u000a      (1995-2002) indicated\u000d\u000a      that the greatest benefit was in patients with certain markers of\u000d\u000a      chromosomal damage\u000d\u000a      (cytogenetics) and that allogeneic HSCT could be avoided in subgroups of\u000d\u000a      patients who had very\u000d\u000a      good results with chemotherapy alone. This trial was led by Burnett in\u000d\u000a      Cardiff, and Goldstone\u000d\u000a      contributed to the conception and design of the trial. The cytogenetic\u000d\u000a      risk classification used in both\u000d\u000a      trials was developed at UCL [2]. This has since been adopted\u000d\u000a      worldwide and is used to select\u000d\u000a      those patients who get the most benefit from transplantation.\u000d\u000a    In parallel with the national trials a DNA\/RNA\/cell bank was established\u000d\u000a      by Professor Linch at UCL\u000d\u000a      and point mutations, insertions and deletions were analysed in selected\u000d\u000a      genes. These landmark\u000d\u000a      biomarker studies from UCL involve the largest cohorts of linked mutation\u000d\u000a      and outcome data in\u000d\u000a      AML worldwide. In 2001, we published the definitive evidence that mutation\u000d\u000a      of the FLT3 gene\u000d\u000a      (FLT-3-ITD), present in approximately a quarter of patients, was a poor\u000d\u000a      prognostic factor [3]. In\u000d\u000a      2008, in an analysis of 1,425 patients, we demonstrated that the combined\u000d\u000a      determination of FLT3-ITD\u000d\u000a      and NPM1 mutation status could be used to further stratify patients into\u000d\u000a      three, therapeutically\u000d\u000a      relevant, prognostic groups [4], thereby further refining the\u000d\u000a      selection of patients for transplantation.\u000d\u000a      Subsequently (2008-13), we have analysed other recurrent gene mutations in\u000d\u000a      AML, refining\u000d\u000a      prognostic stratification and establishing principles of the\u000d\u000a      interpretation of mutation analysis\u000d\u000a      relevant to other forms of cancer. For example, our studies of the CEBPA\u000d\u000a      gene have indicated that\u000d\u000a      biallelic (but not monoallelic) mutations have a sufficiently good\u000d\u000a      prognosis to be spared an\u000d\u000a      allogeneic transplant [5].\u000d\u000a    Acute Lymphoid Leukaemia (ALL)\u000d\u000a    In the second major type of acute leukaemia in adults, acute\u000d\u000a      lymphoblastic leukaemia (ALL),\u000d\u000a      Professor Goldstone, with colleagues from the US, set up the MRC ALL12\u000d\u000a      trial (1993-2004) which\u000d\u000a      explored issues of dose intensification. This trial recruited 1,914\u000d\u000a      patients, the largest ever in adult\u000d\u000a      ALL, and showed that standard maintenance chemotherapy was preferable to\u000d\u000a      consolidation with\u000d\u000a      high dose therapy and an autologous HSCT, and that an allogeneic HSCT from\u000d\u000a      a matched sibling\u000d\u000a      was the treatment of choice in standard risk patients [6].\u000d\u000a    "},{"CaseStudyId":"29109","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Our early work on large animal models underpinned trials undertaken by\u000d\u000a      ourselves and by others, which in turn have resulted in therapeutic\u000d\u000a      hypothermia becoming standard care for infants with moderate to severe\u000d\u000a      neonatal encephalopathy. The importance of the early work at UCL in\u000d\u000a      particular, as the basis for later work and impacts was described in\u000d\u000a      detail in a recent article [a]. As a result of these important\u000d\u000a      international collaborations, over 3,000 infants so far in the UK have\u000d\u000a      benefitted from this treatment, which was incorporated into NICE guidance\u000d\u000a      in 2010. Our work also resulted in the commercial development of the\u000d\u000a      CoolCap.\u000d\u000a    Immediately following the conclusion of the enrolment of the TOBY Trial,\u000d\u000a      the UK TOBY Cooling Register was set up and was operational between Dec\u000d\u000a      2006 and Dec 2012. All newborns treated with cooling in the UK have been\u000d\u000a      eligible to be registered. During this time over 3,000 babies cooled at 74\u000d\u000a      neonatal units were registered, showing how the treatment has been adopted\u000d\u000a      into normal clinical practice [b]. Analysis of these data in 2012\u000d\u000a      suggested that the number of babies registered was close to the estimates\u000d\u000a      of all babies suffering from moderate to severe neonatal encephalopathy [c].\u000d\u000a    The impact on long-term outcomes for these babies is clear. A recent\u000d\u000a      meta-analysis including seven trials and 1,214 infants shows that\u000d\u000a      therapeutic hypothermia results in a reduction in death or major\u000d\u000a      neurodevelopmental disability (risk ratio 0.76; 95% CI 0.69-84) and an\u000d\u000a      increase in the rate of survival with normal neurological function (1.63;\u000d\u000a      1.36-1.95) at age 18 months [d]. Based on the number of infants\u000d\u000a      treated by cooling we can predict that approximately 450 have avoided\u000d\u000a      death or serious neurological disability between 2006 and 2012.\u000d\u000a    Following our trial of the CoolCap, this device received FDA approval in\u000d\u000a      2006 [e] and has been sold commercially since that time [f].\u000d\u000a      It is now in use in 30 hospitals across the United States (many of them\u000d\u000a      covering a wide geographical area, due to the specialist nature of the\u000d\u000a      services provided) [g].\u000d\u000a    In 2009, children's charity Bliss endorsed the positive reports from\u000d\u000a      research into cooling: Carmel Bartley, of the children's charity, Bliss\u000d\u000a      said: \"This is welcome research into an area which is known to save\u000d\u000a        lives. It is a specialist treatment we would like to see used more\u000d\u000a        widely\" [h]\u000d\u000a    In 2010, the recommendation for therapeutic hypothermia was incorporated\u000d\u000a      into NICE guidelines [i]. The British Association of Perinatal\u000d\u000a      Medicine (BAPM) also recommended this treatment in guidelines issued in\u000d\u000a      the same year [j]. Enrolment into the cooling Registry increased\u000d\u000a      dramatically after this, and shows that there has been a timely,\u000d\u000a      systematic implementation of therapeutic hypothermia in the UK to a\u000d\u000a      standard protocol. There has been a steady rise in the uptake of\u000d\u000a      therapeutic hypothermia across the UK. Elsewhere in the world, in October\u000d\u000a      2010, the International Liaison Committee on Resuscitation (ILCOR) and\u000d\u000a      American Heart Association released its revised statement recommending\u000d\u000a      therapeutic hypothermia as a standard of care for moderate to severe HIE [k].\u000d\u000a    A health economic study done by Imperial College London set out the clear\u000d\u000a      economic case for this treatment. Using current lifetime costs for each\u000d\u000a      child with cerebral palsy (about £750,000) and the economic benefit of\u000d\u000a      additional healthy lives (£800,000), the total benefit to the UK economy\u000d\u000a      as a result of the implementation of therapeutic hypothermia is likely to\u000d\u000a      be over £125 million so far [c].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Our early work on large animal models underpinned trials undertaken by\u000d\u000a      ourselves and by others, which in turn have resulted in therapeutic\u000d\u000a      hypothermia becoming standard care for infants with moderate to severe\u000d\u000a      neonatal encephalopathy. In 2010 this was recommended in NICE guidance.\u000d\u000a      Over 3,000 babies have now been given this treatment, and we estimate that\u000d\u000a      450 have avoided death or serious neurological disability. The estimated\u000d\u000a      economic value of this is over £125 million.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Lorek A, Takei Y, Cady E, Wyatt J, Penrice J, Edwards A, et al.\u000d\u000a      Delayed (\"secondary\") cerebral energy failure after acute hypoxia-ischemia\u000d\u000a      in the newborn piglet: continuous 48-hour studies by phosphorus magnetic\u000d\u000a      resonance spectroscopy. Pediatr Res. 1994;36:699-706.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/7898977\u000d\u000a    \u000a\u000a[2] Thoresen M, Penrice J, Lorek A, Cady E, Wylezinska M, Kirkbride V,\u000d\u000a      Cooper C, Brown G, Edwards A, Wyatt J, et al (1995) Mild hypothermia after\u000d\u000a      severe transient hypoxia-ischemia ameliorates delayed cerebral energy\u000d\u000a      failure in the newborn piglet. Pediatr Res 37:667-670.\u000d\u000a      http:\/\/dx.doi.org\/10.1203\/00006450-199505000-00019\u000d\u000a    \u000a\u000a[3] Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero\u000d\u000a      DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective\u000d\u000a      head cooling with mild systemic hypothermia after neonatal encephalopathy:\u000d\u000a      multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. http:\/\/dx.doi.org\/10.1016\/S0140-6736(05)17946-X\u000d\u000a    \u000aFunding\u000d\u000a    The CoolCap trial was funded by Olympic Medical.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Edwards AD (2009) The Discovery of Hypothermic Neural Rescue Therapy\u000d\u000a      for Perinatal Hypoxic-Ischemic Encephalopathy. Seminars in Pediatric\u000d\u000a      Neurology 16:4 p.200-6\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/j.spen.2009.09.007\u000d\u000a    [b] TOBY Register https:\/\/www.npeu.ox.ac.uk\/files\/downloads\/tobyregister\/newsletters\/TCR-Closing-Newsletter-December-2012.pdf\u000d\u000a    [c] Azzopardi D, Strohm B, Linsell L, Hobson A, Juszczak E, Kurinczuk JJ,\u000d\u000a      Brocklehurst P, Edwards AD; UK TOBY Cooling Register. Implementation and\u000d\u000a      conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy\u000d\u000a      in the UK--analysis of national data. PLoS One. 2012;7(6):e38504. http:\/\/dx.doi.org\/10.1371\/journal.pone.0038504.\u000d\u000a    [d] Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia\u000d\u000a      for neonatal hypoxic ischemic encephalopathy: an updated systematic review\u000d\u000a      and meta-analysis. Arch Pediatr Adolesc Med 166:558-566. Arch Pediatr\u000d\u000a      Adolesc Med. 2012 Jun 1;166(6):558-66.\u000d\u000a      http:\/\/dx.doi.org\/10.1001\/archpediatrics.2011.1772\u000d\u000a    [e] FDA approval (citing the 2005 study):\u000d\u000a      http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/2006\/ucm108813.htm\u000d\u000a    [f] Details of the Olympic CoolCap:\u000d\u000a      http:\/\/www.natus.com\/index.cfm?page=products_1&crid=115&contentid=207\u000d\u000a    [g] Dayton Children's Hospital, Ohio, report that 30 hospitals in the US\u000d\u000a      use the device:\u000d\u000a      http:\/\/www.childrensdayton.org\/cms\/resource_library\/grand_round_files\/377038f863063b6f\/index.html.\u000d\u000a      Other examples include:\u000d\u000a    a. Arkansas Children's Hospital: http:\/\/www.archildrens.org\/Services\/Neonatal-Intensive-Care-Unit\/Head-Cooling.aspx\u000d\u000a    b. Various hospitals in Nebraska — an article in the Omaha World Herald\u000d\u000a      reports \"In the past 2½ years, about 50 children have been treated with\u000d\u000a        the cooling cap at Children's, the Nebraska Medical Center, Creighton\u000d\u000a        University Medical Center and Bergan Mercy Medical Center.\"\u000d\u000a      http:\/\/www.omaha.com\/article\/20101006\/NEWS01\/710069904\/1013102\u000d\u000a    c. The cool-cap is used at Boston Medical Centre, and a cooling blanket\u000d\u000a      is used at University of California at San Francisco School of Medicine\u000d\u000a      and Children's Hospital Boston http:\/\/commonhealth.wbur.org\/2012\/01\/oxygen-deprived-newborns-cool-down\/\u000d\u000a    [h] \u000d\u000ahttp:\/\/www.independent.co.uk\/life-style\/health-and-families\/health-news\/cooling-cure-averts-infant-brain-damage-1795740.html\u000d\u000a    [i] NICE (2010) National Institute for Clinical Excellence: Therapeutic\u000d\u000a      hypothermia with intracorporeal temperature monitoring for hypoxic\u000d\u000a      perinatal brain injury: guidance NICE guidelines: interventional\u000d\u000a      procedures\u000d\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/11315\/48809\/48809.pdf\u000d\u000a    [j] BAPM guidelines, June 2010:\u000d\u000a      http:\/\/www.bapm.org\/publications\/documents\/guidelines\/Position_Statement_Therapeutic_Cooling_Neonatal_Encephalopathy_July%202010.pdf\u000d\u000a    [k] Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith\u000d\u000a      JP, Guinsburg R, Hazinski MF, Morley C, Richmond S, Simon WM, Singhal N,\u000d\u000a      Szyld E, Tamura M, Velaphi S; Neonatal Resuscitation Chapter\u000d\u000a      Collaborators. Part 11: Neonatal resuscitation: 2010 International\u000d\u000a      Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular\u000d\u000a      Care Science With Treatment Recommendations. Circulation. 2010 Oct\u000d\u000a      19;122(16 Suppl 2):S516-38. http:\/\/dx.doi.org\/10.1161\/CIRCULATIONAHA.110.971127\u000d\u000a      Recommends: \"Therapeutic hypothermia should be considered for infants\u000d\u000a        born at term or near-term with evolving moderate to severe\u000d\u000a        hypoxic-ischemic encephalopathy, with protocol and follow-up coordinated\u000d\u000a        through a regional perinatal system.\" Cites our study and the others\u000d\u000a      described above.\u000d\u000a    ","Title":"\u000d\u000a    Moderate hypothermia as a therapy for neonatal encephalopathy improves\u000d\u000a      survival and reduces disability\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Problems around the time of birth causing a lack of oxygen to the fetus\u000d\u000a      (birth asphyxia) can lead to disordered brain function called neonatal\u000d\u000a      encephalopathy which can result in death, long-term brain damage, cerebral\u000d\u000a      palsy, epilepsy and other significant cognitive, developmental and\u000d\u000a      behavioural problems. Neonatal encephalopathy occurs in 750-1,125 infants\u000d\u000a      in the UK every year. The financial and human costs to infants affected,\u000d\u000a      their parents, professionals and wider society are enormous.\u000d\u000a    Extensive experimental and clinical research has been carried out at UCL\u000d\u000a      since the early 1980s into the evolution and timing of energy failure and\u000d\u000a      cell death following perinatal hypoxia-ischaemia. Osmond Reynolds and his\u000d\u000a      team of researchers at UCL were struck by the group's magnetic resonance\u000d\u000a      spectroscopy data showing that the infant's brain is normal in the hours\u000d\u000a      after asphyxia and cell death occurs only after a distinct delay of\u000d\u000a      several hours. Delayed brain injury (called \"secondary energy failure\" by\u000d\u000a      Reynolds) was a critical new idea: this secondary deterioration in brain\u000d\u000a      energy metabolism was observed in both babies with neonatal encephalopathy\u000d\u000a      and then in animal models [1]. This delay in cell death opened the\u000d\u000a      possibility of therapeutic intervention in what had previously been\u000d\u000a      considered an impossible situation. A key breakthrough came in 1995 when\u000d\u000a      the UCL team demonstrated that if whole-body cooling was introduced in the\u000d\u000a      period just after hypoxia-ischaemia in the piglet brain, secondary energy\u000d\u000a      failure was ameliorated or prevented and brain cell death reduced [2].\u000d\u000a    Confirmatory studies in Sweden and New Zealand built on these\u000d\u000a      demonstrations, and as a result, the first clinical trial of therapeutic\u000d\u000a      hypothermia was initiated. This was the multicentre CoolCap Trial, which\u000d\u000a      involved selective head cooling. John Wyatt (UCL) and Peter Gluckman\u000d\u000a      (Auckland) were the principal investigators of this trial. The first\u000d\u000a      patient was enrolled in 1999 and the study was published in the Lancet in\u000d\u000a      2005 [3]. The trial used selective head cooling and mild body\u000d\u000a      cooling (to 34.5oC) to minimise potential side effects of\u000d\u000a      cooling. The results were encouraging; although Coolcap showed a\u000d\u000a      non-significant trend to improvement with cooling in the primary outcome\u000d\u000a      of death or disability at 18 months overall, there was a clear and\u000d\u000a      significant benefit when infants with very severe or long-established\u000d\u000a      injury were excluded.\u000d\u000a    Other major studies of cooling followed, building on our early work. As\u000d\u000a      we had demonstrated that there had been no major adverse effects of\u000d\u000a      controlled cooling to 34.5oC and whole body cooling seemed more\u000d\u000a      practical, most of the subsequent cooling studies used whole body cooling\u000d\u000a      to a core temperature of 33.5oC. The next major cooling study\u000d\u000a      to be published was that run by the National Institute for Child Health\u000d\u000a      and Human Development (NICHD), which showed a significant effect of\u000d\u000a      cooling. In the UK, total body hypothermia for neonatal encephalopathy\u000d\u000a      (TOBY) trial was set up. This trial was still recruiting when the results\u000d\u000a      from the CoolCap trial were published showing a marginal benefit from\u000d\u000a      cooling. As a result of this, the TOBY trial size was increased. The\u000d\u000a      results of the TOBY trial were remarkably consistent with previous trials.\u000d\u000a    The most recent systematic review (Jacobs et al. 2013) showed that\u000d\u000a      cooling increases the infants' chance of surviving without neurological\u000d\u000a      deficits at 18 months, reducing neurodevelopmental impairment in\u000d\u000a      survivors. The relative effects of selective head and whole body cooling\u000d\u000a      seemed indistinguishable. In summary the UCL research identified secondary\u000d\u000a      energy failure after neonatal asphyxia, demonstrated the beneficial\u000d\u000a      effects in animal models and illustrated salutary effects in the first\u000d\u000a      clinical trial of brain cooling, later confirmed by many other\u000d\u000a      investigators.\u000d\u000a    "},{"CaseStudyId":"29547","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"294640","Name":"Israel"}],"Funders":[],"ImpactDetails":"\u000d\u000a    There are >2,100 new cases of thyroid cancer each year in the UK,\u000d\u000a      >48,000 in the US, and >213,000 worldwide. It is the most frequently\u000d\u000a      occurring endocrine tumour, and one of the few cancers where the incidence\u000d\u000a      is increasing [a]. Thyroid cancer, unlike most other cancers, is\u000d\u000a      common among younger people (<50 years) who are still in work, and\u000d\u000a      particularly women (many with children). Most cases are\u000d\u000a      well-differentiated thyroid cancer (85-90% of new cases), in which the\u000d\u000a      cure rate is already high; therefore new treatments that are safer,\u000d\u000a      cheaper or easier to administer are the research goals.\u000d\u000a    The results of the HiLo trial provided clear evidence for a shorter and\u000d\u000a      safer treatment for thyroid cancer. Cancer Research UK commented that the\u000d\u000a      results of this trial \"have set a new gold standard for treating\u000d\u000a        thyroid cancer, reducing radiation doses to just one third of the\u000d\u000a        current level... patients taking the lower dose capsule can be treated\u000d\u000a        more easily as an outpatient in hours and experience fewer side effects\"\u000d\u000a      [b].\u000d\u000a    The HiLo trial collected data on clinical efficacy, patient safety\/harms,\u000d\u000a      NHS resource use, and societal costs, allowing a comprehensive assessment\u000d\u000a      of the impact in the clinical setting, as well as on healthcare costs and\u000d\u000a      people's lives. Overall, the research described above showed the following\u000d\u000a      benefits to patients and to the economy:\u000d\u000a    Benefits to patients:\u000d\u000a    \u000d\u000a      New treatment can be delivered as outpatient treatment which is\u000d\u000a        quicker and easier for patient\u000d\u000a      Fewer side effects (e.g. nausea and neck pain)\u000d\u000a      Reduced chance of developing a new tumour in the next 10-30 years,\u000d\u000a        which can often be more difficult to treat than the original thyroid\u000d\u000a        cancer\u000d\u000a      Improved quality of life, as THST does not need to be suspended (of\u000d\u000a        particular relevance to those of working age, or caring for children —\u000d\u000a        which is a relatively high proportion for this type of cancer)\u000d\u000a    \u000d\u000a    Economic benefits:\u000d\u000a    \u000d\u000a      Reduction in side effects is associated with lower costs to treat\u000d\u000a        these side effects.\u000d\u000a      Shorter hospital stay also reduces costs\u000d\u000a      Overall 14% reduction in NHS costs using low dose radioiodine plus\u000d\u000a        thyrotropin alfa compared to the previous standard of high dose plus\u000d\u000a        thyroid hormone withdrawal.\u000d\u000a      Many thyroid cancer patients are in employed work, and the average\u000d\u000a        number of days taken off work during the 2-4 weeks before radioiodine\u000d\u000a        treatment is 1 day (low dose) compared to 5 days (high dose).\u000d\u000a    \u000d\u000a    We have disseminated the results of the HiLo trial through presentations\u000d\u000a      at several international conferences in countries planning to change\u000d\u000a      routine practice (including Europe, Israel and Korea) [c]. Our\u000d\u000a      results were also widely reported in the medical press and in\u000d\u000a      patient-facing resources on thyroid cancer treatment [d].\u000d\u000a    In 2012, the trial findings were used to change the European licence\u000d\u000a      indication for Thyrogen (thyrotropin alfa), so that it can now be used\u000d\u000a      with low dose radioiodine (the previous licence was only for use with the\u000d\u000a      high dose) [e].\u000d\u000a    New guidelines are currently in preparation in both the UK [f]\u000d\u000a      and US [g] to recommend low dose radioactive iodine and\u000d\u000a      thyrotropin alfa for routine practice. In the meantime, this treatment.is\u000d\u000a      already being adopted; the NCRI Clinical Studies Groups 2013 annual\u000d\u000a      report, impact section, states: \"The HiLO study published in the New\u000d\u000a        England Journal of Medicine is now significantly changing the clinical\u000d\u000a        practice of oncologists and endocrinologists giving post-operative\u000d\u000a        radio-iodine ablation to thyroid cancer patients. The dose has now been\u000d\u000a        decreased considerably as a result of this study and adoption has\u000d\u000a        proceeded rapidly in the UK\" [h].\u000d\u000a    An informal survey of clinicians has shown that 16 centres in the UK have\u000d\u000a      implemented the HiLo trial protocols since the publication. Responses\u000d\u000a      included:\u000d\u000a    \"I am routinely using HILO doses as per study in my practice ever\u000d\u000a        since results were confirmed.\"\u000d\u000a    \"Our policy...is to stratify patients needed I131 post thyroidectomy\u000d\u000a        who would have fit the criteria for the Hi-Lo into 2 groups low risk or\u000d\u000a        higher risk. Those patients in who remnant ablation is the aim of\u000d\u000a        management (i.e. well differentiated node negative disease T1-3) are\u000d\u000a        considered low risk and are treated with Thyrogen priming pre ablation\u000d\u000a        and 1.1 GBq I131 as HiLo study\" [i].\u000d\u000a    \"We have been using lower activity RAI for about 18 months\" [j].\u000d\u000a    \"I can confirm that I have implemented one element of the HiLo study\u000d\u000a        before 31\/7\/2013...Specifically this is the lower dose of I131\" [k].\u000d\u000a    Following on from the HiLo trial, a new trial — ION — is underway to\u000d\u000a      determine whether thyroid cancer patients, in whom the risk of the cancer\u000d\u000a      coming back is low, need radioactive iodine (RAI) ablation at all, given\u000d\u000a      that they have already had a total thyroidectomy and are being given\u000d\u000a      thyroid stimulating hormone suppression (TSHS) therapy [l]. The\u000d\u000a      control arm for this trial uses low dose radioactive iodine, demonstrating\u000d\u000a      that this is now entering accepted standard practice in the 35 centres\u000d\u000a      participating in the trial.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The HiLo trial has changed management for patients with\u000d\u000a      well-differentiated thyroid cancer. Patients undergoing radioiodine\u000d\u000a      ablation therapy are now given a low dose of radioactive iodine, which has\u000d\u000a      fewer side effects, compared to the previous (standard) high dose. Also,\u000d\u000a      to prepare patients for ablation they now have recombinant human TSH\u000d\u000a      (thyrotropin alfa), which is associated with a better quality of life\u000d\u000a      before and during ablation. The combination of low dose radioiodine and\u000d\u000a      thyrotropin alfa means that patients can be treated as outpatients rather\u000d\u000a      than inpatients. This is a more convenient treatment package, reducing\u000d\u000a      health service and societal costs.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Hackshaw AK, Harmer C, Mallick U, Haq M, Franklyn J. 131I activity\u000d\u000a      for remnant ablation in patients with differentiated thyroid cancer: a\u000d\u000a      systematic review. J Clin Endocrin Metab 2007; 92(1): 28-38 http:\/\/dx.doi.org\/10.1210\/jc.2006-1345\u000d\u000a    \u000a\u000a[2] Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss L, Nicol A,\u000d\u000a      Clark PM, Farnell K, McCready R, Smellie J, Franklyn JA, John R, Nutting\u000d\u000a      CM, Newbold K, Lemon C, Gerrard G, Abdel-Hamid A, Hardman J, Macias E,\u000d\u000a      Roques T, Whitaker S, Vijayan R, Alvarez P, Beare S, Forsyth S, Kadalayil\u000d\u000a      L, Hackshaw A. Ablation with low-dose radioiodine and thyrotropin alfa in\u000d\u000a      thyroid cancer. N Engl J Med. 2012 May 3;366(18):1674-85. http:\/\/dx.doi.org\/10.1056\/NEJMoa1109589\u000d\u000a    \u000aFunding: Cancer Research UK (2007-2010)\u000d\u000a    Title: Randomised trial of low and high dose radioiodine, with or\u000d\u000a      without, recombinant human thyroid stimulating hormone, in treating\u000d\u000a      thyroid cancer.\u000d\u000a    Applicants: U Mallick (Freeman Hospital, Newcastle), A Hackshaw (UCL), C\u000d\u000a      Harmer (Royal Marsden Hospital)\u000d\u000a    Value: £387,000\u000d\u000a    Sponsor: University College London\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Cancer Research UK. Thyroid cancer statistics, UK: http:\/\/info.cancerresearchuk.org\/cancerstats\/types\/thyroid\u000d\u000a      National Cancer Institute. Thyroid cancer, US: http:\/\/www.cancer.gov\/cancertopics\/types\/thyroid\u000d\u000a    [b] press release http:\/\/www.cancerresearchuk.org\/cancer-info\/news\/archive\/pressrelease\/2012-05-02-thyroid-cancer-trial-results\u000d\u000a    [c] Weblinks to international presentations of HiLo\u000d\u000a    \u000d\u000a      http:\/\/www.ies.org.il\/Winter1211.asp\u000d\u000a      http:\/\/www.gustaveroussy.fr\/service.php?p_m=download&p_file=doc\/agenda\/conference\/pr\u000a          og_management_thyroid_2012.pdf\u000d\u000a      http:\/\/www.eurothyroid.com\/about\/clinical_trials.php\u000d\u000a      http:\/\/www.endo.gr\/?p=2650\u000d\u000a      www.thyroid.org\/wp-content\/uploads\/2012\/04\/BAT_prog_final.pdf\u000d\u000a    \u000d\u000a    [d] Reporting of our trial results:\u000d\u000a    \u000d\u000a      Radioiodine for Thyroid Cancer: Less Is More. Medscape — 3 May 2012 http:\/\/www.medscape.com\/viewarticle\/763197\u000a\u000d\u000a      Trial makes thyroid cancer treatment safer and shorter.\u000d\u000a        HealthCanal.com — May 2012 http:\/\/www.healthcanal.com\/cancers\/28985-Trial-makes-thyroid-cancer-treatment-safer-and-shorter.html\u000a\u000d\u000a      Lower-Dose Radioiodine Effective Against Thyroid Cancer. U.S. News\u000d\u000a        & World Report — 2 May 2012 http:\/\/health.usnews.com\/health-news\/news\/articles\/2012\/05\/02\/lower-dose-radioiodine-effective-against-thyroid-cancer\u000a\u000d\u000a      For Thyroid Cancer, Thyrotropin + Low-Dose Radioiodine Effective.\u000d\u000a        Doctors Lounge — May 2012 http:\/\/www.doctorslounge.com\/index.php\/news\/pb\/28786\u000a\u000d\u000a      Thyroid cancer treatment 'now shorter and safer.' Netdoctor — 3 May\u000d\u000a        2012: http:\/\/www.netdoctor.co.uk\/interactive\/news\/theme_news_detail.php?id=801356066&tab_id=7\u000a\u000d\u000a      Reference [2] is cited twice in http:\/\/www.mythyroid.com\/radioactiveiodinecancer.html\u000a\u000d\u000a    \u000d\u000a    [e] European Medicines Agency (EMEA) revised license for Thyrogen, Oct\u000d\u000a      2012 http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Assessment_Report_-_Variation\/human\/000220\/WC500137229.pdf\u000d\u000a    [f] Corroboration is available from the UK lead. Contact details\u000d\u000a      provided.\u000d\u000a    [g] Corroboration is available from the US lead. Contact details\u000d\u000a      provided.\u000d\u000a    [h] NCRI Head & Neck Cancer Clinical Studies Group 2012\/13 annual\u000d\u000a      report, impact section. http:\/\/www.ncri.org.uk\/csg\/annual_reports\/NCRI_Head_&_Neck_CSG_-_Annual_Report.pdf\u000d\u000a    [i] Correspondence from Clinical Director, Oncology, The Royal\u000d\u000a      Wolverhampton NHS Trust. Available on request.\u000d\u000a    [j] Correspondence from Consultant Clinical Oncologist, Beatson Oncology\u000d\u000a      Centre, Glasgow. Available on request.\u000d\u000a    [k] Correspondence from Divisional Clinical Director, The Ipswich\u000d\u000a      Hospital NHS Trust. Available on request.\u000d\u000a    [l] http:\/\/clinicaltrials.gov\/show\/NCT01398085.\u000d\u000a    ","Title":"\u000d\u000a    A safer and shorter treatment for thyroid cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Prior to the research described below, the standard treatment for most\u000d\u000a      patients with well-differentiated thyroid cancer was as follows: they\u000d\u000a      would first have a total thyroidectomy, then would go on lifelong thyroid\u000d\u000a      hormone suppression therapy (THST); several weeks later they would receive\u000d\u000a      high dose (3.7 GBq) radioactive iodine to destroy remaining cancer cells\u000d\u000a      or residual normal thyroid tissue, at which point they would spend two to\u000d\u000a      five days in hospital isolation, because of radiation protection issues;\u000d\u000a      before radioiodine ablation, patients would have to temporarily stop THST,\u000d\u000a      which would result in hypothyroidism, reducing quality of life.\u000d\u000a    There were two unanswered questions about this treatment, which our\u000d\u000a      research aimed to address. Firstly, high dose radioiodine has side effects\u000d\u000a      and increases the chance of a new cancer in the future, and there has long\u000d\u000a      been discussion over whether low dose radioiodine is just as effective.\u000d\u000a      Secondly, a longstanding research question was whether taking recombinant\u000d\u000a      human thyroid stimulating hormone (thyrotropin alfa) before ablation\u000d\u000a      (which avoids the need to stop THST) would affect treatment success rates.\u000d\u000a    In 2007, Professor Allan Hackshaw (Cancer Research UK and UCL Cancer\u000d\u000a      Trials Centre) initiated and led a comprehensive systematic review of all\u000d\u000a      59 published studies into thyroid cancer, in order to address these two\u000d\u000a      questions. This evaluation showed that it was not possible to reliably\u000d\u000a      determine whether clinicians could use a lower radioiodine dose or not,\u000d\u000a      and there was insufficient evidence to recommend thyrotropin alfa before\u000d\u000a      ablation [1].\u000d\u000a    As a result of these findings, Cancer Research UK (CRUK) funded a large\u000d\u000a      randomised trial, led by Hackshaw and the trial Chief Investigator, Dr\u000d\u000a      Ujjal Mallick (Freeman Hospital, Newcastle). The trial concept originated\u000d\u000a      from Mallick and Hackshaw through the NCRN Head and Neck Cancer Clinical\u000d\u000a      Studies Group. UCL was responsible for trial design, study conduct and\u000d\u000a      statistical analyses, and was the trial Sponsor.\u000d\u000a    HiLo was the first ever UK national trial in thyroid cancer (438 patients\u000d\u000a      recruited 2007-10), and the first factorial study in this cancer. It was\u000d\u000a      independently peer-reviewed by CRUK, conducted across the UK National\u000d\u000a      Cancer Research Networks and published in the New England Journal of\u000d\u000a      Medicine [2]. These attributes confirm the high quality of this\u000d\u000a      seminal and unique trial.\u000d\u000a    Treatment success rates were 85.0% in the group receiving low-dose\u000d\u000a      radioiodine versus 88.9% in the group receiving the high dose; and 87.1%\u000d\u000a      in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid\u000d\u000a      hormone withdrawal — all indicating non-inferiority. Similar results were\u000d\u000a      found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus\u000d\u000a      high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose\u000d\u000a      radioiodine plus thyrotropin alfa (90.2%).\u000d\u000a    "},{"CaseStudyId":"29572","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    About 1,200 people are diagnosed with biliary tract cancer each year in\u000a      the UK and 12,000 in the US. For the majority of patients, it is an\u000a      incurable cancer and before 2010 there was no established standard of\u000a      care; some patients had best supportive care, others single agent drugs.\u000a      Therefore, there was an urgent need to find effective treatments.\u000a    Our research showed that the doublet regimen of gemcitabine and cisplatin\u000a      increases the median survival from 8.2 months (gemcitabine alone) to 11.7\u000a      months, i.e. an extra 3.5 months of life on average. This is equivalent to\u000a      reducing the chance of dying by 36%. Importantly, the side effects\/harm\u000a      associated with the doublet therapy were similar to the single agent. This\u000a      improvement in patient outcomes led to revised international guidelines on\u000a      treating biliary tract cancer, recommending this doublet therapy as\u000a      routine care since 2011:\u000a    \u000a      The European Society for Medical Oncology (ESMO), following the first\u000a        presentation of the ABC02 results in 2011, stated that the trial \"set a\u000a        new standard of care\", and assigned it Level II evidence (`Evidence is\u000a        obtained from at least one well-designed experimental study') [a].\u000a      In 2012, the British Society of Gastroenterology recommended the\u000a        doublet therapy for advanced or metastatic unresectable\u000a        cholangiocarcinoma (with Grade A evidence) [b].\u000a      The United States NCCN Clinical Practice Guidelines recommended the\u000a        use of gemcitabine\/cisplatin and assigned the trial as `Category 1\u000a        evidence' (\"Based upon high-level evidence, there is uniform NCCN\u000a        consensus that the intervention is appropriate\") [c].\u000a    \u000a    The recommendations have been endorsed by the International Liver Cancer\u000a      Association [d]. Subsequent national trials for biliary tract\u000a      cancer must now examine new treatments in addition to\u000a      gemcitabine\/cisplatin [e]. The treatment is recommended on NHS\u000a      Choices [f], and by Macmillan [g] as standard chemotherapy\u000a      for biliary tract cancer. In August 2013, we surveyed 43 key centres\u000a      treating biliary tract cancer, of whom 12 responded. All of these had\u000a      adopted the new regime as standard of care, reporting improved survival\u000a      and a well-tolerated regime. This amounted to over 230 patients treated [h].\u000a    The ABC02 trial data were used to examine cost-effectiveness by an\u000a      independent research group [i]. Total Quality Adjusted Life Years\u000a      (QALYs) for gemcitabine\/cisplatin (0.751) was greater than for gemcitabine\u000a      alone (0.561), with total costs of $44,885 and $33,653 respectively.\u000a      Gemcitabine\/cisplatin had an incremental cost-effectiveness ratio of\u000a      $59,480 per QALY gained, compared to gemcitabine alone. The authors\u000a      concluded that the doublet therapy \"is a cost-effective treatment\u000a      alternative to gemcitabine monotherapy by currently accepted standards of\u000a      willingness to pay\".\u000a    ","ImpactSummary":"\u000a    Before 2010, there was no accepted standard treatment for patients with\u000a      advanced biliary tract cancer. The ABC02 trial showed that the combination\u000a      of two drugs (gemcitabine and cisplatin) significantly improves survival,\u000a      with acceptable side effects. Consequently, national and international\u000a      guidelines have been revised to recommend this regimen as a standard of\u000a      care. Furthermore, in ongoing trials of novel therapies,\u000a      gemcitabine\/cisplatin has become the comparator group, and the aim is to\u000a      improve survival above what this can already achieve.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, Baka S,\u000a      Maraveyas A, Corrie P, Falk S, Gollins S, Lofts F, Evans L, Meyer T,\u000a      Anthoney A, Iveson T, Highley M, Osborne R, Bridgewater J. Gemcitabine\u000a      alone or in combination with cisplatin in patients with advanced or\u000a      metastatic cholangiocarcinomas or other biliary tract tumours: a\u000a      multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer.\u000a      2009 Aug;101(4):621-7. http:\/\/dx.doi.org\/10.1038\/sj.bjc.6605211\u000a    \u000a\u000a[2] Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A,\u000a      Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J;\u000a      ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine\u000a      for biliary tract cancer. N Engl J Med. 2010 Apr;362(14):1273-81. http:\/\/dx.doi.org\/10.1056\/NEJMoa0908721\u000a    \u000aFunding: Cancer Research UK (2005-9)\u000a    Title: Gemcitabine, alone or in combination with cisplatin, in patients\u000a      with advanced or metastatic cholangiocarcinomas and other biliary tract\u000a      tumours: a multicentre, randomised phase III study.\u000a    Applicants: J Bridgewater, J Valle, H Wasan\u000a    Value: £220,000\u000a    Sponsor: University College London\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    [a] Eckel F, Brunner T, Jelic S; ESMO Guidelines Working Group. Biliary\u000a        cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and\u000a        follow-up. Ann Oncol. 2011;22 Suppl 6:vi40-4.\u000a    [b] Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP,\u000a      Rosenberg WM, Tait P, Taylor-Robinson SD, Thillainayagam AV, Thomas HC,\u000a      Wasan H; British Society of Gastroenterology. Guidelines\u000a        for the diagnosis and treatment of cholangiocarcinoma: an update.\u000a      Gut. 2012;61(12):1657-69. doi: 10.1136\/gutjnl-2011-301748. Epub 2012 Aug\u000a      15.\u000a    [c] United States National Comprehensive Cancer Network (NCCN) Clinical\u000a      Practice Guidelines in Oncology, version 2.2012: hepatobiliary cancers.\u000a      Available on request.\u000a    [d] http:\/\/www.ammf.org.uk\/2012\/03\/13\/international-cc-guidelines\u000a    [e] Examples of ongoing national clinical trials in the UK, USA and\u000a      Germany which use gemcitabine\/cisplatin as the control\/standard treatment\u000a      for biliary tract cancer are:\u000a    \u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00939848\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01242605\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00919061\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01679405\u000a    \u000a    [f] NHS Choices website on treatment for biliary tract cancer which\u000a      refers to the results of our trial: http:\/\/www.nhs.uk\/Conditions\/Cancer-of-the-bile-duct\/Pages\/Treatment.aspx\u000a    [g] Macmillan page on biliary tract cancer, referencing Valle et al 2010:\u000a      http:\/\/www.macmillan.org.uk\/Cancerinformation\/Cancertypes\/Bileduct\/Bileductcancer.aspx\u000a    [h] Internal survey conducted among those centres who had taken part in\u000a      the ABC trials. Full survey data available on request.\u000a    [i] Roth JA, Carlson JJ. Cost-effectiveness of gemcitabine + cisplatin\u000a      vs. gemcitabine monotherapy in advanced biliary tract cancer. J\u000a        Gastrointest Cancer 2012;43:215-23. http:\/\/dx.doi.org\/10.1007\/s12029-010-9242-0\u000a    \u000a    ","Title":"\u000a    Standard of care established for advanced biliary tract cancer\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The prognosis for patients with advanced biliary tract cancer\u000a      (cholangiocarcinoma) is poor, with only half of them surviving to about\u000a      eight months. UCL\/UCLH is one of the main UK centres for treating these\u000a      patients, and has been involved in several associated research projects\u000a      over the years. One of these involved developing and participating in a\u000a      randomised phase II study [1] to examine whether doublet\u000a      chemotherapy (gemcitabine and cisplatin) is better than gemcitabine alone\u000a      (UCL\/UCLH Principal Investigator, Dr John Bridgewater, Consultant\u000a      Oncologist; Chief Investigator Dr Juan Valle, Christie Hospital\u000a      Manchester). This study showed very promising results for the doublet\u000a      regimen, and was used to justify and design a large phase III trial\u000a      (ABC02).\u000a    ABC02 successfully received funding from Cancer Research UK, with\u000a      Bridgewater as the Chief Investigator. Professor Allan Hackshaw (CRUK-UCL\u000a      Cancer Trials Centre) had oversight of the design and statistical\u000a      analyses. The trial concept originated from Bridgewater and Valle, with\u000a      support through the NCRN Lower Gastrointestinal Cancer Clinical Studies\u000a      Group. UCL was responsible for trial design, study conduct and statistical\u000a      analyses, and was the trial Sponsor.\u000a    This study was one of the first large scale national studies in biliary\u000a      tract cancer in the UK, involving 37 recruiting hospitals (410 patients\u000a      recruited 2002-8). It was independently peer-reviewed by Cancer Research\u000a      UK, conducted across the UK National Cancer Research Networks (NCRN) and\u000a      published in the New England Journal of Medicine [2]. These\u000a      attributes confirm the high quality of this seminal trial.\u000a    The ABC02 trial showed that the combination of two drugs (gemcitabine and\u000a      cisplatin) significantly improves survival, with acceptable side effects.\u000a      Following the success of ABC02, and the implementation of doublet therapy\u000a      into routine care, UCL has designed, conducted and sponsored all\u000a      subsequent UK national trials in biliary tract cancer developed through\u000a      the NCRN Clinical Studies Group (ABC03, ABC04 and ABC05).\u000a    "},{"CaseStudyId":"29573","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000a    The combination of mitomycin, ifosfamide, and cisplatin (MIC) was\u000a      previously widely used in Europe for the treatment of advanced NSCLC. This\u000a      required patients to stay in hospital overnight, and had adverse effects\u000a      on quality of life. Cisplatin and etoposide (PE) were commonly used\u000a      together to treat poor prognosis SCLC. However, major problems with\u000a      cisplatin treatment were the administration time and significant\u000a      symptomatic non-haematological toxicity.\u000a    Gemcitabine\/carboplatin (gem\/carbo) became popular because it was given\u000a      as an out-patient treatment with short infusion time. It was also better\u000a      tolerated, causing less emesis, renal impairment, hearing loss and\u000a      neurotoxicity compared to other regimens. In addition, many NSCLC patients\u000a      are elderly (median age 72) with poor performance status and have multiple\u000a      co- morbidities, so clinicians often recommend carboplatin instead of\u000a      cisplatin to treat this population group. Gem\/carbo therefore became\u000a      widely used as a first-line treatment in the UK and internationally to\u000a      treat patients with advanced NSCLC (Lilly data). In 2009, NICE guidance\u000a      recommended pemetrexed-based chemotherapy for NSCLC [a], and since\u000a      that time, gem\/carbo has been used mainly to treat SCLC (NICE guidelines\u000a      TA26 [b] and CG121 [c]).\u000a    The following recommendations are from the NICE website (accessed 30\u000a      April 2013), based on the findings of the UCL trials:\u000a    SCLC [d]:\u000a    \"Early stage (broadly T1-2a, N0, M0) or limited disease (broadly T1-4,\u000a        N0-3, M0)\u000a    Consider carboplatin if renal function impaired, poor performance\u000a        status (WHO 2 or more) or significant comorbidity\"\u000a    Extensive disease (broadly T1-4, N0-3, M1a\/b)\u000a    Offer platinum-based combination chemotherapy (maximum 6 cycles) if\u000a        patient can receive chemotherapy\".\u000a    NSCLC [e]:\u000a    \"For advanced NSCLC, offer a combination of a single third-generation\u000a        drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) plus a platinum\u000a        drug (either carboplatin or cisplatin).\"\u000a    As a result of the national guidance, gem\/carbo was used as a reference\u000a      regimen in the BTOG 2 trial (a large national clinical trial of 1,350\u000a      NSCLC patients) to compare low dose and high dose platinum regimens [f].\u000a      The study shows gem\/carbo was well tolerated and superior to low dose\u000a      cisplatin but has similar outcome compared to high dose cisplatin regimen\u000a      [g].\u000a    The Study 10 findings are also quoted in the US National Comprehensive\u000a      Cancer Network (NCCN) guidelines to support the use of carboplatin to\u000a      treat extensive SCLC [h]. Individual patient data from Study 10\u000a      were used for the meta-analysis comparing the efficacy of cisplatin versus\u000a      carboplatin in the first-line treatment of SCLC [i]. There is also\u000a      reference to Study 10 in Canadian guidelines on bladder cancer [j].\u000a    Approximately 4,000 new cases of SCLC are diagnosed in the UK each year.\u000a      The majority of these patients have extensive SCLC and poor performance\u000a      status and hence many are treated with a carboplatin-based regimen instead\u000a      of a cisplatin-based treatment. A carboplatin regimen can be easily\u000a      administered as an out-patient regimen reducing chair time usage and\u000a      avoiding the inconvenience of prolonged hydration or overnight stay\u000a      associated with cisplatin and also fewer of the adverse effects that are\u000a      commonly seen with cisplatin administration.\u000a    The Systemic Anti-Cancer Therapy (SACT) Dataset, within the National\u000a      Cancer Intelligence Network, has been recording data on types of\u000a      treatments for lung cancer since April 2012. For 2012 there were 3,686\u000a      SCLC cases recorded in England and Wales. The SACT dataset shows that\u000a      between April 2012 and March 2013, 710 patients with SCLC received\u000a      carboplatin, though only around 80% of trusts had uploaded data so the\u000a      actual number is likely to be nearer 900, meaning that 26% of SCLC\u000a      patients received carboplatin [k].\u000a    ","ImpactSummary":"\u000a    UCL has conducted a series of national lung cancer trials, which have led\u000a      to wide-scale changes in clinical practice. Two trials compared different\u000a      platinum based therapies, which led to centres switching from using\u000a      chemotherapy with cisplatin to carboplatin-based chemotherapy instead.\u000a      Carboplatin can be given as an outpatient, and has fewer side effects, and\u000a      has been (and still is) recommended as an alternative to cisplatin in the\u000a      UK and US.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Those in bold are UCL-based; James and Gower were in the clinical trials\u000a      centre)\u000a    \u000a[1] Study 10. Lee SM, James LE, Qian W, Spiro S, Eisen T,\u000a      Gower NH, Ferry DR, Gilligan D, Harper PG, Prendiville J, Hocking\u000a      M, Rudd RM. Comparison of gemcitabine and carboplatin versus cisplatin and\u000a      etoposide for patients with poor-prognosis small cell lung cancer. Thorax.\u000a      2009;64(1):75-80. http:\/\/dx.doi.org\/10.1136\/thx.2007.093872\u000a    \u000a\u000a[2] Study 11. Rudd RM, Gower NH, Spiro SG, Eisen TG, Harper PG,\u000a      Littler JA, Hatton M, Johnson PW, Martin WM, Rankin EM, James LE,\u000a      Gregory WM, Qian W, Lee SM. Gemcitabine plus carboplatin versus\u000a      mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV\u000a      non-small-cell lung cancer: a phase III randomized study of the London\u000a      Lung Cancer Group. J Clin Oncol. 2005 Jan;23(1):142-53. http:\/\/dx.doi.org\/10.1200\/JCO.2005.03.037\u000a    \u000aFunding for both trials: Eli Lilly\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    [a] NICE: The diagnosis and treatment of lung cancer. April 2011. NICE\u000a      Clinical Guideline 121. http:\/\/www.nice.org.uk\/nicemedia\/live\/13465\/54202\/54202.pdf\u000a    [b] NICE Guideline TA26. http:\/\/guidance.nice.org.uk\/TA26\u000a    [c] NICE Guideline CG 121. http:\/\/www.nice.org.uk\/CG121\u000a    [d] Full guideline references our studies.\u000a    [e] Full guideline references our studies.\u000a    [f] BTOG 2 trial. http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00112710\u000a    [g] Ferry et al. British Thoracic Oncology Group Trial, BTOG2: Randomised\u000a      phase III clinical trial of gemcitabine combined with cisplatin 50mg\/m2\u000a      (GC50) versus cisplatin 80mg\/m2 (GC80) versus carboplatin AUC 6 (GCb6) in\u000a      advanced NSCLC. Presented at the World Conference on Lung Cancer 2011. http:\/\/abstracts.webges.com\/wclc2011\/myitinerary\u000a      [put `BTOG2' in the search field, and the Ferry et al abstract will be\u000a      shown]\u000a    [h] US NCCN Guideline: Kalemkerian GP, Akerley W, Bogner P, Borghaei H,\u000a      Chow LQ, Downey RJ, Gandhi L, Ganti AK, Govindan R, Grecula JC, Hayman J,\u000a      Heist RS, Horn L, Jahan T, Koczywas M, Loo BW Jr, Merritt RE, Moran CA,\u000a      Niell HB, O'Malley J, Patel JD, Ready N, Rudin CM, Williams CC Jr, Gregory\u000a      K, Hughes M. Small cell lung cancer. J National Comprehensive Cancer\u000a      Network. 2013;11(1):78-98. Available on request.\u000a    [i] Rossi A, Di Maio M, Chiodini P, Rudd R, Okamoto H, Skarlos DV, Früh\u000a      M, Qian W, Tamura T, Samantas E, Shibata T, Perrone F, Gallo C, Gridelli\u000a      C, Martelli O, Lee SM (2012). Carboplatin-or cisplatin-based chemotherapy\u000a      in first-line treatment of small-cell lung cancer. The COCIS meta-analysis\u000a      of individual patient data. Journal of Clinical Oncology 2012;\u000a      30(14):1692-8. http:\/\/dx.doi.org\/10.1200\/JCO.2011.40.4905\u000a    [j] Moretto et al. Management of small cell carcinoma of the bladder:\u000a      Consensus guidelines from the Canadian Association of Genitourinary\u000a      Medical Oncologists (GAGMO). Can Urol Assoc J 2013;7:E44-E56. http:\/\/dx.doi.org\/10.5489\/cuaj.220\u000a    [k] Data and estimated data provided by Clinical Lead, National Cancer\u000a      Intelligence Network (NCIN). Copy available on request.\u000a    ","Title":"\u000a    Lung cancer research at UCL\/UCLH sets standards of care\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Lung cancer is the most common cause of cancer death in the UK and other\u000a      developed countries. The CR-UK & UCL Cancer Trials Centre (CTC), with\u000a      the London Lung Cancer Group (LLCG), has an established history (almost 30\u000a      years) of conducting large scale national trials in lung cancer treatment\u000a      and screening. The chair of the LLCG is Professor Siow Ming Lee, based at\u000a      UCL\/UCLH.\u000a    Gemcitabine\/carboplatin as first-line treatment for lung cancer (known\u000a        as studies 10 and 11)\u000a    These were two national clinical multicentre trials in lung cancer,\u000a      initiated, developed and conducted through UCL, to examine the efficacy\u000a      and safety of gemcitabine\/carboplatin (gem\/carbo) in two different types\u000a      of lung cancer. The Chief Investigator was Professor Siow Ming Lee. Both\u000a      trials were independently peer-reviewed by Cancer Research UK and were\u000a      conducted through the UK National Cancer Research Networks. All of the\u000a      trials were large collaborative multicentre studies involving as many as\u000a      95 hospitals across the UK.\u000a    Study 10 (extensive or limited stage small cell lung cancer\u000a      (SCLC) with poor prognosis): compared gem\/carbo with standard\u000a      cisplatin\/etoposide (PE) in 241 patients. This was the first randomised\u000a      study comparing these two chemotherapy regimens for patients with\u000a      poor-prognosis small cell lung cancer (SCLC). It showed that gem\/carbo had\u000a      similar survival outcomes to PE, but was better tolerated. Patients given\u000a      gem\/carbo received more chemotherapy as outpatients (89% vs. 66%), and\u000a      fewer had nausea and alopecia (the two most commonly reported side effects\u000a      associated with lower quality of life) [1].\u000a    Study 11 (stage IIIb or IV non-small cell lung cancer\u000a      (NSCLC)): gem\/carbo was compared with standard mitomycin, ifosfamide, and\u000a      cisplatin (MIC), This trial, based on 422 patients, showed for the first\u000a      time that outpatient chemotherapy was more effective than conventional\u000a      inpatient chemotherapy, improving median survival from 7.6 to 10.0 months\u000a      (24% reduction in mortality) and one-year survival from 30% to 40%.\u000a      Furthermore, quality of life was significantly improved, because patients\u000a      given gem\/carbo had fewer side effects [2]. An added advantage was\u000a      that gem\/carbo avoided the inconvenience and NHS cost of an overnight stay\u000a      in hospital.\u000a    "},{"CaseStudyId":"29680","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council","Royal Society"],"ImpactDetails":"\u000a    New clinical intervention and impact on health outcomes\u000a      The research described here has led to the development of an entirely new\u000a      therapeutic approach to patients with severe obesity due to congenital\u000a      leptin deficiency. This was a life threatening disorder which their\u000a      research demonstrated could be fully treated with injections of\u000a      recombinant human leptin which were safe and well tolerated. Addenbrooke's\u000a      Hospital is internationally recognised for pioneering treatment of this\u000a      condition which has been provided to 22 patients worldwide on a named\u000a      patient basis since 1997. Following treatment, patients undergo normal\u000a      progression though puberty, have a significant improvement in quality of\u000a      life and all adults are in full time education or employment (personal\u000a      testimonies; www.goos.org.uk).\u000a    Development of diagnostic tests and clinical guidelines for\u000a        investigation\u000a      O'Rahilly and Farooqi's demonstration in 2000 that pathogenic MC4R\u000a      mutations are found in up to 5-6% of children with severe obesity led to\u000a      the evaluation of MC4R sequence as a routine part of the diagnostic\u000a      evaluation of the severely obese child since 2006 (1). The impact of this\u000a      pioneering Cambridge research and the replication of these findings by\u000a      groups worldwide, has led to the development of new genetic tests,\u000a      guidelines and policies established in the UK and in many European and US\u000a      healthcare systems and commercial laboratories (1-3; www.orpha.net\/,\u000a      www.athenadiagnostics.com,\u000a      www.correlagen.com).\u000a    Diagnostic testing for the monogenic obesity syndromes became available\u000a      to Physicians in the UK and worldwide in 2007 through links between the\u000a      GOOS study and the NHS Clinical Genetics Service at Addenbrooke's\u000a      Hospital. Several centres across Europe and North America have offered\u000a      testing for genetic obesity syndromes since 2010 (www.kumc.edu\/gec\/prof\/labs.html,\u000a      www.ncbi.nlm.nih.gov\/sites\/GeneTests\/),\u000a      many of which were discovered in Cambridge. These practical advances have\u000a      led to the development of international guidelines in relation to the\u000a      assessment of severe early onset obesity and University of Cambridge\u000a      researchers have played a leading role in many of these initiatives (1-3).\u000a    Public debate and attitudes\u000a      The stigma associated with obesity in domains of employment, health care\u000a      and education has been well documented, as has its impact on the quality\u000a      of life of obese individuals and their willingness to approach health care\u000a      professionals (Puhl and Heuer, Obesity 2009). Evidence is emerging that\u000a      the comprehensive descriptions of the world's largest cohorts of patients\u000a      with MC4R and leptin receptor deficiency in high impact medical journals\u000a      have altered approaches and attitudes to severe obesity among medical\u000a      professionals (4. personal testimonies). For example, in a recent study of\u000a      medical students, reading about the genetic basis of obesity significantly\u000a      reduced negative stereotyping of obese patients (Persky et al, Ann Behav\u000a      Med 2011).\u000a    Widespread stigma towards obese patients also negatively impacts on\u000a      public support for policies aimed at tackling obesity (4. personal\u000a      testimonies; www.goos.org.uk). In\u000a      studies of interventions that might reduce weight bias in the general\u000a      public, a discussion of the multidimensional aetiology of obesity which\u000a      includes genetic\/biological factors, has been associated with less\u000a      negative attitudes in several studies (reviewed in Sikorski et al. BMC\u000a      Public Health 2011, 11:661). This work has also formed the basis for\u000a      public engagement and debate on translational outcomes of genetics in\u000a      medicine, on the causes of obesity and on the role of the brain in the\u000a      regulation of appetite (5).\u000a    Social policy\u000a      Since 2000, identification of pathogenic mutations in 26 patients with\u000a      leptin receptor, MC4R, SIM1 and SH2B1 mutations by the Cambridge group has\u000a      prevented severely obese children from being taken away from their\u000a      families and placed into the care of social services, under the assumption\u000a      that a dysfunctional family environment was the cause of the child's\u000a      obesity. This has major impact on the health and well-being of the\u000a      families involved (4. personal testimonies).\u000a    Training\u000a      Since 2009, Professor Farooqi, with the Society for Endocrinology, has\u000a      organised an annual symposium `Obesity Management for the\u000a        Endocrinologist', for specialty registrars and consultants with an\u000a      interest in the practicalities of obesity management (6).\u000a    Drug development\u000a      Advances in understanding of the genetic and molecular basis of severe\u000a      obesity, which have been ongoing since 1997, have informed drug\u000a      development with the realisation that targeting central pathways involved\u000a      in the regulation of appetite may have considerable benefit. Current\u000a      collaborations with a number of biotechnology and pharmaceutical companies\u000a      including GSK, Merck, Pfizer, Takeda, Astra Zeneca and Rhythm\u000a      Pharmaceuticals are based on exploiting these observations for the\u000a      development of novel drugs for the treatment of obesity and other\u000a      disorders of weight regulation such as cachexia (CDAs and MTAs in place\u000a      2012; 7). A novel melanocortin receptor agonist targeted specifically at\u000a      patients with MC4R deficiency is scheduled to enter Phase 2 studies in\u000a      2014, with Cambridge as the lead centre.\u000a    Awards and prizes based on this research and its impact\u000a      The achievements of Professor O'Rahilly and Professor Farooqi are\u000a      recognised nationally and internationally. Prof O'Rahilly has received\u000a      numerous awards relating to this work, including the 2010\u000a      InBev-BailletLatour Health Prize (value, EURO 250000) for `his\u000a        pioneering research in the field of human obesity and its relationship\u000a        to type 2 diabetes. He was the first person to show that a change in one\u000a        or two genetic factors may lead to serious forms of obesity and as a\u000a        result he succeeded in negating the accepted hypothesis that obesity is\u000a        mostly the result of individual behaviour' (ref 8). He was\u000a      elected to Fellowship of the Royal Society in 2003, membership of EMBO in\u000a      2009 and became a Foreign Associate of the National\u000a        Academy of Sciences, USA in 2011. He gave the 2011 Croonian Lecture\u000a      to the Royal College of Physicians, London. Additional to be added in late\u000a      2013.\u000a    Professor Farooqi received the European Society for Clinical\u000a      Investigation Award for Excellence in Clinical Research in 2010, the\u000a      Society for Endocrinology Medal (2012) and the Graham Bull Prize of the\u000a      Royal College of Physicians in 2012 in recognition of this research.\u000a    She was elected to Fellowship of the Academy of Medical Sciences in 2013.\u000a    ","ImpactSummary":"\u000a    Professors O'Rahilly and Farooqi were the first to identify monogenic\u000a      causes of severe childhood obesity, leading the way for identification of\u000a      additional genetic causes by their group and others. Their research led to\u000a      the development of diagnostic tests for these conditions, which are now an\u000a      accepted element of clinical guidelines around the world. This work led to\u000a      the understanding that inherited disorders of appetitive drive can\u000a      underlie human obesity which has altered attitudes to obesity and had an\u000a      impact on the management of families with these conditions. Their research\u000a      also led directly to a highly effective therapy for congenital leptin\u000a      deficiency which reverses the severe obesity associated with this\u000a      condition and associated endocrine and immunological deficiencies. This\u000a      treatment is now available throughout the UK and in specialist centres\u000a      worldwide.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1: Montague CT*, Farooqi IS*, Whitehead JP, Soos MA, Rau H, Wareham NJ,\u000a      Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR,\u000a      Barnett AH, Prins JB, O'Rahilly S. Congenital leptin deficiency is\u000a      associated with severe early-onset obesity in humans. Nature\u000a      1997;387:903-8. PMID: 9202122.\u000a      Citations, 1356. Journal impact factor, 34.\u000a    \u000a\u000a2: Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L,\u000a      Montague CT, Hutton JC, O'Rahilly S. Obesity and impaired prohormone\u000a      processing associated with mutations in the human prohormoneconvertase 1\u000a      gene. Nature Genetics 1997;16:303-6. PMID: 9207799.\u000a      Citations, 476. Journal impact factor, 34.\u000a    \u000a\u000a3. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM,\u000a      Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy\u000a      in a child with congenital leptin deficiency. N Engl J Med.\u000a      1999;341:879-84 PMID: 10486419.\u000a      Citations, 638. Journal impact factor, 47.\u000a    \u000a\u000a4: Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S.\u000a      Clinical spectrum of obesity and mutations in the melanocortin 4 receptor\u000a      gene. N Engl J Med. 2003;348:1085-95. PMID: 126466655:\u000a      Citations, 427. Journal impact factor, 47.\u000a    \u000a\u000a5. Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron\u000a      GS, Astruc B, Mayer JP,Brage S, See TC, Lomas DJ, O'Rahilly S, Farooqi IS.\u000a      Modulation of blood pressure by central melanocortinergic pathways. N Engl\u000a      J Med. 2009;360:44-52.\u000a      Citations, 47. Journal impact factor, 47.\u000a    \u000a\u000a6. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K,\u000a      Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME,\u000a      Farooqi IS. Large, rare chromosomal deletions associated with severe\u000a      early-onset obesity. Nature 2010;463:666-70. PMID: 19966786.\u000a      Citations, 41. Journal impact factor, 34.\u000a    \u000aResearch Grant support\u000a    MRC Programme Grant funding held continually by O'Rahilly since 1999\u000a      Most recent renewal: Co-applicants, AP Coll, IS Farooqi, S O'Rahilly, G\u000a      Yeo\u000a      Title: Molecular Mechanisms in Human Obesity\u000a      Amount awarded: £2,475,269; Oct 2009 — Oct 2014\u000a    MRC Centre for Obesity and Related Metabolic Diseases (CORD)\u000a      Director S O'Rahilly, Co-applicants 17 other PIs from Cambridge and\u000a      Oxford.\u000a      Amount awarded: £2,149,149; June 2007- March 2013\u000a    MRC\/University Metabolic Disease Unit\u000a      Director, S O'Rahilly\u000a      Amount Awarded: £10,482,000, April 2013-March 2018\u000a    Wellcome Trust Strategic Award for Institute of Metabolic Science\u000a      Allocation for Clinical Metabolic Research Facilities\u000a      Amount Awarded: £5,000,000, April 2013-March 2018\u000a    Wellcome Trust Senior Research Fellowship in Clinical Science\u000a      Applicant: IS Farooqi (PI)\u000a      Title: The pathophysiology and genetics of human early onset obesity\u000a      Amount awarded: £1,551,212; Dec 2007 — Dec 2012\u000a      Renewed: £2,080,343; Dec 2012 — Dec 2017\u000a    National Institute for Health Research — Cambridge Biomedical Research\u000a      Centre\u000a      Applicants: IS Farooqi, S O'Rahilly\u000a      Title: Metabolism theme — Obesity allocation\u000a      Amount awarded: £1,615,000; Apr 2007 — Apr 2012\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    Review that corroborates the impact of this research on clinical\u000a        practice\u000a    1. Viner\u000a        RM, White\u000a        B, Barrett\u000a        T, Candy\u000a        DC, Gibson\u000a        P, Gregory\u000a        JW, Matyka\u000a        K, Ong\u000a        K, Roche\u000a        E, Rudolf\u000a        MC, Shaikh\u000a        G, Shield\u000a        JP, Wales\u000a        JK. Assessment of childhood obesity in secondary care: OSCA\u000a      consensus statement, Arch Dis Child EducPract Ed 2012;97:3 98-105Guidelines\u000a        that corroborate the impact of this research on clinical practice\u000a    2. Scottish Intercollegiate Guidelines Network (SIGN). Management of\u000a      obesity. A national clinical guideline. Edinburgh: Scottish\u000a      Intercollegiate Guidelines Network (SIGN); 2010 Feb. (SIGN publication;\u000a      no. 115).\u000a    3. The Endocrine Society (TES). Prevention and treatment of pediatric\u000a      obesity: an Endocrine Society clinical practice guideline based on expert\u000a      opinion. Journal of Clinical Endocrinology & Metabolism 2008\u000a      Dec;93(12):4576-99.\u000a    Personal testimonies to corroborate impact on patients and their\u000a        families\u000a    4. http:\/\/www.goos.org.uk\/patients-and-families\/personal-experiences\u000a    Informing public debate\u000a    5. commentary in Newsweek; \"The Real Cause of Obesity\" Sep 9, 2009\u000a      http:\/\/www.thedailybeast.com\/newsweek\/2009\/09\/09\/the-real-cause-of-obesity.html\u000a    Training\u000a    6. (http:\/\/www.endocrinology.org\/meetings\/2010\/oms2010\/index.html).\u000a    Drug Development\u000a    7. CDAs and MTAs available, University of Cambridge Clinical School.\u000a    Awards\u000a    8. http:\/\/www.mrl.ims.cam.ac.uk\/documents\/PR-100419-PrijsGezondheid2010-en-def1.pdf\u000a    \u000a    ","Title":"\u000a    Genetic diagnosis and therapeutic intervention in patients with severe\u000a      early onset obesity\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Obesity represents one of the major challenges to public health in the\u000a      developed world due to increased morbidity and mortality associated with\u000a      cardiovascular disease, Type 2 diabetes and some forms of cancer, and\u000a      results in annual healthcare costs in excess of £1.0 billion in the UK\u000a      alone. Whilst public health initiatives to improve diet and promote\u000a      exercise play a role, these have proved largely ineffective particularly\u000a      in patients with severe obesity, highlighting the need for improved\u000a      therapeutic strategies. The success of such strategies relies upon\u000a      understanding the mechanisms involved in regulating body weight and how\u000a      their disruption leads to obesity.\u000a    This research has been led by Professor S O'Rahilly (University employed\u000a      from 1\/8\/1991) and Professor IS Farooqi (University employed from\u000a      1\/12\/2002; both University of Cambridge School of Clinical Medicine,\u000a      Addenbrooke's Hospital). Given the strong evidence that weight is highly\u000a      heritable, they used genetic approaches to investigate patients with\u000a      severe, early onset obesity. This work led to the discovery, by O'Rahilly\u000a      and Farooqi, of the first two single-gene defects causing human obesity in\u000a      1997 (1, 2) involving the genes encoding leptin and prohormone convertase\u000a      1. In collaboration with the pharmaceutical company AMGEN, O'Rahilly and\u000a      Farooqi were responsible for co-ordinating the first clinical trial of\u000a      recombinant human leptin in patients with severe obesity due to congenital\u000a      leptin deficiency (3). Treatment with recombinant human leptin was safe\u000a      and efficacious and provided the first proof-of-principle that leptin is\u000a      an essential regulator of body weight, T-cell-mediated immunity and the\u000a      onset of puberty in humans. In 2007, in collaboration with Professor Paul\u000a      Fletcher (Department of Psychiatry, University of Cambridge, University\u000a      employed from 1\/11\/1998), they used functional MRI to demonstrate that\u000a      leptin regulates the liking of food, a response that is mediated by\u000a      activation of mesolimbic areas of the brain. These studies constitute a\u000a      body of work that provides seminal insights into the role of leptin in\u000a      human physiology.\u000a    O'Rahilly and Farooqi's research strategy has focussed on a cohort of\u000a      over 4000 patients with severe, early onset obesity recruited to the\u000a      Genetics of Obesity Study (GOOS) in Cambridge in collaboration with\u000a      multiple centres in the UK and worldwide. They showed that\u000a      loss-of-function mutations in the melanocortin 4 receptor (MC4R) cause a\u000a      dominantly inherited obesity syndrome which is the most common genetic\u000a      cause of obesity identified to date, occurring in 5-6% of severely obese\u000a      children (4). They went on to characterise the phenotype of MC4R\u000a      deficiency, demonstrate a genotype-phenotype correlation (4), and\u000a      establish the role of central melanocortin signalling in regulating blood\u000a      pressure (5). Additional findings of patients with mutations in the leptin\u000a      receptor, POMC, BDNF and TrkB demonstrated the critical role of the\u000a      hypothalamic melanocortin pathway in regulating human appetite and body\u000a      weight, and that a range of single-genedefects can cause severe early\u000a      onset obesity.\u000a    In 2010, they used a hypothesis-free approach to show that copy number\u000a      variants contribute to the aetiology of severe childhood obesity,\u000a      highlighting the role of the signalling molecule SH2B1 in human obesity\u000a      and insulin resistance (6).\u000a    "},{"CaseStudyId":"29691","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council","Royal Society"],"ImpactDetails":"\u000a    Direct Impact on classification and diagnosis\u000a      Diagnosis of myeloproliferative neoplasms. The discovery of JAK2\u000a      V617F (Green group and others) and exon 12 mutations (Green group) has\u000a      revolutionized the way in which MPNs are diagnosed (Refs 1-4) and these\u000a      changes became embedded in national and international guidelines between\u000a      2007-2011 (e.g. Refs 5-8, Guidelines from British Committee for Standards\u000a      in Haematology Guidelines, European LeukemiaNet and World Health\u000a      Organisation). Simple PCR-based assays for the mutations now provide\u000a      inexpensive and robust tests that are used throughout UK and in multiple\u000a      other countries as front-line diagnostic tools, improving patient care at\u000a      reduced cost (i.e. rendering unnecessary multiple tests previously\u000a      required for diagnosis).\u000a    Polycythaemia vera. Prior to the identification of the JAK2 V617F\u000a      mutation the distinction of PV from other causes of erythrocytosis was\u000a      based on a complex diagnostic algorithm that included bone marrow\u000a      cytogenetics, growth of erythropoietin-independent erythroid colonies,\u000a      nuclear medicine red cell mass studies and spleen imaging. These\u000a      investigations are now no longer needed. The diagnosis of PV can be made\u000a      on the basis of a raised haemoglobin or haematocrit together with the\u000a      presence of the JAK2 mutation ((Refs 2 and 3), an approach now firmly\u000a      embedded in national and international guidelines (e.g. Ref 5, BCSH\u000a      guidelines for polycythaemia\/erythrocytosis 2007; Ref 6, BCSH guidelines\u000a      for thrombocytosis 2010; Ref 7, European LeukemiaNet guidelines for\u000a      Philadelphia-negative classical myeloproliferative neoplasms 2011; Ref 8,\u000a      WHO guidelines for myeloproliferative neoplasms 2008, all of which cite\u000a      Green's work).\u000a    Essential thrombocythaemia and primary myelofibrosis.\u000a      Thrombocytosis is usually reactive in nature and only a minority of\u000a      patients with a raised platelet count have ET. Prior to discovery of the\u000a      JAK2 V617F mutation, the diagnosis of ET was primarily one of exclusion\u000a      and required eliminating the many possible causes of a reactive\u000a      thrombocytosis. Similarly bone marrow fibrosis has multiple possible\u000a      causes in addition to primary myelofibrosis. Identification of the JAK2\u000a      V617F mutation in ~60% of patients with ET or PMF has provided a simple\u000a      and objective test that removes reliance on subjective bone marrow\u000a      morphology and also the need to undertake investigations to exclude\u000a      reactive causes (Refs 1 and 2). Detection of the JAK2 V617F mutation is\u000a      now a key feature of national and international guidelines for ET and\u000a      primary myelofibrosis (PMF) (Ref 5, BCSH guidelines for\u000a      polycythaemia\/erythrocytosis 2007 (still current); Ref 6, BCSH guidelines\u000a      for thrombocytosis 2010; Ref 7, European LeukemiaNet guidelines for\u000a      Philadelphia-negative classical myeloproliferative neoplasms 2011; Ref 8,\u000a      WHO guidelines for myeloproliferative neoplasms 2008).\u000a    Budd-Chiari syndrome, intra-abdominal thrombosis, cerebral sinus\u000a        thrombosis. The introduction of testing for the JAK2 V617F mutation\u000a      has demonstrated that a subset of patients with a variety of large-vessel\u000a      venous thromboses has an occult MPN despite having normal haemoglobin,\u000a      white cell and platelet counts. Such patients can now be identified and\u000a      monitored for the development of an overt MPN (as described in Ref 4).\u000a    Idiopathic erythrocytosis. Green's discovery of JAK2 exon 12\u000a      mutations in 2007 revealed the existence of a distinctive MPN syndrome,\u000a      patients with which had previously been labelled as having idiopathic\u000a      erythrocytosis. These patients present with an isolated erythrocytosis\u000a      usually without other features of PV, but the course of their disease is\u000a      similar to PV and includes transformation to myelofibrosis and acute\u000a      myeloid leukaemia. Detection of JAK2 exon 12 mutations allows accurate\u000a      diagnosis and is now embedded in national and international guidelines\u000a      (e.g. Refs 2,3,7 and 8).\u000a    Direct impact on patient management\u000a      Therapy of myeloproliferative neoplasms and other malignancies. The\u000a      identification of gain-of-function mutations in most patients with an MPN\u000a      was followed by the rapid development of multiple different JAK2\u000a      inhibitors. Following on from the research of Green and others, the first\u000a      studies in man were reported in 2010 (Verstovcek et al NEJM 2010) only 5\u000a      years after the original reports of the JAK2 V617F mutation. Subsequent\u000a      phase 2 and 3 clinical trials have shown that the JAK inhibitor\u000a      ruxolitinib reduces systemic symptoms and splenomegaly in approximately\u000a      30% of patients with advanced phase disease including myelofibrosis\u000a      (Harrison et al NEJM 2012; Verstovcek et al NEJM 2012). Ruxolitinib is now\u000a      FDA approved for use in patients with myelofibrosis and several other JAK2\u000a      inhibitors are also in clinical trials. The relevance of JAK2 inhibitors\u000a      has significance to cancer research beyond the MPNs since JAK2 mutations\u000a      are seen in other haematological malignancies (e.g. acute lymphoblastic\u000a      leukaemia) and increased levels of JAK\/STAT signalling are seen in many\u000a      forms of cancer.\u000a    ","ImpactSummary":"\u000a    The myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies.\u000a      Research led by Professor Green at Cambridge University reported that many\u000a      MPN patients carry a JAK2V617F mutation and identified JAK2 exon 12\u000a      mutations associated with an MPN variant often previously diagnosed as\u000a      idiopathic erythrocytosis. These outcomes led to tests for JAK2 mutations\u000a      being established in the Eastern Region Haemato-oncology Diagnostic\u000a      Service (Addenbrooke's hospital), providing a paradigm for other UK\u000a      molecular diagnostic services. Tests for JAK2V617F and exon 12 mutations\u000a      have greatly simplified, and improved the accuracy of, the diagnosis of\u000a      MPN patients world-wide, and are now firmly embedded as front-line tests\u000a      in national and international guidelines.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S,\u000a      Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott M, Erber WN, Cancer\u000a      Genome Project, Green AR. Acquired mutation of the tyrosine kinase\u000a      JAK2 in human myeloproliferative disorders. Lancet 365: 1054-61,\u000a      2005.\u000a    \u000a\u000a2. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal\u000a      PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish\u000a      HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and\u000a      idiopathic erythrocytosis, N Engl J Med 356: 459-468, 2007.\u000a    \u000a\u000a3. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech\u000a      Arava, Shocaht C, Cazzaniga G, Biondi A, Basso G, Cario G, Schrappe M,\u000a      Stanulla M, Strehl S, Haas OA, Mann G, Binder V, Borkhardt A, Kempski H,\u000a      Trka J, Bielorei B, Avigad S, Stark B, Smith O, Dastugue N, Bourquin J-P,\u000a      Tal NB, Green AR, Izraeli S. Mutations of JAK in acute\u000a      lymphoblastic leukaemias associated with down's syndrome. Lancet,\u000a      372: 1484-1492, 2008.\u000a    \u000a\u000a4. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy\u000a      A, Boyd EM, Bench AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber\u000a      WN, Bareford D, Wilkins BS, Reilly JT, Harrison CN, Green AR.\u000a      Definition of subtypes of essential thrombocythaemia and relation to\u000a      polycythaemia vera based on JAK2 V617F mutation status: a prospective\u000a      study. Lancet 366: 1945-1953, 2005.\u000a    \u000a\u000a5. Chen E, Beer PA, Godfrey AL, Ortmann CA, Li J, Costa-Pereira AP, Ingle\u000a      CE, Dermitzakis ET, Campbell PJ, and Green AR. Distinct clinical\u000a      phenotypes associated with JAK2V617F reflect differential STAT1\u000a      signaling. Cancer Cell, 18(5): 524-535, 2010.\u000a    \u000a\u000a6. Zhao R, Follows GA, Beer PA, Scott LM, Huntly BJP, Green AR*,\u000a      Alexander DR* (*joint senior authors). Inhibition of the Bcl-xL\u000a      deamidation pathway in myeloproliferative disorders. N. Engl J Med,\u000a      359(26): 2778-2789, 2008.\u000a    \u000aResearch grants support:\u000a    LLR programme grant funding held continually since 1997 by Professor\u000a      Green. Most recent renewal 01.04.2008 - 31.03.2013, Molecular pathogenesis\u000a      of myeloproliferative disorders, £2,230,206.\u000a    LLS Specialized Center of Research held continually by Professor Green\u000a      since 2006. Most recent renewal with co-applicants Dr B Huntly, Dr B\u000a      Gottgens & Dr P Campbell 01.10.2011 - 30.09.2016, $6,250,000.\u000a    CRUK grant funding to support PT-1 held continually by Professor Green\u000a      since 2007. Most recent CRUK CTAAC 01.05.2008 - 31.03.2013, A\u000a      collaborative study of myeloproliferative disorders (COSMYD) (with Dr PJ\u000a      Campbell, MF McMullin, CN Harrison, K Wheatley), £462,865.\u000a    The Kay Kendall Leukaemia Fund, 01.09.2009 - 31.08.2012. Genome-wide\u000a      characterization of somatic mutation in acute lymphoblastic leukaemia and\u000a      myeloproliferative disorders (with co- applicants Professor M Greaves and\u000a      Dr PJ Campbell). £1,632,075.\u000a    Cancer Research UK, project grant to Professor Green, 01.10.2011 -\u000a      30.09.2014. Investigation of interaction between germline and somatic\u000a      genetics at the JAK2 locus in myeloproliferative neoplasms. £240,279\u000a    MRC support for PT-1 Clinical Trial, to Professor Green and Dr C\u000a      Harrison, 01.05.2004 - 30.04.2006. £103,612\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    \u000a      Cervantes F. Management of essential thrombocythemia. Hematology AmSoc\u000a        Hematol Educ Program 2011: 215-221, 2011.\u000a      Harrison C. Rethinking disease definitions and therapeutic strategies\u000a        in essential thrombocythemia and polycythemia vera. Hematology AmSoc\u000a        Hematol: 129-134, 2010.\u000a      Tefferi A, Skoda R, Vardiman JW. Myeloproliferative neoplasms:\u000a        contemporary diagnosis using histology and genetics. Nature\u000a        Reviews\/Clinical Oncology: 627-637, 2009.\u000a      Smalberg J, Arends L, Valla DC, Kiladjian JJ, Janssen HL, Leebeek FW.\u000a        Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein\u000a        thrombosis: a meta-analysis. Blood: 4921-4928, 2012.\u000a    \u000a    5a. Original guidelines (on which subsequent versions are based); McMullin\u000a        MF, Bareford\u000a        D, Campbell\u000a        P, Green\u000a        AR, Harrison\u000a        C, Hunt\u000a        B, Oscier\u000a        D, Polkey\u000a        MI, Reilly\u000a        JT, Rosenthal\u000a        E, Ryan\u000a        K, Pearson\u000a        TC, Wilkins\u000a        B; General\u000a        Haematology Task Force of the British Committee for Standards in\u000a        Haematology. Guidelines for the diagnosis, investigation and\u000a      management of polycythaemia\/erythrocytosis Br\u000a        J Haematol. 2005 Jul;130(2):174-95\u000a    5b. Amended guidelines; McMullin MF, Reilly JT, Campbell P, Bareford D,\u000a      Green AR, Harrison CN, Conneally E; National Cancer Research Institute,\u000a      Myeloproliferative Disorder Subgroup, Ryan K; Amendment to the guideline\u000a      for diagnosis and investigation of polycythaemia\/erythrocytosis. (On\u000a      behalf of the General Haematology Task Force of the British Committee for\u000a      Standards in Haematology). Br J Haematol, 138(6):821-822, 2007 (that\u000a      remain current to date). \u000a    \u000a      Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M,\u000a        Erber W, Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R,\u000a        Nelson-Piercy C, Radia DH, Reilly JT, Van der Walt J, Wilkins B,\u000a        McMullin MF; British Committee for Standards in Haematology. Guideline\u000a        for investigation and management of adults and children presenting with\u000a        a thrombocytosis. Br J Haematol, 149(3): 352-375, 2010\u000a      Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer\u000a        M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ,\u000a        Kröger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM,\u000a        Reiter A, Silver RT, Verstovsek S, Tefferi A. Philadelphia-negative\u000a        classical myeloproliferative neoplasms: critical concepts and management\u000a        recommendations from European LeukemiaNet. J Clin Oncol, 29(6): 761-770,\u000a        2011.\u000a      Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele\u000a        J, Vardiman JW. WHO classification of Tumours of Haematopoietic and\u000a          Lymphoid Tissues: Lyon: IARC Press; 2008.\u000a    \u000a    ","Title":"\u000a    Molecular markers for diagnosis of myeloproliferative neoplasms\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The MPNs are chronic haematological malignancies that result in the\u000a      overproduction of mature blood cells. Their diagnosis has been challenging\u000a      since many non-malignant disorders can also present with raised blood\u000a      counts.\u000a    Identification of JAK2 mutation in MPNs.\u000a      Professor Green's group, (Department of Haematology, 1991-present), in\u000a      collaboration with Professor Mike Stratton (Wellcome Trust Sanger\u000a      Institute), sought to sequence all known tyrosine kinase genes and\u000a      reported in 2005 the presence of the JAK2 V617F mutation in patients with\u000a      MPN (ref 1). Using sensitive assays established by the Green group, the\u000a      mutation was detected in ~95% of patients with polycythemia vera (PV) and\u000a      in 50% of patients with essential thrombocythemia (ET) and primary\u000a      myelofibrosis (PMF) but not in normal controls. Moreover its presence in\u000a      erythropoietin-independent erythroid colonies from patients demonstrated a\u000a      link with growth factor hypersensitivity, a key biological feature of\u000a      myeloproliferative neoplasms. The Green lab subsequently identified\u000a      mutations in JAK2 exon12 which defined a distinctive myeloproliferative\u000a      syndrome related to PV (ref 2), and, in collaboration with Professor\u000a      Izraeli (Tel Aviv), also reported mutations in JAK2 exon16 in acute\u000a      lymphoblastic leukaemia (ref 3).\u000a    Molecular and cellular studies performed in Cambridge.\u000a      Following the discovery in 2005 of the JAK2 V617F mutation, a substantial\u000a      body of work from the Green lab (including papers in NEJM, Lancet and\u000a      Blood) characterised the molecular and cellular consequences of JAK2\u000a      mutations together with their clinical significance. JAK2 mutation status\u000a      identified two distinct sub-groups of patients with ET and demonstrated a\u000a      phenotypic continuum between patients with JAK2 mutated ET and PV (ref 4).\u000a      These observations raised the question of why patients with an identical\u000a      JAK2 mutation develop different diseases (e.g. ET or PV). Clonal analysis\u000a      of haematopoietic colonies indicated that this reflects the presence in PV\u000a      but not in ET of large subclones homozygous for mutant JAK2, together with\u000a      a defect in STAT1 signalling (ref 5). Additional studies by the Green lab\u000a      demonstrated unexpected clonal complexity that the JAK2 V617F mutations\u000a      increase the accumulation of DNA damage (ref 6) and that it gives rise to\u000a      an unexpected haematopoietic stem cell defect.\u000a    Insights into fundamental mechanisms.\u000a      Studies of the JAK2 mutation in normal and leukaemic cells by the Green\u000a      lab (including papers in Nature, Nature Cell Biology and Cancer Cell) have\u000a      also illuminated fundamental biological mechanisms. The demonstration that\u000a      JAK2 functions in the nucleus as a histone kinase (collaboration with\u000a      Professor Kouzarides, Royal Society Napier Professor, Pathology\u000a      Department, University of Cambridge since 2001) provided a new paradigm\u000a      for cytokine signalling and subsequent studies of JAK\/STAT signalling in\u000a      embryonic stem cells uncovered a previously unrecognised role for direct\u000a      signalling to chromatin by JAK2 as an important mediator of ES cell\u000a      self-renewal.\u000a    "},{"CaseStudyId":"29694","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d    BOADICEA: Breast and Ovarian Analysis of Disease Incidence and Carrier\u000d      Estimation Algorithm (1) is a risk model for familial breast and ovarian\u000d      cancer, which computes BRCA1 and BRCA2 mutation carrier probabilities and\u000d      age specific risks for breast and ovarian cancer. This model was developed\u000d      by Antonis and Easton, (Department of Public Health and Primary Care at\u000d      Cambridge) as a direct result of Ponder's work on the relationship between\u000d      BRCA1\/2 and breast cancer susceptibility, and made use of the large data\u000d      sets of epidemiological data developed by Ponder. BOADICEA models the\u000d      simultaneous effects of BRCA1 and BRCA2 mutations. BOADICEA was adopted by\u000d      NICE in 2006 (CG41; 2) and incorporated into subsequent guidance in June\u000d      2013 (3).\u000d    Beneficiaries: The beneficiaries of BOADICEA are: 1) healthcare\u000d      providers, notably organisers of breast cancer screening programmes (e.g.,\u000d      the NHS in the UK); 2) clinicians and genetic counsellors; 3) family\u000d      members of women with breast cancer or otherwise at high risk of the\u000d      disease; 4) the general public; 5) research scientists for planning\u000d      screening or intervention trials and for designing research studies.\u000d    Indicators of extent of impact: The web-interface of BOADICEA has\u000d      been available since November 2007 and currently has more than 1,500\u000d      registered users. These include not only clinical geneticists and genetic\u000d      counsellors but researchers and users from the insurance sector\u000d      (anonymised ethical data). Users are located in the UK, elsewhere in\u000d      Europe, North America, Australia, and several other countries. Recent\u000d      monitoring of the web servers revealed an average of 50 concurrent users\u000d      at any given time. Clinics in North America and Australia recommend\u000d      BOADICEA as part of their guidelines and oncology programmes (4, 5).\u000d    Nature of impacts: BRCA1 and BRCA2 mutation screening is expensive\u000d      and is also associated with adverse psychosocial effects. Hence, it is\u000d      crucial that genetic testing for BRCA1 and BRCA2 is targeted at\u000d      individuals most likely to be carriers, particularly in the context of the\u000d      National Health Service (NHS) and other publicly funded health care\u000d      systems. Use of BOADICEA has had several inter-related impacts in this\u000d      regard:\u000d    (1) To identify women eligible for screening by magnetic resonance\u000d          imaging (MRI)\u000d    Under the guidelines adopted by the UK National Institutes of Health and\u000d      Clinical Excellence (NICE), women at moderate or high risk of developing\u000d      breast cancer are offered mammographic screening from age 40, and a subset\u000d      of high risk women, including BRCA1 and BRCA2 mutation carriers should be\u000d      offered screening by MRI. MRI screening is more sensitive than mammography\u000d      but is approximately ten-fold more expensive. BOADICEA was adopted by NICE\u000d      (2, 3) from 2006 as a risk prediction algorithm for classifying women at\u000d      risk of familial cancer into three risk categories: women at or near\u000d      population risk, raised risk, or high risk and remains the tool of choice\u000d      to date. Since 2006, women predicted to be at raised or high risk by\u000d      BOADICEA have been offered annual mammographic surveillance from age 40,\u000d      compared to age 50 under the standard NHS screening programme. Women at\u000d      high risk are offered MRI screening. As an ancillary impact in the same\u000d      vein, BOADICEA has also been used to determine eligibility for entry into\u000d      the MARIBS screening trial evaluating the efficacy of x-ray mammography\u000d      and MRI (6). Other guidelines also include BOADICEA data (7)\u000d    (2) To refer women for BRCA1 and BRCA2 mutation screening\u000d    Predictions obtained by BOADICEA are used by geneticists to refer\u000d      individuals for BRCA1 and BRCA2 mutation screening (usually a combined\u000d      mutation carrier prediction of over 20%).\u000d    (3) To guide prophylactic surgery and chemoprevention options for\u000d          women at high risk\u000d    The cancer risk predictions of BOADICEA are being used to guide\u000d      prophylactic surgery and chemoprevention options for women at high risk.\u000d      As noted above, BOADICEA is one of the risk prediction algorithms\u000d      recommended in the UK and other countries (e.g. American Cancer Society\u000d      and Ontario Breast Screening program incorporated in guidelines since\u000d      2011) for determining eligibility for high risk screening (8, 9, 10).\u000d    (4) To counsel women carrying BRCA1 and BRCA2 mutations\u000d    BRCA1 and BRCA2 cancer risk estimates obtained from the studies in the\u000d      list of references provided above and based on BOADICEA are being used to\u000d      counsel women carrying such mutations. These estimates have also been\u000d      widely used by various support groups such as FORCE for providing\u000d      information to individuals at risk of hereditary breast and ovarian cancer\u000d      (http:\/\/www.facingourrisk.org\/).\u000d    Process of dissemination:\u000d    BOADICEA is well established internationally as indicated above. A recent\u000d      high impact review noted: \"BOADICEA also provided the best\u000d        discrimination between mutation carriers and non-carriers\" (11)\u000d    A web-based user-friendly interface was developed for BOADICEA\u000d      (http:\/\/www.srl.cam.ac.uk\/genepi\/boadicea\/boadicea_home.html)\u000d      allows users to obtain rapid estimates of BRCA1 and BRCA2 carrier\u000d      probabilities and risks of developing breast or ovarian cancer.\u000d    ","ImpactSummary":"\u000d    Basic, clinical and applied research at the University of Cambridge has\u000d      culminated in a widely-used risk prediction algorithm (\"BOADICEA\") for\u000d      familial breast and ovarian cancer. This web-based, user-friendly tool\u000d      predicts the likelihood of carrying mutations in breast and ovarian cancer\u000d      high risk genes (BRCA1 and BRCA2), and the risk of developing breast or\u000d      ovarian cancer. In 2006, BOADICEA was been recommended by the UK National\u000d      Institutes of Health and Clinical Excellence (NICE: CG41, 2006) and the\u000d      American Cancer Society (since 2011). In June 2013, NICE recommended\u000d      BOADICEA in subsequent guidance (CG164). Furthermore, several national\u000d      bodies have designated BOADICEA as the standard tool to assess eligibility\u000d      for high risk breast cancer screening.\u000d    ","ImpactType":"Health","Institution":"\u000d    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000d    \u000a1. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop\u000d      DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J,\u000d      Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S,\u000d      Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA,\u000d      Zelada-Hedman M, et al. Genetic heterogeneity and penetrance analysis of\u000d      the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer\u000d      Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676-89. (cited >\u000d      1,500)\u000d    \u000a\u000a2. Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M,\u000d      Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, Love R, Evans G, Easton D,\u000d      Clayton D, Stratton MR, Ponder BA. Germline mutations of the BRCA1\u000d      gene in breast and ovarian cancer families provide evidence for a\u000d      genotype-phenotype correlation. Nat Genet. 1995 Dec;11(4):428-33. (cited\u000d      > 350)\u000d    \u000a\u000a3. Ponder BAJ, Day NE, Easton DF, Pharoah PDP, Lipscombe JM,\u000d      Redman K, Antoniou A, Basham V, Gregory J, Gayther S & Dunning A\u000d      (2000). Prevalence and penetrance of BRCA1 and BRCA2 mutations in a\u000d      population-based series of breast cancer cases. Br J Cancer 83,\u000d      1301-1308. Peer-reviewed article, citations as of July 2013: 62\u000d    \u000a\u000a4. Cornelis RS, Neuhausen SL, Johansson O, Arason A, Kelsell D, Ponder\u000a        BA, Tonin P, Hamann U, Lindblom A, Lalle P, et al. High allele loss\u000d      rates at 17q12-q21 in breast and ovarian tumors from BRCA1-linked\u000d      families. The Breast Cancer Linkage Consortium. Genes Chromosomes Cancer.\u000d      1995 Jul;13(3):203-10.\u000d    \u000a\u000a5. Wooster R, Bignell G, Lancaster J,.......Ponder BAJ, ...et al,\u000d      , Stratton MR. Identification of the breast cancer susceptibility gene\u000d      BRCA2. Nature. 1995;378(6559):789-92. (cited > 1,900)\u000d    \u000a\u000a6. Wooster R, Neuhausen SL, Mangion J, .... Ponder BAJ, Skolnick\u000d      MH, Easton DF, Goldgar DE, Stratton MR. Localization of a breast cancer\u000d      susceptibility gene, BRCA2, to chromosome 13q12-13. Science.\u000d      1994;265(5181):2088-90. (cited > 1,000)\u000d    \u000a\u000a7. Easton DF, Pooley KA, .... Ponder BAJ (2007) Genome-wide\u000d      association study identifies novel breast cancer susceptibility loci.\u000d      Nature 447: 1087-93, DOI: 10.1038\/nature05887. (cited > 1,000)\u000d    \u000a\u000a8. Ghoussaini M, Fletcher O, Michailidou K, et al, Ponder BA,\u000d      Chenevix-Trench G, Pharoah PD, Lathrop M, Dunning AM, Rahman N, Peto J,\u000d      Easton DF. Genome-wide association analysis identifies three new breast\u000d      cancer susceptibility loci. Nat Genet. 2012 Mar;44(3):312-8\u000d    \u000a\u000a9. French JD, Ghoussaini M, Edwards SL, Meyer KB, .... et al, Ponder BA,\u000d      Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, Dunning AM.\u000d      Functional variants at the 11q13 risk locus for breast cancer regulate\u000d      cyclin D1 expression through long-range enhancers. Am J Hum Genet. 2013\u000d      Apr 4;92(4):489-503.\u000d    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d    \u000d      Antoniou AC, Pharoah PDP, Smith P, Easton DF (2004). The BOADICEA\u000d        model of genetic susceptibility to breast and ovarian cancer. Br J\u000d        Cancer 91:1580-90\u000d      National Institutes of Health and Clinical Excellence, UK: CG41\u000d        Familial breast cancer: full guideline (the new recommendations and the\u000d        evidence they are based on), October 2006: http:\/\/guidance.nice.org.uk\/cg41\/guidance\/pdf\/English\u000a\u000d      National Institutes of Health and Clinical Excellence, UK: CG164.\u000d        Familial breast cancer. June 2013. http:\/\/www.nice.org.uk\/nicemedia\/live\/14188\/64202\/64202.pdf\u000a\u000d      https:\/\/www.cancercare.on.ca\/common\/pages\/UserFile.aspx?fileId=99500\u000d      http:\/\/canceraustralia.gov.au\/clinical-best-practice\/gynaecological-cancers\/familial-risk-assessment-fra-boc\/references\u000d      DGR Evans, Lennard et al Eligibility for Magnetic Resonance Imaging\u000d        Screening in the United Kingdom: Effect of Strict Selection Criteria and\u000d        Anonymous DNA Testing on Breast Cancer Incidence in the MARIBS Study\u000d        Cancer Epidemiol Biomarkers Prev 2009;18:2123-2131\u000d      Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, Morris E,\u000d        Pisano E, Schnall M, Sener S, Smith RA, Warner E, Yaffe M, Andrews KS,\u000d        Russell CA for the American Cancer Society Breast Cancer Advisory Group\u000d        (2007) American Cancer Society guidelines for breast screening with MRI\u000d        as an adjunct to mammography CA Cancer J Clin 57: 75-89\u000d      American Cancer Society mammographic screening guidelines: Smith RA,\u000d        et al. Cancer screening in the United States, 2011: A review of current\u000d        American Cancer Society guidelines and issues in cancer screening. CA\u000d        Cancer J Clin. 2011 Jan-Feb;61(1):8-30\u000d      Ontario Breast Screening Program:\u000d        https:\/\/www.cancercare.on.ca\/pcs\/screening\/breastscreening\/OBSP\/\u000a\u000d      Cancer Australia (Australian Government): Familial Risk Assessment —\u000d        Breast and Ovarian Cancer. http:\/\/canceraustralia.gov.au\/clinical-best-practice\/gynaecological-\u000a          cancers\/familial-risk-assessment-fra-boc\u000a\u000d      Amir E, Freedman OC, Seruga B, et al. (2010) Assessing Women at High\u000d        Risk of Breast Cancer: A Review of Risk Assessment Models. J Natl Cancer\u000d        Inst: 102: 680-691\u000d    \u000d    ","Title":"\u000d    Development of risk prediction algorithms for familial breast and\u000d        ovarian cancer and their use for genetic counselling and screening.\u000d    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    The defined impact: BOADICEA was developed by researchers (Antonis and\u000d      Easton) based in the Department of Public Health and Primary Care at\u000d      Cambridge in 2004 , which was underpinned by primary research carried out\u000d      over many years by Ponder. The large meta-analysis of BRCA 1 and 2\u000d      families ascertained through population based methods (1 - 3) and\u000d      performed by researchers at Cambridge formed the basis of development for\u000d      this clinical tool.\u000d    Sir Bruce Ponder (Professor of Human Cancer Genetics; 1993; Professor of\u000d      Oncology 1996 — present; Director, CRUK Cambridge Research Institute\u000d      2005-2013; Director, Cambridge Cancer Centre 2005-present) led efforts to\u000d      collect blood samples and clinical data on large numbers of high risk\u000d      families with breast cancer, and from 10,000 prevalent and incident cases\u000d      within the Anglian region. He did this because he realised that these\u000d      would be required to support the on-going scientific efforts to identify\u000d      the BRCA1 and 2 genes; and subsequently to define the clinico pathological\u000d      correlates of these mutations and also for GWAS to find other novel\u000d      predisposition alleles, which were more common, but less penetrant.\u000d      Consequently Ponder established the UK Consortium for Breast Cancer\u000d      Linkage (a national\/worldwide network of oncology specialists\/\u000d      researchers) and was the first chair of the International Consortium for\u000d      Breast and Ovarian cancer linkage (1989-1993). In order to carry out the\u000d      collection and genetic research on these large data sets he also\u000d      co-founded and was Director of the Strangeways Laboratories for Genetic\u000d      Epidemiology where much of the internationally leading work on the\u000d      genetics of breast, ovarian and prostate cancer has been done (1996 -\u000d      2008).\u000d    Work by Ponder and collaborators others refined the mapping of the BRCA1\u000d      gene within chromosome 17 q12-21 in 1994\/5 (4). In 1995, Ponder's\u000d      laboratory contributed to the linkage mapping that identified a second\u000d      susceptibility gene (BRCA2) within a 6-centimorgan interval on chromosome\u000d      13q12-13 (5, 6). Ponder's highly significant and ongoing research\u000d      contributions have led to over 150 high impact papers on breast cancer\u000d      genetics; 70 of them on BRCA1 and BRCA2, with over 20 of them cited\u000d      >100 times. Following the cloning of BRCA1 and 2 by MYRIAD Genetics in\u000d      Utah, Ponder and others led the work to define the penetrance and\u000d      clinic-pathological correlates of BRCA1 and BRCA2 mutations in familial\u000d      cancers of the breast, ovary and prostate in 1995 onwards, and also showed\u000d      the phenotype such cancers in familial cases (2) and the incidence of such\u000d      mutations in apparently sporadic cases (3). His more recent work sought to\u000d      uncover the mechanisms whereby the single nucleotide polymorphisms in the\u000d      genome (7, 8) that underpin the common genetic risk factors for breast\u000d      cancer, affect breast cell biology. He recently contributed critical\u000d      functional analysis to elucidation of the mechanism by which the SNP\u000d      rs554219 affects risk through altered regulation of cyclin D1, providing\u000d      new, generalizable, insights into the mechanisms by which risk SNPs have\u000d      their effects (9).\u000d    "},{"CaseStudyId":"29785","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The JAMA paper of 2002 had reported that although planned repeat\u000d\u000a      caesarean section was\u000d\u000a      associated with a lower risk of perinatal death during delivery, the\u000d\u000a      absolute risk of attempting\u000d\u000a      vaginal birth was lower than had previously been reported and was similar\u000d\u000a      to that of women in their\u000d\u000a      first pregnancy. Prior to this publication, much higher absolute risks of\u000d\u000a      death had been used for\u000d\u000a      counselling (e.g. see an editorial in NEJM 2001;345:54-55).\u000d\u000a      Following on from Smith's programme\u000d\u000a      of research, counselling both in the UK and internationally has moved to\u000d\u000a      quoting the much lower\u000d\u000a      rates reported first in the JAMA paper and confirmed in subsequent\u000d\u000a      analyses. The direct influence\u000d\u000a      of Smith's work is demonstrated by his results in the JAMA paper being\u000d\u000a      extensively discussed in\u000d\u000a      the RCOG Guideline.[1] The estimates of absolute risk from the JAMA paper\u000d\u000a      are presented in\u000d\u000a      Table 2 of the current US Guideline published in 2010.[2] The Canadian\u000d\u000a      guideline published in\u000d\u000a      2005 devotes a full paragraph to summarising the results of this paper.[3]\u000d\u000a      All three guidelines have\u000d\u000a      been current for all or part of the interval from 2008 to 2013.\u000d\u000a    The 2002 BMJ paper was the first to report an increased risk of perinatal\u000d\u000a      death among vaginally\u000d\u000a      delivered second twins at term in Scotland. The 2007 paper confirmed that\u000d\u000a      the same association\u000d\u000a      was present in England and Wales. The importance of Smith's research in\u000d\u000a      identifying the\u000d\u000a      increased risk for second twins is discussed in the NICE Guideline, CG132\u000d\u000a      Caesarean section\u000d\u000a      (2011).[4]\u000d\u000a    The Lancet paper of 2003 had reported an increased risk of stillbirth\u000d\u000a      among women with a previous\u000d\u000a      caesarean section and as a result of this research, there has been a\u000d\u000a      widespread change in the\u000d\u000a      counselling of women considering delivery by caesarean section, as\u000d\u000a      evidenced by changes in\u000d\u000a      clinical guidelines. For example, a whole paragraph is devoted to\u000d\u000a      describing the findings of this\u000d\u000a      paper in the 2011 NICE Guideline, CG132 Caesarean section (2011, page\u000d\u000a      180).[4] Another\u000d\u000a      practical consequence of this research was that among women with a\u000d\u000a      previous caesarean section,\u000d\u000a      it became possible to predict that there would be a significant risk of\u000d\u000a      antepartum stillbirth\u000d\u000a      associated with a decision to have a vaginal birth. Both the current RCOG\u000d\u000a      and ACOG Guidelines\u000d\u000a      comment on this risk.[1,2] Although this was seen as controversial at the\u000d\u000a      time (see\u000d\u000a      correspondence in Lancet 2004;363:402), the prediction was subsequently\u000d\u000a      confirmed by a large\u000d\u000a      scale US study by the NICHD Maternal-Fetal Medicine Units Network (Landon\u000d\u000a      et al NEJM\u000d\u000a      2004;351:2581-2589).\u000d\u000a    The 2004 BMJ paper was the first to report an increased risk of perinatal\u000d\u000a      death due to uterine\u000d\u000a      rupture associated with induction of labour using prostaglandins. These\u000d\u000a      findings are discussed in\u000d\u000a      detail in the current RCOG Guideline, Birth after previous caesarean\u000d\u000a      section (2007).[1] A whole\u000d\u000a      pararagraph is devoted to the results of this study in the NICE Guideline,\u000d\u000a      CG70 Induction of Labour\u000d\u000a      (2008).[5] The study has been less quoted internationally as different\u000d\u000a      prostaglandin preparations\u000d\u000a      tend to be used in North America.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Smith identified four novel findings around the relationship between\u000d\u000a      caesarean section and\u000d\u000a      perinatal death (i.e. stillbirth or neonatal death). 1. Vaginal birth\u000d\u000a      after previous caesarean had a low\u000d\u000a      absolute risk of death, but the risk was lower still with planned\u000d\u000a      caesarean delivery. 2. The second\u000d\u000a      twin had a higher risk of death at term. 3 Caesarean section was\u000d\u000a      associated with an increased\u000d\u000a      future risk of stillbirth. 4. Use of prostaglandins to induce labour in\u000d\u000a      women with a previous\u000d\u000a      caesarean increased the risk of death. The studies subsequently led to\u000d\u000a      changes in national and\u000d\u000a      international clinical guidelines, which remain current.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Cambridge\u000d\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Smith GC, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death\u000d\u000a      associated with labor after\u000d\u000a      previous cesarean delivery in uncomplicated term pregnancies. JAMA\u000d\u000a      2002;287:2684-90. [125\u000d\u000a      citations]\u000d\u000a    \u000a\u000a2. Smith GC, Pell JP, Dobbie R. Birth order, gestational age, and risk of\u000d\u000a      delivery related\u000d\u000a      perinatal death in twins: retrospective cohort study. BMJ 2002;325:1004.\u000d\u000a      [40 citations]\u000d\u000a    \u000a\u000a3. Smith GCS, Fleming K, White IR. Birth order of twins and the risk of\u000d\u000a      delivery-related perinatal\u000d\u000a      death in England, Northern Ireland and Wales, 1994-2003. BMJ 2007;334:576.\u000d\u000a      [30 citations]\u000d\u000a    \u000a\u000a4. Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of\u000d\u000a      unexplained stillbirth in\u000d\u000a      subsequent pregnancy. Lancet 2003;362:1779-84. [151 citations]\u000d\u000a    \u000a\u000a5. Smith GCS, Pell JP, Pasupathy D, Dobbie, R Factors predisposing to\u000d\u000a      perinatal death related to\u000d\u000a      uterine rupture during attempted vaginal birth after caesarean section:\u000d\u000a      retrospective cohort study.\u000d\u000a      BMJ 2004:329:375-377. [50 citations]\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000d\u000a    \u000d\u000a      Birth after previous caesarean section: Guideline No 45. Royal College\u000d\u000a        of Obstetricians &\u000d\u000a        Gynaecologists, London, UK. February 2007.\u000d\u000a        See http:\/\/www.rcog.org.uk\/files\/rcog-corp\/GTG4511022011.pdf\u000d\u000a        Note: although published in 2007, this guideline remained current from\u000d\u000a        July 2008 onwards and was\u000d\u000a        accessed on 25 July 2013 from the following site:\u000d\u000a        http:\/\/www.rcog.org.uk\/womens-health\/clinical-guidance\/birth-after-previous-caesarean-birth-green-top-45\u000a\u000d\u000a      The American College of Obstetricians and Gynecologists Practice\u000d\u000a        Bulletin: Vaginal birth after\u000d\u000a        previous cesarean delivery. Obstetrics & Gynecology 2010;116:450-463.\u000d\u000a      Society of Obstetrics and Gynecology, Canada, Guideline Guidelines for\u000d\u000a        Vaginal Birth After\u000d\u000a        Previous Caesarean Birth, number 155.\u000d\u000a        Note: although published in 2005, this guideline remained current from\u000d\u000a        July 2008 onwards and was\u000d\u000a        accessed on 25 July 2013 from the following site:\u000d\u000a        http:\/\/www.sogc.org\/guidelines\/public\/155E-CPG-February2005.pdf\u000a\u000d\u000a      National Institute of Clinical Excellence. CG132 Caesarean section.\u000d\u000a        November 2011.\u000d\u000a        See http:\/\/www.nice.org.uk\/nicemedia\/live\/13620\/57162\/57162.pdf\u000a\u000d\u000a      National Institute of Clinical Excellence. CG70. Induction of labour.\u000d\u000a        July 2008.\u000d\u000a        See http:\/\/www.nice.org.uk\/nicemedia\/live\/12012\/41255\/41255.pdf\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Caesarean section and the risk of perinatal death\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Gordon Smith, Department of Obstetrics & Gynaecology at\u000d\u000a      University of Cambridge from\u000d\u000a      1st September 2001, has had the risks and benefits of Caesarean section as\u000d\u000a      a major theme of his\u000d\u000a      research group. All of the research cited below was the result of Smith's\u000d\u000a      original ideas and he\u000d\u000a      initiated all the studies.\u000d\u000a    Smith's group's JAMA paper of 2002 [1] reported a high quality study of\u000d\u000a      over 300,000 births at term\u000d\u000a      which was the first to address the risk of perinatal death among women\u000d\u000a      with a previous caesarean\u000d\u000a      section which focused on delivery related deaths at term. Previous studies\u000d\u000a      had included deaths at\u000d\u000a      preterm gestational ages and deaths unrelated to mode of delivery and\u000d\u000a      their findings had been\u000d\u000a      extrapolated to inform the risks associated with vaginal birth at term.\u000d\u000a      However, Smith's research\u000d\u000a      was able to demonstrate that the inclusion of preterm losses and deaths\u000d\u000a      unrelated to mode of\u000d\u000a      delivery in previous studies led to two sources of error (i) an\u000d\u000a      overestimation of the absolute risk of\u000d\u000a      death with all modes of delivery, and (2) an underestimation of the\u000d\u000a      relative risk of death associated\u000d\u000a      with attempted vaginal delivery.\u000d\u000a    Smith's BMJ paper of 2002 [2] reported a high quality study of over 4,500\u000d\u000a      twin births using\u000d\u000a      nationally collected NHS data which was the first rigorous analysis of the\u000d\u000a      risk of death related to\u000d\u000a      birth order in twins. Previous studies had failed to confine analyses to\u000d\u000a      deaths which were truly\u000d\u000a      related to mode of delivery. Moreover, all previous large scale studies\u000d\u000a      had used statistical tests\u000d\u000a      which assumed statistical independence; i.e. there was an assumption that\u000d\u000a      the two twins were not\u000d\u000a      related and drawn at random from the population. Smith reported that this\u000d\u000a      assumption was self-evidently\u000d\u000a      flawed and the use of statistical tests based on this assumption resulted\u000d\u000a      in biased\u000d\u000a      (underestimated) risks to the second twin. The 2002 BMJ paper [1] reported\u000d\u000a      an increased risk of\u000d\u000a      death to the second twin using Scottish data, and subsequent research\u000d\u000a      published in the 2007 BMJ\u000d\u000a      paper [3] applied similar methods and confirmed the same finding in births\u000d\u000a      from England and\u000d\u000a      Wales.\u000d\u000a    Smith's Lancet paper of 2003 [4] was the first report of an association\u000d\u000a      between previous caesarean\u000d\u000a      section and future stillbirth, analysing ~120,000 second births in\u000d\u000a      Scotland, 1992-1998. The finding\u000d\u000a      was subsequently confirmed by analysis of the next 3 years of data\u000d\u000a      (1999-2001) from Scotland\u000d\u000a      (see Am J Epidemiol 2007;165:194-202), thus essentially eliminating the\u000d\u000a      possibility that Smith's\u000d\u000a      research published in the Lancet report was a chance finding. Further\u000d\u000a      research and meta-analyses\u000d\u000a      have also confirmed the association (Lancet. 2011;377:1331-40,\u000d\u000a      Supplementary Web Appendix &\u000d\u000a      PLoS One 2013;8(1):e54588).\u000d\u000a    Smith's group's research published in the BMJ paper of 2004 [5] was the\u000d\u000a      first to show that use of\u000d\u000a      prostaglandins to induce labour among women with a previous caesarean\u000d\u000a      section increased the\u000d\u000a      risk of delivery-related perinatal death. Moreover, it demonstrated that,\u000d\u000a      although rates of uterine\u000d\u000a      rupture among women with a previous caesarean section were similar in\u000d\u000a      different sized obstetric\u000d\u000a      units, delivery related perinatal death was more frequent in low\u000d\u000a      throughput units.\u000d\u000a    The above research involved some innovative methodologies. For example,\u000d\u000a      the 2003 Lancet paper\u000d\u000a      [3] described the first use of Cox proportional hazards modelling to\u000d\u000a      assess stillbirth risk and the\u000d\u000a      2002 BMJ paper [1] described the first use of conditional logistic\u000d\u000a      regression in the comparison of\u000d\u000a      death rates in first and second twins. These methods have been adopted in\u000d\u000a      multiple subsequent\u000d\u000a      studies by other researchers. Two of the five papers have been cited by\u000d\u000a      >100 subsequent\u000d\u000a      publications and the other three have been cited 30, 40 & 50 times,\u000d\u000a      which should be interpreted in\u000d\u000a      the context that the leading specialist journals in the field have impact\u000d\u000a      factors of ~4.\u000d\u000a    "},{"CaseStudyId":"29786","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    Impact of Newcastle research on patient survival and quality of life\u000a      The drug has led to a near doubling of patient survival rate (R3), which\u000a      was reported in two national and European guidelines. In 2010, the\u000a      European Society for Medical Oncology published Clinical Practice\u000a      Guidelines (EV a) that include R1 and R2, stating, \"The update of the\u000a        IRIS study has confirmed and extended the earlier results, reporting a\u000a        progression-free survival of 84% and an overall survival of 88% after 6\u000a        years.\"\u000a    These results are also reported in NICE Technology Appraisal 251 (EV b),\u000a      which states: \"Standard-dose imatinib is associated with improved\u000a        survival, with the latest results of the follow-up of the IRIS\u000a        (International Randomised Study of Interferon versus STI571) trial\u000a        (8-year follow-up) [R3] showing overall survival of 85%. After\u000a        the introduction of imatinib into routine clinical practice, 5-year\u000a        relative survival increased from 27.1% in 1990-92 to 48.7% in 2002-04,\u000a        for all age groups combined (p<0.0001)\".\u000a    A January 2013 report from the National Cancer Intelligence Network (EV\u000a      c) showed that deaths from CML in men reduced from 163 in 2001-2003 to 105\u000a      in 2006-2008. This report confirms that the increase in survival is due to\u000a      the introduction of imatinib: \"The improvement in prognosis seen is due\u000a        to the introduction of a new drug — Imatinib which was being used\u000a        increasingly to treat patients with CML.\"\u000a    According to a 2011 study (EV d), imatinib is well-tolerated and has few\u000a      side-effects. This study used the cancer-specific questionnaire FACT-BRM\u000a      (functional assessment of cancer therapy-biologic response modifiers) to\u000a      assess patient quality of life, including physical function and\u000a      well-being. The mean score increased significantly from 75.5 at baseline\u000a      to 85.2 at six months, where an increase of >5 represents a clinically\u000a      significant improvement. Scores for fatigue, emotional and cognitive\u000a      dysfunction and side effects all decreased significantly from baseline to\u000a      six months.\u000a    Impact of Newcastle research on guidelines\u000a      The use of imatinib is recommended in two European guidelines and UK-wide\u000a      NICE guidelines. Clinical Practice Guidelines from 2010 (EV a), published\u000a      by the European Society for Medical Oncology, (ESMO) state \"On the\u000a        basis of a randomized trial of imatinib... (IRIS study, [R1, 2]), imatinib\u000a        400 mg daily has been established as standard, frontline treatment of\u000a        all patients with CP CML.\" The updated ESMO guidelines from 2012 (EV\u000a      e) directly cite R1 and R2 as two of the \"high quality reports of phase\u000a        2 and phase 3 studies, single-arm, and randomized, that have been\u000a        published in peer-reviewed journals over the last 10 years\" that\u000a      inform the guidelines: of these, R1 was the first to be published. These\u000a      guidelines recommend imatinib, stating \"Imatinib was the first TKI to\u000a        be used and is still the gold standard of first-line treatment\u000a        worldwide.\"\u000a    Imatinib is recommended in NICE Technical Appraisal 251 (EV f), published\u000a      in April 2012. The evidence that informs this report includes two papers\u000a      (Saglio et al., DOI: 10.1056\/NEJMoa0912614 and Kantarjian et\u000a        al. DOI: 10.1056\/NEJMoa1002315 both 2010 N Eng J Med) that\u000a      are based on Newcastle research: the former cites R2, and the latter cites\u000a      both R1 and R2.\u000a    The Technical Appraisal states:\u000a    \u000a      \"...the progression of CML can be slowed by imatinib. Imatinib\u000a          produces high rates of remission in the chronic phase.\" (pg 3)\u000a      \"The primary outcome was complete cytogenetic response within 12\u000a          months.\" (pg 10)\u000a      \"The primary outcome was major molecular response at 12 months.\u000a          Secondary outcomes included complete cytogenetic response by 12\u000a          months.\" (pg 11, from Saglio et al.)\u000a      \"Standard-dose imatinib is recommended as an option for the\u000a          first-line treatment of adults with chronic phase\u000a          Philadelphia-chromosome-positive chronic myeloid leukaemia (CML),\"\u000a        (pg 53, from Kantjarian et al.)\u000a    \u000a    In summary, Newcastle research found that imatinib had a higher\u000a      cytogenetic response and was better tolerated than the previous standard\u000a      of care. This work almost doubled five-year survival rates, improved\u000a      patient quality of life and adoption of the drug into guidelines.\u000a    ","ImpactSummary":"\u000a    A new class of drug known as tyrosine kinase inhibitors for the treatment\u000a      of chronic myeloid leukemia (CML) has been tested in Newcastle-led\u000a      international clinical trials. One of these drugs, imatinib, was found to\u000a      almost double five-year survival rates and significantly improve quality\u000a      of life with few side effects. Subsequent follow up studies found an\u000a      estimated eight-year overall survival of 85%. Imatinib is now recommended\u000a      in national and international guidelines and is used increasingly to treat\u000a      patients with CML.\u000a    ","ImpactType":"Health","Institution":"\u000a    Newcastle University\u000a    ","Institutions":[{"AlternativeName":"Newcastle upon Tyne (University of)","InstitutionName":"Newcastle University","PeerGroup":"A","Region":"North East","UKPRN":10007799}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (Scopus citation data as at July 2013, Newcastle researchers in bold)\u000a    \u000aR1. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M,\u000a      Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K,\u000a      Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B,\u000a      Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE,\u000a      Capdeville R, Druker BJ. Imatinib Compared with Interferon and Low-Dose\u000a      Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia.\u000a      2003. The New England Journal of Medicine. 348 (11):994-1004. DOI:\u000a      10.1056\/NEJMoa022457. Citation count 1746\u000a    \u000a\u000aR2. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H,\u000a      Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F,\u000a      Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen\u000a      JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl\u000a      A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak\u000a      L, Larson RA. Five-year follow-up of patients receiving imatinib for\u000a      chronic myeloid leukemia. 2006. The New England Journal of Medicine\u000a      355(23):2408-17. DOI: 10.1056\/NEJMoa062867. Citation count 1440.\u000a    \u000a \u000a    Newcastle contribution: Professor O'Brien was heavily involved in\u000a      the design of the original study, recruited patients and contributed data.\u000a      Crucially, together with Professors Druker, Guilhot and Larson, he was\u000a      part of the Study Management Committee (SMC) for this trial. The SMC\u000a      managed to study and approved all crossovers.\u000a    \u000aR3. Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A,\u000a      Hughes TP, Radich JP, Hatfield AK, Mone M, Filian J, Reynolds J, Gathmann\u000a      I, Larson RA, Druker BJ. International Randomized Study of Interferon Vs\u000a      STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for\u000a      Progression or Events in Patients with Newly Diagnosed Chronic Myeloid\u000a      Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. 2009. Blood:\u000a      51st Annual Meeting of the American Society of Hematology. 114 (22): 462.\u000a      Peer-reviewed conference abstract. https:\/\/ash.confex.com\/ash\/2009\/webprogram\/Paper23968.html.\u000a    \u000aNewcastle contribution: Prof O'Brien was heavily involved in the\u000a      design of the original study, recruited patients and contributed data.\u000a      Together with the other authors of the SMC, Professor Deininger and\u000a      colleagues from Novartis, Professor O'Brien led the data analysis for this\u000a      abstract\/presentation.\u000a    \u000aR4. Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda J, Foroni L,\u000a      Druker BJ, Guilhot F, Larson RA, O'Brien SG, Rudoltz MS, Mone M,\u000a      Wehrle E, Modur V, Goldman JM, Radich JP. Long-term prognostic\u000a      significance of early molecular response to imatinib in newly diagnosed\u000a      chronic myeloid leukemia: an analysis from the International Randomized\u000a      Study of Interferon and STI571 (IRIS). 2010. Blood 116: 3758-3765. DOI:\u000a      10.1182\/blood-2007-10-116475 Citation count 133.\u000a    \u000aNewcastle contribution: Prof O'Brien was heavily involved in the\u000a      design of the original study, recruited patients and contributed data. As\u000a      above, he was a member of the SMC who contributed to the data analysis,\u000a      presentation and manuscript writing and revision.\u000a    Relevant funding awards\u000a    • The work was supported by ten awards from Novartis Pharmaceuticals UK,\u000a      totalling £752,179\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    EV a. Baccarani M and Dreyling M. (2010). Chronic myeloid leukaemia: ESMO\u000a      Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals\u000a        of Oncology. 21 Suppl 5:v165-7. doi: 10.1093\/annonc\/mdq201.\u000a      http:\/\/annonc.oxfordjournals.org\/content\/21\/suppl_5\/v165.full.pdf\u000a    EV b. NICE Technology Appraisal Guidance 251 April 2012.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/13716\/58911\/58911.pdf\u000a    EV c. National Cancer Intelligence Network report January 2013.\u000a      www.ncin.org.uk\/view?rid=1787\u000a    EV d. Aziz Z, Iqbal J, Aaqib M, Akram M, Saeed A. (2011) Assessment of\u000a      quality of life with imatinib mesylate as first-line treatment in chronic\u000a      phase-chronic myeloid leukemia. Leukaemia and lymphoma.\u000a      52(6):1017-23. doi: 10.3109\/10428194.2011.560310.\u000a    EV e. Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling\u000a      M. (2012). Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for\u000a      diagnosis, treatment and follow-up. Annals of Oncology. Suppl\u000a      7:vii72-7. doi:10.1093\/annonc\/mds228.\u000a      http:\/\/annonc.oxfordjournals.org\/content\/23\/suppl_7\/vii72.full.pdf+html\u000a    EV f. NICE technology appraisal guidance 241 January 2012.\u000a      http:\/\/publications.nice.org.uk\/dasatinib-nilotinib-and-standard-dose-imatinib-for-the-first-line-treatment-of-chronic-myeloid-ta251\/evidence-and-interpretation\u000a    ","Title":"\u000a    Innovations in the treatment of chronic myeloid leukemia have almost\u000a      doubled 5-year survival rates.\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Key Newcastle research staff\u000a      Professor Stephen O'Brien was the sole member of Newcastle University\u000a      research staff involved. He was senior lecturer 1999-2010, and Clinical\u000a      Professor of Haematology from 2010 to date.\u000a    The challenge of chronic myeloid leukaemia\u000a      Chronic myeloid leukaemia (CML), a cancer of the white blood cells, is\u000a      characterised by overproduction of myeloid cells in the bone marrow. In\u000a      around 90% of cases, it is caused by a genetic fault known as the\u000a      Philadelphia chromosome, where the ABL gene is inadvertently translocated\u000a      to the BCR gene on another chromosome, creating the fusion gene BCR-ABL, a\u000a      dysregulated tyrosine kinase responsible for the disease (see R1).\u000a    CML is relatively rare, with a prevalence of 2500 new cases a year in\u000a      England (EV f). It is often asymptomatic or presents with generic symptoms\u000a      such as weight loss and headaches. As a consequence, CML is often only\u000a      diagnosed as a result of a blood test. At the onset of research described\u000a      below, the prognosis for the disease was relatively poor, with a five-year\u000a      survival rate of 57% in patients given interferon alpha plus cytarabine\u000a      (see R1). The only cure is bone marrow transplant, but this carries\u000a      substantial risks and, in any event, is an option in only 25% of patients\u000a      (see R1).\u000a    The development of imatinib\u000a      Clinical development of tyrosine kinase inhibitors (TKIs) directed at the\u000a      cancer-causing gene BCR-ABL began in the 1990s. The first phase 3 trial\u000a      was the IRIS trial (ClinicalTrials.gov number NCT00006343). Professor\u000a      Stephen O'Brien was the lead investigator for this study, which was\u000a      conducted in 106 centres in 16 countries. The first paper to be published\u000a      (R1) compared imatinib to interferon alpha plus cytarabine (the previous\u000a      standard of care) in 1106 patients. As well as being better tolerated,\u000a      imatinib produced significantly higher rates of cytogenetic response,\u000a      where the Philadelphia chromosome disappears (87.1% vs 34.7%). A five-year\u000a      follow up study (R2) found an estimated 89% survival rate at 60 months,\u000a      with few side effects. The eight-year follow-up study (R3) found that 92%\u000a      of patients given imatinib and who continued treatment were free from\u000a      progression to accelerated-phase or blast crisis phase, and overall\u000a      survival was estimated to be 85%; if causes of death other than CML are\u000a      excluded, then overall survival was estimated to be 93% at eight years.\u000a    Further work (R4) investigated the link between eventual outcome and\u000a      early response to imatinib. Results showed that a major cytogenetic\u000a      response — where bone marrow cells have returned to normal and no longer\u000a      have the Philadelphia chromosome — was predictive of long-term event-free\u000a      survival. Specifically, patients who achieved major cytogenetic response\u000a      within 18 months showed no progression to the advanced phases of CML, and\u000a      seven-year event-free survival was 95% in these patients.\u000a    "},{"CaseStudyId":"29787","Continent":[],"Country":[],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Direct impact on patient management\u000a    The MRC high-risk PT-1 study (NEJM 2005) remains the world's largest\u000a      randomised study of any\u000a      MPN, defined first line therapy for patients with essential\u000a      thrombocythemia and has been widely\u000a      acknowledged as having had a major influence on the management of ET\u000a      patients around the\u000a      world (e.g. refs 1-4). Prior to the PT-1 trial, only a single much smaller\u000a      randomised study of\u000a      patients with ET had been reported, and this compared hydroxyurea with no\u000a      cyto-reductive\u000a      therapy. The approval of anagrelide by the FDA was having a major effect\u000a      on prescribing patterns,\u000a      with many clinicians using it as first line therapy despite the absence of\u000a      randomised trial data.\u000a      Publication of the results of the PT-1 trial firmly established\u000a      hydroxyurea plus aspirin as first line\u000a      therapy for patients with ET and a high risk of thrombosis (refs 1-6). The\u000a      trial also demonstrated\u000a      that anagrelide was less effective at reducing thrombosis than\u000a      hydroxyurea, and was much less\u000a      well tolerated, with twice as many patients withdrawing from treatment\u000a      because of side effects.\u000a      Importantly the PT-1 results showed that anagrelide increases the risk of\u000a      myelofibrotic\u000a      transformation and so, when anagrelide is used as a second-line agent, it\u000a      is now recognised that\u000a      patients need regular bone marrow trephine biopsies to look for the\u000a      development of myelofibrosis.\u000a      This trial defined hydroxyurea and aspirin as first line therapy, an\u000a      outcome that is estimated to\u000a      have saved the NHS over £22M per year in drug costs (based on cost of\u000a      Anagrelide and\u000a      hydroxyurea in 2005) and has influenced management of ET worldwide. The\u000a      central role of the PT-\u000a      1 study in defining current first-line therapy is described in multiple\u000a      reviews (refs 1-4) and its\u000a      findings were embedded in current national and international guidelines\u000a      (e.g. refs 5 and 6) in 2010\u000a      and 2011, that remain current.\u000a    Impact on classification and diagnosis\u000a    Essential thrombocythemia has long been recognised to be a heterogeneous\u000a      entity which overlaps\u000a      with other MPNs, particularly polycythemia vera (PV) and primary\u000a      myelofibrosis, but the\u000a      demarcation between these various disorders was unclear. This led to\u000a      difficulties in classifying\u000a      individual patients and in determining optimum therapy. The banking of\u000a      samples from the\u000a      beginning of the PT-1 trial in 1997 combined with the collection of\u000a      comprehensive prospective\u000a      clinical data, generated a unique resource for studying the\u000a      classification, diagnosis and\u000a      pathogenesis of ET. Multiple studies by University of Cambridge\u000a      researchers have utilised this\u000a      resource over the past seven years, and the insights thus gained have\u000a      altered the way ET is\u000a      classified and how it is distinguished from other MPNs. Particular\u000a      highlights with practical impact\u000a      include: (i) the demonstration that JAK2 mutation status (now a routine\u000a      diagnostic test; for\u000a      example of usage see ref 7) identifies two distinct subtypes of ET with\u000a      JAK2 mutation-positive\u000a      patients resembling a forme fruste of PV - the realisation that\u000a      JAK2-mutant ET forms a phenotypic\u000a      spectrum with PV has led to simpler diagnostic algorithms that are\u000a      embedded in guidelines (e.g.\u000a      refs 5 and 6); (ii) the results of the PT1 trial also led to the concept\u000a      that primary myelofibrosis in\u000a      fact represents patients presenting in accelerated phase of an occult\u000a      undiagnosed MPN; (iii) the\u000a      demonstration that the WHO category \"prefibrotic myelofibrosis\" is not\u000a      clearly distinguished from\u000a      ET and may not exist as a distinct entity has resulted in a reduced\u000a      requirement for bone marrow\u000a      trephine histology in the BCSH diagnostic guidelines (ref 5); (iv) the\u000a      demonstration that LDH levels\u000a      are not useful in distinguishing ET from primary myelofibrosis; (v) the\u000a      demonstration that reticulin\u000a      levels provide an important prognostic marker in ET.\u000a    ","ImpactSummary":"\u000a    Essential thrombocythemia (ET) is a pre-leukaemic chronic\u000a      myeloproliferative neoplasm (MPN) the\u000a      management of which had been hampered by a lack of prospective randomised\u000a      studies. Professor\u000a      Green (University of Cambridge Department of Haematology) was Chief\u000a      Investigator for the MRC\u000a      primary thrombocythemia-1 (PT-1) study, initiated in 1997, which compared\u000a      hydroxyurea plus\u000a      aspirin with anagrelide plus aspirin in patients with ET at high risk of\u000a      thrombosis. This clinical trial\u000a      remains the world's largest randomised study of any MPN and its results\u000a      demonstrated that\u000a      hydroxyurea plus aspirin should be first line therapy, a result embedded\u000a      in current guidelines. This\u000a      outcome had a major effect on the world-wide use of anagrelide for\u000a      patients with ET and is\u000a      estimated to have saved the NHS over £22M per year in drug costs since the\u000a      results of the trial\u000a      were published in the NEJM.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Reference to research:\u000a    \u000a1. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D,\u000a      Wilkins BS, van der\u000a      Walt JD, Reilly JT, Grigg, AP Revell P, Woodcock BE, Green AR.\u000a      Hydroxyurea compared\u000a      with anagrelide in high-risk essential thrombocythemia. N Engl J Med\u000a      353: 33-45, 2005.\u000a    \u000a\u000a2.Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, Duffy\u000a      A, Boyd EM, Bench\u000a      AJ, Scott MA, Vassiliou GS, Milligan DW, Smith SR, Erber WN, Bareford D,\u000a      Wilkins BS, Reilly\u000a      JT, Harrison CN, Green AR. Definition of subtypes of essential\u000a      thrombocythaemia and\u000a      relation to polycythaemia vera based on JAK2 V617F mutation status: a\u000a      prospective study.\u000a      Lancet 366: 1945-1953, 2005.\u000a    \u000a\u000a3. Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ, Erber\u000a      WN, Kusec R,\u000a      Larsen TS, Giraudier S, Le Bousse-Kerdiles MC, Griesshammer M, Reilly JT,\u000a      Cheung BY,\u000a      Harrison CN and Green AR. Mutation of JAK2 in the\u000a      myeloproliferative disorders: timing,\u000a      clonality studies, cytogenetic associations and role in leukemic\u000a      transformation. Blood 108\u000a      (10): 3548-3555, 2006.\u000a    \u000a\u000a4. Wilkins BS, Erber WN, Bareford D, Buck G, Wheatley K, East CL, Paul B,\u000a      Harrison CN, Green\u000a        AR*, Campbell PJ*. Bone marrow pathology in essential\u000a      thrombocythemia: interobserver\u000a      reliability and utility for identifying disease subtypes. Blood,\u000a      111: 60-70, 2008. (*joint\u000a        authors).\u000a    \u000a\u000a5. Campbell PJ, Bareford D, Erber WN, Wilkins BS, Wright P, Buck G,\u000a      Wheatley K, Harrison CN,\u000a      Green AR. Reticulin accumulation in essential thrombocythemia:\u000a      prognostic significance and\u000a      relationship to therapy. J Clin Oncol, 27: 2991-2999 2009.\u000a    \u000a\u000a6. Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D,\u000a      Wilkins BS, Reilly JT,\u000a      Hasselbalch HC, Bowman R, Wheatley K, Buck G, Harrison CN, Green AR.\u000a      MPL mutations in\u000a      myeloproliferative disorders: analysis of the PT-1 cohort. Blood,\u000a      112: 141-149, 2008.\u000a    \u000aResearch grant support:\u000a    LLR programme grant funding held continually since 1997 by Professor\u000a      Green.\u000a      Most recent renewal 01.04.2008-31.03.2013, Molecular pathogenesis of\u000a      myeloproliferative\u000a      disorders, £2,230,206.\u000a    LLS Specialized Center of Research held continually by Professor Green\u000a      since 2006.\u000a      Most recent renewal with co-applicants Dr B Huntly, Dr B Gottgens & Dr\u000a      P Campbell 01.10.2011 -\u000a      30.09.2016, $6,250,000.\u000a    CRUK grant funding to support PT-1 held continually by Professor Green\u000a      since 2007.\u000a      Most recent CRUK CTAAC 01.05.2008-31.03.2013, A collaborative study of\u000a      myeloproliferative\u000a      disorders (COSMYD) (with Dr PJ Campbell, MF McMullin, CN Harrison, K\u000a      Wheatley), £462,865.\u000a    The Kay Kendall Leukaemia Fund, 01.09.2009-31.08.2012. Genome-wide\u000a      characterization of\u000a      somatic mutation in acute lymphoblastic leukaemia and myeloproliferative\u000a      disorders (with co-\u000a      applicants Professor M Greaves and Dr PJ Campbell). £1,632,075.\u000a    Cancer Research UK, project grant to Professor Green,\u000a      01.10.2011-30.09.2014. Investigation of\u000a      interaction between germline and somatic genetics at the JAK2 locus in\u000a      myeloproliferative\u000a      neoplasms. £240,279\u000a    MRC support for PT-1 Clinical Trial, to Professor Green and Dr C\u000a      Harrison, 01.05.2004 -\u000a      30.04.2006. £103,612\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    Reviews that corroborate the impact of this research on clinical\u000a        practice:\u000a    \u000a      Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia\u000a        vera and essential\u000a        thrombocythemia. Blood Rev, 26(5): 205-211, 2012.\u000a      Cervantes F. Management of essential thrombocythemia. Hematology AmSoc\u000a        Hematol Educ\u000a        Program 2011: 215-221, 2011.\u000a      Levine RL and Gilliland DG. Myeloproliferative disorders. Blood,\u000a        112(6): 2190-2197, 2008.\u000a      Tefferi A. Polycythemia vera and essential thrombocythemia: 2012\u000a        update on diagnosis, risk\u000a        stratification and management. Am J Hematol, 87: 285-293, 2012\u000a    \u000a    Guidelines that corroborate the impact of this research on clinical\u000a        practice:\u000a    \u000a    \u000a      \u000a      Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M,\u000a        Erber W, Everington\u000a        T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy C,\u000a        Radia DH, Reilly JT, Van\u000a        der Walt J, Wilkins B, McMullin MF; British Committee for Standards in\u000a        Haematology. Guideline\u000a        for investigation and management of adults and children presenting with\u000a        a thrombocytosis. Br J\u000a        Haematol, 149(3): 352-375, 2010\u000a      Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer\u000a        M, Harrison C,\u000a        Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kröger N, Mesa R,\u000a        McMullin MF,\u000a        Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek\u000a        S, Tefferi A.\u000a        Philadelphia-negative classical myeloproliferative neoplasms: critical\u000a        concepts and management\u000a        recommendations from European LeukemiaNet. J Clin Oncol, 29(6): 761-770,\u000a        2011.\u000a      http:\/\/www.nbt.nhs.uk\/sites\/default\/files\/filedepot\/incoming\/JAK2_V617F_and_Exon_12_Service_at_BGL.pdf\u000a    \u000a    ","Title":"\u000a    Defining first line therapy for high risk essential thrombocythemia\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Green (Department of Haematology, University of Cambridge\u000a      1991-date) has been chief\u000a      investigator for the PT-1 suite of clinical trials since their inception\u000a      in 1997, a role initially shared\u000a      with Professor Tom Pearson and, following his retirement, with Dr Claire\u000a      Harrison (both Dept of\u000a      Haematology, St Thomas' Hospital). The study of patients at high risk of\u000a      thrombosis remains the\u000a      world's largest randomised trial of any MPN, having recruited over 800\u000a      patients from 138 centres in\u000a      three countries. Low and intermediate risk PT-1 studies (also led by\u000a      Professor Green) have been\u000a      on-going since, each representing the world's largest study in their\u000a      respective risk categories.\u000a    Prior to the high-risk PT-1 trial (NEJM 2005), use of the inexpensive\u000a      drug hydroxyurea was being\u000a      widely replaced by the newer and considerably more expensive drug\u000a      anagrelide, an agent which\u000a      selectively blocks megakaryocyte differentiation. Anagrelide had received\u000a      FDA approval despite\u000a      lack of evidence of efficacy from a randomised trial. Professor Green\u000a      negotiated a subvention from\u000a      the Department of Health to support the considerable additional drug costs\u000a      associated with a\u000a      randomised comparison of hydroxyurea with anagrelide. This multicentre\u000a      study opened in 1997\u000a      and closed in 2003. The primary end point was the risk of arterial\u000a      thrombosis, venous thrombosis,\u000a      serious haemorrhage or death from thrombotic or haemorrhagic causes. The\u000a      results were\u000a      presented in a plenary talk by Professor Green at the American Society of\u000a      Hematology in 2004 and\u000a      were published in the New England Journal of Medicine the following year\u000a      (ref 1). The results\u000a      demonstrated a clear superiority for hydroxyurea plus aspirin in that\u000a      anagrelide plus aspirin was\u000a      associated with higher rates of arterial thrombosis, serious haemorrhage,\u000a      transformation to\u000a      myelofibrosis and treatment withdrawal. This trial defined hydroxyurea and\u000a      aspirin as first line\u000a      therapy.\u000a    A substantial body of work from the Green lab has utilised samples and\u000a      clinical data from patients\u000a      enrolled in PT-1, and has generated additional insights into the\u000a      classification, diagnosis and\u000a      management of ET. These include the demonstration that (i) JAK2 mutation\u000a      status identifies two\u000a      distinct sub-types of ET (ref 2), (ii) transformation to acute myeloid\u000a      leukaemia is frequently\u000a      associated with unexpected `loss' of the JAK2 mutation, an observation\u000a      thought to reflect the\u000a      existence of a `pre-JAK2' phase of disease (e.g. ref 3); (iii) the concept\u000a      that prefibrotic\u000a      myelofibrosis is an entity distinct form ET is of questionable utility\u000a      since diagnostic criteria cannot\u000a      be applied reproducibly (refs 4 and 5); (iv) MPL mutations define a subset\u000a      of ET patients with\u000a      clinico-pathological features distinct to those with JAK2\u000a      mutation-positive ET (ref 6); (v) a haplotype\u000a      including the JAK2 locus itself accounts for much of the inherited\u000a      predisposition to JAK2 mutation-\u000a      negative as well as JAK2 mutation-positive MPNs.\u000a    "},{"CaseStudyId":"29792","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Research by Cox and collaborators has led to i) innovative therapy for\u000a      glycosphingolipidoses now approved for Gaucher's disease and Niemann-Pick\u000a      type C disease, UK\/worldwide, ii) further adoption of this strategy in\u000a      Phase 3 clinical trials iii) development of novel monitoring and\u000a      diagnostic tests for managing Gaucher's disease — adopted by the NHS and\u000a      international clinical trials.\u000a    Impact on health and welfare\u000a      New clinical interventions: After Cox's paper in the Lancet (2000)\u000a      on the efficacy of miglustat in adults with Gaucher's disease, with a\u000a      2-year extension phase, Oxford Glycosciences gained approval as (Zavesca®)\u000a      in 2002 and 2003 from the EMA and FDA for Gaucher Disease; the drug was\u000a      acquired by Actelion in 2005. The suggestion by Cox (Lancet 2000), that\u000a      the therapy warranted exploration in other glycosphingolipid disorders,\u000a      prompted trials by Actelion (2002-2008; NCT00517153) in Niemann Pick type\u000a      C disease; ultimately leading to approval of miglustat (in the UK\/ world)\u000a      for both conditions [1, 2]. Cox has also led post-marketing studies into\u000a      the efficacy of miglustat for disease maintenance in Gaucher disease [3].\u000a      Cox is currently lead investigator of the multinational Phase 3 \"ENCORE\"\u000a      trial (sponsored by Genzyme) for the compound eliglustat with the same\u000a      therapeutic target in Gaucher disease (NST00943111); early results (9th\u000a      Annual Lysosomal Disease Network WORLD Symposium in Orlando, Florida\u000a      February 2013), show that this study has met its primary efficacy endpoint\u000a      [4].\u000a      Novel diagnostics: After showing that high concentrations of\u000a      CCL18\/PARC in Gaucher disease decreased after treatment; this biomarker\u000a      was incorporated into NHS's Standard Operating Procedures (2007 updated\u000a      2012) for determining disease severity and treatment success [5] The\u000a      chemokine is now in widespread use and is a primary outcome in therapeutic\u000a      trials where it is used as a response marker and to compare competing\u000a      preparations e.g. velaglucerase alfa and imiglucerase (for example see ref\u000a      6)\u000a      Impact on society, culture, creativity\u000a      Public understanding and debate: Professor Cox has been actively\u000a      engaged in raising awareness of lysosomal disorders amongst both the\u000a      general public and patient groups and their families so that they may\u000a      better understand the aetiology and management of these disorders. He made\u000a      a presentation interview with The Naked Scientists (BBC radio programme;\u000a      19th April 2011), regarding gene therapy for lysosomal diseases attracted\u000a      approximately 55,000 downloads worldwide with an equivalent audience\u000a      estimated for the live radio show (The Naked Scientists, personal\u000a      communication; Ref 7). Cox frequently communicates with charitable patient\u000a      organizations to apprise them of advancements in the field. He hosted a\u000a      WebEx (20th May 2013) for the UK Gaucher Association. On 14th\u000a      October 2012 delivered the 17th McFadzean Oration at the Hong Kong College\u000a      of Physicians on the funding of treatment for rare disorders such as\u000a      Gaucher disease was delivered to a multi-faculty audience of practitioners\u000a      during the principal training days of the Hong Kong Academy of Medicine.\u000a      In 2011 he helped start the UK Cure Tay-Sachs Foundation (Patron) and\u000a      interacts with the National Tay-Sachs and Allied diseases Foundation,\u000a      Boston USA through the Tay-Sachs Gene Therapy (TSGT) Consortium, which was\u000a      founded on the discoveries of the Cox group in gene transfer.\u000a      Impact on commerce\u000a      New product development and business performance: Firstly,\u000a      publication of the Lancet (2000) article (ref 2, section 3) and marketing\u000a      of Zavesca® by Oxford Glycosciences reduced the stock value of Genzyme\u000a      corporation which had the exclusive market for Cerezyme, the enzyme\u000a      therapy for Gaucher disease [8]. This drove Genzyme to forge an academic\u000a      partnership to develop other orally active UDP-glucosylceramide synthase\u000a      inhibitor molecules — thus generating the licensed eligustat tartrate\u000a      programme with late-phase 3 clinical trials in Gaucher disease. Secondly,\u000a      approval of the drug miglustat, facilitated for Oxford GlycoSciences by\u000a      the research of Cox, Lachmann (Clinical Research Fellow) in Cambridge and\u000a      FM Platt and T Butters (cell biologist and biochemist in Oxford) and\u000a      colleagues has brought substantial revenue; the Actelion website citing\u000a      sales figures of approximately CHF20m (Swiss franc) per quarter since 2012\u000a      [9]. Thirdly, the assay for CCL18\/PARC, mentioned above, based on ELISA,\u000a      sold by R&D systems (product DY394; £450 per kit) whose website cites\u000a      Cox TM et al. as evidence for use as a biomarker of Gaucher\u000a      disease.\u000a      Academic consultancy: Beyond senior academic and clinical roles Cox\u000a      is specialist advisor to several organisations (including: charities\u000a      (Gaucher Association. Cure Tay-Sachs, Tay-Sachs Gene Therapy Consortium\u000a      and pharmaceutical companies (trial design, regulatory issues). He is a\u000a      member of the Scientific (Rare diseases) Board of Genzyme-Sanofi (2013-)\u000a      and has advised EMA (marketing approval and trial design for aldurazyme\u000a      (for MPS1), Replagal (for Fabry disease), miglustat and velaglucerase\u000a      alpha (Gaucher disease) — and on Clinical use of Biomarkers workshop of\u000a      the Food & Drug administration, Washington DC (2011) Through\u000a      membership of the TSGT consortium he advised the US Food and Drug\u000a      Administration on the design of a Clinical trial of Gene Therapy. Cox is\u000a      chairman of the Scientific Advisory board of the Niemann-Pick Research\u000a      Foundation.\u000a      Impact on practitioners and services\u000a      Professional standards and guidelines: Cox's research has directly\u000a      introduced miglustat as second-line therapy in adults with Type 1 Gaucher\u000a      disease, for whom enzyme replacement therapy is not suitable. His research\u000a      into biomarkers has directly led to the incorporation of the CCL18\/PARC\u000a      diagnostic test into the NHS SOP for management of this disorder, as above\u000a      [5]. Miglustat is the first and only licensed therapy for children and\u000a      adults with Niemann-Pick disease type C [1].\u000a      Professional training: Cox's paper entitled \"Gaucher disease:\u000a      clinical features and natural history\" (1997) continues to have impact on\u000a      healthcare practitioners in their understanding of the disease. The paper\u000a      is currently cited on the Gaucher Care website as a source of information\u000a      to aid healthcare professionals in making a diagnosis [10].Professor Cox\u000a      has frequently lectured at training courses for metabolic clinicians in\u000a      the University of Mainz from 2006, and from 1996 the biennial European\u000a      Working Group for the Study of Lysosomal diseases (ESGLD) as well as the\u000a      Gaucher leadership forum (2008-) - all targeted to healthcare\u000a      professionals looking to develop improved management protocols and\u000a      innovative therapies. Professor Cox is joint Editor (2003-) of the\u000a      three-volume Oxford Textbook of Medicine, 5th edition OUP\u000a      (2010) - the most comprehensive work of its kind with international sales\u000a      ~10,000.\u000a      Professional Services; In 1997 Professor Cox founded the first\u000a      National Gaucher service at Addenbrooke's Hospital, Cambridge (now the\u000a      Lysosomal Disorders Unit [11]), paving the way for a further seven\u000a      National Centres by 2005. The Unit continues to provide a unique service\u000a      of clinical management and support that is essential for patients with\u000a      these disorders, and for their families.\u000a    ","ImpactSummary":"\u000a    Research conducted by Professor TM Cox has led to several advances in the\u000a      management of lysosomal storage disorders; i) development of miglustat\u000a      (Zavesca®); now available throughout the world (EMA and FDA approved) for\u000a      adult patients with Gaucher's disease and throughout the European Union\u000a      and five other countries worldwide for adult and pediatric patients with\u000a      Niemann- Pick type C disease, ii) development of the potential successor\u000a      eliglustat; now in Phase 3 clinical trials, iii) identification of a\u000a      biomarker for Gaucher's: CCL18\/PARC, now incorporated into NHS standard\u000a      operating procedures for monitoring therapeutic intervention. His\u000a      pre-clinical research into gene therapy for Tay-Sachs disease also helped\u000a      establish the NIH-funded Gene Therapy Consortium and gain the FDA's\u000a      pre-IND approval for clinical trials in 2013, which together have raised\u000a      public awareness of this disease.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4930956","Name":"Boston"},{"GeoNamesId":"1819729","Name":"Hong Kong"}],"References":"\u000a    \u000a1) Mistry PK, Wraight EP, Cox TM (1996).Therapeutic delivery of\u000a      proteins to macrophages: implications for treatment of Gaucher's disease.\u000a      Lancet; 348: 1555-9. DOI: 10.1016\/S0140- 6736(96)04451-0\u000a    \u000a\u000a2) Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebícek M,\u000a      Platt F, Butters T, Dwek R, Moyses C, Gow I, Elstein D, Zimran A (2000).\u000a      Novel oral treatment of Gaucher's disease with N- butyldeoxynojirimycin\u000a      (OGT 918) to decrease substrate biosynthesis. Lancet; 355: 1481-5. DOI:\u000a      10.1016\/S0140-6736(00)02161-9\u000a    \u000a\u000a3) Lachmann, RH, te Vruchte, D., Lloyd-Evans E, Reinkensmeier G,\u000a      Sillence DJ, Fernandez Guillen L., Dwek RA., Butters TD, Cox TM, Platt FM\u000a      (2004). Treatment with miglustat reverses the lipid- trafficking defect in\u000a      Niemann-Pick disease type C. Neurobiology of Disease 16: 654-658. DOI:\u000a      10.1016\/j.nbd.2004.05.002\u000a    \u000a\u000a4) Boot R.G., Verhoek M., de Cost M, Hollak CE, Maas M,\u000a      Bleijtevens B., Van Breemen MJ., van Meurs M., Boven LA., Laman JD., Moran\u000a      MT, Cox TM., Aerts JM. (2004). Marked elevation of the chemokine\u000a      CCL18\/PARC in Gaucher disease: a novel surrogate marker for assessing\u000a      therapeutic intervention. Blood 103: 33-39. DOI:\u000a      10.1182\/blood-2003-05-1612\u000a    \u000a\u000a5) Moran MT, Schofield JP, Hayman AR, Shi GP, Young E, Cox TM\u000a      (2000) Pathologic gene expression in Gaucher disease: up-regulation of\u000a      cysteine proteinases including osteoclastic cathepsin K. Blood. Sep\u000a      1;96(5):1969-78.PMID: 10961902\u000a    \u000a\u000a6) Deegan, PB., Moran, M-T., McFarlane, I., Schofield, JP., Boot,\u000a      RG., Aerts, JMFG., and Cox, TM. (2005) Clinical evaluation of chemokine\u000a      and enzymatic biomarkers of Gaucher disease. Blood Cells, Molecules and\u000a      Disease 35: 259-267. DOI: 10.1016\/j.bcmd.2005.05.005\u000a    \u000a\u000a7) Cachón-González MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox\u000a      TM (2006). Effective gene therapy in an authentic model of\u000a      Tay-Sachs-related diseases. Proc Natl Acad Sci (U S A); 103: 10373-8. DOI:\u000a      10.1073%2Fpnas.0603765103\u000a    \u000a\u000a8) Bradbury AM , Cochran JN, McCurdy VJ, Johnson AK, Brunson BL ,\u000a      Gray-Edwards H, Leroy SG, Hwang M, Randle AN, Jackson LS, Morrison NE,\u000a      Baek RC, Seyfried TN, Cheng SH, Cox NR, Baker HJ, Cachón-González MB, Cox\u000a      TM, Sena-Esteves M, Martin DR.(2013). Therapeutic response in feline\u000a      Sandhoff disease despite immunity to intracranial gene therapy. Molecular\u000a      Therapy;21(7):1306-15. doi: 10.1038\/mt.2013.86\u000a    \u000aPeer-reviewed Research Funding:\u000a      Charities; Sparks, the children's charity; CLIMB; National\u000a      Tay-Sachs & Allied Diseases Association (USA); Croucher Foundation\u000a      Hong Kong, MPS Society, UK Gaucher's Association, Hunter's Hope and Paul\u000a      Morgan Trust and Niemann-Pick Disease Group totalling £1.32m.\u000a      Government sources; MRC and MRC\/FEC joint funding (DTI-LINK\u000a      award 8\/CE09147 and Confidence in Concepts award to University) totalling\u000a      £3.845m over the research period, including on-going funding. NIH\u000a      totalling £1.741m over the research period, including on-going funding.\u000a      European Commission FP7-HEALTH-201678; £265,000 over the research period.\u000a      Future funding secured; MRC Stratified Medicine Consortium award\u000a      (1\/10\/2013-31\/12\/2017; one of only three UK programmes funded for research\u000a      into rare disease) GAUCHERITE consortium: http:\/\/www.mrc.ac.uk\/Newspublications\/News\/MRC008947\u000a      Lead applicant; Cox (FEC £3.728m. MRC contribution (£2.922m) and MRC\u000a      Biomedical Catalyst MR\/K025570\/1 (1\/10\/2013-31\/12\/2017 £2.804m) Lead\u000a      applicant; Cox.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    \u000a\u0009\u000ahttp:\/\/www.medicinescomplete.com\/mc\/bnf\/current\/PHP6351-miglustat.htm\u000a      BNF entry for miglustat being indicated in Gaucher's disease and Niemann\u000a      Pick type C disease.\u000a    \u000ahttp:\/\/www1.actelion.com\/documents\/corporate\/fact_sheets\/FS_MarketedProduct.pdf\u000a      Actelion's information on product development (miglustat\/Zavesca®) citing\u000a      Elstein et al 2004 (Cox is co- author) and dates for EU approval in Type 1\u000a      Gaucher (date) and Niemann Pick Type C (2009)\u000a    Cox TM, Amato D, Hollak CEM, Luzy C, Silkey M, Giorgino R and\u000a      Steiner RD. (2013). Evaluation of miglustat as maintenance therapy after\u000a      enzyme therapy in adults with stable type 1 Gaucher disease: a\u000a      prospective, open-label non-inferiority study. Orphanet Journal of Rare\u000a      Diseases MS: 2012714044731433 (published 7 December 2012).\u000a    \u000ahttp:\/\/news.genzyme.com\/press-release\/genzyme-announces-positive-new-data-two-phase-3-studies-oral-eliglustat-tartrate-gauch\u000a      Study sponsor's website confirming primary endpoint of Phase 3 trial has\u000a      been met.\u000a    http:\/\/www.specialisedservices.nhs.uk\/library\/23\/SOP_for_adult_Gauchers_disease.pdf\u000a    \u000ahttp:\/\/apps.who.int\/trialsearch\/trial.aspx?trialid=EUCTR2007-002840-21-ES\u000a      CCL18\/PARC as biomarker in primary outcome of a trial on WHO clinical\u000a      trials register EUCTR2007-002840-21-ES\u000a    Personal communication from the founder of The Naked Scientists\u000a    \u000awww.secinfo.com\/dVut2.2AXk.3.htm\u000a      Market response to Actelion developing Zavesca®.\u000a\u000a    Company website for sales of (Zavesca®) of approximately CHF\u000a      20m per quarter since 2012. http:\/\/www.actelion.com\/en\/investors\/financial-information\/marketed-products\/zavesca-sales.page\u000a\u000a    http:\/\/www.gauchercare.com\/en\/healthcare\/diagnosing.aspx\u000a    Lysosomal Disorders Unit: Box 135, Cambridge University\u000a      Hospitals NHS Foundation Trust: http:\/\/www.cuh.org.uk\/addenbrookes\/services\/clinical\/lysosomal\/lysosomal_index.html\u000a    \u000a\u0009\u000a    ","Title":"\u000a    Therapeutic Developments for Sphingolipidoses\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The underpinning research led by Professor Cox (Dept of Medicine, since\u000a      1989), sought to develop innovative treatments for glycosphingolipid\u000a      disorders (sphingolipidoses). These inherited conditions arise from\u000a      genetic defects in lysosomal proteins; principally acid hydrolases which\u000a      break down glycolipids. Pathological accumulation of macromolecular\u000a      substrates and other metabolites in the lysosomal compartment impairs\u000a      cellular integrity and function and affects many tissues including the\u000a      bone marrow, liver, spleen, bone, lungs; in neuronopathic Gaucher's and\u000a      Tay-Sachs diseases, neurodegeneration is relentless and often severe with\u000a      onset in infancy and childhood.\u000a    Potential therapies could act by i) inhibiting the enzyme responsible for\u000a      glycolipid synthesis or ii) augmenting the enzyme responsible for its\u000a      degradation, both approaches being dependent on therapeutic delivery to\u000a      the target tissue; finally iii) gene transfer offers the prospect of\u000a      definitive therapeutic correction. Cox and colleagues (Mistry, Clinical\u000a      Lecturer and Wraight, Consultant Radiologist) conducted a definitive\u000a      proof-of-principle study for enzyme therapy that was specifically aimed at\u000a      measuring enzyme half-life and exploring targeting in living patients\u000a      affected by Gaucher's disease. Here, deficient glucocerebrosidase activity\u000a      causes systemic accumulation of glucocerebroside by pathological\u000a      macrophages in viscera and bone marrow. Radiolabelled enzymatically active\u000a      human glucocerebrosidase (modified to increase its affinity for macrophage\u000a      glycoprotein receptors), was administered intravenously to eight patients\u000a      with Gaucher disease with scintigraphic monitoring of its distribution,\u000a      pharmacodynamics and metabolism. It was found that natural and recombinant\u000a      enzymes were avidly taken up into liver, spleen and bone marrow; that\u000a      uptake was saturable, indicating targeting of receptors on macrophages,\u000a      and that enzyme turnover was consistent with therapeutic posology;\u000a      specific correction of the enzyme defect in Gaucher cells purified from\u000a      surgically removed fresh spleen tissue was also shown [1].\u000a    After scientific discussions with Platt and Butters (University of\u000a      Oxford), in 1998 Cox chose the target disease, designed and led the\u000a      pivotal trial (with clinical collaborators, Hollak, The Netherlands;\u000a      Hrebicek, Czech Republic, and Zimran, Israel) of a multicentre, 1-year\u000a      open-label study in patients with non-neuronopathic Gaucher's disease. In\u000a      this study the intervention was the UDP-glucosylceramide synthase\u000a      inhibitor; N-butyldeoxynojirimycin (miglustat), an approach based on\u000a      modulating glycosphingolipid synthesis (substrate reduction therapy). This\u000a      treatment was tolerable and improved several clinical features, including\u000a      low blood counts and enlargement of the liver and spleen [2]. In an\u000a      exploratory clinical experiment in 2003-4, with Lachmann (MRC Clinician\u000a      Scientist and Clinical Lecturer until 2005, now The National Hospital for\u000a      Neurology and Neurosurgery, London) and the Platt laboratory, it was shown\u000a      that the same agent had corrective cellular effects on the related\u000a      disorder, Niemann-Pick disease type C (NPC). Here, treatment with\u000a      miglustat reduced pathological lipid storage and corrected the defective\u000a      lysosomal trafficking in NPC readily detected in circulating B lymphocytes\u000a      [3].\u000a    From 1997-2000 Cox and colleagues led studies with Aerts and colleagues\u000a      (The Netherlands) to identify biomarkers associated with Gaucher disease.\u000a      By comparing rare gene expression subtractively in spleen tissue and\u000a      plasma samples from control subjects and patients, and from patients\u000a      before and after therapeutic intervention, they ascertained that the\u000a      chemokine CCL18\/PARC was elevated in this disease and reduced following\u000a      therapy [4]. CCL18\/PARC met criteria as a novel biomarker to assess\u000a      disease management [4, 5, 6]. In 2004-6 Cox and colleagues conducted a\u000a      gene-therapy study using a rodent model for acute Tay-Sachs disease — the\u000a      Sandhoff mouse also has genetic deficiency of lysosomal\u000a      beta-hexosaminidase A. Cachón-González et al. used intracranial\u000a      adeno-associated viral vectors to transduce human beta- hexosaminidase\u000a      alpha and beta subunits into the brain: while untreated mice died before\u000a      18 weeks of age, gene transfer rescued the mice for over a year [7].\u000a      Furthermore, disease onset was delayed and neurological function was\u000a      preserved. Experiments, in collaboration with researchers at Auburn\u000a      University, Alabama in Sandhoff cats confirmed these findings [8] and\u000a      validated the principle of gene transfer widely in the neuraxis for these\u000a      disorders.\u000a    "},{"CaseStudyId":"29899","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2542007","Name":"Morocco"},{"GeoNamesId":"2245662","Name":"Senegal"},{"GeoNamesId":"2300660","Name":"Ghana"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"3057568","Name":"Slovakia"},{"GeoNamesId":"2233387","Name":"Cameroon"},{"GeoNamesId":"2328926","Name":"Nigeria"},{"GeoNamesId":"226074","Name":"Uganda"},{"GeoNamesId":"241170","Name":"Seychelles"},{"GeoNamesId":"2134431","Name":"Vanuatu"},{"GeoNamesId":"3057568","Name":"Slovakia"},{"GeoNamesId":"2440476","Name":"Niger"},{"GeoNamesId":"878675","Name":"Zimbabwe"},{"GeoNamesId":"1694008","Name":"Philippines"},{"GeoNamesId":"927384","Name":"Malawi"},{"GeoNamesId":"895949","Name":"Zambia"},{"GeoNamesId":"2287781","Name":"Ivory Coast"},{"GeoNamesId":"1062947","Name":"Madagascar"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"192950","Name":"Kenya"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2589581","Name":"Algeria"},{"GeoNamesId":"1733045","Name":"Malaysia"},{"GeoNamesId":"2464461","Name":"Tunisia"},{"GeoNamesId":"3077311","Name":"Czech Republic"}],"Funders":["Wellcome Trust","Economic and Social Research Council"],"ImpactDetails":"\u000a    The two technology platforms (SAS for protein targets and SAMBA for\u000a      nucleic acid targets) have\u000a      been successfully commercialised by DDU's spinout company, Diagnostics for\u000a      the Real World\u000a      (DRW) established in 2002, with the Wellcome Trust and the University of\u000a      Cambridge as corporate\u000a      shareholders (Ref 1 in section 5). To meet the diagnostic needs of the\u000a      developing world, the\u000a      company limits its profit to 10%. In the past 10 years, the spinout\u000a      company has raised >$30 million\u000a      using a diversified funding strategy (Ref 2 in section 5), of which\u000a      >$20million is since 2008\u000a      (including $8million from NIH, $12million from the Children's Investment\u000a      Fund Foundation and\u000a      £0.5million from the UK Technology Strategy Board).\u000a    Both the female and the male Chlamydia SAS-based rapid tests have\u000a      undergone clinical trial in 3\u000a      UK clinics and in the Philippines (Refs 3 & 4 in section 5).). Since\u000a      their launch in 2008 at the\u000a      national OB-GYN conference in the Philippines, >150,000 tests have been\u000a      provided to diverse\u000a      geographic regions through its distribution partner (Oxoid Thermo-Fisher)\u000a      and direct sales: France,\u000a      Italy, the Czech Republic, Slovakia, Senegal, Madagascar, the Republic of\u000a      Niger, the Ivory Coast,\u000a      Morocco, Algeria, Tunisia, Kenya, Malaysia, the Seychelles, Vanuatu,\u000a      Samoa, the Falkland\u000a      Islands, Ghana, and St. Vincent and the Grenadines. They were used as a\u000a      diagnostic tool for\u000a      Chlamydia infection in symptomatic individuals as well as a screening tool\u000a      in pregnant women (e.g.\u000a      Samoa where Chlamydia is endemic), military personnel in the Falklands and\u000a      in asymptomatic\u000a      populations in general. The Chlamydia rapid test was funded by the UK\u000a      Technology Strategy\u000a      Board in 2012 as a tool to generate a cost effective model for `test and\u000a      treat' at the point of care vs.\u000a      centralised testing in 3 UK sexual health clinics. The FirstBurstf0e4\u000a      first void urine collection device\u000a      received the 2003 Medical Futures Best Diagnostic Innovation Award and\u000a      continues to be used in\u000a      the DRW Chlamydia test with on-going impact in studies such the UK\u000a      national survey for sexually\u000a      transmitted diseases in the general population.\u000a    DRW has also launched the first CE marked HBsAg rapid test kit on the\u000a      market due to its improved\u000a      sensitivity and has begun its launch activities in north African countries\u000a      and in France after a\u000a      successful evaluation. The test generated a large number of internet-based\u000a      articles during the\u000a      World Hepatitis Day in 2010, including comments from Prof Baruch Blumberg,\u000a      the Nobel Prize\u000a      laureate for the discovery of the Hepatitis B virus and invention of the\u000a      HBV vaccine: \"Approval of\u000a      the new Hepatitis B Rapid Test is positive news for the estimated 400\u000a      million HBV carriers\u000a      worldwide. Being able to identify carriers, initiate immediate treatment\u000a      of appropriate candidates,\u000a      and vaccinate family members and close contacts, has the potential to\u000a      greatly accelerate the\u000a      programme to control HBV infection and spread. The Hepatitis B Rapid Test\u000a      developed by\u000a      Diagnostics for the Real World can make a significant contribution to the\u000a      solution\" (Ref 5 in section\u000a      5).\u000a    The first assay based on the SAMBA platform is the HIV-1\u000a      Semi-Quantitative Test for the\u000a      monitoring of patients on antiretroviral therapy. Having been successfully\u000a      trialled by Medecins sans\u000a      Frontieres (MSF), the first batch of 4,000 tests and 10 SAMBA instruments\u000a      were shipped to 3 MSF\u000a      clinics in Malawi and Uganda in Q2, 2013. This is the first time a nucleic\u000a      acid amplification test is\u000a      implemented in a point-of-care setting. MSF has already committed to\u000a      screening >30,000 patients\u000a      for treatment efficacy using SAMBA. Product registration for the SAMBA\u000a      HIV-1 Semi-Q Test is\u000a      currently being sought in 6 other high-burden African countries (Cameroon,\u000a      Kenya, Nigeria, South\u000a      Africa, Zambia, Zimbabwe). Given the recent WHO recommendation to monitor\u000a      all HIV infected\u000a      patients at least once a year, the SAMBA HIV test will be an effective\u000a      tool for the monitoring of HIV\u000a      infected individuals in sub Saharan Africa (estimated to be 15 million in\u000a      2015).\u000a    Currently, HIV-exposed babies in sub-Saharan Africa can only be tested by\u000a      nucleic acid\u000a      amplification methods at centralised laboratories. This requires the\u000a      transport of dried blood spots\u000a      from peripheral clinics and leads to unacceptable delays to treatment due\u000a      to long turn-around times\u000a      and loss to follow up ranging from 30 to 70% depending on the country. A\u000a      quantitative SAMBA HIV\u000a      test has been developed for the early infant diagnosis at the point of\u000a      care, and access to this\u000a      simple, rapid and effective molecular test at peripheral clinics where\u000a      mothers can receive the\u000a      results in one visit will fill the current diagnostic gap. Ethical\u000a      approvals have been obtained in\u000a      Malawi, Uganda, South Africa and Kenya for clinical trials in Q3-Q4 2013.\u000a      A Memorandum of\u000a      Understanding was signed with the Ministry of Health, Zimbabwe for\u000a      implementation of the SAMBA\u000a      EID test.\u000a    ","ImpactSummary":"\u000a    Communicable diseases are a major health burden in the developing world.\u000a      Early detection and\u000a      accurate identification of infectious agents is key to their management.\u000a      However, the complex\u000a      procedures and logistics of current diagnostic tests often make them\u000a      unsuitable for use in\u000a      developing countries. Two technology platforms have been developed that\u000a      have led to a new\u000a      generation of simple and inexpensive rapid tests that can be applied in\u000a      resource-limited settings. A\u000a      spinout company was set up to allow translation of these platforms into\u000a      new products. Three tests\u000a      (Chlamydia, Hepatitis B and HIV) were launched since 2008, with test kits\u000a      marketed, allowing\u000a      patients to receive treatment for infections which would have previously\u000a      gone unnoticed and\u000a      untreated. The spinout company has raised >$30 million, of which\u000a      >$20million is since 2008.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    A. Publications\u000a    \u000a1. C.A. Wisniewski, White JA, Michel CE, et al. Optimal\u000a        method of collection of first-void urine for diagnosis of Chlamydia\u000a        trachomatis infection in men. J. Clin. Microbiol. 2008.\u000a      46:1466-1469.\u000a    \u000a\u000a2. Y-H. Lin, Y. Wang, A. Loua et al. Evaluation of a new sensitive\u000a      HBsAg rapid test with improved\u000a      sensitivity. J. Clin. Microbiol. 2008. 46: 3319-3324.\u000a    \u000a\u000a3. H.H. Lee, M.A. Dineva, Y.L. Chua et al. Simple\u000a      amplification-based assay: a nucleic acid-based\u000a      point-of-care platform for HIV-1 testing. J Infect Dis. 2010. 201:\u000a      Suppl 1:S65-72.\u000a    \u000a\u000a4. L.T. Wu, M.D. Curran, J. Ellis, S. et al. 2010. Nucleic acid\u000a      dipstick test for molecular diagnosis\u000a      of pandemic H1N1. J. Clin. Microbiol. 2010. 48(10): 3608-3613.\u000a    \u000aB. Intellectual properties: Eight patents have been issued in\u000a      territories including Australia,\u000a      France, Germany, India, Italy Spain, UK and USA and include:\u000a    1. Improved capture and detection format: versatility for Dipstick Assays\u000a      (PCT\/GB01\/03030).\u000a      GB0016833.6,7 Jul 2000. Granted: EU Validating: FR, DE, IN, UK,\u000a      USA\u000a    2. Signal enhancement system with multiple labeled-moieties\u000a      (PCT\/GB01\/05325). GB0029154.2,\u000a      30 Nov 2000 Granted: CN, FR, DE, IT, ES, UK, USA\u000a   C. Peer-reviewed funding: During the period between 1st\u000a      Jan 1993 and July 2013, over £17\u000a      million funding was received by DDU with selected funding listed below:\u000a    1. World Health Organization, Nucleic acid based dipstick assay\u000a      for the detection of C.\u000a        trachomatis infection from urine. Awarded Sep 1995, $ 315,250\u000a    2. National Institutes of Health, USA, Nucleic acid dipstick for\u000a      Chlamydia trachomatis detection.\u000a      Awarded Jan 1996, £ 1,356,985\u000a    3. Sentinel Biosciences, Inc., Discovery of new HIV related\u000a      viruses in 3 West African countries.\u000a      Awarded Apr 1996, £ 1,764,138\u000a    4. Wellcome Trust Programme Grant: Development of a rapid DNA\u000a      dipstick for detection of\u000a      Chlamydia trachomatis. Awarded Mar 1997, £ 2,224,916\u000a    5. Wellcome Trust Translation Award: Evaluation of Chlamydia\u000a        trachomatis infection in clinical\u000a      settings. Awarded Feb 2005, £ 1,256,963\u000a    6. Wellcome Trust Strategic Award: Meeting the diagnostic needs\u000a      of resource-poor settings:\u000a      development of a simple amplification test, Awarded Jun 2007, £\u000a        2,885,434\u000a    7. National Institutes of Health, USA SAMBA HIV Point-of-Care\u000a      Nucleic Acid System for\u000a      Resource Limited Settings. Awarded Nov 2009, $4,654,673\u000a    8. UK Technology Strategy Board, Point-of-care nucleic acid-based\u000a      tests for detection of\u000a      Chlamydia trachomatis (CT) and Neisseria gonorrhea (NG),\u000a      Awarded Oct 2010, £841,327\u000a    9. Children's Investment Fund Foundation, Point\u000a        of care nucleic acid test for detection of HIV infections in infants.\u000a      Awarded Jul 2011, $4,917,586\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000a    \u000a      \u000aWellcome Trust Technology Transfer Showcase\u000a        http:\/\/www.wellcome.ac.uk\/Funding\/Technology-transfer\/Technology-transfer-showcase\/WTX052911.htm\u000a\u000a      \u000a Global Health Innovation Insight Series, Diagnostics for the\u000a        Real World - Raising funds for a\u000a        niche solution (2012)\u000a      http:\/\/www.google.co.uk\/url?sa=t&rct=j&q=&esrc=s&source=web&cd=6&ved=0CFIQFjAF&url=http%3A%2F%2Fwww.gsb.stanford.edu%2Fsites%2Fdefault%2Ffiles%2Fdocuments%2FDRWII-RaisingFunds.pdf&ei=T_95UrHQLfGM7Ab6y4GABA&usg=AFQjCNGSjqIxsnFJ3QZCMkZ-2fBPYuvBRA&sig2=oDcHxIjV7IAoSRRxHrLBRg&bvm=bv.55980276,d.ZGU\u000a\u000a      L. Mahilum-Tapay, V. Laitila, J.J. Wawrzynia et al. New point of care\u000a        Chlamydia Rapid Test -\u000a        bridging the gap between diagnosis and treatment: performance evaluation\u000a        study. British Medical\u000a          Journal 2007. 335: 1190-1194.4.\u000a      E-C. Nadala, B. T Goh, J-P. Magbanua, et al. Performance evaluation of\u000a        a new rapid urine test\u000a        for chlamydia in men: prospective cohort study British Medical\u000a          Journal 2009. 339:b2655;\u000a        doi:10.1136\/bmj.b2655.\u000a      \u000a Wellcome Trust Press Release, 2010 \"EU gives green\u000a        light for while-you-wait Hepatitis B test\"\u000a        http:\/\/www.wellcome.ac.uk\/News\/Media-office\/Press-releases\/2010\/WTX059435.htm\u000a\u000a    \u000a    ","Title":"\u000a    Meeting the diagnostic needs in resource-limited settings\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Diagnostics Development Unit (DDU) was established in 1996 by Dr\u000a      Helen Lee, Reader in\u000a      Medical Biotechnology, Dept of Haematology (since 1991), who left the\u000a      diagnostic industry with the\u000a      goal of developing simple, high-performance, robust yet affordable assays\u000a      for resource-limited\u000a      settings. A multi-disciplinary team was assembled to develop the\u000a      diagnostic technologies and\u000a      translate them into products. Key researchers, all in the Dept of\u000a      Haematology include C Wisniewski\u000a      (Senior Res Associate, engineering, 01\/09\/2007 to present), M Dineva\u000a      (Senior Res Associate, nucleic\u000a      acid chemistry, 01\/10\/2004 - 30\/09\/2010), A Ritchie (Res Associate,\u000a      molecular biology, 11\/09\/2006 to\u000a      present ), C Michel (Res Assistant, pilot plant manufacturing, 02\/02\/1998\u000a      - 31\/08\/2011), N Goel (Res\u000a      Assistant, quality control and probe synthesis, 23\/04\/2009 to present).\u000a    Two generic platform technologies that greatly improve the performance of\u000a      rapid tests have since\u000a      been developed: the Signal Amplification System (SAS)\u000a      for protein-based targets (Lin et al, JCM\u000a      2008), and Simple AMplification Based Assay\u000a      (SAMBA) for nucleic acid-based targets (Lee et al,\u000a      JID 2010).\u000a    Platform 1 - SAS, the protein-based point-of-care platform (1996 -\u000a          2008)\u000a      Current membrane-based lateral flow tests are rapid because no complex\u000a      reagent additions,\u000a      washing or incubation steps are required. However, the ease-of-use and\u000a      short assay time are\u000a      achieved at the expense of sensitivity. Whereas antibody-based rapid tests\u000a      tend to have\u000a      equivalent sensitivity to the more complex and machine-dependent Enzyme\u000a      Immunoassays (EIA),\u000a      rapid tests for the detection of antigen usually suffer from lower\u000a      sensitivity. This limitation is\u000a      particularly evident in infectious disease diagnosis for which high\u000a      sensitivity is required and yet a\u000a      low analyte level may be present.\u000a    Research in the DDU resulted in the\u000a      development of SAS, which is based on\u000a      multiplying a visual signal via an increase in\u000a      Format\u000a      the valency and size of the coloured\u000a      immune complex in the assay, by\u000a      chemically coupling multiple copies of a\u000a      hapten moiety to the primary detection\u000a      antibodies. The resulting lattice formed\u000a      between the analyte, multiple hapten-\u000a      labelled antibody and the anti-hapten colour\u000a      conjugate yields a strong visual signal. This\u000a      increases the valency and the size of\u000a      immune complexes and thereby greatly increases the visual sensitivity of\u000a      lateral flow-based rapid\u000a      tests (Fig 1).\u000a\u000aFig 1 Effect of SAS on sensitivity of Chlamydia lipopolysaccharide (LPS) detection\u000a\u000a    The sensitivity improvement of SAS for the detection of the Chlamydial\u000a      lipopolysaccharide was\u000a      used to develop a simple Chlamydia rapid test with sufficient sensitivity\u000a      that enabled the use, for\u000a      the first time of non-invasive samples such as self-collected vaginal swab\u000a      from women and urine\u000a      from men. To further improve the sensitivity of the Chlamydia Rapid test\u000a      for testing male urine, a\u000a      unique and innovative device, FirstBurstf0e4, was developed by DDU for\u000a      convenient collection of the\u000a      initial fraction of the urine stream containing 84% of the bacterial load\u000a      (Wisniewski et al, JCM\u000a      2008). SAS was also the underpinning technology that allowed the\u000a      development of a hepatitis B\u000a      surface antigen (HBsAg) rapid test which became the first rapid test to\u000a      receive the CE mark\u000a      because it was able to meet the stringent sensitivity requirement (Lin et\u000a      al, JCM 2008).\u000a    Platform 2 - SAMBA, the nucleic acid-based point-of-care platform\u000a          (2002-2008)\u000a      Existing nucleic acid tests are expensive, complex and time-consuming,\u000a      requiring sophisticated\u000a      instrumentation and highly-trained personnel. Thus, even in developed\u000a      countries, only a small\u000a      minority of clinical laboratories are capable of performing nucleic acid\u000a      amplification tests (NAT's).\u000a    The lack of simple and inexpensive nucleic acid extraction methods from\u000a      complex biological\u000a      samples with high efficiency is an important bottleneck for the\u000a      application of NAT's in resource-\u000a      limited settings. To address this critical issue, DDU developed SAMBA: a\u000a      point-of-care molecular\u000a      diagnostics platform (Fig 2) which uses novel chemistry to enable the\u000a      visual detection of nucleic\u000a      acid hybridisation at a sensitivity and specificity equal to that of\u000a      complex methods, underpinned by\u000a      a robust and simplified isothermal amplification process. The SAMBA sample\u000a      preparation protocol\u000a      takes <25 min, without requiring alcohol or chaotropic salts, and the\u000a      cartridge provides ready-made\u000a      unit dose reagents (Lee et al, JID 2010). Key\u000a      advantages of the SAMBA system include simplicity,\u000a      low technical complexity and the use of freeze-dried\u000a      reagents that are extremely stable in high temperature\u000a      and high humidity, thus circumventing the need for cold\u000a      chain storage or transport. This simplification of\u000a      complex chemistry without the need of expensive\u000a      instrumentation or highly-trained personnel is essential\u000a      to moving nucleic acid testing beyond sophisticated\u000a      clinical laboratories to the point-of-care environment in\u000a      resource-limited settings (Wu et al, JCM 2010).\u000a\u000aFig 2: Simplifying NAT with SAMBA\u000a\u000a    "},{"CaseStudyId":"29985","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The research described has had a major impact on renal and other types of\u000a      organ transplantation: it has helped increase access to deceased donor\u000a      kidney transplantation and informed organ storage and allocation policy,\u000a      locally and nationally, particularly for kidneys from circulatory death\u000a      (DCD) donors.\u000a    The novel finding that organs derived from patients dying from primary\u000a      intracranial malignancy, including those with high-grade tumours, posed a\u000a      very small risk of tumour transmission has helped change practice in the\u000a      UK and internationally. The Department of Health Advisory Committee on the\u000a      Safety of Blood, Tissues and Organs (SaBTO) in the UK recently (2012)\u000a      published a report (1), citing the Cambridge findings as key evidence, and\u000a      recommended that organs donated by donors with primary CNS cancer should\u000a      generally be used for transplantation, thereby increasing access to\u000a      transplantation and giving an estimated gain of 320 life-years in UK\u000a      kidney transplant recipients annually (1). The Cambridge research was also\u000a      instrumental in determining international policy for transplanting organs\u000a      from donors with intracranial malignancy (2).\u000a    The Cambridge study on time-to-circulatory-death after withdrawal of life\u000a      sustaining treatment in potential organ donors has been recognized as the\u000a      most authoritative publication on this subject. It has influenced planning\u000a      and resourcing of organ recovery after cardiac death and helped maximize\u000a      donor numbers locally and nationally. Extending the stand-down time after\u000a      withdrawal of life supporting treatment in potential DCD donors from one\u000a      to four hours has increased DCD numbers by 30% and Cambridge became in\u000a      2009\/10 (and remains in 2013) the largest UK centre for DCD kidney\u000a      transplantation (3, 4). This influenced practice nationally and the\u000a      National Organ Retrieval Service in the UK recently increased the stand\u000a      down time for potential DCD donors from two to three hours (plus a further\u000a      two hours if the potential donor became unstable)(5).\u000a    In the UK the number of kidneys donated after circulatory death rose from\u000a      264 in 2008 to 674 in 2011\/12 and continues to increase (6). The\u000a      Cambridge-led Lancet study showing that long-term transplant outcome was\u000a      equivalent in recipients of kidneys from DCD and brain death (BD) donors\u000a      greatly stimulated the use of such kidneys. The article was accompanied by\u000a      a complimentary editorial and initiated correspondence, a review and\u000a      considerable media interest (7). While kidneys from BD donors have been\u000a      shared according to a national allocation scheme, kidneys from DBD donors\u000a      have not been shared nationally but used locally instead. On the basis of\u000a      the two Lancet papers, which also identified the key factors influencing\u000a      outcome after DCD kidney transplantation, a working party of the Kidney\u000a      Advisory Group of NHSBT was established (8), and advised a national\u000a      sharing scheme for kidneys from DCD donors. The second Lancet paper,\u000a      showing that kidneys from DCD donors were more susceptible to cold\u000a      ischaemic injury than kidneys from brain death donors, led the Kidney\u000a      Advisory Group working party to recommend a regional (three regional\u000a      zones) rather than full national sharing to minimise transport times of\u000a      shared DCD kidneys. The Kidney Advisory Group and the policy\u000a      implementation group of NHSBT fully accepted the report and a UK sharing\u000a      scheme for DCD kidneys is currently being implemented\u000a    The multi-centre, randomised controlled trials led by Watson and Bradley\u000a      which reported that machine perfusion offered no advantage over cold\u000a      storage, which was cheaper and more straightforward, were used by NICE in\u000a      preparing NICE technology appraisal guidance 165 `Machine perfusion\u000a      systems and cold static storage of kidneys from deceased donors'. The NICE\u000a      Committee took into consideration the Group's clinical effectiveness\u000a      evidence and concluded, in agreement with this evidence, that the LifePort\u000a      kidney transporter could not be preferentially recommended over other\u000a      forms of storage of kidneys from deceased donors (9).\u000a    Finally, the Cambridge experience which demonstrated for the first time\u000a      the safety and feasibility of selective omission of the pre-transplant\u000a      cross-match test to reduce cold ischaemic times during kidney\u000a      transplantation was incorporated into the British Society of\u000a      Histocompatibility and Immunogenetics\/ British Transplantation Society\u000a      Guidelines for the Detection and Characterisation of Clinically Relevant\u000a      Antibodies in Allotransplantation and has had a major impact on UK\u000a      practice (10).\u000a    ","ImpactSummary":"\u000a    Research led by Bradley, Watson and Pettigrew (Department of Surgery,\u000a      University of Cambridge) since 2000 has improved patient access to renal\u000a      transplantation significantly, changed UK kidney transplant policy\u000a      radically, and informed policy internationally. Their findings have\u000a      increased considerably the use of kidneys (and other organs) from\u000a      circulatory death donors (DCD), including those with extended time to\u000a      cardio-respiratory arrest, and primary brain malignancy. Their randomised\u000a      trial of machine perfusion for DCD kidneys has informed NICE guidance,\u000a      while their analysis of factors that determine transplant outcome in\u000a      recipients of DCD kidneys has informed national guidance for DCD kidney\u000a      retrieval and organ allocation policy at NHS Blood and Transplant.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a(1) Watson CJ, Roberts R, Wright KA, Greenberg DC, Rous BA, Brown CH,\u000a      Counter C, Collett D, Bradley JA. How safe is it to transplant organs from\u000a      deceased donors with primary intracranial malignancy? An analysis of UK\u000a      Registry data. Am J Transplant. 2010 Jun;10(6):1437-44. doi:\u000a      10.1111\/j.1600-6143.2010.03130.x. Epub 2010 May 10. PMID: 20486904\u000a    \u000a\u000a(2) Suntharalingam C, Sharples L, Dudley C, Bradley JA, Watson CJ. Time\u000a      to cardiac death after withdrawal of life-sustaining treatment in\u000a      potential organ donors. Am J Transplant. 2009 Sep;9(9):2157-65. doi:\u000a      10.1111\/j.1600-6143.2009.02758.x. Epub 2009 Jul 22. PMID: 19681825\u000a    \u000a\u000a(3) Reid AW, Harper S, Jackson CH, Wells AC, Summers DM, Gjorgjimajkoska\u000a      O, Sharples LD, Bradley JA, Pettigrew GJ. Expansion of the kidney donor\u000a      pool by using cardiac death donors with prolonged time to\u000a      cardiorespiratory arrest. Am J Transplant. 2011 May;11(5):995-1005. doi:\u000a      10.1111\/j.1600-6143.2011.03474.x. Epub 2011 Mar 30. PMID: 21449941\u000a    \u000a\u000a(4) Summers DM, Johnson RJ, Allen J, Fuggle SV, Collett D, Watson CJ,\u000a      Bradley JA. Analysis of factors that affect outcome after transplantation\u000a      of kidneys donated after cardiac death in the UK: a cohort study. Lancet.\u000a      2010 Oct 16;376(9749):1303-11. doi: 10.1016\/S0140-6736(10)60827-6. Epub\u000a      2010 Aug 18. PMID: 20727576\u000a    \u000a\u000a(5) Summers DM, Johnson RJ, Hudson A, Collett D, Watson CJ, Bradley JA.\u000a      Effect of donor age and cold storage time on outcome in recipients of\u000a      kidneys donated after circulatory death in the UK: a cohort study. Lancet.\u000a      2012 Dec 19. doi:pii: S0140-6736(12)61685-7.\u000a      10.1016\/S0140-6736(12)61685-7. [Epub ahead of print] PMID: 23261146\u000a    \u000a\u000a(6) Taylor CJ, Kosmoliaptsis V, Sharples LD, Prezzi D, Morgan CH, Key T,\u000a      Chaudhry AN, Amin I, Clatworthy MR, Butler AJ, Watson CJ, Bradley JA.\u000a      Ten-year experience of selective omission of the pretransplant crossmatch\u000a      test in deceased donor kidney transplantation. Transplantation. 2010 Jan\u000a      27;89(2):185-93. doi: 10.1097\/TP.0b013e3181c926f2. PMID: 20098281\u000a    \u000a\u000a(7) Watson CJ, Wells AC, Roberts RJ, Akoh JA, Friend PJ, Akyol M, Calder\u000a      FR, Allen JE, Jones MN, Collett D, Bradley JA. Cold machine perfusion\u000a      versus static cold storage of kidneys donated after cardiac death: a UK\u000a      multicenter randomized controlled trial. Am J Transplant. 2010\u000a      Sep;10(9):1991-9. doi: 10.1111\/j.1600-6143.2010.03165.x. PMID: 20883534\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    (1) Warrens A, et al., Advising potential recipients on the use of organs\u000a      from donors with primary central nervous system tumours. (for the Advisory\u000a      Committee on the Safety of Blood, Tissues and Organs, UK) Transplantation\u000a      2012; 93(4): 348-353\u000a    (2) Watson CJ, Bradley JA. Evaluating\u000a        the risk of cancer transmission to optimize organ usage. Am J\u000a      Transplant. 2011 Jun;11(6):1113-4.\u000a    (3) Reid AW,\u000a        Harper S, Jackson CH, Wells AC, Summers DM, Gjorgjimajkoska O, Sharples\u000a        LD, Bradley JA, Pettigrew GJ. Expansion of the Kidney Donor Pool by\u000a        Using Cardiac Death Donors with Prolonged Time to Cardiorespiratory\u000a        Arrest. Am J Transplant. 2011 May;11(5):995-1005\u000a    (4) NHSBT statistics on kidney transplantation.\u000a    http:\/\/www.uktransplant.org.uk\/ukt\/statistics\/transplant_activity_report\/transplant_activity_report.\u000a      jsp\u000a    (5) NHSBT National standards for organ retrieval from deceased donors.\u000a      www.bts.org.uk\/Documents\/9.1.13%20Retrieval%20Standards%20Document%20v2%206%20effective%20010113.pdf\u000a    (6)http:\/\/www.organdonation.nhs.uk\/statistics\/transplant_activity_report\/current_activity_reports\/ukt\/kidney_activity.pdf\u000a    (7)http:\/\/www.guardian.co.uk\/society\/2010\/aug\/19\/kidney-transplant-revolution-cardiac-organs\u000a    (8)http:\/\/www.organdonation.nhs.uk\/newsroom\/news_releases\/printTemplate.asp?releaseId=250\u000a    (9) http:\/\/guidance.nice.org.uk\/TA165\u000a    (10) see BSHI\u000a        and BTS Guidelines for the Detection and Characterisation of Clinically Relevant Antibodies\u000a        in Allotransplantation (section 9.3.3) at:- http:\/\/www.bts.org.uk\/MBR\/Clinical\/Guidelines\/Current\/Member\/Clinical\/Current_Guidelines.aspx\u000a    ","Title":"\u000a    Increasing Access to Kidney Transplantation\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    There is a worldwide shortage of organs for transplantation and\u000a      increasing the number of deceased donor organs transplanted has been a\u000a      major strategic initiative, addressed by research led by Cambridge\u000a      academics in the Department of Surgery (Andrew Bradley, Prof of Surgery\u000a      01\/08\/1997 to present, Chris Watson, Senior Lecturer\u000a      01\/10\/2001-30\/09\/2007, Reader 01\/10\/2007 - 30\/09\/2011, Professor of\u000a      transplantation 01\/10\/2011 to present and Gavin Pettigrew, Clinical Senior\u000a      Research Associate 01\/10\/2003 - 30\/09\/2006, University Lecturer\u000a      01\/10\/06-30\/09\/2013, Reader 01\/10\/2013 to present). This research was\u000a      published between 2008-2012.\u000a    Patients dying from primary intracranial malignancy are a potentially\u000a      important source of organs for transplantation but a perceived risk of\u000a      tumour transfer to the recipient had previously limited their use. In 2008\u000a      Watson and Bradley (1) led research using information from UK Transplant\u000a      and cancer registries and found no instance of tumour transmission from\u000a      the 179 donors with a primary intracranial malignancy who gave organs to\u000a      448 recipients. The research team therefore concluded that organs from all\u000a      patients dying from primary intracranial malignancy should be considered\u000a      for transplantation, balancing the small risk of tumour transmission\u000a      against likely mortality on the transplant waiting list.\u000a    Donation after circulatory death (DCD) donors are an increasingly\u000a      important source of kidney transplants but the time to cardiac death\u000a      following withdrawal of life-supporting treatment varies widely and is an\u000a      important determinant of whether organ donation occurs. Because of\u000a      concerns about ischemic injury during the agonal phase, many clinicians\u000a      abandon donation if cardiorespiratory arrest has not occurred within one\u000a      hour of controlled withdrawal of life-supporting treatment. Watson and\u000a      Bradley (2) led a multicentre study of potential DCD donors to evaluate\u000a      the time to death and to identify associated factors. Their results have\u000a      aided planning and resourcing of DCD organ recovery and helped maximize\u000a      DCD donor numbers. Pettigrew and Bradley (3) subsequently investigated the\u000a      impact on donor numbers and transplant function of using instead a maximum\u000a      'cut-off' time of 4 hours. The agonal phase of 173 potential DCD donors\u000a      was characterized according to the presence or absence of various factors\u000a      and their impact on transplant outcome evaluated. Of referrals who became\u000a      donors, 23% arrested more than one hour after withdrawal of life support,\u000a      but it was shown that neither agonal phase instability nor its duration\u000a      influenced transplant outcome. DCD kidney numbers could therefore be\u000a      increased by 30%, without compromising transplant outcome, by lengthening\u000a      the maximum waiting time after withdrawal of life support from one to four\u000a      hours.\u000a    Kidneys from DCD donors have long been recognised as having great\u000a      potential to address the shortfall in kidneys available for\u000a      transplantation. However, there has been concern that the long-term\u000a      outcome may be inferior to that from using kidneys from brain-death\u000a      donors. Research led by Bradley, Watson and Pettigrew in 2009, and based\u000a      on an extensive analysis of the UK registry data (4,5) showed that kidneys\u000a      from DCD donors provided graft survival and function equivalent to that of\u000a      grafts from brain death donors. The team also identified key determinants\u000a      of graft survival in recipients of DCD kidneys. Their findings strongly\u000a      supported increased use of kidneys from DCD donors, and recommended that\u000a      an allocation policy for DCD donor kidneys avoid large age mismatches,\u000a      restrict the use of kidneys poorly matched for HLA in younger recipients,\u000a      and minimise cold ischaemic time. Pettigrew, Watson and Bradley have\u000a      similarly reported satisfactory outcomes for pancreas and liver\u000a      transplants using organs from DCD donors.\u000a    A factor contributing to cold ischaemia is the \"mandatory\" cross match\u000a      test to exclude donor specific antibodies in the potential recipient.\u000a      Bradley and Watson (6), in conjunction with Dr Craig Taylor (NIHR\u000a      Biomedical Research Centre) were the first to report the safety and\u000a      clinical efficacy of omitting the cross-match test, when it was predicted\u000a      to be negative, based on sensitization history and rigorous HLA-specific\u000a      antibody screening (6). Adoption of this policy, when allowed in selected\u000a      patients, was safe and effective, allowing a 2 hour reduction in cold\u000a      ischaemic time which for DCD kidneys has improved transplant outcome.\u000a    Finally, Watson and Bradley (7) led a UK multicentre, randomized\u000a      controlled trial showing that pre-transplant storage of DCD kidneys by\u000a      cold pulsatile machine perfusion offered no advantage in transplant\u000a      outcome over simple cold storage which remains cheaper and more\u000a      straightforward.\u000a    "},{"CaseStudyId":"29986","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Although not due to complete until 2015, the importance of AM and the\u000a      critical role of the final outcome of ProtecT have already had major\u000a      impact on National Health Policy through developing the role of\u000a      conservative approaches that underpin NICE Guidance, and decisions on\u000a      screening.\u000a    Active monitoring (AM) was developed in late 1998 within ProtecT as a\u000a      method for deferring radical treatment in men with low risk prostate\u000a      cancer, whilst keeping them in a \"window of curability\". Over-treatment is\u000a      clearly identified world-wide as the major problem of early detection of\u000a      prostate cancer. AM has been adopted and adapted internationally through\u000a      the use of additional biopsies into a management protocol known as active\u000a      surveillance (AS). Critically, these conservative approaches have been\u000a      incorporated into the NICE Guidance published in 2008 (1) and later\u000a      clarified through a joint statement with the British Association of\u000a      Urology (led by Neal) (2). The guidelines stated that men with low risk\u000a      prostate cancer should be offered conservative approaches such as Active\u000a      Surveillance.\u000a    The trial underpinned the hugely important medico-political decision not\u000a      to introduce screening for prostate cancer in 2010. Screening would only\u000a      be introduced if it was known what the best treatment was for\u000a      screen-detected cancers, and that this was cost-effective. A recent\u000a      overview for the Department of Health by ScHARR (3) has explicitly and\u000a      extensively referred to knowing the outcome of ProtecT as being a key\u000a      benchmark. A reference from ProtecT (4) was one of only five quoted in the\u000a      expert review for the main national screening document (5) and the\u000a      requirement for ProtecT to report was by one leading international opinion\u000a      leader (Wilt) as being of critical importance to national health policy on\u000a      prostate cancer screening (6). A recent independent review; published in\u000a      the Lancet confirmed that \"ProtecT has affected clinical practice, even\u000a      before announcement of its results, by allowing the UK to reaffirm its\u000a      policy of no routine screening\". (7) Also we recognised within the ProtecT\u000a      Trial the critical importance of presenting men with information in a\u000a      neutral way to allow them to make an informed decision, so that they\u000a      understood the uncertainty behind the requirement for a RCT. Our\u000a      experience of developing such information was recognised through the\u000a      appointment of Neal to a group tasked by the Department of Health to\u000a      produce an \"informed decision making aid\". This involved collaboration\u000a      with health service researchers in Boston and Ontario and the urological\u000a      input to the final document was led by Neal. This decision aid was then\u000a      rolled out within the NHS via NHS Direct (8). The work on shared decision\u000a      making between patients and their advisors is now part of Health Policy:\u000a      \"no decision about me without me\" and the Urological Decision Aid has been\u000a      used as an exemplar in documents produced for the Health Foundation by\u000a      Coulter (9). Neal also led the Clinical Advisory Group for the Department\u000a      of Health on the development of a new patient website where the role of\u000a      conservative approaches to the management of localised prostate cancer is\u000a      fully explained (10).\u000a    Advice about prostate cancer and the pros and cons of early detection has\u000a      been sent out by the Department of Health to all General Practitioners\u000a      under the government's Prostate Cancer Risk Management Programme, which\u000a      builds on quoted evidence that has already come out of ProtecT (11, 12).\u000a      The report noted: \"The Prostate Cancer Risk Management Programme ....\u000a        will be piloting a recent finding from the ProtecT study which showed\u000a        that two PSA tests performed 7 weeks apart allowed more accurate risk\u000a        prediction and may assist in decision-making as to whether or not to\u000a        proceed with referral...\u000a    ProtecT has made a major difference to the quality of care for men with\u000a      prostate cancer in that more men nationally and internationally with low\u000a      risk disease are now being offered conservative approaches such as AM to\u000a      keep them \"in a window of curability\", which will have reduced\u000a      significantly the impact of morbidity associated with unnecessary radical\u000a      treatments: an approach supported by the US NIH (13). The concept of\u000a      strategies to keep men in a window of curability so that those who\u000a      progress are offered radical treatments, is the principle within the\u000a      active monitoring arm within ProtecT and other active surveillance\u000a      protocols being developed.\u000a    ","ImpactSummary":"\u000a    ProtecT (Neal, Cambridge; Donovan, Bristol; Hamdy, Oxford), funded by\u000a      NIHR in 1999, is the largest randomised controlled trial in localised\u000a      prostate cancer; and compares a deferred conservative approach (Active\u000a      Monitoring — developed by the Trial PIs) with surgery and radiotherapy.\u000a      Avoiding \"over-treatment\" in low risk cancer is important and Active\u000a      Monitoring (AM) and Surveillance (AS) have now had a major impact on\u000a      patients and on national health policy through NICE guidance, which\u000a      recommends such management approaches. The linked bio-repository was\u000a      critical to characterising the genetic pre-disposition alleles (SNPs) in\u000a      prostate cancer, which are now being used to identify high risk\u000a      populations.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4930956","Name":"Boston"}],"References":"\u000a    \u000a1. Frankel S, Smith GD, Donovan J, Neal D. 2013. Screening for\u000a      prostate cancer. Lancet. 2003 Mar;361(9363):1122-8. Impact Factor 38,\u000a      (Citations > 100).\u000a    \u000a\u000a2. Lane JA, Hamdy FC, Martin RM, Turner EL, Neal DE, Donovan JL.\u000a      Latest results from the UK trials evaluating prostate cancer screening and\u000a      treatment: the CAP and ProtecT studies. Eur J Cancer. 2010\u000a      Nov;46(17):3095-101.(Cited > 50)\u000a    \u000a\u000a3. DONOVAN, J., MILLS, N., SMITH, M., BRINDLE, L., JACOBY, A., PETERS,\u000a      T., FRANKEL, S., NEAL, D. & HAMDY, F. 2002. Quality\u000a      improvement report — Improving design and conduct of randomised trials by\u000a      embedding them in qualitative research: ProtecT (prostate testing for\u000a      cancer and treatment) study. British Medical Journal, 325,\u000a      766-769. Impact factor 14. (Citations >190).\u000a    \u000a\u000a4. EELES, R. A., KOTE-JARAI, Z., GILES, G. G., ......., NEAL, D. E.\u000a      & EASTON, D. F. 2008. Multiple newly identified loci associated with\u000a      prostate cancer susceptibility. Nat Genet, 40, 316-21. Impact\u000a      factor 35. (Citations > 350).\u000a    \u000a\u000a5. Ghoussaini M, Song H, Koessler T,..... Neal DE, Pharoah PD,\u000a      Ponder BA, Eeles RA, Easton DF, Dunning AM. Multiple loci with different\u000a      cancer specificities within the 8q24 gene desert. J Natl Cancer Inst. 2008\u000a      Jul 2;100(13):962-6. (Cited > 150)\u000a    \u000a\u000a6. Gudmundsson J, Besenbacher S, Sulem P,et al .....Neal DE,\u000a      Thorsteinsdottir U, Rafnar T, Stefansson K. Genetic correction of PSA\u000a      values using sequence variants associated with PSA levels. Sci Transl Med.\u000a      2010 Dec 15;2(62):62ra92. (Cited > 35)\u000a    \u000a\u000a7. WHITAKER, H. C., KOTE-JARAI, Z., ROSS-ADAMS, H, .................,\u000a      EASTON, D., COOPER, C., EELES, R. & NEAL, D. E. 2010. The\u000a      rs10993994 Risk Allele for Prostate Cancer Results in Clinically Relevant\u000a      Changes in Microseminoprotein-Beta Expression in Tissue and Urine. PLoS\u000a        One, 5.\u000a    \u000a\u000a8. Gunnell D, Oliver SE, Peters TJ, et al, ......... Neal DE,\u000a      Holly JM. Are diet-prostate cancer associations mediated by the IGF axis?\u000a      A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy\u000a      middle-aged men. Br J Cancer. 2003 Jun 2;88(11):1682-6.\u000a    \u000aAssociated Funding\u000a    Hamdy FC, Donovan J, Neal DE. NIHR funding for ProteCT. £36M.;\u000a      Neal DE, Hamdy FC, Maitland NJ, Donovan JL, Clarke N. The Northern (and\u000a      Bristol) Prostate Cancer Collaborative. MRC £5M.; Neal DE. CRUK £3M;\u000a      Neal DE CRUK: £0.9M; Donovan JL, Hamdy FC, Neal DE, Martin R. CRUK\u000a      £2.4M; Eeles R, Easton D, and Neal DE. CR UK £ 4M; Eeles R,\u000a      Cooper C, Neal DE and Stratton M. Next generation sequencing for prostate\u000a      cancer (CRUK: ICR, Sanger and Cambridge) £4M\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      NICE. Prostate Cancer, diagnosis and treatment. 2008.\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/11924\/39687\/39687.pdf\u000a\u000a      BAUS and NICE. Joint Implementation Statement. 2009.\u000a        http:\/\/www.nice.org.uk\/nicemedia\/live\/11924\/44396\/44396.pdf\u000a\u000a      Chilcott J, Hummel S, Mildred M. SCHARR. 2010. Option appraisal:\u000a        screening for prostate cancer. Report to the UK National Screening\u000a        Committee. May 2010. Version 2.0. Option appraisal: screening for\u000a        prostate cancer [ScHARR] (PDF document, 1.11MB, 02\/08\/10): www.screening.nhs.uk\/policydb_download.php?doc=79\u000a\u000a      MOORE, A. L., DIMITROPOULOU, P., LANE, A., POWELL, P. H., GREENBERG,\u000a        D. C., BROWN, C. H., DONOVAN, J. L., HAMDY, F. C., MARTIN, R. M. &\u000a        NEAL, D. E. 2009. Population-based prostate-specific antigen testing in\u000a        the UK leads to a stage migration of prostate cancer. BJU Int, 104,\u000a        1592-8.\u000a      UK National Screening Committee. Prostate Cancer. 2010. The UK NSC\u000a        policy on Prostate cancer screening\/PSA testing in men over the age of\u000a        50. Accessed in 2012. Expert Review from 2010. http:\/\/www.screening.nhs.uk\/prostatecancer.\u000a      Wilt TJ. 2008. SPCG-4: a needed START to PIVOTal data to promote and\u000a        protect evidence-based prostate cancer care. J Natl Cancer Inst.\u000a        100(16):1123-5. doi: 10.1093\/jnci\/djn259. Epub 2008 Aug 11.\u000a      Raftery J, and Powell J. Health Technology Assessment in the UK.\u000a        Lancet. 2013. 382: 1278-85.\u000a      NHS Direct. Localised Prostate Cancer: Decision Aid (accessed 2012):\u000a        http:\/\/sdm.rightcare.nhs.uk\/pda\/prostate-cancer\/\u000a\u000a      Coulter A. Implementing shared decision making in the UK. A report for\u000a        the Health Foundation. Produced as a scoping paper for the Health\u000a        Foundation in 2009.\u000a        (http:\/\/www.health.org.uk\/public\/cms\/75\/76\/313\/595\/\u000a          Implementing%20shared%20decision%20making%20in%20the%20UK.pdf?\u000a          realName=vgvUMW.pdf)\u000a       http:\/\/admin.decisionaids.nhsdirect.nhs.uk\/localisedprostatecancer\/node\/6\u000a\u000a      Burford DC, Kirby M, Austoker J. http:\/\/www.cancerscreening.nhs.uk\/prostate\/prostate-booklet-text.pdf.\u000a        Prostate Cancer Risk Management Programme information for primary care.\u000a        PSA testing in asymptomatic men. 2009.\u000a      Burford DC, Kirby M, Austoker J. Prostate Cancer Risk Management\u000a        Programme information for primary care. PSA testing in asymptomatic men.\u000a        Evidence document. January 2010. (http:\/\/www.cancerscreening.nhs.uk\/prostate\/pcrmp02.pdf\u000a\u000a      http:\/\/www.nih.gov\/news\/health\/dec2011\/od-07.htm\u000a    \u000a    ","Title":"\u000a    The ProtecT Trial and Associated Translational Research — Management of\u000a      Localised Prostate Cancer.\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"},{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Neal is Group Leader in the CRUK Cambridge Institute and Urologist (Chair\u000a      of Surgical Oncology, 2002, tenured). Prostate cancer is the most common\u000a      cancer in men and results in 41,000 new cases and 10,700 deaths in the UK\u000a      p.a.; it is predicted to increase to over 60,000 cases p.a.\u000a      in the coming two decades because of an ageing population. Early diagnosis\u000a      is based on measurement of prostate specific antigen (PSA), but this is of\u000a      low sensitivity and specificity. Neal and Donovan have for many years\u000a      highlighted the considerable controversy over screening, early detection\u000a      and treatment because of risks of \"over-diagnosis\" and \"over-treatment\"\u000a      (1). Most men with \"low risk\" localised disease do not die of prostate\u000a      cancer and radical treatments carry sexual, rectal and urinary morbidity.\u000a    In 1998, because of the long natural history and low rate of progression\u000a      of prostate cancer, the three ProtecT PIs (Neal, Cambridge; Donovan,\u000a      Bristol; Hamdy, Oxford) developed the novel concept of Active Monitoring\u000a      (AM) and comparing this with surgery and radiotherapy in a RCT (2). AM\u000a      aims to keep men in a \"window of curability\" whereby only those showing\u000a      progression on careful re-assessment triggered by PSA change and \/ or\u000a      change on rectal examination, are treated radically, this is very\u000a      different from \"watchful waiting\" (where there is no intervention till\u000a      advanced disease is present).\u000a    ProtecT approached 229,000 men in nine centres in the UK: 82,000 were\u000a      enrolled, 8,000 men had high PSA levels and underwent prostate biopsy.\u000a      Almost 3,000 men were diagnosed with prostate cancer and 62% of eligible\u000a      men were recruited (2). Current trials of screening and of treatment have\u000a      confirmed the continued international importance of ProtecT, because only\u000a      ProtecT has a \"screen-detected\" cohort treated by AM. ProtecT is due to\u000a      reach its primary clinical outcome in late 2015, but has already produced\u000a      over 100 papers.\u000a    Intermediate end-points\u000a    Firstly, we showed in ProtecT that novel collaborative methodologies\u000a      between Social Science and Clinical Researchers could ensure recruitment\u000a      to trials that were seen as difficult to recruit to (3), leading to the\u000a      adoption of such approaches to other trials via the NIHR.\u000a    Secondly, many high impact discoveries have been made. We developed an\u000a      internationally important clinically well-annotated bio-repository\u000a      of tissue, blood and serum from 82,000 randomly selected men.\u000a    Research involving Easton and Pharoah (Strangeways, Cambridge) and Eeles\u000a      (ICR, London) was funded by Cancer Research UK (£ 4M) in 2007 to carry out\u000a      genome-wide association studies (GWAS). Neal, Eeles and Easton reasoned\u000a      that the use of an extreme experiment (comparing very low risk and very\u000a      high risk men) would uncover significantly more single nucleotide\u000a      polymorphisms (SNPs) in prostate cancer (4). This proved to be the case.\u000a      This collaboration has led to almost 20 papers in high impact journals\u000a      leading to almost 1,000 cites since 2008. To date, 73 SNPs (4, 5) have\u000a      been found, accounting for around a third of the known genetic background\u000a      in prostate cancer; and this will be used to identify populations for\u000a      targeted screening.\u000a    Other important discoveries have included the observation that genetic\u000a      corrections for PSA can be made, improving sensitivity and specificity\u000a      (6); new biomarkers have been discovered (7) which are dependent on SNP\u000a      risk alleles; and that the known impact of diet on prostate cancer\u000a      development may be mediated by IGF family members (8).\u000a    "},{"CaseStudyId":"30000","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Royal Society"],"ImpactDetails":"\u000a    The research led by Professor O'Rahilly has had impact on patients,\u000a      practitioners and the wider public as follows;\u000a    Impact on Health\u000a    Public health and wellbeing has improved.\u000a    Patients who have serious diseases, the cause of which is not known to\u000a      medical science, suffer not only from the direct adverse effects of their\u000a      disorders but also from the anxiety and demoralisation that result when\u000a      they cannot be provided with any meaningful explanation for their disease.\u000a      O'Rahilly's research has provided patients with meaningful explanations\u000a      for the causes of their serious sometimes life-threatening disorders when\u000a      previously there were none, leading to an immediate and positive impact on\u000a      patient wellbeing and satisfaction and, in an increasing number of cases,\u000a      initiation of trials of novel approaches to therapy. Specifically,\u000a      O'Rahilly, Savage and Semple have discovered or made major contributions\u000a      to the discovery of 10, previously unrecognised, genetic syndromes of\u000a      severe insulin resistance \/ lipodystrophy and two further syndromes of\u000a      excessive insulin-like action. In several of these disorders understanding\u000a      the molecular basis has suggested specific new treatment strategies which\u000a      are currently being explored in pre-clinical models and a subset in the\u000a      clinic. The publication of these discoveries and their presentation at\u000a      international meetings has led to the same benefits being conferred on\u000a      patients world-wide (1).\u000a    The team have, together with several remarkable patients, also\u000a      established a patient support group for lipodystrophy, one of the more\u000a      common causes of severe insulin resistance, with a website that commenced\u000a      in August 2006 (2). The support group now comprises >150 members and\u000a      the website is visited ~500-1000 times per month on average by people in\u000a      the UK and internationally. The patient support group is autonomous but\u000a      the Cambridge team (led by Dr Savage) provide medical advice where\u000a      requested and host annual meetings for the patient group, the most recent\u000a      of which took place in March 2013. Feedback collected at this meeting\u000a      shows support group members greatly value the clinical and research\u000a      insights into the condition that it provides, as well as the opportunity\u000a      to meet others with similar conditions (3).\u000a    New diagnostics have been adopted\u000a    The success of this research programme has played an important role in\u000a      driving clinical diagnostic innovations. This has permitted the use of a\u000a      simple, cheap, biochemical screen that involves measurement of serum\u000a      adiponectin (4) for these patients, allowing highly efficient (by limiting\u000a      inappropriate and expensive genetic analysis of large genes (INSR gene has\u000a      >20 exons)), targeted genetic testing of the gene encoding the insulin\u000a      receptor and greatly accelerating molecular diagnosis (5). This work\u000a      culminated in publication of a proposed revised classification of severe\u000a      insulin resistance syndromes which facilitates both accelerated diagnosis\u000a      and optimises intervention strategies (reference 1; Section 3).\u000a    The development in Cambridge of novel diagnostic algorithms (first\u000a      implemented in 2008) to expedite molecular diagnosis in insulin resistance\u000a      has resulted in rapidly increasing rates of genetic diagnosis among\u000a      patients with severe insulin resistance and lead to increasing numbers of\u000a      patients receiving a specific molecular diagnosis (~42% of new referrals\u000a      to the service). The diagnostic improvements made by the Cambridge team\u000a      have been complemented by access to and clinical use of new peptide-based\u000a      treatments with rarely available therapeutic agents including recombinant\u000a      human leptin (made available by Amylin Inc. solely to Cambridge within the\u000a      UK for named patient use since 2008) and recombinant human IGF-1.\u000a    Impact on commerce and economy\u000a    Amylin was recently acquired by Bristol Myers Squibb Ltd who are\u000a      currently pursuing the licensing of leptin as a therapy for orphan\u000a      diseases of metabolism in the USA and Europe. This work culminated in a\u000a      successful application to the (now) NHS England National Specialist\u000a      Commissioning Team for national commissioning of a multidisciplinary\u000a      clinical service for patients with severe insulin resistance (6,7). This\u000a      was commissioned in April 2011, with support totalling £450,000 per annum,\u000a      funding a full-time NHS consultant and specialist nurse, part-time\u000a      dietician and administrative support, a full range of diagnostic testing,\u000a      and clinical use of leptin and IGF1. This service, which opened in July\u000a      2011, provides clinical, biochemical and genetic assessment for patients\u000a      with severe insulin resistance (7).\u000a    Impact on practitioners and services\u000a    The multi-disciplinary team also provides management advice to referring\u000a      physicians and, in a subset of patients, they initiate and supervise\u000a      either leptin or IGF-1 therapy. To date 88 patients have been seen in this\u000a      specialist clinic and rates of referral are increasing rapidly. Diabetic\u000a      patients with suboptimal glucose (glycaemic) control who have attended our\u000a      service have already, since July 2011, achieved an average reduction in\u000a      HBA1c (standard index for diabetes control) of 1.1%. This level of\u000a      reduction exceeds the goal of a 1% reduction in HBA1c for novel treatments\u000a      for type 2 diabetes and is expected to significantly delay micro- and\u000a      macrovascular complications. Results from a patient feedback survey of the\u000a      service are included in (8).\u000a    ","ImpactSummary":"\u000a    Long-standing research led by Prof. O'Rahilly (Department of Clinical\u000a      Biochemistry) into the genetic and biochemical basis of severe insulin\u000a      resistance syndromes, has led to improvements in diagnosis and care of\u000a      patients internationally. These advances have facilitated revision of\u000a      existing clinical classifications and implementation of novel diagnostic\u000a      and management algorithms for these conditions. The clinical applicability\u000a      of this research was recognised in 2011 by the Department of\u000a      Health-England who have commissioned a national severe insulin resistance\u000a      service in Cambridge, with support totalling ~£450,000 per annum.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. Genetic\u000a      syndromes of severe insulin resistance. Endocr Rev.\u000a      2011;32:498-514.Citations:19 (Scopus 10\/09\/13)\u000a    \u000a\u000a2. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y,\u000a      Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M,\u000a      Lascols O, Capeau J, O'Rahilly S, Magré J, Savage DB, Vigouroux C.\u000a      Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl\u000a      J Med. 2011;364:740-8.Citations: 30 (Scopus 10\/09\/13)\u000a    \u000a\u000a3. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA,\u000a      Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S.\u000a      Dominant negative mutations in human PPARgamma associated with severe\u000a      insulin resistance, diabetes mellitus and hypertension. Nature\u000a      1999;402:880-3.Citations: 30 (Scopus 10\/09\/13)\u000a    \u000a\u000a4. Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A,\u000a      Scott C, Harris J, Smillie BJL, Savage DB, Ramaswami U, De Lonlay P,\u000a      O'Rahilly S, Barroso I, Semple RK. An Activating Mutation of AKT2 and\u000a      Human Hypoglycemia. Science 2011;334:474. Citations: 20 (Scopus 10\/09\/13)\u000a    \u000a\u000a5. Lindhurst MJ, Parker VER, Payne F, Sapp JC, Rudge S, Harris J,\u000a      Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL,\u000a      Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon\u000a      AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJO, Barroso I, Biesecker\u000a      LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused\u000a      by somatic activating mutations in PIK3CA. Nat Genet\u000a      2012;44:928-33.Citations: 12 (Scopus 10\/09\/13)\u000a    \u000a\u000a6. Semple RK, Halberg NH, Burling K, Soos MA, Schraw T, Luan J, Cochran\u000a      EK, Dunger DB, Wareham NJ, Scherer PE, Gorden P, O'Rahilly S. Paradoxical\u000a      elevation of high-molecular weight adiponectin in acquired extreme insulin\u000a      resistance due to insulin receptor antibodies. Diabetes 2007;56:1712-7.\u000a      Citations: 39 (Scopus 10\/09\/13)\u000a    \u000aEvidence of Quality\u000a    In recognition of the importance of this work Prof O'Rahilly has received\u000a      many national and international honours including the Fellowship of the\u000a      Royal Society, Foreign Associateship of the National Academy of Sciences\u000a      of the USA and Hon Membership of the German Society for Internal Medicine.\u000a      He has received Honorary Doctorates from University College Dublin and the\u000a      Universities of Warwick and Dundee Among the international prizes he has\u000a      been awarded are the Heinrich Wieland Prize, the Feldberg Prize, the\u000a      Clinical Endocrinology Award of the Endocrine Society of North America,\u000a      the Luft Award and the Inbev Baillet Latour Prize. He was knighted in June\u000a      2013 for services to medical research. Drs Semple and Savage have been\u000a      awarded highly prestigious Wellcome Trust Senior Research Fellowships to\u000a      purse basic and translational research in this area.\u000a    Selected Research Grant Support\u000a    Stephen O'Rahilly has held continuous Wellcome Trust Programme\u000a      Grant\/Senior Investigator funding since 1999 Most recent renewal: Title:\u000a      Insulin Resistance: lessons from extreme phenotypes Period: 2011-2016\u000a      Amount: £2,072,000\u000a    PI: Stephen O'Rahilly, Wellcome Trust Consortium Grant\u000a    Title: Integrative physiology of common metabolic disease Sponsor:\u000a      Wellcome Trust Period: 2002- 2008Amount: £5,000,000 (£3,199,360 for\u000a      Cambridge)\u000a    PI: David Savage, Wellcome Trust Senior Clinical Fellowship\u000a    Title: Lipodystrophy- A Paradigm For Elucidating Pathogenic Mechanisms In\u000a      The Metabolic Syndrome Sponsor: Wellcome Trust Period: 2010-2015Amount:\u000a      £1,302,000\u000a    PI: Robert Semple, Wellcome Trust Senior Clinical Fellowship\u000a    Title: Genetic Dissection of Mechanisms Linking Insulin Resistance to\u000a      Major Human Diseases Sponsor: Wellcome Trust Period: 2012-2017 Amount:\u000a      £1,609,000\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Letter from Director Emeritus National Institute of Diabetes Digestive\u000a        and Kidney Disorders, Bethesda MD USA (held in University repository)\u000a      Lipodystrophy support group\u000a        http:\/\/www.lipodystrophy.co.uk\u000a\u000a      Feedback from attendees of the Lipodystrophy Support Group Meeting\u000a        hosted in Cambridge 2013 (held in University repository)\u000a      Supraregional Assay Service (SAS)\u000a        http:\/\/www.sas-centre.org\/centres\/hormones\/cambridge.html\u000a\u000a      Registered Genetic Tests\u000a        UK Genetic Testing Network: http:\/\/www.ukgtn.nhs.uk\/gtn\u000a        Orphanet: http:\/\/www.orpha.net\/consor\/cgi-bin\/index.php\u000a\u000a      National Commissioning\u000a        http:\/\/www.specialisedservices.nhs.uk\/service\/insulin-resistant-diabetes-service\u000a        National Specialised Commissioning Team; 2nd Floor, Southside; 105\u000a        Victoria Street; London\u000a        SW1E 6QT; Direct Line: 020 7932 2601; Email: Commissioners@nsct.nhs.uk\u000a\u000a      National Severe Insulin Resistance Service\u000a        http:\/\/www.cuh.org.uk\/addenbrookes\/services\/clinical\/severe_insulin_resistance_service\/severe_insulin_resistance_service_index.html\u000a\u000a      Results of a Patient Satisfaction Questionnaire for the National\u000a        Severe Insulin Resistance Service (February 2013) (held in University\u000a        repository)\u000a    \u000a    ","Title":"\u000a    Translating Genetic Insights into Improved Clinical Diagnosis and Therapy\u000a      of Severe Insulin Resistance.\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Severe insulin resistance and lipodystrophy are rare but devastating\u000a      disorders associated with high morbidity and early mortality. Their rarity\u000a      has denied patients suffering from them widespread access to diagnostic\u000a      expertise, commonly leaving them subject to suboptimal clinical management\u000a      and often very poor outcomes, including badly controlled diabetes, with\u000a      attendant micro- and macrovascular complications, pancreatitis, chronic\u000a      liver disease and subfertility.\u000a    The underpinning research was instigated by Stephen O'Rahilly (Professor\u000a      of Metabolic Medicine 1996-2001, Professor of Clinical Biochemistry and\u000a      Medicine 2001-present) at the University of Cambridge, with more recent\u000a      co-direction by Drs David Savage (Senior Research Associate since 2006)\u000a      and Robert Semple (Senior Research Associate since 2008), each of whom\u000a      trained in the O'Rahilly laboratory. The specific findings leading to the\u000a      described impact arose from genetic, biochemical and physiological studies\u000a      undertaken between 1996 and 2011.\u000a    The guiding strategy was to identify and recruit, through widespread\u000a      international collaboration, patients with severe forms of insulin\u000a      resistance but not severe obesity, to a genetic and clinical study. These\u000a      efforts led to the establishment of a unique collection (`biobank') of DNA\u000a      and blood samples from patients with severe insulin resistance. Since 1996\u000a      the cohort has grown to include samples from over 1000 patients worldwide.\u000a      The research used the best available genetic techniques to determine the\u000a      genetic aetiology of the severe metabolic derangement. The precise genetic\u000a      basis for 10 previously uncharacterised syndromes characterised by\u000a      impaired or excessive insulin action have been identified to date. The\u000a      disorders are now primarily classified according to the gene in which\u000a      pathogenic mutations were identified: 1) PPARG (1999); 2) PPARG\/PPP1R3A\u000a      (2002); 3) AKT2 (2004); 4) TBC1D4 (2009); 5) CIDEC (2009); 6) PLIN (2011);\u000a      7) LMNA (2000); 8) BSCL2 (2001); 9) CAV1 (2008); and 10) PCNT (2011) (1-5)\u000a      (underpinning research summarised in reference 1). These syndromes have\u000a      been characterised in detail in terms of both the cellular dysfunction and\u000a      their impact on whole body physiology. This information has aided the\u000a      identification of similarly affected patients worldwide. The research has\u000a      also recently identified two genetic syndromes characterised by excessive\u000a      insulin-like action (4,5) Using biomarkers not in routine clinical use they were able to establish\u000a      a novel biochemical fingerprint that reliably identifies certain subgroups\u000a      and allows targeting of subsequent genetic analyses (6).Highly related\u000a      research, led by Professor O'Rahilly (1997-present), regarding the effects\u000a      of recombinant leptin therapy on severely obese children with congenital\u000a      leptin deficiency also provided underpinning information and experience\u000a      important in later impact on treating patients with severe insulin\u000a      resistance.\u000a    "},{"CaseStudyId":"30008","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    This research has identified two important reasons why infection rates of\u000a      M. abscessus are\u000a      increasing in patients with CF, namely predisposition to infection through\u000a      azithromycin therapy\u000a      and person-to-person transmission of infection.\u000a    This work has impacted on patients with Cystic Fibrosis in the UK and\u000a      internationally, their\u000a      families and the health professionals who care for them by: a) increasing\u000a      understanding of how\u000a      people acquire M. abscessus infection; b) changing the way\u000a      azithromycin is used to treat\u000a      patients with Cystic Fibrosis; c) driving changes to how CF patients are\u000a      cared for and protected\u000a      from cross-infection within hospital and at home and d) changing how air\u000a      ventilation systems\u000a      are designed in Cystic Fibrosis centres, such as the planned unit in new\u000a      Papworth Hospital.\u000a      The finding that long-term azithromycin therapy impairs host immunity to\u000a      NTM was widely\u000a      discussed within the CF community (1,2), the media (3) and at CF\u000a      conferences (4) has led to\u000a      the following specific changes in guidelines for clinical practice to\u000a      ensure safer use of this drug\u000a      (1,5):\u000a    \u000a      increased the frequency of sputum sampling for NTM in CF and non-CF\u000a        patients receiving\u000a        long term azithromycin\u000a      patients with previous or current NTM infection should not receive\u000a        azithromycin apart from\u000a        as a component of multidrug treatment regimens\u000a      Azithromycin should not be used as a component in treatment regimens\u000a        for macrolide\u000a        resistant NTM infection.\u000a    \u000a    The finding that person-to-person transmission of M. abscessus\u000a      occurs frequently amongst\u000a      patients with Cystic Fibrosis was widely disseminated by national (BBC;\u000a      ref 6) and international\u000a      (7-10) media organisations and the UK CF Trust (11).\u000a      Since these transmission events occurred through indirect spread and\u000a      despite national\u000a      standards of infection control, there is concern that urgent changes to\u000a      cross-infection protocols\u000a      are required (11).\u000a    This research has already led to changes in infection control at Papworth\u000a      Hospital (12):\u000a    \u000a      Individuals with M. abscessus infection now wear a surgical\u000a        mask at all times within the\u000a        hospital buildings except when in a ward side room or a clinic room and\u000a        are nursed in a\u000a        negative pressure single room separate from the CF ward;\u000a      staff with structural lung disease are advised against working with\u000a        these individuals;\u000a      staff caring for NTM infected patients now wear protective clothing\u000a        when performing\u000a        aerosol-generating procedures and room and equipment cleaning policies\u000a        have been\u000a        changed\u000a    \u000a    This work has also led to changes in the design of the Cystic Fibrosis\u000a      centre within the new\u000a      Papworth Hospital building to ensure all rooms have balanced ventilation\u000a      allowing negative\u000a      pressure isolation for individuals with M. abscessus.\u000a    ","ImpactSummary":"\u000a    Infection of patients with cystic fibrosis (CF) with the\u000a      multidrug-resistant Nontuberculous\u000a      mycobacteria (NTM), Mycobacterium abscessus, has rapidly increased over\u000a      the past decade and\u000a      currently affects 5-10% of CF patients worldwide. Our work has identified\u000a      two possible\u000a      mechanisms by which M. abscessus infection rates may be increasing:\u000a      chronic azithromycin\u000a      therapy may predispose individuals to infection through inhibition of\u000a      autophagic-killing of\u000a      mycobacteria; secondly, there is frequent person-to-person transmission of\u000a      M. abscessus despite\u000a      conventional infection control measures. This research has had a direct\u000a      impact on how CF is\u000a      treated, and has influenced infection control guidelines throughout the\u000a      UK.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000aRenna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ,\u000a      Cusens D, Coulter\u000a      S, Cooper J, Bowden AR, Newton SM, Kampmann B, Helm J, Jones A, Haworth\u000a      CS, Basaraba\u000a      RJ, DeGroote MA, Ordway DJ, Rubinsztein DC, Floto RA. Azithromycin\u000a        blocks autophagy and may predispose cystic fibrosis patients to\u000a        mycobacterial infection. J Clin Invest. 2011. 121:3554-63.\u000a    \u000a\u000aBryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T, Reacher\u000a      M, Haworth CS,\u000a      Curran MD, Harris SR, Peacock SJ, Parkhill J, Floto RA (2013) Whole-genome\u000a        sequencing to identify transmission of Mycobacterium abscessus between\u000a        patients with cystic fibrosis: a retrospective cohort study. Lancet.\u000a      2013 May 4;381(9877):1551-60.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    \u000a      http:\/\/www.cff.org\/treatments\/Therapies\/Respiratory\/Azithromycin\/\u000a      http:\/\/www.osservatoriomalattierare.it\/fibrosi-cistica\/1152--fibrosi-cistica-luso-di-azitromicina-\u000a          predispone-i-pazienti-ad-infezioni-da-micobatteri\u000a      http:\/\/medicalxpress.com\/news\/2012-04-autophagy-self-eating-good.html\u000a      NACFC 2012 Orlando Florida Azithromycin pro\/con debate Prof Lisa\u000a        Saiman and Prof Kors van\u000a        de Ent http:\/\/www.officiumroma.it\/Doc._Info_files\/News%20dal%20NACF%20Meeting%20-%20Majo.pdf\u000a\u000a      Papworth Hospital Adult Cystic Fibrosis Unit Protocols for management\u000a        of Nontuberculous\u000a        Mycobacterial infection (Published June 2013)\u000a\u000a      BBC Radio 4 Today programme April 1st 2013; BBC Radio\u000a        Cambridgeshire Breakfast\u000a        programme April 1st 2013; http:\/\/www.bbc.co.uk\/news\/health-21965088\u000a\u000a      http:\/\/www.healio.com\/infectious-disease\/emerging-diseases\/news\/online\/%7B45939DC7-8055-44A5-9990-F21B26E001A2%7D\/Patient-to-patient-transmission-of-M-abscessus-common-in-cystic-fibrosis\u000a      http:\/\/www.sciencedaily.com\/releases\/2013\/03\/130329090307.htm\u000a      http:\/\/www.medscape.com\/viewarticle\/781727\u000a      http:\/\/ntmnews.com\/index.php\/ntm-news-flash\/179-emerging-cf-pathogen-is-transmissible\u000a      \u000ahttps:\/\/www.cysticfibrosis.org.uk\/news\/latest-news\/lancet-cross-infection-report.aspx\u000a       https:\/\/www.cysticfibrosis.org.uk\/news\/latest-news\/new-cross-infection-guidelines-taking-shape.aspx\u000a\u000a      Papworth Hospital Infection Control Policy (June 2013)\u000a    \u000a    ","Title":"\u000a    Transforming the management of Cystic Fibrosis patients infected with\u000a      Nontuberculous\u000a      mycobacteria\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Dr Andres Floto (Principal Investigator; Cambridge Institute for Medical\u000a      Research & Department of\u000a      Medicine, 2008-current).\u000a    Floto and colleagues used a number of complementary approaches to study\u000a      the link between long-term\u000a\u0009  azithromycin use by adults with CF and M. abscessus\u000a      infection. An epidemiological analysis\u000a      of CF patients attending Papworth Hospital from 2003 to 2008 showed that\u000a      azithromycin use was\u000a      strongly associated with M. abscessus infection (Renna et al\u000a      2011). Furthermore, they\u000a      demonstrated by ex vivo analysis of primary human macrophages that\u000a      concentrations of\u000a      azithromycin achieved during therapeutic dosing blocked autophagosome\u000a      clearance, by preventing\u000a      lysosomal acidification, thereby impairing autophagic and phagosomal\u000a      killing of M. abscessus\u000a      (Renna et al 2011). They also studied the effect of azithromycin\u000a      treatment in vivo in mice exposed\u000a      to M. abscessus and showed that animal treated with this agent\u000a      developed chronic infection and\u000a      more severe inflammatory lung damage (Renna et al 2011). These findings\u000a      emphasized the\u000a      essential role for autophagy in the host response to infection with NTM,\u000a      and revealed why chronic\u000a      use of azithromycin may predispose to mycobacterial disease, and\u000a      highlighted the dangers of\u000a      inadvertent pharmacological blockade of autophagy in patients at risk of\u000a      infection with drug-resistant pathogens.\u000a    In a separate publication (Bryant et al 2013), Floto and colleagues\u000a      performed whole genome\u000a      sequencing and antimicrobial susceptibility testing on 168 consecutive\u000a      isolates of M. abscessus\u000a      from 31 patients attending an adult CF centre between 2007-2011. In\u000a      parallel, they undertook\u000a      detailed environmental testing for NTM and defined potential opportunities\u000a      for contact between\u000a      patients both in and out of hospital using social network analysis. This\u000a      study revealed for the first\u000a      time that M. abscessus could be transmitted from\u000a      patient-to-patient through an indirect, most likely\u000a      aerosol route, and that transmission events occurred frequently despite\u000a      rigorous implementation of\u000a      national standards of infection control.\u000a    "},{"CaseStudyId":"30010","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    PREDICT is implemented online as a national resource with the web\u000a      interface being hosted on a\u000a      NHS web-server at www.predict.nhs.uk.\u000a      The monthly hits (> 4,000) on the website indicate clearly\u000a      the impact of the tool.\u000a    One of the key decisions in the management of women with early breast\u000a      cancer is whether or not\u000a      to offer adjuvant chemotherapy in conjunction with primary surgery and\u000a      radiotherapy. The key\u000a      output of PREDICT is the expected absolute reduction in mortality at five\u000a      and ten years associated\u000a      with adjuvant chemotherapy.\u000a    Cambridge Breast Unit (CBU)\u000a    Until 2010 the CBU estimated absolute benefits of chemotherapy were\u000a      estimated using Adjuvant!\u000a      Online. During 2010 and 2011 both PREDICT and Adjuvant! Online were used\u000a      in parallel.\u000a    Clinical audit\u000a    Demographically, the use of PREDICT could benefit 18% of women worldwide.\u000a      The Cambridge\u000a      Breast Unit carried out an audit of the first 200 patients discussed when\u000a      both Adjuvant! Online and\u000a      PREDICT were used by the multi-disciplinary team [1]. The chemotherapy\u000a      recommendations that\u000a      would have been made based on the output from each model were then\u000a      compared. In 163\u000a      patients (82 per cent) the chemotherapy decision would have been the same\u000a      whichever model was\u000a      used. A different recommendation would have occurred for 37 patients (18\u000a      per cent), which would\u000a      benefit them, some women avoiding unnecessary chemotherapy, others having\u000a      effective treatment\u000a      which would not otherwise have been given.\u000a    Change in practice\u000a    Since 2012 PREDICT has been the only model used routinely in Cambridge\u000a      for all patients being\u000a      discussed at the weekly multi-disciplinary team meeting. The absolute\u000a      benefit of adjuvant\u000a      chemotherapy estimated by PREDICT is used to guide the use of adjuvant\u000a      chemotherapy\u000a      according to the guideline described in section 2.\u000a    Other clinical departments in the UK\u000a    We have had multiple requests from clinicians for the incorporation of\u000a      additional features indicating\u000a      that the model is being widely used. PREDICT is used by the\u000a      multi-disciplinary clinical teams in\u000a      Belfast, Brighton, Derby, Dundee, Oxford and Sheffield, but the web usage\u000a      statistics from 2011\u000a      suggest that PREDICT is also being used widely across the country.\u000a      The impact of PREDICT on clinical practice is clearly demonstrated from\u000a      the extensive use of the\u000a      web interface (see below).\u000a    Public, Patient Partnership\u000a    PREDICT has been widely reported in regional and national media including\u000a      ITV, The Times and\u000a      The Daily Mail (ref 2). We have clear evidence that women with early\u000a      breast cancer are accessing\u000a      the interface in order to determine their own risk and to help them in\u000a      their discussion with their\u000a      oncologists about treatment options — this is very much in keeping with\u000a      current thinking to\u000a      empower patients through knowledge to play an important role in their own\u000a      care.\u000a    Web usage data\u000a    PREDICT was designed to have a user-friendly interface to help clinicians\u000a      in making clinical\u000a      management decisions. Informal feedback from clinicians from both\u000a      Cambridge and elsewhere\u000a      has indicated that the interface is easy to use.\u000a    The number of visits to the web site each month has increased steadily\u000a      since its launch in January\u000a      2011, with 3,266 visits in April 2013.\u000a\u0009  \u000a\u0009  Monthly web usage statistics for the PREDICT website, Jan 2011-Jan\u000a        2013\u000a\u0009  \u000a    There have been 43,870 visits to the web site with 70 per cent of the\u000a      visits (30,563) being\u000a      accessed from UK and ten per cent (4,468) from USA. The web site is\u000a      visited from all over the UK,\u000a      with London accounting for 17 per cent and Cambridge accounting for just 1\u000a      per cent of all traffic\u000a      on the web site (ref 3).\u000a    ","ImpactSummary":"\u000a    PREDICT is a prognostication and treatment benefit decision aid aimed at\u000a      aiding the breast cancer\u000a      multi-disciplinary team in the management of women with early breast\u000a      cancer. The user-friendly,\u000a      web-based tool was developed in collaboration with the Cambridge Breast\u000a      Unit multi-disciplinary\u000a      team, the Eastern Cancer Registration and Information Centre. Implemented\u000a      online, PREDICT is\u000a      hosted on a NHS web-server. Since 2012 PREDICT has been used widely by\u000a      clinicians\u000a      throughout the UK and world-wide.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Wishart GC, Azzato EM, Greenberg DC, Rashbass J, Kearins O, Lawrence\u000a      G, Caldas C,\u000a      Pharoah PD. PREDICT: a new UK prognostic model that predicts survival\u000a      following surgery\u000a      for invasive breast cancer. Breast Cancer Res. 2010;12(1):R1.\u000a    \u000a\u000a2. Wishart GC, Bajdik CD, Azzato EM, Dicks E, Greenberg DC, Rashbass J,\u000a      Caldas C,\u000a      Pharoah PD. A population-based validation of the prognostic model PREDICT\u000a      for early\u000a      breast cancer. Eur. J. Surg. Oncol. 2011;37(5):411-7.\u000a    \u000a\u000a3. Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling\u000a      J, Cheang MC,\u000a      Gelmon K, Nielsen TO, Blomqvist C, Heikkila P, Heikkinen T, Nevanlinna H,\u000a      Akslen LA,\u000a      Begin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L,\u000a      Giles GG,\u000a      Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME,\u000a      Lissowska\u000a      J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning\u000a      AM,\u000a      Humphreys M, Easton DF, Garcia-Closas M, Caldas C, Pharoah PD, Huntsman D.\u000a      Subtyping of breast cancer by immunohistochemistry to investigate a\u000a      relationship between\u000a      subtype and short and long term survival: a collaborative analysis of data\u000a      for 10,159 cases\u000a      from 12 studies. PLoS Med 2010;7(5):e1000279.\u000a    \u000a\u000a4. Wishart GC, Bajdik CD, Dicks E, Provenzano E, Schmidt MK, Sherman M,\u000a      Greenberg DC,\u000a      Green AR, Gelmon KA, Kosma VM, Olson JE, Beckmann MW, Winqvist R, Cross\u000a      SS,\u000a      Severi G, Huntsman D, Pylkas K, Ellis I, Nielsen TO, Giles G, Blomqvist C,\u000a      Fasching PA,\u000a      Couch FJ, Rakha E, Foulkes WD, Blows FM, Begin LR, Van't Veer LJ, Southey\u000a      M,\u000a      Nevanlinna H, Mannermaa A, Cox A, Cheang M, Baglietto L, Caldas C,\u000a      Garcia-Closas M,\u000a      Pharoah PD. PREDICT Plus: development and validation of a prognostic model\u000a      for early\u000a      breast cancer that includes HER2. Br. J. Cancer 2012;107(5):800-7.\u000a    \u000a\u000a5. Ali HR, Dawson SJ, Blows FM, Provenzano E, Leung S, Nielsen T, Pharoah\u000a      PD, Caldas C.\u000a      A Ki67\/BCL2 index based on immunohistochemistry is highly prognostic in\u000a      ER-positive\u000a      breast cancer. J. Pathol. 2012;226(1):97-107.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a\u0009\u000a    Loh S-W, Rodriguez-Miguelez M, Pharoah P, Wishart G. A\u000a      comparison of chemotherapy\u000a      recommendations using the Predict and Adjuvant models. Eur. J. Surg.\u000a        Oncol.\u000a      2011;37(5):S21-S22.\u000a    Press coverage: see http:\/\/www.predict.nhs.uk\/press.shtml\u000a      for details.\u000a    Web usage statistics from Google Analytics at https:\/\/www.google.com\/analytics\u000a\u000a\u0009\u000a    ","Title":"\u000a    PREDICT: A prognostication and treatment benefit decision aid for early\u000a      breast cancer\u000a    ","UKLocation":[{"GeoNamesId":"2651347","Name":"Derby"},{"GeoNamesId":"2654710","Name":"Brighton"},{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"2655984","Name":"Belfast"},{"GeoNamesId":"2638077","Name":"Sheffield"},{"GeoNamesId":"2640729","Name":"Oxford"},{"GeoNamesId":"2650752","Name":"Dundee"},{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The PREDICT model was developed in 2010 by a team jointly led by\u000a      Professor Carlos Caldas\u000a      (University Professor 2006-present, in the department of Oncology) and\u000a      Professor Paul Pharoah\u000a      (UOA 2: CR-UK Senior Clinical Research Fellow 1999-2009, University Reader\u000a      2009-13,\u000a      University Professor 2013-present, in the department of Public Health and\u000a      Primary Care).\u000a    Patients treated in the Cambridge Breast Unit are stratified for adjuvant\u000a      chemotherapy according to\u000a      a guideline developed in 2004. This takes into account the serious adverse\u000a      events that occur with\u000a      chemotherapy and that as a consequence, \"many physicians consider a\u000a      cut-off of an additional 3%\u000a      or more added benefit sufficient to justify recommending treatment\". Thus,\u000a      for an absolute survival\u000a      benefit of < 3%, chemotherapy is not recommended, for an absolute\u000a      survival benefit of 3-5% the\u000a      benefits and harms are considered equivalent and discussed with the\u000a      patient, for an absolute\u000a      benefit of >5% chemotherapy is recommended.\u000a    Until 2010 the absolute benefits of chemotherapy were estimated using\u000a      Adjuvant! Online, an online\u000a      prognostic model developed over a decade ago by an American oncologist\u000a      (Peter Ravdin). This is\u000a      based on US data and has not been validated with UK data. Furthermore,\u000a      Adjuvant! Online does\u000a      not include several important prognostic variables including mode of\u000a      detection and molecular\u000a      biomarkers such as tumour HER2 status. Thus there was a clinical need for\u000a      an equivalent model,\u000a      based on and validated using UK data that was flexible and able to\u000a      incorporate additional\u000a      prognostic variables.\u000a    Research carried out in Cambridge allowed the development of the PREDICT\u000a      model, which was\u000a      based on survival-time data on 5,700 women with early breast cancer\u000a      treated between 1999 and\u000a      2003. These data were obtained through the Eastern Cancer Registration and\u000a      Information Centre\u000a      and used to determine the influence of key prognostic variables on\u000a      survival [1]. The model was\u000a      then validated using an independent data set from the West Midlands Cancer\u000a      Intelligence Unit [1].\u000a      The PREDICT web interface was developed in 2010 and is hosted by the\u000a      Eastern Cancer\u000a      Registration and Information Centre.\u000a    In order to compare directly the performance of Adjuvant! Online and\u000a      PREDICT, a second\u000a      validation of PREDICT was carried out using the same data set. While both\u000a      models performed\u000a      well, the breast cancer specific survival calibration for PREDICT was\u000a      significantly better than that\u000a      of Adjuvant! Online with similar discrimination [2].\u000a    In parallel with the PREDICT model development work, Caldas and Pharoah\u000a      have led a research\u000a      programme investigating the molecular pathology of breast cancer in\u000a      collaboration with other\u000a      groups from the international Breast Cancer Association Consortium (BCAC).\u000a      This research has\u000a      enabled further development of PREDICT in response to feedback from\u000a      clinicians and requests for\u000a      additional features in the model. In particular, there were many requests\u000a      to incorporate tumour\u000a      HER2 and KI67 status into the model. Results from one of the BCAC projects\u000a      were used to enable\u000a      the incorporation of HER2 into the model [3], with the new PREDICT model\u000a      being further validated\u000a      using the British Columbia data set used to validate the original model\u000a      [4]. More recently, the\u000a      results from another of our molecular pathology studies has informed the\u000a      incorporation of tumour\u000a      KI67 status into the model [5].\u000a    "},{"CaseStudyId":"30012","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Impact on health: Work by Clark on producing a non-depleting and\u000d\u000a      non-mitogenic Fc modified\u000d\u000a      antibody through use of an aglycosylated IgG1 Fc region in the anti-CD3\u000d\u000a      antibody (Bolt et al 1993)\u000d\u000a      led to the development of otelixizumab, which was licensed to GSK in\u000d\u000a      October 2007. It has since\u000d\u000a      been tested in 8 clinical trials, including phase 3 trials for Type 1\u000d\u000a      Diabetes Mellitus (NCT00678886\u000d\u000a      13\/5\/2008 & NCT01123083 11\/5\/2010) and on-going Phase 1 trials in\u000d\u000a      Rheumatoid Arthritis\u000d\u000a      (NCT01077531 25\/2\/2010 & NCT01101555 8\/4\/2010). The two phase 3 trials\u000d\u000a      for Type 1 diabetes\u000d\u000a      both failed to reach significance for the primary end points and a current\u000d\u000a      on-going trial is now\u000d\u000a      exploring a different dosing and delivery route (NCT00946257 23\/7\/2009).\u000d\u000a    The published human clinical volunteer studies by Clark and colleagues\u000d\u000a      have demonstrated that\u000d\u000a      antibodies with selected modifications to the Fc regions have the desired\u000d\u000a      properties for the\u000d\u000a      intended purposes (Armour et al 2006, Ghevaert et al 2013). These\u000d\u000a      volunteer studies showed that\u000d\u000a      cells coated with the Fc modified antibody had longer survival times than\u000d\u000a      cells coated with wild\u000d\u000a      type IgG1 and that this could extend to situations where there was a\u000d\u000a      mixture of the two antibodies\u000d\u000a      on the cell surface as would be encountered in an affected foetus. These\u000d\u000a      results identify an\u000d\u000a      alternative strategy for the treatment of FMAITP, a disorder that\u000d\u000a      currently is usually treated with\u000d\u000a      high doses of intravenous IVIg and prednisone, an expensive therapy that\u000d\u000a      also is associated with\u000d\u000a      serious side effects and potential risks of infection (IVIg is a prepared\u000d\u000a      from pooled human plasma\u000d\u000a      donations).\u000d\u000a    The pharmaceutical company Pfizer has taken a license (agreement dated\u000d\u000a      Dec 18th 2009) to\u000d\u000a      develop a number of therapeutic antibodies that incorporate the mutations\u000d\u000a      described in Armour et\u000d\u000a      al 1999, protected by world patent application WO1999058572 and US7597889.\u000d\u000a      Pfizer had a\u000d\u000a      clinical requirement that their antibodies would be non-depleting and\u000d\u000a      non-activating, with a low in-vivo\u000d\u000a      toxicity profile, which could be provided by incorporation of our modified\u000d\u000a      Fc regions into their\u000d\u000a      products. They initiated clinical trials with several licensed antibodies\u000d\u000a      within the period 2008-2013\u000d\u000a      that are listed on the US NIH website ClinicalTrials.gov. These include 25\u000d\u000a      listed trials with the anti-nerve\u000d\u000a      growth factor antibody tanezumab, several of which have been in phase 3\u000d\u000a      (NCT00744471\u000d\u000a      29\/8\/2008, NCT00809783 16\/12\/2008, NCT00733902 11\/8\/2008, NCT00863304\u000d\u000a      13\/4\/2009).\u000d\u000a      Another antibody ponezumab to the beta-amyloid protein has been tested in\u000d\u000a      8 listed trials for the\u000d\u000a      treatment of Alzheimer's disease including three phase 2 trials\u000d\u000a      (NCT00722046 23\/7\/2008,\u000d\u000a      NCT00945672 22\/7\/2009, NCT01821118 4\/3\/2013). RN316 specific for\u000d\u000a      Proprotein Convertase\u000d\u000a      Subtilisin Kexin type 9 (PCSK9) is a therapeutic antibody aimed at\u000d\u000a      lowering cholesterol levels and\u000d\u000a      has been used in 7 listed trials, including two at phase 2 (NCT01342211\u000d\u000a      25\/4\/2011, NCT01592240\u000d\u000a      3\/5\/2012). A fourth antibody RN564 has recently entered phase 1 clinical\u000d\u000a      trials for treatment of\u000d\u000a      osteoporosis (NCT01293487 9\/2\/2011). The constant region used in these\u000d\u000a      antibodies have\u000d\u000a      behaved as expected in that the antibodies had extended half-lives, normal\u000d\u000a      biodistribution, and no\u000d\u000a      reported side-effects attributable to Fc mediated functions. Full results\u000d\u000a      of the Phase III trial with\u000d\u000a      Tanezumab in osteoarthritis have just been published (Spierings et al\u000d\u000a      2013) and this reports\u000d\u000a      significant efficacy in pain relief and no additional safety issues with\u000d\u000a      the antibody.\u000d\u000a    Commercial impact: The modifications that have been identified in\u000d\u000a      Dr Clark's research have been\u000d\u000a      protected by a number of patent families with patents that are still in\u000d\u000a      force and that have been\u000d\u000a      assigned by the inventors and Cambridge University to BTG plc.\u000d\u000a    The aglycosylated IgG1 CD3 antibody otelixizumab is protected by the\u000d\u000a      world patent family\u000d\u000a      WO1993019196 (Bolt et al 1993) and a recently granted patent US RE43898\u000d\u000a      (Gorman et al 2013)\u000d\u000a      and US6767996 (Bolt et al 2004). These have all been assigned to BTG plc.\u000d\u000a      Other intellectual\u000d\u000a      property relating to this antibody has been created by Waldmann and\u000d\u000a      colleagues at Oxford\u000d\u000a      University and this too was assigned to BTG plc. In an agreement dated 18th\u000d\u000a      Sep 2012 the two\u000d\u000a      Universities of Oxford and Cambridge entered into a joint revenue sharing\u000d\u000a      arrangement with BTG\u000d\u000a      plc under which all the income arising from the various IPRs is to be\u000d\u000a      pooled and then shared\u000d\u000a      equally. Between 2008 and 2013 £2.8 million has been received by Cambridge\u000d\u000a      under these\u000d\u000a      arrangements.\u000d\u000a    Mutations resulting in non-depleting and non-activating Fc regions but\u000d\u000a      retaining low\u000d\u000a      immunogenicity and also binding to the neonatal Fc receptor FcRn have been\u000d\u000a      protected by the\u000d\u000a      world patent family WO1999058572 (Armour, Clark and Williamson 1999) with a\u000d\u000a      granted US patent\u000d\u000a      US7597889 (Armour, Clark and Williamson 2009). This patent has been\u000d\u000a      licensed to Pfizer for use\u000d\u000a      in multiple products, four of which are already in clinical trials (see\u000d\u000a      above) with others still at the\u000d\u000a      pre-clinical stage (e.g. RN 307). In an agreement dated 20th\u000d\u000a      Feb 2013, GSK have taken out a\u000d\u000a      research license to explore the applicability of this technology to one of\u000d\u000a      their research programmes\u000d\u000a      in order to reduce the unwanted toxicity that they have encountered with\u000d\u000a      their antibody. Between\u000d\u000a      2008 and 2013 these licenses have returned £382,148 in revenue to\u000d\u000a      Cambridge Enterprise Ltd.\u000d\u000a      Vectors encoding these mutations for research use are available from the\u000d\u000a      San Diego based\u000d\u000a      company Invivogen under license and a number of preclinical and research\u000d\u000a      studies have made use\u000d\u000a      of the mutations (e.g. Richter et al 2013)..\u000d\u000a    Recent research by Clark and colleagues has led to further findings\u000d\u000a      identifying residue changes\u000d\u000a      from a human pseudo-gamma sequence that, when introduced into human IgG1,\u000d\u000a      result in\u000d\u000a      increased binding affinity for the inhibitory human Fc receptor FcgRIIb.\u000d\u000a      This receptor is of interest\u000d\u000a      because it plays a role in dampening down and regulating immune responses,\u000d\u000a      such as inhibiting\u000d\u000a      mast cell degranulation mediated by IgE, thereby preventing allergic\u000d\u000a      hypersensitivity reactions.\u000d\u000a      World patent applications have been made under WO2012146934 (Armour and\u000d\u000a      Clark 2012) and\u000d\u000a      the potential to further exploit this technology by commercial licensing\u000d\u000a      and incorporation into\u000d\u000a      therapeutic antibodies is being explored.\u000d\u000a    Specialist Advisory roles: In addition to the licensing of patents\u000d\u000a      and know-how to industry, further\u000d\u000a      commercial impact arises from consultancy and advisory roles of Dr Clark\u000d\u000a      to several established\u000d\u000a      international biotech companies and to several smaller start-up and early\u000d\u000a      stage biotech companies\u000d\u000a      operating in the UK that are developing therapeutic antibody based\u000d\u000a      programmes. In the period\u000d\u000a      2009-2013 Dr Clark has been a member (and since 2012 Chair) of the\u000d\u000a      Scientific Advisory Board of\u000d\u000a      the Centre d'Immunologie Pierre Fabre in France. In 2013 he joined the\u000d\u000a      Scientific Advisory Board\u000d\u000a      of UCB. Smaller biotech companies with which he has worked as an\u000d\u000a      advisor\/consultant during the\u000d\u000a      period 2008-2013 include Antitope Ltd, Crescendo Biologics Ltd, Kymab Ltd\u000d\u000a      & VHsquared Ltd. Dr\u000d\u000a      Clark also provided advice and assistance to licensees of the patents and\u000d\u000a      know-how derived from\u000d\u000a      his laboratory research to the companies: BioAnalab (Millipore), BTG plc,\u000d\u000a      Genzyme, GSK and\u000d\u000a      Pfizer.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research into modified Fc regions for therapeutic antibodies has resulted\u000d\u000a      in the development of\u000d\u000a      antibodies with novel and optimised functions. An aglycosylated anti-CD3\u000d\u000a      antibody called\u000d\u000a      otelixizumab has reached phase 3 clinical trials with GSK and a novel\u000d\u000a      antibody for treatment of\u000d\u000a      fetomaternal alloimmune thrombocytopenia has been tested in human\u000d\u000a      volunteers. The patented\u000d\u000a      technology has been licensed to Pfizer and to GSK for incorporation into\u000d\u000a      their therapeutic antibody\u000d\u000a      programmes with four of these already in clinical trials (tanezumab,\u000d\u000a      ponezumab, RN316 & RN564).\u000d\u000a      Licensing revenue totalling £3.2 million has been returned to the\u000d\u000a      University's company Cambridge\u000d\u000a      Enterprise Ltd in the impact period. In addition, consultancy and advisory\u000d\u000a      services on antibody\u000d\u000a      engineering have been provided to a number of other biopharma companies.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University Cambridge\u000d\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Bolt S,\u000d\u000a\u0009Routledge E,\u000d\u000a\u0009Lloyd I,\u000d\u000a\u0009Chatenoud L,\u000d\u000a\u0009Pope H,\u000d\u000a\u0009Gorman SD,\u000d\u000a\u0009Clark M,\u000d\u000a\u0009Waldmann H.\u000d\u000a      (1993) The generation of a humanized, non-mitogenic CD3 monoclonal\u000d\u000a      antibody which\u000d\u000a      retains in vitro immunosuppressive properties. Eur J Immunol. 23: 403-411.\u000d\u000a    \u000a\u000a2. Abbs IC, Clark M, Waldmann H, Chatenoud L, Koffman CG, Sacks\u000d\u000a      SH (1994) Sparing of\u000d\u000a      first dose effect of monovalent anti-CD3 antibody used in allograft\u000d\u000a      rejection is associated\u000d\u000a      with diminished release of pro-inflammatory cytokines. Ther Immunol 1:\u000d\u000a      325-331\u000d\u000a    \u000a\u000a3. Redpath S, Michaelsen T, Sandlie I, Clark MR. (1998) Activation\u000d\u000a        of complement by human\u000d\u000a        IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52.\u000d\u000a      Immunology\u000d\u000a      93: 595-600\u000d\u000a    \u000a\u000a4. Armour KL, Clark MR, Hadley AG, Williamson LM (1999)\u000d\u000a      Recombinant human IgG\u000d\u000a      molecules lacking Fc receptor I binding and monocyte triggering activities\u000d\u000a      Eur J Immunol\u000d\u000a      29: 2613-2624\u000d\u000a    \u000a\u000a5. Armour KL, Van De Winkel JGJ, LM Williamson LM, Clark MR\u000d\u000a      (2003) Differential binding to\u000d\u000a      human FcgRIIa and FcgRIIb receptors by human IgG wildtype and mutant\u000d\u000a      antibodies\u000d\u000a      Molecular immunology 40: 585-593\u000d\u000a    \u000a\u000a6. Armour KL, Parry-Jones DR, Beharry N, Ballinger JR, Mushens R,\u000d\u000a      Williams RK, Beatty C,\u000d\u000a      Stanworth S, Lloyd-Evans P, Scott M, Clark MR, Peters AM,\u000d\u000a      Williamson LM (2006)\u000d\u000a      Intravascular survival of red cells coated with a mutated human anti-D\u000d\u000a      antibody engineered\u000d\u000a      to lack destructive activity. Blood 107: 2619-2626\u000d\u000a    \u000a\u000a7. Ghevaert C, Wilcox DA, Fang J, Armour KL, Clark MR, Ouwehand\u000d\u000a      WH, Williamson LM\u000d\u000a      (2008) Developing recombinant HPA-1a-specific antibodies with abrogated\u000d\u000a      Fcg receptor\u000d\u000a      binding for the treatment of fetomaternal alloimmune thrombocytopenia\u000d\u000a      J Clinical Invest 118: 2929-2938\u000d\u000a    \u000a\u000a8. Ghevaert C, Herbert N, Hawkins L, Grehan N, Cookson P, Garner SF,\u000d\u000a      Crisp-Hihn A, Lloyd-Evans\u000d\u000a      P, Evans A, Balan K, WH Ouwehand WH, Armour KL, Clark MR,\u000d\u000a      Williamson LM\u000d\u000a      (2013) Recombinant HPA-1a antibody therapy for treatment of fetomaternal\u000d\u000a      alloimmune\u000d\u000a      thrombocytopenia: proof of principle in human volunteers Blood 122:313-320\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    \u000d\u000a      Bolt SL, Clark MR, Gorman SD, Routledge EG, Waldmann H (1993)\u000d\u000a        Anti-CD3\u000d\u000a        Aglycosylated IgG Antibody World Patent WO\/1993\/019196\u000d\u000a      Bolt SL, Clark MR, Gorman SD, Routledge EG, Waldmann H (2004)\u000d\u000a        Humanized anti-CD3\u000d\u000a        specific antibodies. US Patent 6,706,265\u000d\u000a      Gorman SD, Clark MR, Cobbold SP, Waldmann H (2013) Altered\u000d\u000a        antibodies and their\u000d\u000a        preparation. US Patent RE43,898\u000d\u000a      Armour KL, Clark MR, Williamson LML (2009) Binding molecules\u000d\u000a        derived from\u000d\u000a        immunoglobulins which do not trigger complement mediated lysis US Patent\u000d\u000a        7,597,889\u000d\u000a      Armour KL, Clark MR (2012) Binding molecules with biased\u000d\u000a        recognition. World Patent\u000d\u000a        application WO\/2012\/146,934\u000d\u000a      Ghevaert C, Herbert N, Hawkins L, Grehan N, Cookson P, Garner SF,\u000d\u000a        Crisp-Hihn A, Lloyd-Evans\u000d\u000a        P, Evans A, Balan K, WH Ouwehand WH, Armour KL, Clark MR,\u000d\u000a        Williamson LM\u000d\u000a        (2013) Recombinant HPA-1a antibody therapy for treatment of fetomaternal\u000d\u000a        alloimmune\u000d\u000a        thrombocytopenia: proof of principle in human volunteers Blood\u000d\u000a        122:313-320\u000d\u000a      Spierings ELH, Fidelholtz J, Wolfram G, Smith MD, Brown MT, West CR\u000d\u000a        (2013) A phase III\u000d\u000a        placebo- and oxycodone- controlled study of tanezumab in adults with\u000d\u000a        osteoarthritis pain of\u000d\u000a        the hip or knee. Pain 154: 1603-1612\u000d\u000a      Richter F, Liebig T, Guenzi E, Herrmann A, Scheurich P, Pfizenmaier K,\u000d\u000a        Kontermann RE\u000d\u000a        (2013) Antagonistic TNF Receptor One-specific antibody (ATROSAB):\u000d\u000a        Receptor binding\u000d\u000a        and in vitro bioactivity. PLoS ONE 8(8):e72156.\u000d\u000a        doi:10.1371\/journal.pone.0072156\u000d\u000a      Letter of corroboration from the CSO of Antitope Ltd\u000d\u000a      Letter of corroboration from the CEO of Crescendo Biologics Ltd.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Engineering of recombinant therapeutic antibodies to optimize\u000d\u000a      effectiveness\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Dr Mike Clark was a graduate student of the inventor of monoclonal\u000d\u000a      antibodies Dr Cesar Milstein\u000d\u000a      between1978-1981, and then joined Herman Waldmann's group to work on\u000d\u000a      therapeutic antibodies\u000d\u000a      as a Post-doctoral Research Associate (1981-1990). In 1990 Dr Clark was\u000d\u000a      appointed to a\u000d\u000a      Lectureship and in 2007 was promoted to Reader in Therapeutic Immunology\u000d\u000a      in the Department of\u000d\u000a      Pathology. During his post as a Senior Research Associate in Waldmann's\u000d\u000a      group and in\u000d\u000a      collaboration with Greg Winter's group (MRC LMB) he was a co-inventor of\u000d\u000a      the first fully\u000d\u000a      humanized antibody Campath-1H (alemtuzumab) specific for the CD52 antigen\u000d\u000a      on lymphocytes.\u000d\u000a      Campath was approved for treatment of BCLL by both the FDA and EMA in\u000d\u000a      2001. More recently\u000d\u000a      (2013) it was approved by the EMA for treating multiple sclerosis.\u000d\u000a      Campath's properties and\u000d\u000a      therapeutic success formed the basis of subsequent translational research\u000d\u000a      at Cambridge.\u000d\u000a    In the research period, Clark and colleagues continued the theme of\u000d\u000a      research into therapeutic\u000d\u000a      applications of antibodies, in particular investigating the structural\u000d\u000a      features that determine the\u000d\u000a      effector functions of the different human IgG subclasses, and determining\u000d\u000a      how to exploit these\u000d\u000a      structural differences through the generation of optimised and novel\u000d\u000a      mutant Fc regions. The CD52\u000d\u000a      specific Campath-1H (alemtuzumab) antibody was used as one of the key\u000d\u000a      model systems in this\u000d\u000a      research from Clark's laboratory. Work by Clark's group (Redpath et al\u000d\u000a      1998) demonstrated that it\u000d\u000a      was an ideal choice for complement activation. Subsequent work published\u000d\u000a      by Armour et al (1999\u000d\u000a      & 2003) using alemtuzumab as the wildtype example emphasised the\u000d\u000a      importance of the IgG1\u000d\u000a      isotype in binding to human FcgRI and FcgRII receptors. The results of\u000d\u000a      this research have\u000d\u000a      underpinned the ideal choice of the IgG1 subclass for cytotoxic\u000d\u000a      cell-depleting antibodies such as\u000d\u000a      alemtuzumab. However for some therapeutic applications it became clear to\u000d\u000a      Clark that such\u000d\u000a      antibodies could exhibit severe side-effects through cross-linking of Fc\u000d\u000a      receptors. This was\u000d\u000a      particularly evident in the use of anti-CD3 antibodies for\u000d\u000a      immunosuppression in renal allograft\u000d\u000a      rejection where severe side effects resulting from cytokine release\u000d\u000a      syndrome were encountered\u000d\u000a      that could not be completely avoided even with a monovalent CD3 antibody\u000d\u000a      (Abbs et al 1994). This\u000d\u000a      study indicated to Clark and colleagues that further modifications to\u000d\u000a      reduce Fc receptor binding\u000d\u000a      and cross-linking might lead to improved efficacy and with reduced\u000d\u000a      side-effects In 1993 a first\u000d\u000a      step in that direction was taken in collaboration with Waldmann's group\u000d\u000a      when a therapeutic CD3\u000d\u000a      antibody was rendered non-depleting and non-mitogenic through mutation of\u000d\u000a      the conserved N-linked\u000d\u000a      glycosylation site in the Fc region (Bolt et al 1993).\u000d\u000a    In September 1995, Clark began a long term research programme in\u000d\u000a      collaboration with Drs Lorna\u000d\u000a      Williamson and Willem Ouwehand of the National Blood and Transplant\u000d\u000a      Service and University\u000d\u000a      Department of Haematology, based at Addenbrookes Hospital, to try to\u000d\u000a      develop a treatment for\u000d\u000a      fetomaternal alloimmune thrombocytopenia (FMAITP). The disease results\u000d\u000a      from maternal IgG\u000d\u000a      alloantibodies directed towards platelets crossing the placenta and\u000d\u000a      causing platelet destruction in\u000d\u000a      the developing foetus. The research programme sought to develop a\u000d\u000a      recombinant antibody with\u000d\u000a      novel and desired properties: high affinity for the platelet alloantigen\u000d\u000a      HPA-1a, the ability to cross\u000d\u000a      the human placenta via the receptor FcRn, inability to trigger any\u000d\u000a      complement activation or Fc\u000d\u000a      mediated cytotoxicity. The antibody also needed to appear as human as\u000d\u000a      possible so as to avoid an\u000d\u000a      antiglobulin response. Ideally the antibody should block the killing of\u000d\u000a      platelets by natural allo-antibodies\u000d\u000a      produced by the mother during pregnancy. The first stage of the research\u000d\u000a      programme\u000d\u000a      was to produce new mutant antibodies by exchanging residues between the\u000d\u000a      natural human\u000d\u000a      subclasses IgG1, IgG2 and IgG4. These new mutants were tested in model\u000d\u000a      systems using the\u000d\u000a      lymphocyte antigen CD52 (Campath-1H) and the red cell antigen RhD as\u000d\u000a      target antigens (Armour\u000d\u000a      et al 1999 & 2003). In progressing from the pre-clinical to the\u000d\u000a      clinical phase human volunteer\u000d\u000a      studies were conducted of the best candidate Fc region using the red cell\u000d\u000a      antigen RhD as the test\u000d\u000a      system The RhD antigen was selected because of the extensive clinical\u000d\u000a      experience and research\u000d\u000a      literature on the in-vivo properties of anti-D antibodies. This work was\u000d\u000a      successful and identified a\u000d\u000a      mutation called G1-delta-ab as the lead candidate with the desired\u000d\u000a      properties listed above and thus\u000d\u000a      ideal for development of a therapeutic anti-HPA1a antibody (Armour et al\u000d\u000a      1999, 2003, 2006).\u000d\u000a    In 2004 Clark and colleagues began work on expressing and developing the\u000d\u000a      HPA-1a specific\u000d\u000a      antibody for use in a second human volunteer study to demonstrate the\u000d\u000a      in-vivo effectiveness of the\u000d\u000a      antibody in prolonging the survival of platelets. In April 2004, Dr Cedric\u000d\u000a      Ghevaert of the\u000d\u000a      Department of Haematology was recruited as the clinical researcher to help\u000d\u000a      carry out this clinical\u000d\u000a      study. However following the bad clinical experience in volunteers with\u000d\u000a      TeGenero's antibody\u000d\u000a      TGN1412 (March 2006), the MHRA tightened up the regulations of first in\u000d\u000a      man antibody based\u000d\u000a      trials which required Clark and colleagues to do extra testing in-vitro\u000d\u000a      and in-vivo in animal models\u000d\u000a      to minimise any risks of adverse reactions (Ghevaert et al 2008). The\u000d\u000a      results proved satisfactory\u000d\u000a      and the MHRA granted approval for the human volunteer study, which was\u000d\u000a      then completed in late\u000d\u000a      2012; the results have recently been published (Ghevaert et al 2013).\u000d\u000a    "},{"CaseStudyId":"30149","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    X-ray crystallography has grown to be one of the pillars of research and\u000a      development in the\u000a      pharmaceutical industry, where the atomic interactions with drug targets\u000a      of many candidate\u000a      molecules are studied to optimise them in the development of new drugs.\u000a      Industrial\u000a      crystallographers examine numerous complexes with the same target or many\u000a      examples from\u000a      \"druggable\" families of proteins such as kinases, so molecular replacement\u000a      is one of their most\u000a      important tools.\u000a    Phaser met a real need for both academic and industrial\u000a      crystallographers, indicated by its rapid\u000a      adoption in preference to previous programs for carrying out molecular\u000a      replacement calculations.\u000a      After it was released in 2003, it quickly caught on because of success in\u000a      solving a number of\u000a      structures that had resisted years of effort. The 1000th\u000a      download was marked within 15 months of\u000a      the initial release. Already by 2008, 1190 of 6248 X-ray crystal\u000a      structures (19%) released in the\u000a      Protein Data Bank (PDB: www.rcsb.org) cited the use of Phaser (ref. 1).\u000a      From 2008, this has\u000a      continued to grow: 1648 of 6746 (24%) structures released in 2009, 2122 of\u000a      7296 (29%) in 2010,\u000a      2705 of 7468 (36%) in 2011, 3067 of 8302 (37%) in 2012 and 2367 of 5962\u000a      (40%) up to the end of\u000a      August in 2013. Given that X-ray crystal structures account for about 90%\u000a      of new entries in the\u000a      PDB, Phaser has accounted for over 1\/3 of all new macromolecular\u000a      structures in the last three\u000a      years.\u000a    Though most structures in the PDB are contributed by academic\u000a      researchers, it should be noted\u000a      that the pharmaceutical industry makes heavy use of these data, including\u000a      the many structures\u000a      solved with the use of Phaser. Industrial scientists have also rapidly\u000a      adopted Phaser, for the same\u000a      reasons as their academic colleagues.\u000a    Specific examples of impact in the pharmaceutical industry are documented\u000a      in two letters. A\u000a      research fellow at Bristol-Myers Squibb(ref. 2) describes several cases in\u000a      which the use of Phaser\u000a      allowed the solution of structures that had previously been difficult or\u000a      even impossible. In one\u000a      specific example he describes working on the structure of a\u000a      biologic\/target complex, where he had\u000a      only a limited amount of protein and a limited number of crystals and for\u000a      which he states that\u000a      Phaser was \"crucial to the determination of this structure\". An Associate\u000a      Principal Scientist at\u000a      AstraZeneca (ref. 3) states that \"Phaser has been instrumental in solving\u000a      several target structures\u000a      recently, and helped the progress of these projects by making a costly and\u000a      lengthy experimental\u000a      phasing unnecessary, which would otherwise be a bottleneck in a structure\u000a      based drug discovery\u000a      campaign\". AstraZeneca employs about 30 FTEs in structural biology, and\u000a      they \"consider Phaser\u000a      as a tool of choice when solving novel structures by molecular\u000a      replacement\". She also states that\u000a      \"Phaser outperforms other programs and gives better confidence in the\u000a      solution\". Both of these\u000a      researchers in industry emphasise that, by making difficult problems easy,\u000a      valuable time is saved.\u000a    We have clear evidence of wider take-up by industrial users. Licences to\u000a      use Phaser are\u000a      available as part of two packages: CCP4 (about 120 site licences of the\u000a      package, at $9500 per\u000a      licence, to industry including AstraZeneca, Bristol-Myers Squibb,\u000a      GlaxoSmithKline, Hoffmann-La\u000a      Roche, Merck, Novartis and Vertex Pharmaceuticals, ref. 4) and Phenix (13\u000a      industrial participants\u000a      in its consortium, ref. 5). A search of US patents (ref. 6) reveals that\u000a      42 patents filed since the\u000a      beginning of 2008 cite the use of Phaser in the research underlying the\u000a      new intellectual property.\u000a      Considering that there is an average of nearly three years between these\u000a      patent applications being\u000a      filed and granted, this is very much a lower bounds estimate of the impact\u000a      of Phaser on the\u000a      development of new IP. These patents have been assigned to a variety of\u000a      entities, including\u000a      Genentech, Janssen Pharmaceutica, Novo Nordisk and, in the UK, MedImmune\u000a      and Heptares\u000a      Therapeutics.\u000a    The Phaser development team has answered queries about the use of Phaser\u000a      from scientists at\u000a      22 different companies, including Abbott, AstraZeneca, Bristol-Myers\u000a      Squibb, Johnson&Johnson,\u000a      Heptares Therapeutics, Novartis and Sanofi-Aventis. In addition,\u000a      industrial crystallographers\u000a      attend the annual CCP4 Study Weekend and the biannual Phenix Developers'\u000a      Workshop, where\u000a      they take the opportunity to ask questions about the use of Phaser and to\u000a      request new features.\u000a    Industrial royalty revenues received by the Phenix team are shared among\u000a      the partners. The\u000a      Cambridge share of about £180,000 to March 2013 has been distributed among\u000a      the University,\u000a      CIMR, Catalyst (Wellcome Trust) and the Phaser developers.\u000a    ","ImpactSummary":"\u000a    Knowledge of the three-dimensional structures of macromolecules is a\u000a      prerequisite for\u000a      understanding their function at the atomic level, an essential component\u000a      of modern drug\u000a      development. Most structures are determined by X-ray crystallography: the\u000a      majority using\u000a      molecular replacement (MR, which exploits known structures of related\u000a      proteins), and about half of\u000a      the remainder using single-wavelength anomalous diffraction (SAD). The\u000a      Phaser crystallographic\u000a      software, developed by Read and colleagues, implements powerful new\u000a      likelihood-based methods\u000a      for MR and SAD phasing and has made a large impact, accelerating over the\u000a      period 2008-2013.\u000a      At the pharma giant, AstraZeneca, Phaser is considered the \"tool of\u000a      choice\" for solving structures\u000a      by MR.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000aRead, R.J. Pushing the boundaries of molecular replacement with maximum\u000a      likelihood. 2001. Acta\u000a      Cryst. D57: 1373-1382. PMID: 11567148. Citations: 548. Journal impact\u000a      factor: 14.1\u000a    \u000a\u000aStoroni, L.C., McCoy, A.J. and Read, R.J. Likelihood-enhanced fast\u000a      rotation functions. 2004. Acta\u000a      Cryst. D60: 432-438. PMID: 14993666. Citations: 834. Journal impact\u000a      factor: 14.1\u000a    \u000a\u000aMcCoy, A.J., Storoni, L.C. and Read, R.J. Simple algorithm for a\u000a      maximum-likelihood SAD\u000a      function. 2004. Acta Cryst. D60: 1220-1228. PMID: 15213383. Citations: 39.\u000a      Journal impact\u000a      factor: 14.1\u000a    \u000a\u000aMcCoy, A.J., Grosse-Kunstleve, R.W., Storoni, L.C. and Read, R.J.\u000a      Likelihood-enhanced fast\u000a      translation functions. 2005. Acta Cryst. D61: 458-464. PMID: 15805601.\u000a      Citations: 1177.\u000a      Journal impact factor: 14.1\u000a    \u000a\u000aMcCoy, A.J., Grosse-Kunstleve, R.W., Adams, P.D., Winn, M.D., Storoni,\u000a      L.C. and Read, R.J.\u000a      Phaser crystallographic software. 2007. J. Appl. Cryst. 40: 658-674. PMID:\u000a      19461840.\u000a      Citations: 2968. Journal impact factor: 3.3\u000a    \u000a\u000aQian, B., Raman, S., Das, R., Bradley, P., McCoy, A.J., Read, R.J. and\u000a      Baker, D. High-resolution\u000a      structure prediction and the crystallographic phase problem. 2007. Nature\u000a      450: 259-264.\u000a      PMID: 17934447. Citations: 145. Journal impact factor: 38.6\u000a    \u000a\u000aDiMaio, F., Terwilliger, T.C., Read, R.J., Wlodawer, A., Oberdorfer, G.,\u000a      Wagner, U., Valkov, E.,\u000a      Alon, A., Fass, D., Axelrod, H.L., Das, D., Vorobiev, S.M., Iwaï, H.,\u000a      Pokkuluri, P.R. and Baker,\u000a      D. Improved molecular replacement by density- and energy-guided protein\u000a      structure\u000a      optimization. 2011. Nature 473: 540-543. PMID: 21532589. Citations: 43.\u000a      Journal impact\u000a      factor: 38.6\u000a    \u000a\u000aRead RJ and McCoy AJ. Using SAD data in Phaser. 2011. Acta Cryst. D67:\u000a      338-344. PMID:\u000a      21460452. Citations: 12. Journal impact factor: 14.1.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"1","Level2":"4","Subject":"Statistics"},{"Level1":"10","Level2":"6","Subject":"Computer Hardware"},{"Level1":"8","Level2":"1","Subject":"Artificial Intelligence and Image Processing"}],"Sources":"\u000a    \u000a       Statistics on Phaser usage were obtained from the PDB search\u000a        facility:\u000a        www.rcsb.org\/pdb\/search\/advSearch.do,\u000a        searching for \"phaser\" in the \"Text Search\" query\u000a        type.\u000a       Letter from Research Fellow, Protein Science and Structure,\u000a        Bristol-Myers Squibb Research\u000a        and Development, 1 January 2013.\u000a       Letter from Associate Principal Scientist, Structure and Biophysics,\u000a        Discovery Sciences, Astra\u000a        Zeneca. 23 January 2013.\u000a       CCP4 industrial licence holders are listed each year in the special\u000a        edition of Acta\u000a        Crystallographica Section D containing the proceedings of the annual\u000a        CCP4 Study Weekend,\u000a        published most recently in part 4 of volume 68, April 2012.\u000a       Phenix industrial consortium members are listed at http:\/\/www.phenix-online.org\/consortium\/participants\/\">\u000a\u000a       The US PTO website was searched by looking for granted patents\u000a        containing the terms\u000a        \"Phaser\" and \"crystal\", and filed since the beginning of 2008, by using\u000a        the query\u000a        \"APD\/1\/1\/2008->12\/31\/2013 and phaser and crystal\" in the advanced\u000a        search tool at\u000a        http:\/\/patft.uspto.gov\/netahtml\/PTO\/search-adv.htm, then verifying\u000a        whether the Phaser\u000a        technology was indeed referenced in each patent.\u000a    \u000a    ","Title":"\u000a    Accelerating structural biology with Phaser crystallographic software\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The conception and development of Phaser (and its predecessor Beast) have\u000a      all taken place since\u000a      Read became Professor of Protein Crystallography, on his arrival as a\u000a      Wellcome Trust Principal\u000a      Research Fellow at the Department of Haematology, University of Cambridge\u000a      in 1998, though it\u000a      continues a long-running theme of research into the application of\u000a      likelihood to crystallography.\u000a      The research towards the development of Phaser was led by Read and\u000a      conducted by a team of\u000a      post-doctoral researchers based in the Department of Haematology in the\u000a      Cambridge Institute for\u000a      Medical Research: Airlie McCoy (2000-present), Laurent Storoni\u000a      (2001-2004), Hamsapriye (2004-2006),\u000a      Gábor Bunkóczi (2007-present) and Robert Oeffner (2007-present).\u000a    Traditional methods for solving protein crystal structures by molecular\u000a      replacement (MR) suffer\u000a      from a number of drawbacks, largely arising from the inability of these\u000a      methods to take account of\u000a      the effects of errors such as differences between the known structure and\u000a      the unknown target.\u000a      Maximum likelihood provides a way to account statistically for such\u000a      errors; likelihood targets for MR\u000a      searches were derived by Read and implemented in the computer program\u000a      Beast, and were\u000a      indeed shown to be significantly more sensitive (Read, 2001). Beast was\u000a      very slow, but success in\u000a      determining several difficult unsolved structures encouraged the\u000a      development of a faster, more\u000a      powerful new program, Phaser. Speed was increased by deriving and\u000a      implementing fast\u000a      approximations to the likelihood targets for orientation (Storoni et\u000a        al., 2004) and translation\u000a      searches (McCoy et al., 2005). Automation algorithms, built on the\u000a      advantages of likelihood for\u000a      decision-making, made it much easier to solve the structures of large\u000a      complexes at the forefront of\u000a      structural biology in both academia and industry. The first version of\u000a      Phaser was released to the\u000a      crystallographic community in late 2003, through open-source downloads to\u000a      academic users, and\u000a      to industrial users as part of the CCP4 and Phenix packages.\u000a    The development of a likelihood target for the SAD phasing experiment\u000a      (McCoy et al., 2004)\u000a      next gave Phaser the power to solve novel structures with no prior\u000a      structural knowledge.\u000a      Facilitated by the unified underlying mathematical foundation of the MR\u000a      and SAD likelihood targets,\u000a      combined methods were developed and implemented, allowing different\u000a      sources of information to\u000a      be used together in solving particularly recalcitrant structures (McCoy et\u000a        al., 2007; Read and\u000a      McCoy, 2011).\u000a    Phaser is still under continuous development in the Read lab to improve\u000a      the algorithms and\u000a      automation features. New versions are released formally, as part of the\u000a      CCP4 and Phenix\u000a      crystallographic software packages, about twice each year.\u000a    The increased sensitivity of the likelihood targets in Phaser, compared\u000a      to methods used previously,\u000a      has opened new applications of the molecular replacement method. Read has\u000a      collaborated to\u000a      combine Phaser with the advanced modelling techniques of the Rosetta\u000a      program (David Baker, the\u000a      University of Washington), making it possible to solve crystal structures\u000a      using ab initio folding\u000a      models (Qian et al., 2007); with the further addition of automated\u000a      rebuilding software (contributed\u000a      by Tom Terwilliger, Los Alamos National Laboratory), structures could be\u000a      solved with considerably\u000a      more distantly-related starting models than previously possible (DiMaio \u000a        et al., 2011). Read is also\u000a      collaborating with Isabel Usón (Molecular Biology Institute of Barcelona)\u000a      to strengthen her\u000a      Arcimboldo procedure for ab initio structure solution, which uses\u000a      Phaser to place small molecular\u000a      fragments such as helices that seed completion of the rest of the\u000a      structure.\u000a    "},{"CaseStudyId":"30233","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":["Economic and Social Research Council","Medical Research Council"],"ImpactDetails":"\u000a    Age-related macular degeneration (AMD) is the most common cause of\u000a      blindness in Western populations, reducing the quality of life of tens of\u000a      millions of older people worldwide. It affects the central macular region\u000a      of the retina causing loss of central vision which has devastating\u000a      consequences, preventing patients from reading, writing, driving or even\u000a      recognising faces. The macular changes develop slowly and are asymptomatic\u000a      in the early stages. There are two end stage forms of the disease that\u000a      affect vision, namely geographic atrophy and choroidal neovascularisation,\u000a      commonly referred to as `dry' and `wet' AMD respectively. The wet form is\u000a      more likely to cause blindness but can be treated with anti-VEGF antibody\u000a      therapy. This treatment is most successful if instituted early before\u000a      there is irreversible damage to the retina.\u000a    Susceptibility to AMD is influenced by several genetic variants and DNA\u000a      testing can be used to determine an individual's risk of developing the\u000a      disease (1). Those found to be at high risk can be offered regular eye\u000a      examinations to detect early development of wet AMD. The common functional\u000a      variant rs2230199 in the C3 gene discovered by Professor Yates and\u000a      colleagues in 2007 has a major influence on AMD susceptibility. This\u000a      variant is therefore an essential component of genetic tests to determine\u000a      AMD risk and it has been included in all the AMD tests currently on the\u000a      market. Cambridge Enterprise Limited on behalf of the University of\u000a      Cambridge submitted a provisional US patent application based on the C3\u000a      discovery and its potential use in a genetic test for AMD in March 2008\u000a      leading to the granting of a US patent in February 2012 (2). In July 2008\u000a      Cambridge Enterprise granted a licence to the Canadian company ArcticDx to\u000a      use the finding to develop a genetic test for AMD. Their Macula Risk test\u000a      (3) determines the genotypes for rs2230199 and three other variants which\u000a      together with smoking status are used to assign an individual to one of\u000a      five risk categories for AMD. The test was launched in North America in\u000a      2009 and subsequently in Europe and India.\u000a    AMD is a major public health problem and all the more so as the elderly\u000a      population grows. As a measure of the magnitude of the issue, it has been\u000a      estimated that in Europe and North America some 10,000 individuals\u000a      progress from dry to wet AMD every day. It has been shown that genetic\u000a      variants determining susceptibility to AMD including rs2230199 also\u000a      influence the risk of progression (4) and ArcticDx have promoted the\u000a      Macula Risk test as a means of planning the management of patients who are\u000a      identified by ophthalmologists, optometrists and others as having early or\u000a      intermediate disease.\u000a    On their website, ArcticDx offer recommendations for the frequency and\u000a      nature of follow up based on the patient's current stage of disease, age\u000a      and Macular Risk test result (3). This programme, referred to as the\u000a      Nashville Protocol, has been developed by a group of ophthalmologists in\u000a      Tennessee and aims to make the best use of health care resources by\u000a      targeting those at highest risk for intensive surveillance. Patients who\u000a      go on to develop wet AMD and receive prompt treatment will have a better\u000a      outcome. This should also save money since anti-VEGF therapy is expensive\u000a      and most effective when given early. A health economic study carried out\u000a      by ArcticDx has shown that around $300,000 per patient can be saved in\u000a      those identified early in their conversion to wet AMD (5). However,\u000a      independent cost benefit studies will be needed to confirm that the\u000a      Nashville Protocol achieves the expected health care and resource\u000a      benefits. In any event, it is likely that genetic testing for AMD\u000a      susceptibility will have an important role in reducing the impact of AMD\u000a      on the elderly. This breakthrough has generated considerable public\u000a      interest and been welcomed by organisations representing blind people (6).\u000a    ArcticDx reports that 3,500 health care professionals were using the\u000a      Macula Risk test as of April, 2013 with over 50,000 tests carried out (5).\u000a      Utilization of the test is increasing by 30% every quarter. In the USA the\u000a      test is covered by most insurance providers, including Medicare, for the\u000a      ICD-9 diagnostic codes 362.50 (non-specific AMD), 362.51 (non-exudative\u000a      senile macular degeneration), 362.52 (exudative senile macular\u000a      degeneration) and 362.57 (drusen). To meet the demand for the Macular Risk\u000a      test in the USA, a new $1.9m molecular genetics laboratory employing 6\u000a      full-time staff has been opened in Grand Rapids, Michigan by the company\u000a      ArcticAx US Ltd, an offshoot of Toronto-based ArcticDx. Cambridge\u000a      Enterprise Ltd is benefitting from the licence fees received from ArcticDx\u000a      and has recovered all patenting expenses and is entitled to a royalty\u000a      revenue stream that is expected to exceed £1m in 2013 (5).\u000a    ArcticDx has recently launched the Macular Risk PGx test which predicts a\u000a      patient's risk of progression to advanced AMD with vision loss within 2, 5\u000a      and 10 years based on 15 genetic variants in 12 AMD associated genes\u000a      (including rs2230199 in C3) and taking into account age, extent of early\u000a      changes of AMD, smoking history, body mass index and educational status\u000a      (7). A subset of the genetic test results are intended for use to identify\u000a      patients who would benefit from treatment with a combination of high dose\u000a      vitamins and minerals (8).\u000a    An alternative genetic test for AMD is being marketed by Sequenom CMM.\u000a      Their RetnaGene test uses 13 genetic variants in the major AMD associated\u000a      genes (including rs2230199 in C3) to predict the risk of choroidal\u000a      neovascularisation, based on a study by Hageman et al (9). The importance\u000a      of including rs2230199 in genetic tests for AMD has led to Sequenom\u000a      mounting a legal challenge to the Cambridge patent (2).\u000a    ","ImpactSummary":"\u000a    Age-related macular degeneration (AMD) is the most common cause of\u000a      blindness in Western populations and reduces the quality of life of tens\u000a      of millions of older people worldwide. In 2007 a research group at\u000a      Cambridge University led by Professor John Yates in the Cambridge\u000a      Institute for Medical Research discovered that a common genetic variant in\u000a      the complement C3 gene was associated with an increased risk for AMD. This\u000a      finding is now being used in a genetic test in North America and Europe to\u000a      estimate individual risks for AMD. Those found to be at high risk are\u000a      offered regular eye examinations to detect early development of the wet\u000a      form of the disease before symptoms arise. This can be treated with\u000a      anti-VEGF therapy. Early treatment gives the best chance of preserving\u000a      sight by preventing irreversible damage to the retina.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4662168","Name":"Tennessee"}],"References":"\u000a    \u000a(1) Khan JC, Thurlby DA, Shahid H, Clayton DG, Yates JRW, Bradley M,\u000a      Moore AT, Bird AC for the Genetic Factors in AMD Study. Smoking and age\u000a      related macular degeneration: the number of pack years of cigarette\u000a      smoking is a major determinant of risk for both geographic atrophy and\u000a      choroidal neovascularisation. British Journal of Ophthalmology,\u000a      2006;90:75-80.\u000a    \u000a\u000a(2) Sepp T, Khan JC, Thurlby DA, Shahid H, Clayton DG, Moore AT, Bird AC,\u000a      Yates JRW and the Genetic Factors in AMD Study Group. Complement factor H\u000a      variant Y402H is a major risk determinant for geographic atrophy and\u000a      choroidal neovascularisation in smokers and non- smokers. Investigative\u000a      Ophthalmology and Visual Science, 2006;47:536-40.\u000a    \u000a\u000a(3) Yates JRW, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton\u000a      DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ,\u000a      Redmond E, Bird AC, Moore AT for the Genetic Factors in AMD Study Group.\u000a      Complement C3 variant and the risk of age-related macular degeneration.\u000a      New England Journal of Medicine, 2007;357:553-61.(4) Shahid H, Khan JC,\u000a      Sepp T, Matharu BK, Cipriani V, Bunce C, Harding SP, Clayton DG, Moore AT,\u000a      Yates JRW, for the Genetic Factors in AMD Study Group. Age-related macular\u000a      degeneration: the importance of family history as a risk factor. British\u000a      Journal of Ophthalmology 2012;96:427-31.\u000a    \u000a\u000a(5) Cipriani V, Leung HT, Plagnol V, Bunce C, Khan JC, Shahid H, Moore\u000a      AT, Harding SP, Bishop PN, Hayward C, Campbell S, Armbrecht AM, Dhillon B,\u000a      Deary IJ, Campbell H, Dunlop M, Dominiczak AF, Mann SS, Jenkins SA,\u000a      Webster AR, Bird AC, Lathrop M, Zelenika D, Souied EH, Sahel JA,\u000a      Léveillard T; French AMD Investigators, Cree AJ, Gibson J, Ennis S, Lotery\u000a      AJ, Wright AF, Clayton DG, Yates JRW. Genome-wide association study of\u000a      age-related macular degeneration identifies associated variants in the\u000a      TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3. Human Molecular Genetics\u000a      2012;21:4138-50.\u000a    \u000a(6) The AMD Gene Consortium, Fritsche LG*, Chen W*, Schu M*, Yaspan BL*,\u000a      Yu Y*, Thorleifsson G, Zack DJ, Arakawa S, Cipriani V, Ripke S, Igo RP Jr,\u000a      Buitendijk GH, Sim X, Weeks DE, Guymer RH, Merriam JE, Francis PJ, Hannum\u000a      G, Agarwal A, Armbrecht AM, Audo I, Aung T, Barile GR, Benchaboune M, Bird\u000a      AC, Bishop PN, Branham KE, Brooks M, Brucker AJ, Cade WH, Cain MS,\u000a      Campochiaro PA, Chan CC, Cheng CY, Chew EY, Chin KA, Chowers I, Clayton\u000a      DG, Cojocaru R, Conley YP, Cornes BK, Daly MJ, Dhillon B, Edwards AO,\u000a      Evangelou E, Fagerness J, Ferreyra HA, Friedman JS, Geirsdottir A, George\u000a      RJ, Gieger C, Gupta N, Hagstrom SA, Harding SP, Haritoglou C, Heckenlively\u000a      JR, Holz FG, Hughes G, Ioannidis JP, Ishibashi T, Joseph P, Jun G,\u000a      Kamatani Y, Katsanis N, N Keilhauer C, Khan JC, Kim IK, Kiyohara Y, Klein\u000a      BE, Klein R, Kovach JL, Kozak I, Lee CJ, Lee KE, Lichtner P, Lotery AJ,\u000a      Meitinger T, Mitchell P, Mohand-Saïd S, Moore AT, Morgan DJ, Morrison MA,\u000a      Myers CE, Naj AC, Nakamura Y, Okada Y, Orlin A, Ortube MC, Othman MI,\u000a      Pappas C, Park KH, Pauer GJ, Peachey NS, Poch O, Priya RR, Reynolds R,\u000a      Richardson AJ, Ripp R, Rudolph G, Ryu E, Sahel JA, Schaumberg DA, Scholl\u000a      HP, Schwartz SG, Scott WK, Shahid H, Sigurdsson H, Silvestri G,\u000a      Sivakumaran TA, Smith RT, Sobrin L, Souied EH, Stambolian DE, Stefansson\u000a      H, Sturgill-Short GM, Takahashi A, Tosakulwong N, Truitt BJ, Tsironi EE,\u000a      Uitterlinden AG, van Duijn CM, Vijaya L, Vingerling JR, Vithana EN,\u000a      Webster AR, Wichmann HE, Winkler TW, Wong TY, Wright AF, Zelenika D, Zhang\u000a      M, Zhao L, Zhang K, Klein ML, Hageman GS, Lathrop GM, Stefansson K,\u000a      Allikmets R**, Baird PN**, Gorin MB**, Wang JJ**, Klaver CC**, Seddon\u000a      JM**, Pericak-Vance MA**, Iyengar SK**, Yates JRW**, Swaroop A**, Weber\u000a      BH**, Kubo M**, Deangelis MM**, Léveillard T**, Thorsteinsdottir U**,\u000a      Haines JL**, Farrer LA**, Heid IM**, Abecasis GR**. Seven new loci\u000a      associated with age-related macular degeneration. Nature Genetics\u000a      2013;45:433-9. *These authors contributed equally to this work. **These\u000a      authors share senior authorship.\u000a    Funding\u000a      J.R.W. Yates, A.T. Moore, D.G. Clayton, A.C. Bird, S.S. Bhattacharya, N.E.\u000a      Day. Genetic Susceptibility to Age-Related Macular Degeneration. Medical\u000a      Research Council programme grant, £1.8m, 2001 - 2007. Ref G0000067.\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    (1) Zanke\u000a        B, Hawken\u000a        S, Carter\u000a        R, Chow\u000a        D. A genetic approach to stratification of risk for age- related\u000a      macular degeneration. Can\u000a        J Ophthalmol. 2010;45:22-7. doi: 10.3129\/i09-209.\u000a    (2) US Provisional Application No. 61\/037,411 filed 18 March 2008; US\u000a      Patent No. 8,114,592 filed 18 March 2009 and issued 12 February 2012.\u000a      (Subsequently subject to legal challenge (Patent Interference No 105,897)\u000a      resulting in a judgement by the US Patent and Trademark Office on 16\u000a      August 2013 that the discovery is unpatentable).\u000a    (3) http:\/\/www.arcticdx.com\/genetics-of-amd\/why-get-tested-\u000a    (4) Yu\u000a        Y, Reynolds\u000a        R, Rosner\u000a        B, Daly\u000a        MJ, Seddon\u000a        JM. Prospective assessment of genetic effects on progression to\u000a      different stages of age-related macular degeneration using multistate\u000a      Markov models. Invest\u000a        Ophthalmol Vis Sci. 2012;53:1548-56. doi:10.1167\/iovs.11-8657.\u000a    (5) Personal communication from, Chief Medical Officer of ArcticAx.\u000a    (6)\u000ahttp:\/\/www.dailymail.co.uk\/health\/article-1038572\/New-test-identify-vulnerable-AMD--UKs-common-form-blindness.html#axzz2KarQoxFj\u000a    (7) http:\/\/www.macularisk.com\/home\/\u000a    (8) \u000a        http:\/\/www.google.co.uk\/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=2&cad=rja&ved=0CDMQFjAB&url=http%3A%2F%2Fwww.hsc.nihr.ac.uk%2Ffiles%2Fdownloads%2F2168%2F2474.9f47aa3c.FinalArcticDxMacularRiskPGx.pdf&ei=enVeUp_jFqGK0AWFjoDoBg&usg=AFQjCNH2Tgy5dxC7pdud2STiZIxtbvvaKA\u000a    (9) Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a\u000a      genetic model to estimate the risk of developing choroidal neovascular\u000a      age-related macular degeneration. Hum Genomics. 2011;5:420-40.\u000a    ","Title":"\u000a    Genetic risk assessment for age-related macular degeneration\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The research was led by Professor John Yates (Department of Medical\u000a      Genetics, University of Cambridge, since 1987) who was the Principle\u000a      Investigator. Key collaborators were Professor Tony Moore (UCL Institute\u000a      of Ophthalmology) and Professor Alan Wright (MRC Human Genetics Unit,\u000a      Edinburgh). The research was carried out, between 2001 - 2008, with\u000a      funding from a Medical Research Council programme grant on which Professor\u000a      Yates was the lead applicant.\u000a    Age-related macular degeneration (AMD) is a major cause of blindness.\u000a      Susceptibility is influenced by age, genetic and environmental factors.\u000a      Initial efforts were directed at recruiting cases of AMD and controls for\u000a      genetic association studies. Later in the project, extensive genetic\u000a      studies were carried out. Because complement activation had been\u000a      implicated in the pathogenesis of AMD, genetic studies focused on variants\u000a      in complement regulators and other complement pathway genes. This led in\u000a      2007 to the discovery, by Yates et al. of an association between AMD and a\u000a      variant in the complement C3 gene which was reported in the New\u000a        England Journal of Medicine (3). In this study 13 single nucleotide\u000a      polymorphisms spanning the complement C3 and C5 genes were tested for\u000a      association with AMD in 603 cases and 350 controls from the South East of\u000a      England. All subjects were examined by an ophthalmologist and had\u000a      independent grading of fundus photographs to confirm their disease status.\u000a      To test for replication of the most significant findings, a second set of\u000a      Scottish cases (244) and controls (351) were genotyped. The common\u000a      functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding\u000a      to the electrophoretic variants C3S (slow) and C3F (fast), was strongly\u000a      associated with AMD in both the English sample (P = 5.9 x 10-5)\u000a      and the Scottish sample (P = 5.0 x 10-5). Compared with\u000a      C3 S\/S homozygotes, the odds ratio for AMD was 1.7 (CI 1.3 - 2.1) in S\/F\u000a      heterozygotes and 2.6 (CI 1.6 - 4.1) in F\/F homozygotes. This provided\u000a      strong evidence that C3, and the complement pathway, were important in the\u000a      pathogenesis of AMD.\u000a    The association between C3 rs2230199 and AMD has been confirmed by\u000a      several independent reports. A recent meta-analysis of all the available\u000a      data carried out by other researchers has reported an effect size for this\u000a      association which is very similar to our original report (Thakkinstian et\u000a      al, J Epidemiol 2012). Genotyping of this variant and other genetic\u000a      variants associated with susceptibility to AMD is now being used to\u000a      identify individuals at increased risk of developing the disease as\u000a      described below.\u000a    Other investigations undertaken as part of this programme of research\u000a      confirmed the importance of smoking and family history as risk factors for\u000a      AMD (1, 4) and provided additional information about the influence of the\u000a      Y402H variant in the complement factor H gene on AMD susceptibility (2). A\u000a      genome-wide association study which was carried out in 2007 as part of\u000a      this research lead to the identification of novel AMD associated variants\u000a      in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3 (5) and these data\u000a      were contributed to a GWAS meta-analysis that identified seven new AMD\u000a      associated loci (6).\u000a    The key researchers contributing to this discovery were:\u000a    \u000a      Professor John Yates, Professor of Medical Genetics, Cambridge\u000a        Institute for Medical Research and Department of Medical Genetics,\u000a        University of Cambridge (1987 - 2008)\u000a      Dr Tiina Sepp, Research Associate, Cambridge Institute for Medical\u000a        Research and Department of Medical Genetics, University of Cambridge\u000a        (2002 - 2007).\u000a      Professor David Clayton, Professor of Statistical Genetics, Cambridge\u000a        Institute for Medical Research and Department of Medical Genetics,\u000a        University of Cambridge (2000 - 2012)\u000a      Professor Anthony T Moore, Professor of Ophthalmology, UCL Institute\u000a        of Ophthalmology, London\u000a      Professor Alan Wright, Medical Research Council Human Genetics Unit,\u000a        Edinburgh\u000a    \u000a    "},{"CaseStudyId":"30246","Continent":[{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"1269750","Name":"India"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Solomon's research at the UoL has been pivotal in changing the way a life\u000d\u000a      threatening illness is understood, diagnosed and prevented across Asia.\u000d\u000a      Through a partnership with a consortium of Governments, Academic Partners,\u000d\u000a      and Health agencies, facilitated by a series of meetings ranging from WHO\u000d\u000a      small working groups to large international conferences, critical\u000d\u000a      information on the prevalence, diagnostics, treatment and prevention of\u000d\u000a      Japanese Encephalitis has been disseminated to at risk populations\u000d\u000a      supported by guidelines and awareness campaigns. For example, the UoL Team\u000d\u000a      developed the online e-learning tools for Clinical Assessment of Children,\u000d\u000a      and for using the disease outcome score UoL developed (now known as the\u000d\u000a      Liverpool Outcome Score). By tackling each of the core issues relating to\u000d\u000a      the lack of vaccine uptake, the impacts of Solomon's research have been\u000d\u000a      felt throughout the entire REF period; this has benefited individuals in\u000d\u000a      at risk areas by massively limiting the number of cases, which has in\u000d\u000a      turn, benefited governments by significantly reducing the economic burden\u000d\u000a      of caring for individuals disabled by this devastating disease.\u000d\u000a    The JE surveillance guidelines that the UoL developed on the back of its\u000d\u000a      clinical-epidemiological research, have been used across Asia since 2008,\u000d\u000a      and are helping with disease recognition. In 2012, 18 (75%) of the 24\u000d\u000a      countries with JE virus transmission risk conducted at least some JE\u000d\u000a      surveillance [8].\u000d\u000a    The UoL rapid diagnostic kit for diagnosing JE was the prototype for kits\u000d\u000a      developed by the UoL, and others, some of which have gone through to\u000d\u000a      commercialisation, such as that produced by Venture Technologies,\u000d\u000a      Singapore, and since 2008, Pan Bio, Australia, and Excyton Diagnostics,\u000d\u000a      India [9]. Such kits are now widely used across Asia, through the JE\u000d\u000a      laboratory diagnostic network that the UoL helped establish [10]. This is\u000d\u000a      playing an essential role in helping recognition of JE so that the disease\u000d\u000a      burden can be ascertained.\u000d\u000a    The Liverpool Outcome Score has been disseminated widely through the WHO\u000d\u000a      and PATH partners, and the biannual WHO JE Regional meetings in Southeast\u000d\u000a      Asia. It is publicly available (www.path.org\/vaccineresources\/details.php?i=677)\u000d\u000a      and is used in many Asian countries to help quantify the disease burden of\u000d\u000a      JE [11,12,13].\u000d\u000a    In the 1990s, other than China which had developed its own vaccine,\u000d\u000a      sustained JE vaccination programmes were restricted to wealthier Asian\u000d\u000a      countries. The UoL work on establishing the disease burden through\u000d\u000a      improved surveillance, diagnosis and quantification of disability has\u000d\u000a      played a major role in helping Governments decide on JE vaccination\u000d\u000a      programmes. The UoL team had a leading role in the JE control partnership\u000d\u000a      which included other HEIs, Governments across Asia, WHO, and\u000d\u000a      non-governmental organisations. Together, with US$ 14m funding from the\u000d\u000a      Bill and Melinda Gates Foundation, the partnership supported vaccine roll\u000d\u000a      out [14]. The UoL research was disseminated by way of participation in all\u000d\u000a      the main WHO working groups, committees, meetings and conferences,\u000d\u000a      advising, for example on vaccine development, and surrogate markers of\u000d\u000a      vaccine efficacy [15].\u000d\u000a    The impact of this research can be examined through the new vaccination\u000d\u000a      programmes across Asia, which the UoL has catalysed and supported. In the\u000d\u000a      summer of 2006, 19 million children were immunised in India, and by the\u000d\u000a      end of 2013, 88 million Indian children had been vaccinated. By 2013\u000d\u000a      vaccination had begun in 11 countries outside China (eight of them since\u000d\u000a      2008), and the vaccine had reached more than 200 million people;\u000d\u000a      approximately 170 million since Jan 2008.\u000d\u000a    The public health benefits can be estimated from a health economic\u000d\u000a      modelling study: in a cohort of 100 000 unvaccinated children followed up\u000d\u000a      from birth to 30 years of age, the model predicted 488 cases and 122\u000d\u000a      deaths associated with JE [16]. In the absence of JE immunization it was\u000d\u000a      estimated that the treatment of acute JE would cost US$ 483,672 and that\u000d\u000a      7,441 Disability Adjusted Life Years (DALYs) would be lost because of JE.\u000d\u000a      Relative to the no-vaccination strategy, the use of the vaccine would\u000d\u000a      result in 427 fewer JE cases, 107 fewer deaths, and 6556 fewer DALYs lost.\u000d\u000a      For the 170 million people vaccinated since 2008, this equates to 660,000\u000d\u000a      cases and 165,000 deaths avoided. The estimated total direct costs\u000d\u000a      associated with the treatment of JE and disability during the 30-year\u000d\u000a      follow-up of 100 000 neonates who were not vaccinated is US$ 738,315, and\u000d\u000a      the corresponding costs of using the vaccine are US$ 225,859 [16]. The\u000d\u000a      savings per 100 000 neonates are thus US$ 512 456, or US$ 791m for the 170\u000d\u000a      million people vaccinated since 2008.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Globally the most important cause of encephalitis (inflammation and\u000d\u000a      swelling of the brain) is the mosquito-borne Japanese encephalitis virus\u000d\u000a      (JEV), which causes an estimated 70,000 cases annually across Asia.\u000d\u000a      Although vaccines were developed years ago, their uptake in Asian\u000d\u000a      countries has been hampered through lack of disease burden data, a\u000d\u000a      consequence of poor surveillance, complicated diagnostics, and\u000d\u000a      insufficient knowledge about disease outcomes. Research at the University\u000d\u000a      of Liverpool has addressed each of these areas in turn, to overcome the\u000d\u000a      roadblocks in vaccine implementation. The University of Liverpool (UoL),\u000d\u000a      through its leading role on all the relevant WHO committees groups and\u000d\u000a      meetings, has ensured that its research findings are translated through to\u000d\u000a      impact by supporting new vaccination programmes across Asia. By 2013\u000d\u000a      vaccination had begun in 11 new countries, and the vaccine had reached\u000d\u000a      more than 200 million people. The public health benefits, estimated from a\u000d\u000a      health economic modelling study, are 854,000 cases and 214,000 deaths\u000d\u000a      avoided, with an associated saving across Asia of US$ 1.024 billion.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    UNIVERSITY OF LIVERPOOL and LIVERPOOL SCHOOL OF TROPICAL MEDICINE\u000d\u000a    ","Institutions":[{"AlternativeName":"Liverpool (University of)","InstitutionName":"University of Liverpool","PeerGroup":"A","Region":"North West","UKPRN":10006842},{"AlternativeName":"Liverpool School of Tropical Medicine","InstitutionName":"Liverpool School of Tropical Medicine","PeerGroup":"G","Region":"North West","UKPRN":10003958}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"}],"References":"\u000d\u000a    \u000a1. Solomon T, Kneen R, Dung NM, Khanh VC, Thuy TTN, Ha\u000d\u000a      DQ, Day NPJ, Nisalak A, Vaughn DW, White NJ. Poliomyelitis-like illness\u000d\u000a      due to Japanese encephalitis virus. Lancet. 1998;351:1094-7. Citations: 3\u000d\u000a      Impact Factor: 39.060\u000d\u000a    \u000a\u000a2. Solomon T, Thao TT, Lewthwaite P, Ooi MH,\u000d\u000a      Kneen R, Dung NM, White N. A cohort study to assess the new WHO Japanese\u000d\u000a      encephalitis surveillance standards. Bulletin of the World Health\u000d\u000a      Organization. 2008;86:178-86. Citations: 30 Impact Factor: 5.250\u000d\u000a    \u000a\u000a3. Solomon T, Thao LT, Dung NM, Kneen R, Hung NT, Nisalak\u000d\u000a      A, Vaughn DW, Farrar J, Hien TT, White NJ, Cardosa MJ. Rapid diagnosis of\u000d\u000a      Japanese encephalitis by using an immunoglobulin M dot enzyme immunoassay.\u000d\u000a      Journal of Clinical Microbiology. 1998;36:2030-4. Citations: 53 Impact\u000d\u000a      Factor: 4.068\u000d\u000a    \u000a\u000a4. Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LTT,\u000d\u000a      Raengsakulrach B, Day NPJ, Farrar J, Myint KSA, Nisalak A, White\u000d\u000a      NJ. Neurological manifestations of dengue infection. Lancet.\u000d\u000a      2000;355:1053-59. Citations: 218 Impact Factor: 39.060\u000d\u000a    \u000a\u000a5. Ooi MH, Wong SC, Podin Y, Akin W, Sel SD, Mohan A, Chieng CH,\u000d\u000a      Perera D, Clear D, Wong D, Blake E, Cardosa J, Solomon T. Human\u000d\u000a      enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical,\u000d\u000a      virological, and molecular epidemiological study. Clinical Infectious\u000d\u000a      Diseases. 2007;44:646-56. Citations: 64 Impact Factor: 9.374\u000d\u000a    \u000a\u000a6. Solomon T, Dung NM, Wills B, Kneen R, Gainsborough M,\u000d\u000a      Diet TV, Thuy TTN, Loan HT, Khanh VC, Vaughn DW, White NJ, Farrar JJ.\u000d\u000a      Interferon alfa-2a in Japanese encephalitis: a randomised double-blind\u000d\u000a      placebo-controlled trial. Lancet. 2003;361:821-6. Citations: 80 Impact\u000d\u000a      Factor: 39.060\u000d\u000a    \u000a\u000a7. Lewthwaite P, Begum A, Ooi MH, Faragher B, Lai BF,\u000d\u000a      Sandaradura I, Mohan A, Mandhan G, Meharwade P, Subhashini S, Abhishek G,\u000d\u000a      Penkulinti S, Shankar MV, Ravikumar R, Young C, Cardosa MJ, Ravi\u000d\u000a      V, Wong SC, Kneen R, Solomon T. Disability after\u000d\u000a      encephalitis: development and validation of a new outcome score. Bulletin\u000d\u000a      of the World Health Organization. 2010;88:584-92. Citations: 3 Impact\u000d\u000a      Factor: 5.250\u000d\u000a    \u000aKey Research Grants\u000d\u000a    2005 - 2011. Medical Research Council Senior Clinical Fellowship\u000d\u000a      (T Solomon). Inflammation in Japanese encephalitis. £946,704\u000d\u000a    2005 - 2008. Wellcome Trust Training Fellowship, (Dr Mong How\u000d\u000a      Ooi), Enterovirus-71 associated hand foot and mouth disease in Sarawak,\u000d\u000a      £110,845\u000d\u000a    2000 - 2005. Wellcome Trust Career Development Fellowship (T.\u000d\u000a      Solomon; Grant no. 054682). The Host Immune Response and Strain Virulence\u000d\u000a      Determinants in Japanese Encephalitis. £498,505, University of Liverpool,\u000d\u000a      UK, and University of Texas Medical Branch, Galveston, USA.\u000d\u000a    2005 - 2007. Gates Japanese Encephalitis Control Fellowship\u000d\u000a      (funded through PATH, Seattle). £206,982\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000d\u000a    Each source listed below provides evidence for the corresponding numbered\u000d\u000a      claim made in section 4 (details of the impact). \u000d\u000a    \u000d\u000a      Centers for Disease C, Prevention. Japanese encephalitis surveillance\u000d\u000a        and immunization-- Asia and the Western Pacific, 2012. MMWR Morbidity\u000d\u000a        and Mortality Weekly Report. 2013;62:658-62.\u000d\u000a      Khalakdina A, Shrestha SK, Malla S, Hills S, Thaisomboonsuk B,\u000d\u000a        Shrestha B, Gibbons RV, Jacobson J. Field evaluation of commercial\u000d\u000a        immunoglobulin M antibody capture ELISA diagnostic tests for the\u000d\u000a        detection of Japanese encephalitis virus infection among encephalitis\u000d\u000a        patients in Nepal. International Journal of Infectious Diseases 2010;14\u000d\u000a        Suppl 3:e79-84.\u000d\u000a      World Health Organization. Japanese encephalitis laboratory network -\u000d\u000a        overview; accessed June 2013 at http:\/\/www.wpro.who.int\/immunization\/laboratory\/je\/overview\/en\/index.html.\u000d\u000a      Ma J, Jiang L. Outcome of children with Japanese encephalitis and\u000d\u000a        predictors of outcome in southwestern China. Transactions of the Royal\u000d\u000a        Society of Tropical Medicine and Hygiene. 2013;107:660-5.\u000d\u000a      Maha MS, Moniaga VA, Hills SL, Widjaya A, Sasmito A, Hariati R,\u000d\u000a        Kupertino Y, Artastra IK, Arifin MZ, Supraptono B, Syarif I, Jacobson\u000d\u000a        JA, Sedyaningsih ER. Outcome and extent of disability following Japanese\u000d\u000a        encephalitis in Indonesian children. International Journal of Infectious\u000d\u000a        Diseases. 2009;13:e389-93.\u000d\u000a      Hills SL, Van Cuong N, Touch S, Mai HH, Soeung SC, Lien TT, Samnang C,\u000d\u000a        Sovann L, Van Diu P, Lac LD, Heng S, Huong VM, Grundy JJ, Huch C,\u000d\u000a        Lewthwaite P, Solomon T, Jacobson JA. Disability from Japanese\u000d\u000a        encephalitis in Cambodia and Viet Nam. Journal of Tropical Pediatrics.\u000d\u000a        2011;57:241-4.\u000d\u000a      Solomon T. Control of Japanese encephalitis--within our grasp? New\u000d\u000a        England Journal of Medicine. 2006;355:869-71.\u000d\u000a      Hombach J, Solomon T, Kurane I, Jacobson J, Wood D. Report on a WHO\u000d\u000a        consultation on immunological endpoints for evaluation of new Japanese\u000d\u000a        encephalitis vaccines, WHO, Geneva, 2-3 September, 2004. Vaccine.\u000d\u000a        2005;23:5205-11.\u000d\u000a      Ding D, Kilgore PE, Clemens JD, Wei L, Zhi-Yi X. Cost-effectiveness of\u000d\u000a        routine immunization to control Japanese encephalitis in Shanghai,\u000d\u000a        China. Bulletin of the World Health Organization. 2003;81:334-42.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Control of Japanese Encephalitis\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Encephalitis is inflammation of the brain, most often caused by a virus.\u000d\u000a      Numerically, the most important cause of epidemic encephalitis in the\u000d\u000a      world is the mosquito-borne Japanese encephalitis virus (JEV), which UoL\u000d\u000a      led research has shown to cause an estimated 70,000 cases annually across\u000d\u000a      Asia. The virus's natural cycle is among wading birds and pigs; humans\u000d\u000a      become infected when bitten by an infected mosquito. Approximately 4\u000d\u000a      billion people live in areas at risk of Japanese encephalitis (JE).\u000d\u000a      Although vaccines were developed years ago, their uptake by governments\u000d\u000a      has been hampered through lack of disease burden data. There were no\u000d\u000a      reliable methods of diagnosing and tracking the disease, no standard\u000d\u000a      diagnostic tests, no surveillance systems, and little knowledge about\u000d\u000a      disease outcomes. Without these it was hard for countries in Asia to\u000d\u000a      understand the extent of JE, prioritize it, and focus prevention efforts\u000d\u000a      on the regions and people most needing protection.\u000d\u000a    At UoL, Professor Tom Solomon, of the Institute of Infection and Global\u000d\u000a      Health, along with the multidisciplinary Brain Infections Group has been\u000d\u000a      addressing these challenges. To strengthen surveillance the team\u000d\u000a      demonstrated (1995-8), with Wellcome Trust funding, the wide range of\u000d\u000a      clinical presentations the virus can cause, including a previously unknown\u000d\u000a      poliomyelitis-like illness [1], and acute symptomatic seizure\u000d\u000a      presentations. This was achieved through careful clinical descriptive and\u000d\u000a      epidemiological studies led by Solomon in Vietnam\u000d\u000a    The UoL has had a leading role in the development by WHO of Surveillance\u000d\u000a      Standards, Solomon chaired the WHO Group producing the Clinical Care\u000d\u000a      Guidelines (2005), and then field-tested the Standards, by applying them\u000d\u000a      to a cohort of patients with suspected central nervous system infections\u000d\u000a      in Asia to see how many patients with JE were accurately identified [2].\u000d\u000a    To improve diagnostics, the UoL worked with colleagues at the University\u000d\u000a      of Malaysia, Sarawak from 1995-8 to develop and field-test simple rapid\u000d\u000a      kits for diagnosing JE in the rural field hospitals where it occurs [3].\u000d\u000a      Many of these have subsequently been further refined over subsequent\u000d\u000a      years. These diagnostic kits allow JE to be distinguished from the related\u000d\u000a      dengue virus, which can also cause neurological disease [4], and from\u000d\u000a      other emerging causes of acute central nervous system infection such as\u000d\u000a      enterovirus 71 [5]. In 2003, the team showed with a randomised controlled\u000d\u000a      trial that interferon treatment, which was being used increasingly for JE\u000d\u000a      and related flaviviruses such as West Nile virus, was ineffective [6],\u000d\u000a      thus focusing attention on the importance of disease control through\u000d\u000a      vaccination.\u000d\u000a    Approximately 20% of children with JE die, but those that survive with\u000d\u000a      severe disability are actually a greater socio-economic burden. However\u000d\u000a      there were no good data on the extent of the problem, making it difficult\u000d\u000a      for governments to make rational choices on the cost effectiveness of\u000d\u000a      vaccine implementation programmes. With funding from PATH\/Gates Foundation\u000d\u000a      and MRC, the UoL developed a simple outcome score (2008-10) with\u000d\u000a      colleagues in India and Malaysia to assess disability after JE [7], and\u000d\u000a      using it showed the extent of the problem in survivors.\u000d\u000a    "},{"CaseStudyId":"30337","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    On national guidelines\u000d\u000a    The clearest impact has been on national guidelines published by the\u000d\u000a      British Hypertension Society, then NICE and the onward influence of these\u000d\u000a      upon trends in use of antihypertensive drugs.\u000d\u000a    BHS 2004 and BHS\/NICE 2006\u000d\u000a    In 2004, the BHS published the fourth update of national guidelines,\u000d\u000a      which adopted AB\/CD. In the same year NICE published its own guidance9-12.\u000d\u000a      Because it became rapidly clear that primary care doctors found BHS-4 much\u000d\u000a      easier to enact than NICE's guidance, NICE decided within a year to revise\u000d\u000a      its own guidance, in conjunction with the relevant specialist society. The\u000d\u000a      resulting NICE\/BHS guidance of 2006 was the first time NICE partnered a\u000d\u000a      specialist society. The NICE-BHS guidance of 2006 adopted A(B)\/CD, with\u000d\u000a      β-blockade relegated to second-line because of several trials which by\u000d\u000a      then had reported worse outcome on β-blockade than comparator — and\u000d\u000a      explanation for this provided by Brown's crossover studies above (refs.\u000d\u000a      3&5). With regards to the impact period; both of these were valid from\u000d\u000a      2008-2011 (when NICE updated the guidance as described below).\u000d\u000a    NICE 2011\u000d\u000a    The principle underlying the AB\/CD rule that there are but two broad\u000d\u000a      types of hypertension, and two ways in which blood pressure can be\u000d\u000a      lowered, led NICE to retain the rule in its 2011 guidance, simplified to\u000d\u000a      an A\/C rule, with B remaining as second-line therapy. (Ref 10, section 5).\u000d\u000a      This simplification was controversial, and NICE took some criticism for\u000d\u000a      the contradiction of relegating D(iuretic) from a 1st to 3rd\u000d\u000a      choice, while at the same time making D the cornerstone of managing\u000d\u000a      patients with resistant hypertension. Here the advice to use\u000d\u000a      spironolactone — the only specific drug mentioned by NICE (rather than an\u000d\u000a      overall class of drugs) — was dependent on Brown's formal 2007 comparison\u000d\u000a      of spironolactone with other diuretics (ref 6 above). Spironolactone is a\u000d\u000a      type of diuretic, different from the class (`thiazides') commonly used in\u000d\u000a      Hypertension. The discovery by Brown of a common group of patients whose\u000d\u000a      blood pressure was not controlled by thiazide diuretics, but was\u000d\u000a      controlled by spironolactone, followed from his 1999 work, of\u000d\u000a      investigations into the causes of salt-dependent (low-renin) hypertension.\u000d\u000a    Other countries\u000d\u000a    The NICE version of the AB\/CD algorithm has been adopted by other\u000d\u000a      countries; for example in Hong Kong in 200812 and in New\u000d\u000a      Zealand in 2010.13\u000d\u000a    Blood Pressure Control Rates\u000d\u000a    A secondary impact of Brown's research is on blood pressure control rates\u000d\u000a      in England, which used to be among the lowest in Europe, and are now among\u000d\u000a      the highest.14 Between first publication of AB\/CD and the\u000d\u000a      introduction of the GPs' `Quality Outcomes Framework' in 2004, few other\u000d\u000a      external influences are likely to have impacted on the improvement.\u000d\u000a      Thereafter, payment incentives to GPs clearly contributed, but they still\u000d\u000a      required — and widely acknowledged — a simple and effective guideline for\u000d\u000a      achieving the prescribed targets.\u000d\u000a    Complications of hypertension (stroke, myocardial infarction)\u000d\u000a    The most important potential impact, but most difficult to document cause\u000d\u000a      and effect, is a reduction in the complications of hypertension as a\u000d\u000a      consequence of improvements in blood pressure control. The goal for the\u000d\u000a      treatment of hypertension is prevention of stroke and heart disease.\u000d\u000a      Clearly any change in incidence of these multifactorial diseases is\u000d\u000a      multifactorial. It is interesting, according to figures on www.heartstats.org\u000d\u000a      that annual rates for stroke in the UK — the complication of hypertension\u000d\u000a      with the steepest dependence on blood pressure — were static from 2000-3,\u000d\u000a      and then fell progressively from 130 to 100 per 10,000 over just 3 years.\u000d\u000a    This was before the introduction of `QOF' — payments to GPs for screening\u000d\u000a      and treatment of hypertension — which are likely to have contributed to\u000d\u000a      further improvements, in concert with the more tailored treatment regimen.\u000d\u000a    Mainstream Teaching and Clinical Training\u000d\u000a    AB\/CD, and subsequent NICE derivatives, are part of mainstream teaching\u000d\u000a      in Medicine, appearing in textbooks (e.g the Oxford Textbook of Medicine15\u000d\u000a      ) and Wikipedia.\u000d\u000a    Public understanding and patient awareness\u000d\u000a    Patients rarely comment on not suffering a stroke, but are hugely\u000d\u000a      grateful for a cure that may save them 50 years of taking tablets! So the\u000d\u000a      impact of the research on recognition of curable causes of hypertension\u000d\u000a      may be smaller on a population scale, but for individuals affected the\u000d\u000a      impact is more perceptible. The BHF uses a video, which cites Brown's\u000d\u000a      work, in order to illustrate patient satisfaction with the successful use\u000d\u000a      of BHF research funds.16\u000d\u000a    Lay media\u000d\u000a    The BBC story in 2011, about the development of PET CT for Conn's\u000d\u000a      Syndrome, generally appears on the first page of a Google search on this\u000d\u000a      condition.17 The population significance of Brown's 2013 Nature\u000d\u000a      Genetics paper, describing mutations in a common sub-type of adrenal\u000d\u000a      tumours, was recognised by the Times and BBC; both reported that many\u000d\u000a      patients with hypertension will now be found to have a distinct,\u000d\u000a      anatomical cause which can be cured by surgery.18,19\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research led by Professor Brown has led to widespread changes in clinical\u000d\u000a      practice regarding the management of Hypertension. Following his\u000d\u000a      demonstration that patients' response to drugs for Hypertension is\u000d\u000a      variable (in a systematic manner), subsequent clinical guidelines\u000d\u000a      acknowledged the variability among patients, and changed from recommending\u000d\u000a      the same treatment for all patients, to an algorithm based on the\u000d\u000a      Cambridge AB\/CD rule. The simplicity of the AB\/CD rule led to popularity\u000d\u000a      among doctors, and adoption by national bodies — British Hypertension\u000d\u000a      Society, NICE, and foreign guidelines, and by textbooks of Medicine. The\u000d\u000a      guidelines arising from his research have contributed to improved health\u000d\u000a      outcomes in the UK. Specifically, NICE's simple and rational guidance how\u000d\u000a      to reach strict targets for blood pressure is credited with changing the\u000d\u000a      UK from the poorest to best performing country in Europe.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Cambridge\u000d\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1819729","Name":"Hong Kong"}],"References":"\u000d\u000a    \u000a1. Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ.\u000d\u000a      Optimisation of anti-hypertensive treatment by crossover rotation of four\u000d\u000a      major classes. Lancet. 1999; 353: 2008-13.\u000d\u000a    \u000a\u000a2. Deary A, Schumann A, Murfet H, Haydock S, Foo R, Brown M.\u000d\u000a      Double-blind, placebo-controlled crossover comparison of five classes of\u000d\u000a      antihypertensive drugs. Journal of Hypertension. 2002; 20: 771-7.\u000d\u000a    \u000a\u000a3. Deary AJ, Schumann AL, Murfet H, Haydock S, Foo RS, Brown MJ.\u000d\u000a      Influence of drugs and gender on the arterial pulse wave and natriuretic\u000d\u000a      peptide secretion in untreated patients with essential hypertension. Clin\u000d\u000a      Sci (Lond). 2002; 103(5): 493-9.\u000d\u000a    \u000a\u000a4. Cockcroft JR, Brown MJ. Losartan for cardiovascular disease in\u000d\u000a      patient's with and without diabetes in the LIFE study. Lancet. 2002;\u000d\u000a      359(9324): 2202; discussion 3-4.\u000d\u000a    \u000a\u000a5. Brown MJ, Palmer CR, Castaigne A, De Leeuw PW, Mancia G, Rosenthal T,\u000d\u000a      Ruilope LM. Morbidity and mortality in patients randomised to double-blind\u000d\u000a      treatment with once-daily calcium channel blockade or diuretic in the\u000d\u000a      International Nifedipine GITS Study: Intervention as a Goal in\u000d\u000a      Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366-42\u000d\u000a    \u000a\u000a6. Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The Spironolactone, Amiloride,\u000d\u000a      Losartan, and Thiazide (SALT) double-blind crossover trial in patients\u000d\u000a      with low-renin hypertension and elevated aldosterone-renin ratio.\u000d\u000a      Circulation. 2007; 116: 268-75.\u000d\u000a    \u000a\u000a7. Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan\u000d\u000a      EA, Aigbirhio F, Gurnell M, Brown MJ. Evaluation of the sensitivity and\u000d\u000a      specificity of (11)C-metomidate positron emission tomography (PET)-CT for\u000d\u000a      lateralizing aldosterone secretion by Conn's adenomas. J Clin Endocrinol\u000d\u000a      Metab. 2012; 97: 100-9.\u000d\u000a    \u000a\u000a8. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C,\u000d\u000a      Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport\u000d\u000a      AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I,\u000d\u000a      Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J,\u000d\u000a      Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic\u000d\u000a      mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal\u000d\u000a      hypertension. Nat Genet. 2013; 45:1055-1060.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a       NICE\/BHS. CG34 Hypertension 2006.- NICE guideline (all the\u000d\u000a        recommendations). http:\/\/www.nice.org.uk\/nicemedia\/pdf\/cg034niceguideline.pdf\u000a\u000d\u000a        Williams B, Poulter NR, Brown MJ, Davies M, McInnes G, Potter J, et\u000d\u000a        al. Guidelines for management of hypertension: report of the fourth\u000d\u000a        working party of the British Hypertension Society, 2004 . BHS IV.\u000d\u000a        Journal of Human Hypertension. 2004; 18(3) 139-185.\u000d\u000a       NICE. Hypertension: clinical management of primary hypertension in\u000d\u000a        adults. Clinical guideline CG127. 2011. http:\/\/www.nice.org.uk\/nicemedia\/live\/13561\/56008\/56008.pdf\u000a\u000d\u000a       http:\/\/www.pdqa.gov.hk\/english\/primarycare\/clinical\/files\/htguideline2008.pdf\u000a\u000d\u000a       http:\/\/www.bpac.org.nz\/BPJ\/2010\/October\/antihypertensive.aspx\u000a\u000d\u000a       Falaschetti E, Chaudhury M, Mindell J, Poulter N. Continued\u000d\u000a        Improvement in Hypertension Management in England: Results From the\u000d\u000a        Health Survey for England 2006. Hypertension. 2009; 53(3):\u000d\u000a        480-6.\u000d\u000a       Oxford Textbook of Medicine: Chapter on Hypertension. http:\/\/oxfordmedicine.com\/view\/10.1093\/med\/9780199204854.001.1\/med-9780199204854-chapter-161702#med-9780199204854-figureGroup-161702006\u000a\u000d\u000a      BHF video. http:\/\/www.youtube.com\/watch?v=qBqfhk05RQo\u000a\u000d\u000a      BBC coverage of hypertension diagnosis. http:\/\/www.bbc.co.uk\/news\/health-15935070\u000a\u000d\u000a      Tests can lead to cure for early type of hypertension. http:\/\/www.thetimes.co.uk\/tto\/health\/news\/article3834204.ece.\u000d\u000a      \u000aTiny adrenal\u000d\u000a          tumours 'cause high blood pressure'. http:\/\/www.bbc.co.uk\/news\/health-23534101\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    The AB\/CD of treating hypertension\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The research was led by Professor Brown (Clinical Pharmacology Unit of\u000d\u000a      the Department of Medicine 1985-present), aided by Claire Dickerson,\u000d\u000a      (research nurse), Dr Aroon Hingorani, (MRC Training Fellow, Clinical\u000d\u000a      Pharmacology Unit of the Department of Medicine, 1996-1999) and Dr Chris\u000d\u000a      Palmer, (statistician, Department of Public Health and Primary Care,\u000d\u000a      1996-present).\u000d\u000a    From 1997-1999, Brown led his first study into personalised treatments\u000d\u000a      for hypertension. The study aimed to test the hypothesis that four groups\u000d\u000a      of patients could be defined, in whom each of the four drug classes was\u000d\u000a      the most efficacious treatment. The research group designed what Brown\u000d\u000a      called a `rotation study' in which 56 patients referred to Brown's clinic\u000d\u000a      at Addenbrooke's with untreated hypertension were prescribed each drug for\u000d\u000a      a month, with a month's washout between each treatment. Because this\u000d\u000a      design entailed several months on no treatment, Brown recruited younger\u000d\u000a      patients than in most hypertension studies, aged <50, so as to minimise\u000d\u000a      risks. This decision proved critical, since it was found that the AB drugs\u000d\u000a      (= ACE inhibitors and Beta-blockers) were on average twice as effective as\u000d\u000a      CD drugs (=Calcium Blockers and Diuretics) in lowering blood pressure (BP)\u000d\u000a      in the younger patients. The researchers deduced that this was due to\u000d\u000a      younger patients having a higher blood level of the kidney hormone renin,\u000d\u000a      compared to older patients — and that what AB drugs had in common was\u000d\u000a      their action on various components of `the renin system'. Conversely, CD\u000d\u000a      drugs work primarily by eliminating salt, which typically plays a greater\u000d\u000a      role in the hypertension of patients older than 50. Although a small\u000d\u000a      number of the younger patients did respond better to CD than AB, tellingly\u000d\u000a      Brown found them all to have a low plasma renin at baseline. The finding\u000d\u000a      reflects the kidneys' ability to detect salt excess in the circulation,\u000d\u000a      and showed these few patients to be the exceptions within a young cohort.\u000d\u000a      The results, and the proposed AB\/CD rule emanating from these, was\u000d\u000a      published in the Lancet.1\u000d\u000a    In contrast to the prior hypothesis, of four different patterns of\u000d\u000a      response (best, that is, to one each of A,B,C,D), this study concluded\u000d\u000a      that there are only two main patterns of BP response to therapy, with\u000d\u000a      patients responding better to either A and B, or to C and\u000d\u000a      D. The findings prompted a further study to test the AB\/CD rule, funded by\u000d\u000a      Pfizer. Once again, C and D were less effective on average than A and B\u000d\u000a      drugs in reducing blood pressure in young patients.2 On this\u000d\u000a      occasion, as well as BP, the group measured a haemodynamic parameter,\u000d\u000a      called augmentation index, and serum biomarker, plasma BNP, which is a\u000d\u000a      measure of heart strain. Although A and B had a similar effect on BP,\u000d\u000a      plasma BNP and augmentation index were elevated several-fold by B\u000d\u000a      (03b2-blockers), while all other classes (A,C,D) reduced (i.e. improved)\u000d\u000a      these parameters.3 The results became available at the same\u000d\u000a      time in 2002 as the first outcome comparison — a clinical trial, published\u000d\u000a      in the Lancet, called `LIFE' — of β-blockade with another class (ARBs);\u000d\u000a      the coincidence allowed Brown to publish a response in the Lancet\u000d\u000a      explaining the inferior protection by β-blockade against strokes.4\u000d\u000a      At the time, LIFE received considerable Pharma-promotion that ARBs\u000d\u000a      superiority over f062-blockade represented a proprietary `benefit beyond\u000d\u000a      blood pressure control'. Brown suggested, rather, that it was\u000d\u000a      f062-blockade which caused an additional harm — by increasing augmentation\u000d\u000a      index and hence heart strain — and that no class achieved benefits beyond\u000d\u000a      blood pressure control.\u000d\u000a    Brown's prediction that older subjects would respond better to CD than AB\u000d\u000a      drugs, was confirmed by several large outcome trials conducted around the\u000d\u000a      world, published from 2000 onwards in leading medical journals, such as\u000d\u000a      JAMA and Lancet, and the subject of an authoritative, prospectively\u000d\u000a      designed meta-analysis of which Brown was a part. One of the first of\u000d\u000a      these outcome trials was the INSIGHT study, led by Professor Brown, which\u000d\u000a      compared C with D in 6321 patients aged >55, (published in 2000 in the\u000d\u000a      Lancet.)5 This reported an average reduction in BP of 32\/17\u000d\u000a      mmHg, almost identical in both arms of the trial and achieved on single\u000d\u000a      therapy in two thirds of patients. This was substantially larger than the\u000d\u000a      reductions in trials using AB drugs in similar patients.\u000d\u000a    A consequence of identifying two broad types of Hypertension, each with\u000d\u000a      its more effective options for treatment, was the ability to recognise\u000d\u000a      patients where salt excess is the main cause, who often need better\u000d\u000a      treatment with diuretics and sometimes have specific underlying causes —\u000d\u000a      particularly a benign hormone-secreting tumour of the adrenal gland. Brown\u000d\u000a      found that these salt-dependent patients had a level of renin in their\u000d\u000a      blood that was inappropriately low for their age and\/or drug treatment\u000d\u000a      (most of which should elevate renin). In 2007, Brown led a study comparing\u000d\u000a      `low-renin' patients' response to each of 2 doses of 3 different\u000d\u000a      diuretics, showed that two older diuretics, not currently licensed or used\u000d\u000a      for hypertension, were more effective than the UK standard,\u000d\u000a      bendroflumethiazide.6 The discovery of a specific adrenal\u000d\u000a      tumour in some of these patients led Brown to develop a novel PET CT scan,\u000d\u000a      using the radiotracer 11C-metomidate, which permits\u000d\u000a      non-invasive diagnosis of patients whose hypertension might be cured by\u000d\u000a      keyhole surgery to remove the tumour.7 Taking Brown's research\u000d\u000a      in a rather beautiful full circle, the PET CT led to the recognition of a\u000d\u000a      common variant of the adrenal tumour caused by somatic mutations of the\u000d\u000a      L-type Ca++ channel — the very target of the C drugs used to\u000d\u000a      treatment hypertension8.\u000d\u000a    "},{"CaseStudyId":"30378","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    A. Clinical studies and Guidelines\u000a      Jayne has co-ordinated the European vasculitis network since 2001 and\u000a      founded the European Vasculitis Society (EUVAS) in 2011. EUVAS has taken a\u000a      strategic and collaborative approach to the development of an evidence\u000a      base to drive therapeutic advances in vasculitis Studies via the EUVAS\u000a      collaboration led by Jayne have informed changes in the classification of\u000a      disease, the 2012 Chapel Hill consensus statement, on clinical (1),\u000a      epidemiological (2), histological (3) and genetic (4) grounds, allowing\u000a      recommendations to be made to enhance clinical trial design and have\u000a      provided a framework for personalised medicine in vasculitis (1).\u000a      Such trials have improved patient outcomes by optimising the balance of\u000a      current therapies between efficacy and toxicity. They have also stratified\u000a      treatment according to severity and resulted in the publication of 5\u000a      consensus treatment recommendations, between 2006 and 2012, sponsored by\u000a      the European League against Rheumatism (EULAR) and the British Society of\u000a      Rheumatology, now used widely through Europe (5-8). Uptake of EUVAS\u000a      methodology and guidance has extended beyond the EU, with collaborative\u000a      studies in USA, Canada, Japan and Australia. NICE is conducting its first\u000a      Health Technology Appraisal (HTA) in vasculitis this year based, in part,\u000a      on work from this group.\u000a    The RITUXVAS trial (NCT 00748644, Jayne was PI) and other studies\u000a      contributed to the licensing of Rituximab for ANCA associated vasculitis\u000a      by the FDA in 2011 and EMA in 2013, and used in consultation in a NICE HTA\u000a      `Further Appraisal Consultation Document' (released September 2013) (9,\u000a      10). On-going studies by Jayne's group are defining pharmacogenomic\u000a      markers to guide dosing and patient stratification, which it is hoped will\u000a      provide long-term control of disease with a reduction in morbidity and\u000a      mortality and improve the cost-effectiveness and safety of this therapy.\u000a    Establishing an evidence base for conventional therapy of AAV\u000a      David Jayne has extended the EUVAS group to include vasculitis networks in\u000a      Japan, North America, Australia and New Zealand permitting large scale\u000a      clinical trials and parallel biomarker and epidemiologic studies. The\u000a      Cambridge team has lead an international consortium since 2001, that\u000a      firstly developed and validated clinical assessment tools and a\u000a      methodology for performing large scale interventional clinical trials,\u000a      then co-ordinated eleven randomised controlled trials that now define the\u000a      standard of care in ANCA vasculitis (6,7). The team are leading on a study\u000a      examining the applicability of plasma exchange (funded by government\u000a      agencies in the UK, USA, Canada, Australia and Japan; PEXIVAS NCT00987389,\u000a      Jayne is PI, commenced 2010). They have also shown the efficacy of\u000a      maintenance therapy in preventing relapse in AAV, and are leading an\u000a      international trial RITAZAREM (NCT01697267, Jayne is PI, commenced April\u000a      2013), contributing to a stratification approach for individual patient\u000a      care.\u000a    B. Novel Therapeutics; B cell depletion with Rituximab in vasculitis\u000a      The outcome of the initial use of rituximab in vasculitis in Cambridge has\u000a      been the completion of two phase 3 studies of its use as induction\u000a      therapy, one was Jayne-led, which were published together in the New\u000a      England Journal of Medicine. The introduction of rituximab since 2005 for\u000a      ANCA associated vasculitis has been hailed by patient groups and the\u000a      medical press alike (9, 10), and resulting in immediate widespread changes\u000a      to clinical practice.\u000a    C. Personalised Medicine in vasculitis\u000a      Prognostic biomarker discovery by the Cambridge group has led to great\u000a      interest in the clinical and scientific community, successful patent\u000a      protection (11), and the development of on-going clinical studies prior to\u000a      commercialisation. These biomarkers are now undergoing clinical validation\u000a      for their utility in patient stratification and personalised medicine\u000a      (12). Validation of this biomarker in a prospective study in AAV (ARC\u000a      grant funded) and Crohn's Disease (Wellcome Trust Translational Award\u000a      funded) is about to commence led by the Smith team.\u000a    ","ImpactSummary":"\u000a    Jayne's team have co-ordinated a sequence of randomised clinical trials,\u000a      that have defined the standard of care for ANCA vasculitis treatment and\u000a      shaped national and international guideline statements, NHS national\u000a      commissioning guidance and an on-going NICE assessment. Together with Ken\u000a      Smith his group have pioneered the use of the B cell-depleting agent\u000a      rituximab, in vasculitis, contributing key evidence that led to its\u000a      licence approval (USA and EU) for this indication. Ken Smith's group\u000a      supported by Jayne's clinical team have discovered novel therapeutic\u000a      biomarkers, patented and being assessed in Phase II clinical studies, that\u000a      promise to deliver \"personalised medicine\" in this and related conditions.\u000a      These activities have harmonised the management of vasculitis, are\u000a      improving patient outcomes, and have provided a resource for on-going\u000a      scientific and clinical studies.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, Hauser\u000a      T, Neumann I, Tesar V, Wissing KM, Pagnoux C, Schmitt W, Jayne DR;\u000a      European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs.\u000a      azathioprine for remission maintenance in antineutrophil cytoplasmic\u000a      antibody-associated vasculitis: a randomized controlled trial. JAMA.\u000a      2010;304:2381-2388.\u000a    \u000a\u000a2. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage\u000a      CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K,\u000a      Jayne DR; European Vasculitis Study Group. \"Rituximab versus\u000a      cyclophosphamide in ANCA-associated renal vasculitis.\" N Engl J Med.\u000a      2010;363:211-220\u000a    \u000a\u000a3. Willcocks LC, Lyons PA, Clatworthy MR, Robinson JI, Yang W, Newland\u000a      SA, Plagnol V, McGovern NN, Condliffe AM, Chilvers ER, Adu D, Jolly EC,\u000a      Watts R, Lau YL, Morgan AW, Nash G, Smith KGC. Copy number of FCGR3B,\u000a      which is associated with systemic lupus erythematosus, correlates with\u000a      protein expression and immune complex uptake. J Exp Med.\u000a      2008;205:1573-1582.\u000a    \u000a\u000a4. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC,\u000a      Koukoulaki M, Hatton A, MacAry PA, Brazma A, Chaudhry AN and Smith KGC. \"A\u000a      CD8 memory T cell transcription signature predicts prognosis in autoimmune\u000a      diseases.\" Nature Medicine, 2010;16:586-589.\u000a    \u000a\u000a5. Lee JC, Lyons PA, McKinney EF, Carr EJ, Bredin F, Rickman HR,\u000a      Ratlamwala H, Hatton A, Rayner TF, Parkes M, Smith KGC. \"Gene expression\u000a      profiling in CD8 T-cells predicts disease course in Crohn's disease and\u000a      ulcerative colitis.\" Journal of Clinical Investigation,\u000a      2011;121:4170-9.\u000a    \u000a\u000a6. Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DRW, Baslund\u000a      B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P,\u000a      Feighery C, Gross WL, Guillevin L,Gunnarsson I, Harper L, Hrušková Z,\u000a      Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD,\u000a      Salama AD, Sanders J-S F, Savage CO, Segelmark M, Stegeman CA, Tesař V,\u000a      Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG and Smith\u000a        KGC. \"Genetically Distinct Subsets within ANCA-Associated\u000a      Vasculitis\" New England Journal of Medicine, 2012;367:214-223.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    A. Clinical studies via the EUVAS collaboration\u000a    \u000a      Hellmich B, Flossmann O, Gross WL et al. EULAR recommendations for\u000a        conducting clinical studies and\/or clinical trials in systemic\u000a        vasculitis: focus on anti-neutrophil cytoplasm antibody- associated\u000a        vasculitis. Ann Rheum Dis. 2007;66:605-617.\u000a      Watts RA, Scott DG, Jayne DR et al. Renal vasculitis in Japan and the\u000a        UK--are there differences in epidemiology and clinical phenotype?\u000a        Nephrol Dial Transplant. 2008;23:3928-3931.\u000a      Berden AE, Ferrario F, Hagen EC et al. Histopathologic Classification\u000a        of ANCA-Associated Glomerulonephritis. J Am Soc Nephrol. 2010\u000a        21(10):1628-36\u000a      Lyons PA, Rayner TF, Trivedi S et al. Genetically distinct subsets\u000a        within ANCA-Associated Vasculitis. N Engl J Med. 2012;367: 214-223.\u000a      Lapraik C, Watts R, Bacon P et al. BSR and BHPR guidelines for the\u000a        management of adults with ANCA associated vasculitis. Rheumatology\u000a        (Oxford). 2007;46:1615-1616.\u000a      Mukhtyar C, Guillevin L, Cid MC et al. EULAR Recommendations for the\u000a        management of primary small and medium vessel vasculitis. Ann Rheum Dis.\u000a        2009;68:310-317.\u000a      Mukhtyar C, Guillevin L, Cid MC et al. EULAR Recommendations for the\u000a        management of large vessel vasculitis. Ann Rheum Dis. 2009;68:318-323.\u000a      Guerry MJ, D'Cruz D, Brogan P, et al. Recommendations for the use of\u000a        rituximab in ANCA vasculitis. Rheumatology 2012 Apr;51(4):634-43.\u000a    \u000a    B. B cell depletion with Rituximab in vasculitis\u000a    \u000a      \u000ahttp:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm251946.htm\u000a        - Patient Organisations such as the Vasculitis Foundatiion\u000a        http:\/\/guidance.nice.org.uk\/TAG\/334\/Consultation\/DraftGuidance\u000a\u000a    \u000a    C. Personalised Medicine in vasculitis\u000a    \u000a      US Provisional patent application number 61\/145,824 — priority date:\u000a        20 January 2009. Title: Methods for classifying subjects (1). US\u000a        Provisional patent application number 61\/145,831 - priority date 20\u000a        January 2009. Title: Methods for classifying subjects (2)\u000a      McKinney EF, Lyons PA, Carr EJ et al. \"A CD8 memory T cell\u000a        transcription signature predicts prognosis in autoimmune diseases.\"\u000a        Nature Medicine, 2010;16:586-591.\u000a    \u000a    ","Title":"\u000a    Establishing an evidence-based therapeutic approach to ANCA-associated\u000a      vasculitis\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Over the last decade Professor Ken Smith, Chair of Medicine and Dr David\u000a      Jayne, University Reader in Vasculitis (both tenured appointments in the\u000a      Department of Medicine, respectively from 1996 and September 2013; Jayne\u000a      was previously Associate Lecturer through the office of the School of\u000a      Clinical Medicine from March 2013 and NHS Consultant, Renal Unit,\u000a      Addenbrooke's Hospital since 2001), have built up a translational\u000a      programme focussed on biomarker identification and delivering improved\u000a      therapy for Anti-neutrophil cytoplasmic antibody (ANCA) — associated\u000a      vasculitis (AAV). AAV is a severe systemic inflammatory condition, with 20\u000a      new cases per million in the UK each year. It commonly causes renal\u000a      failure or pulmonary haemorrhage and has a fatality rate of up to 30% at 5\u000a      years, while causing substantial long — term morbidity in survivors. David\u000a      Jayne co-ordinates an expanding international vasculitis network\u000a      supporting clinical trials and biomarker studies (1).\u000a    Bringing a novel therapeutic approach into the clinic: B cell\u000a        depletion in AAV\u000a      Rituximab is a depleting monoclonal antibody against the B cell-specific\u000a      surface antigen CD20, previously developed for the treatment of B cell\u000a      lymphoma. Following basic research in Cambridge defining the humoral\u000a      contribution to pathogenesis of AAV, Smith and Jayne commenced the first\u000a      pilot study of B cell depletion as a potential induction therapy in 2001.\u000a      This demonstrated a high remission rate for patients with disease\u000a      refractory to the standard of care and suggested rituximab might provide\u000a      an effective alternative to the relatively toxic cyclophosphamide and\u000a      inspired a subsequent international trial, RITUXVAS, led by Jayne (2). The\u000a      response permitted withdrawal of immunosuppressives and glucocorticoids,\u000a      improvement in quality of life, reduced hospitalisations and protection of\u000a      vital organ function.\u000a    Defining new biomarkers and targets for future therapy\u000a      Personalised therapy, that would allow those with mild disease to receive\u000a      reduced therapy, (with reduced toxicity), and those with an aggressive\u000a      disease course to benefit from intensified therapy (with increased\u000a      efficacy), is a major goal in AAV as in other autoimmune diseases. The\u000a      Smith group have identified polymorphisms underlying disease\u000a      susceptibility (3). Such an approach also requires prognostic biomarkers —\u000a      Smith and colleagues, using a transcriptomic approach studying pre-sorted\u000a      circulating leucocytes, have identified phenotypic differences in an\u000a      immune activation pathway of use both as a biomarker and for the study of\u000a      disease pathogenesis, this CD8-T cell transcriptional signature predicts\u000a      long-term prognosis in those presenting with AAV (4), and is likely to\u000a      have widespread application as it also effective in SLE, Crohn's Disease\u000a      and Inflammatory Bowel Disease (5).\u000a    An additional approach to define novel therapeutic pathways has involved\u000a      a genetic study of AAV. Building on a number of candidate gene studies\u000a      performed in Cambridge and elsewhere, the first Genome-Wide Association\u000a      Study of the disease performed in 2012 by a European Consortium led by Ken\u000a      Smith and funded by the British Heart Foundation and NIHR Cambridge\u000a      Biomedical Research Centre. This compared DNA samples 2,500 AAV patients\u000a      with those from healthy controls. This has demonstrated conclusively that\u000a      Wegener's Granulomatosis and Microscopic Polyangiitis are genetically\u000a      distinct diseases, raising the possibility that they may respond to\u000a      different therapeutic approaches rather than to the identical ones\u000a      currently used. It has also shown that the primary disease causing factor\u000a      and genetic abnormality in Wegener's Granulomatosis is the response to a\u000a      single autoantigen, as the MHC, alpha1-antitrypsin, and its substrate the\u000a      autoantigen proteinase 3, are all risk factors for disease. That a single\u000a      antigenic response lies at the core of disease susceptibility suggests\u000a      novel future approaches to therapy (6).\u000a    "},{"CaseStudyId":"32078","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":["Medical Research Council","Royal Society"],"ImpactDetails":"\u000a    The MCM technology and associated intellectual property has had impacts\u000a      on commerce and on healthcare systems internationally. It has also\u000a      improved public understanding of the importance of early cancer detection.\u000a    Impacts on commerce: industry has invested in research and\u000a        development, a new product is in production\u000a      In 2004, the MCM technology was licensed by Cancer Research Technology to\u000a      TriPath Imaging (U.S.) in the field of cervical cancer. In 2007, TriPath\u000a      and its associated licences were bought by Becton Dickinson (BD), who\u000a      developed the BD ProExTM C reagent, based on antibodies against\u000a      MCM2 and DNA-topoisomerase 2α. This has been in widespread use\u000a      internationally since 2008, particularly in USA and Canada, as well as in\u000a      European centres (most notably Scandinavia and Southern Europe). [text\u000a      removed for publication]\u000a    Impacts on commerce: highly skilled people have taken up specialist\u000a        roles in companies, jobs have been created\u000a      The research of Laskey and Coleman led to the creation of the MRC Cancer\u000a      Cell Unit (CCU), a new MRC Unit, in 2001, with Laskey as founding\u000a      director. The purpose of the Unit was to build on and extend translational\u000a      cancer research, particularly MCM-based cancer detection. The MRC CCU\u000a      receives over £3M in funding p.a. and continues to provide over 100 new\u000a      jobs in the UK. [text removed for publication] In addition, Becton\u000a      Dickinson has invested heavily in developing the BD ProExTM C\u000a      reagent (based on MCM detection), creating new highly-skilled jobs (number\u000a      withheld by BD) in the USA.\u000a    Impacts on healthcare: a new diagnostic has been adopted; disease\u000a        prevention has been enhanced\u000a      An important use of the BD ProExTM C reagent is for triage of\u000a      cervical smears and biopsies showing `borderline' changes, referred to as\u000a      atypical squamous cells of uncertain significance (ASCUS). These\u000a      abnormalities are seen in 5-7% of cervical smears in developed countries,\u000a      and provide a major clinical challenge, as they include cases of\u000a      pre-cancer, as well as non-neoplastic processes such as repair and\u000a      reaction to inflammation. BD ProExTM C significantly improves\u000a      the accuracy of pre-cancer detection in cervical smears in this sample\u000a      group, reducing patient over-investigation and potentially therefore\u000a      overall screening costs7.\u000a    Since 2010, several independent groups in Europe and USA have evaluated\u000a      the BD ProExTM C reagent in combination with human\u000a      papillomavirus (HPV) testing, as a more accurate and cost-effective\u000a      replacement for cervical Papanicolaou (Pap) screening. There is an\u000a      important clinical need for a biomarker-based approach to primary cervical\u000a      screening, as the Pap test is based on subjective interpretation and a\u000a      single test has a sensitivity for cancer\/pre-cancer of only ~50%. A recent\u000a      major study compared eight primary cervical screening strategies and\u000a      concluded that the optimal combination was HPV testing followed by triage\u000a      using the BD ProExTM C reagent8; it had the highest\u000a      level of accuracy and reduced the number of patient procedures required.\u000a      As a result, BD pre-adapted its new screening machines worldwide to run BD\u000a      ProExTM C in combination with HPV testing (BD Totalys system).\u000a    To date, over 30 publications from independent research groups have\u000a      demonstrated the value of the BD ProExTM C reagent, in a\u000a      variety of clinical settings. The product has also been used by\u000a      histopathology services across the NHS in the UK10. It is not\u000a      yet possible to state with accuracy the number of patients who have\u000a      benefitted from BD ProExTM C in USA\/Canada and Europe since\u000a      2008, as BD is still in the process of commercialising the products and\u000a      providing local support to cytology laboratories worldwide.\u000a    To date, licenses based on the MCM technology have generated income in\u000a      excess of £800K for Cancer Research Technology on behalf of Cancer\u000a      Research UK, and the University of Cambridge11.\u000a    Impacts on health and welfare: public awareness of a health benefit\u000a        has been raised\u000a      The MCM work has featured prominently in the national press, including\u000a      several articles since 200812,13. Coleman and Laskey have given\u000a      numerous invited talks on MCM testing, to both specialist and lay\u000a      audiences, thereby improving public and professional understanding of the\u000a      importance of early cancer detection14.\u000a    Due to the impacts of this work, both Laskey and Coleman have received\u000a      major scientific awards. In 2009, Laskey was awarded the Royal Medal of\u000a      the Royal Society for `his pivotal contributions to our understanding of\u000a      the control of DNA replication and nuclear protein transport, which has\u000a      led to a novel screening method for cancer diagnosis'. In 2010, Coleman\u000a      received the Goudie Medal, The Pathological Society of Great Britain and\u000a      Ireland, which is awarded `to a distinguished active scientist who is\u000a      making seminal contributions to pathological science'.\u000a    ","ImpactSummary":"\u000a    An antibody screening test for early detection of cancer was developed in\u000a      the laboratories of Prof Nick Coleman (Pathology) and Prof Ron Laskey\u000a      (Zoology; UoA5) and Patent applications arising from their research were\u000a      filed by Cancer Research Technology (CRT) and licensed to multiple\u000a      diagnostic companies, including Becton Dickinson (BD). The BD ProExTM\u000a      C reagent is in use internationally, including for the triage of cervical\u000a      smears and biopsies showing `borderline' abnormalities (~5-7% of cervical\u000a      smears in developed countries). Additional licensing deals have been\u000a      negotiated for screening in a range of other cancers, including bladder,\u000a      pancreas and prostate. The licences have generated in excess of £800K for\u000a      CRT and the University to date.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Madine MA, Khoo C-Y, Mills AD and Laskey RA (1995). MCM3 complex\u000a      required for cell cycle regulation of DNA replication in vertebrate cells.\u000a      Nature 375 : 421-424 doi:10.1038\/375421a0\u000a    \u000a\u000a2. Gonzalez MA, Tachibana KK, Laskey RA, Coleman N (2005) Control of DNA\u000a      replication and its potential clinical exploitation. Nature Reviews\u000a        Cancer 5:135-41 doi:10.1038\/nrc1548\u000a    \u000a\u000a3. Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH,\u000a      Coleman N (1999) The minichromosome maintenance proteins as biological\u000a      markers of dysplasia and malignancy. Clinical Cancer Research 5:\u000a      2121-2132\u000a    \u000a\u000a4. Williams GH, Romanowski P, Morris L, Madine M, Mills AD, Stoeber K,\u000a      Marr J, Laskey RA, Coleman N (1998) Improved cervical smear assessment\u000a      using antibodies against proteins that regulate DNA replication. Proceedings\u000a        of the National Academy of Sciences USA 95: 14932-14937\u000a    \u000a\u000a5. Mukherjee G, Muralidhar B, Bafna UD, Laskey RA, Coleman N (2007) MCM\u000a      immunocytochemistry as a first line cervical screening test in developing\u000a      countries: a prospective cohort study in a regional cancer centre in\u000a      India. British Journal of Cancer 96:1107-11\u000a      doi:10.1038\/sj.bjc.6603679\u000a    \u000a\u000a6. Davies RJ, Freeman A, Morris LS, Bingham S, Dilworth S, Scott IS,\u000a      Laskey RA, Miller R, Coleman N (2002) Analysis of minichromosome\u000a      maintenance proteins as a novel method for detecting colorectal cancer in\u000a      stool. Lancet 359 1917-19 doi: 10.1016\/S0140-6736(02)08739-1\u000a    \u000aGrant support\u000a      The MRC CCU (directed by Ron Laskey 2001 -2010) has received over £3M in\u000a      funding each year since 2001. From 2001 to the present, Coleman and Laskey\u000a      have been funded by Programme Grants within the MRC CCU and from Cancer\u000a      Research UK, with a combined value of over £6.2M.\u000a    The current funding round extends to November 2016. The principal grants\u000a      are:\u000a    • `Translational approaches to improving cancer screening and diagnosis'\u000a      (Coleman) Medical Research Council Programme Grants, within MRC Cancer\u000a      Cell Unit: (2006-2011) £1,190,722; (2001-2006) £1,230,385.\u000a    • 'Viral and host mechanisms in cervical carcinogenesis' (Coleman) Cancer\u000a      Research UK Programme Grant (2011-16) £1,125,002\u000a    • 'Eukaryotic DNA replication and novel cancer markers' (jointly\u000a      Laskey\/Coleman) Cancer Research UK Programme Grants: (2006-2011)\u000a      £1,431,085; (2001-6) £1,245,700\u000a    Intellectual property\u000a      The use of MCMs as biomarkers to detect cancer\/pre-cancer is protected by\u000a      multiple international patents, granted to Cancer Research Technology on\u000a      behalf of Cancer Research UK, and Cambridge University. The principal\u000a      patent is: `Determination of Cellular Growth Abnormality', reference: US\u000a      Patent Office 6,303,323 (16\/10\/2001) [and divisionals]; World Intellectual\u000a      Property Organisation 1999\/021014 (29\/04\/1999); Canada 2305872\u000a      (29\/04\/1999); China 98812478 (31\/01\/01); European Patent Office EP1025444\u000a      (09\/08\/00).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Badr RE et al, 2008, BD ProEx C: a sensitive and specific marker of\u000a        HPV-associated squamous lesions of the cervix. Am J Surg Pathol.\u000a        32:899-906\u000a      Depuydt et al, 2011, BD-ProExC as adjunct molecular marker for\u000a        improved detection of CIN2+ after HPV primary screening. Cancer\u000a          Epidemiol Biomarkers Prev. 20:628-37\u000a      BD ProExTM C reagent website: www.bd.com\/tripath\/products\/proexc\/index.asp\u000a\u000a      Histopathology Reporting in Cervical Screening — an integrated\u000a        approach. NHS Cervical Screening Programme. NHSCSP Publication Number 10\u000a        (second edition). September 2012\u000a        www.cancerscreening.nhs.uk\/cervical\/publications\/nhscsp10.pdf\u000a\u000a      Personal communication, Business Management Director, Cancer Research\u000a        Technology\u000a      24 October 2008, Virtual Medical Centre, `A new test to prevent anal\u000a        cancer'. http:\/\/www.virtualmedicalcentre.com\/news\/a-new-smear-test-to-prevent-anal-cancer\/12707\u000a\u000a      10 November 2008, Pink News, `Thousands of lives could be saved by new\u000a        anal cancer test'.\u000a        http:\/\/www.pinknews.co.uk\/2008\/11\/10\/thousands-of-lives-could-be-saved-by-new-anal-cancer-test\/\u000a\u000a      Talks by Coleman include European Cancer Organisation and European\u000a        Society for Medical Oncology [ECCO15:ESMO34] Teaching lecture jointly\u000a        with Laskey (Berlin 2009); Goudie Medal Lecture, The Pathological\u000a        Society of GB and Ireland (London 2010); Plenary lecture Society for\u000a        General Microbiology Human Papillomavirus UK meeting, (Lake District,\u000a        2012)\u000a    \u000a    ","Title":"\u000a    Minichromosome maintenance proteins as biomarkers for improving the early\u000a      detection of common cancers\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Nick Coleman is in the Department of Pathology (from 1992, Associate\u000a      Senior Lecturer 2001-2011, Professor of Molecular Pathology 2011-present\u000a      and also previously Programme Leader in the Medical Research Council\u000a      Cancer Cell Unit, MRC CCU).\u000a    Ron Laskey was Honorary Director of the MRC CCU in Cambridge, from its\u000a      commencement in 2001 to his retirement in 2010. Throughout this period he\u000a      remained Charles Darwin Professor of Embryology in Cambridge University\u000a      Department of Zoology. He is now Emeritus Professor in the Dept. Zoology.\u000a    Laskey has a long-standing interest in the control of DNA replication. In\u000a      1994, he showed that MCM (Mini-Chromosome Maintenance) proteins coupled\u000a      DNA synthesis to the cell cycle, by forming an active complex in the G1\u000a      phase of the cell cycle, which was dissociated in the G2 phase. Laskey's\u000a      group raised polyclonal and monoclonal antibodies against human MCM\u000a      proteins and showed that they are absent from non-proliferating cells1.\u000a    In 1997 and 1998, Coleman collaborated with Laskey in a study of cell\u000a      lines and human tissue sections to show that MCMs were abundant in nuclei\u000a      throughout the cell cycle, but were lost following cell cycle exit into\u000a      differentiation, quiescence or senescence2. They concluded that\u000a      MCMs would make excellent biomarkers of the abnormal cell proliferation\u000a      that characterises malignancy and pre-malignancy.\u000a    In 1999, the two groups used immunohistochemistry to demonstrate that,\u000a      whereas MCMs were confined to the basal cells of normal stratified\u000a      epithelia, MCMs were expressed in the full thickness of equivalent\u000a      epithelia showing malignant or pre-malignant changes. This observation\u000a      applied to most common cancers (e.g. cervix, large bowel, lung, bladder,\u000a      etc.)3.\u000a    Importantly, many cancer-screening tests use cells sampled from\u000a      epithelial surfaces (e.g. in cervical smears, stool, sputum, urine, etc.).\u000a      As MCM proteins were present in the surface cells of cancers\/pre-cancers,\u000a      but absent from the surface cells of normal epithelia, they represented\u000a      biomarkers with the potential to identify cancer\/pre-cancer cells in\u000a      screening samples3. Laskey and Coleman hypothesized that an\u000a      objective assay based on biomarkers would offer improved accuracy,\u000a      throughput and affordability for many of the tests used to screen for\u000a      common cancers. In all tumours tested, MCM proteins were significantly\u000a      more abundant at the epithelial surface than other markers of cycling\u000a      cells, such as Ki-67 and PCNA2,3.\u000a    Between 1997 and 2003, the two groups tested whether MCMs could\u000a      accurately detect malignant\/pre-malignant cells in cervical smears4.\u000a      In a clinical evaluation study of over 1,500 women, MCM testing showed\u000a      very high (>95%) sensitivity for cancer and high-grade pre-cancer, at\u000a      good levels of specificity (>90%), and detected several cases that were\u000a      missed by conventional testing.\u000a    In 2007, Coleman and Laskey collaborated with Professor Geeta Mukherjee\u000a      (Kidwai Institute, Bangalore, India) in an immunocytochemical study, which\u000a      showed that MCM detection was also suitable for cervical screening in\u000a      developing countries, as a low-cost, objective approach that substantially\u000a      increased accuracy and reduced time, expertise and costs required for\u000a      slide assessment5.\u000a    From 2001, the two groups also collaborated to assess the suitability of\u000a      MCM testing for other common cancers. For bowel cancer screening, they\u000a      studied colonocytes retrieved from the surface of stool, in a\u000a      `proof-of-principle' study. MCM testing distinguished between normal and\u000a      malignant cells, with positive staining in 37\/40 cancers, including all\u000a      nine early-stage tumours, but in none of 25 control subjects6.\u000a      A novel method for retrieving stool-derived mucus, developed between 2005\u000a      and 2009, improved cell yield over 30-fold.\u000a    Between 2003 and 2008 the two groups also determined the performance of\u000a      MCM testing in detecting lung cancer in sputum, using over 800 samples\u000a      from patients referred for investigation of possible lung cancer. MCMs\u000a      provided similar sensitivity for detecting lung cancer as a screening\u000a      check by consultant pathologists (27-31%) and offered the advantage of\u000a      automated detection.\u000a    "},{"CaseStudyId":"34476","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1269750","Name":"India"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The outcome of the CRASH2 trial has been a worldwide change in protocols\u000d\u000a      and practice, with treatment using TXA now being regarded as the standard\u000d\u000a      of care in severe injury.\u000d\u000a    Once fully implemented, TXA could prevent 15% of in-hospital deaths from\u000d\u000a      bleeding following trauma each year (around 100,000 per year), giving a\u000d\u000a      worldwide health cost-benefit of £26 billion per year (assuming £20,000\u000d\u000a      per Quality Adjusted Life Year). Around 600 lives could be saved in\u000d\u000a      Britain each year. A single dose of TXA costs around £3, so there are no\u000d\u000a      substantial cost implications to its widespread adoption.\u000d\u000a    Impact on the battlefield\u000d\u000a      As uncontrolled bleeding is the leading cause of preventable death among\u000d\u000a      combat casualties, it was not surprising that within weeks the British\u000d\u000a      armed forces and US military were working with the CRASH2 team to\u000d\u000a      implement the use of TXA on the battlefield. British armed forces\u000d\u000a      protocols were changed in 20101 (A) and the US military Standard\u000d\u000a      Operation Procedures changed in 2012 (B).\u000d\u000a    A 2011 registry-based study of combat injured troops receiving blood at\u000d\u000a      the Bastion Role 3 facility in Afghanistan has demonstrated findings\u000d\u000a      supportive of TXA use: the group receiving TXA had a lower mortality rate\u000d\u000a      (17.4%) than the no-TXA group (23.9%) despite being more severely injured.\u000d\u000a    In 2012 the drug box onboard the US presidential plane `Air Force One'\u000d\u000a      was updated to include TXA (supporting evidence not available as\u000d\u000a      classified).\u000d\u000a    Impact on civilian practice in the UK\u000d\u000a      The rotation of Territorial Army \/ Home Guard trauma clinicians through\u000d\u000a      combat deployments greatly aided in spreading the implementation of the\u000d\u000a      results into civilian practice. In the UK, the research has changed\u000d\u000a      patient care, being incorporated into both national and local trauma care\u000d\u000a      guidelines across the UK (C,D).\u000d\u000a    The Joint Royal Colleges Ambulance Liaison Committee has changed\u000d\u000a      ambulance protocols (2013) to mandate that all severely injured patients\u000d\u000a      in the UK are given TXA in the prehospital phase of trauma care (E).\u000d\u000a    The National Institute for Health and Care Excellence (NICE) was\u000d\u000a      initially unable to comment on the research as its constitution does not\u000d\u000a      allow it to comment on `off label' indications; however, after some\u000d\u000a      discussion a new category of NICE activity has been developed and the\u000d\u000a      research has resulted in the first NICE Evidence Summary of\u000d\u000a      Unlicensed\/off-label Medicine (F).\u000d\u000a    Within the wider NHS the results of the research have been chosen as one\u000d\u000a      of the key components of the 2013\/14 `Payment by Results' system for\u000d\u000a      trauma care, with the supporting documentation specifically mentioning the\u000d\u000a      high quality of the evidence (G).\u000d\u000a    International impact\u000d\u000a      The standard European Guideline for the management of bleeding after\u000d\u000a      trauma (for which Prof. Coats is a co-author) was modified in 2013 to\u000d\u000a      include the results of this research as a Grade 1A recommendation (there\u000d\u000a      are only four recommendations of this grade in the guidelines; H).\u000d\u000a    In 2012 the CRASH2 team successfully applied to the WHO `Essential\u000d\u000a      Medicines' Committee for tranexamic acid to be included in the WHO List of\u000d\u000a      Essential Medicines, which guarantees availability of tranexamic acid in\u000d\u000a      the developing world (I). This is a very important step towards\u000d\u000a      maximising the impact of this research, as trauma is a disease epidemic in\u000d\u000a      the developing world: 90% of trauma deaths are in low and middle-income\u000d\u000a      countries, and the potential of TXA to reduce premature mortality is\u000d\u000a      likely to be much greater in these settings. Of the 100,000 lives that\u000d\u000a      could potentially be saved each year, around a quarter are in India and\u000d\u000a      China (J). TXA is cheap to produce, widely available and easy to\u000d\u000a      administer, making it ideal for use in low and middle-income countries\u000d\u000a      where healthcare budgets may be limited.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Trauma is a rapidly increasing global healthcare problem which is\u000d\u000a      predicted by the World Health Organisation (WHO) to overtake infectious\u000d\u000a      disease globally by 2020. The discovery of the acute coagulopathy of\u000d\u000a      trauma (uncontrolled bleeding) and the subsequent establishment of the\u000d\u000a      clot stabiliser tranexamic acid (TXA) as a treatment for this condition\u000d\u000a      has led to a change in national and international trauma management\u000d\u000a      protocols. British armed forces and the US military implemented the use of\u000d\u000a      the drug soon after the results were published. Every injured British or\u000d\u000a      American soldier now receives this treatment. The use of TXA has been\u000d\u000a      included in national and international guidance for trauma care.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Leicester\u000d\u000a    ","Institutions":[{"AlternativeName":"Leicester (University of)","InstitutionName":"University of Leicester","PeerGroup":"A","Region":"East Midlands","UKPRN":10007796}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Antifibrinolytic drugs for acute traumatic injury. Coats TJ, Roberts\u000d\u000a      I, Shakur H, Cochrane Database Syst Rev. 2004; 4.\u000d\u000a    \u000a\u000a2. Effects of tranexamic acid on death, vascular occlusive events, and\u000d\u000a      blood transfusion in trauma patients with significant haemorrhage\u000d\u000a      (CRASH-2): a randomised, placebo-controlled trial. CRASH-2 trial\u000d\u000a      collaborators. The Lancet. 2010;\u000d\u000a      376(9734):23-32.doi:10.1016\/S0140-6736(10)60835-5\u000d\u000a    \u000a\u000a3. The importance of early treatment with tranexamic acid in bleeding\u000d\u000a      trauma patients: an exploratory analysis of the CRASH-2 randomised\u000d\u000a      controlled trial. CRASH-2 collaborators. The Lancet 2011; 377: 1096 -\u000d\u000a      1101. doi:10.1016\/S0140-6736(11)60278-X\u000d\u000a    \u000a\u000a4. Effect of tranexamic acid on mortality in patients with traumatic\u000d\u000a      bleeding: pre-specified analysis of data from a randomised controlled\u000d\u000a      trial. Roberts I, Perel P, Prieto-Merino, Shakur H, Coats T, Hunt B, Lecky\u000d\u000a      F, Brohi K, Willett K, CRASH-2 Collaborators BMJ. 2012 Sep 11;345. http:\/\/www.bmj.com\/content\/345\/bmj.e5839\u000d\u000a    \u000a\u000a5. Antifibrinolytic drugs for acute traumatic injury. Roberts I, Shakur\u000d\u000a      H, Ker K, Coats T; CRASH-2 Trial collaborators. Cochrane Database Syst\u000d\u000a      Rev. 2012;12: CD004896. doi: 10.1002\/14651858.CD004896.pub3\u000d\u000a    \u000aGrants\u000d\u000a      BUPA Foundation (2005) £220, 000\u000d\u000a      Molton Foundation (2005) £196, 000\u000d\u000a      NIHR HTA (2007) £2.8 million (Coats was a co-applicant)\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    A. British Forces News: Injured soldiers in Afghanistan saved by\u000d\u000a      blood-clotting drug (19 January 2011). http:\/\/www.youtube.com\/watch?v=oj6P2cwwRYw\u000d\u000a    B. Tranexamic Acid (TXA) in Tactical Combat Casualty Care Guideline\u000d\u000a      Revision Recommendation Committee on Tactical Combat Casualty Care. 11\u000d\u000a      August 2011.\u000d\u000a      http:\/\/www.medicalsci.com\/files\/tranexamic_acid__txa__in_tactical_combat_casualty_care.pdf\u000d\u000a    C. Peninsula CLAHRC Tranexamic Acid Guideline. http:\/\/www.clahrc-peninsula.nihr.ac.uk\/includes\/site\/files\/files\/CRASH%202\/SW%20Hospital%20TXA%20guideline%20final.pdf\u000d\u000a    D. RCPCH Evidence Statement — Major trauma and the use of tranexamic acid\u000d\u000a      in children. Royal College of Paediatrics and Child Health. November 2012.\u000d\u000a      https:\/\/www.tarn.ac.uk\/content\/downloads\/3100\/121112_TXA%20evidence%20statement_final%20v2.pdf\u000d\u000a    E. Joint Royal Colleges Ambulance Liaison Committee. Guidelines 2012 —\u000d\u000a      Trauma. (no electronic copy available as a restricted document).\u000d\u000a    F. ESUOM1 Significant haemorrhage following trauma: tranexamic acid.\u000d\u000a      National Institute for Health and Care Excellence. October 2012.\u000d\u000a      http:\/\/www.nice.org.uk\/mpc\/evidencesummariesunlicensedofflabelmedicines\/ESUOM1.jsp\u000d\u000a    G. Payment by Result Guidance for 2013-14. Department of Health 2013.\u000d\u000a      https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/127296\/Draft-PbR-Guidance-for-2013-14-not-accessible.pdf.pdf\u000d\u000a      (Paragraph 424)\u000d\u000a    H. Management of bleeding and coagulopathy following major trauma: an\u000d\u000a      updated European guideline. Spahn DR, Bouillon B, Cerny V, Coats TJ,\u000d\u000a      Duranteau J, Enrique Fernández-Mondéjar E, Filipescu D, Hunt BJ, Komadina\u000d\u000a      R, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL and\u000d\u000a      Rossaint R Critical Care 2013, 17:R76 http:\/\/ccforum.com\/content\/17\/2\/R76\/\u000d\u000a      (Recommendation 24)\u000d\u000a    I. WHO 18th Expert Committee on the Selection and Use of Essential\u000d\u000a      Medicines Proposal for the inclusion of Tranexamic Acid (anti-fibrinolytic\u000d\u000a      — lysine analogue) in the WHO Model List of Essential Medicines. World\u000d\u000a      Health Organisation 2011.\u000d\u000a      http:\/\/www.who.int\/selection_medicines\/committees\/expert\/18\/applications\/TRANEXAMIC_ACID_10_2.pdf\u000d\u000a    J. Ker K, Kiriya J, Perel P, Edwards P, Shakur H, Roberts I. Avoidable\u000d\u000a      mortality from giving tranexamic acid to bleeding trauma patients: an\u000d\u000a      estimation based on WHO mortality data, a systematic literature review and\u000d\u000a      data from the CRASH-2 trial. BMC Emerg Med 2012; 12: 3. \u000d\u000a    ","Title":"\u000d\u000a    A new use for an old drug: administration of tranexamic acid to prevent\u000d\u000a      trauma deaths from bleeding\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Background\u000d\u000a      Prior to Professor Tim Coats' appointment to the University of Leicester\u000d\u000a      as Professor of Emergency Medicine in 2004, he had published the first\u000d\u000a      description of the acute coagulopathy of trauma (uncontrolled bleeding).\u000d\u000a      Coats had the idea that an antifibrinolytic (a drug that prevents clots\u000d\u000a      from breaking down) might be a potential treatment for this newly\u000d\u000a      discovered condition. The original CRASH trial (of steroids in head injury\u000d\u000a      — no University of Leicester involvement) had just finished, so upon\u000d\u000a      joining Leicester Coats had discussions with Professor Ian Roberts of the\u000d\u000a      London School of Hygiene and Tropical Medicine (LSHTM) to see if the same\u000d\u000a      set of research sites could be used for an antifibrinolytic trial in major\u000d\u000a      trauma. The drug was tranexamic acid (TXA), a cheap-to-produce and widely\u000d\u000a      available treatment that had been used for some time in operating theatres\u000d\u000a      to prevent the need for blood transfusions. In 2004 Coats published a\u000d\u000a      Cochrane Review (1) of the evidence for the use of TXA in trauma,\u000d\u000a      which demonstrated that the existing evidence was very poor and that a\u000d\u000a      large clinical trial was needed to answer the question.\u000d\u000a    CRASH2 trial\u000d\u000a      In 2005 a large randomised trial, called CRASH2, of tranexamic acid\u000d\u000a      treatment in patients who had or were suspected to have significant\u000d\u000a      bleeding was initiated. Coats, who had originated the idea and developed\u000d\u000a      the methodology, was the clinical lead and Leicester was the lead clinical\u000d\u000a      centre for the UK. Roberts was the Lead Applicant and Chief Investigator\u000d\u000a      for the worldwide CRASH2 trial (20,000 patients in 274 hospitals in 40\u000d\u000a      countries) and LSHTM's clinical trials unit, with its large-scale delivery\u000d\u000a      system, ran the trial, assisted by a worldwide group of trauma clinicians.\u000d\u000a    The unit was responsible for input into the design of a practical\u000d\u000a      pragmatic trial that could be delivered in emergency care, the estimate of\u000d\u000a      the likely mortality for the sample size calculation, the engagement of\u000d\u000a      emergency physicians, and the practicalities of trial delivery in the new\u000d\u000a      regulatory framework. Coats was a member of the Trial Management Group,\u000d\u000a      the Trial Steering Group and the Writing Committee.\u000d\u000a    One life saved for every 67 patients treated\u000d\u000a      The trial showed that treatment with tranexamic acid reduced patient\u000d\u000a      mortality from 16% (control group) to 14.5% (TXA group), thus preventing\u000d\u000a      9% of all trauma deaths — in other words one life was saved for every 67\u000d\u000a      patients treated. The reduction in the relative risk of death due to\u000d\u000a      bleeding was even higher, at 15%. There was no increase in adverse events\u000d\u000a      such as thrombosis. The economic analysis estimated that approximately\u000d\u000a      100,000 lives per year worldwide (15% of in-hospital trauma deaths from\u000d\u000a      bleeding) could be saved by widespread use of the results of this\u000d\u000a      research.\u000d\u000a    The trial results were published in The Lancet in 2010 (2) and a\u000d\u000a      subsequent subgroup analysis (on time from injury to administration) was\u000d\u000a      published as a separate paper in The Lancet in 2011 (3). An\u000d\u000a      analysis of the specific effects in bleeding patients was published in the\u000d\u000a      BMJ in 2012 (4). The original 2004 Cochrane Review (for which Coats\u000d\u000a      was first author) was updated in 2012 (5; Coats became last\u000d\u000a      author).\u000d\u000a    "},{"CaseStudyId":"34811","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    ATAC was the first trial to show that an aromatase inhibitor alone is\u000d\u000a      more effective than tamoxifen for adjuvant treatment of early breast\u000d\u000a      cancer, with fewer adverse effects. This has now been confirmed by\u000d\u000a      subsequent studies [a, b, c]. ATAC has been the only trial to\u000d\u000a      perform a direct head-to-head comparison of anastrozole against tamoxifen\u000d\u000a      alone. The trial has the longest duration of follow-up, with benefits of\u000d\u000a      anastrozole maintained out to at least 10 years. Anastrozole is now the\u000d\u000a      most widely prescribed aromatase inhibitor worldwide, with more than twice\u000d\u000a      as many prescriptions annually as the next most widely prescribed\u000d\u000a      aromatase inhibitor. Over 5.5 million patient years of experience with\u000d\u000a      anastrozole has now accrued, and global sales totalled $2.8bn for the\u000d\u000a      period 2010-12, with the manufacturers citing the ATAC trial as the basis\u000d\u000a      of this success [d].\u000d\u000a    National and international guidelines now advocate use of an aromatase\u000d\u000a      inhibitor as first-line adjuvant therapy instead of tamoxifen, based\u000d\u000a      principally on the results of the ATAC trial. In 2005, a technology\u000d\u000a      assessment from the American Society of Clinical Oncology on the use of\u000d\u000a      aromatase inhibitors as adjuvant therapy for post-menopausal women with\u000d\u000a      hormone receptor-positive early-stage breast cancer recommended that: \"Based\u000a        on results from multiple large randomized trials, adjuvant therapy for\u000d\u000a        postmenopausal women with hormone receptor-positive breast cancer should\u000d\u000a        include an aromatase inhibitor in order to lower the risk of tumor\u000d\u000a        recurrence\" [e]. The document refers to the ATAC trial\u000d\u000a      throughout. The following year, a NICE technology assessment recommended\u000d\u000a      that \"The aromatase inhibitors anastrozole, exemestane and letrozole,\u000d\u000a        within their licensed indications, are recommended as options for the\u000d\u000a        adjuvant treatment of early oestrogen-receptor-positive invasive breast\u000d\u000a        cancer in postmenopausal women\" [f]. In March 2009, NICE\u000d\u000a      Clinical Guideline 80 on `Early and locally advanced breast cancer'\u000d\u000a      recommended that \"Postmenopausal women with ER-positive early invasive\u000d\u000a        breast cancer who are not considered to be low risk should be offered an\u000d\u000a        aromatase inhibitor, either anastrozole or letrozole, as their initial\u000d\u000a        adjuvant therapy\" [g]. This was listed as a key priority.\u000d\u000a    Anastrozole is now become standard treatment. A commentary on our 10-year\u000d\u000a      analysis (ref [4] above) in the Lancet Oncology in 2010 stated that \"Mainly\u000a        on basis of the initial results of ATAC, aromatase inhibitor treatment\u000d\u000a        has now been declared the standard adjuvant treatment of\u000d\u000a        endocrine-responsive breast cancer by the St Gallen International Expert\u000d\u000a        Consensus\" [h].\u000d\u000a    Anastrozole offers significant benefits to patients. While anastrozole\u000d\u000a      and tamoxifen demonstrate similar outcomes in terms of overall survival,\u000d\u000a      anastrozole increased absolute progression-free survival by 3%. Patients\u000d\u000a      were also less likely to stop treatment because of treatment-related\u000d\u000a      adverse effects. The following adverse effects were less common with\u000d\u000a      anastrozole than with tamoxifen: hot flushes (5% absolute risk reduction),\u000d\u000a      vaginal bleeding (5%) or discharge (9%), venous thrombosis (2%), stroke\u000d\u000a      (1%) and endometrial cancer (0.4%) [i].\u000d\u000a    Anastrozole has been estimated to lead to 0.26 QALYs gained per patient,\u000d\u000a      with an incremental cost-effectiveness ratio of approximately £12,600 per\u000d\u000a      QALY gained and £14,700 per life-year gained [j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The ATAC trial was conceived, designed and implemented by UCL\u000d\u000a      investigators, and has resulted in a dramatic, global change in the\u000d\u000a      management of breast cancer. It directly compared tamoxifen, the standard\u000d\u000a      treatment for breast cancer for 25 years, with anastrozole, a\u000d\u000a      novel aromatase inhibitor. It convincingly demonstrated superiority for\u000d\u000a      the new agent, in terms of both progression-free survival and adverse\u000d\u000a      effect profile. Tamoxifen had been the world's most widely prescribed\u000d\u000a      anti-cancer drug but was supplanted by anastrozole as a consequence of\u000d\u000a      this trial.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2658822","Name":"Sankt Gallen"}],"References":"\u000d\u000a    \u000a[1] Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud\u000d\u000a      T; ATAC Trialists' Group. Anastrozole alone or in combination with\u000d\u000a      tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal\u000d\u000a      women with early breast cancer: first results of the ATAC randomised\u000d\u000a      trial. Lancet. 2002 Jun 22;359(9324):2131-9. http:\/\/dx.doi.org\/10.1016\/S0140-6736(02)09088-8\u000d\u000a    \u000a\u000a[2] Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF,\u000d\u000a      Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group.\u000d\u000a      Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial\u000d\u000a      after completion of 5 years' adjuvant treatment for breast cancer. Lancet.\u000d\u000a      2005 Jan 1-7;365(9453):60-2. http:\/\/dx.doi.org\/10.1016\/S0140-6736(04)17666-6\u000d\u000a    \u000a\u000a[3] Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group,\u000d\u000a      Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of\u000d\u000a      anastrozole and tamoxifen as adjuvant treatment for early-stage breast\u000d\u000a      cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008\u000d\u000a      Jan;9(1):45-53. http:\/\/dx.doi.org\/10.1016\/S1470-2045(07)70385-6\u000d\u000a    \u000a\u000a[4] Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes J;\u000d\u000a      ATAC\/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant\u000d\u000a      treatment for early-stage breast cancer: 10-year analysis of the ATAC\u000d\u000a      trial. Lancet. 2010 Dec;11(12):1135-41. http:\/\/dx.doi.org\/10.1016\/S1470-2045(10)70257-6\u000d\u000a    \u000a\u000a[5] Ring A, Sestak I, Baum M, Howell A, Buzdar A, Dowsett M, Forbes JF,\u000d\u000a      Cuzick J. Influence of comorbidities and age on risk of death without\u000d\u000a      recurrence: a retrospective analysis of the Arimidex, Tamoxifen Alone or\u000d\u000a      in Combination trial. J Clin Oncol. 2011 Nov 10;29(32):4266-72. http:\/\/dx.doi.org\/10.1200\/JCO.2011.35.5545\u000d\u000a    \u000aFunder: Cancer Research UK\u000d\u000a    Sponsor: University College London\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Aydiner A, Tas F. Meta-analysis of trials comparing anastrozole and\u000d\u000a      tamoxifen for adjuvant treatment of postmenopausal women with early breast\u000d\u000a      cancer. Trials 2008;9:47.\u000d\u000a      http:\/\/dx.doi.org\/10.1186\/1745-6215-9-47\u000d\u000a    [b] Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase\u000d\u000a      inhibitors in adjuvant therapy for hormone receptor positive breast\u000d\u000a      cancer: a systematic review. Cancer Treatment Rev 2008;34:157-74. http:\/\/dx.doi.org\/10.1016\/j.ctrv.2007.11.001\u000d\u000a    [c] Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for\u000d\u000a      treatment of advanced breast cancer in postmenopausal women (Review).\u000d\u000a      Cochrane Database Syst Rev 2009;(4).\u000d\u000a      http:\/\/dx.doi.org\/10.1002\/14651858.CD003370.pub3.\u000d\u000a    [d] http:\/\/www.astrazeneca-annualreports.com\/2012\/documents\/eng_download_centre\/annual_report.pdf.\u000d\u000a      Sales figures p.65. ATAC trial mentioned p.66 as follows: \"Arimidex,\u000d\u000a        first launched in 1995, remains a leading global hormonal therapy for\u000d\u000a        patients with early breast cancer. This success is largely based on the\u000d\u000a        extensive long-term efficacy and safety results of the ATAC study, which\u000d\u000a        showed Arimidex to be significantly superior to tamoxifen at preventing\u000d\u000a        breast cancer recurrence during and beyond the five year treatment\u000d\u000a        course.\"\u000d\u000a    [e] Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN,\u000d\u000a      Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP,\u000d\u000a      Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun\u000d\u000a      S, Langer AS, Browman GP, Somerfield MR. American Society of Clinical\u000d\u000a      Oncology technology assessment on the use of aromatase inhibitors as\u000d\u000a      adjuvant therapy for post-menopausal women with hormone receptor-positive\u000d\u000a      early-stage breast cancer: status report 2004. J Clin Oncol 2005; 23:9-29.\u000d\u000a      http:\/\/dx.doi.org\/10.1200\/JCO.2005.09.121\u000d\u000a    [f] http:\/\/guidance.nice.org.uk\/TA112\/Guidance\/pdf\/English\u000d\u000a    [g] http:\/\/www.nice.org.uk\/nicemedia\/live\/12132\/43413\/43413.pdf\u000d\u000a      See p. 6 for key priority recommendation. Three of our papers are\u000d\u000a      referenced extensively, along with another two papers from the ATAC group\u000d\u000a      of investigators.\u000d\u000a    [h] Gnant M. 10 years of ATAC: one question answered, many others\u000d\u000a      unresolved. Lancet Oncol. 2010 Dec;11(12):1109-10. http:\/\/dx.doi.org\/10.1016\/S1470-2045(10)70270-9.\u000d\u000a    [i] http:\/\/www.macmillan.org.uk\/Cancerinformation\/Cancertreatment\/Treatmenttypes\/Hormonalther\u000a        apies\/Individualhormonaltherapies\/Anastrozole.aspx\u000d\u000a    [j] Locker GY, Mansel R, Cella D, Dobrez D, Sorensen S, Gandhi SK, on\u000d\u000a      behalf of the ATAC Trialists' Group. Cost-effectiveness analysis of\u000d\u000a      anastrozole versus tamoxifen as primary adjuvant therapy for\u000d\u000a      postmenopausal women with early breast cancer: a US healthcare system\u000d\u000a      perspective. The 5-year completed treatment analysis of the ATAC\u000d\u000a      (`Arimidex', Tamoxifen Alone or in Combination) trial. Breast Cancer Res\u000d\u000a      Treat 2007;106:229-238.\u000d\u000a      http:\/\/dx.doi.org\/10.1007\/s10549-006-9483-6\u000d\u000a    ","Title":"\u000d\u000a    Introduction of aromatase inhibitors for the treatment of breast cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Breast cancer is the most common form of cancer in the UK, with around\u000d\u000a      50,000 new diagnoses annually, and the second most common cause of cancer\u000d\u000a      death in women (approximately 12,000 deaths per year). Almost all newly\u000d\u000a      diagnosed women will undergo hormone manipulation therapy to block the\u000d\u000a      effects of endogenous oestrogen. Until the introduction of the aromatase\u000d\u000a      inhibitors, the principal oestrogen antagonist was tamoxifen.\u000d\u000a    The ATAC trial was based on the recognition that aromatase inhibitors, a\u000d\u000a      novel class of breast cancer agents, had theoretical advantages over\u000d\u000a      tamoxifen [1]. Tamoxifen was used after surgery for breast cancer,\u000d\u000a      and known to reduce the risk of recurrent disease; it works via blockade\u000d\u000a      of oestrogen receptors in breast tissue. The essential benefit of\u000d\u000a      aromatase inhibitors is that they block all extra-ovarian post-menopausal\u000d\u000a      production of oestrogens, the synthesis of which depends on metabolism of\u000d\u000a      testosterone and androstenedione by the aromatase enzyme. This represented\u000d\u000a      a fundamental approach to oestrogen deprivation, in contrast to tamoxifen\u000d\u000a      which only blocked oestrogen uptake at the cellular level while\u000d\u000a      leaving its production unchanged.\u000d\u000a    At the time the ATAC trial was designed, there was considerable\u000d\u000a      resistance to the concept of novel therapy using anastrozole alone, since\u000d\u000a      tamoxifen was already so well established and indeed was the world's most\u000d\u000a      widely prescribed anti-cancer drug. UCL investigators took the view that,\u000d\u000a      although tamoxifen was an effective and relatively safe drug, it was not\u000d\u000a      without hazards, some of which could be life-threatening. The ATAC trial\u000d\u000a      was the first to offer a `head to head' comparison with tamoxifen, both\u000d\u000a      alone (single agent) and in combination, and demonstrated that the newer\u000d\u000a      agent was both more effective and less toxic [1-5].\u000d\u000a    The ATAC trial recruited 6,241 patients, with long-term follow-up of\u000d\u000a      approximately 24,000 woman-years [3, 4]. Anastrozole reduced the\u000d\u000a      absolute risk of recurrence of breast cancer by 3% compared to tamoxifen,\u000d\u000a      and treatment-related serious adverse events by 5%.\u000d\u000a    "},{"CaseStudyId":"34815","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    As a result of the underpinning research described above, buccal\u000d\u000a      midazolam has become the drug of choice for the treatment of status\u000d\u000a      epilepticus in the community, quoted in guidelines as part of the care\u000d\u000a      pathway for status epilepticus. It was included as first-line therapy in\u000d\u000a      the Advanced Paediatric Life Support (APLS) status epilepticus algorithm\u000d\u000a      for the first time in 2005 [a]. In the same year, the Scottish\u000d\u000a      Intercollegiate Guidelines Network recommended the same, citing our study\u000d\u000a      directly [b].\u000d\u000a    Both available pharmaceutical formulations of buccal midazolam have\u000d\u000a      arisen as a result of work conducted at UCL. The first, Epistatus\u000d\u000a      (midazolam maleate), was developed by Scott and Neville at ICH, and was\u000d\u000a      brought to market under a commercial licence agreement between UCL\u000d\u000a      Business and Special Products Ltd [c]. It has been employed\u000d\u000a      clinically for over 10 years, being manufactured under a `specials'\u000d\u000a      licence issued by the MHRA. The second, Buccolam (midazolam\u000d\u000a      hydrochloride), arose from work conducted at UCL School of Pharmacy and\u000d\u000a      resulted in the foundation of Therakind Limited, a spin-out company\u000d\u000a      designed to develop the product further. In 2010, a controlling\u000d\u000a      interest in Therakind was sold to ViroPharma Inc. [d], and in\u000d\u000a      2011, Therakind was granted a centralised Paediatric Use Marketing\u000d\u000a      Authorisation (PUMA) by the European Medicines Agency (EMA) for Buccolam\u000d\u000a      as a treatment of prolonged acute seizures in individuals 3 months to 18\u000d\u000a      years of age, the first of its kind [e]. The pharmacokinetic and\u000d\u000a      pharmacodynamic properties of Buccolam described within the EMA\u000d\u000a      application cite and rely upon the initial data generated on buccal\u000d\u000a      midazolam at the ICH [1, above] [f].\u000d\u000a    This authorisation has allowed distribution and access to Buccolam to the\u000d\u000a      one million children and adolescents with epilepsy in Europe. Importantly,\u000d\u000a      as Buccolam is a licensed product (unlike almost all other paediatric\u000d\u000a      prescriptions), it is easier to obtain as a repeat prescription in the\u000d\u000a      community rather than having to return to secondary or tertiary care — a\u000d\u000a      significant advantage for patients\/caregivers.\u000d\u000a    In 2012, buccal midazolam was recommended in NICE Clinical Guideline 137\u000d\u000a      on Epilepsy as first line therapy for treating children, young people and\u000d\u000a      adults with prolonged or repeated generalised, convulsive seizures in the\u000d\u000a      community [g].\u000d\u000a    In addition to the inclusion in National Guidelines, buccal midazolam is\u000d\u000a      included in many local guidelines for treatment of status epilepticus in\u000d\u000a      the UK, for example North Bristol NHS Trust [h] and Great Ormond\u000d\u000a      Street Hospital [i] and in other parts of the world [j].\u000d\u000a      The charity Young Epilepsy report that: \"Professor Scott's work on\u000d\u000a        buccal midazolam has fundamentally changed practice in the management of\u000d\u000a        status epilepticus. The research has led to the development of a new\u000d\u000a        product that has not only proven to be an effective drug therapy for\u000d\u000a        status epilepticus but also a more socially acceptable method of\u000d\u000a        administration\" [k]. Buccal midazolam has now clearly\u000d\u000a      superseded rectal diazepam as the drug of choice for treating status\u000d\u000a      epilepticus in the pre-hospital setting [l].\u000d\u000a    Scott and colleague have worked with the charity Young Epilepsy to\u000d\u000a      develop training programmes for professionals and schools on all aspects\u000d\u000a      of epilepsy in children, including training packages for the\u000d\u000a      administration of emergency medication.\u000d\u000a    Benefits are not isolated to clinical metrics such as seizure termination\u000d\u000a      rate, requirement for hospital or intensive care admission. Patients and\u000d\u000a      their care-givers are afforded a higher quality of life through freedom of\u000d\u000a      activity, retention of dignity and security in the knowledge that they may\u000d\u000a      safely give\/receive an effective treatment. The Scottish Medicines\u000d\u000a      Consortium approved buccal midazolam in Scotland in 2012 and estimated\u000d\u000a      that for the approximately 1,000 patients who will receive it annually\u000d\u000a      there would be a cost saving on the drugs budget of £100,000 per annum [m].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    As a direct result of work led by Professor Rod Scott and colleagues at\u000d\u000a      the UCL Institute of Child Health (ICH) midazolam, administered by the\u000d\u000a      buccal cavity, has become first-line therapy in the NICE pathway for\u000d\u000a      treating children, young people and adults with prolonged or repeated\u000d\u000a      generalised, convulsive seizures in the community. It also forms part of\u000d\u000a      the APLS guidelines. Buccal midazolam has demonstrated clinical\u000d\u000a      superiority over the previous paediatric standard of care (rectal\u000d\u000a      diazepam) with an equivalent safety profile and greater patient\/social\u000d\u000a      acceptability. Its use is now widespread in Europe and the USA and a\u000d\u000a      licensed preparation is now available.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Scott RC, Besag FM, Boyd SG, Berry D, Neville BG. Buccal absorption\u000d\u000a      of midazolam: pharmacokinetics and EEG pharmacodynamics. Epilepsia. 1998\u000d\u000a      Mar;39(3):290-4.\u000d\u000a      http:\/\/dx.doi.org\/10.1111\/j.1528-1157.1998.tb01375.x\u000d\u000a    \u000a\u000a[2] Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam\u000d\u000a      for treatment of prolonged seizures in childhood and adolescence: a\u000d\u000a      randomised trial. Lancet. 1999 Feb 20;353(9153):623-6. http:\/\/dx.doi.org\/10.1016\/S0140-6736(98)06425-3\u000d\u000a    \u000a\u000a[3] Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC.\u000d\u000a      Treatment of community-onset, childhood convulsive status epilepticus: a\u000d\u000a      prospective, population-based study. Lancet Neurol. 2008 Aug;7(8):696-703.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/S1474-4422(08)70141-8\u000d\u000a    \u000a\u000a[4] Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC; NLSTEPSS\u000d\u000a      Collaborative Group. Incidence, cause and short term outcome of convulsive\u000d\u000a      status epilepticus in childhood: prospective population based study.\u000d\u000a      Lancet 2006; 368: 222-9 http:\/\/dx.doi.org\/10.1016\/S0140-6736(06)69043-0\u000d\u000a    \u000a\u000a[5] Scott RC, King MD, Gadian DG, Neville BG, Connelly A. Hippocampal\u000d\u000a      abnormality after prolonged febrile convulsion: A longitudinal MRI study.\u000d\u000a      Brain 2003; 126(11):2551-7 http:\/\/dx.doi.org\/10.1093\/brain\/awg262\u000d\u000a    \u000a\u000a[6] Martinos MM, Yoong M, Patil S, Chin RF, Neville BG, Scott RC, de Haan\u000d\u000a      M. Recognition memory is impaired in children after prolonged febrile\u000d\u000a      seizures. Brain. 2012 Oct;135(Pt 10):3153-64. http:\/\/dx.doi.org\/10.1093\/brain\/aws213\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    [a] Advanced Paediatric Life Support (APLS), status epilepticus\u000d\u000a      guidelines. https:\/\/www.apls.org.au\/sites\/default\/files\/uploadedfiles\/Algorithms%20-%20Status%20Epilepticus.pdf\u000d\u000a    [b] SIGN National Clinical Guideline 81: Diagnosis and management of\u000d\u000a      epilepsies in children and young people. http:\/\/www.sign.ac.uk\/pdf\/sign81.pdf\u000d\u000a      See p. 21 and ref. 212\u000d\u000a    [c] Commercial agreement between UCLB and Special Products Ltd.\u000d\u000a      http:\/\/www.sciencebusiness.net\/news\/75300\/UCLB-and-NCYPE-announce-a-commercialisation-agreement-with-special-products-limited-for-Epistatus\u000d\u000a    [d] http:\/\/www.therakind.com\/news\/sale-interest-product\u000d\u000a    [e] Award of PUMA for Buccolam®. http:\/\/www.therakind.com\/news\/granted-european-marketing-authorisation-treatment-acute-seizures\u000d\u000a    [f] European Medicines Agency marketing authorisation.\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Public_assessment_report\/human\/002267\/WC500112312.pdf\u000d\u000a    [g] Guidelines on the diagnosis and management of the epilepsies in\u000d\u000a      primary and secondary care National Institute of Health and Clinical\u000d\u000a      Excellence, 2004, update 2012 http:\/\/guidance.nice.org.uk\/CG137\/Guidance\/pdf\/English.\u000d\u000a      See Appendix N, ref. 126\u000d\u000a     [h] \u000a        http:\/\/www.nbt.nhs.uk\/sites\/default\/files\/filedepot\/incoming\/Buccal%20midazolam%20NBT002519.pdf\u000d\u000a    [i] http:\/\/www.gosh.nhs.uk\/medical-conditions\/medicines-information\/buccal-midazolam\/\u000d\u000a    [j] For example, in Australia: http:\/\/www.rch.org.au\/kidsinfo\/fact_sheets\/Buccal_midazolam\/.\u000d\u000a    [k] http:\/\/youngepilepsy.org.uk\/\u000d\u000a      Supporting statement from Director of Operations, Young Epilepsy. Copy\u000d\u000a      available on request.\u000d\u000a    [l] Sutcliffe A and Bhome R. Buccolam® (buccal midazolam) for acute,\u000d\u000a      prolonged seizures in children: a new treatment option. British Journal of\u000d\u000a      Clinical Pharmacy. 2012;Sept:e1-4 http:\/\/www.clinicalpharmacy.org.uk\/images\/stories\/Article_1_Indesign__copyright.pdf\u000d\u000a    [m] \u000a        http:\/\/www.scottishmedicines.org.uk\/files\/advice\/midazolam_Buccolam_FINAL_Jan_2012_Amended_310112_for_website.pdf\u000d\u000a    ","Title":"\u000d\u000a    Buccal midazolam: a novel treatment for generalised convulsive seizures\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Convulsive status epilepticus (CSE), where epileptic seizures last at\u000d\u000a      least 30 minutes, is the commonest neurological medical emergency in\u000d\u000a      childhood and is associated with significant morbidity and mortality. For\u000d\u000a      many years, a rectal preparation of diazepam was the most commonly\u000d\u000a      recommended treatment for this condition, but this route was unacceptable\u000d\u000a      to many parents and carers and was associated with treatment delay and\u000d\u000a      avoidance, increasing the risk of intensive care admission for treatment\u000d\u000a      of status epilepticus. As most seizures start in the community setting, a\u000d\u000a      safe, effective and socially acceptable agent that can be administered by\u000d\u000a      emergency medical technicians and parents\/carers was required. We\u000d\u000a      therefore developed buccal midazolam as an alternative to rectal\u000d\u000a      diazepam\u000d\u000a    Our initial studies (1996-9) evaluated the pharmacokinetics and\u000d\u000a      pharmacodynamics of midazolam (midazolam maleate; a benzodiazepine)\u000d\u000a      administered via the buccal route, using blood sample and\u000d\u000a      electroencephalography (EEG)-based methods, and demonstrated both the\u000d\u000a      drug's easy absorption and rapid effect on the brain [1]. Once we\u000d\u000a      had determined the correct dose, we carried out a randomised controlled\u000d\u000a      trial comparing buccal midazolam with rectally administered diazepam. In\u000d\u000a      this study of 79 prolonged seizures in children with very severe epilepsy\u000d\u000a      in a residential school setting, we showed that buccal midazolam was at\u000d\u000a      least as effective as rectal diazepam, and was more socially acceptable [2].\u000d\u000a      Subsequent trials in Europe and Africa have confirmed our findings, and\u000d\u000a      have even demonstrated clinical superiority (seizure termination rate) to\u000d\u000a      rectal diazepam in certain circumstances, along with significantly quicker\u000d\u000a      administration and greater acceptability.\u000d\u000a    Our research has subsequently moved to exploring the epidemiology of\u000d\u000a      status epilepticus and whether status epilepticus can damage the brain. In\u000d\u000a      2002 we established the North London Convulsive Status Epilepticus in\u000d\u000a      Childhood Surveillance Study, in which we prospectively collected data on\u000d\u000a      the management of CSE in the community. We demonstrated a low pre-hospital\u000d\u000a      treatment rate (61%) for CSE, with termination of only 22% of episodes.\u000d\u000a      For each minute of delay from CSE onset to arrival at Accident and\u000d\u000a      Emergency, there was a 5% increased risk of seizures lasting >60minutes\u000d\u000a      with attendant risk of adverse outcomes and requirement of higher levels\u000d\u000a      of care (intensive care) [3]. This work also confirmed that status\u000d\u000a      epilepticus is common and that the range of causes differs in children\u000d\u000a      when compared to adults [4].\u000d\u000a    In other research, we have shown that status epilepticus leads to\u000d\u000a      swelling of the hippocampus and that part of the brain subsequently fails\u000d\u000a      to grow as expected during childhood [5]. We have also shown that\u000d\u000a      status epilepticus is associated with learning difficulties and\u000d\u000a      difficulties with memory [6]. As at least part of these\u000d\u000a      difficulties result directly from the prolonged seizure, this work further\u000d\u000a      demonstrates the need for treatments such as buccal midazolam.\u000d\u000a    "},{"CaseStudyId":"35185","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The results of the research have been successfully translated into\u000a      improved patient care in the UK and also changed transfusion policy and\u000a      practice internationally. The impacts are illustrated by the following\u000a      examples:\u000a    i) Postgraduate education of medical staff and training of\u000a      scientific NHS staff has changed on basis of the research findings.\u000a      Particularly the use of HPA matched donor platelets for patients with HPA\u000a      antibodies is now taught as `best care' and since 2008 it is taught that\u000a      intrauterine transfusion should be considered only as last resort for\u000a      FMAIT cases. The research findings have been disseminated at international\u000a      educational and committee meetings.\u000a    ii) The British Committee for Standards in Haematology guidelines\u000a      for transfusion do now stipulate that the use of HPA matched donor\u000a      platelets for neonates with HPA antibodies is `best care'7. The\u000a      policy is also adopted in the 2013 Guidelines for the Blood Services\u000a        of England, Northern Ireland, Scotland and Wales which regulate the\u000a      preparation of blood and platelet products from donors and related patient\u000a      services8.\u000a    iii) Substantial improvements in HPA antibody detection have been\u000a      achieved in the UK and internationally and the research has been\u000a      instrumental for nearly all the achievements of an international platelet\u000a      immunogenetics Quality Assurance (QA) scheme for 36 service labs9,10.\u000a      The scheme has led to a) the development of World Health Organisation\u000a      sensitivity and potency standards for HPA antibody detection, b)\u000a      standardised reference tests for the HPA antibody detection —\u000a      international WHO-approved references for the detection of HPA-1 and -5\u000a      antibodies have been developed at the NIBSC and are currently distributed\u000a      worldwide to monitor the sensitivity and specificity of assays to detect\u000a      HPA antibodies11, c) consistent improvements in the proficiency\u000a      of HPA antibody detection9 and DNA-based HPA typing10\u000a      and d) the international adaptation of the HPA nomenclature in routine\u000a      clinical practice12. The latter is supported by a website,\u000a      developed and maintained by the Cambridge researchers, together with the\u000a      European Bioinformatics Institute12. The proficiency of the\u000a      NHSBT platelet laboratory in the QA scheme ranks between 2008 and 2013\u000a      consistently in the upper decile of performance confirming that University\u000a      research has brought tangible and long-lasting benefits to NHS patient\u000a      care. Notwithstanding the above achievements, assays for HPA antibody\u000a      detection currently used remain expensive (>£1000\/sample with about 800\u000a      referrals\/year). NHSBT scientists have demonstrated platform feasibility\u000a      in 2009 and completed in 2013 the largest ever multi-centre validation\u000a      study of recombinant HPA-1 proteins which showed that Cambridge\u000a      researchers have succeeded in developing affordable HPA antibody detection\u000a      tests for use in NHS service delivery6. Collaboration between\u000a      the University, Sanger Institute and NHSBT has in 2013 resulted in the\u000a      successful production of HPA-5\/-15 proteins, which means that all\u000a      clinically relevant HPAs, but HPA-3 have been produced by recombinant\u000a      techniques.\u000a    iv) HPA typing: Up until the late nineties in the UK almost no\u000a      blood donors had been typed for the clinically relevant HPA groups.\u000a      Patients with HPA antibodies therefore received non-matched and clinically\u000a      inferior donor platelets. Tests for high throughput and affordable\u000a      HPA-1-15 genotyping and HPA-1a phenotyping4 were developed and\u000a      clinically validated in the Cambridge research laboratory and these have\u000a      been used over the 2008-13 period by NHSBT to HPA type 90,000\u000a      donors. This effort has resulted in a) the routine provision of\u000a      HPA-matched platelets for cancer patients with HPA antibodies (per year\u000a      300-400 HLA\/HPA matched concentrates are provided), b) Since 2008 \"off the\u000a      shelf universally matched\" HPA-1a\/-5b negative donor platelets for the\u000a      treatment of neonates with low platelet counts to reduce the risk of\u000a      bleeding13, because Cambridge research showed that >90% of\u000a      FMAIT cases are caused by HPA-1a\/-5b antibodies2. As a direct\u000a      result of the Cambridge research these superior transfusion products have\u000a      become available across the country. The NHSBT platelet laboratory\u000a      receives per year ~800 FMAIT referrals and the majority of cases with\u000a      counts <20x109\/L will have been transfused with the novel\u000a      therapy of universally HPA matched donor platelets, which was previously\u000a      unavailable. The University received a £150,000 down payment for a license\u000a      of the recombinant HPA-1a antibody to the diagnostic company DiaMed for\u000a      use in other countries. All together translational research has resulted\u000a      during the 2008-13 period in sustained improvements in patient care by\u000a      better diagnosis and treatment of FMAIT and improved HPA matching of\u000a      transfusion products. This has reduced the use of costly concentrates\u000a      because matched platelets survive longer and are clinically superior to\u000a      random ones. As a direct consequence of the research the risk of\u000a      life-threatening bleeding has been reduced and patients experience fewer\u000a      side effects and in addition a reduced exposure to donor products also\u000a      diminishes the risk of serious hazards of transfusion, e.g. death by\u000a      bacteria or HIV, HepB\/C transmission.\u000a    ","ImpactSummary":"\u000a    Annually in the UK ~110,000 donor platelet concentrates are used to\u000a      prevent bleeding in cancer patients and ~660 newborns are born with an\u000a      increased risk of bleeding because of a low platelet count caused by\u000a      maternal platelet antibodies. These newborns and ~10% of the cancer\u000a      patients require donor platelet transfusions matched for the platelet\u000a      antibody because non-matched donor platelets are clinically less\u000a      effective. University researchers have developed better methods for\u000a      platelet antibody detection and typing and as a direct consequence of this\u000a      research NHS Blood and Transplant (NHSBT) has from 2009 onwards been able\u000a      to make platelet transfusions safer and clinically more effective, thereby\u000a      reducing the number of severe, and on occasions life- threatening,\u000a      bleeding episodes.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Cambridge\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000a    (indicative maximum of six references)\u000a    \u000a1. Williamson LM, Hackett G, Rennie J, Palmer CR, Maciver C,\u000a      Hadfield R, Hughes D, Jobson S, Ouwehand WH: (1998) The natural\u000a      history of fetomaternal alloimmunization to the platelet- specific antigen\u000a      HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood\u000a      92:2280-2287. Epub 1998\/09\/25. PubMed PMID: 9746765;\u000a    \u000a\u000a2. Ghevaert C, Campbell K, Walton J, Smith GA, Allen D, Williamson,\u000a        LM Ouwehand WH, and Ranasinghe E: (2007) Management and outcome of\u000a      200 cases of fetomaternal alloimmune thrombocytopenia. Transfusion\u000a      47:901-910. Epub 2007; \u000a    \u000a\u000a3. Griffin HM, Ouwehand WH: (1995) A human monoclonal\u000a      antibody specific for the leucine-33 (P1A1, HPA-1a) form of platelet\u000a      glycoprotein IIIa from a V gene phage display library. Blood 86:4430-4436.\u000a      Epub 1995\/12\/15. PubMed PMID: 8541531;\u000a    \u000a\u000a4. Ghevaert C, Wilcox DA, Fang J, Armour KL, Clark MR, Ouwehand\u000a        WH and Williamson LM: (2008) Developing recombinant\u000a      HPA-1a-specific antibodies with abrogated Fcgamma receptor binding for the\u000a      treatment of fetomaternal alloimmune thrombocytopenia. J Clin Invest 118,\u000a      2929- 2938. Epub 2008\/07\/26. doi: 10.1172\/JCI34708.\u000a    \u000a\u000a5. Schuh AC, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JYA,\u000a      Campbell K, Sutherland DR, Metcalfe P, Horsfall W, and Ouwehand WH:\u000a      (2002) A Tyrosine703Serine Polymorphism of CD109 Defines the Gov Platelet\u000a      Alloantigens. Blood 99:1692-1698. Epub 2002\/02\/28. PubMed PMID: 11861285.\u000a    \u000a\u000a6. Chong W, Metcalfe P, Mushens R, Lucas G, Ouwehand WH\u000a      & Navarrete CV (2011) Detection of human platelet antigen-1a\u000a      alloantibodies in cases of fetomaternal alloimmune thrombocytopenia using\u000a      recombinant 03b23 integrin fragments coupled to fluorescently labeled\u000a      beads. Transfusion, 51, 1261-1270. Epub 2010\/12\/21. doi:\u000a      10.1111\/j.1537-2995.2010.02977.x.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    7. British Committee for Standard in Haematology: (2004)\u000a      Transfusion guidelines for neonates and older children, Brit J Haemat,\u000a      124, 433-453. doi:10.1111\/j.1365-2141.2004.04815.x\u000a    8. National Blood Service: (2013) Guidelines for the blood\u000a      transfusion services in the UK, The UK Stationary Office, 8th\u000a      Edition, ISBN 9780117081673, Chapter 18: Platelets, paragraphs 18.1-18.4 http:\/\/www.transfusionguidelines.org.uk\/index.aspx?Publication=RB&Section=25&pageid=7942\u000a    9. Clinical study in collaboration with the Regional Blood\u000a      Transfusion Centre (Oxford); Allen DL, Chapman J, Phillips PK, Ouwehand\u000a      WH: (1994) Sensitivity of the platelet immunofluorescence test (PIFT) and\u000a      the MAIPA assay for the detection of platelet-reactive alloantibodies: a\u000a      report on two U.K. National Platelet Workshop exercises. Transfus Med\u000a      4:157-164. Epub 1994\/06\/01. PubMed PMID: 7921052.\u000a    10. Clinical study in collaboration with the National Institute\u000a      for Biological Standards and Control (NIBSC) and National Blood Service\u000a      (Newcastle, Cambridge); Metcalfe P, Cavanagh G, Hurd C, Ouwehand WH:\u000a      (1999) HPA genotyping by PCR-SSP: report of 4 exercises. Vox Sang\u000a      77:40-43. Epub 1999\/09\/04. doi: vox77040 [pii].\u000a    11. WHO\/NIBSC documents. http:\/\/www.who.int\/biologicals\/BS%202079%20HPA-1a.pdf\u000a      http:\/\/www.nibsc.org\/Science\/Diagnostics\/Transfusion_-_Transplantation\/Platelets\/Standardisation.aspx\u000a      http:\/\/apps.who.int\/iris\/bitstream\/10665\/69955\/1\/WHO_BS_05.2011_eng.pdf\u000a    12. Clinical study in collaboration with the NIBSC; Metcalfe P,\u000a      Watkins NA, Ouwehand WH, Kaplan C, Newman P, Kekomaki R,\u000a      Haas M de, Aster R, Shibata Y, Smith\u000a\u0009  J, Kiefel V, Santoso S: (2003) Nomenclature\u000a      of Human Platelet Antigens (HPA). Vox Sang 85:240-245. Epub 2003\/10\/01.\u000a      doi: 331 [pii] and associated website can be found at\u000a      http:\/\/www.ebi.ac.uk\/ipd\/hpa\/ (most recent access date July, 2013).\u000a    13. Clinical study in collaboration with the National Blood\u000a      Service (Cambridge); Ranasinghe E, Walton JD, Hurd CM, Saul L, Smith G,\u000a      Campbell K, Ouwehand WH: (2001) Provision of platelet support for fetuses\u000a      and neonates affected by severe fetomaternal alloimmune thrombocytopenia.\u000a      Br J Haem 113:40-42. Epub 2001\/05\/01. PubMed PMID: 11328278. \u000a    ","Title":"\u000a    Improved matching of therapeutic platelet concentrates for cancer\u000a      patients and newborns\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    From 1993-13 Professor Willem Ouwehand (tenured since 1989, Reader since\u000a      2004, Professor since 2010) and Dr Lorna Williamson (tenured since 1991,\u000a      Reader 2005-2009) at the Cambridge University Haematology Department led,\u000a      together with NHSBT service laboratories, translational research in the\u000a      field of Human Platelet Antigens (HPAs). HPAs are the platelet equivalent\u000a      of red blood cell groups, like ABO and D. HPA antibodies can be formed in\u000a      pregnancy or after transfusion and antibody binding to donor platelets\u000a      leads to their rapid removal from the circulation. Therefore patients with\u000a      HPA antibodies who require transfusions should ideally receive HPA matched\u000a      donor platelets, because non-matched ones are destroyed rapidly and are\u000a      clinically less effective. Cancer patients with HPA antibodies and\u000a      thrombocytopenic neonates born to mothers with HPA antibodies, also called\u000a      Fetal-Maternal Alloimmune Thrombocytopenia (FMAIT) are the two main\u000a      patient groups.\u000a    At the outset of the research NHSBT could not provide HPA matched\u000a      platelets and blood for patients with HPA antibodies because the typing of\u000a      donors and patients for HPA groups and the detection of HPA antibodies was\u000a      laborious and tests results were not specific. Furthermore the number of\u000a      FMAIT cases born per year and the best way to treat cases were not known.\u000a      Therefore the objectives of the research were to i) determine the\u000a      prevalence of FMAIT, ii) obtain evidence on how to treat severe cases and\u000a      iii) develop more affordable laboratory tests for HPA matching of donor\u000a      platelets with the recipient. The outcomes are:\u000a      i) A population study showed that 1 in ~365 mothers form HPA antibodies in\u000a      pregnancy and as a consequence 1 in 1200 newborns have severe FMAIT\u000a      requiring treatment by transfusion of HPA matched platelets1. With nearly\u000a      800,000 births in the UK annually ~660 severe FMAIT cases are born and if\u000a      not treated bleeding may ensue, which if in the brain may cause life-long\u000a      disability;\u000a\u0009  ii) The analysis of clinical outcomes of the largest FMAIT\u000a      case series provided evidence that the intrauterine transfusion of HPA\u000a      matched donor platelets to foetuses results in inferior outcomes if\u000a      compared with more conservative treatments2; this observation has led to a\u000a      reduction of the number of intrauterine procedures from >100 to <40;\u000a      iii) The laboratory research led to the following results: a) A\u000a      recombinant human HPA-1a antibody was engineered and applied for rapid\u000a      donor and patient typing3. A genetically modified version of the antibody\u000a      has been shown in Proof-of-Concept studies in humans to be a possible\u000a      effective treatment for FMAIT4, b) The genetic basis of novel HPA groups\u000a      has been discovered5, and this was used together with existing knowledge,\u000a      to develop affordable high-throughput DNA-based HPA typing tests for\u000a      donors and patients, c) Recombinant HPA proteins for the sensitive\u000a      detection of HPA antibodies were engineered6. The results of the research\u000a      were disseminated through 33 peer-reviewed publications, 12 invited review\u000a      articles, 7 chapters in medical textbooks and guidelines by the British\u000a      Committee for Standards in Haematology and for the UK Blood Transfusion\u000a      Services.\u000a    "},{"CaseStudyId":"35186","Continent":[],"Country":[],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Dixon's research has had a direct and major impact on how patients with a\u000d\u000a      variety of different common and life threatening conditions are\u000d\u000a      investigated radiologically throughout the UK and Europe. The evaluative\u000d\u000a      frameworks he developed, together with his clinical research, have\u000d\u000a      informed clinical guidelines. The resulting changes in clinical practice\u000d\u000a      have resulted in benefits regarding both health outcomes and\u000d\u000a      cost-effectiveness.\u000d\u000a    Impact on Health and Welfare\u000d\u000a    Outcomes for Patients have Improved & New Diagnostic Technologies\u000d\u000a      have been Adopted\u000d\u000aHis CT research, in particular his randomised controlled\u000d\u000a      trial (Ref 3 Section 2) is recognised by the Guidelines as having\u000d\u000a      contributed to a major change in the way that patients are now\u000d\u000a      investigated for suspected pulmonary embolus. Pulmonary angiography and\u000d\u000a      then ventilation\/scintigraphy, a nuclear medicine technique were abandoned\u000d\u000a      in 2009 in favour of pulmonary CT angiography (1). Similarly his work is\u000d\u000a      still influential in the use of CT imaging in patients with acute\u000d\u000a      abdominal pain (2).\u000d\u000a    There are now numerous CT-based diagnostic and interventional procedures\u000d\u000a      in widespread use, whose introduction to clinical practice was pioneered\u000d\u000a      by Dixon and reported in medical journals. This includes the biopsy of\u000d\u000a      retroperitoneal lymph nodes, deep seated paediatric tumours and other\u000d\u000a      malignant lesions without the need for formal surgery and often under\u000d\u000a      simple local anaesthesia. Dixon developed CT drainage procedures that were\u000d\u000a      initially experimental but are now standard clinical procedures (4,5).\u000d\u000a      Such help to the surgical community has allowed considerable progress in\u000d\u000a      transplant, pancreatic and other complex surgery because postoperative\u000d\u000a      complications can be treated by interventional radiological procedures\u000d\u000a      (usually CT guided).\u000d\u000a    Impact on the Economy\u000d\u000a    The Costs of Treatment or Healthcare has Changed as a Result of\u000d\u000a      Research-Led Changes in Practice\u000d\u000a    Dixon's work has also made an important contribution to the health\u000d\u000a      economics of radiology. High cost diagnostic tools must be used\u000d\u000a      appropriately, ideally replacing existing less effective technologies,\u000d\u000a      rather than being additional. Dixon's studies, for example those on lumbar\u000d\u000a      spine MRI, the investigation of auditory canal tumours (acoustic\u000d\u000a      neurinomas), MRI knee and shoulder problems have all shown that\u000d\u000a      appropriate and prompt (e.g. immediately upon hospital admission) use of\u000d\u000a      high technology can save the patient numerous less effective and\u000d\u000a      cumulatively expensive investigations and subsequent outpatient\u000d\u000a      appointments. This is corroborated by independent health economic analyses\u000d\u000a      of the strategies pioneered by Dixon.(3,4)\u000d\u000a    Impact on Practitioners and Services\u000d\u000a    Professional Standards, guidelines or training have been influenced by\u000d\u000a      research\u000d\u000a    In 2001 Dixon was asked to develop the pan-European Referral Criteria\u000d\u000a      by the European Commission (3). This guidance document remains current and\u000d\u000a      continues to be extensively used by imaging departments around Europe.\u000d\u000a    Dixon chaired the highly successful Royal College of Radiologists \"Making\u000a        the best use of the Department of Clinical Radiology: Clinical\u000d\u000a        Guidelines\" (4) originally issued free-of-charge to all general\u000d\u000a      practitioners and now available online as iRefer (5). This gives\u000d\u000a      information on which imaging pathway to follow for different clinical\u000d\u000a      problems. The process that was used to create the guidance was accredited\u000d\u000a      by NHS Evidence-National Institute for Health and Clinical Excellence\u000d\u000a      (NICE) in June 2010 (6).\u000d\u000a    The UK and European guidelines are greatly influenced by Dixons research\u000d\u000a      (Ref 1-8, Section 3) in two areas 1) The early evaluation of CT and\/or MRI\u000d\u000a      compared to established imaging strategies in a wide variety of common and\u000d\u000a      life threatening conditions led to increased appropriate use of these\u000d\u000a      sophisticated techniques in secondary care. 2) The increased use of CT or\u000d\u000a      MRI to extend the remit of imaging to assist with diagnosis and treatment\u000d\u000a      of patients with clinical problems where previous imaging techniques were\u000d\u000a      unable to make significant contributions. As evidenced by numerous\u000d\u000a      citations in the Guidelines, the studies undertaken by Dixon made major\u000d\u000a      contributions to CT becoming the preferred investigative tool in the\u000d\u000a      evaluation of: an abdominal mass, the acute abdomen, the adrenal gland,\u000d\u000a      aortic aneurysms and dissection, appendicitis and large bowel problems,\u000d\u000a      particularly in the elderly (3,4,5).\u000d\u000a    Dixon also realised the potential applications of CT technology to\u000d\u000a      radiotherapy planning and to quantify functional aspects of tissues. For\u000d\u000a      example his pioneering work with Professor Ken Miles on perfusion CT was\u000d\u000a      the proof of concept demonstrating that in vivo clinical imaging could\u000d\u000a      measure changes dynamically, resulting in this technique being tested as a\u000d\u000a      potential biomarker in clinical trials in 2010 (7). Intriguingly the\u000d\u000a      industrial partners did not originally see the need for such detailed\u000d\u000a      analysis and thus the software for this technique, pioneered in Cambridge,\u000d\u000a      was made freely available to the research community and healthcare\u000d\u000a      systems; it can now be incorporated on most clinical CT and MR systems.\u000d\u000a    The research collaboration in Cambridge with industry provided extremely\u000d\u000a      valuable feedback on their prototypes which was essential for both Siemens\u000d\u000a      and GE leading to significant improvements in their MR and CT machines.\u000d\u000a    The Government became extremely concerned about cancer waiting times in\u000d\u000a      2000. Dixon worked with the Department of Health (DH) to advise on CT\u000d\u000a      specifications in a national scheme which oversaw the installation of £1.5\u000d\u000a      billion of CT equipment (personal work with the National Cancer Tsar, Sir\u000d\u000a      Michael Richards and others in the DH). When the Government's scheme for\u000d\u000a      outsourcing MRI services ran into early problems in 2003, the DH again\u000d\u000a      turned to Dixon to provide leadership and quality control. The technical\u000d\u000a      lead for Imaging in the Department of Health states that Dixon was\u000d\u000a      responsible for implementing increased CT availability and MR for NHS\u000d\u000a      England (8). On part-time secondment to the DH (2004-2007) as MR Clinical\u000d\u000a      Guardian, he helped introduce audit and dual reporting for remote\u000d\u000a      teleradiological sites to raise standards and ensure a high quality\u000d\u000a      service from external providers (9). Dixon showed that the standard of\u000d\u000a      routine NHS reporting was high but the turnaround time was slow; this led\u000d\u000a      to increased government funding to allow NHS machines to be used for an\u000d\u000a      extended working day- the forerunner of the now imminent 7 day working for\u000d\u000a      Radiology Departments (see letter from the Minister of State for Health),\u000d\u000a      (10).\u000d\u000a    High cost diagnostic tools must be used appropriately, ideally replacing\u000d\u000a      existing less effective technologies, rather than being additional.\u000d\u000a      Dixon's studies on Lumbar spine MRI, the investigation of auditory canal\u000d\u000a      tumours (acoustic neurinomas), MRI knee and shoulder problems have all\u000d\u000a      shown that appropriate and prompt (e.g. immediately upon hospital\u000d\u000a      admission) use of high technology can save the patient numerous less\u000d\u000a      effective investigations and subsequent outpatient appointments. Dixon's\u000d\u000a      work has also shown that these novel uses of CT and MRI can save costs for\u000d\u000a      society.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Computed tomography (CT) and Magnetic Resonance Imaging (MRI) have\u000d\u000a      revolutionised the practice of medicine by providing improved diagnostic\u000d\u000a      accuracy resulting in improved clinical management and outcome. The\u000d\u000a      evidence-based medicine approach developed by Professor Dixon and his team\u000d\u000a      contributed to the timely evaluation of these technologies. Several of his\u000d\u000a      studies proved improved outcome measures, including reduced mortality,\u000d\u000a      shorter in-patient stay and enhanced diagnostic confidence. Examples\u000d\u000a      include: CT of patients with acute abdominal problems and possible large\u000d\u000a      bowel disease; CT for suspected pulmonary embolism; MRI for lumbar spine\u000d\u000a      disease; MRI for knee and shoulder problems. These informed radiological\u000d\u000a      guidelines adopted across Europe.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Cambridge\u000d\u000a    ","Institutions":[{"AlternativeName":"Cambridge (University of)","InstitutionName":"University of Cambridge","PeerGroup":"A","Region":"East","UKPRN":10007788}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Mackenzie R, Dixon AK. Measuring the effects of imaging: an evaluative\u000d\u000a      framework. Clin Radiol 1995;50:513-8.\u000d\u000a    \u000a\u000a2. Dixon AK. Evidence based diagnostic radiology. Lancet 1997;350:509-512\u000d\u000a    \u000a\u000a3. Cross JJ, Kemp PM, Walsh CG, Flower CD, Dixon AK A\u000d\u000a        randomized trial of spiral CT and ventilation perfusion scintigraphy for\u000d\u000a        the diagnosis of pulmonary embolism. Clin Radiol 1998; 53:177-82.\u000d\u000a    \u000a\u000a4. Ng CS, Watson CJ, Palmer CR, See TC, Beharry NA, Housden BA, Bradley\u000d\u000a      JA, Dixon AK. Evaluation of early abdominopelvic computed tomography in\u000d\u000a      patients with acute abdominal pain of unknown cause: prospective\u000d\u000a      randomised study. British Medical Journal 2002; 14:325: 1387\u000d\u000a    \u000a\u000a5. Hollingworth W, Todd CJ, Bell MI, Arafat Q, Girling IS, Karia KR,\u000d\u000a      Dixon AK. The Diagnostic and Therapeutic Impact of MRI: an Observational\u000d\u000a      Multi-centre Study. Clin Radiol 2000:55:825-831\u000d\u000a    \u000a\u000a6. Miles KA, Hayball MP, Dixon AK. Functional images of hepatic perfusion\u000d\u000a      obtained with dynamic computed tomography. Radiology 1993;188:405-11.\u000d\u000a    \u000a\u000a7. Somers JM, Lomas DJ, Hacking JC, Coleman N, Broadbent VA, Dixon AK.\u000d\u000a      Radiologically guided cutting needle biopsy for suspected malignancy in\u000d\u000a      childhood. Clin Radiol 1993;48:236-40.\u000d\u000a    \u000a\u000a8. Fink M, Freeman AH, Dixon AK, Coni NK. Computed tomography of the\u000d\u000a      colon in the elderly: computed tomography as the first investigation. Br\u000d\u000a      Med J 1994;308:1018\u000d\u000a    \u000aDixon's intensive charitable fund raising, research grant income and\u000d\u000a      industrial support to the value of over £20M over the last 20 years has\u000d\u000a      allowed patients and research workers throughout the Cambridge University\u000d\u000a      Hospitals Biomedical Campus to benefit from the latest CT and MRI\u000d\u000a      technology. Research gained from industry included funding of the\u000d\u000a      Professorship of Clinical Magnetic Resonance Imaging (Nycomed Amersham) -\u000d\u000a      current holder Professor David J Lomas (£1M) and a programme of research\u000d\u000a      studentships in MRI funded by GE.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      Henzler T, Schoenberg SO, Schoepf UJ, Fink C. Diagnosing acute\u000d\u000a        pulmonary embolism: systematic review of evidence base and\u000d\u000a        cost-effectiveness of imaging tests. J Thorac Imaging. 2012\u000d\u000a        Sep;27(5):304-14. doi: 10.1097\/RTI.0b013e31825da2bc.\u000d\u000a      Stoker J, van Randen A, Laméris W, Boermeester MA. Imaging patients\u000d\u000a        with acute abdominal pain. Radiology. 2009 Oct;253(1):31-46. doi:\u000d\u000a        10.1148\/radiol.2531090302.\u000d\u000a      European Commission. Referral guidelines for imaging. Radiation\u000d\u000a        Protection 118. Luxembourg: Office for Official Publications of the\u000d\u000a        European Communities. 2001-125pp. ISBN 92-828-9454-1. These guidelines\u000d\u000a        remain current to date.\u000d\u000a      Remedios D, Barter S, Dixon AK et al. Making the best use of clinical\u000d\u000a        radiology services (Referral Guidelines). The Royal College of\u000d\u000a          Radiologists 2007; Sixth Edition.\u000d\u000a        http:\/\/www.rcr.ac.uk\/content.aspx?PageID=995-\u000d\u000a      iRefer, 2012 see http:\/\/portal.e-lfh.org.uk\/\u000a\u000d\u000a      https:\/\/www.evidence.nhs.uk\/documents\/accreditation\/reports\/nice-data-users-profilefolders-mderry-desktop-maggie-rcr-final-accreditation-report-1.3.pdf\u000d\u000a      Padhani AR & Miles KA. Multiparametric imaging of tumour response\u000d\u000a        to therapy. Radiology 2010 256:348-364\u000d\u000a      Letter from Imaging technical lead, NHS contracting, Department of\u000d\u000a        Health\u000d\u000a      \u000aDixon\u000a          AK, FitzGerald\u000a          R. Outsourcing and teleradiology: potential benefits, risks and\u000d\u000a        solutions from a UK\/European perspective J\u000d\u000a          Am Coll Radiol. 2008; 5(1):12-8.\u000d\u000a      Letter from, Minister of State for Health, Department of Health\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Evidence based imaging — Impact of Body CT and MRI in clinical practice.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Professor Adrian K Dixon (Department of Radiology, University of\u000d\u000a      Cambridge, UGC Funded, tenured since 1979, Professor since 1994) and his\u000d\u000a      team have been at the forefront of introducing new Body CT and MRI\u000d\u000a      techniques into the UK for the last three decades. His main research\u000d\u000a      contribution has been to pioneer the rigorous evaluation of evolving\u000d\u000a      imaging techniques in patients, wherever possible by randomised trials\u000d\u000a      comparing the effectiveness and cost effectiveness of the novel imaging\u000d\u000a      against the existing conventional management pathway. He also pioneered\u000d\u000a      the development of image guided interventional techniques.\u000d\u000a    Technology Assessment\u000d\u000a    In 1995 Dixon developed templates for assessing technical efficacy,\u000d\u000a      diagnostic impact, clinical impact, therapeutic impact and impact on\u000d\u000a      health outcome of imaging technology using MRI of the knee as the exemplar\u000d\u000a      (1). This framework facilitated further work by Dixon into the cost\u000d\u000a      effectiveness of CT and MRI in 1997 (2). In 1998 Dixon reported a large\u000d\u000a      clinical trial demonstrating the superiority of CT over nuclear medicine\u000d\u000a      techniques for the diagnosis of pulmonary embolism (3). In the area of\u000d\u000a      abdominal pain, Dixons randomized controlled trials demonstrated the\u000d\u000a      effectiveness of early CT imaging in patients presenting with acute\u000d\u000a      abdominal pain (4) Working with W Hollingworth (Department of Public\u000d\u000a      Health and Primary Care, now at Bristol), an MRC funded research fellow,\u000d\u000a      Dixon showed that MRI improved diagnostic accuracy and confidence in\u000d\u000a      patients with knee, cervical and lumbar spine problems and multiple\u000d\u000a      sclerosis and then assessed the health outcomes for a variety of MRI\u000d\u000a      indications (in 2017 patients) (5).\u000d\u000a    Novel applications of CT\u000d\u000a    In 1993 with KA Miles (radiology trainee at Cambridge, now Professor of\u000d\u000a      Radiology, Brisbane and honorary appointment, UCL) he developed a dynamic\u000d\u000a      contrast CT method for quantifying arterial and portal blood perfusion of\u000d\u000a      the liver in 24 patients (some with cirrhosis); producing a high\u000d\u000a      resolution functional map of the liver (6). Rapidly acquired data using CT\u000d\u000a      allowed Dixon with his physics team to develop software to quantify\u000d\u000a      contrast enhancement in tissues. In 1993 Dixon pioneered the use of image\u000d\u000a      guided biopsies to replace open surgical biopsy in children, demonstrating\u000d\u000a      the importance of guided needle placement to accurately obtain diagnostic\u000d\u000a      specimens safely (7) leading onto development by Dixon of CT guided\u000d\u000a      drainage procedures. In 1994, in collaboration with M Fink (Radiology\u000d\u000a      trainee at Cambridge, now paediatric radiologist, University of Melbourne)\u000d\u000a      Dixon developed CT colonography and showed that this was a safe effective\u000d\u000a      technique in frail, elderly patients (8).\u000d\u000a    Both Siemens (CT) and General Electric (MRI) have collaborated\u000d\u000a      extensively with Dixon with regards to long-term provision of their most\u000d\u000a      modern research hardware and software on a rolling programme in\u000d\u000a      recognition of the pioneering work performed on their equipment in\u000d\u000a      Cambridge and there is on-going collaboration with regard to cardiac and\u000d\u000a      body MRI (Martin Graves, David Lomas, Fiona Gilbert).\u000d\u000a    "},{"CaseStudyId":"35203","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2510769","Name":"Spain"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    It is estimated that as many as 400,000 people worldwide suffer from\u000d\u000a      Primary Ciliary Dyskinesia (PCD). Most affected children and all adults\u000d\u000a      will develop chronic severe lung infection (bronchiectasis), with 25% of\u000d\u000a      adults going on to develop respiratory failure leading to premature death.\u000d\u000a      Patients also suffer from recurrent nasal symptoms and sinusitis, and\u000d\u000a      approximately half will ultimately require hearing aids due to the\u000d\u000a      development of conductive hearing loss.\u000d\u000a    Benefits of early diagnosis\u000d\u000a      It is now accepted that analysis of ciliary function is the most important\u000d\u000a      test in the diagnosis of PCD. These methods have been adopted in the UK\u000d\u000a      and worldwide for the diagnosis of patients suspected of PCD.\u000d\u000a    Early diagnosis makes a very significant impact on both short-term and\u000d\u000a      long-term morbidity and mortality. The diagnostic methods and diagnostic\u000d\u000a      algorithm developed by the group have led to a number of phenotypes of PCD\u000d\u000a      being recognised that would have previously been missed using the old\u000d\u000a      diagnostic tests, which resulted in an under-diagnosis of around 15%. The\u000d\u000a      old tests only identified the phenotypes of PCD which have a normal beat\u000d\u000a      frequency, whereas all cilia, being dyskinetic, are picked up by\u000d\u000a      high-speed videomicroscopy analysis. As well as faster screening of\u000d\u000a      patient samples this has increased the number of people being diagnosed by\u000d\u000a      around 20% (3).\u000d\u000a    First nationally funded diagnostic service for patients with PCD\u000d\u000a      The group's research was the basis for its leading the successful\u000d\u000a      application to the National Commissioning Group of the NHS to set up a\u000d\u000a      National Diagnostic Service for patients with PCD. In 2006, three highly\u000d\u000a      specialised diagnostic centres were established in Leicester, London and\u000d\u000a      Southampton. This was the first nationally funded diagnostic service for\u000d\u000a      patients with PCD worldwide. Around 30 scientists and support staff are\u000d\u000a      involved in this service, with funding at £2.26 million per annum (1).\u000d\u000a    Prior to the establishment of these centres, there were problems with the\u000d\u000a      diagnostic process. This was due to several factors, including the\u000d\u000a      landscape of isolated units with a special interest, limited access to\u000d\u000a      diagnostic equipment, and long waiting times for diagnostic test results.\u000d\u000a    Since the centres were implemented in 2006, the following improvements\u000d\u000a      have been made to the diagnosis of PCD patients:\u000d\u000a    \u000d\u000a      Reduced waiting times for PCD diagnostic testing\u000d\u000a      More equal access for patients (i.e. not such a postcode lottery to\u000d\u000a        the diagnostic service)\u000d\u000a      Development of standardised processes (with equal access to equipment)\u000d\u000a        for the diagnostic testing which are audited across the three centres\u000d\u000a      Coordination and sharing of best practice — the three centres meet on\u000d\u000a        a regular basis to compare and refine the PCD Diagnostic Service\u000d\u000a      Establishment of a database used for capturing data of patients\u000d\u000a        referred to the diagnostic centres (authored by the group).\u000d\u000a    \u000d\u000a    Fiona Copeland, chair of the PCD Family Support Group, says: \"The\u000d\u000a      diagnostic service has led to research, development and audit programmes,\u000d\u000a      which have resulted in a big increase in the understanding of the cell\u000d\u000a      biology involved in ciliopathy diseases, as well as improving clinical\u000d\u000a      testing.\" (2).\u000d\u000a    Development of services in other countries\u000d\u000a      The model has led directly to the development of services for PCD in other\u000d\u000a      countries. The diagnostic algorithm has been adopted by the European\u000d\u000a      Taskforce Recommendations (3) that have been published in the\u000d\u000a      European Respiratory Journal and also by the PCD groups in the US (4).\u000a      Over the last 5 years the group has hosted and trained scientists and\u000d\u000a      clinicians from China, Singapore, Canada, Australia, Spain, Denmark,\u000d\u000a      Holland and Italy in high-speed videomicroscopy of ciliary biopsies to\u000d\u000a      diagnose PCD and to establish national diagnostic centres.\u000d\u000a    Establishment of a Patient Management Service for children with PCD\u000d\u000a      Following establishment of the UK National Diagnostic Service many more\u000d\u000a      patients than suspected were diagnosed with PCD (around 300 since 2006).\u000d\u000a      Their condition is very different from other chronic diseases such as\u000d\u000a      cystic fibrosis, and it became obvious that their care was substandard in\u000d\u000a      many cases. The group and colleagues from the other National Diagnostic\u000d\u000a      Centres jointly led a bid to establish a nationally commissioned Patient\u000d\u000a      Management Service for children with PCD, concentrated at four centres\u000d\u000a      (Leicester, London, Southampton and Leeds) (5).This again is the\u000d\u000a      first of its kind worldwide and was signed off by the Secretary of State\u000d\u000a      in February 2012. The new clinical management service, with funding of\u000d\u000a      £1,708,843 per annum on a long-term basis, will transform the management\u000d\u000a      of children with PCD and reduce the degree of bronchiectasis and\u000d\u000a      respiratory failure they experience later in life.\u000d\u000a    Other impact\u000d\u000a      The group sits on and has co-chaired the medical advisory board of the\u000d\u000a      Primary Ciliary Dyskinesia Family Support Group and has been instrumental\u000d\u000a      in the development of their website which offers support for children and\u000d\u000a      adults with PCD (6).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The Leicester Cilia Group (LCG) established methods to study ciliary\u000d\u000a      damage and dysfunction, transforming the diagnosis and management of\u000d\u000a      Primary Ciliary Dyskinesia (PCD), a genetic disorder that causes severe\u000d\u000a      permanent lung damage in children. The group developed diagnostic methods,\u000d\u000a      adopted in the UK and internationally, that increased the accuracy and\u000d\u000a      speed of diagnosis, uncovering a number of previously unrecognised\u000d\u000a      phenotypes. The group was instrumental in the establishment of the first\u000d\u000a      nationally funded diagnostic service (three centres, including Leicester)\u000d\u000a      in the world. This has resulted in the group jointly leading a successful\u000d\u000a      bid (2012) to set up the first nationally funded management service for\u000d\u000a      children with PCD.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Leicester\u000d\u000a    ","Institutions":[{"AlternativeName":"Leicester (University of)","InstitutionName":"University of Leicester","PeerGroup":"A","Region":"East Midlands","UKPRN":10007796}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"}],"References":"\u000d\u000a    \u000a1. Chilvers MA, Rutman A, O'Callaghan C. Ciliary beat pattern is\u000d\u000a      associated with specific ultrastructural defects in primary ciliary\u000d\u000a      dyskinesia. J Allergy Clin Immunol 2003;112(3):518-24.\u000d\u000a    \u000a\u000a2. Thomas B, Rutman A, O'Callaghan C. Disrupted ciliated\u000d\u000a      epithelium shows slower ciliary beat frequency and increased dyskinesia.\u000d\u000a      Eur Respir J 2009;34:401-4.\u000d\u000a    \u000a\u000a3. Stannard W, Chilvers M, Rutman A, Williams CD, O'Callaghan C.\u000d\u000a      Diagnostic testing of patients suspected of primary ciliary dyskinesia. Am\u000d\u000a      J Respir Crit Care Med 2010;181(4):307-314.\u000d\u000a    \u000a\u000a4. Mitchison H, Schmidts M, Loges N, Freshour J, Dritsoula A, Hirst R,\u000d\u000a      O'Callaghan C, Blau H, Al Dabbagh M, Olbrich H, Beales PL, Yagi T,\u000d\u000a      Mussaffi H, Chung E, Omran H, Mitchell DR. Mutations in axonemal dynein\u000d\u000a      assembly factor DNAAF3 cause primary ciliary dyskinesia. Nat Genet. 2012\u000d\u000a      Mar 4;44(4):381-9, S1-2\u000d\u000a    \u000a\u000a5. Panizzi JR, Becker-Heck A, Castleman VH, Al-Mutairi D, Liu Y, Loges\u000d\u000a      NT, Pathak N, Austin-Tse C, Sheridan E, Schmidts M, Olbrich H, Werner C,\u000d\u000a      Haffner K, Hellman N, Chodhari R, Gupta A, O'Callaghan C et al.\u000d\u000a      Schmalhans \/ CCDC103 encodes a novel cilia dynein arm assembly factor that\u000d\u000a      is mutated in primary ciliary dyskinesia. Nat Genet. 2012 May\u000d\u000a      13;44(6):714-9\u000d\u000a    \u000a\u000a6. O'Callaghan\u000d\u000a          C, Chetcuti\u000d\u000a        P, Moya\u000d\u000a        E. High prevalence of primary ciliary dyskinesia in a British Asian\u000d\u000a      population. Arch\u000d\u000a        Dis Child. 2010 Jan;95(1):51-2. doi: 10.1136\/adc.2009.158493. Epub\u000d\u000a      2009 Aug 30.\u000d\u000a    \u000a\u000a7. Hirst RA, Rutman A, Williams G, O'Callaghan C. Ciliated\u000d\u000a      air-liquid cultures as an aid to diagnostic testing of primary ciliary\u000d\u000a      dyskinesia (PCD). Chest 2010 138(6):1441-7.\u000d\u000a    \u000aSelected grant income over the past decade\u000d\u000a      2003: The effect of RSV infection on pneumococcal adherence and invasion\u000d\u000a      of the ciliated respiratory epithelium. Dr Wendy Stannard. Action Medical\u000d\u000a      Research: £129,000\u000d\u000a      2005: Pneumococcal infection in primary ciliary dyskinesia. Liverpool\u000d\u000a      Children's Charity. O'Callaghan C: £60,000\u000d\u000a      2005: Primary ciliary dyskinesia and bacterial infection: SPARKS:\u000d\u000a      O'Callaghan C, Andrew PW: £129,000\u000d\u000a      2007: Investigation of the synergy between RSV and Pneumococcal infection.\u000d\u000a      Action Medical Research. O'Callaghan C, Andrew PW. £87,000\u000d\u000a      2008: Investigating the molecular process of ciliogenesis in normal and\u000d\u000a      disease states. MRC\/Faculty funded Translational Studentship. O'Callaghan\u000d\u000a      C, Fry A. £52,620\u000d\u000a      2009: A new approach to the treatment of pneumococcal induced toxaemia\u000d\u000a      using drugs that selectively inhibit the activity of the pneumococcal\u000d\u000a      toxin, pneumolysin. Wellcome Trust. Andrew PW, O'Callaghan C, El-Rachkidy\u000d\u000a      Lonnen R. £3,498,098\u000d\u000a      2009: Why is invasive pneumococcal disease more common following viral\u000d\u000a      infection? Action Medical Research. O'Callaghan C, Andrew PW, Easton A.\u000d\u000a      £119,218\u000d\u000a      2010: Can naturally occurring stress hormones and prescribed\u000d\u000a      catecholamines increase the risk of serious infections in newborns?\u000d\u000a      SPARKS. O'Callaghan C, Freestone P, Field DJ. £140,098.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a      National Commissioning Group: NHS Specialised Services — Primary\u000d\u000a        Ciliary Dyskinesia\u000d\u000a        http:\/\/www.specialisedservices.nhs.uk\/service\/primary-ciliary-dyskinesia\u000a\u000d\u000a      Letter from the Chairman of the PCD Family Support Group, 22 April\u000d\u000a        2013\u000d\u000a      Barbato A, Frischer T, Kuehni CE, Snijders D, Azevedo I, Baktai G,\u000d\u000a        Bartoloni L, Eber E, Escribano A, Haarman E, Hesselmar B, Jaspers M,\u000d\u000a        Lucas J, Nielsen KG, O'Callaghan C, Omran H, Pohunek P,\u000d\u000a        Strippoli MPF, Bush A. Primary ciliary dyskinesia: a consensus statement\u000d\u000a        on diagnostic and treatment approaches and future perspectives. Eur\u000d\u000a        Respir J 2009;34:1264-1276.\u000d\u000a      Leigh MW, O'Callaghan C, Knowles MR. The challenges of diagnosing\u000d\u000a        primary ciliary dyskinesia. Proc Am Thorac Soc 2011;8(5):434-7.\u000d\u000a      National Commissioning Group: Primary Ciliary Dyskinesia (PCD) A\u000d\u000a        National Management Service for Children\u000d\u000a        http:\/\/www.specialisedservices.nhs.uk\/library\/36\/Service_Specification_and_Standards___Primary_Cilliary_Dyskinesia_Service_1.pdf\u000a\u000d\u000a      Primary Ciliary Dyskinesia Family Support Group: http:\/\/www.pcdsupport.org.uk\/forum\/\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Redefining ciliary function: improving diagnostic testing and management\u000d\u000a      of ciliary disorders and phenotyping of other respiratory diseases\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2637487","Name":"Southampton"},{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"2644688","Name":"Leeds"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Cilia are microscopic hair-like projections from the lining of the air\u000d\u000a      conducting tubes which protect our lungs from damage and infection. These\u000d\u000a      cilia, together with the mucus that covers them, constantly remove inhaled\u000d\u000a      foreign particles by coordinated movements. Normally, cilia beat 10 to 15\u000d\u000a      times per second, and any impairment can result in poor mucociliary\u000d\u000a      clearance, with subsequent upper and lower respiratory infection. Over the\u000d\u000a      past decade, the Leicester Ciliary Group (LCG) group has redefined how\u000d\u000a      cilia from the respiratory tract function, overturning previous theories\u000d\u000a      in this area.\u000d\u000a    Importance of ciliary analysis in CPD\u000d\u000a      Work by Stannard, Chilvers, Thomas, Hirst and Rutman in Professor Chris\u000d\u000a      O'Callaghan's laboratory using novel high speed video imaging and cell\u000d\u000a      culture has defined normal ciliary function (papers in 1999, 2000, 2003\u000d\u000a      & 2009), and the effect of secondary damage on ciliary function\u000d\u000a      (papers in 2001, 2009 & 2010). By applying this research to the study\u000d\u000a      of disease states, they have shown the huge importance of ciliary analysis\u000d\u000a      in PCD. Previous diagnostic testing simply relied on measuring beat\u000d\u000a      frequency as a screening test, however, a major discovery by Chilvers (1)\u000d\u000a      that ciliary beat pattern predicted ultrastructural abnormalities in PCD\u000d\u000a      led to the discovery by Stannard and colleagues that beat pattern analysis\u000d\u000a      in addition to frequency measurement significantly increased the\u000d\u000a      diagnostic yield (2). The landmark paper of Stannard in 2010 (3),\u000a      using these methods to diagnose patients suspected of PCD, has been\u000d\u000a      adopted internationally as the `gold standard'. This has been followed by\u000d\u000a      the development of additional methods to allow diagnostic testing to be\u000d\u000a      performed in resource-poor countries.\u000d\u000a    Discovery of previously unrecognised phenotypes of PCD\u000d\u000a      The development of high-speed videomicroscopy of ciliary biopsies obtained\u000d\u000a      from brushing or scraping the lining of the nose has not only enabled\u000d\u000a      rapid diagnosis of known phenotypes of PCD but also led to the discovery\u000d\u000a      of previously unrecognised phenotypes of PCD. (The defect is universal\u000d\u000a      throughout the respiratory tract, including the nose, from which it is\u000d\u000a      easier and less painful to remove a specimen.) This has significantly\u000d\u000a      increased the ability to diagnose patients with atypical PCD who are at\u000d\u000a      risk of developing long-term complications. The group has also pioneered\u000d\u000a      the use of ciliated cell culture to identify and confirm these previously\u000d\u000a      unrecognised phenotypes of PCD. This work has contributed to the discovery\u000d\u000a      of the genes of four different types of PCD out of the 21 discovered to\u000d\u000a      date (O'Callaghan 2012 — also Leicester LCG; 4,5). The group is\u000d\u000a      now involved in developing gene therapy for this disease following on from\u000d\u000a      grant funded work to study gene therapy in cystic fibrosis.\u000d\u000a    In addition, the research has highlighted the very large numbers of\u000d\u000a      patients with this condition in the Asian community in Bradford, UK, where\u000d\u000a      the group has shown it is more common than cystic fibrosis, with the\u000d\u000a      prevalence the highest reported at 1 in 2,265 (6).\u000d\u000a    Improving the interpretation of diagnostic tests\u000d\u000a      The group has also defined the effect of epithelial disruption on ciliary\u000d\u000a      function and identified for the first time that viral infections cause\u000d\u000a      defects in ciliary beat pattern, while beat frequency may be maintained.\u000d\u000a      The appreciation of these effects has significantly improved the\u000d\u000a      interpretation of diagnostic tests. Successfully growing ciliated cells\u000d\u000a      from children with PCD at an air interface culture allowed Hirst (7)\u000d\u000a      to confirm suspected new phenotypes of PCD and markedly reduce secondary\u000d\u000a      damage in the original sample, reducing the need for further biopsies.\u000d\u000a      This method has been adopted as part of the national diagnostic service.\u000d\u000a    Furthermore, this research has also allowed other respiratory diseases to\u000d\u000a      be studied in detail, for example, in adults with severe asthma. The group\u000d\u000a      has shown that these patients have the equivalent of a functional PCD in\u000d\u000a      addition to their asthma. This discovery suggests that both the asthma and\u000d\u000a      the PCD phenotype need to be treated and helps to explain why this group\u000d\u000a      is so refractory to traditional asthma medication and why so many of these\u000d\u000a      patients develop bronchiectasis, a long-term condition where the airways\u000d\u000a      of the lungs become abnormally widened, leading to a build-up of excess\u000d\u000a      mucus.\u000d\u000a    Leicester Cilia Group\u000d\u000a    \u000d\u000a      Professor Chris O'Callaghan, Professor of Paediatrics, 1991-2012\u000d\u000a      Dr Wendy A Stannard, Clinical Research Fellow, 2000-2004\u000d\u000a      Dr Biju Thomas, Clinical Research Fellow, 2003\u000d\u000a      Dr Mark A Chilvers, Clinical Research Fellow, 1999 - present\u000d\u000a      Dr Prtiti Kenia, Clinical Research Fellow, 2007 - present\u000d\u000a      Dr Mina Fahdee-Shoad, PhD student\u000d\u000a      Dr Robert A Hirst, Post-doctoral Scientist, 2001-present\u000d\u000a      Dr Andrew Rutman 1999-present\u000d\u000a      CD Williams, 2006-present\u000d\u000a      G Williams 2006 - present\u000d\u000a    \u000d\u000a    "},{"CaseStudyId":"35205","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2411586","Name":"Gibraltar"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Type 2 diabetes currently accounts for the majority (around 90%) of the\u000a      diabetes burden. A further\u000a      10 million individuals are at high risk of progressing to T2DM, identified\u000a      through impaired blood\u000a      glucose regulation below the threshold for diabetes, and will form the\u000a      majority of the diabetes\u000a      burden in the future — the cost to the NHS, already high at 10%, is\u000a      projected to increase to 17% by\u000a      2035. Given these trends, the effective prevention and treatment of\u000a      diabetes is a stated national\u000a      healthcare priority. Unhealthy lifestyle behaviours account for the vast\u000a      majority (80%) of T2DM\u000a      cases, so lifestyle interventions play an integral role in prevention and\u000a      management strategies.\u000a    The Diabetes Research Centre runs the largest portfolio of translational\u000a      research for the prevention\u000a      and management of type 2 diabetes nationally and, in collaboration with\u000a      its NHS partners, has had\u000a      a significant impact on how diabetes is targeted in routine clinical care.\u000a    Impacting on national and international guidance\u000a    NICE guidance: The Unit's work was used to inform NICE through\u000a      their Quality Standard for\u000a      Diabetes 2011, which states that structured education programmes should be\u000a      available for all\u000a      individuals with T2DM (A).The Diabetes Research Unit (Khunti is\u000a      Chair; Yates and Davies\u000a      members) significantly contributed to, and shaped, new NICE Guidance for\u000a      the prevention of type\u000a      2 diabetes issued in 2012 (B). The Walking Away programme was\u000a      presented as expert testimony\u000a      to NICE as part of the new guidance for the prevention of T2DM, and is\u000a      listed by NICE as an\u000a      example of best practice around the implementation of the new guidance for\u000a      the prevention of\u000a      T2DM (C).\u000a    Department of Health: The DoH continues to recognise the DESMOND\u000a      programme as the only\u000a      nationally available structured education programme for T2DM (D).\u000a      Davies and Khunti are part of\u000a      the Vascular Board, which helps inform government policy, including the\u000a      Vascular Checks\u000a      Programme — lately the NHS Health Checks Programme. The impact of the work\u000a      around diabetes\u000a      management and prevention lead to both academics being invited, by the UK\u000a      National Screening\u000a      Committee to lead on developing the content and structure of The Handbook\u000a      of Vascular Risk\u000a      Assessment, Risk Reduction and Risk Management (both the original 2008\u000a      version and updated\u000a      2012 version). The handbook is widely used within the Department of Health\u000a      (E).\u000a    Other: In 2009 Khunti, Davis and Yates significantly contributed\u000a      to guidance issued by the South\u000a      Asian Health Foundation for diabetes research priorities in British South\u000a      Asians (F). Work around\u000a      self-management in T2DM significantly informed the latest edition (2011)\u000a      of the prestigious Oxford\u000a      Textbook of Endocrinology and Diabetes, co-edited by Davies (G).\u000a    International: Walking Away contributed to a widely circulated\u000a      collection of examples of\u000a      international best practice in the implementation of diabetes prevention\u000a      programmes\u000a      commissioned by the World Congress on the Prevention of Diabetes and its\u000a      Complications; this\u000a      document is widely used by policy makers nationally and internationally (H).\u000a      Davies and Yates\u000a      contributed to an international level expert review, 2012, of the evidence\u000a      for nonpharmacological\u000a      interventions for the prevention of type 2 diabetes mellitus and this\u000a      article has had a significant\u000a      impact on diabetes prevention initiatives internationally (I).\u000a    Improving patient care and outcomes through DESMOND and Walking\u000a          Away\u000a    Clinical commissioning groups (CCGs): DESMOND has been implemented\u000a      in over half of all CCGs\u000a      (formerly PCTs) nationally and has substantially improved the quality and\u000a      breadth of treatment\u000a      offered to those with T2DM. It has been found to be highly effective at\u000a      improving clinical outcomes\u000a      in those with T2DM and microalbuminuria, which occurs when the kidney\u000a      leaks small amounts of\u000a      protein into the urine (J). DESMOND is the mostly widely used\u000a      structured education programme in\u000a      primary care nationally, benefiting thousands of people annually (K).\u000a      It has been tailored to diverse\u000a      non-English speaking South Asian communities within the UK in order to\u000a      increase the reach of the\u000a      programme within primary care (L). The Centre has on-going\u000a      collaborations with CCGs nationally\u000a      to ensure that prevention and self-management programmes continue to be\u000a      commissioned and\u000a      improve health care.\u000a    International reach: The Centre has supported the translation and\u000a      implementation of DESMOND\u000a      across large regions of both Ireland and Australia as part of routine\u000a      diabetes management\u000a      pathways, as well as informed patient education models in the Netherlands\u000a      and Denmark.\u000a    Walking Away: This prevention programme has generated substantial\u000a      national and international\u000a      interest and has been commissioned and implemented across diverse primary\u000a      care organisations\u000a      in England, Gibraltar, Ireland and Australia. To date, 66 educators have\u000a      been trained to deliver the\u000a      programme (59 in UK and Ireland, 5 in Australia, and 2 in Gibraltar).\u000a    Audit data and interviews with stakeholders have confirmed that the\u000a      programme promotes\u000a      improved health behaviour in routine clinical care and is widely\u000a      appreciated by participants and\u000a      healthcare professionals alike. Walking Away continues to attract new\u000a      implementation sites\u000a      nationally. The implementation of the programme has been achieved at a\u000a      very low cost; one site\u000a      estimated the total cost to be £30 per patient per course (results\u000a      presented at the Diabetes UK\u000a      professional conference 2011, London).\u000a    Notable awards\u000a    Davies was awarded a prestigious NIHR Senior Investigator status in 2009\u000a      and this was renewed\u000a      to the maximum term in 2012.\u000a    The implementation of Walking Away in routine care won the Health\u000a      Foundation prize for the best\u000a      contribution to improvement in science at the 2011 `Delivering better\u000a      health services' conference,\u000a      Liverpool and was awarded silver at the national Quality In Care (QIC)\u000a      Diabetes Awards 2011.\u000a    Research around Walking Away led to a rising star award for Yates from\u000a      Primary Care Diabetes\u000a      Europe, Barcelona, 2012.\u000a    ","ImpactSummary":"\u000a    Elevated blood glucose levels — the hallmark of diabetes — is estimated\u000a      by the World Health\u000a      Organization to be the third leading cause of premature death globally.\u000a      Around 4 million people in\u000a      the UK have been diagnosed with diabetes; their treatment accounts for 10%\u000a      (£10 billion) of NHS\u000a      expenditure. Self-management strategies and the promotion of a healthy\u000a      lifestyle are fundamental\u000a      to the treatment and prevention of type 2 diabetes (T2DM). Since 2008,\u000a      Leicester's Diabetes\u000a      Research Centre has developed, evaluated, disseminated and implemented a\u000a      range of\u000a      programmes based on a technique called structured education. The flagship\u000a      DESMOND\u000a      programme is run in over half of all clinical commissioning groups (CCGs),\u000a      affecting thousands of\u000a      people with newly diagnosed T2DM. The Walking Away prevention programme\u000a      has been widely\u000a      implemented in the UK, Ireland and Australia. These programmes are the\u000a      only nationally available\u000a      evidence-based structured education programmes for the prevention and\u000a      management of T2DM.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leicester\u000a    ","Institutions":[{"AlternativeName":"Leicester (University of)","InstitutionName":"University of Leicester","PeerGroup":"A","Region":"East Midlands","UKPRN":10007796}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3128760","Name":"Barcelona"},{"GeoNamesId":"1266622","Name":"Khunti"}],"References":"\u000a    \u000a1. Davies MJ, Heller S, Campbell MJ, Carey ME, Dallosso HM, Daly\u000a      H, Eaton S, Fox C,\u000a      Rantell K, Rayman G, Skinner TC & Khunti K. Effectiveness of a\u000a      structured education\u000a      programme on individuals newly diagnosed with Type 2 diabetes: a cluster\u000a      randomised\u000a      controlled trial of the DESMOND programme. BMJ 2008 336: 491-495.\u000a    \u000a\u000a2. Gillett M, Dallosso HM, Dixon S, Brennan A, Carey ME, Campbell MJ,\u000a      Heller S, Khunti K,\u000a      Skinner T, Davies MJ. Delivering the diabetes education and\u000a      self-management for ongoing\u000a      and newly diagnosed (DESMOND) programme for people with newly diagnosed\u000a      type 2\u000a      diabetes: cost effectiveness analysis. BMJ, 2010; 341,c4093.\u000a    \u000a\u000a3. Yates T, Davies M, Gorely T, Bull F, Khunti K.\u000a      Effectiveness of a pragmatic education\u000a      programme aimed at promoting walking activity in individuals with impaired\u000a      glucose\u000a      tolerance: a randomized controlled trial. Diabetes Care 2009; 32: 1404-10.\u000a    \u000a\u000a4. Yates T, Daves M, Sehmi S, Gorely T, Khunti K. The\u000a      Prediabetes Risk Education and\u000a      Physical Activity Recommendation and Encouragement (PREPARE) programme\u000a      study: Are\u000a      improvements in glucose regulation sustained at two years? Diabetic\u000a      Medicine, 2011; 28,\u000a      1268-1271\u000a    \u000a\u000a5. Khunti K, Gray LJ, Skinner T, Carey ME, Realf K, Dallosso H,\u000a      Fisher H, Campbell M,\u000a      Heller S, Davies MJ. Effectiveness of a diabetes education and\u000a      self-management\u000a      programme (DESMOND) for people with newly diagnosed type 2 diabetes\u000a      mellitus: three\u000a      year follow-up of a cluster randomised controlled trial in primary care. BMJ\u000a      2012;344:e2333 (doi: 10.1136\/bmj.e2333)\u000a    \u000a\u000a6. Gillies, C, Lambert P, Abrams K, Sutton A, Cooper N, Hsu R, Davies\u000a        M, and Khunti K.\u000a      Different strategies for screening and prevention of type 2 diabetes in\u000a      adults: cost\u000a      effectiveness analysis. BMJ 2008;336: 1180-1185.\u000a    \u000aGrants\u000a      Since 2008, the centre has been awarded over £12 million in research\u000a      grants directly aimed at\u000a      furthering knowledge around the use of structured education and lifestyle\u000a      factors in the\u000a      management and prevention of T2DM, from funders including NIHR, HTA and\u000a      MRC.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    A. NICE: Diabetes in adults. Quality Standards, QS6 - Issued: March 2011.\u000a      http:\/\/www.nice.org.uk\/guidance\/qualitystandards\/diabetesinadults\/diabetesinadultsqualitystandard.jsp\u000a    B. NICE: Preventing type 2 diabetes — risk identification and\u000a      interventions for individuals at\u000a      high risk http:\/\/www.nice.org.uk\/PH38\u000a    C. NICE: Shared learning implementing NICE guidance.\u000a      http:\/\/www.nice.org.uk\/usingguidance\/sharedlearningimplementingniceguidance\/examplesofimplementation\/eximpresults.jsp?o=578\u000a    D. National service frameworks and strategies: Standards for diabetes.\u000a      http:\/\/www.nhs.uk\/nhsengland\/NSF\/pages\/Diabetes.aspx\u000a    E. Head, UK National Screening Committee\/NHS Screening Programmes\u000a    F. Davies M, Khunti K and Yates T. (contribution to chapters 5, 6, 7, 12)\u000a      Diabetes UK and\u000a      South Asian Health Foundation recommendations on diabetes research\u000a      priorities for British\u000a      South Asians. 2009. http:\/\/www.diabetes.org.uk\/upload\/Reports\/South_Asian_report.pdf\u000a    G. Wass JAH, Stewart P, Amiel SA, Davies MJ. Oxford Textbook of\u000a      Endocrinology and\u000a      Diabetes. Oxford Textbook of Endocrinology and Diabetes, 2011, 2nd Edition\u000a    H. Yates T, Davies M, Troughton J, Daley H, Martin-Stacey L, Khunti K,\u000a      2010. \"Walking Away\u000a      from Type 2 Diabetes: development of a diabetes prevention programme for\u000a      implementation within England\" in Diabetes Prevention in Practice. TUMAIMI\u000a      institute for\u000a      Prevention Management, Dresden, Germany.\u000a    I. Schwarz P, Greaves C, Lindstrom J, Yates T, Davies M.\u000a      Non-pharmacological intervention\u000a      for diabetes mellitus prevention in populations: Where do we stand? Nat\u000a      Rev Endocrinol.\u000a      2012; 8:363-73.\u000a    J. Crasto W, Jarvis J, Khunti K, Skinner TC, Gray LJ, Brela J, Troughton\u000a      J, Daly H, Lawrence\u000a      IG, McNally PG, Carey ME, Davies MJ. Multifactorial intervention in\u000a      individuals with type 2\u000a      diabetes and microalbuminuria: The Microalbuminuria Education and\u000a      Medication\u000a      Optimisation (MEMO) study. Diabetes Research and Clinical Practice 2011;\u000a      93:328-36.\u000a    K. Head, NHS Leicester City Clinical Commissioning Group.\u000a    L. Stone M, Patel N, Daly H, Martin-Stacey L, Sayjal A, Marian M, Khunti\u000a      K & Davies M. Using\u000a      qualitative research methods to inform the development of a modified\u000a      version of a patient\u000a      education module for non-English speakers with type 2 diabetes: action\u000a      research project on\u000a      two south Asian populations in the UK. Diversity in Health and Social Care\u000a      2008;3:199-206\u000a    \u000a    ","Title":"\u000a    Self-management in the prevention and treatment of type 2 diabetes:\u000a      revolutionising patient care within usual healthcare practice\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Background\u000a      In 2000 the national service framework (NSF) acknowledged that structured\u000a      education, a group-based\u000a\u0009  person-centred method of promoting self-management skills and a\u000a      healthy lifestyle, was\u000a      pivotal to T2DM care. However, evidenced-based self-management programmes\u000a      suitable for\u000a      translation into routine care were lacking, and NICE were unable to find\u000a      studies that had\u000a      adequately evaluated the benefits of structured education. The Diabetes\u000a      Education and Self-Management\u000a\u0009  for On-going and Newly Diagnosed (DESMOND) programme was set up\u000a      in response\u000a      to this need by the University's Diabetes Research Unit (now Centre). The\u000a      aim was to develop and\u000a      evaluate a structured education programme to the same rigorous standards\u000a      as pharmaceutical\u000a      interventions; this was achieved by adhering to the Medical Research\u000a      Council's framework for\u000a      complex interventions, including multiple R&D pilot phases. The\u000a      six-hour programme, led by\u000a      trained educators, offers groups of up to 10 people up-to-date information\u000a      about diabetes and risk;\u000a      practical advice on diet, activity and medication; and an opportunity to\u000a      meet and talk to others in\u000a      the same situation.\u000a    Evaluation of DESMOND\u000a      DESMOND was evaluated in national multi-centre cluster randomised\u000a      controlled trial involving 207\u000a      GP practices and 824 participants. After 12 months, the programme was\u000a      found to be effective at\u000a      promoting some health behaviours, reducing depression and reducing\u000a      cardiovascular disease risk\u000a      (1). A later high-impact publication demonstrated that DESMOND was\u000a      likely to be highly cost-effective\u000a\u0009  with a mean incremental cost per quality-adjusted life year\u000a      gained of £2,092 (2).\u000a      DESMOND remains the only T2DM self-management programme in the UK that has\u000a      been subject\u000a      to a national multi-centre evaluation in primary care and a rigorous\u000a      cost-effectiveness analysis.\u000a      This has provided health care commissioners and policy makers with the\u000a      high level of evidence\u000a      needed to make informed decisions about prioritisation and resource\u000a      allocation for diabetes\u000a      management.\u000a    Expansion of the approach into prevention\u000a      The Centre expanded the DESMOND approach into the prevention of T2DM. The\u000a      launch of the\u000a      Vascular Checks programme in 2008 (renamed NHS Health Checks) signified a\u000a      shift in health care\u000a      priority towards prevention, and 40% of the budget for this new initiative\u000a      was modelled on the\u000a      identification and management of T2DM risk. However, there was no relevant\u000a      evidence from\u000a      interventions that were suitable for implementation within the NHS, so the\u000a      PREPARE programme\u000a      was developed to the same rigorous standards as those for DESMOND. The\u000a      programme was\u000a      found, through a proof-of-concept randomised controlled trial, to be\u000a      highly effective at promoting\u000a      improved health behaviour and glucose regulation at 12-months and\u000a      24-months (3,4).\u000a    The Centre demonstrated, through complex modelling, that the prevention\u000a      of T2DM is likely to be\u000a      cost-effective when integrated into diabetes care (5,6). PREPARE\u000a      was expanded to meet the\u000a      needs of all individuals with a high risk of type 2 diabetes and renamed\u000a      Walking Away from Type 2\u000a      Diabetes. A full educator training and quality assurance programme was\u000a      developed and piloted\u000a      through the local CLAHRC (Collaboration for Leadership in Applied Health\u000a      Research and Care).\u000a    The research platform is an exemplar of an NIHR funded translational\u000a      pathway (through dedicated\u000a      Biomedical Research Unit (BRU) and CLAHRC funding) whereby new lifestyle\u000a      therapies continue\u000a      to be developed, evaluated and translated into routine care in order to\u000a      meet the on-going needs of\u000a      patients and the NHS. This will ensure the Centre stays at the forefront\u000a      of translational diabetes\u000a      research and continues to shape the evidence-base, national and\u000a      international health care\u000a      guidance and recommendations, and patient care.\u000a    Key researchers: Melanie J Davies, Professor of Diabetes Medicine\u000a      (2006-present); Kamlesh\u000a      Khunti, Professor of Primary Care Diabetes and Vascular Medicine\u000a      (2007-present); Dr Thomas\u000a      Yates, Senior Lecturer in Physical Activity, Sedentary Behaviour and\u000a      Health (2008-present).\u000a    "},{"CaseStudyId":"35207","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Background\u000d\u000a    Postmortem imaging is now a rapidly growing field. Rutty and Morgan,\u000d\u000a      together with their collaborators, have helped advance postmortem imaging\u000d\u000a      to the stage where it has become `routine consideration to confirm cause\u000d\u000a      of death' (A) and `standard procedure in the forensic examination\u000d\u000a      of human remains both after a disaster and in individual cases' (B).\u000d\u000a    Impact on policymakers\u000d\u000a    Rutty and Morgan as founding members of a Department of Health National\u000d\u000a      Imaging Board helped produce national guidance documents with the Ministry\u000d\u000a      of Justice and Royal Colleges of Pathology and Radiology. Rutty was lead\u000d\u000a      author of a `vision' document for the introduction of a national PMCT\u000d\u000a      service (C). The team's sharing of their research has been the\u000d\u000a      `driving force' (D) behind the new recommendations.\u000d\u000a    Rutty and Morgan's research has had a particularly significant influence\u000d\u000a      in the area of disaster victim identification (DVI). Lessons learnt from\u000d\u000a      `Operation Torch' have been published in an official report (E)\u000d\u000a      which will assist member states of the EC in planning for and responding\u000d\u000a      to similar incidents. As a consequence of Torch, Professor Rutty was\u000d\u000a      awarded a Metropolitan Police Service Assistant Commissioner Commendation\u000d\u000a      (2009). In 2010 he was awarded an MBE.\u000d\u000a    The FiMag system has been presented to the International Red Cross and\u000d\u000a      Interpol, and similar systems are now being planned in the Netherlands and\u000d\u000a      Australia. PMCT is part of the latest working version of Interpol's\u000d\u000a      general guidance for mass fatality incidents, and the International\u000d\u000a      Society of Forensic Radiology and Imaging (ISFRI) Disaster Victim\u000d\u000a      Identification group's positional statement (F). Rutty represents\u000d\u000a      the UK at the Interpol Standing Committee on Disaster Victim\u000d\u000a      Identification and is Vice-Chair (Chair in 2013-4) of ISFRI. A\u000d\u000a      representative of Queensland Health Forensic and Scientific Services said:\u000d\u000a      \"One of the many positive aspects of the technology is that it lends\u000d\u000a      itself to multicentre utilisation and interdepartmental communication.\" (B)\u000d\u000a    Impact on practitioners\u000d\u000a    Following successful use of PMCT in the 2009 Black Saturday bushfires,\u000d\u000a      the Australasian Disaster Victim Identification Committee prepared a\u000d\u000a      business case for service implementation. They asked for the help of\u000d\u000a      Professor Rutty for background information, a description of FiMag, and\u000d\u000a      costing for the purchase of a `BodyTom' mobile scanner, which appears to\u000d\u000a      `do everything ADVIC would want' (G).\u000d\u000a    Within the field of DVI, PMCT has a major impact on investigation, such\u000d\u000a      as identifying component parts of an improvised explosive device or\u000d\u000a      identification of the dead using odontology or old injuries. It allows\u000d\u000a      efficient management of personnel and limited resources. Offsite\u000d\u000a      specialists can be involved in disaster response, which has `enormous\u000d\u000a      cost-benefit yet to be recognised.' (B). The Chief Constable,\u000d\u000a      National Pathology and Disaster Victim Identification Lead says: \"Due to\u000d\u000a      the work at Leicester, contingency plans for mass fatality incidents now\u000d\u000a      include an option to source mobile CT scanners to enhance operations at\u000d\u000a      designated mortuaries.\" (H)\u000d\u000a    The research is impacting on police investigations in the UK, and PMCT in\u000d\u000a      `single death' postmortems is being `monitored with interest' by senior\u000d\u000a      officers and forensic specialists' (H). The technology can be a\u000d\u000a      strong investigative tool in trauma and can also be useful for\u000d\u000a      re-examination if suspicions arise after a body has been cremated (a\u000d\u000a      `virtual exhumation').\u000d\u000a    In September 2012 the group launched the UK's first training course in\u000d\u000a      PMCT and from 2014, PMCT based teaching will be offered to all medical\u000d\u000a      students attending the University, the first such initiative in the\u000d\u000a      country.\u000d\u000a    Impact on the public\u000d\u000a    Increasing media profile has disseminated this research to a wider\u000d\u000a      audience (I). Demand for a less invasive post-mortem procedure is\u000d\u000a      expected to grow, particularly in Muslim and Jewish communities, whose\u000d\u000a      religious and cultural principles oppose invasive autopsies. The Saad\u000d\u000a      Foundation was set up by a former police superintendent to provide support\u000d\u000a      and assistance to the Muslim community in dealing with sudden death\u000d\u000a      procedures (J). He used the Leicester team's research on imaging to\u000d\u000a      help persuade the Charity Commission to grant `registered status'. The\u000d\u000a      Coroners' Society, thanks to lobbying from Rutty and other academics,\u000d\u000a      professionals, and politicians such as Baroness Warsi, is now allowing\u000d\u000a      imaging as an alternative to intrusive autopsies. Rutty has been involved\u000d\u000a      in the training of all Coroners' Officers in West Yorkshire, resulting in\u000d\u000a      a `change in mindset' among previously resistant practitioners (Saad\u000d\u000a      Foundation).\u000d\u000a    Other impact\u000d\u000a    The group has collaborated with other international groups such as the\u000d\u000a      Technical Working Group Postmortem Angiography Methods (TWGPAM), an\u000d\u000a      international cooperation establishing a database for post-mortem\u000d\u000a      angiography. Rutty and Morgan united other researchers across the world in\u000d\u000a      2012 with the first publication outlining a common nomenclature in this\u000d\u000a      field.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The East Midlands Forensic Pathology Unit (EMFPU) and Academic Imaging,\u000d\u000a      both based at the University of Leicester, have led the development of\u000d\u000a      post-mortem computed tomography (PMCT) — CT scanning — as an alternative\u000d\u000a      or adjunct to conventional autopsy since 2002. The team has the largest\u000d\u000a      experience in the UK in terms of number of cases investigated and\u000d\u000a      publications, covering natural, traumatic, mass fatality and homicide\u000d\u000a      deaths. It has also contributed directly to national and international\u000d\u000a      guidelines, recommendations, protocols and operational systems. Since\u000d\u000a      2008, this research has had an impact on public authorities, (contributing\u000d\u000a      to guidelines ranging from natural death to national disaster planning),\u000d\u000a      and on the community.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    University of Leicester (UoL)\u000d\u000a    ","Institutions":[{"AlternativeName":"Leicester (University of)","InstitutionName":"University of Leicester","PeerGroup":"A","Region":"East Midlands","UKPRN":10007796}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1 Rutty G.N, Swift B. Accuracy of magnetic resonance imaging in\u000d\u000a      determining cause of sudden death in adults: comparison with conventional\u000d\u000a      autopsy. Histopathology. 2004 Feb;44(2):187-9.\u000d\u000a    \u000a\u000a2 Rutty G.N, Robinson C.E, BouHaidar R, Jeffery A.J, Morgan B. The Role\u000d\u000a      of Mobile Computed Tomography in Mass Fatality Incidents. J Forensic Sci.\u000d\u000a      2007; 52: 1343-1349\u000d\u000a    \u000a\u000a3 Rutty GN, Rutty JE. Did the participants of the mass fatality exercise\u000d\u000a      Operation Torch learn anything? Forensic Sci, Med Pathol. 2012; 8: 88-93\u000d\u000a    \u000a\u000a4 Rutty G.N, Robinson C, Morgan B, Black S, Adams C, Webster P. Fimag:\u000d\u000a      the United Kingdom Disaster Victim\/Forensic Identification Imaging System.\u000d\u000a      J Forensic Sci. 2009; 54(6): 1438-1442.\u000d\u000a    \u000a\u000a5 Saunders SL, Morgan B, Raj V, Robinson C, Rutty GN. Targeted\u000d\u000a      Post-mortem Computed Tomography Cardiac Angiography; Proof of concept. Int\u000d\u000a      J Legal Med 2011; 125:609-16\u000d\u000a    \u000a\u000a6 Morgan B, Biggs MJ, Barber J, Raj V, Amoroso J, Hollingbury FE,\u000d\u000a      Robinson C, Rutty GN. Accuracy of targeted post-mortem computed tomography\u000d\u000a      coronary angiography compared to assessment of serial histological\u000d\u000a      sections. Int J Legal Med. 2012 Nov 10. [Epub ahead of print]\u000d\u000a    \u000a\u000a7 Saunders S, Amorosa J, Morgan B, Rutty G. Consent of the recently\u000d\u000a      bereaved to post-mortem targeted angiography research: 207 adult cases. J\u000d\u000a      Clin Path 2013 Apr;66(4):326-9 and Rutty GN, Rutty JE Perceptions of near\u000d\u000a      virtual autopsies. J Forensic Leg Med. 2011;18:306-9\u000d\u000a    \u000a\u000a8 Robinson C, Eisma R, Morgan B, Jeffery A, Graham EA, Black S, Rutty GN.\u000d\u000a      Anthropological measurement of lower limb and foot bones using\u000d\u000a      multi-detector computed tomography. J Forensic Sci. 2008;53(6):1289-95.\u000d\u000a    \u000a\u000a9 Adlam D, Joseph S, Robinson C, Rousseau C, Barber J, Biggs M, Morgan B,\u000d\u000a      Rutty G. Coronary optical coherence tomography: minimally invasive virtual\u000d\u000a      histology as part of targeted post-mortem computed tomography angiography.\u000d\u000a      Int J Leg Med 2013 [Epub]).\u000d\u000a    \u000aFunding:\u000d\u000a    Mass Fatality: Home Office £150,000 (2006) and European Commission\u000d\u000a      CBRN exercise grant €498,902 (2007).\u000d\u000a    Anthropology: Home Office £17,850 (2007). Awarded to investigate\u000d\u000a      the role of remote anthropology reporting of PMCT imaging for mass\u000d\u000a      fatality investigations.\u000d\u000a    Cardiac PMCTA: National Institute for Health Research £196,742\u000d\u000a      (2010). Awarded to investigate a novel system of targeted PMCTA.\u000d\u000a    Medico-legal PMCT: Home Office: £50,000 (2012). Awarded to\u000d\u000a      investigate role of PMCT in road traffic collisions, suspicious and\u000d\u000a      homicide deaths, and role of ventilated PMCT in criminal courts.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    A. National Clinical Director for Diagnostics, NHS England. 26 June 2013\u000d\u000a    B. Regional Senior Forensic Pathologist, Queensland Health Forensic and\u000d\u000a      Scientific Services, Australia. 5 July 2013\u000d\u000a    C. Report from the NHS Implementation Sub-Group of the Department of\u000d\u000a      Health Post Mortem, Forensic and Disaster Imaging Group (PMFDI). Can\u000d\u000a      Cross-Sectional Imaging as an Adjunct and\/or Alternative to the Invasive\u000d\u000a      Autopsy be implemented within the NHS? October 2012.\u000d\u000a    D. Associate Director- Molecular Imaging, Alliance Medical Group.\u000d\u000a    E. Home Office Guidelines `The safe handling of contaminated fatalities',\u000d\u000a      2009 (Restricted).\u000d\u000a    F. Article in Journal of Forensic Radiology and Imaging. Use\u000a        of Radiology in Disaster Victim identification: Positional statement of\u000d\u000a        the members of the Disaster Victim Identification working group of the\u000d\u000a        International Society of Forensic Radiology and Imaging. May 2013\u000d\u000a    G. Detective Superintendent, Forensic Services Department, Victoria\u000d\u000a      Police\u000d\u000a    H. Chief Constable, National Pathology and Disaster Victim,\u000d\u000a      Identification Lead, National Police Business Areas, England, Wales and N\u000d\u000a      Ireland. 20 June 2013\u000d\u000a    I. The Guardian: Virtual autopsy: does it spell the end of the scalpel?\u000d\u000a      23 Feb 2013\u000d\u000a      http:\/\/www.theguardian.com\/science\/2013\/feb\/23\/virtual-autopsy-virtopsy-forensic-science\u000d\u000a    J. Saad Foundation. 28 July 2013\u000d\u000a    ","Title":"\u000d\u000a    Post-mortem computer tomography (PMCT) as an alternative, or adjunct, to\u000d\u000a      invasive autopsy\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Background\u000d\u000a    Professor Guy Rutty (Chief Forensic Pathologist) and Professor Bruno\u000d\u000a      Morgan (Radiologist) lead this project with a multidisciplinary team\u000d\u000a      including forensic pathologists, an academic cardiologist (Dr David\u000d\u000a      Adlam), cardiac radiologists, the UK's first specific NHS forensic\u000d\u000a      radiographer, and outside collaboration with a forensic anthropologist and\u000d\u000a      odontologist (Professor Black, Dundee and Dr Adams, Wales).\u000d\u000a    In 2002 the team was the first to apply PMCT to UK adult forensic\u000d\u000a      practice (proposing the term `necroradiology' to indicate a new\u000d\u000a      subspecialty; 1). The team has developed, tested and validated\u000d\u000a      PMCT systems to enable them to work in the dead and improve diagnostic\u000d\u000a      accuracy. Their work is recognised internationally for both natural and\u000d\u000a      unnatural deaths -- including trauma, mass fatality and homicide\u000d\u000a      investigations — in relation to disaster planning, victim identification\u000d\u000a      and anthropology.\u000d\u000a    Research into use of PMCT in mass fatalities\u000d\u000a    The group was commissioned by the Home Office (see grants 2006) to\u000d\u000a      develop investigation of mass fatalities. They were the first to report\u000d\u000a      the use of mobile CT scanners in a temporary mortuary, showing this could\u000d\u000a      provide more, and faster, information than the multiple radiological\u000d\u000a      sources normally used (2). The team was instrumental in subsequent\u000d\u000a      national guidance documents.\u000d\u000a    With EC funding (see grants 2007), Rutty led the UK's largest\u000d\u000a      multi-agency, international supported contaminated mass fatality exercise\u000d\u000a      (Operation Torch), which was a simulation exercise involving cooperation\u000d\u000a      from ALL emergency services and a mobile CT radiology provider (3).\u000d\u000a    In 2009 the group proposed a system to the DOH to deal with scan data in\u000d\u000a      the event of a mass fatality — the forensic identification imaging system,\u000d\u000a      `FiMag'. This system ensures appropriate image reporting and secure data\u000d\u000a      transfer from scene to mortuary to ID completion, meeting the stringent\u000d\u000a      requirements of the criminal justice system (4).\u000d\u000a    The work on FiMag encouraged the Department of Health to form a new\u000d\u000a      advisory body for post-mortem imaging with Professors Rutty and Morgan\u000d\u000a      amongst the founding members. Subsequently, the advisory body has produced\u000d\u000a      a `Ministerial requested' national strategy and related guidance\u000d\u000a      documents.\u000d\u000a    Research into techniques to advance use of virtual imaging\u000d\u000a    Morgan and Rutty have developed a novel form of PMCT angiography\u000d\u000a      (targeted PMCTA) to assess the coronary arteries after death, a major\u000d\u000a      obstacle to replacing invasive autopsy with PMCT in natural sudden death (5,6).\u000d\u000a      Since 2008 the group has scanned over 500 corpses referred from HM Coroner\u000d\u000a      with autopsy control and consent from the next-of-kin, specifically\u000d\u000a      studying road traffic deaths and sudden death due to cardiac causes. Their\u000d\u000a      research suggests that PMCT angiography could reduce the number of HM\u000d\u000a      coroner requested autopsies in the UK by thousands per year (7).\u000d\u000a    The researchers introduced the concept of using PMCT for remote\u000d\u000a      anthropological assessment of bones. This avoids defleshing the bones,\u000d\u000a      essential for standard assessment (8). Developing from this,\u000d\u000a      further research has additionally shown high resolution `virtual\u000d\u000a      histology' imaging of the coronary arteries using optical coherence\u000d\u000a      tomography for the first time in a cadaver (9), and has also\u000d\u000a      developed ventilation during PMCT to examine the lungs.\u000d\u000a    "},{"CaseStudyId":"35239","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    There are 3 impacts from our new AFTER intervention research, namely:\u000a    (1) A new readily attainable measure of fear of recurrence.\u000a    (2) The delivery of training and implementation of the AFTER intervention\u000a      into clinical practice.\u000a    (3) Improvement in quality of patient care.\u000a    In the enhancement of the AFTER intervention, Humphris and Ozakinci\u000a      designed a new readily\u000a      attainable fear of recurrence measure developed at St Andrews in 2007. It\u000a      has good psychometric\u000a      qualities, is brief and is being used in a major case-control study (NIHR)\u000a      known as the H&N5000\u000a      study which Humphris acted as a consultant. Over 1000 cases have been\u000a      collected — the largest\u000a      cancer patient sample with this assessment.S6The identification\u000a      of high FoR patients is vital to\u000a      enable efficient referral for important support services of which AFTER is\u000a      the only dedicated\u000a      intervention currently available for targeting this major clinical issue.\u000a    A Clinical Service is provided by Humphris (Consultant Clinical\u000a      Psychologist) and Ozakinci\u000a      (Cognitive Behaviour Therapist) who use the AFTER intervention in the\u000a      internationally renowned\u000a      NHS Lothian Edinburgh Cancer Centre for out-patients referred by clinical\u000a      specialists. This case\u000a      series has been applied (2009 to present) so that approximately a sixth of\u000a      patients referred to the\u000a      service will benefit from the therapeutic elements contained in the AFTER\u000a      intervention. The\u000a      success of this application has prompted the Head of Psychological Service\u000a      at the Edinburgh\u000a      Cancer Centre to report: \"I have seen at first hand the benefit of\u000a        their innovative research on\u000a        AFTER with patients referred to my service.\" S1\u000a    The intervention has generated both recognition and invitations to run\u000a      training events for the North\u000a      of England Cancer Network. Training workshops were conducted on the AFTER\u000a      intervention with\u000a    UK Cancer Units:\u000a    \u000a      North East of England Regional Clinical Psychology Services (18th\u000a        Feb 2013)\u000a      North of England Cancer Network (18th Mar 2013) for cancer\u000a        service `roll-out' in North of\u000a        England.S7\u000a\u000a    \u000a    Approximately 25-30 delegates attended each one-day workshop, run by\u000a      Humphris, to: (i) translate\u000a      the research, (ii) explain the intervention manual, and (iii) enable\u000a      health professionals attending\u000a      (psychologists, counsellors and specialist cancer nurses) to deploy the\u000a      intervention. The Head of\u000a      Cumbria Psychological Services' Consultant Clinical Psychologist has\u000a      employed a staff member\u000a      (May 2013) specifically for AFTER intervention application has stated: \"We\u000a        are therefore able to\u000a        use this work of the Health Psychology team at the University of St\u000a        Andrews to deliver\u000a        improvements in Health care in routine practice\"S2Furthermore,\u000a      the Consultant Clinical\u000a    Psychologist from the Northern Centre for Cancer Care provides additional\u000a      support by saying: \"All\u000a        of us ... are aware what a significant issue Fear of Recurrence is for\u000a        our patients and their carers.\u000a        Your work provides a very useful framework for enabling practitioners to\u000a        address this with patients,\u000a        in order to facilitate enhanced coping and reduce psychological\u000a        distress\" S3\u000a    On the strength of these events, other European and International\u000a        Cancer Centres are adopting\u000a      the AFTER for use in the EU and North America for example:\u000a    \u000a      The Centre de Psycho-oncologie, Brussels, Belgium (6th May\u000a        2013) the only centre of its kind\u000a        in Belgium, invited Humphris to train their 15 psychologists and\u000a        specialist cancer nurses in the\u000a        practice of using AFTER. This attracted 30 delegates and was strongly\u000a        positively rated. The\u000a        Head of the Unit of Psychosomatic and Psycho-oncology Research states\u000a        that \"this\u000a          intervention will have an impact on the care of cancer patients and\u000a          reduce the distress many of\u000a          them experience during recovery from treatment\"S4\u000a\u000a      A similar event was held in McGill University, Montreal (5th\u000a        April 2013), Canada. Within\u000a        Quebec the internationally recognised Psycho-oncologist has stated\u000a        recently that: \" ...the\u000a          AFTER intervention has made a great contribution to our efforts to\u000a          attempt to assist cancer\u000a          patients with high levels of fear of recurrence\" S5\u000a\u000a      It has recently (2013) received independent support in a major\u000a        randomised controlled trial\u000a        conducted in the Netherlands.S6\u000a\u000a    \u000a    These training activities across key centres has attracted a 12 month\u000a      Innovation Grant Award in\u000a      April 2013 from NHS Fife R&D (£20k) to develop further implementation\u000a      of the AFTER intervention\u000a      into cancer services. The grant includes resources for training workshops,\u000a      and staff supervision to\u000a      build a targeted service for NHS patients. These workshops were run\u000a      locally (August-October\u000a      2013) and engaged multi-disciplinary staff. Currently, the intervention is\u000a      being applied routinely in\u000a      the breast cancer services under supervision from Humphris. License\u000a      preparation is in final stages\u000a      for health service users to receive downloadable copies of the AFTER\u000a      manual for a small\u000a      consideration to cover production costs and receive email supervision of\u000a      use of material with\u000a      oncology patients.\u000a    Finally, the Throat Cancer Foundation has endorsed the manual and\u000a      provides support for this\u000a      approach to be adopted in Cancer Units.\u000a    ","ImpactSummary":"\u000a    Fears of recurrence (FoR) are the major concern for cancer patients. The\u000a      Adjustment of Fear,\u000a      Threat or Expectation of a Recurrence (AFTER) was initiated in Liverpool\u000a      and developed\u000a      significantly at the University of St Andrews by the originator (Prof.\u000a      Humphris) and colleague Dr\u000a      Ozakinci for general cancer patients, including an innovative validated\u000a      Fear of Recurrence\u000a      measure. The measure identifies patients with high FoR in NHS oncology\u000a      services to enable\u000a      psychological therapeutic treatments to be targeted. AFTER is being widely\u000a      employed with cancer\u000a      survivors successfully in UK cancer services and international oncology\u000a      centres to reduce their\u000a      FoR and depression.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of St Andrews\u000a    ","Institutions":[{"AlternativeName":"St Andrews (University of)","InstitutionName":"University of St Andrews","PeerGroup":"B","Region":"Scotland","UKPRN":10007803}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"6115047","Name":"Québec"},{"GeoNamesId":"6077243","Name":"Montréal"},{"GeoNamesId":"2800867","Name":"Bruxelles-Capitale"}],"References":"\u000a    \u000a1. Rogers S, Scott B, Lowe D, Ozakinci G, Humphris G. Fear of recurrence\u000a      following head and\u000a      neck cancer in the out-patient clinic. European Archives of\u000a        Oto-Rhino-Laryngology and Head\u000a        and Neck 2010;267(12):1943-9. doi: 10.1007\/s00405-010-1307-y\u000a      (9 citations)\u000a    \u000a\u000a2. Simard S, Thewes B, Humphris G, Dixon M, Hayden C, Mireskandari S,\u000a      Ozakinci G. Fear of\u000a      cancer recurrence in adult cancer survivors: a systematic review of\u000a      quantitative studies. J\u000a        Cancer Surviv 2013. September doi: 10.1007\/s11764-013-0272-z\u000a      (2 citations)\u000a    \u000a\u000a3. Llewellyn CD, Weinman J, McGurk M, Humphris G. Can we predict which\u000a      head and neck cancer\u000a      survivors develop fears of recurrence? J Psychosom Res\u000a      2008;65(6):525-32. doi:\u000a      10.1016\/j.jpsychores.2008.03.014\u000a      (33 citations)\u000a    \u000a\u000a4. Humphris G, Ozakinci G. The AFTER intervention: A structured\u000a      psychological approach to\u000a      reduce fears of recurrence in patients with head and neck cancer. British\u000a        Journal of Health\u000a        Psychology 2008;13:223-30. doi: 10.1348\/135910708X283751\u000a      (28 citations)\u000a    \u000a\u000a5. Hodges LJ, Humphris GM. Fear of recurrence and psychological distress\u000a      in head and neck\u000a      cancer patients and their carers. Psycho-Oncology\u000a      2009;18(8):841-48. doi: 10.1002\/pon.1346.\u000a      (27 citations).\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"17","Level2":"1","Subject":"Psychology"}],"Sources":"\u000a    S1 Letter of endorsement of AFTER intervention: Consultant Clinical\u000a      Psychologist, Head of\u000a      Service for Physical Health and Neuropsychology, Honorary Senior Research\u000a      Fellow at Coventry\u000a      University, Chair for Division of Clinical Psychology in Scotland\u000a    S2 Letter of endorsement from NHS Cumbria, where it is used as part of\u000a      their job roles.\u000a    S3 Letter of endorsement from Northern Centre for Cancer Care, stressing\u000a      the importance of the\u000a      intervention with cancer survivors.\u000a    S4 Letter of thanks and endorsement from Head of the Unit of\u000a      Psychosomatic and Psycho-\u000a      oncology Research, The Centre de Psycho-oncologie, Brussels, Belgium,\u000a      corroborates the\u000a      importance of the intervention as used in Brussels.\u000a    S5 Letter of endorsement from McGill University, Montreal, Quebec,\u000a      corroborates the use of the\u000a      intervention as part of their services in Quebec.\u000a    S6.van der Meulen IC, May AM, Ros WJG, Oosterom M, Hordijk G-J, Koole R,\u000a      de Leeuw RJ.One-\u000a      year effect of a nurse-led psychosocial intervention on depressive\u000a      symptoms in patients with Head\u000a      and Neck Cancer: A randomized controlled trial. The Oncologist 2013\u000a      September vol. 18 no. 3\u000a      336-344. doi: 10.1634\/theoncologist.2012-0299.\u000a    S7 Head & Neck 5000 Protocol V2.8. 28th April 2010.pdf see\u000a      Page 19, You and Cancer section for\u000a      the 4 questions (one half page) psychometrically validated and designed.\u000a    S8 http:\/\/www.necn.nhs.uk\/group\/psychology-group\/\u000a      link to notice of workshop run by Prof\u000a      Humphris on AFTER and Fears of Cancer Recurrence (see Minutes 18th\u000a      April 2013 page 4 Item 8;\u000a      workshop presentation 18th March 2013 EVOLVE NECN.\u000a    \u000a    ","Title":"\u000a    Development and implementation of a new psychological intervention\u000a        for cancer patients to alleviate heightened fears of recurrence\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Fear of recurrence is a major concern for many cancer patients1,\u000a      as highlighted in a major review2\u000a      conducted by Prof. G. Humphris (University of St Andrews since 2003) and\u000a      Dr G. Ozakinci\u000a      (Lecturer, University of St Andrews since 2004) with others, reported in\u000a      2013. Cancer survival has\u000a      improved, to the extent that many health commentators now regard it as a\u000a      chronic disease. This\u000a      has strengthened the field of cancer survivorship to the extent that\u000a      services are being developed to\u000a      serve patient concerns more closely. We have shown that recurrence fears\u000a      are related to\u000a      psychological variables not clinical factors such as the severity of the\u000a      treated disease3.\u000a    Over a third of patients find the prospect of a recurrence troubling and\u000a      anxiety provoking to the\u000a      extent that longer-term rumination of this concern results in mood change\u000a      and depressive\u000a      symptomology. The effects are insidious and can feature many years after\u000a      active treatment2.\u000a      Patients respond to high fear of recurrence by demanding multiple health\u000a      checks and avoiding\u000a      making future plans. The AFTER intervention creates a completely new\u000a      approach based upon a\u000a      cognitive behavioural theory developed by Howard Leventhal. The theory\u000a      predicts that patients\u000a      regard every unusual physical sensation as a signal for cancer return4.\u000a      The novel feature of\u000a      AFTER adopted in 2008 is that it makes this process explicit and\u000a      encourages patients to reflect on\u000a      other possibilities and how characteristic behaviours can be modified and\u000a      communicated to close\u000a      family members5 and the clinical team. Other inaccuracies in\u000a      thinking are elucidated in a personal\u000a      approach to planning incremental changes. Fears are exposed, discussed and\u000a      managed using\u000a      therapeutic techniques that are built upon clinical skills of rapport\u000a      building, reinforcement, sharing\u000a      of concerns within a family context and explicitly engaged to change\u000a      behaviour and management\u000a      of anxiety and potential mood change. This work was published in leading\u000a      international journal and\u000a      highly cited.\u000a    Following his move to the University of St Andrews in 2003, Humphris with\u000a      Ozakinci from a\u000a      SUPAC NCRI grant (2007-08; £80k) developed a new AFTER intervention built\u000a      upon the original to\u000a      include detailed supervisory notes, aide memoires for specialist staff in\u000a      the `field' (i.e. clinics) with\u000a      source materials referenced to explicate therapeutic procedures. AFTER\u000a      consists of 6 structured\u000a      sessions conforming to a close fidelity assessment to ensure that all\u000a      elements of the intervention\u000a      are delivered as intended, so that patients gain the maximum benefit. New\u000a      materials were\u000a      developed (2010) to train experienced clinical members with psychological\u000a      expertise (counsellors,\u000a      cognitive behaviour therapists and clinical psychologists).\u000a    We have shown (2008) that the intervention can be employed with a wider\u000a      spectrum of cancer\u000a      patients with disease located in areas in addition to head and neck,\u000a      including breast and colorectal\u000a      cancer. This study used the AFTER intervention embedded within nurse-led\u000a      services. Humphris\u000a      was consultant to this project (design and staff training stages) from St\u000a      Andrews. Improvements in\u000a      depressive symptomology were significantly identified in cancer patients\u000a      (n=200) at the one year\u000a      assessment.\u000a    "},{"CaseStudyId":"35240","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"149590","Name":"Tanzania"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"2750405","Name":"Netherlands"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Impact on commercial partnerships development\u000a    The research described is of value to the commercial companies, public\/\u000a      private partnerships that are developing novel regimens and trial designs\u000a      for TB drug development by speeding development and reducing its cost.\u000a      Tuberculosis trials are hugely expensive (> $50 million) due to the\u000a      large number of patients that must be recruited. They are slow because of\u000a      the time taken to grow the organism in the laboratories supporting the\u000a      trial. The assays that we have developed directly address this as they\u000a      take just a few hours in comparison to 42 days of conventional methods1.\u000a      Justin Green of GSK states \"Of real importance, it reduces the time\u000a        taken to obtain a positive culture from approximately 42 days to just a\u000a        few hours\" [1]. This means that go-no-go decisions in our adaptive\u000a      trials paradigm can be made in real time2. By quantifying the\u000a      number of viable organisms there is the potential to reduce the sample\u000a      size of the trial (http:\/\/c-path.org\/CPTR.cfm).\u000a    In particular, developing an understanding of the role of bacterial load\u000a      and the relationship between load and cavities has had a major influence\u000a      on commercial and academic researchers performing and developing clinical\u000a      trials for tuberculosis (example GATB\u000a        Consultants meeting) [3]. The MBL assay has now been incorporated\u000a      into the industry- academic development project funded to develop\u000a      model-based systems to shorten TB drug development by the Innovative\u000a        Medicines Initiative in collaboration with GSK, Janssen and Sanofi\u000a      Aventis [4]. The value of this technique to determine treatment response\u000a      has been identified in an authoritative review that gives it the highest\u000a      level of certainty to this statement [5].\u000a    Current impact on drug development and trials\u000a    The MBL Assay has been taken up rapidly and is being applied to the\u000a      design of current trials by international researchers in the PanACEA\u000a      consortium's MAMS phase IIb study of four novel regimens started in March\u000a      2013 in South Africa and Tanzania that is recruiting up to 400 patients\u000a      [2]. From March 2012, its utility is being evaluated in comparison with\u000a      other commercial assays and a novel assay in development is being funded\u000a      by a grant from the European Developing Country Clinical trials\u000a      partnership [4] in collaboration with Pharma company Sequella Incorporated\u000a      who are providing co-funding, bringing the total funding €1.7m.\u000a    Impact of pre and early phase clinical trials\u000a    The St Andrews research is being developed and applied as part of our\u000a      partnership with the pharmaceutical industry and is being taken up by our\u000a      research collaborators who have been awarded funding via the Innovative\u000a      Medicines Initiative [4]. Justin Green from the GSK states \"this novel\u000a        assay that detects live mycobacteria is felt to be an important new tool\u000a        for commercial drug developers like GSK\" [1].\u000a    The CSO of Helperby Therapeutics, a pharmaceutical SME note \"The work\u000a        of Professor Stephen Gillespie is having considerable impact on the\u000a        field of tuberculosis. For example, his new assay (MBL) for the\u000a        measurement of the total quantity of Mycobacterium tuberculosis\u000a        in sputum and other tissues is highly significant. This is because it is\u000a        becoming clear that conventional culture and microscopy techniques\u000a        underestimate the bacterial load. Using the Gillespie assay, it is now\u000a        possible to objectively detect and quantify all the different\u000a        subpopulations of M. tuberculosis including those that are\u000a        missed by conventional methods. The combination of MBL and modelling is\u000a        transforming the speed of pre-clinical studies by short circuiting the\u000a        need for culture and supporting the development of new models. It is\u000a        possible that one day, the Gillespie technique or one which is based\u000a        upon it, will replace all conventional methods of detection of M.\u000a      tuberculosis.\" [2]\u000a    Pre-clinical model development\u000a    The mathematical model has been used to demonstrate the value of a new\u000a      more human-like mouse model of tuberculosis treatment and this allows the\u000a      evaluation of novel drugs more rapidly shortening the duration of the\u000a      pre-clinical pathway [2]. This model has also been used to test a new\u000a      mouse treatment model that mimics human disease more closely in an\u000a      industry academic research partnership. The modified MBL assay for M.\u000a        marinum is being used by an SME, ZF-screens (Holland), in the rapid\u000a      evaluation of tuberculosis drugs in Zebra fish reducing the costs and\u000a      allowing drugs to be evaluated more rapidly.\u000a    As GSK state \"the Mycobacterial Load [assay] is one of the early\u000a        success....could now be applied not only to human studies, but also\u000a        cutting edge animal models.\" [1]\u000a    By reducing costs and timelines in clinical and pre-clinical tuberculosis\u000a      drug development research in this way patients benefit with the prospect\u000a      of new medicines for tuberculosis coming closer.\u000a    ","ImpactSummary":"\u000a    There are 10 million new infections and one million deaths from\u000a      tuberculosis annually and there is an increase in resistant diseases. Yet\u000a      there have been no new anti-tuberculosis agents developed for forty years.\u000a      TB drug development is expensive because of the time taken for the\u000a      organism to grow and because trials are expensive and the sample size is\u000a      high. The biomarker and mathematical methods developed at St Andrews\u000a      address these problems by making preclinical development faster and\u000a      cheaper and is being used by three commercial companies and eight drug\u000a      development groups. These methodologies shorten the time taken to complete\u000a      trials and reduce cost.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of St Andrews\u000a    ","Institutions":[{"AlternativeName":"St Andrews (University of)","InstitutionName":"University of St Andrews","PeerGroup":"B","Region":"Scotland","UKPRN":10007803}],"Panel":"A         ","PlaceName":[],"References":"\u000a    The underpinning research for this case study has been published in the\u000a      leading clinical microbiological, infectious diseases and clinical\u000a      tuberculosis journals. The quality of the work is exemplified by its use\u000a      to support the award of a €1.2m to Innovative Medicines Initiative grant (PreDiCT-TB) and a €1.7m grant from\u000a      the European Developing Country Clinical Trials Partnership (PANBIOME)\u000a      to the St Andrews research group.\u000a    \u000a1. Honeyborne I, McHugh TD, Phillips PPJ, et al. Molecular\u000a      Bacterial Load Assay, a Culture-Free Biomarker for Rapid and Accurate\u000a      Quantification of Sputum Mycobacterium tuberculosis Bacillary Load during\u000a      Treatment. J Clin Microbiol 2011; 49: 3905-11. doi: 10.1128\/JCM.00547-11\u000a    \u000a\u000a2. Phillips PPJ, Gillespie SH, Boeree M, et al. Innovative Trial\u000a      Designs Are Practical Solutions for Improving the Treatment of\u000a      Tuberculosis. J Infect Dis 2012; 205: S250-7. doi: 10.1093\/infdis\/jis041\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"10","Level2":"4","Subject":"Medical Biotechnology"}],"Sources":"\u000a    [1] Letter GSK, Director Clinical Development Late Stage Corroborating\u000a      the importance of the tool for commercial drug developers.\u000a    [2] Letter from The Chief Scientific Officer and Director Helperby\u000a      Therapeutics Corroborating the impact on commercial drug developers of\u000a      this technique in terms speed and accuracy.\u000a    [3] GATB Web-site: www.tballiance.org\/newscenter\/view-brief.php?id=1026\u000a      corroborating the importance of bacterial load measurement in reducing\u000a      sample size of clinical trials\u000a    [4] http:\/\/www.edctp.org\/Newly_signed_grants.500.0.html\u000a      Confirming the award to University of St Andrews\u000a    [5] Wallis et al., Tuberculosis biomarkers discovery: developments needs\u000a      and challenges Lancet Infectious Diseases 2013; 13:363-372\u000a      doi: 10.1016\/S1473-3099(13)70034-3\u000a      an authoritative review that confirms that our assay measures viable count\u000a      accurately.\u000a    ","Title":"\u000a    Improving tuberculosis treatment and trials using a novel biomarker\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The research conducted by Professor Stephen Gillespie, a researcher at\u000a      University of St Andrews since 2010, has shown that, in human\u000a      tuberculosis, bacterial load can be used as a critical determinant of\u000a      treatment outcome1. This breaks a crucial logjam in thinking\u000a      about the design of clinical trials. A key part of such research is being\u000a      able to plan future trials, yet monitoring clinical trials in real time is\u000a      extremely difficult, prone to error, costly and slow. Current measures\u000a      depend on culture of the bacteria, taking a minimum of three months, and a\u000a      significant component of the bacteria present will not grow although they\u000a      are viable and can cause disease. This reduces the speed of drug\u000a      development and adds to the noise in pre-clinical and clinical studies. In\u000a      2010 we developed a simple biomarker of cell viability for M.\u000a        tuberculosis (Molecular bacterial load assay MBLA) based on the\u000a      16SrRNA gene together with a new RNA extraction control to reduce assay\u000a      variability through Prof. Gillespie's MRC grant (Rapid Evaluation of\u000a      Biomarkers for TB grant)1. As it uses a single assay in\u000a      comparison to competing systems that use a multiplicity of immune response\u000a      measures it is simple to apply in high burden countries. The choice of\u000a      this target increases the sensitivity of measurement, allows viable but\u000a      non-culturable organisms to be detected, and is not confounded by the\u000a      presence of typical mycobacterial cords that reduce accuracy. Importantly,\u000a      the test takes four hours, potentially reducing the time to a read-out by\u000a      98%.\u000a    The data derived from this assay are evaluated using a basic model Prof.\u000a      Gillespie described to follow treatment and in 2012 this was developed\u000a      into an unique semi-mechanistic model of tuberculosis treatment that uses\u000a      markers of bacterial load to predict the outcomes of different regimens.\u000a      This provides a method to input data from pre-clinical and early phase\u000a      clinical studies to predict the outcome of future trials, allowing\u000a      pharmaceutical companies or public private partnerships to make go-no-go\u000a      decisions. The facility that this provides has allowed the development of\u000a      an effective Multi-arm, Multi-stage TB trial2. In the\u000a      pre-clinical sphere, time taken to measure the number of viable bacilli\u000a      adds considerably to the length of studies to evaluate novel agents. This\u000a      technique reduces this process from weeks to minutes.\u000a    Thus, the MBL assay has now been developed to be able to specifically\u000a      detect non-tuberculosis mycobacteria such as M. smegmatis and M.\u000a        marinum that are used in pre-clinical phases. This permits\u000a      pre-clinical experiments to be conducted more rapidly and the results to\u000a      be available in four hours compared with a minimum of four days presently.\u000a      This approach has been taken up rapidly by the PreDiCT-TB consortium (an\u000a      academic industry consortium of 22 members).\u000a    "},{"CaseStudyId":"35241","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"597427","Name":"Lithuania"},{"GeoNamesId":"3489940","Name":"Jamaica"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    During the period 2008-12 the group has placed particular emphasis on\u000d\u000a      achieving societal impact employing an experienced homicide detective to\u000d\u000a      assist. The beneficial impact of our gang violence reduction work on local\u000d\u000a      communities has received widespread media coverage. M1, M2\u000d\u000a      Police and Local authority leadership are clear about the importance of\u000d\u000a      our contribution. Since the start of our 2008 evaluation and the\u000d\u000a      publication of our 2011 results we have changed Police and Social Work,\u000d\u000a      attitudes, policy and tactics. We have substantially altered what these\u000d\u000a      professional groups think is possible in dealing with violent young men.\u000d\u000a      For example an, Assistant Chief Constable at the Scottish Police Service\u000d\u000a      explains how we have helped the police see that violence is not inevitable\u000d\u000a      but can be prevented S1\u000d\u000a    \"Working with police colleagues, Professor Donnelly and his team\u000d\u000a          have revolutionised expectations as to what is possible. The team have\u000d\u000a          recast violence not just as a Public Health issue but one that\u000d\u000a          actually can in many instances be prevented. The results of the CIRV\u000d\u000a          Programme were praised by the Prime Minister in Parliament and the\u000d\u000a          subject of a visit by the Home Secretary in the wake of the London\u000d\u000a          riots. Police Forces elsewhere have been encouraged to learn from\u000d\u000a          Glasgow's experiences with its record fall in offending.\"\u000d\u000a    Our work has changed the way social workers practice and how they are\u000d\u000a      managed such that they now focus on what these young men can contribute to\u000d\u000a      society rather than what trouble they may have caused in the past as the\u000d\u000a      Head of Social Work Services in North East Glasgow explains.S2\u000d\u000a    \"I have used Professor Donnelly's research to inform the practice\u000d\u000a          of Social Workers and managers across the service I manage.......(His)\u000d\u000a          work helps to demonstrate what can be achieved in terms of true\u000d\u000a          collaborative working in this area, when individuals, communities and\u000d\u000a          professionals focus on positive reinforcement as opposed to deficit\u000d\u000a          models of working with young people involved in gang violence. The\u000d\u000a          value of the work undertaken by Professor Donnelly and his team cannot\u000d\u000a          be overstated.\"\u000d\u000a    The fundamental impact of this work since late 2008\/ early 2009 has been\u000d\u000a      that lives are saved and injury caused by violent crime is reduced. The\u000d\u000a      head of community safety for the Scottish Government is very clear that we\u000d\u000a      are beneficially impacting on violent crime rates S3\u000d\u000a    \"I have had very direct experience of the work done by Professor\u000d\u000a          Peter Donnelly and his group at the University of St Andrews on\u000d\u000a          violence reduction over the past few years. As policy lead for\u000d\u000a          violence reduction for the Scottish Government, I am happy to confirm\u000d\u000a          that this important work has had a direct impact on our policy and\u000d\u000a          practice in the area of violence reduction, which has helped\u000d\u000a          contribute to a 38 year low in recorded violent crime.\"\u000d\u000a    The impact has been developed internationally. This is particularly true\u000d\u000a      in the Western Cape Province of South Africa who following visits from us\u000d\u000a      2009-11 now have a cross Government violence reduction strategy for the\u000d\u000a      very first time. A violence reduction expert at the University of Cape\u000d\u000a      Town writes S4\u000d\u000a    \".......with regard to the impact of Prof. Donnelly's work in the\u000d\u000a          field of violence reduction. There is no question that he and his\u000d\u000a          research group at the University of St Andrews are having impact\u000d\u000a          internationally. It is a measure of the impact of his work and that of\u000d\u000a          his team, and the respect they have earned internationally, that he is\u000d\u000a          often asked to take senior leadership roles in meetings of the\u000d\u000a          Violence Prevention Alliance.\"\u000d\u000a    In addition Donnelly was one of two subject experts invited to address a\u000d\u000a      closed-door meeting of senior Republican and Democratic politicians on the\u000d\u000a      issue of firearms and injury in San Diego in August 2013. He has been\u000d\u000a      selected to design and lead a special Board highlighted 90-minute session\u000d\u000a      on the Sandy Hook School shootings at the 2013 American Public Health\u000d\u000a      Association meeting (typical attendance 13,000) involving key individuals\u000d\u000a      present on the day of the shootings and relevant gun control experts.\u000d\u000a      These are both highly unusual honours for a non-US citizen. Much more\u000d\u000a      importantly they seek to use research to reduce violent deaths. Working\u000d\u000a      closely with the World Health Organisation (2008-13) we are helping other\u000d\u000a      nations realise that violence reduction is possible and are helping them\u000d\u000a      develop strategies and interventions. A WHO official speaks to this impact\u000d\u000a      S5\u000d\u000a    \"Through his regular and important contribution to the VPA steering\u000d\u000a          committee, to VPA Project Groups (such as the project group on\u000d\u000a          preventing violence in weak institutional settings), and to the annual\u000d\u000a          VPA meetings and Milestones in a Global Campaign for Violence\u000d\u000a          Prevention meetings (many of which he has chaired), Professor Donnelly\u000d\u000a          has had a very significant influence over the shaping of international\u000d\u000a          violence prevention policy.\"\u000d\u000a    Our leadership in this area of work resulted in a commission from Oxford\u000d\u000a      University Press to edit a book of international violence research\u000d\u000a      contributions and this nears completion.\u000d\u000a    The most important impact is the effect on young men most at risk of\u000d\u000a      drifting into a life of violence. We dramatically change their life\u000d\u000a      trajectories and consequently the impact they have on others and on\u000d\u000a      society. The quotation below from a young man involved in the project\u000d\u000a      illustrates this (Edited version taken from the CIRV final report,\u000d\u000a      reference 2 in section 3 of this document).\u000d\u000a    \"When I got to 14, I started carrying knives and it became a bit\u000d\u000a          more serious because I wasn't stood at the back watching any more. I\u000d\u000a          was at the front, looking to do damage and not caring. By the age of\u000d\u000a          15, I was involved in selling drugs and was taking cocaine, Valium and\u000d\u000a          Ecstasy. My parents had serious addiction problems and they found it\u000d\u000a          difficult to provide for me and my young brother. Your gang becomes\u000d\u000a          your family. At 15 I was expelled from school for violence against a\u000d\u000a          teacher. It was at that point I got involved with guns.\"\u000d\u000a    \"By 17 I was in prison for a firearms charge. I did three and a\u000d\u000a          half years. When I got out I got involved with their football coaching\u000d\u000a          programme. From there, I heard about the CIRV East End Football League\u000d\u000a          and got together a group of local boys to enter a team. Through being\u000d\u000a          involved with the football, I found out more about CIRV, got involved\u000d\u000a          with them and started giving workshops to help others break away from\u000d\u000a          gangs. I'm now a Peer Advocate, working with gangs on a daily basis.\"\u000d\u000a    \"It takes a lot of courage to change. You're throwing away\u000d\u000a          everything you've ever stood for, and it's hard to leave your pals and\u000d\u000a          say I don't want a part of that. But I'm glad I did. The future's\u000d\u000a          looking pretty bright now. I'm training an amateur football side, I've\u000d\u000a          got a baby and I don't touch drugs. If I hadn't changed, I'd probably\u000d\u000a          be dead, or serving a long prison sentence. I know I wouldn't be\u000d\u000a          anywhere I would want to be. If I can do it so can these guys. Working\u000d\u000a          with them is a better buzz than any drug.\"\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Our evaluation of gang member rehabilitation and violence reduction\u000d\u000a      programme in Glasgow has had considerable and enduring policy impact.\u000d\u000a      Scottish Government policy is built on the principals our research\u000d\u000a      espouses. Homicide rates in Scotland are now at a thirty-year low. The\u000d\u000a      Prime Minister and national newspapers cited the initiative as a solution\u000d\u000a      after the London riots and the UK Government incorporated the ethos of\u000d\u000a      this program into their policy and practice. Working jointly with the WHO,\u000d\u000a      we are having impact in South Africa, Jamaica and Lithuania. For example,\u000d\u000a      the Western Cape Province of South Africa has, following our involvement\u000d\u000a      and for the first time, initiated a violence reduction strategy. The most\u000d\u000a      important impact of our work, however, is the change it creates in young\u000d\u000a      people's lives, transforming their prospects from those of a lifetime of\u000d\u000a      intermittent imprisonment to one of useful and meaningful societal\u000d\u000a      involvement and contribution.\u000d\u000a    ","ImpactType":"Societal","Institution":"\u000d\u000a    University of St Andrews\u000d\u000a    ","Institutions":[{"AlternativeName":"St Andrews (University of)","InstitutionName":"University of St Andrews","PeerGroup":"B","Region":"Scotland","UKPRN":10007803}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"5391811","Name":"San Diego"},{"GeoNamesId":"1085599","Name":"Province of the Western Cape"},{"GeoNamesId":"2640729","Name":"Oxford"}],"References":"\u000d\u000a    \u000a1. Donnelly, P. D., Tomes, J., An unusual day in court BMJ\u000d\u000a      2008; 337:a2959. DOI. 10.1136\/bmj.a2959\u000d\u000a      Graphically describes the gang member self referral session which\u000d\u000a        started the CIRV gang member rehabilitation process. Published in a\u000d\u000a        leading international medical journal.\u000d\u000a    \u000a\u000a2. VRU. A public health approach to the evaluation of the\u000d\u000a        Glasgow Community Initiative to Reduce Violence in Glasgow's\u000d\u000a      Community Initiative to Reduce Violence in Second year report. Violence\u000d\u000a      Reduction Unit, Glasgow 2011. Reports publically for the first time\u000d\u000a        research done by our group showing a significant fall in violent\u000d\u000a        offending and knife carrying; a finding of considerable international\u000d\u000a        significance which rapidly led to changes in police and social work\u000d\u000a        practice.\u000d\u000a      http:\/\/www.actiononviolence.com\/content\/cirv-second-year-report\u000d\u000a    \u000a\u000a3. Harvey, M., Williams, D. J., & Donnelly, P. D. Testing a\u000d\u000a      method to develop preliminary cost estimates of homicide in Glasgow: A\u000d\u000a      research note. Criminal Justice Policy Review, 2012 DOI:\u000d\u000a      10.1177\/0887403412448819. Emphasises the cost of not running a\u000d\u000a        violence reduction program by calculating the cost of investigating a\u000d\u000a        homicide. Helps make the economic case for violence reduction work in a\u000d\u000a        well regarded and appropriate international specialist journal.\u000d\u000a      http:\/\/cjp.sagepub.com\/content\/early\/2012\/06\/19\/0887403412448819\u000d\u000a    \u000a\u000a4. Gordon, V., Williams, D. J., & Donnelly, P. D. Exploring\u000d\u000a      the relationship between ADHD symptoms and prison breaches of discipline\u000d\u000a      amongst youths in four Scottish prisons. Public Health, 2012 126(4),\u000d\u000a      343-348. DOI: 10.1016\/j.puhe.2012.01.004\u000d\u000a      Demonstrates the excess prevalence of ADHD symptomatology in youth\u000d\u000a        offenders and links to breaches in prison discipline; a finding of\u000d\u000a        practical significance to justice authorities. Published in a leading\u000d\u000a        specialist journal.\u000d\u000a    \u000a\u000a5. Coid, J.W., Ullrich, S,, Keers, R., Bebbington, P., DeStavola,\u000d\u000a      B., Kallis, C., Yang, M., Reiss, D., Jenkins, R., Donnelly, P. Gang\u000d\u000a      membership, violence, and psychiatric morbidity. American Journal of\u000d\u000a        Psychiatry 2013 DOI: 10.1176\/appi.ajp.2013.12091188\u000d\u000a      Demonstrates high levels of psychiatric morbidity amongst gang members\u000d\u000a        with traumatisation and fear of further violence particularly prominent.\u000d\u000a        Published in the leading international psychiatry journal with\u000d\u000a        accompanying editorial. The first article on this subject ever published\u000d\u000a        by the journal in its 169 year history.\u000d\u000a    \u000a\u000a6. Williams, D.J., Neville, F., House, K. and Donnelly, P. D.\u000d\u000a      Association between old firm football matches and reported domestic\u000d\u000a      (violence) incidents in Strathclyde, Scotland. Sage Open 2013 3:\u000d\u000a      DOI: 10.1177\/2158244013504207\u000d\u000a      Shows for the first time this suspected link and thus helps inform\u000d\u000a        police and health service expectations and operational tactics in the\u000d\u000a        period around such games. Published in a quality open access peer\u000d\u000a        reviewed journal. Generated huge media interest.\u000d\u000a    \u000a\u000a7. Neville, F. G., Williams, D. J., Murer, J. S., Donnelly,\u000d\u000a      P. D., Goodall, C. An Experimental Trial Exploring the Impact of\u000d\u000a      Continuous Transdermal Alcohol Monitoring upon Alcohol Consumption in a\u000d\u000a      Cohort of Male Students 2013 PLoS One. 2013; 8: e67386. DOI:\u000d\u000a      10.1371\/journal.pone.0067386\u000d\u000a      http:\/\/www.plosone.org\/article\/info%3Adoi%2F10.1371%2Fjournal.pone.0067386\u000d\u000a    \u000aProves that continuous transdermal alcohol monitoring has a beneficial\u000d\u000a        effect on assisting sobriety and provides suggestions as to why that\u000d\u000a        might be. This was an important prelude to our ongoing prisoner\u000d\u000a        discharge randomised control trial of this technology. Published in\u000d\u000a      a high impact peer reviewed open access journal\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"16","Level2":"7","Subject":"Social Work"}],"Sources":"\u000d\u000a    Letters of support (S1 to S5)\u000d\u000a    S1. Assistant Chief Constable, Scottish Police Service\u000d\u000a      Corroborates change in police policy and tactics and fall in violent crime\u000d\u000a      rates.\u000d\u000a    S2. Head of Social Work Services in North East Glasgow\u000d\u000a      Corroborates change in social work training and practice.\u000d\u000a    S3. Head of Community Safety for the Scottish Government\u000d\u000a      Corroborates impact on policy formulation and fall in violent crime rates.\u000d\u000a    S4. Associate Professor at the University of Cape Town\u000d\u000a      Corroborates international impact with the Western Cape Province of South\u000d\u000a      Africa as an example.\u000d\u000a    S5. Technical Officer, World Health Organisation\u000d\u000a      Corroborates international policy leadership with the World Health\u000d\u000a      Organisation.\u000d\u000a    Example media coverage (M1 and M2)\u000d\u000a    M1. Guardian http:\/\/www.guardian.co.uk\/uk\/2011\/aug\/11\/glasgow-gangs-peace-crackdown,\u000d\u000a      Corroborates beneficial impact on communities of our gang reduction work.\u000d\u000a    M2. BBC http:\/\/www.bbc.co.uk\/news\/uk-scotland-19915113\u000d\u000a      Corroborates endorsement of Scotland's new Police Chief Constable for our\u000d\u000a      approach.\u000d\u000a    ","Title":"\u000d\u000a    Reducing violence to improve health; in the UK and Internationally\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The Public Health and Health Policy group at St Andrews University was\u000d\u000a      established in 2008 and has become a leading centre in Violence Reduction\u000d\u000a      Research. The group who all still work at St Andrews joined and are graded\u000d\u000a      as follows; Donnelly, 2008 Professor, Williams 2009 Research fellow\u000d\u000a      becoming lecturer 2013, Gehring PhD student 2009 becoming Research fellow\u000d\u000a      2013, Neville Research fellow 2011. Our work includes evaluations of\u000d\u000a      interventions and the study of factors that facilitate or prevent the\u000d\u000a      adoption of effective violence prevention policies in the UK and\u000d\u000a      internationally. The team started evaluating a gang member rehabilitation\u000d\u000a      and violence reduction initiative (the Community Initiative to Reduce\u000d\u000a      Violence) (CIRV) in Glasgow in 2008. The initial dramatic self-referral\u000d\u000a      session was described in the British Medical Journal1.\u000d\u000a    \u000d\u000a    \u000d\u000a    \u000d\u000a    Our 2009 project funded by the Wellcome Trust explored motivations for\u000d\u000a      positive change among gang members. Gaining work experience and obtaining\u000d\u000a      and holding on to employment were identified as being particularly\u000d\u000a      important. The group then moved on to a detailed quantitative evaluation,\u000d\u000a      using an innovative quasi experimental design, which demonstrated a fall\u000d\u000a      of nearly 50% in violent acts and a fall of 85% in knife carriage amongst\u000d\u000a      those engaged in the programme.2, Williams and Donnelly\u000d\u000a      won the inaugural Elizabeth Russell Prize of the Faculty of Public Health\u000d\u000a      for this work. The 2009\/10 development of a methodology to cost a homicide\u000d\u000a      investigation emphasised that violence prevention is not only a moral\u000d\u000a      imperative but also sound economics.3 Throughout 2009\/11\u000d\u000a      the group set about understanding factors that may underlie or precipitate\u000d\u000a      violence. They were able to show that young prisoners in Scotland have an\u000d\u000a      excess of symptoms related to ADHD and also that the presence of these\u000d\u000a      symptoms are predictive of violent breaches of prison discipline 4.\u000d\u000a      Cooperating with other centres Donnelly co-authored a paper that shows\u000d\u000a      very high rates of psychiatry morbidity in gang members 5.\u000d\u000a      A 2011\/12 project in cooperation with Strathclyde Police explored the\u000d\u000a      relationship between Old Firm (Rangers vs Celtic) football matches and\u000d\u000a      rates of domestic violence, demonstrating an excess of domestic violence\u000d\u000a      calls in the 24hrs following match kick off time. 6 The\u000d\u000a      relationship between football and violence is almost certainly mediated by\u000d\u000a      alcohol and alcohol plays an important part in many violent acts in\u000d\u000a      Scotland. The group therefore in 2011\/12 piloted innovative trans-dermal\u000d\u000a      alcohol monitoring technology, which allows continual sobriety monitoring,\u000d\u000a      as a possible means to reduce levels of alcohol-related violent\u000d\u000a      reoffending. A mixed methods pilot project demonstrated the benefits of\u000d\u000a      such an approach 7 and this work informed a further pilot in\u000d\u000a      Barlinnie prison. An international project 2009-13 funded by the Scottish\u000d\u000a      Government (£250,000) undertaken in conjunction with the World Health\u000d\u000a      Organisation (2008-2013) looked at the way in which violence reduction\u000d\u000a      policy is developed and implemented in Jamaica, the Western Cape Province\u000d\u000a      of South Africa and Lithuania. Important lessons were learned about the\u000d\u000a      historical context of policy making.\u000d\u000a    "},{"CaseStudyId":"35387","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Glaucoma affects 70 million people worldwide, of whom seven million are\u000d\u000a      blind. It is the\u000d\u000a      commonest cause of irreversible blindness in the world, and the commonest\u000d\u000a      neuropathy in the\u000d\u000a      world. There are no well-established figures for the number of glaucoma\u000d\u000a      surgeries which are\u000d\u000a      carried out globally. However, based on relatively conservative figures it\u000d\u000a      is likely that more than 2%\u000d\u000a      of glaucoma sufferers will require surgery during their lifetime — that is\u000d\u000a      around 1.4m individuals.\u000d\u000a      Our work has improved treatments — both pharmacological and surgical — for\u000d\u000a      these patients,\u000d\u000a      enabling the surgery to be used more widely and with greater success.\u000d\u000a    1) Intraoperative application of 5-FU\u000d\u000a    The use of 5-Fluorouracil (5-FU) to modify the wound healing in glaucoma\u000d\u000a      surgery was first\u000d\u000a      investigated in the early 1980s, with the treatment initially consisting\u000d\u000a      of a series of post-operative\u000d\u000a      injections. Our work established that a single intra-operative application\u000d\u000a      of 5-FU can be used with\u000d\u000a      the same effect. The benefits to patients are a reduction in the number of\u000d\u000a      visits, and reduction in\u000d\u000a      discomfort or pain from the injections. There is also a reduced cost,\u000d\u000a      which has enabled the\u000d\u000a      treatment to be extended widely, particularly in developing countries. A\u000d\u000a      recent Cochrane review\u000d\u000a      (2009 update) stated that \"Clinicians now appear to prefer the\u000d\u000a        intra-operative application of agents\u000d\u000a        for the modification of wound healing and routine postoperative\u000d\u000a        injections of 5-FU are now rarely\u000d\u000a        used\" [a].\u000d\u000a    Our work is referenced extensively in the European Glaucoma Society's\u000d\u000a      guidelines on use of 5-FU\u000d\u000a      in glaucoma surgery, which recommend a five-minute sponge exposure for\u000d\u000a      intra-operative use [b].\u000d\u000a      Intra-operative use of 5-FU is also recommended in Asia-Pacific glaucoma\u000d\u000a      guidelines, which also\u000d\u000a      specifically reference our work with regard to mode of application and\u000d\u000a      surgical techniques [c].\u000d\u000a    2) Improved surgical techniques\u000d\u000a    Glaucoma surgery has in the past had significant complications, including\u000d\u000a      soft eye with bleeding\u000d\u000a      and visual loss, and late infections from thin areas of fluid drainage\u000d\u000a      associated with the surgery.\u000d\u000a      Previously, virtually all of these complications would increase with the\u000d\u000a      use of anticancer agents.\u000d\u000a      The principles learnt from our earlier cell culture and in vivo\u000d\u000a      experiments enabled us to establish\u000d\u000a      how these agents worked as local applications and thus develop the\u000d\u000a      Moorfields Safer Surgery\u000d\u000a      System. This consists of several simple changes to surgical techniques,\u000d\u000a      and the development of\u000d\u000a      improved components which dramatically reduced the incidence of\u000d\u000a      potentially blinding\u000d\u000a      complications. The incidence of infection of the drainage area due to\u000d\u000a      thinning varies from 6% to\u000d\u000a      20% in three- to five-year follow up. This is reduced to approximately 0.5\u000d\u000a      - 1% with the wide area\u000d\u000a      anticancer treatment technique in the Moorfields system [d].\u000d\u000a    A review of clinical practice in 2011 stated that: \"While\u000d\u000a        complications are a risk, modern glaucoma\u000d\u000a        surgery techniques as developed by Khaw and colleagues have greatly\u000d\u000a        reduced the risk of both\u000d\u000a        intra- and postoperative complications\" [e].\u000d\u000a    One of the main benefits to the Moorfields Safer Surgery system is that\u000d\u000a      the techniques described\u000d\u000a      are relatively inexpensive and can be accessed by most surgeons around the\u000d\u000a      world including those\u000d\u000a      from the poorer countries. This has enabled the system to spread widely,\u000d\u000a      and it is now the\u000d\u000a      standard technique used around the globe [f].\u000d\u000a    We have distributed information about this techniques free online [g],\u000d\u000a      and the system has reached\u000d\u000a      all continents. Khaw has given many invited lectures in the USA, South\u000d\u000a      America, Africa, India,\u000d\u000a      South East Asia and Australia to highly receptive audiences, who have in\u000d\u000a      turn spread the\u000d\u000a      Moorfields Safe Surgery system. One surgeon from the All India Institute\u000d\u000a      of Medical Sciences, who\u000d\u000a      was trained in our techniques in 2005, now reports that \"Currently all\u000d\u000a        residents and fellows that\u000d\u000a        pass from our university are trained in the Moorfields Safe Surgery\u000d\u000a        System... This system is now\u000d\u000a        being adopted across all major ophthalmic centres in our country and\u000d\u000a        also in south east Asia. The\u000d\u000a        Moorfields Safe Surgery system has significantly impacted both general\u000d\u000a        ophthalmologists and\u000d\u000a        glaucoma specialists, improved the standard of care and also the quality\u000d\u000a        of life of glaucoma\u000d\u000a        patients across India\" [h].\u000d\u000a    In addition, Khaw has worked with a UK commercial company, Duckworth\u000d\u000a      & Kent, to develop a\u000d\u000a      comprehensive set of instruments which can be used in line with the Safer\u000d\u000a      Surgery System [i].\u000d\u000a    The complications of trabeculectomy surgery have improved considerably\u000d\u000a      since the UK national\u000d\u000a      survey of trabeculectomy 15 years ago. Early complications occurred in\u000d\u000a      46.6% and late\u000d\u000a      complications in 42.3%. With the Safer Surgery System and 5-FU there were\u000d\u000a      no cases of\u000d\u000a      endophthalmitis, hypotonous maculopathy, retinal detachment or blindness.\u000d\u000a      Studies around the\u000d\u000a      world have found similar improved outcomes using our protocols which is of\u000d\u000a      direct relevance to\u000d\u000a      many hundreds of thousands of individuals across the world [j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Glaucoma is the commonest cause of irreversible blindness world-wide and,\u000d\u000a      in many parts of the\u000d\u000a      world, surgery to create a new drainage channel is the only practical\u000d\u000a      treatment. The commonest\u000d\u000a      cause of surgical failure is scarring, and the use of injections of\u000d\u000a      cytotoxic agents prevents scarring\u000d\u000a      but has many complications. Our research identified how convenient single\u000d\u000a      5-minute treatments\u000d\u000a      with cytotoxic drugs work and led us to carry out pilot and randomised\u000d\u000a      trials, which showed they\u000d\u000a      reduced post-operative scarring. Combined with other refinements of\u000d\u000a      surgical technique (named\u000d\u000a      the Moorfields Safer Surgery System) this has improved outcomes of\u000d\u000a      glaucoma surgery world-wide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Khaw PT, Doyle JW, Sherwood MB, Grierson I, Schultz G, McGorray S.\u000d\u000a      Prolonged localized\u000d\u000a      tissue effects from 5-minute exposures to fluorouracil and mitomycin C.\u000d\u000a      Arch Ophthalmol. 1993\u000d\u000a      Feb;111(2):263-7. http:\/\/dx.doi.org\/10.1001\/archopht.1993.01090020117035\u000d\u000a    \u000a\u000a[2] Khaw PT, Doyle JW, Sherwood MB, Smith MF, McGorray S. Effects of\u000d\u000a      intraoperative 5-fluorouracil\u000d\u000a      or mitomycin C on glaucoma filtration surgery in the rabbit.\u000d\u000a      Ophthalmology. 1993\u000d\u000a      Mar;100(3):367-72. Copy available.\u000d\u000a    \u000a\u000a[3] Lanigan L, Stürmer J, Baez KA, Hitchings RA, Khaw PT. Single\u000d\u000a      intraoperative applications of\u000d\u000a      5-fluorouracil during filtration surgery: early results. Br J Ophthalmol.\u000d\u000a      1994 Jan;78(1):33-7.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/bjo.78.1.33\u000d\u000a    \u000a\u000a[4] Yorston D, Khaw PT. A randomised trial of the effect of\u000d\u000a      intraoperative 5-FU on the outcome of\u000d\u000a      trabeculectomy in east Africa. Br J Ophthalmol. 2001 Sep;85(9):1028-30.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/bjo.85.9.1028\u000d\u000a    \u000a\u000a[5] Wong TT, Khaw PT, Aung T, Foster PJ, Htoon HM, Oen FT, Gazzard G,\u000d\u000a      Husain R, Devereux\u000d\u000a      JG, Minassian D, Tan SB, Chew PT, Seah SK. The singapore 5-Fluorouracil\u000d\u000a      trabeculectomy\u000d\u000a      study: effects on intraocular pressure control and disease progression at\u000d\u000a      3 years.\u000d\u000a      Ophthalmology. 2009 Feb;116(2):175-84. http:\/\/dx.doi.org\/10.1016\/j.ophtha.2008.09.049.\u000d\u000a    \u000a\u000a[6] Jones E, Clarke J, Khaw PT. Recent advances in trabeculectomy\u000d\u000a      technique. Curr Opin\u000d\u000a      Ophthalmol. 2005 Apr;16(2):107-13. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15744141\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"13","Subject":"Ophthalmology and Optometry"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Wormald R, Wilkins MR, Bunce C. Post-operative 5-Fluorouracil for\u000d\u000a      glaucoma surgery.\u000d\u000a      Cochrane Database Syst Rev. 2001 http:\/\/dx.doi.org\/10.1002\/14651858.CD001132\u000d\u000a    [b] European Glaucoma Society guidelines. http:\/\/www.eugs.org\/eng\/EGS_guidelines.asp.\u000d\u000a      See\u000d\u000a      section 3.6\u000d\u000a    [c] Asia-Pacific Glaucoma guidelines.\u000d\u000a      http:\/\/www.apglaucomasociety.org\/toc\/APGGuidelinesNMview.pdf\u000d\u000a    [d] Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and\u000d\u000a      related complications in\u000d\u000a      limbus- versus fornix-based conjunctival flaps in pediatric and young\u000d\u000a      adult trabeculectomy with\u000d\u000a      mitomycin C. Ophthalmology. 2003 Nov;110(11):2192-7. http:\/\/dx.doi.org\/10.1016\/S0161-6420(03)00800-5\u000d\u000a    [e] King AJ, Stead RE, Rotchford AP. Treating patients presenting with\u000d\u000a      advanced glaucoma —\u000d\u000a      should we reconsider current practice? Br J Ophthalmol. 2011\u000d\u000a      Sep;95(9):1185-92.\u000d\u000a      http:\/\/dx.doi.org\/10.1136\/bjo.2010.188128\u000d\u000a    [f] Corroborating testimonies provided by:\u000d\u000a    \u000d\u000a      Professor of Ophthalmology, Bascom Palmer Eye Institute, University of\u000d\u000a        Miami School of\u000d\u000a        Medicine. Copy of letter available on request.\u000d\u000a      Head of Ophthalmology, University of Melbourne \/ Managing Director,\u000d\u000a        Centre for Eye\u000d\u000a        Research Australia. Available on request.\u000d\u000a    \u000d\u000a    [g] http:\/\/www.ucl.ac.uk\/ioo\/research\/khawlibrary\u000d\u000a      and see also\u000d\u000a      www.glaucomatoday.com\/art\/0305\/0305sp.pdf\u000d\u000a    [h] Corroborating letter from Professor of Ophthalmology, Dr. Rajendra\u000d\u000a      Prasad Center for\u000d\u000a      Ophthalmic Sciences, All India Institute of Medical Sciences. Copy\u000d\u000a      available on request.\u000d\u000a    [i] http:\/\/www.duckworth-and-kent.com\/products\/feature_Khaw.asp\u000d\u000a    [j] Examples of studies showing improved outcomes using our protocols:\u000d\u000a    \u000d\u000a      Gruber D. Trabeculectomy according to P. Khaw's protocol: medium-term\u000d\u000a        results.J Fr\u000d\u000a        Ophtalmol. 2008 Jan;31(1):17-22. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18401294\u000a\u000d\u000a      Shah P, Agrawal P, Khaw PT, Shafi F, Sii F. ReGAE 7: long-term\u000d\u000a        outcomes of augmented\u000d\u000a        trabeculectomy with mitomycin C in African Caribbean patients. Clin\u000d\u000a        Experiment\u000d\u000a        Ophthalmol. 2012 May-Jun;40(4):e176-82. http:\/\/doi.org\/bvmkjd\u000a\u000d\u000a      Solus JF, Jampel HD, Tracey PA, Gilbert DL, Loyd TL, Jefferys JL,\u000d\u000a        Quigley HA.\u000d\u000a        Comparison of limbus-based and fornix-based trabeculectomy: success,\u000d\u000a        bleb-related\u000d\u000a        complications, and bleb morphology. Ophthalmology. 2012\u000d\u000a        Apr;119(4):703-11.\u000d\u000a        http:\/\/doi.org\/fznpcm\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    The Moorfields Safer Surgery System: new techniques revolutionise\u000d\u000a      glaucoma surgery.\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Glaucoma affects approximately 70 million people world-wide, of whom 7\u000d\u000a      million are blind. A key\u000d\u000a      risk factor for the development and progression of glaucoma is increased\u000d\u000a      intraocular pressure. A\u000d\u000a      surgical approach to this problem is to create a drainage pathway for\u000d\u000a      fluid to escape which in turn\u000d\u000a      lowers intraocular pressure. The most important cause of failure of these\u000d\u000a      so-called filtration surgery\u000d\u000a      procedures is scarring of the drainage pathway under the conjunctiva, the\u000d\u000a      thin membrane that\u000d\u000a      covers the white of the eye.\u000d\u000a    Research in the early 1990s at the UCL Institute of Ophthalmology\u000d\u000a      developed in vivo cell culture\u000d\u000a      models of the ocular wound healing process. This led to the discovery that\u000d\u000a      very short (five minute)\u000d\u000a      applications of anticancer agents including 5-fluorouracil (5-FU) and\u000d\u000a      mitomycin-c (MMC) had long\u000d\u000a      lasting effects on ocular fibroblasts that were responsible for scarring\u000d\u000a      after surgery [1]. A series of\u000d\u000a      intracellular protective events including the expression of p53 were\u000d\u000a      associated with the cells going\u000d\u000a      into long term cell growth arrest but not death. At that time\u000d\u000a      5-fluorouracil was given clinically, as a\u000d\u000a      series of 14 painful injections around the eye in the first two weeks\u000d\u000a      after surgery. Our experiments\u000d\u000a      suggested that an equivalent effect could be achieved with a single\u000d\u000a      inexpensive five-minute\u000d\u000a      painless exposure at the time of surgery. We then developed a much more\u000d\u000a      consistent and\u000d\u000a      predictable model of glaucoma surgery in the rabbit and used this to\u000d\u000a      establish that a single\u000d\u000a      administration of 5-FU was equivalent to seven injections in terms of\u000d\u000a      accumulation of scar tissue\u000d\u000a      and cellularity and functioning of the drainage area. We also carried out\u000d\u000a      a series of experiments\u000d\u000a      which clarified the principles of focal, titratable long term inhibition\u000d\u000a      of scarring in the subconjunctival\u000d\u000a      area [2].\u000d\u000a    We then carried out the world's first pilot human trials with five minute\u000d\u000a      exposures to 5-FU which\u000d\u000a      strongly suggested that this treatment (which costs just £1) is\u000d\u000a      efficacious [3]. We undertook further\u000d\u000a      randomised trials with colleagues in in Africa [4] and Asia [5]\u000d\u000a      which showed that 5-FU was\u000d\u000a      effective in reducing scarring after glaucoma filtration surgery.\u000d\u000a    The principles of how to use of anticancer agents including the\u000d\u000a      associated surgical technique were\u000d\u000a      further developed, based on our early studies and clinical observation,\u000d\u000a      into the Moorfields Safer\u000d\u000a      Surgery System. These principles of which are now used around the\u000d\u000a        world to make surgery\u000d\u000a        much safer than in the past [6].\u000d\u000a    "},{"CaseStudyId":"35393","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000aWork on PBDs has been commercialised over the last 13 years through spin-out company\u000d\u000aSpirogen, which was set up in 2000 with Hartley as one of the founding scientists [a]. Initial funding\u000d\u000acame from the Bloomsbury Bioseed Fund, and laboratories were established at the UCL Cancer\u000d\u000aInstitute and UCL School of Pharmacy. As at July 2013, the company has a broad intellectual\u000d\u000aproperty base with >40 published patents and patent filings covering the use of PBDs as stand-\u000d\u000aalone anticancer drugs and as targeted agents. The company is currently based at the Queen\u000d\u000aMary BioEnterprise Innovation Centre, London and has 25 employees [b].\u000d\u000aBetween 2001 and 2003, the company went through two rounds of funding, and SG2000 was\u000d\u000alicensed to Ipsen. This drug successfully completed Phase I Clinical Trials in the UK and US, and\u000d\u000aresults were reported in 2008 [c]. 69 Patients were treated in multiple phase I trials, with 15 cases\u000d\u000aof stable disease and three partial responses of note [d].\u000d\u000aIn October 2009, Spirogen regained development and commercialisation rights for SG2000 from\u000d\u000aIpsen, and entered into an option agreement with Celtic Therapeutics to fund the Phase IIa trials of\u000d\u000aSG2000 in ovarian cancer, with investment of up to $15m [e]. Phase II trials began in 2010 [f],\u000d\u000aevaluating the overall response rate of SG2000 in approximately 50 patients with recurrent,\u000d\u000aresistant or refractory epithelial ovarian, primary peritoneal, or fallopian tube carcinoma.\u000d\u000aMore recently, significant further inward investment has been obtained by Spirogen with multiple\u000d\u000acollaborations with pharmaceutical companies in the area of PBD drug conjugates. In particular,\u000d\u000athe PBDs are beginning to have an impact in the area of antibody drug conjugates, which is fast\u000d\u000aemerging as one of the principal approaches in the field of monoclonal antibody cancer\u000d\u000atherapeutics:\u000d\u000aJanuary 2011: Announced a research collaboration and license agreement with Genentech, a\u000d\u000amember of the Roche Group, for the discovery and development of antibody drug conjugates\u000d\u000ainvolving Spirogen's proprietary PBD drugs and associated linker technology [g].\u000d\u000aMarch 2012: Celtic Therapeutics formed a new company, ADC Therapeutics, headquartered from\u000d\u000aLausanne, Switzerland with a pipeline of ten proprietary ADC oncology development programs,\u000d\u000atargeting multiple major cancers, including prostate, renal, breast, lung and blood cancers and an\u000d\u000ainitial budget of $50million.2028Celtic Therapeutics is also the majority owner of Spirogen, and ADC\u000d\u000aTherapeutics' development plan for the ADCs will use well-characterized monoclonal antibodies\u000d\u000aagainst these ten antigens for conjugation with best-in-class warhead and linker chemistry based\u000d\u000aon proprietary pyrrolobenzodiazepines (\"PBDs\") \"payload\" technology developed by, and licensed\u000d\u000afrom Spirogen. Stephen Evans-Freke, Co-Founder and Managing General Partner of Celtic\u000d\u000aTherapeutics commented in the press release: \"We believe that ADCs will represent a significant\u000d\u000amedical breakthrough in cancer therapy over the coming decade, and that Spirogen's PBDs\u000d\u000aconstitute `best-in-class' ADC warheads. We anticipate investment of up to $50m into ADC\u000d\u000aTherapeutics to achieve clinical proof of concept in 2-3 lead oncology programs. We are committed\u000d\u000ato fully fund ADC Therapeutics and will raise additional capital if warranted\" [h].\u000d\u000aApril 2012: Began a collaboration with a School of Pharmacy spin-out company, PolyTherics1, to\u000d\u000ause their ThioBridge technology to conjugate Spirogen's potent PBD cytotoxic agents site-\u000d\u000aspecifically to antibodies and antibody fragments [i].\u000d\u000aFebruary 2013: Began a research collaboration with Ablynx to evaluate the potential of a novel\u000d\u000aanti-cancer drug conjugate combining Spirogen's proprietary cytotoxic drugs,\u000d\u000apyrrolobenzodiazepines (PBD), and associated linker technology, with Nanobodies® generated\u000d\u000ausing Ablynx's proprietary technology platform [j].\u000d\u000a[text removed for publication].\u000d\u000aIn late 2013 Spirogen was acquired by Astra-Zeneca for a total of $440million ($200million upfront\u000d\u000aplus $240million deferred consideration on meeting defined developmental goals\/milestones) [k].\u000d\u000a","ImpactSummary":"\u000d\u000aResearch at the UCL Cancer Institute into drug-DNA interactions has led to spin-out company\u000d\u000aSpirogen Ltd resulting in job creation (currently 25 employees) and significant investment from\u000d\u000awithin the UK and overseas. Pyrrolobenzodiazepine dimer drug (SJG-136, SG2000) is currently in\u000d\u000aclinical trials in the USA and collaborative research and licence agreements in the area of antibody\u000d\u000adrug conjugates have been established with large pharmaceutical partners including in 2011 with\u000d\u000aGenentech, a member of the Roche group. In 2013, Spirogen was acquired by Astra-Zeneca for\u000d\u000a$200m.\u000d\u000a","ImpactType":"Technological","Institution":"\u000d\u000aUniversity College London\u000d\u000a","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a\u000a[1] Hartley JA, Spanswick VJ, Brooks N, Clingen PH, McHugh PJ, Hochhauser D, Pedley RB,\u000d\u000aKelland LR, Alley MC, Schultz R, Hollingshead MG, Schweikart KM, Tomaszewski JE,\u000d\u000aSausville EA, Gregson SJ, Howard PW, Thurston DE. SJG-136 (NSC 694501), a novel\u000d\u000arationally designed DNA minor groove interstrand cross-linking agent with potent and broad\u000d\u000aspectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor\u000d\u000aactivity. Cancer Res. 2004 Sep 15;64(18):6693-9. http:\/\/dx.doi.org\/10.1158\/0008-5472.CAN-03-2941\u000d\u000a\u000a\u000a[2] Alley MC, Hollingshead MG, Pacula-Cox CM, Waud WR, Hartley JA, Howard PW, Gregson SJ,\u000d\u000aThurston DE, Sausville EA. SJG-136 (NSC 694501), a novel rationally designed DNA minor\u000d\u000agroove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2:\u000d\u000aefficacy evaluations. Cancer Res. 2004 Sep 15;64(18):6700-6. http:\/\/dx.doi.org\/10.1158\/0008-5472.CAN-03-2942\u000d\u000a\u000a\u000a[3] Puzanov I, Lee W, Chen AP, Calcutt MW, Hachey DL, Vermeulen WL, Spanswick VJ, Liao CY,\u000d\u000aHartley JA, Berlin JD, Rothenberg ML. Phase I pharmacokinetic and pharmacodynamic study\u000d\u000aof SJG-136, a novel DNA sequence selective minor groove cross-linking agent, in advanced\u000d\u000asolid tumors. Clin Cancer Res. 2011 Jun 1;17(11):3794-802. http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-10-2056\u000d\u000a\u000a\u000a[4] Wu J, Clingen PH, Spanswick VJ, Mellinas-Gomez M, Meyer T, Puzanov I, Jodrell D,\u000d\u000aHochhauser D, Hartley JA. 03b3-H2AX foci formation as a pharmacodynamic marker of DNA\u000d\u000adamage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136\u000d\u000a(SG2000). Clin Cancer Res. 2013 Feb 1;19(3):721-30. http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-12-2529\u000d\u000a\u000a\u000a[5] Hartley JA, Hamaguchi A, Coffils M, Martin CR, Suggitt M, Chen Z, Gregson SJ, Masterson LA,\u000d\u000aTiberghien AC, Hartley JM, Pepper C, Lin TT, Fegan C, Thurston DE, Howard PW. SG2285, a\u000d\u000anovel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and\u000d\u000aexerts highly potent antitumor activity. Cancer Res. 2010 Sep 1;70(17):6849-58.\u000d\u000ahttp:\/\/dx.doi.org\/10.1158\/0008-5472.CAN-10-0790\u000d\u000a\u000a\u000a[6] Hartley JA, Hamaguchi A, Suggitt M, Gregson SJ, Thurston DE, Howard PW. DNA interstrand\u000d\u000across-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine\u000d\u000adimer SG2057. Invest New Drugs. 2012 Jun;30(3):950-8. http:\/\/dx.doi.org\/10.1007\/s10637-011-9647-z\u000d\u000a\u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"3","Level2":"2","Subject":"Inorganic Chemistry"}],"Sources":"\u000d\u000a[a] http:\/\/www.spirogen.com\/spirogen\/history.php\u000d\u000a[b] Claims regarding Spirogen can be corroborated by:\u000d\u000a1. Senior Business Manager (Biopharm), UCL Business PLC. Contact details provided.\u000d\u000a2. CEO, Spirogen. Contact details provided.\u000d\u000a[c] The Results of the Phase I Studies of SG2000 (SJG-136) to be Presented at ASCO, Chicago,\u000d\u000aJune 2008: http:\/\/www.spirogen.com\/news\/press-archive.php?id=210&cpg=1\u000d\u000a[d] SG2000 Highlights http:\/\/www.spirogen.com\/pdf\/SG2000-Highlights.pdf\u000d\u000a[e] Celtic Therapeutics to invest up to $15m in the development of Spirogen's cancer drug\u000d\u000aSG2000: http:\/\/www.spirogen.com\/news\/press-archive.php?id=196&cpg=1\u000d\u000a[f] Commencement of a phase II clinical trial of SG2000: http:\/\/www.spirogen.com\/news\/press-archive.php?id=189&cpg=1\u000d\u000a[g] Spirogen Ltd. announces a research collaboration and license agreement with Genentech for\u000d\u000athe discovery and development of antibody drug conjugates.\u000d\u000ahttp:\/\/www.spirogen.com\/news\/latest.php\u000d\u000a[h] http:\/\/www.adctherapeutics.com\/news\/2012\/03\/celtic-therapeutics-launches-50m-antibody-drug-conjugates-development-company\u000d\u000a[i] http:\/\/www.genengnews.com\/gen-news-highlights\/polytherics-spirogen-to-research-antibody-drug-conjugates-for\/81246576\/\u000d\u000a[j] http:\/\/www.collegehill-lifesciences.com\/news\/2013\/02\/ablynx-and-spirogen-enter-into-a-research-collaboration-to-evaluate-the-potential-of-novel-toxin-nanobody-drug-conjugates-in-cancer\u000d\u000a[k] http:\/\/www.astrazeneca.com\/Media\/Press-releases\/Article\/20131015--astrazeneca-oncology-portfolio-strengthened\u000d\u000a\u000a1 Case study on PolyTherics submitted to UoA 3.\u000d\u000a\u000d\u000a\u000d\u000a","Title":"\u000d\u000aThe development of pyrrolobenzodiazepine dimers as cancer therapeutics\u000d\u000a","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000aJoint research between Professor John Hartley (UCL, 1988-date) and David Thurston (UCL School\u000d\u000aof Pharmacy, 2001-11; now Kings College London) led to the rational design, synthesis and\u000d\u000aevaluation of novel pyrrolobenzodiazepine (PBD) dimers as potent anticancer agents. These drugs\u000d\u000abind sequence-selectively in the minor groove of DNA, forming non-distorting DNA interstrand\u000d\u000across-links which are refractory to repair [1, 2]. In collaboration with the US National Cancer\u000d\u000aInstitute (NCI), lead molecule SJG-136 (SG2000) was found to exhibit potent, differential\u000d\u000acytotoxicity in vitro, have a novel mechanism of action through COMPARE analysis, and broad\u000d\u000aspectrum antitumour activity in vivo.\u000d\u000aThis drug has been evaluated in four Phase I clinical trials in the UK (UCL) through Cancer\u000d\u000aResearch UK (CRUK) and in the USA through the NCI. It has completed a Phase II trial in platinum\u000d\u000arefractory ovarian cancer, and a haematological Phase I\/II is currently open. The clinical trials have\u000d\u000abeen facilitated through use of novel pharmacodynamics endpoints of DNA cross-linking and\u000d\u000adamage response developed at UCL [3, 4].\u000d\u000aAs part of detailed structure activity relationship studies we found that the potency of PBD dimers\u000d\u000acan be enhanced by introducing unsaturation about the C2-position of the PBD C-ring and\u000d\u000ainstalling substituents that are directed along the floor of the DNA minor groove. The next\u000d\u000ageneration of PBD dimers, which are more potent than SG2000, have been developed, including\u000d\u000aSG2057 and SG2202. They exhibit picomolar\/sub-picomolar activity against a range of human\u000d\u000atumour cell lines and demonstrate curative activity in human tumour xenograft models. SG2285, a\u000d\u000aprodrug of SG2202 is currently in pre-clinical development [5, 6].\u000d\u000aThe ability to generate such cytotoxic molecules that display exquisite potency suggested a\u000d\u000apotential role in strategies aimed at targeting and releasing highly cytotoxic agents directly at a\u000d\u000atumour site. An example is as the `warhead' component of an antibody drug conjugate (ADC). The\u000d\u000afully synthetic PBD dimers are ideally suited for the role of warhead in an ADC approach. They\u000d\u000acombine potency with a demonstrated therapeutic index (unlike other warheads such as\u000d\u000acalicheamycin), are not cross-resistant with widely used chemotherapy agents, and their unique\u000d\u000amode of action sets them apart from the tubulin binders (maytansinoids and auristatins) that\u000d\u000acurrently dominate the ADC arena. Several PBD dimer-containing ADCs, targeting both\u000d\u000ahaematological malignancies and solid tumours, are currently undergoing preclinical and clinical\u000d\u000aevaluation.\u000d\u000a"},{"CaseStudyId":"35395","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Our research has influenced policies and initiatives to improve nutrition\u000a      in children, tackling childhood obesity, and improving the long-term\u000a      health of the population. Our work has benefited children from birth\u000a      onwards, covering breast feeding, production and use of infant formulas,\u000a      and novel public health programmes for children of different ages. Our\u000a      growth acceleration hypothesis and the results of our randomised\u000a      controlled trials provided firm scientific evidence that slower growth in\u000a      infancy has long-term benefits for health, which has been used worldwide\u000a      to bring about a change in policy and practice.\u000a    Slow growth and breastfeeding: impacts on national and international\u000a        policies and initiatives\u000a    Contrary to previous public opinion and paediatric clinical practice, a\u000a      slower rate of weight gain in infancy (as seen in breast-fed compared to\u000a      formula-fed infants) is now regarded as desirable for long-term health.\u000a      Such growth patterns are now actively promoted in statements by official\u000a      bodies. Our work has provided important evidence to support the importance\u000a      of breast-feeding for long-term as well as short-term health outcomes, and\u000a      has been widely cited in health and public health policies and initiatives\u000a      in this area.\u000a    In 2006, the World Health Organisation produced revised child growth\u000a      charts, based on the slower rate of growth of breast-fed infants (previous\u000a      charts based on faster growing formula-fed infants). Our research provided\u000a      scientific evidence that a slower pattern of growth had long-term benefits\u000a      for health, which supported the adoption of these charts in the UK and\u000a      elsewhere. The Scientific Advisory Committee on Nutrition (SACN) and Royal\u000a      College of Paediatrics and Child Health joint report on the WHO growth\u000a      charts cited our work, stating that: `current evidence suggests that\u000a        such a (slower) pattern of growth could potentially reduce the later\u000a        risk of obesity' [a]. These charts have now been adapted and\u000a      adopted for use in the UK.\u000a    The research above led to the commission of a review for the UK\u000a      government's Foresight report on `Tackling Obesities: Future Choices'.\u000a      This report states that `Breast-feeding and early growth patterns\u000a        provide the only period in which there is clear evidence to support the\u000a        concept of a critical period of development associated with long-term\u000a        consequences' and `while there is less evidence of a direct link\u000a        between birth weight and obesity, weight gain in early life appears to\u000a        be critical'. It adds `Breast-fed babies show slower\u000a        growth rates than formula-fed babies and this may contribute to the\u000a        reduced risk of obesity later in life shown by breast-fed babies' [b].\u000a    The Scientific Advisory Committee for Nutrition report on the influence\u000a      of maternal, fetal and child nutrition on the development of chronic\u000a      disease later in life, cites references 1-3 above and states: `In\u000a        particular birthweight and birth size, early feeding, and the rate of\u000a        growth in early life modify the prevalence of cardiovascular disease and\u000a        its risk factors (such as blood pressure, adiposity and glucose\u000a        tolerance) and certain cancers' [c].\u000a    In 2011, the US Institute of Medicine's policy on childhood obesity\u000a      stated that health care professionals should `consider the children's\u000a        rate of weight gain when determining which children are at highest risk\u000a        of developing obesity' and they need to `support breast-feeding\u000a        to help prevent future obesity' [d]. Michelle Obama's\u000a      initiative to tackle childhood obesity cites our work on the mechanisms by\u000a      which breast-feeding is beneficial for later risk of obesity along with\u000a      reviews directly based on our work and patents [e].\u000a    Infant formulas: impacts on their formulation and use.\u000a    This research has also led to changes in the nutrition content of infant\u000a      formula with an emphasis on changes to both infant formula composition\u000a      (e.g. lowering of protein content) and volume of consumption in order to\u000a      produce a growth pattern more similar to the breast-fed infant. For\u000a      example, formula manufacturers SMA have detailed on their website aimed at\u000a      professionals how our research has influenced their products [f].\u000a      We have also patented research relating to the composition of infant\u000a      formula and this intellectual property is currently under licence to\u000a      Abbott Nutrition PLC who fund a phase 3 clinical trial to develop a new\u000a      infant formula designed to mimic the growth rate of the breast-fed infant.\u000a      This trial has so far generated [text removed for publication] in\u000a      royalty income for MRC\/ICH and over £2.8m in research funding [g].\u000a    Our evidence that promotion of faster growth may have adverse\u000a      consequences for long-term health in infants born small for their\u000a      gestational age (SGA) has led to changes in the management of these\u000a      infants. Regarding long-term metabolic complications in such infants, a\u000a      consensus statement by the International Societies of Paediatric\u000a      Endocrinology and Growth Hormone Research on the management of SGA infants\u000a      (to which Singhal contributed), advised that: `obesity and accelerated\u000a        weight gain are likely to be major risk factors' and `calorie\u000a        dense feeding for SGA infants may not be appropriate' [h].\u000a      As a consequence, nutrient-enriched formulas are no longer recommended for\u000a      use in otherwise healthy infants born low birth weight at term.\u000a    The MEND Programme and Trim Tots: lifestyle interventions for children\u000a    The first MEND programme was developed at Great Ormond Street Hospital\u000a      and the UCL Institute of Child Health, and then in 2004, MEND Central Ltd\u000a      was set up, operating as a social enterprise, to provide the programme\u000a      more widely. Since that time, more than 55,000 individuals have benefitted\u000a      from the programme. It is currently running in more than 200 locations\u000a      across England and Wales, and has been adapted for use in a number of\u000a      other countries around the world [i]. The Greenwich Healthy Living\u000a      Service, who have been running the MEND programme for four years, report\u000a      the following case study about one of their participants: \"Since\u000a        attending the MEND programme at the Waterfront Leisure Centre with her\u000a        12 year old daughter Elise, Carmen, a mum from Eltham, has noticed a\u000a        huge improvement in her daughter's eating habits. Carmen has made\u000a        healthy changes to the way she cooks and Elise now tries new things and\u000a        eats a wider range of foods. Carmen and Elise have also been spending\u000a        time together whilst improving their health: `We both joined the gym\u000a        together and we are definitely much more active. The graduate children's\u000a        exercise sessions were also very encouraging because you don't just\u000a        finish the programme; you have something to do which continues to\u000a        motivate the children'\" [j].\u000a    We are now piloting a new intervention for younger children, called Trim\u000a      Tots. This is a 24-week programme for families with under-fives, which\u000a      teaches the principles of a healthy lifestyle through art and play. One\u000a      parent who has taken part in this pilot reported: \"The simple fact is,\u000a        the lessons we learned and knowledge I have passed on to friends and\u000a        family, has made a big difference to our lives... The Trim Tots\u000a        programme and support for children and families at this vital age needs\u000a        to be widespread. It should be available for all parents as they are the\u000a        building blocks to nurturing a generation of health conscious, educated\u000a        young people\" [k].\u000a    ","ImpactSummary":"\u000a    Clinical research conducted at the UCL Institute of Child Health between\u000a      1998 and 2011 under the direction of Professors Alan Lucas and Atul\u000a      Singhal showed that a slower rate of infant weight gain had long-term\u000a      benefits to reduce the risk of obesity and cardiovascular disease. This\u000a      contradicted the accepted view, which favoured the promotion of rapid\u000a      weight gain in infancy. This work has had a significant influence on\u000a      public health policies and initiatives in the UK and elsewhere. It has\u000a      changed the way infant formulas are made and used. Two new interventions\u000a      for overweight children have been developed and are helping families\u000a      around the world.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and\u000a      later blood pressure: two cohorts after randomised trials. Lancet. 2001\u000a      Feb 10;357(9254):413-9.\u000a        http:\/\/doi.org\/dmc57r\u000a    \u000a\u000a[2] Singhal A, Fewtrell M, Cole TJ, Lucas A. Low nutrient intake and\u000a      early growth for later insulin resistance in adolescents born preterm.\u000a      Lancet. 2003 Mar 29;361(9363):1089-97. http:\/\/dx.doi.org\/10.1016\/S0140-6736(03)12895-4\u000a    \u000a\u000a[3] Singhal A, Lucas A. Early origins of cardiovascular disease: is there\u000a      a unifying hypothesis? Lancet. 2004 May 15;363(9421):1642-5.\u000a        http:\/\/dx.doi.org\/10.1016\/S0140-6736(04)16210-7\u000a    \u000a\u000a[4] Singhal A, Cole TJ, Fewtrell M, Deanfield J, Lucas A. Is slower early\u000a      growth beneficial for long-term cardiovascular health? Circulation. 2004\u000a      Mar 9;109(9):1108-13. http:\/\/doi.org\/b5ckms\u000a    \u000a\u000a[5] Singhal A, Cole TJ, Fewtrell M, Lucas A. Breastmilk feeding and\u000a      lipoprotein profile in adolescents born preterm: follow-up of a\u000a      prospective randomised study. Lancet. 2004 May 15;363(9421):1571-8.\u000a        http:\/\/dx.doi.org\/10.1016\/S0140-6736(04)16198-9\u000a    \u000a\u000a[6] Singhal A, Lanigan J. Breastfeeding, early growth and later obesity.\u000a      Obes Rev. 2007 Mar;8 Suppl 1:51-4. http:\/\/dx.doi.org\/10.1111\/j.1467-789X.2007.00318.x\u000a    \u000a\u000a[7] Singhal A, Cole TJ, Fewtrell M, Kennedy K, Stephenson T, Elias-Jones\u000a      A, Lucas A. Promotion of faster weight gain in infants born small for\u000a      gestational age: is there an adverse effect on later blood pressure?\u000a      Circulation. 2007 Jan 16;115(2):213-20. http:\/\/doi.org\/c7nj83\u000a    \u000a\u000a[8] Singhal A, Kennedy K, Lanigan J, Fewtrell M, Cole TJ, Stephenson T,\u000a      Elias-Jones A, Weaver LT, Ibhanesebhor S, MacDonald PD, Bindels J, Lucas\u000a      A. Nutrition in infancy and long-term risk of obesity: evidence from 2\u000a      randomized controlled trials. Am J Clin Nutr. 2010 Nov;92(5):1133-44. http:\/\/dx.doi.org\/10.3945\/ajcn.2010.29302.\u000a    \u000a\u000a[9] Sacher PM, Kolotourou M, Chadwick PM, Cole TJ, Lawson MS, Lucas A,\u000a      Singhal A. Randomized controlled trial of the MEND program: a family-based\u000a      community intervention for childhood obesity. Obesity. 2010 Feb;18 Suppl\u000a      1:S62-8. http:\/\/doi.org\/cmv6xd\u000a    \u000aRelevant Funding\u000a    MRC Programme Grant: `The early nutritional origins of cardiovascular\u000a      disease' (PI: Singhal; £1.3m; 2007-12). Funding for commercialisation from\u000a      Abbott Nutrition Plc: 'Phase three randomised controlled trial to assess\u000a      the effects of early nutrition on long-term body composition, growth and\u000a      risk factors for cardiovascular disease (PI: Singhal; £2.6m; 2010-12).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    [a] Scientific Advisory Committee on Nutrition & Royal College of\u000a      Paediatrics and Child Health: Application of the WHO growth standards in\u000a      the UK. 2007. Report prepared by the joint SACN\/RCPCH Expert Group on\u000a      Growth Standards. Cites ref [3] on p.10\u000a      http:\/\/www.sacn.gov.uk\/reports_position_statements\/reports\/application_of_the_who_growth_s\u000a        tandards_in_the_uk.html\u000a    [b] Tackling obesity. Government Office for Science. See ref 20 to\u000a        our work.\u000a      http:\/\/www.bis.gov.uk\/assets\/foresight\/docs\/obesity\/17.pdf.\u000a    [c] Scientific Advisory Committee on Nutrition. 2011. The Influence of\u000a      maternal, fetal and child nutrition on the development of chronic disease\u000a      later in life. Section 5: Human Intervention studies. Cites references\u000a        [1-3].\u000a      http:\/\/www.sacn.gov.uk\/reports_position_statements\/reports\/the_influence_of_maternal_fetal_and_child_nutrition_on_the_development_of_chronic_disease_in_later_life.html\u000a    [d] National Institute of Medicine. Early Childhood Obesity Prevention\u000a      Policies Report: 23 June 2011. http:\/\/www.iom.edu\/Reports\/2011\/Early-Childhood-Obesity-Prevention-Policies.aspx\u000a      This document cites reviews from the US, all of which include our\u000a        work..\u000a    [e] Solving the problem of childhood obesity within a generation. White\u000a      House Task Force on Childhood Obesity Report to the President. May 2010. Cites\u000a        our work on early nutrition and leptin concentrations in later life (as\u000a        reviewed in [3] above).\u000a      http:\/\/www.letsmove.gov\/sites\/letsmove.gov\/files\/TaskForce_on_Childhood_Obesity_May2010\u000a        _FullReport.pdf\u000a    [f] SMA resource for healthcare professionals detailing how Lucas and\u000a      Singhal's work underpins the composition of their formula milk: http:\/\/www.smahcp.co.uk\/professional-know-\u000a     how\/nutrition-for-babies\/early-nutrition-and-health\/information-945.aspx?catid=26\u000a    [g] Patent number 0304482.3. Details can be verified by UCL Business.\u000a      Contact details provided.\u000a    [h] Clayton PE, Cianfarani S, Czernichow P, et al: Consensus statement:\u000a      management of the child born small for gestational age through to\u000a      adulthood: a consensus statement of the International societies of\u000a      pediatric endocrinology and the growth hormone research society. J Clin\u000a      Endocrinol Metab 2007;92:804-10. Makes the recommendation that\u000a        \"calorie-dense feeding for SGA infants may not be appropriate\",\u000a        referencing a number of papers (e.g. refs 12, 14 and 16) which build on\u000a        our earlier work in this area.\u000a      http:\/\/www.ghresearchsociety.org\/files\/2007_Consensus_SGA.pdf\u000a    [i] All details taken from the MEND website (1Sep 2013). http:\/\/www.mendprogramme.org\/\u000a    [j] [j]\u000a        http:\/\/greenwichhealthyliving.nhs.uk\/510\/healthy-lifestyle-programme-for-children-and-their-families-3\/\u000a    [k] http:\/\/blog.gosh.org\/research\/trim-tots-improving-child-health\/\u000a      And see bottom of this page for `Lennon's Story' of being in Trim Tots: http:\/\/www.gosh.nhs.uk\/research-and-innovation\/our-research-themes\/patient-stories\/\u000a    ","Title":"\u000a    Prevention and treatment of childhood obesity\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    This work was initially based on long-term follow-up during the late\u000a      1990s of randomised controlled trials which had originally been set up in\u000a      the 1980s by Lucas to investigate the impact of early nutrition on\u000a      long-term health, a concept termed programming [1]. Although\u000a      extensive data from animal models and small-scale epidemiological studies\u000a      in humans had suggested that growth and nutrition in early life could\u000a      affect, or program, long-term health, the lack of data from experimental\u000a      studies had prevented a causal interpretation in humans.\u000a    Whilst initially studying adolescents born preterm who had been\u000a      randomised to different diets at birth, Singhal showed for the first time\u000a      in humans a causal link between infant nutrition and long-term risk of\u000a      cardiovascular disease and type 2 diabetes [2-5]. He noted large\u000a      benefits for breast-milk feeding in reducing the major risk factors for\u000a      cardiovascular disease (high blood pressure, risk of obesity, insulin\u000a      resistance, markers of inflammation, and high cholesterol concentration)\u000a      and that, contrary to public health and medical opinion at the time,\u000a      faster weight gain in infancy increased the risk of obesity, insulin\u000a      resistance, dyslipidaemia, high blood pressure and endothelial dysfunction\u000a      up to 16 years later [1-6]. Together with Lucas, he proposed the\u000a      `Growth Acceleration' hypothesis which suggested that the long-term\u000a      benefits of breast-feeding for obesity and cardiovascular disease were\u000a      related to slower weight gain in breast-fed compared to formula-fed\u000a      infants and that faster infant growth had adverse consequences for later\u000a      health [3].\u000a    Subsequently, this hypothesis was confirmed by his team in randomised\u000a      trials in infants born at term [7, 8] and by others in over 50\u000a      studies internationally. The proposed impact of infant growth on later\u000a      health was substantial. Studies at UCL, and elsewhere building on this\u000a      work, have suggested that nearly a third of the risk of obesity in\u000a      childhood could be explained by the pattern of infant growth and, on a\u000a      population basis, lowering diastolic blood pressure by breast-feeding or\u000a      by slower infant growth could prevent over 100,000 cardiovascular events\u000a      per year in the US alone (as reviewed [3]).\u000a    As highlighted by a Cochrane systematic review, while childhood obesity\u000a      is a major public health problem, there are few evidence-based\u000a      interventions for its treatment. From 2004, Singhal's team has developed\u000a      and tested community based interventions for the prevention and treatment\u000a      of obesity in both preschool and school aged children. `MEND' (Mind,\u000a      Exercise, Nutrition, Do it), a family-based, community program for obese\u000a      children aged 7-13 years, was designed by Singhal and his PhD student,\u000a      Paul Sacher, as a multi-component, community-based intervention that\u000a      fulfilled NICE guidelines and included behaviour modification, nutrition\u000a      education and physical activity components. The group conducted a\u000a      randomised controlled trial of this intervention and showed it to be\u000a      suitable for widespread prevention and treatment for paediatric obesity [9].\u000a      A related programme `Trim tots' has been introduced for children under the\u000a      age of 5 years.\u000a    "},{"CaseStudyId":"35397","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000a    The underpinning research described above has provided the key evidence\u000a      base to inform national and international strategy on the treatment of\u000a      HIV. Our work provided an initial understanding of the molecular basis of\u000a      drug resistance, and was pivotal to the development and implementation of\u000a      sequence-based resistance testing across the NHS, along with the\u000a      establishment of a national surveillance scheme. With more appropriate\u000a      first-line therapy, based on individual resistance patterns, the\u000a      subsequent risk of drug failure due to resistance has been reduced,\u000a      leading to an overall reduction in resistance. Transmitted drug resistance\u000a      in the UK has fallen from over 15% of new infections in 2000-2, to fewer\u000a      than 10% in 2007 and onwards [a] representing a reduction of 300\u000a      new infections with such resistance per year.\u000a    Our work is referenced widely in treatment guidelines around the world.\u000a      The British HIV Association recommend, based on our evidence of\u000a      significant levels of transmitted resistance, that drug resistance testing\u000a      is undertaken BEFORE initiating therapy [b] Our data represent the\u000a        first such demonstration in the UK in 2001, leading directly to a change\u000a        in national guidleines. The International AIDS Society-USA\u000a      guidelines also cite our research and named input in support of their\u000a      recommendations on the mutational definitions of antiretroviral drug\u000a      resistance [c].\u000a    Through a linked biological-epidemiological approach to measuring drug\u000a      resistance, we have established the national surveillance structure, on\u000a      behalf of Public health England. In 2011, we provided evidence to the\u000a      House of Lords Select Committee on HIV and AIDS, the report from which\u000a      stated; \"It is essential, though, that treatment does not cause\u000a        longer-term harm. If a person fails to stick to a regime of\u000a        antiretroviral drugs, it can lead to the development of drug resistance,\u000a        as has been seen with antibiotics. Were such resistance to become\u000a        widespread, treatment efforts would be hampered in the long-term. This\u000a        is closely monitored. The United Kingdom has the largest resistance\u000a        database linked to clinical data in the world, to ensure that any\u000a        problems are quickly identified. With no vaccine and no cure, it is\u000a        important that surveillance systems robustly monitor and contain the\u000a        risk of emerging antiretroviral resistance (see paras 227 to 228)\" [d].\u000a    In 2012, UCL led a major Seminar on the \"Impact of HIV drug resistance in\u000a      the resource poor world\" in conjunction with the WHO in Geneva, 2012 [e].\u000a      This was the first such meeting to include both generic and proprietary\u000a      drug producers, to establish the future of rational drug treatment for the\u000a      developing world. As a consequence, in 2013, the World Health Organisation\u000a      (WHO) changed its surveillance strategy to better guide appropriate\u000a      interventions in the developing world. Based on our findings from the UK\u000a      population, WHO established a monitoring function, in parallel with the\u000a      rollout of antiretroviral therapy [f]. As one of five such\u000a      specialist Laboratories worldwide, we supported this monitoring. In light\u000a      of our recent finding of an increase in transmitted drug resistance in\u000a      Eastern Africa, the WHO has altered their surveillance approach towards a\u000a      more feasible and cost-effective approach of those individuals starting\u000a      therapy. We are currently in the vanguard of a major policy change within\u000a      the WHO regarding recommendations for first and second line therapies for\u000a      the developing world. This will affect 35 million infected individuals,\u000a      with the likely impact being the introduction of viral quantification\u000a      monitoring to guide switch from first to second line therapy. This is\u000a      evidenced through a joint publication with WHO (e) and reference to our\u000a      work in the 2013 revised WHO Guidelines [Chapter 7 ref 165 g].\u000a    ","ImpactSummary":"\u000a    UCL investigators have been at the forefront of characterising and\u000a      assessing HIV drug resistance since 1990, soon after the very first HIV\u000a      drug was licenced. There are currently more than 25 drugs available, and\u000a      our work over the last 23 years has directly determined how best these\u000a      therapies are used, and monitored in infected patients. We have extended\u000a      our work to a global perspective, in conjunction with the current rollout\u000a      of antiretroviral therapy to areas of the world devastated by the epidemic\u000a      - work which now informs guidelines of the World Health Organisation\u000a      (WHO), and has resulted in a marked reduction in mortality.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2660646","Name":"Genève"}],"References":"\u000a    \u000a[1] Loveday C, Kaye S, Tenant-Flowers M, Semple M, Ayliffe U, Weller IV,\u000a      Tedder RS. HIV-1 RNA serum-load and resistant viral genotypes during early\u000a      zidovudine therapy. Lancet. 1995 Apr 1;345(8953):820-4. http:\/\/dx.doi.org\/10.1016\/S0140-6736(95)92963-0.\u000a    \u000a\u000a[2] Brun-Vézinet F, Boucher C, Loveday C, Descamps D, Fauveau V, Izopet\u000a      J, Jeffries D, Kaye S, Krzyanowski C, Nunn A, Schuurman R, Seigneurin JM,\u000a      Tamalet C, Tedder R, Weber J, Weverling GJ; The National Virology Groups.\u000a      Delta Virology Working Group and Coordinating Committee. HIV-1 viral load,\u000a      phenotype, and resistance in a subset of drug-naive participants from the\u000a      Delta trial. Lancet. 1997 Oct 4;350(9083):983-90. http:\/\/dx.doi.org\/10.1016\/S0140-6736(97)03380-1\u000a    \u000a\u000a[3] Cane P, Chrystie I, Dunn D, Evans B, Geretti AM, Green H, Phillips A,\u000a      Pillay D, Porter K, Pozniak A, Sabin C, Smit E, Weber J, Zuckerman M; UK\u000a      Group on Transmitted HIV Drug Resistance. Time trends in primary\u000a      resistance to HIV drugs in the United Kingdom: multicentre observational\u000a      study. BMJ. 2005 Dec 10;331(7529):1368.\u000a      http:\/\/dx.doi.org\/10.1136\/bmj.38665.534595.55\u000a    \u000a\u000a[4] Phillips AN, Leen C, Wilson A, Anderson J, Dunn D, Schwenk A, Orkin\u000a      C, Hill T, Fisher M, Walsh J, Pillay D, Bansi L, Gazzard B, Easterbrook P,\u000a      Gilson R, Johnson M, Sabin CA; UK Collaborative HIV Cohort (CHIC) Study.\u000a      Risk of extensive virological failure to the three original antiretroviral\u000a      drug classes over long-term follow-up from the start of therapy in\u000a      patients with HIV infection: an observational cohort study. Lancet. 2007\u000a      Dec 8;370(9603):1923-8.\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(07)61815-7\u000a    \u000a\u000a[5] Wittkop L, Günthard HF, de Wolf F, Dunn D, Cozzi-Lepri A, de Luca A,\u000a      Kücherer C, Obel N, von Wyl V, Masquelier B, Stephan C, Torti C, Antinori\u000a      A, García F, Judd A, Porter K, Thiébaut R, Castro H, van Sighem AI, Colin\u000a      C, Kjaer J, Lundgren JD, Paredes R, Pozniak A, Clotet B, Phillips A,\u000a      Pillay D*, Chêne G* (* joint senior author); for theEuroCoord-CHAIN study\u000a      group. Effect of transmitted drug resistance on virological and\u000a      immunological response to initial combination antiretroviral therapy for\u000a      HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet\u000a      Infect Dis. 2011 May;11(5):363-71. http:\/\/dx.doi.org\/10.1016\/S1473-3099(11)70032-9\u000a    \u000a\u000a[6] Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DH, Gregson J, Sawyer\u000a      AW, Hamers RL, Ndembi N, Pillay D, Bertagnolio S. Global trends in\u000a      antiretroviral resistance in treatment-naïve individuals with HIV after\u000a      rollout of antiretroviral treatment in resource-limited settings: a global\u000a      collaborative study and meta-regression analysis. Lancet. 2012 Oct\u000a      6;380(9849):1250-8.\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(12)61038-1\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    [a] UK Collaborative Group on HIV Drug Resistance, Dolling D, Sabin C,\u000a      Delpech V, Smit E, Pozniak A, Asboe D, Brown AL, Churchill D, Williams I,\u000a      Geretti AM, Phillips A, Mackie N, Murphy G, Castro H, Pillay D, Cane P,\u000a      Dunn D, Dolling D. Time trends in drug resistant HIV-1 infections in the\u000a      United Kingdom up to 2009: multicentre observational study. BMJ. 2012 Aug\u000a      21;345:e5253. http:\/\/dx.doi.org\/10.1136\/bmj.e5253.\u000a    [b] British HIV Association Treatment Guidelines. First edition, and all\u000a      subsequent updates.\u000a      http:\/\/www.bhiva.org\/documents\/Guidelines\/Treatment%20Guidelines\/Archive\/2003\/Treatment%20Guidelines%202003.pdf.\u000a    [c] International AIDS Society-USA HIV Treatment Guidelines 2012.\u000a      https:\/\/www.iasusa.org\/content\/antiretroviral-treatment-adult-hiv-infection-0\u000a    [d] No Vaccine, no cure: HIV and AIDS in the United Kingdom. Select\u000a      Committee on HIV and AIDS in the United Kingdom.\u000a      http:\/\/www.publications.parliament.uk\/pa\/ld201012\/ldselect\/ldaids\/188\/18802.htm\u000a    [e] Bertagnolio S, Perno CF, Vella S, Pillay D. The Impact of HIV Drug\u000a      Resistance on the Selection of First- and Second-Line ART in\u000a      Resource-Limited Settings. J Infect Dis. 2013 Jun 15;207 Suppl 2 http:\/\/jid.oxfordjournals.org\/content\/207\/suppl_2.toc\u000a    [f] WHO HIV Drug Resistance Report 2012.\u000a      http:\/\/www.who.int\/hiv\/pub\/drugresistance\/report2012\/en\/index.html.\u000a      References the worldwide importance of UCL based work in guiding WHO\u000a      surveillance schemes\u000a    [g] Consolidated Guidelines on The use of antiretroviral drugs for\u000a      treating and preventing HIV Infection. World Health Organisation, June\u000a      2013\u000a      http:\/\/apps.who.int\/iris\/bitstream\/10665\/85321\/1\/9789241505727_eng.pdf\u000a    ","Title":"\u000a    Biological characterisation and impact of HIV drug resistance\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    An estimated 35 million people are infected with HIV worldwide, with the\u000a      vast majority living in the resource poor world. HIV therapy is now\u000a      provided as a combination of three drugs, in order to prevent drug\u000a      resistance developing. Our research has been at the forefront of\u000a      understanding the nature and impact of drug resistance and has therefore\u000a      shaped all national and international treatment guidelines since the early\u000a      1990's.\u000a    Our work started with the development of novel gene sequencing and\u000a      allele-specific methods to show that drug resistance underpinned the lack\u000a      of treatment effect within the first European pivotal trial of zidovudine\u000a      monotherapy (Concorde trial) [1] and subsequent dual therapy Delta\u000a      trial [2] (Tedder, Loveday, Weller). Indeed, this\u000a      established for the first time the use of genetic markers to directly\u000a      inform clinical practice. Subsequent rollout of viral gene sequence\u000a      technology to UK diagnostic laboratories led to the establishment of the\u000a      UK HIV Drug Resistance Database in 1999, based within UCL (Pillay)\u000a      and the MRC Clinical Trials Unit, now part of UCL (Dunn, Porter).\u000a      The purpose was to map the spread of drug resistance by HIV in the UK,\u000a      including the transmission of resistance [3] (Pillay, Phillips,\u000a        Sabin, Geretti). Indeed, applying new phylogenetic approaches, we\u000a      have demonstrated a continual spread of drug resistance viruses (Hue,\u000a        Kellam), and their ability to replicate fully, thus requiring new\u000a      classes of HIV therapy [4]. From this base we have extended our\u000a      national collaboration into a large European dataset, to provide the\u000a      definitive evidence for the detrimental impact of transmitted drug\u000a      resistance on outcome of therapy [5] (Pillay, Phillips, Cozzi\u000a        Lepri, Dunn, Porter), and thus determine the optimal therapeutic\u000a      strategies to maximise patient benefit.\u000a    During the last 10 years, we have taken this knowledge to map\u000a      transmission of drug resistance on a global scale. Through describing\u000a      resistance emerging during the pivotal MRC-funded DART trial of therapy in\u000a      Africa (Dunn, Pillay), and subsequently determining the risks and\u000a      predictors of such resistance (Gupta, Cozzi Lepri), we highlighted\u000a      the risk of a large scale transmission of resistance across the resource\u000a      poor world. Recently, we have indeed demonstrated that such transmission\u000a      is now a reality, in a paper co-authored with the World Health\u000a      Organisation [6] (Gupta, Pillay). This commitment to apply our\u000a        research to the areas of greatest need has led Deenan Pillay to be\u000a        seconded from UCL to become Director of the Wellcome Trust Africa Centre\u000a        for Health and Population Sciences, in South Africa-in the highest HIV\u000a        prevalance area in the world.\u000a    UCL Investigators\u000a    Richard Tedder, Senior Lecturer, Reader, then Professor of Virology\u000a      (1986-)\u000a      Clive Loveday, Senior Lecturer then Professor of Virology (1990- 2005)\u000a      Ian Weller Professor of HIV Medicine (1987-2010)\u000a      Deenan Pillay, Reader, then Professor of Virology (2003-)\u000a      Andrew Phillips, Senior Lecturer, Reader, then Professor of Epidemiology\u000a      (1990-)\u000a      Caroline Sabin, Senior Lecturer, Reader then Professor of Medical\u000a      Statistics (1996-)\u000a      Paul Kellam, Senior Lecturer, Reader then Professor of Host Pathogen\u000a      Research (2000-) (now joint appointment with Wellcome Trust Sanger\u000a      Institute)\u000a      Stephane Hue, Post-Doctoral Research Assistant, then Lecturer in Virology\u000a      (2006-)\u000a      Ravi Gupta, Clinical Research Fellow, then WT Intermediate Clinical\u000a      Fellow, Senior Lecturer in Infectious Diseases (2007-)\u000a      Alessandra Cozzi Lepri, Senior Lecturer in Epidemiology (2005-)\u000a      Anna Maria Geretti, Senior Lecturer in Virology (2005-2011)\u000a      David Dunn, Senior Lecturer, Reader (2000-)\u000a      Kholoud Porter, Senior Lecturer, Reader, Professor (1997-)\u000a    "},{"CaseStudyId":"35399","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The research described above underpins the routine use in clinical\u000a      practice of tocilizumab for patients with sJIA and RA. Widespread use of\u000a      the drug is reflected by the high levels of sales reported by\u000a      manufacturers Roche, who report 496m CHF (£335m) in sales of the drug in\u000a      just the first half of 2013 (up 33% on the previous year, due to\u000a      increasing demand) [a].\u000a    Rheumatoid Arthritis (RA): Our 2002 paper was the first randomised\u000a      controlled trial showing that inhibition of IL-6 significantly improved\u000a      the signs and symptoms of RA and normalised the acute- phase reactants.\u000a      The first phase III study (CHARISMA [b]) built on our work, citing\u000a      ref [3] as the proof-of-concept, randomised, controlled, dose escalation\u000a      study upon which its design was based. This trial is in turn cited by all\u000a      of the later phase clinical studies that ultimately led to tocilizumab\u000a      being approved by the EMA in January 2009 [c] and by the FDA in\u000a      January 2010 [d] for use in RA. NICE approved its use within the\u000a      UK in August 2010 [e].\u000a    Since this date tocilizumab has been prescribed in every rheumatology\u000a      centre in the UK for patients with severe RA. There is evidence that\u000a      tocilizumab halts joint damage, improves function and increases quality of\u000a      life [f] and hence allows engagement with employment. This is\u000a      articulated well by one patient with RA treated with tocilizumab,\u000a      highlighted in a case study from the National Rheumatoid Arthritis\u000a      Society, who was able to return to work as a result [g].\u000a    Around 690,000 people (~1% population) in the UK have RA. At University\u000a      College London Hospital (UCLH) around 25% of patients with RA are treated\u000a      with a biologic drug, of whom around 10-15% receive tocilizumab (amounting\u000a      to around 50 patients) where other biologic treatments have failed.\u000a      Extrapolating more widely, this suggests that between 15,000 and 20,000\u000a      patients with RA may be being treated with tocilizumab within the UK, and\u000a      hundreds of thousands worldwide.\u000a    sJIA: The initial basic science work of Prof Woo and the first\u000a      early-phase clinical study led by UCL underpinned the large phase III\u000a      study by De Benedetti el al published in the NEJM in 2012, to which UCL\u000a      was the largest UK contributor. This seminal phase III study (also known\u000a      as the TENDER trial) has ultimately led to tocilizumab being licensed for\u000a      use in sJIA by the FDA in May 2013 [h] and by the EMA in June 2013\u000a      [i]. It is adopted as treatment for sJIA around the world.\u000a    The National Institute for Health and Clinical Excellence (NICE)\u000a      recommended use of tocilizumab for sJIA in a technology appraisal in\u000a      December 2011 [j]. This was based on data presented in abstract\u000a      form by De Benedetti et al. prior to the NEJM publication of the full\u000a      article in 2012. This reflects how compelling the data were and the\u000a      potential severity of the condition thus warranting guidelines to be\u000a      issued prior to publication of the full article.\u000a    The use of tocilizumab for sJIA has also been endorsed by the British\u000a      Society of Paediatric and Adolescent Rheumatology (BSAPR) and incorporated\u000a      into their national standards of care [k]. Hence this is now in\u000a      routine use within clinical practice for sJIA and offers patients with\u000a      this severe condition another option in case they do not respond to\u000a      standard treatment with methotrexate.\u000a    Impact on patients with sJIA treated with tocilizumab: Data from\u000a      the national registry of patients being treated with tocilizumab have not\u000a      been published yet, but based on the prevalence of JIA and the proportion\u000a      of those with sJIA refractory to methotrexate it is likely to run into the\u000a      many hundreds. At Great Ormond Street Hospital and UCLH there are\u000a      currently 21 children and adolescent patients being treated with\u000a      tocilizumab who would otherwise have had active disease with its potential\u000a      problems and most likely would have been on high dose steroids and\u000a      suffering the complications of this also.\u000a    There is now evidence to demonstrate that tocilizumab halts radiological\u000a      structural damage of the joints in patients with sJIA [l]. There\u000a      is a direct relationship between prevention of joint damage and\u000a      preservation of function. There is also evidence that tocilizumab restores\u000a      normal growth velocity, which is typically impaired in active sJIA [m].\u000a      The preservation of joints and hence function coupled with the restoration\u000a      of normal growth in children with sJIA being treated with tocilizumab all\u000a      point towards less disability in these patients and hence less dependence\u000a      on healthcare and social services as they progress into adulthood. Hence\u000a      biologic treatment has transformed the long-term outcome of these patients\u000a      as in the pre-biologic era, sJIA was associated with the worst\u000a      disabilities and outcomes in adults [n]. This prevention of\u000a      disability is more likely to lead to patients being able to engage in\u000a      active employment. This extrapolation is supported by long-term outcome\u000a      data showing that adults with childhood onset arthritis are more likely to\u000a      be employed if they have good function, which occurs if arthritis is\u000a      better controlled during childhood due to prevention of damage to joints [o].\u000a    ","ImpactSummary":"\u000a    Research at UCL into the use of tocilizumab has led to a new treatment\u000a      and improved care for patients with juvenile idiopathic arthritis (JIA)\u000a      and rheumatoid arthritis (RA) in adults. The drug is now approved around\u000a      the world and recommended by NICE guidelines and is the standard of care\u000a      in children with systemic onset JIA. It has been prescribed in every\u000a      rheumatology centre in the UK for patients with severe RA. The impact of\u000a      the drug on patients is to prevent disability, halt joint damage, improve\u000a      function and increase quality of life.\u000a    ","ImpactType":"Health","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries\u000a      S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6)\u000a      gene on IL-6 transcription and plasma IL-6 levels, and an association with\u000a      systemic-onset juvenile chronic arthritis. J Clin Invest. 1998 Oct\u000a      1;102(7):1369-76. http:\/\/dx.doi.org\/10.1172\/JCI2629.\u000a    \u000a\u000a[2] Ogilvie EM, Fife MS, Thompson SD, Twine N, Tsoras M, Moroldo M,\u000a      Fisher SA, Lewis CM, Prieur AM, Glass DN, Woo P. The -174G allele of the\u000a      interleukin-6 gene confers susceptibility to systemic arthritis in\u000a      children: a multicenter study using simplex and multiplex juvenile\u000a      idiopathic arthritis families. Arthritis Rheum. 2003 Nov;48(11):3202-6.\u000a      http:\/\/dx.doi.org\/10.1002\/art.11300\u000a    \u000a\u000a[3] Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung\u000a      N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T,\u000a      Panayi GS. Therapeutic benefit of blocking interleukin-6 activity with an\u000a      anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a\u000a      randomized, double-blind, placebo-controlled, dose-escalation trial.\u000a      Arthritis Rheum. 2002 Dec;46(12):3143-50. http:\/\/dx.doi.org\/10.1002\/art.10623\u000a    \u000a\u000a[4] Woo, P, Wilkinson, N, Prieur, AM, Southwood, T, Leone, V, Livermore,\u000a      P, Wythe, H, Thomson, D, and Kishimoto, T. Open label phase II trial of\u000a      single, ascending doses of MRA in Caucasian children with severe systemic\u000a      juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6\u000a      receptor blockade in this type of arthritis and demonstration of prolonged\u000a      clinical improvement. Arthritis Res Ther, 2005. 7(6): R1281-8. http:\/\/dx.doi.org\/10.1186\/ar1826\u000a    \u000a\u000a[5] De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo\u000a      I, Cuttica R, Ravelli A, Schneider R, Woo P, Wouters C, Xavier R, Zemel L,\u000a      Baildam E, Burgos-Vargas R, Dolezalova P, Garay SM, Merino R, Joos R, Grom\u000a      A, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A; PRINTO; PRCSG.\u000a      Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.\u000a      N Engl J Med. 2012 Dec 20;367(25):2385-95. http:\/\/dx.doi.org\/10.1056\/NEJMoa1112802.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    [a] Roche Half-Year Report 2013: http:\/\/www.roche.com\/hy13e.pdf\u000a    [b] Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G,\u000a      Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T; CHARISMA\u000a      Study Group. Double-blind randomized controlled clinical trial of the\u000a      interleukin-6 receptor antagonist, tocilizumab, in European patients with\u000a      rheumatoid arthritis who had an incomplete response to methotrexate.\u000a      Arthritis Rheum. 2006 Sep;54(9):2817-29. http:\/\/dx.doi.org\/10.1002\/art.22033\u000a    [c] EMA approval for toculizumab for adults\u000a    [d] Roche announce FDA approval for toculizumab for adults with RA:\u000a      http:\/\/www.roche.com\/media\/media_releases\/med-cor-2010-01-11.htm\u000a    [e] NICE Technology Assessment 198. Tocilizumab for rheumatoid arthritis.\u000a      http:\/\/guidance.nice.org.uk\/TA198\u000a    [f] Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon\u000a      E, Ambs P, Fleischmann R. Tocilizumab inhibits structural joint damage in\u000a      rheumatoid arthritis patients with inadequate responses to methotrexate:\u000a      results from the double-blind treatment phase of a randomized\u000a      placebo-controlled trial of tocilizumab safety and prevention of\u000a      structural joint damage at one year. Arthritis Rheum. 2011\u000a      Mar;63(3):609-21.\u000a      http:\/\/dx.doi.org\/10.1002\/art.30158.\u000a    [g] National Rheumatoid Arthritis Society\u000a      http:\/\/www.nras.org.uk\/about_rheumatoid_arthritis\/living_with_rheumatoid_arthritis\/case_studies\/female\/my_experiences_on_tocilizumab.aspx\u000a    [h] Roche press release about the approval of tocilizumab for JIA,\u000a      stating that \"This approval was based on positive data from a Phase III\u000a        study known as TENDER.\"\u000a      http:\/\/www.roche.com\/media\/media_releases\/med-cor-2011-04-18.htm\u000a    [i] http:\/\/www.arthritisresearchuk.org\/news\/general-news\/2013\/june\/tocilizumab-approved-in-europe-to-treat-rare-childhood-arthritis.aspx\u000a    [j] NICE TA238. Tocilizumab for rheumatoid arthritis. Aug 2010 http:\/\/www.nice.org.uk\/ta198\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/13627\/57489\/57489.pdf.\u000a    [k] British Society for Paediatric and Adolescent Rheumatology Standards\u000a      of care in JIA\u000a      http:\/\/bspar.org.uk\/downloads\/clinical_guidelines\/Standards_of_Care.pdf\u000a    [l] Inaba Y, Ozawa R, Imagawa T, Mori M, Hara Y, Miyamae T, Aoki C, Saito\u000a      T, Yokota S. Radiographic improvement of damaged large joints in children\u000a      with systemic juvenile idiopathic arthritis following tocilizumab\u000a      treatment. Ann Rheum Dis. 2011 Sep;70(9):1693-5.\u000a      http:\/\/dx.doi.org\/10.1136\/ard.2010.145359\u000a    [m] Yokota S, Imagawa T, Mori M, Miyamae T, Takei S, Iwata N, Umebayashi\u000a      H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T. Long-term\u000a      treatment of systemic juvenile idiopathic arthritis with tocilizumab:\u000a      results of an open-label extension study in Japan. Ann Rheum Dis. 2013\u000a      Apr;72(4):627-8. http:\/\/dx.doi.org\/10.1136\/annrheumdis-2012-202310.\u000a    [n] Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile\u000a      idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002\u000a      Dec;41(12):1428-35.\u000a    [o] Malviya A, Rushton SP, Foster HE, Ferris CM, Hanson H, Muthumayandi\u000a      K, Deehan DJ. The relationships between adult juvenile idiopathic\u000a      arthritis and employment. Arthritis Rheum. 2012 Sep;64(9):3016-24. http:\/\/dx.doi.org\/10.1002\/art.34499.\u000a    ","Title":"\u000a    Tocilizumab — a new treatment for Rheumatoid Arthritis in adults and\u000a      Juvenile Idiopathic Arthritis in children\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Context: Juvenile idiopathic arthritis (JIA) is the most common\u000a      rheumatological inflammatory disease of children, affecting ~15,000\u000a      children in the UK. The most severe form of JIA is systemic onset (sJIA)\u000a      accounting for around 10% of all JIA patients. This sub-type can cause\u000a      joint pain, damage, blindness, disability and even death, as well as long\u000a      term sequelae (poor growth, low bone density). sJIA is associated with\u000a      potentially fatal complications such as macrophage activation syndrome.\u000a      Some problems such as growth delay and osteoporosis also arise from\u000a      steroids, which may be necessary to treat life-threatening aspects of sJIA\u000a      or very severe arthritis. The level of disability which progresses into\u000a      adulthood often results in long-term dependence. Rheumatoid arthritis in\u000a      adults is a separate condition but shares many features with JIA, notably\u000a      joint pain, destructive joint inflammation with consequent disability and\u000a      systemic complications which if left untreated can be serious or rarely\u000a      life-threatening; similarly, treatment can be limited due to adverse\u000a      effects or loss of effectiveness.\u000a    Early translational work: Interleukin (IL)-6 is a powerful driver\u000a      of inflammation and is produced in response to infection. The UCL group\u000a      led by Professor Woo were the first in 1998 to demonstrate that specific\u000a      genetic variations in the genes that control production of IL6 were\u000a      present in patients with sJIA and that these variations were associated\u000a      with elevated levels of IL6 in the blood of these patients [1]. A\u000a      further study in 2003 Woo's group defined these genetic abnormalities of\u000a      IL6 genes in more detail in different families [2]. These robust\u000a      scientific studies underpinned the rationale for subsequent clinical\u000a      studies targeting IL6 as a treatment for sJIA.\u000a    Early Clinical Studies: Tocilizumab is a monoclonal antibody\u000a      targeted toward the IL6-receptor. In 1999, UCL was one of two UK centres\u000a      running a study into the use of tocilizumab in adult patients, and the\u000a      first outside of Japan to treat adult patients with RA with this drug [3].\u000a      This work was published in 2002 and showed the range of doses of\u000a      toculizumab that had beneficial effects to reduce joint inflammation. In\u000a      2005, Woo led the first clinical, early (phase II) study outside of Japan\u000a      that investigated escalating doses of the drug in sJIA [4]. This\u000a      proof-of-principle study was run by UCL as lead centre with additional\u000a      centres recruiting in Birmingham (UK) and France. The escalating protocol\u000a      was based on the adult trial described above. Of the 18 children who\u000a      participated in the study, 11 were recruited by the UCL lead site.\u000a    Late-Phase Clinical Study: The early phase dose escalation study\u000a      (ref [3]) informed a phase III, multi-centre, international study\u000a      investigating the safety and efficacy of tocilizumab in sJIA. This\u000a      represents the largest randomised, placebo-controlled study ever in this\u000a      relatively rare disease group and in total 112 children participated. This\u000a      study was conducted over five years in 43 participating centres around\u000a      Europe. In total UK contributed eight patients of whom five were from\u000a      UCL\/ICH. This study unequivocally demonstrated clear efficacy of\u000a      tocilizumab in sJIA [5].\u000a    "},{"CaseStudyId":"35401","Continent":[],"Country":[],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Pepys's drug discovery intellectual property portfolio, comprising more\u000d\u000a      than 20 granted patents [a], is held by the UCL spin out company,\u000d\u000a      Pentraxin Therapeutics Ltd, which he founded in 2001 [b]. The\u000d\u000a      company, created as a vehicle for commercialisation of the IP, was\u000d\u000a      initially funded exclusively by loans from UCL totalling more than £1.5\u000d\u000a      million and has not sought external investment. It conducts its activities\u000d\u000a      entirely through its relationship with UCL and its external collaborations\u000d\u000a      and has no employees. In 2009 and 2010, Pentraxin licensed two of its drug\u000d\u000a      programmes to GlaxoSmithKline (GSK) in multi-million pound deals and is\u000d\u000a      developing them in close collaboration with GSK where several hundred\u000d\u000a      employees participate at various levels [c, d]. Pentraxin has\u000d\u000a      repaid all its loans from UCL and is now in profit with substantial\u000d\u000a      further milestone and royalty payments in prospect if programmes are\u000d\u000a      successful.\u000d\u000a    The most advanced programme, aiming to eliminate visceral amyloid\u000d\u000a      deposits, is the first in class obligate therapeutic partnership of CPHPC,\u000d\u000a      a small molecule drug, and a mouse monoclonal anti-human SAP antibody\u000d\u000a      which has been fully humanised by GSK. The first human patient studies are\u000d\u000a      now in progress and are progressing very well [d, e]. The\u000d\u000a      programme has been chosen by GSK as its flagship candidate for potential\u000d\u000a      adaptive licensing in the process being led by the MIT Centre for\u000d\u000a      Biomedical Innovation through its New Drug Development Paradigms (NEWDIGS)\u000d\u000a      initiative. There is a very strong movement towards streamlining and\u000d\u000a      improvement of the regulatory licensing pathway for new medicines so that\u000d\u000a      patients with unmet medical needs get access to novel treatments more\u000d\u000a      rapidly and more efficiently than at present. The UCL\/Pentraxin\/GSK\u000d\u000a      amyloidosis programme is in the vanguard.\u000d\u000a    GSK also licensed Pepys's IP covering compounds for treatment of\u000d\u000a      transthyretin amyloidosis and the programme has passed its initial\u000d\u000a      developability milestone. Typical industry costs for a drug development\u000d\u000a      programme to this stage are £6-8 million.\u000d\u000a    The discovery and development of CRP inhibitors for myocardial\u000d\u000a      infarction, stroke, cancer cachexia and inflammatory diseases has been\u000d\u000a      supported by the MRC and BHF and has received expert guidance from GSK.\u000d\u000a    Work on SAP depletion by CPHPC for Alzheimer's disease has been supported\u000d\u000a      at the experimental level by the MRC. Via the UCLH\/UCL BRC, the NIHR is\u000d\u000a      now funding preparatory work for the first clinical trial of CPHPC in\u000d\u000a      Alzheimer's disease, with GSK as major participants contributing crucially\u000d\u000a      to project management, funding and provision of their existing CPHPC\u000d\u000a      results. Furthermore GSK have an option to licence CPHPC for this\u000d\u000a      indication.\u000d\u000a    The transmission of drug discovery directly from a university into big\u000d\u000a      pharma is a very rare achievement, particularly across such a broad range\u000d\u000a      of different programmes. In 2011, GSK named Professor Pepys as the first\u000d\u000a      \"academic superstar\" in its programme to develop long term ongoing\u000d\u000a      partnerships with academia as part of its drug discovery programme [d,\u000d\u000a        f]. GSK has changed its R&D model over the last 5 years,\u000d\u000a      including the creation of the Academic Discovery Partnership Unit and\u000d\u000a      Discovery Partnerships with Academia. The aim is to make the company more\u000d\u000a      productive, agile, and focussed on areas of scientific potential [g].\u000d\u000a    The Head of the Academic Discovery Partnership Unit at GSK confirmed the\u000d\u000a      ways in which close working with the UCL team has been important in\u000d\u000a      progress towards bringing a drug to market:\u000d\u000a    [Text removed for publication] [d].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The UCL Centre for Amyloidosis and Acute Phase Proteins has designed and\u000d\u000a      developed new chemical entities targeting serum amyloid P component (SAP),\u000d\u000a      C-reactive protein (CRP) and transthyretin, for novel therapeutic\u000d\u000a      approaches to amyloidosis, Alzheimer's disease, cardiovascular and\u000d\u000a      inflammatory diseases. The UCL spin out company, Pentraxin Therapeutics\u000d\u000a      Ltd, founded by Sir Mark Pepys to hold his intellectual property (IP), has\u000d\u000a      licensed two programmes to GlaxoSmithKline (GSK). These highly\u000d\u000a      synergistic, collaborative multi-million pound developments, strikingly\u000d\u000a      exemplify new working relationships between academia and the\u000d\u000a      pharmaceutical industry.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ,\u000d\u000a      Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T,\u000d\u000a      Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW,\u000d\u000a      Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN. Targeted\u000d\u000a      pharmacological depletion of serum amyloid P component for treatment of\u000d\u000a      human amyloidosis. Nature. 2002 May 16;417(6886):254-9. http:\/\/doi.org\/fq58gj\u000d\u000a    \u000a\u000a[2] Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC,\u000d\u000a      Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV,\u000d\u000a      Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe\u000d\u000a      SE, Thompson D, Wood SP. Targeting C-reactive protein for the treatment of\u000d\u000a      cardiovascular disease. Nature. 2006 Apr 27;440(7088):1217-21.\u000d\u000a      http:\/\/dx.doi.org\/10.1038\/nature04672\u000d\u000a    \u000a\u000a[3] Kolstoe SE, Ridha BH, Bellotti V, Wang N, Robinson CV, Crutch SJ,\u000d\u000a      Keir G, Kukkastenvehmas R, Gallimore JR, Hutchinson WL, Hawkins PN, Wood\u000d\u000a      SP, Rossor MN, Pepys MB. Molecular dissection of Alzheimer's disease\u000d\u000a      neuropathology by depletion of serum amyloid P component. Proc Natl Acad\u000d\u000a      Sci U S A. 2009 May 5;106(18):7619-23.\u000d\u000a      http:\/\/dx.doi.org\/10.1073\/pnas.0902640106\u000d\u000a    \u000a\u000a[4] Gillmore JD, Tennent GA, Hutchinson WL, Gallimore JR, Lachmann HJ,\u000d\u000a      Goodman HJ, Offer M, Millar DJ, Petrie A, Hawkins PN, Pepys MB. Sustained\u000d\u000a      pharmacological depletion of serum amyloid P component in patients with\u000d\u000a      systemic amyloidosis. Br J Haematol. 2010 Mar;148(5):760-7. http:\/\/dx.doi.org\/10.1111\/j.1365-2141.2009.08036.x\u000d\u000a    \u000a\u000a[5] Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA,\u000d\u000a      Hutchinson WL, Mangione PP, Gallimore JR, Millar DJ, Minogue S, Dhillon\u000d\u000a      AP, Taylor GW, Bradwell AR, Petrie A, Gillmore JD, Bellotti V, Botto M,\u000d\u000a      Hawkins PN, Pepys MB. Antibodies to human serum amyloid P component\u000d\u000a      eliminate visceral amyloid deposits. Nature. 2010 Nov 4;468(7320):93-7.\u000d\u000a      http:\/\/dx.doi.org\/10.1038\/nature09494\u000d\u000a    \u000a\u000a[6] Kolstoe, S.E., Mangione, P.P., Bellotti, V., Taylor, G.W., Tennent,\u000d\u000a      G.A., Deroo, S., Morrison, A.J., Cobb, A.J.A., Coyne, A., McCammon, M.G.,\u000d\u000a      Warner, T.D., Mitchell, J., Gill, R., Smith, M.D., Ley, S.V., Robinson,\u000d\u000a      C.V., Wood, S.P. and Pepys, M.B. (2010) Trapping of palindromic ligands\u000d\u000a      within native transthyretin prevents amyloid formation. Proc. Natl.\u000d\u000a        Acad. Sci. USA, 107: 20483-20488. http:\/\/dx.doi.org\/10.1073\/pnas.1008255107\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000d\u000a    [a] Major Patents\u000d\u000a      Pepys, M.B. CRP binding agents. US Patent No. 7,390,795, granted 24 June\u000d\u000a      2008.\u000d\u000a      Pepys, M.B. Treatment and prevention of tissue damage. European Patent No.\u000d\u000a      1 503 800, granted 28 October 2009.\u000d\u000a      Pepys, M.B. Treatment and prevention of tissue damage. US Patent No.\u000d\u000a      7,615,543, granted 10 November 2009.\u000d\u000a      Pepys, M.B. Therapeutic agent. US Patent No. 7,691,897, granted April\u000d\u000a      2010.\u000d\u000a      Pepys, M.B. and Hawkins, P.N. Compounds inhibiting the binding of SAP for\u000d\u000a      treating osteoarthritis.\u000d\u000a      US Patent No. 7,659,299, granted 9 February 2010.\u000d\u000a      Pepys, M.B. Therapeutic agent for depletion of an unwanted protein\u000d\u000a      population from plasma.\u000d\u000a      European Patent No. 1 820 501, granted 14 September 2011.\u000d\u000a      Pepys, M.B. and Hawkins, P.N. Compounds inhibiting the binding of SAP for\u000d\u000a      treating osteoarthritis.\u000d\u000a      European Patent No. 1 633 345, granted 21 September 2011.\u000d\u000a      Pepys, M.B. Therapeutic agent. US Patent No. 8,173,694, granted 8 May,\u000d\u000a      2012\u000d\u000a      Pepys, M.B. Combinations of SAP depleting agents and anti-SAP antibodies.\u000d\u000a      US Patent No. 7,910,106, granted 22 March 2011.\u000d\u000a    [b] Pentraxin Therapeutics Ltd\u000d\u000a      Corroboration can be obtained from the Managing Director, UCL Business\u000d\u000a      PLC.\u000d\u000a    [c] Commercial deals\u000d\u000a      http:\/\/www.europharmatoday.com\/2009\/03\/gsks-vallance-teams-up-with-exuniversity-london-colleagues-in-pentraxin-deal.html\u000d\u000a    http:\/\/medicalintelligencenews.blogspot.co.uk\/2012\/01\/professorsir-mark-pepys-frs-md-phd.html\u000d\u000a    http:\/\/pentraxin.wordpress.com\/news\/\u000d\u000a    [d] Engagement with GSK\u000d\u000a      Letter of support from the Head of the Academic Discovery Partnership\u000d\u000a      Unit, GSK.\u000d\u000a      Available on request.\u000d\u000a    [e] Phase I Clinical trial of a combination of CPHPC and an anti-SAP\u000d\u000a        antibody\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01777243\u000d\u000a    [f] Financial Times on Professor Pepys being chosen as an academic\u000d\u000a        superstar\u000d\u000a      http:\/\/www.ft.com\/cms\/s\/0\/d1e31184-37a5-11e0-b91a-00144feabdc0.html\u000d\u000a    [g] Details of GSK's R&D model is available in their evidence to\u000d\u000a        the Parliamentary Science and Technology Committee, March 2013\u000d\u000a      http:\/\/www.publications.parliament.uk\/pa\/cm201213\/cmselect\/cmsctech\/348\/348we24.htm\u000a        \u000d\u000a    ","Title":"\u000d\u000a    Amyloidosis and acute phase proteins: development of new drugs and a new\u000d\u000a      approach to academia-industry collaboration\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Elucidation by Pepys of the role of SAP in amyloidosis (1977-95) led to\u000d\u000a      his invention, in collaboration with Roche, of the bis D-proline drug,\u000d\u000a      CPHPC, which produces sustained depletion of circulating SAP by a novel\u000d\u000a      pharmacological mechanism, first demonstrated at UCL in the early 2000's [1].\u000d\u000a      Patients with systemic amyloidosis are significantly stabilised while\u000d\u000a      being treated with CPHPC but the drug does not remove all SAP from their\u000d\u000a      amyloid deposits and the amyloid does not regress [4]. These\u000d\u000a      observations led Pepys to invent the use of anti-SAP antibodies to target\u000d\u000a      residual SAP in the amyloid deposits of CPHPC treated subjects [5].\u000d\u000a      The antibodies trigger remarkable, clinically silent elimination of\u000d\u000a      visceral amyloid in experimental models, which has not previously been\u000d\u000a      achieved. GSK licensed the invention in 2009. They have conducted phase I\u000d\u000a      studies of CPHPC in healthy volunteers and amyloidosis patients, have\u000d\u000a      fully humanised Pepys's optimal mouse monoclonal anti-human SAP antibody,\u000d\u000a      and the first clinical trial of CPHPC plus antibody is currently in\u000d\u000a      progress, so far with no adverse effects.\u000d\u000a    SAP is universally present in human amyloid deposits, including the\u000d\u000a      cerebral and cerebrovascular amyloid deposits in Alzheimer's disease (AD).\u000d\u000a      SAP also binds to most neurofibrillary tangles. Brain content of SAP is\u000d\u000a      thus higher in AD than in normal subjects, and since SAP is directly\u000d\u000a      neurocytotoxic it likely contributes to neurodegeneration, in addition to\u000d\u000a      its role in amyloidogenesis. The complete removal of SAP from the\u000d\u000a      cerebrospinal fluid, by administration of CPHPC in Alzheimer's disease, is\u000d\u000a      thus an attractive therapeutic approach [3]. Experimental work has\u000d\u000a      been supported by the MRC and preparatory work for a first clinical trial\u000d\u000a      in Alzheimer's disease is currently in progress funded by the NIHR through\u000d\u000a      the UCLH\/UCL Biomedical Research Centre (BRC) and strongly supported by\u000d\u000a      GSK.\u000d\u000a    Transthyretin causes both acquired senile cardiac amyloidosis, a hitherto\u000d\u000a      grossly under diagnosed condition, and hereditary systemic amyloidosis.\u000d\u000a      The Pepys team designed and patented novel small molecule compounds\u000d\u000a      targeting transthyretin [6], pursued possible development\u000d\u000a      supported by one of the first Wellcome Trust Seeding Drug Discovery\u000d\u000a      Initiative awards (£3.89 million), but then licensed the IP to GSK for a\u000d\u000a      close collaboration which has yielded new IP.\u000d\u000a    Human CRP potently activates complement when it binds to dead and damaged\u000d\u000a      cells and this exacerbates tissue damage after ischaemic injury in the\u000d\u000a      heart and brain, validating inhibition of CRP binding as a therapeutic\u000d\u000a      strategy [2]. Development of Pepys's small molecule CRP inhibitor\u000d\u000a      approach has been funded by the first award (£4 million) made by the MRC\u000d\u000a      under their Developmental Clinical Studies scheme and latterly also by the\u000d\u000a      British Heart Foundation (BHF).\u000d\u000a    Pepys joined UCL in 1999, when he was appointed Professor and Head of the\u000d\u000a      Department of Medicine at the Royal Free Campus of University College\u000d\u000a      London, and is currently Principal Clinical Research Associate and\u000d\u000a      Emeritus Professor of Medicine. He was awarded a Knighthood in the 2012\u000d\u000a      New Year Honours list for services to biomedicine.\u000d\u000a    "},{"CaseStudyId":"35589","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust","Medical Research Council","Royal Society"],"ImpactDetails":"\u000a    1) Diagnostic genetic testing is now available for all patients\u000a        diagnosed with neonatal diabetes. Multiple laboratories in Europe\u000a      and the USA have set up testing for neonatal diabetes. However, for those\u000a      patients in countries without genetic testing laboratories or for whom the\u000a      cost of testing is prohibitive, the Exeter laboratory provides rapid\u000a      testing at no cost to the patient or their parents (funded by the Wellcome\u000a      Trust). Patients continue to be referred for testing from across the world\u000a      and, to October 2013, 1169 referrals had been received from 77 countries\u000a      across 5 continents. The number of patients diagnosed with a KATP\u000a      channel mutation causing neonatal diabetes had increased from 10 reported\u000a      in the first publication (2004) to 454 in October 2013.\u000a    2) Public awareness of neonatal diabetes and the need for genetic\u000a        testing has been raised. In July 2009, the Royal Society hosted the\u000a      first Neonatal Diabetes Open Day for families whose lives have been\u000a      changed by this research. 45 families came from across the world to\u000a      celebrate the life-changing transformations they have experienced.\u000a      Colleagues in Chicago (USA) were inspired to create a US registry and held\u000a      their first Neonatal Diabetes Family Meeting in June 2010. Facebook groups\u000a      have been created by parents and parent-led meetings have followed.\u000a    3) Most patients found to have a KATP channel\u000a        mutation can stop insulin treatment and achieve better glucose control\u000a        with sulphonylurea tablets. For most patients their glucose control\u000a      on insulin was outside treatment targets but on sulphonylureas glucose\u000a      levels are maintained within treatment targets and often close to the\u000a      levels in people without diabetes. More than 500 patients worldwide have\u000a      now had their diabetes therapy changed and many more newly diagnosed\u000a      individuals who would otherwise have been prescribed insulin therapy, are\u000a      being treated with tablets.\u000a    4) Changing from insulin injections to sulphonylurea tablets improves\u000a        quality of life by stopping pain at injection sites and removing the\u000a      many restrictions on life that are imposed by multi-injection or insulin\u000a      pump therapy. The regulation of insulin secretion in response to ingestion\u000a      of food means that the patients' diet is no longer tightly restricted.\u000a      They also experience fewer hypoglycaemic episodes.\u000a    5) The better glycaemic control achieved with sulphonylureas will\u000a        reduce the future risk of diabetic complications including heart\u000a      attack, stroke, kidney failure, blindness and neuropathy.\u000a    6) Many of the 20% of patients with neurological impairment have seen\u000a        an improvement in their motor skills, cognitive function, speech,\u000a        concentration, sleep and behaviour. Reports from parents have been\u000a      substantiated by teachers and healthcare professionals. The early\u000a      diagnosis made possible by clinical diagnostic genetic testing means that\u000a      the maximum number of patients can benefit from improved neurological\u000a      outcome as well as better diabetes control and lifestyle gains.\u000a    7) Reduced healthcare costs due to the cheaper treatment\u000a      (sulphonylurea tablets vs insulin), reduction in blood glucose monitoring\u000a      and reduced risk of diabetic complications later in life. For example,\u000a      colleagues in the USA (g; below) estimate that genetic testing followed by\u000a      transfer to sulphonylureas and consequent improved glycaemic control saves\u000a      $12,528 per patient at 10 years and $30,437 at 30 years.\u000a    8) This work has informed public debate on genomic medicine.\u000a    ","ImpactSummary":"\u000a    The treatment of patients with neonatal diabetes has been transformed by\u000a      the research of Professors Sian Ellard and Andrew Hattersley at Exeter.\u000a      Childhood diabetes usually presages a life-long requirement for insulin\u000a      injections and a reduction in quality of life. This research revealed that\u000a      ~50% of patients with permanent neonatal diabetes have mutations in a\u000a      potassium channel regulating insulin secretion. A new diagnostic test was\u000a      introduced and relevant patients were switched from insulin injections to\u000a      oral therapy. As a result, patients in 77 countries across 5 continents\u000a      now benefit from improved care, a better quality of life and reduced\u000a      healthcare costs.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Exeter\u000a    ","Institutions":[{"AlternativeName":"Exeter (University of)","InstitutionName":"University of Exeter","PeerGroup":"B","Region":"South West","UKPRN":10007792}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4887398","Name":"Chicago"}],"References":"\u000a    Evidence of the quality of the research is provided via a\u000a      selection of highly-cited, peer reviewed, publications and by the award of\u000a      external grant support.\u000a    \u000a1. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland\u000a      AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM,\u000a      Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P,\u000a      Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT.\u000a      Activating mutations in the gene encoding the ATP-sensitive\u000a      potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J\u000a      Med. 2004 350: 1838-1849. (692 citations to Oct 13)\u000a    \u000a\u000a2. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations\u000a      in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed\u000a      in the first 6 months of life, with the phenotype determined by genotype.\u000a      Diabetologia. 2006 49: 1190-1197. (130 citations to Oct 13)\u000a    \u000a\u000a3. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin\u000a      B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J,\u000a      Robert JJ, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M, Hattersley AT;\u000a      Neonatal Diabetes International Collaborative Group. Switching from\u000a      insulin to oral sulfonylureas in patients with diabetes due to Kir6.2\u000a      mutations. N Engl J Med. 2006 355: 467-777. (423 citations to Oct 13)\u000a    \u000a\u000a4: Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A,\u000a      Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ,\u000a      Shield JP, Hattersley AT, Ashcroft FM. Permanent neonatal diabetes caused\u000a      by dominant, recessive, or compound heterozygous SUR1 mutations with\u000a      opposite functional effects. Am J Hum Genet. 2007 81:375-82. (81 citations\u000a      to Oct 13)\u000a    \u000a\u000a5: Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT;\u000a      Neonatal Diabetes International Collaborative Group. Effective treatment\u000a      with oral sulfonylureas in patients with diabetes due to sulfonylurea\u000a      receptor 1 (SUR1) mutations. Diabetes Care. 2008 31:204-9. (76 citations\u000a      to Oct 13)\u000a    \u000a\u000a6: Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ.\u000a      Improved motor development and good long-term glycaemic control with\u000a      sulfonylurea treatment in a patient with the syndrome of intermediate\u000a      developmental delay, early-onset generalised epilepsy and neonatal\u000a      diabetes associated with the V59M mutation in the KCNJ11 gene.\u000a      Diabetologia. 2006 49:2559-63. (57 citations to Oct 13).\u000a    \u000aGrants:\u000a    1) Wellcome Trust 2003-2008 £1.13M (Prof Hattersley)\u000a      Title: Monogenic and Polygenic Influences on human fetal growth and\u000a      development — Wellcome Research Leave Award for Clinical Academics\u000a    2) Wellcome Trust 2008-2011 £430K (Prof Frayling co-PI)\u000a      Title: An investigation of genes in key beta-cell pathways following the\u000a      type 2 diabetes WTCCC genome wide association study.\u000a    3) MRC 2007-2010 £1.19M (Prof Frayling co-PI)\u000a      Title: Translating Genome-Wide Association Data from the WTCCC Study into\u000a      Biological and Clinical Insights in Type 2 Diabetes.\u000a    4) European Commission FP7 Initial Training Networks (Marie Curie)\u000a      2009-2013 €400K (PI Prof Hatterley and 12 others)\u000a      Title: BOLD — Biology of Liver and Pancreatic Development and Disease\u000a    5) Wellcome Trust 2012-2019 £2.9M (Joint PIs Prof Ellard and Hattersley)\u000a      Title: New insights from neonatal diabetes\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    Diagnostic genetic testing for all patients diagnosed with neonatal\u000a        diabetes.\u000a    a) The Exeter website www.diabetesgenes.org\u000a      provides information on genetic testing for neonatal diabetes and has\u000a      received >115000 hits (at Sept 2013).\u000a    Raised public awareness of neonatal diabetes and the need for\u000a      genetic testing.\u000a    b) The Wellcome Trust made a video which is available on their website\u000a      http:\/\/www.wellcome.ac.uk\/Education-resources\/Teaching-and-education\/Big-Picture\/All-issues\/Genes-Genomes-and-Health\/WTDV027170.htm\u000a    c) Diabetes UK includes neonatal diabetes within its website \"Guide to\u000a      diabetes\"\u000a      http:\/\/www.diabetes.org.uk\/Guide-to-diabetes\/Introduction-to-diabetes\/What_is_diabetes\/Neonatal-diabetes\/\u000a    d) A documentary entitled \"Journey to a Miracle: Freedom from Insulin\" is\u000a      in production. A pilot is available at http:\/\/www.tmktv.com\/result.php?title=Journey-to-a-Miracle:-Freedom-from-Insulin---Pilot\u000a    Improved quality of life for patients with a KATP channel\u000a      mutation who stop insulin treatment\u000a    Transfer from insulin to sulphonylurea tablets has transformed patient\u000a      lives. Patients and parents describe the effect this has had on their\u000a      lives in the video filmed by the Wellcome Trust and TMKTV Documentary (see\u000a      b and d).\u000a    e) The Exeter team were awarded the ISPAD (International Society for\u000a      Paediatric and Adolescent Diabetes) Prize for Innovation in Pediatric\u000a      Diabetes Care in 2012 see http:\/\/www.ispad.org\/\u000a    f) There have been numerous reports on the TV news and in newspapers\u000a      about the improved quality of life for patients. One example can be seen\u000a      on the BBC website http:\/\/news.bbc.co.uk\/1\/hi\/health\/8176275.stm\u000a      (August 2009)\u000a    Reduced healthcare costs due to the cheaper treatment\u000a      (sulphonylurea tablets vs insulin), reduction in blood glucose monitoring\u000a      and reduced risk of diabetic complications later in life.\u000a    g) Colleagues in Chicago (USA) demonstrated by modelling that genetic\u000a      testing for neonatal diabetes is cost-effective with savings achieved\u000a      within 10 years from testing (Greeley et al 2011 Diabetes Care 34,\u000a      622-627).\u000a    Informed public debate on genomic medicine\u000a    h) The House of Lords Select Committee on Science and Technology\u000a      conducted an enquiry into genomic medicine. Their report was published in\u000a      2009 and includes the example of neonatal diabetes (see page 18 http:\/\/www.parliament.uk\/business\/committees\/committees-archive\/lords-s-t-select\/genomic\/).\u000a      \u000a    ","Title":"\u000a    Stopping insulin; a life-changing therapeutic intervention for\u000a        patients with neonatal diabetes\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Before this research, most patients diagnosed with diabetes in the first\u000a      six months of life faced a lifetime of insulin treatment. In 2002, Prof\u000a      Hattersley (FRS; appointed to University of Exeter in 1995) initiated an\u000a      international search for patients with neonatal diabetes and Prof Ellard\u000a      (appointed in 1997) began the search for disease-causing mutations. As a\u000a      result, their postdoctoral fellow, Dr Anna Gloyn, found that the most\u000a      common cause was a mutation in a subunit (Kir6.2) of the pancreatic beta\u000a      cell ATP-sensitive potassium (KATP) channel [1,2].\u000a    The pancreatic KATP channel controls electrical activity,\u000a      linking raised blood glucose levels to insulin secretion. Binding of ATP\u000a      to the Kir6.2 subunit closes the channel to initiate insulin secretion.\u000a      Molecular modelling suggested that the patients' mutations would affect\u000a      ATP binding and hence prevent insulin secretion. This was confirmed by\u000a      functional studies of isolated potassium channels expressed either in\u000a      Xenopus oocytes [1] or cultured pancreatic beta-cells (with Prof Noel\u000a      Morgan in Exeter).\u000a    The pivotal stage in the research was recognising the possibility for\u000a      pharmaceutical intervention. The KATP channel defect suggested\u000a      that, in affected patients, the glucose sensing and insulin\u000a      synthesis\/secretion processes are intact, but failure to secrete insulin\u000a      is due to the channel remaining open in the presence of ATP. Sulphonylurea\u000a      drugs used to treat type 2 diabetes act by binding to the sulphonylurea\u000a      receptor (SUR1) subunits of the channel to cause their closure,\u000a      independently of ATP. Prof Hattersley proposed that sulphonylureas might\u000a      close the channels and facilitate insulin secretion when administered to\u000a      patients in vivo.\u000a    Clinical evidence from \"proof of principle\" studies supported this\u000a      possibility and in 2005 Prof Hattersley and PhD student Dr Ewan Pearson\u000a      led an international clinical trial in which >90% of patients with\u000a      Kir6.2 mutations were able to stop insulin treatment and achieve better\u000a      blood glucose control [3]. The improved glycaemic control predicts a lower\u000a      risk of diabetic complications later in life. In 2006, Prof Ellard found\u000a      that mutations in the SUR1 subunit also cause neonatal diabetes [4].\u000a      Overall, around 50% of patients with permanent neonatal diabetes have a\u000a      mutation in either the Kir6.2 or SUR1 subunits and most patients respond\u000a      to sulphonylurea therapy [5].\u000a    Approximately 20% of patients with Kir6.2 or SUR1 mutations also have\u000a      impaired neurological function. A small number have severe developmental\u000a      delay, epilepsy and neonatal diabetes (named by the Exeter group as DEND\u000a      syndrome). Prof FM Ashcroft's group (Oxford) showed that the mutations in\u000a      these patients have the greatest effect on channel function. A more common\u000a      intermediate form of DEND syndrome with moderate developmental delay was\u000a      also recognised and the researchers investigated the responses of these\u000a      patients to sulphonylurea treatment. Reports have described improved\u000a      cognitive function (particularly speech and concentration), behaviour,\u000a      sleeping patterns and motor development [6]. The neurological benefits are\u000a      likely to be greatest in those children treated with sulphonylureas from\u000a      diagnosis since brain plasticity is greatest in early childhood.\u000a    This research has provided one of the first examples of genomic medicine\u000a      where detailed knowledge of a patient's genome determines their optimal\u000a      treatment.\u000a    "},{"CaseStudyId":"35590","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000d\u000a    Impacts on health and welfare\u000d\u000a    1) The research has impacted dramatically on the lives of an estimated\u000d\u000a      15,000 patients throughout the world who have MODY caused by mutations in\u000d\u000a      the HNF1A, HNF4A or GCK genes. Up to 90% of patients with\u000d\u000a      MODY were previously misdiagnosed with type 1 or 2 diabetes and received\u000d\u000a      inappropriate treatment. The team's research has shown that, for patients\u000d\u000a      with HNF1A or HNF4A mutations, oral hypoglycaemic agents should be the\u000d\u000a      first pharmacological intervention. They also showed that patients with GCK\u000d\u000a      mutations can stop treatment, with no detrimental effect to their glucose\u000d\u000a      control or long term health.\u000d\u000a    2) For most patients their genetic diagnosis has led to a complete change\u000d\u000a      in their treatment such that they no longer rely on daily insulin\u000d\u000a      injections but can control their blood glucose levels with tablets (HNF1A\/4A\u000d\u000a      MODY) or can stop all treatment (GCK MODY). This has led to a\u000d\u000a      marked improvement in patient care and their quality of life.\u000d\u000a    Patient testimony 1, Mary: \"It's so much easier to take tablets each\u000d\u000a        day rather than having to inject with all the inconvenience and\u000d\u000a        discomfort\"\u000d\u000a    Patient testimony 2, Margaret: \"Even though I take these tablets I\u000d\u000a        don't feel like a diabetic anymore\"\u000d\u000a    Impacts on public services\u000d\u000a    3) Sulphonylurea therapy for HNF1A\/4A MODY has been adopted\u000d\u000a      internationally such that more than 10,000 patients worldwide have had\u000d\u000a      their diabetes therapy changed since this discovery.\u000d\u000a    4) A genetic testing service for the UK was established in Prof Ellard's\u000d\u000a      laboratory in 2000 and has continued throughout the REF period. To October\u000d\u000a      2013, a total of 2695 UK patients had been confirmed as having MODY.\u000d\u000a      Patient samples are also referred from clinics worldwide to establish an\u000d\u000a      accurate molecular diagnosis of MODY.\u000d\u000a    5) Prof Ellard introduced a European Quality Assessment Scheme that has\u000d\u000a      run since 2006 under the auspices of the European Molecular Genetics\u000d\u000a      Quality Network (http:\/\/www.emqn.org)\u000d\u000a      and by 2013, included 43 laboratories from 15 countries in Europe and\u000d\u000a      Australia. The scheme tests both genotyping and clinical interpretation,\u000d\u000a      providing feedback to improve the quality of genetic testing.\u000d\u000a    Impacts on practitioners\u000d\u000a    6) This research has impacted on diabetes care through revision to\u000d\u000a      clinical guidelines (Prof Hattersley led the 2009 ISPAD guidelines for\u000d\u000a      monogenic diabetes that include MODY) and diagnosis\/classification of\u000d\u000a      diabetes through Prof Hattersley's membership of the WHO Expert Committee.\u000d\u000a      Prof Ellard led the development of best practice guidelines for molecular\u000d\u000a      genetic testing in MODY. Originally published in 2008, these have been\u000d\u000a      adopted by laboratories throughout Europe via the European Molecular\u000d\u000a      Genetics Quality Network.\u000d\u000a    7) The group's website provides information for patients and healthcare\u000d\u000a      professionals. The online MODY calculator that predicts an individual's\u000d\u000a      risk of MODY from their clinical characteristics, family history and\u000d\u000a      biochemical test results is used by clinicians, scientists and patients\u000d\u000a      (>6000 hits to October 2013). It provides a systematic approach to\u000d\u000a      selecting those patients most likely to benefit from genetic testing, an\u000d\u000a      approach that is very much lacking for most other genetic tests.\u000d\u000a    8) The discovery that HNF4A mutations can cause macrosomia and\u000d\u000a      neonatal hypoglycaemia has led to the inclusion of HNF4A testing\u000d\u000a      into routine genetic testing for neonatal hypoglycaemia. This is important\u000d\u000a      as it highlights a high risk of developing diabetes in adolescence\/early\u000d\u000a      adulthood for these babies. The risk of macrosomia in future pregnancies\u000d\u000a      has clinical application in decisions regarding timing and mode of\u000d\u000a      delivery to avoid obstetric complications for the baby and mother.\u000d\u000a    Impacts on education and training\u000d\u000a    9) The researchers recognised that dissemination of the new knowledge\u000d\u000a      about genetic forms of diabetes was crucial in order to benefit the\u000d\u000a      maximal number of patients. An educational initiative to train UK Diabetes\u000d\u000a      Specialist Nurses to recognise and manage patients with MODY started in\u000d\u000a      2002 and, to October 2013, 47 nurses have received training about\u000d\u000a      monogenic diabetes. The Genetic Diabetes Nurse (GDN) network spans\u000d\u000a      England, Scotland and Wales and an on-going evaluation indicates that GDNs\u000d\u000a      have a higher positive pick up rate than patients referred from elsewhere\u000d\u000a      (245\/649, 38% v 726\/3364, 22%,p<0.0001) and increased referrals of\u000d\u000a      family members for genetic testing (157\/245 (64%) v\u000d\u000a      317\/733(43%),p<0.0001).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The diagnosis and treatment of patients with Maturity Onset Diabetes of\u000d\u000a      the Young (MODY) has been revolutionised by the research of Professors\u000d\u000a      Andrew Hattersley (FRS) and Sian Ellard at Exeter. Prior to this research,\u000d\u000a      up to 90% of patients with MODY were misdiagnosed as having type 1 or type\u000d\u000a      2 diabetes. To address this, the team developed new tests and integrated\u000d\u000a      these into routine diagnosis. They showed that patients could be\u000d\u000a      stratified to achieve delivery of the most appropriate therapy and, as a\u000d\u000a      result, as many as 15000 patients worldwide have now gained a better\u000d\u000a      quality of life.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Exeter\u000d\u000a    ","Institutions":[{"AlternativeName":"Exeter (University of)","InstitutionName":"University of Exeter","PeerGroup":"B","Region":"South West","UKPRN":10007792}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Evidence of the quality of the research is provided via a\u000d\u000a      selection of highly-cited, peer reviewed, publications and by the award of\u000d\u000a      external grant support.\u000d\u000a    \u000a1: Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley\u000d\u000a      AT. Genetic cause of hyperglycaemia and response to treatment in diabetes.\u000d\u000a      Lancet. 2003 362:1275-81. (269 citations to Oct 13).\u000d\u000a    \u000a\u000a2: Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard\u000d\u000a      S, Ferrer J, Hattersley AT. Macrosomia and hyperinsulinaemic hypoglycaemia\u000d\u000a      in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007\u000d\u000a      4:e118. (159 citations to Oct 13).\u000d\u000a    \u000a\u000a3: Stride A, Gill-Carey O, Shields B, Chakera AJ, Colclough K, Ellard S,\u000d\u000a      Hattersley AT. Cross sectional and longitudinal studies suggest\u000d\u000a      pharmacological treatment used in patients with glucokinase mutations does\u000d\u000a      not alter glycaemia. Diabetologia. 2013 (DOI 10.1007\/s00125-013-3075-x)\u000d\u000a    \u000a\u000a4: McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P,\u000d\u000a      Williams A, Hattersley AT, Ellard S. Islet autoantibodies can discriminate\u000d\u000a      maturity-onset diabetes of the young (MODY) from Type 1 diabetes. Diabet\u000d\u000a      Med. 2011 Sep;28(9):1028-33. (31 citations to Oct 13).\u000d\u000a    \u000a\u000a5: Besser RE, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Ellard\u000d\u000a      S,Hattersley AT. Urinary C-peptide creatinine ratio is a practical\u000d\u000a      outpatient tool for identifying hepatocyte nuclear factor\u000d\u000a      1-{alpha}\/hepatocyte nuclear factor4-{alpha} maturity-onset diabetes of\u000d\u000a      the young from long-duration type 1 diabetes. Diabetes Care. 2011\u000d\u000a      34:286-91. (32 citations to Oct 13).\u000d\u000a    \u000a\u000a6: Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT.\u000d\u000a      The development and validation of a clinical prediction model to determine\u000d\u000a      the probability of MODY in patients with young-onset diabetes.\u000d\u000a      Diabetologia. 2012 55:1265-72. (17 citations to Oct 13).\u000d\u000a    \u000aGrants:\u000d\u000a    1) Department of Health 2002-2007 £240K (Joint PIs: Prof Hattersley, Dr\u000d\u000a      Shepherd, Prof Ellard) Title: Educational model for the integration of\u000d\u000a      genetics into diabetes care\u000d\u000a    2) EU FP6 2006-2010 £6M (Prof Hattersley co-applicant with 16 others)\u000d\u000a      Title: EURODIA\u000d\u000a    3) NIH via the University of Washington, Seattle 2008-2010 £192K (Joint\u000d\u000a      PIs: Prof Hattersley and Prof Ellard) Title: SEARCH for diabetes in youth:\u000d\u000a      monogenic diabetes\u000d\u000a    4) The Diabetes Foundation 2007-2014 £110K (Joint PIs: Prof Hattersley,\u000d\u000a      Dr Shepherd, Prof Ellard) Title: The integration of genetics into diabetes\u000d\u000a      care: The genetic diabetes nurse project\u000d\u000a    5) Wellcome Trust\/NIHR Health Challenge Innovation Fund 2010-2013 £1.6M\u000d\u000a      (PI Prof Hattersley and 9 others, including Prof Ellard).Title: Using\u000d\u000a      pharmacogenetics to improve treatment in young-onset diabetes (UNITED).\u000d\u000a    6) Diabetes UK 2011-2014 £123K (Joint PIs: Prof Hattersley, Prof Ellard,\u000d\u000a      Dr Weedon and Dr Shields) Title: Finding novel MODY genes using exome\u000d\u000a      sequencing.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    Impacts on health and welfare\u000d\u000a    a) \"Novel diabetes therapy paves way for personalised medicine for all\"\u000d\u000a      The Times June 2008 http:\/\/www.thetimes.co.uk\/tto\/health\/article1881329.ece\u000d\u000a    b) Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A\u000d\u000a      genetic diagnosis of HNF1A diabetes alters treatment and improves\u000d\u000a      glycaemic control in the majority of insulin-treated patients. Diabet\u000d\u000a        Med. 2009 26:437-41.\u000d\u000a    c) Shepherd M. Stopping insulin injections following genetic testing in\u000d\u000a      diabetes: impact on identity. Diabet Med. 2010 27:838-43.\u000d\u000a    Impacts on public services\u000d\u000a    d) The Exeter website www.diabetesgenes.org\u000d\u000a      provides information on genetic testing for neonatal diabetes and has\u000d\u000a      received >115000 hits, including more than 10000 in the first 6 months\u000d\u000a      of 2013.\u000d\u000a    Impacts on practitioners\u000d\u000a    e) Ellard S, Bellanné-Chantelot C, Hattersley AT; European Molecular\u000d\u000a      Genetics Quality Network (EMQN) MODY group. Best practice guidelines for\u000d\u000a      the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia.\u000a        2008; 51: 546-553.\u000d\u000a    f) Murphy R, Ellard S, Hattersley AT. Clinical implications of a\u000d\u000a      molecular genetic classification of monogenic beta-cell diabetes. Nat\u000d\u000a        Clin Pract Endocrinol Metab. 2008 4:200-13.\u000d\u000a    g) Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The\u000d\u000a      diagnosis and management of monogenic diabetes in children and\u000d\u000a      adolescents. Pediatric Diabetes. 2009 Suppl 12:33-42.\u000d\u000a    h) US National Registry for MODY: Recommendations for treating MODY —\u000d\u000a      available online at: http:\/\/monogenicdiabetes.uchicago.edu\/treatment\/treatment-for-mody\/\u000d\u000a    i) Colom C, Corcoy R. Maturity onset diabetes of the young and pregnancy.\u000d\u000a      Best Pract Res Clin Endocrinol Metab. 2010 24:605-15.\u000d\u000a    Impacts on education and training\u000d\u000a    j) Shepherd M, Ellard S, Colclough K, Hattersley, AT. Do genetic diabetes\u000d\u000a      nurses make a difference? A 10 year evaluation of increasing knowledge of\u000d\u000a      monogenic diabetes through a national network Diabetic Medicine 2013\u000d\u000a      30: (Suppl 1) 8, A21.\u000d\u000a    ","Title":"\u000d\u000a    Personalised medicine in patients with Maturity Onset Diabetes of the\u000d\u000a        Young\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    MODY is a familial form of diabetes whose molecular basis was elucidated\u000d\u000a      in the 1990s. Genetic testing for MODY gene mutations was initially\u000d\u000a      established in Exeter by Professor Sian Ellard (appointed in 1997).\u000d\u000a      Identification of a mutation in the HNF1A gene in a patient with\u000d\u000a      an unexpected response to oral sulphonylureas led Professor Andrew\u000d\u000a      Hattersley (appointed in 1995) to design a randomised controlled crossover\u000d\u000a      study to investigate the response to sulphonylureas in a group of patients\u000d\u000a      with HNF1A MODY and a matched group with type 2 diabetes. The\u000d\u000a      results showed a 4-fold improvement in blood glucose levels in HNF1A\u000d\u000a      MODY compared to type 2 diabetes [1] and provided the first example of the\u000d\u000a      successful application of pharmacogenetics (i.e. personalised medicine) in\u000d\u000a      diabetes,. The team then showed that patients with mutations in a related\u000d\u000a      gene, HNF4A, were also sensitive to sulphonylurea treatment and,\u000d\u000a      in 2007, two novel phenotypes caused by HNF4A mutations were\u000d\u000a      defined; macrosomia and neonatal hypoglycaemia [2].\u000d\u000a    Another cause of MODY is mutation within the gene encoding glucokinase (GCK)\u000d\u000a      which leads to mild, stable, hyperglycaemia from birth. Although most\u000d\u000a      individuals are asymptomatic and do not require treatment, ~20% are\u000d\u000a      misdiagnosed with type 1 or 2 diabetes and treated with insulin or oral\u000d\u000a      hypoglycaemic agents. The research group has recently studied the effects\u000d\u000a      of pharmacological treatment on glycaemic control and found no\u000d\u000a      deterioration in glucose control in patients who stopped treatment after a\u000d\u000a      GCK mutation was diagnosed [3]. In a separate study the researchers\u000d\u000a      showed that these patients had no increased risk of diabetic complications\u000d\u000a      compared to population controls [4].\u000d\u000a    On the basis of these studies it became clear that a strong case could be\u000d\u000a      made to initiate routine genetic testing in diabetes to identify patients\u000d\u000a      with MODY and to stratify them according to the optimal treatment (a\u000d\u000a      personalised medicine approach). However, genetic testing is expensive and\u000d\u000a      selection of patients for testing is historically based on recognition of\u000d\u000a      key clinical characteristics by clinicians. Therefore, the team has now\u000d\u000a      developed an entirely new approach to distinguish patients likely to have\u000d\u000a      MODY from the more common type 1 diabetes. This is based on the\u000d\u000a      measurement of C-peptide, a by-product of insulin biosynthesis. Tim\u000d\u000a      McDonald (Exeter PhD student) found that C-peptide was stable in urine\u000d\u000a      samples for up to 72 hours, thereby providing a new opportunity to develop\u000d\u000a      an inexpensive but informative test. In 2011 Dr Rachel Besser (Exeter PhD\u000d\u000a      student) demonstrated that this test is extremely useful for\u000d\u000a      discriminating patients with MODY from those with type 1 diabetes [5].\u000d\u000a      Additional research demonstrated the utility of measurement of two\u000d\u000a      circulating autoantibodies, GAD and IA2, to refine the selection of\u000d\u000a      patients for genetic testing [4]. Prof Hattersley and Dr Bev Shields\u000d\u000a      (Exeter) then developed a clinical prediction model based on logistic\u000d\u000a      regression analysis of large data sets to calculate the likelihood that an\u000d\u000a      individual will have MODY based on their test results [6]. The \"MODY\u000d\u000a      Calculator\" is available online (www.diabetesgenes.org)\u000d\u000a      and to October 2013 had been used 5947 times by clinicians, patients and\u000d\u000a      scientists throughout the world to refine the selection of patients for\u000d\u000a      genetic testing.\u000d\u000a    "},{"CaseStudyId":"35614","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2623032","Name":"Denmark"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Research undertaken directly by Melzer & Galloway generated the first\u000d\u000a      large scale studies on the human health effects of BPA; one of the most\u000d\u000a      widely used chemicals in the world. This research has combined\u000d\u000a      observational epidemiology with detailed mechanistic studies to provide\u000d\u000a      enhanced research evidence of the human health effects of BPA. They showed\u000d\u000a      that the 25% of the population with the highest exposure to BPA have on\u000d\u000a      average a 1.5-2 fold increased risk of developing heart disease and that\u000d\u000a      this is independent of established risk factors such as smoking, blood\u000d\u000a      lipids or obesity. This research has yielded the following specific\u000d\u000a      identifiable impacts.\u000d\u000a    International policy debate has been stimulated. Publication of\u000d\u000a      their 2008 paper in JAMA [1] provoked a large number of policy discussion\u000d\u000a      documents such that Melzer & Galloway were invited in person to\u000d\u000a      provide verbal evidence to the FDA Congressional Review of the Safety\u000d\u000a        of BPA, Washington DC (September 2008). Policy papers discussing the\u000d\u000a      results and their impact on legislation and the current advice on\u000d\u000a      tolerable daily intakes were subsequently published in various countries\u000d\u000a      including by the US FDA, European Food Standards Agency, (Statement of the\u000d\u000a      European Food Safety Authority on a Study Associating bisphenol A with\u000d\u000a      Medical Disorders' (EFSA Journal 2008 838:1-3) [a]), the Advisory\u000d\u000a      Board of the German Society of Toxicology and Health Canada amongst\u000d\u000a      others. EFSA issued further debate in the 2010 paper [b] in EFSA\u000d\u000a        Journal 2010 8:9 `Scientific opinion on bisphenol A: evaluation of\u000d\u000a      studies investigating toxicity.'This review highlighted the need for `additional\u000a        longitudinal and mechanistic studies', which Melzer, Galloway and\u000d\u000a      team have since published [key references 3-6].\u000d\u000a    International policy has been influenced to restrict the use of\u000d\u000a      BPA in food contact materials. For example, in January 2010, US federal\u000d\u000a      officials at the FDA stated \"some concern\" about BPA's safety,\u000d\u000a      particularly for infants and young children. The case study research\u000d\u000a      undertaken by Melzer & Galloway [key references 1, 2] was included in\u000d\u000a      the cited evidence. Canada declared BPA a toxin and banned it from baby\u000d\u000a      bottles in 2008, followed by France and Denmark in 2010. Similar\u000d\u000a      restrictions have been instituted across various US states. In July 2012\u000d\u000a      FDA acknowledged `substantial uncertainties with respect to the overall\u000d\u000a      interpretation of human health studies and their implications'. and has\u000d\u000a      banned BPA from infant feeding containers. In January 2011, the European\u000d\u000a      Commission adopted Directive 2011\/8\/EU, prohibiting the use of BPA in\u000d\u000a      infant feeding bottles and has instigated a systematic re-evaluation of\u000d\u000a      research to inform current legislation further.\u000d\u000a    Public awareness of health risks has been raised through public\u000d\u000a      debate and critical media reviews [d-j]. There are over 3000 items of\u000d\u000a      editorial and commentary material discussing this work in the\u000d\u000a      international peer reviewed literature, international media, newspapers,\u000d\u000a      specialist scientific and popular press, e.g. national newspapers such as\u000d\u000a      The Independent, Times, Daily Mail, New York Times, popular journals e.g.\u000d\u000a      Marie Claire, Men's Health, Women's Health, National Geographic, Elle, BBC\u000d\u000a      Food Magazine. The research featured in a German TV documentary broadcast\u000d\u000a      to a target audience of >6 million across Europe. The research also\u000d\u000a      features in an online popular science blog and podcast from the BBC:\u000d\u000a      http:\/\/www.thenakedscientists.com\/HTML\/podcasts\/show\/2010.02.07\/;\u000d\u000a      Feb 7th 'Pollution and plastics'.\u000d\u000a    Industries have invested in research and development of safer chemical\u000d\u000a        alternatives. The 2008 paper [1] is specifically referenced as a\u000d\u000a      major piece of research influencing global market trends in several major\u000d\u000a      market research reports, including `BPA- A Global Strategic Business\u000d\u000a      Report (c).\u000d\u000a    BPA is the leading end-use segment for the phenol market and drives the\u000d\u000a      phenol market globally. Demand for BPA in 2010 was in excess of 2.7\u000d\u000a      million metric tonnes and, despite the health concerns, this figure is\u000d\u000a      predicted to continue to rise to 2018 with increased demand driven\u000d\u000a      especially by markets in the Far East (http:\/\/www.prweb.com\/releases\/bisphenolA_market\/phenol_market\/prweb10992205.htm). Nevertheless, earlier\u000d\u000a      growth estimates have been tempered by global health concerns (BPA 2012\u000d\u000a      World Market Outlook and Forecast to 2017) leading to a concerted effort\u000d\u000a      to develop viable, safer, alternatives by the plasticiser industry. This\u000d\u000a      has spawned a rise in green chemistry approaches and has led to the\u000d\u000a      synthesis and testing of alternative monomers, development of systems to\u000d\u000a      identify endocrine activity in novel materials and promotion of novel\u000d\u000a      polymerisation techniques to reduce unbound residues in polycarbonate.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research by Professors David Melzer and Tamara Galloway on the\u000d\u000a      bioactivity of Bisphenol A (BPA) an oestrogenic chemical widely used in\u000d\u000a      plastics, has influenced public policy on an international scale and led\u000d\u000a      to improvements in human health. They demonstrated that BPA is active in\u000d\u000a      the human body at commonly experienced concentrations and that higher\u000d\u000a      exposures are associated with hormonal imbalance and coronary artery\u000d\u000a      disease. The outcomes have stimulated policy debate and led to a\u000d\u000a      reappraisal of the environmental risks associated with BPA exposure.\u000d\u000a      Regulatory authorities across the world are now committed to reducing BPA\u000d\u000a      residues in food and beverages.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Exeter\u000d\u000a    ","Institutions":[{"AlternativeName":"Exeter (University of)","InstitutionName":"University of Exeter","PeerGroup":"B","Region":"South West","UKPRN":10007792}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Evidence of the quality of the research is provided via a\u000d\u000a      selection of highly-cited, peer reviewed, publications and by the award of\u000d\u000a      external grant support.\u000d\u000a    \u000a1. Lang IA, Galloway TS, Scarlett A, Henley W, Depledge M, Wallace RB,\u000d\u000a      Melzer D (2008) Association of urinary Bisphenol A concentration with\u000d\u000a      medical disorders and laboratory abnormalities in adults. Journal of\u000d\u000a        the American Medical Association 300(11) 1303-1310 (495 citations to\u000d\u000a      Oct 2013) accompanying editorial JAMA 300: 1353-1355; media\u000d\u000a      summary\u000d\u000a      http:\/\/pubs.ama-assn.org\/media\/2008jer\/0916.dtl#vnrscript)\u000d\u000a    \u000a\u000a2. Melzer D, Gates P, Osborn NJ, Henley WE, Cipelli R, Young A, Money C,\u000d\u000a      McCormack P, Schofield P, Mosedale D, Grainger D, Galloway TS. Urinary\u000d\u000a      bisphenol a concentration and angiography-defined coronary artery\u000d\u000a      stenosis. PLoS One. 2012;7(8):e43378. (9 citations to Oct 2013).\u000d\u000a    \u000a\u000a3. Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS (2010) Association\u000d\u000a      of urinary Bisphenol A concentration with heart disease: Evidence from\u000d\u000a      NHANES 2003\/06. PLoS One 5(1) e8673 (137 citations to Oct 2013)\u000d\u000a      see also editorials in Environ. Health Perspect. 118(3) A116 and Nature\u000d\u000a      doi:10.1038\/news.2010.7.\u000d\u000a    \u000a\u000a4. Melzer D, Osborne NJ, Henley WE, Cipelli R, Young A, Money C,\u000d\u000a      McCormack P, Luben R, Khaw KT, Wareham NJ, Galloway TS. Urinary Bisphenol\u000d\u000a      A concentration and risk of future coronary artery disease in apparently\u000d\u000a      healthy men and women. Circulation. 2012 Mar 27;125(12):1482-1490. (29\u000d\u000a      citations to Oct 2013).\u000d\u000a    \u000a\u000a5. Galloway T, Cipelli R, Guralnik J, Ferrucci L, Bandinelli S, Corsi AM,\u000d\u000a      Money C, McCormack P, Melzer D (2010) Daily Bisphenol A excretion and\u000d\u000a      associations with sex hormone concentrations: results from the InCHIANTI\u000d\u000a      adult population study. Environ Health Perspect.118(11):1603-1608\u000d\u000a      (38 citations to Oct 2013)\u000d\u000a    \u000a\u000a6. Melzer D, Harries L, Cipelli R, Henley W, Money C, McCormack P, Young\u000d\u000a      A, Guralnik J, Ferrucci L, Bandinelli S, Corsi AM, Galloway T. Bisphenol A\u000d\u000a      exposure is associated with in-vivo estrogenic gene expression in adults.\u000d\u000a      Environ Health Perspect. 2011 Dec;119(12):1788-1793. (16 citations\u000d\u000a      to Oct 2013).\u000d\u000a    \u000aGrants:\u000d\u000a    1) Chemical Exposure and risk of cardiovascular disease in adults: The\u000d\u000a      \"CARDIS\" Study; Project grant. Melzer D (PI), Galloway T, plus several\u000d\u000a      collaborators. The British Heart Foundation. Dates: 03\/2010 to 03\/2012.\u000d\u000a      Total grant: £125000\u000d\u000a    2) The Role of Bisphenol A In The Development Of Chronic Disease. Project\u000d\u000a      grant APP1022923. Magliano, D (PI) and colleagues, Baker IDI Heart and\u000d\u000a      Diabetes Institute, Australia. Melzer D: PI for Exeter UK work —\u000d\u000a      Aus$250000. National Health and Medical Research Council, Australia. Total\u000d\u000a      Grant Aus$384,000\u000d\u000a    3) Peninsula Clinical Research Facility 2009-2010 Title: Determination of\u000d\u000a      Bisphenol A concentrations in clinical samples from the InCHIANTI study.\u000d\u000a      £10000\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    a) EFSA Journal 2008:838 p1-3. `Statement of the European Food Safety\u000d\u000a      Authority on a study associating bisphenol A with medical disorders'.\u000d\u000a      References Melzer p.3\u000d\u000a      http:\/\/www.efsa.europa.eu\/en\/scdocs\/doc\/cef_ej838_statement_bpa_medical_disorders_en.pdf\u000d\u000a    b) EFSA Journal 2010 8(9) `Scientific Opinion on Bisphenol A: evaluation\u000d\u000a      of a study investigating its neurodevelopmental toxicity and review of\u000d\u000a      recent scientific literature on its toxicity ` — EFSA Panel on food\u000d\u000a      contact materials, enzymes, flavourings and processing aids '. References\u000d\u000a      Melzer p.85 and p.86.http:\/\/www.efsa.europa.eu\/it\/scdocs\/doc\/1829.pdf\u000d\u000a    c) BPA- A Global Strategic Business Report\/April 2010\/Global Industry\u000d\u000a      Analysts Ltd\u000d\u000a      http:\/\/www.strategyr.com\/bisphenol_A_market_report.asp.\u000d\u000a      see section II 10.\u000d\u000a    d) Naked Scientist Podcast 'Pollution and plastics' 26th\u000d\u000a      September 2010\u000d\u000a      http:\/\/www.thenakedscientists.com\/HTML\/podcasts\/show\/2010.02.07\/\u000d\u000a    e) `BPA Linked to Higher Testosterone Levels' 30th of August\u000d\u000a      2010.\u000d\u000a      http:\/\/www.webmd.com\/news\/20100826\/stidy-bpa-linked-to-higher-testosterone-levels\u000d\u000a    f) Bisphenol A Link to Heart Disease Confirmed Nature News. 13th of\u000d\u000a      January 2010\u000d\u000a      http:\/\/www.nature.com\/news\/2010\/100113\/full\/news.2010.7.html\u000d\u000a    g) Environmental Health News `Bisphenol A linked o Diabetes and Heart\u000d\u000a      Disease in Humans' 16th September 2008. http:\/\/www.environmentalhealthnews.org\/ehs\/news\/bisphenol-a-linked-to-diabetes-heart-disease-in-humans\u000d\u000a    h) USA Today `Bisphenol A `What You Need to Know'' 27th\u000d\u000a      October 2010\u000d\u000a      http:\/\/www.usatoday.com\/news\/health\/bpa.htm\u000d\u000a    i) Chemistry World December 2012 p46-49, `BPA, Friend or Foe?, by Nina\u000d\u000a      Notman, features an interview with Tamara Galloway. http:\/\/www.rsc.org\/chemistryworld\/2012\/11\/bpa-bisphenol\u000d\u000a    j) BBC One `Bang Goes the Theory' Plastics and their environmental and\u000d\u000a      health impacts; to be broadcast Spring 2013.\u000d\u000a      http:\/\/www.environmentalhealthnews.org\/ehs\/news\/bisphenol-a-linked-to-diabetes-heart-disease-in-humans\u000d\u000a    ","Title":"\u000d\u000a    The plastics chemical Bisphenol A and its potential human health effects\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Bisphenol A, a synthetic oestrogen, is added to polycarbonate plastics\u000d\u000a      and resins, from where it leaches into food and beverages and is readily\u000d\u000a      ingested by humans. It is then absorbed from the gut, processed in the\u000d\u000a      liver, circulated in the blood and excreted in the urine. By contrast, BPA\u000d\u000a      is excreted in the bile of laboratory rodents, with little entering the\u000d\u000a      peripheral circulation. Hence, animal models have proved unreliable as a\u000d\u000a      means to understand the disposition of BPA in humans, despite the use of a\u000d\u000a      variety of animal strains coupled with varying exposure routes and dosing\u000d\u000a      regimens. In humans, 95% of the US population has detectable urinary BPA\u000d\u000a      and, in a programme of epidemiological and human cell model analyses,\u000d\u000a      Melzer & Galloway demonstrated that circulating BPA may be more\u000d\u000a      bioactive than was previously thought and is associated with hormonal\u000d\u000a      imbalance and coronary heart disease. They have:\u000d\u000a    \u000d\u000a      Conducted the first cross-sectional associations between BPA\u000d\u000a        concentrations and adult diseases in a representative sample of the US\u000d\u000a        population — NHANES study, published in the Journal of the American\u000d\u000a        Medical Association in 2008 [1].\u000d\u000a      Performed the first replication study of these findings, confirming\u000d\u000a        that BPA exposure is associated with an elevated risk of coronary artery\u000d\u000a        disease [2;3].\u000d\u000a      Undertaken the first prospective study, showing that higher urinary\u000d\u000a        BPA concentrations predict onset of coronary heart disease in apparently\u000d\u000a        healthy adults in Norfolk, UK; thereby, augmenting any existing risk\u000d\u000a        factors [4].\u000d\u000a      Shown that these associations were specific to angiographically\u000d\u000a        defined coronary artery narrowings, in patients from Papworth Hospital,\u000d\u000a        Cambridgeshire UK [2].\u000d\u000a      Shown for the first time that men with higher concentrations of BPA\u000d\u000a        have higher testosterone concentrations [5]\u000d\u000a      Shown for the first time that expression of BPA target genes is\u000d\u000a        altered in association with higher BPA concentrations, with the first\u000d\u000a        evidence that BPA might activate the alternative oestrogen receptor\u000d\u000a        (ESRRA), a key controller of energy metabolism [6]\u000d\u000a      Obtained the first evidence that human cell models are responsive to\u000d\u000a        BPA exposure at extremely low concentrations relative to human exposures\u000d\u000a        (in progress)\u000d\u000a    \u000d\u000a    Throughout the course of their research, Melzer and Galloway have been\u000d\u000a      careful to note that definitive experimental proof of the adverse effects\u000d\u000a      of BPA in humans cannot be obtained. Nevertheless, they have been\u000d\u000a      instrumental in providing a solid body of underpinning evidence which\u000d\u000a      questions the safety of this environmental pollutant in human populations.\u000d\u000a    All of the work was developed and led in the University of Exeter by\u000d\u000a      Melzer (Professor of Epidemiology and Public Health; appointed 2005) and\u000d\u000a      Galloway (Professor of Toxicology; appointed 2007). The gene expression\u000d\u000a      studies were undertaken in collaboration with Dr Lorna Harries, Senior\u000d\u000a      Lecturer, University of Exeter Medical School.\u000d\u000a    "},{"CaseStudyId":"35837","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Change in the understanding of atopy pathogenesis has led to change\u000d\u000a          in clinical practice\u000d\u000a    A significant minority (9%) of the UK population carries one or more FLG\u000d\u000a      null alleles [1], therefore the increased risk of atopic disease affects\u000d\u000a      an estimated 5.7 million people, of whom approximately 2.4 million (42%)\u000d\u000a      [2] are likely to develop atopic eczema which is directly attributable to\u000d\u000a      FLG haploinsufficiency [3,4]. An additional 10.6% of the population\u000d\u000a      are homozygous for the lowest copy number variants of FLG,\u000d\u000a      associated with an increased risk of eczema (odds ratio ~1.67) [vi]. FLG\u000d\u000a      mutations increase the risk of disease at every stage of the so-called\u000d\u000a      `atopic march', from eczema early in life, to asthma, food allergy and\u000d\u000a      later allergic rhinitis [1,2].\u000d\u000a    The paradigm shift in understanding atopy has changed the focus of\u000d\u000a      clinical care to epidermal barrier function [5,6]. Since 2008, the\u000d\u000a      filaggrin\/atopy link has been the subject of 90 review articles [PubMed\u000d\u000a      search: filaggrin AND atopic 31\/10\/2013]. The research has attracted six\u000d\u000a      major national\/international research prizes, including the American Skin\u000d\u000a      Association Achievement Award 2009.\u000d\u000a    The research focus on barrier function has informed the development of\u000d\u000a      therapeutic guidelines. Thus, the NICE guidelines state: \"Atopic eczema\u000d\u000a      often has a genetic component that leads to the breakdown of the skin\u000d\u000a      barrier. This makes the skin susceptible to trigger factors, including\u000d\u000a      irritants and allergens, which can make the eczema worse\" (http:\/\/guidance.nice.org.uk\/CG57\/QuickRefGuide\/pdf\/English).\u000a      The NICE guideline on treatment emphasises the importance of emollient use\u000d\u000a      to improve skin barrier function, now a key quality statement: \"Children\u000d\u000a      with atopic eczema are prescribed sufficient quantities (250-500 g weekly)\u000d\u000a      from a choice of unperfumed emollients for daily use.\" (http:\/\/publications.nice.org.uk\/atopic-eczema-in-children-qs44\/list-of-quality-statements).\u000a      This\u000a      new understanding has been conveyed in undergraduate and postgraduate\u000d\u000a      teaching. Examples include the UK Advanced Paediatric Dermatology Course,\u000d\u000a      a lecture at the British Association of Dermatologists' Annual meeting\u000d\u000a      2013 and the NHS educational web pages `NHS inform' and `NHS choices' [7].\u000d\u000a    National and international public interest has increased awareness\u000d\u000a          of atopic disease\u000d\u000a    The eczema genetic discovery has led to improved public understanding of\u000d\u000a      science: Irwin McLean and Sara Brown have spoken to\u000d\u000a      capacity audiences at Café Science Dundee [8]; on a wider scale, they have\u000d\u000a      achieved major worldwide publicity, including front-page coverage by every\u000d\u000a      major newspaper in the UK, BBC News website [9] and Newsnight, ITV, Sky\u000d\u000a      News and a total of >100 TV and radio interviews. Media exposure has\u000d\u000a      continued with the intense interest in peanut allergy.\u000d\u000a    The message of skin barrier impairment in eczema has increased public\u000d\u000a      understanding of atopic disease, which improves compliance with emollient\u000d\u000a      therapy [10]. The National Eczema Society explains: \"If you have eczema\u000d\u000a        ...the protective barrier is therefore not as good as it should be...\u000d\u000a        skin with eczema is more liable to become red and inflamed on contact\u000d\u000a        with substances that are known to irritate or cause an allergic reaction.\"\u000d\u000a      http:\/\/www.eczema.org\/what-is-eczema.\u000d\u000a      The British Association of Dermatologists' patient information leaflet on\u000d\u000a      atopic eczema (http:\/\/www.bad.org.uk\/site\/792\/default.aspx)\u000d\u000a      explains the genetically-determined skin barrier defect and use of\u000d\u000a      emollient.\u000d\u000a    FLG genotype is used to stratify patients for clinical care and\u000d\u000a          clinical trials\u000d\u000a    The knowledge that FLG-null genotype is most strongly associated\u000d\u000a      with persistent, severe eczema and multiple atopic co-morbidities has\u000d\u000a      facilitated clinical sub-classification [2]. In patients with signs of\u000d\u000a      filaggrin deficiency, specific attention may be paid to the possible\u000d\u000a      development of asthma and food allergy. Asthma management in particular is\u000d\u000a      optimised by early recognition in children (http:\/\/www.brit-thoracic.org.uk\/guidelines\/asthma-guidelines.aspx).\u000d\u000a    Clinical trials of barrier enhancement interventions are underway. The\u000d\u000a      Barrier Enhancement for Eczema Prevention study (2010-11) demonstrated a\u000d\u000a      50% reduction in eczema incidence in babies receiving daily emollients,\u000d\u000a      interacting with FLG genotype (http:\/\/www.controlled-trials.com\/ISRCTN84854178).\u000a     A larger study is funded by the NIHR HTA Programme: `A randomised controlled\u000d\u000a      trial to determine whether skin barrier enhancement with emollients can\u000d\u000a      prevent eczema in high risk children' in which 1282 high-risk babies will\u000d\u000a      be screened for FLG mutations and monitored for development of\u000d\u000a      eczema, asthma and hay fever (http:\/\/www.nets.nihr.ac.uk\/projects\/hta\/126712).\u000d\u000a      Collectively, these three allergic diseases rank sixth for annual\u000d\u000a      expenditures among chronic health conditions in the US, with a total\u000d\u000a      estimated bill of ~$24billion (http:\/\/www.epa.gov\/ORD\/gems\/scinews_aeroallergens.htm).\u000a      A randomised controlled trial of silk therapeutic clothing for the\u000d\u000a      long-term management of eczema in children (http:\/\/www.hta.ac.uk\/project\/2984.asp)\u000d\u000a      also includes our FLG genotype-stratified analysis.\u000d\u000a    The finding that intragenic copy number variation determines eczema risk\u000d\u000a      with a dose-dependent effect [vi] indicates that an increase\u000d\u000a      in functional filaggrin of only 5-10% is sufficient to significantly\u000d\u000a      reduce eczema risk. This gives added impetus to the search for filaggrin\u000d\u000a      up-regulation therapies which would be applicable to 33% of the population\u000d\u000a      carrying low copy number [vi].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Atopic eczema and associated conditions — asthma, food allergy and hay\u000d\u000a      fever — affect ~40% of the population in developed nations. They cause\u000d\u000a      significant morbidity and create a multibillion-pound global healthcare\u000d\u000a      burden. The discovery that loss-of-function mutations in the gene encoding\u000d\u000a      filaggrin represent a strong risk factor for eczema, asthma and peanut\u000d\u000a      allergy has defined a key pathological mechanism in atopic disease. This\u000d\u000a      breakthrough in understanding has brought new focus on the skin barrier.\u000d\u000a      It has shown impact in treatment approaches to maintain barrier function,\u000d\u000a      translational research targeting epithelial dysfunction and improved\u000d\u000a      public and professional awareness of the role of skin in atopic disease.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Dundee\u000d\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000ai. Smith FJD, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE,\u000d\u000a      Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro\u000d\u000a      CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, Digiovanna JJ, Presland\u000d\u000a      RB, Fleckman P, McLean WHI (2006) Loss-of-function mutations in\u000d\u000a      the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet.\u000d\u000a      38, 337-42 (DOI: 10.1038\/ng1743).\u000d\u000a    \u000a\u000aii. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP,\u000d\u000a      Goudie DR, Sandilands A, Campbell LE, Smith FJD, O'Regan GM, Watson RM,\u000d\u000a      Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S,\u000d\u000a      Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer\u000d\u000a      LB, Bisgaard H, Mukhopadhyay S and McLean WHI (2006) Common\u000d\u000a      loss-of-function variants of the epidermal barrier protein filaggrin are a\u000d\u000a      major predisposing factor for atopic dermatitis. Nat. Genet. 38,\u000d\u000a      441-6 (DOI: 10.1038\/ng1767).\u000d\u000a    \u000a\u000aiii. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH,\u000d\u000a      Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M,\u000d\u000a      Gruber R, Janecke AR, Elias PM, van Steensel MAM, Nagtzaam I, van Geel M,\u000d\u000a      Steijlen PM, Munro CS, Bradley DG, Palmer CNA, Smith FJD, McLean\u000d\u000a      WHI* and Irvine AD* (*joint senior authorship). (2007) Comprehensive\u000d\u000a      analysis of the gene encoding filaggrin uncovers prevalent and rare\u000d\u000a      mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39,\u000d\u000a      650-4 (DOI: 10.1038\/ng2020).\u000d\u000a    \u000a\u000aiv. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan\u000d\u000a      NE, Callanan JJ, Kawasaki H, Shiohama A, Kubo A, Sundberg J, Presland RB,\u000d\u000a      Fleckman P, Shimizu N, Kudoh J, Irvine AD, Amagai M and McLean\u000d\u000a      WHI. A homozygous frameshift mutation in the mouse Flg gene facilitates\u000d\u000a      enhanced percutaneous allergen priming. Nat. Genet. 41,\u000d\u000a      602-8 (DOI: 10.1038\/ng.358).\u000d\u000a    \u000a\u000av. Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y, Liao H,\u000d\u000a      Northstone K, Henderson J, Alizadehfar R, Ben-Shoshan M, Morgan K, Roberts\u000d\u000a      G, Masthoff LJ, Pasmans SG, van den Akker PC, Wijmenga C, Hourihane JO,\u000d\u000a      Palmer CN, Lack G, Clarke A, Hull PR, Irvine AD, McLean WHI (2011)\u000d\u000a      Loss-of-function variants in the filaggrin gene are a significant risk\u000d\u000a      factor for peanut allergy. J. Allergy Clin. Immunol. 127,\u000d\u000a      661-7 (DOI: 10.1016\/j.jaci.2011.01.031).\u000d\u000a    \u000a\u000avi. Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E,\u000d\u000a      Kezic S, Cordell HJ, McLean WHI, Irvine AD (2012) Intragenic copy\u000d\u000a      number variation within filaggrin contributes to the risk of atopic\u000d\u000a      dermatitis with a dose-dependent effect. J. Invest. Dermatol. 132,\u000d\u000a      98-104 (DOI: 10.1038\/jid.2011.342).\u000d\u000a    \u000aPatents\u000d\u000a    • McLean WHI and Smith FJD (2005). \"Identification of\u000d\u000a      loss-of-function mutations in filaggrin causing ichthyosis vulgaris and\u000d\u000a      predisposing to other diseases\" PCT\/GB2006004707. Priority GB\/15.2.05\/ GBA\u000d\u000a      0525492. Date of filing 15.12.06. Date of publication 27.08.2008.\u000d\u000a    • McLean WHI and Smith FJD (2006). \"Prevention\/treatment of\u000d\u000a      ichthyosis vulgaris, atopy and other disorders.\" PCT\/GB2007000109.\u000d\u000a      Priority GB\/18.01.06\/ GBA 0600948. Date of filing 17.01.07. Date of\u000d\u000a      publication 25.12.2012.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    Reviews in medical and scientific journals:\u000d\u000a    \u000d\u000a      McAleer MA and Irvine AD (2011) The multifunctional role of filaggrin\u000d\u000a        in allergic skin disease. J. Allergy Clin. Immunol. 131,\u000d\u000a        208-91 (DOI: 10.1016\/j.jaci.2012.12.668).\u000d\u000a      Irvine AD, McLean WHI and Leung DY (2011) Filaggrin mutations\u000d\u000a        associated with skin and allergic diseases. New Engl. J. Med. 365,\u000d\u000a        1315-27 (DOI: 10.1056\/NEJMra1011040).\u000d\u000a    \u000d\u000a    Meta-analyses of FLG effect:\u000d\u000a    \u000d\u000a      Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell\u000d\u000a        HJ, Irvine AD and Weidinger S (2009) Meta-analysis of filaggrin\u000d\u000a        polymorphisms in eczema and asthma: robust risk factors in atopic\u000d\u000a        disease. J. Allergy Clin. Immunol. 123, 1361-70 (DOI:\u000d\u000a        10.1016\/j.jaci.2009.03.036).\u000d\u000a      van den Oord RA and Sheikh A (2009) Filaggrin gene defects and risk of\u000d\u000a        developing allergic sensitisation and allergic disorders: systematic\u000d\u000a        review and meta-analysis. Brit. Med. J. 339, b2433 (DOI:\u000d\u000a        10.1136\/bmj.b2433).\u000d\u000a    \u000d\u000a    Reviews in science media and the cosmetic industry:\u000d\u000a    \u000d\u000a      Ainsworth C (2011) SKIN into the breach. A focus on skin barrier\u000d\u000a        disorders has opened up new thinking about how allergies kick in. Nature\u000d\u000a        479, S12-14 (DOI: 10.1038\/479S12a).\u000d\u000a      Harding CR, Aho S and Bosko CA (Unilever) (2013) Filaggrin —\u000d\u000a        revisited. Int. J. Cosmetic Science 35, 412-423 (DOI:\u000d\u000a        10.1111\/ics.12049).\u000d\u000a    \u000d\u000a    NHS educational resources:\u000d\u000a    \u000d\u000a      \u000ahttp:\/\/www.nhsinform.com\/health-library\/articles\/e\/eczema-atopic\/causes\u000d\u000a        and\u000d\u000a        http:\/\/www.nhs.uk\/news\u000a          \/2011\/03March\/Pages\/peanut-allergy-faulty-gene-research.aspx.\u000d\u000a    \u000d\u000a    Examples of public engagement:\u000d\u000a    \u000d\u000a      Café Science Dundee http:\/\/www.cafesciencedundee.co.uk\/?p=1235\u000d\u000a        and http:\/\/www.cafesciencedundee.co.uk\/?p=1019\u000a\u000d\u000a      BBC news has given extensive coverage to the filaggrin story including\u000d\u000a        skin barrier and eczema (http:\/\/news.bbc.co.uk\/1\/hi\/scotland\/tayside_and_central\/4817512.stm)\u000d\u000a        and genetic risk for peanut allergy (http:\/\/www.bbc.co.uk\/news\/uk-scotland-tayside-central-12698727)\u000d\u000a        which reached number 7 most-read on the BBC news webpage.\u000d\u000a      Eczema Outreach Scotland (http:\/\/eczemaoutreachscotland.org.uk\/.)\u000a        a support group for patients and their families, established in 2011. Dr\u000d\u000a        Sara Brown is a medical adviser and attends educational and\u000d\u000a        outreach events.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Filaggrin — the major predisposing gene for atopic disease and a\u000d\u000a        target for stratified therapeutic intervention\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Atopic eczema is a complex trait, in which multiple genetic risk factors\u000d\u000a      interact with environmental factors in disease pathogenesis. Historically,\u000d\u000a      research in atopic disease has focused on the immune response in the\u000d\u000a      investigation of disease pathogenesis and in therapy development.\u000d\u000a    The research underpinning our breakthrough in understanding atopy\u000d\u000a      pathogenesis dates back to 2006, when the group of Prof Irwin McLean\u000d\u000a      (Professor of Human Genetics and Head of the Division of Molecular\u000d\u000a      Medicine, University of Dundee) reported that the common monogenic skin\u000d\u000a      disease, ichthyosis vulgaris (characterised by dry, scaly skin), is caused\u000d\u000a      by loss-of-function mutations in the gene encoding filaggrin (FLG)\u000d\u000a      [i]. The gene product profilaggrin is cleaved to produce monomeric\u000d\u000a      filaggrin, playing a role in keratin filament aggregation, skin barrier\u000d\u000a      formation and cutaneous hydration.\u000d\u000a    The McLean group made a seminal discovery, demonstrating that up\u000d\u000a      to 50% of severe childhood eczema cases carry FLG loss-of-function\u000d\u000a      mutations [ii,iii]. This created a paradigm shift in the eczema\/allergy\u000d\u000a      field by showing that one of the primary driving forces underlying common\u000d\u000a      atopic disorders is impaired skin barrier function. These findings support\u000d\u000a      a model for eczema aetiology whereby skin barrier dysfunction allows entry\u000d\u000a      of allergens and irritants resulting in skin and systemic inflammation.\u000d\u000a      Additional compelling evidence in support of this hypothesis was provided\u000d\u000a      in 2009 when the McLean group published the first mouse model of\u000d\u000a      filaggrin-related eczema and demonstrated that impaired skin barrier\u000d\u000a      function leads to skin and systemic inflammation triggered by percutaneous\u000d\u000a      allergen stimulation [iv].\u000d\u000a    The gene FLG is difficult to analyse due to its large size and\u000d\u000a      highly repetitive sequence [i-iii]. Techniques developed by Prof McLean\u000d\u000a      and colleagues to analyse other epidermal structural genes led to\u000d\u000a      ground-breaking discoveries in rare genodermatoses throughout the 1990s\u000d\u000a      and subsequently enabled the sequencing of FLG in advance of\u000d\u000a      international competitors. A complex pattern of prevalent and rare FLG\u000d\u000a      mutations in different population groups has now been identified.\u000d\u000a      Longitudinal population-based genetic studies have confirmed that FLG\u000d\u000a      is a major genetic factor in eczema, asthma and allergic rhinitis and that\u000d\u000a      FLG haploinsufficiency is particularly associated with severe,\u000d\u000a      early onset and persistent disease. Five recent genome-wide association\u000d\u000a      studies and one meta-analysis have confirmed that FLG is the\u000d\u000a      strongest genetic risk in atopic eczema, with an odds ratio >3.\u000d\u000a      Furthermore FLG remains the only locus in which a relationship has\u000d\u000a      been unequivocally demonstrated between gene and disease pathomechanism.\u000d\u000a    In 2011 Prof McLean and Dr Sara Brown (Wellcome Trust\u000d\u000a      Intermediate Clinical Fellow, Clinical Senior Lecturer and Honorary\u000d\u000a      Consultant Dermatologist, University of Dundee) led an international\u000d\u000a      collaboration to investigate the role of FLG mutations in\u000d\u000a      IgE-mediated peanut allergy. They reported a strong association with\u000d\u000a      replication in independent population groups [v], representing the first\u000d\u000a      established genetic risk factor in this severe food allergy. Dr Brown\u000d\u000a      also demonstrated in 2012 that copy number variation within FLG\u000d\u000a      contributes to eczema risk with a dose-dependent effect [vi], illustrating\u000d\u000a      the potential clinical utility of therapies aimed to increase filaggrin\u000d\u000a      expression.\u000d\u000a    The University of Dundee has filed two patents in developing FLG\u000d\u000a      genotyping as part of a personalised medicine approach for the\u000d\u000a      treatment\/prevention of atopic disease and for enhancement of filaggrin\u000d\u000a      expression as a novel therapy. These patents underpin grant income to the\u000d\u000a      McLean group from MRC and MRC Developmental Pathway Funding Scheme\u000d\u000a      (totalling ~£1.6million) in collaboration with the Drug Discovery Unit,\u000d\u000a      University of Dundee.\u000d\u000a    "},{"CaseStudyId":"35838","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"285570","Name":"Kuwait"}],"Funders":["Wellcome Trust","Economic and Social Research Council","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Government Policy Impact\u000d\u000a    Following publication of the underpinning research, Scottish Government\u000d\u000a      endorsed the need for nationwide clinical information systems to support\u000d\u000a      diabetes care through the Scottish Diabetes Group in the Scottish Diabetes\u000d\u000a      Framework (2002) and the Scottish Diabetes Action Plans (2006 and 2010\u000d\u000a      [1]). The Government commissioned further informatics research at the\u000d\u000a      University of Dundee to develop DARTS into a national technology product,\u000d\u000a      the Scottish Care Information-Diabetes Collaboration (SCI DC; http:\/\/www.sci-diabetes.scot.nhs.uk\/)\u000d\u000a      [2,3]. NHS Scotland Quality retinopathy screening [4]. E-very NHS Board in\u000d\u000a      Scotland was instructed to deploy SCI DC. TheImprovement Scotland also\u000d\u000a      endorsed its implementation for national clinical standards and Government\u000d\u000a      has funded SCI DC as a joint venture between the University of Dundee and\u000d\u000a      NHS — Tayside (~£750K per annum during the assessment period), and it is\u000d\u000a      now the national clinical information system for the care of all people\u000d\u000a      with diabetes in Scotland. SCI DC uses state of the art informatics to\u000d\u000a      combine information from heterogeneous data sources, including the\u000d\u000a      national community health index, general practices, hospitals,\u000d\u000a      laboratories and the national retinopathy screening service. Since 2004\u000d\u000a      SCI DC has been implemented in all 14 Scottish Health Boards, and since\u000d\u000a      2008 it has been used in 1038 general practices and 38 hospitals,\u000d\u000a      monitoring the care of over 271,000 people with diabetes. Since 2008 the\u000d\u000a      SCI-DC has supported the nationwide retinopathy screening programme (http:\/\/www.ndrs.scot.nhs.uk\/),\u000a      arguably the most complete, quality assured screening programme\u000d\u000a      internationally, performing digital retinal photography on 200,000 people\u000d\u000a      with diabetes annually. SCI-DC also produces the Scottish Diabetes Survey\u000d\u000a      [5] which has recorded year-on-year improvements in the quality of\u000d\u000a      diabetes care, delivers national diabetes patient-led information and\u000d\u000a      education packages (e.g. http:\/\/www.mydiabetesmyway.scot.nhs.uk\/)\u000d\u000a      and is embedded within national quality standards. In December 2008 SCI-DC\u000d\u000a      commissioned an independent review of its products with a view to\u000d\u000a      consolidating into a single system (SCI-DC Phase III) for diabetic care\u000d\u000a      across Scotland, as well as moving to the latest relevant technologies,\u000d\u000a      and in April 2013 the SCI-DC Team successfully completed the migration of\u000d\u000a      Health Boards from SCI-DC Network to the single SCI-DC Phase III product\u000d\u000a      now known as SCI-Diabetes [6].\u000d\u000a    Other impacts include:\u000d\u000a    \u000d\u000a      \u000aImproved patient care and health outcomes: SCI-DC supports the\u000d\u000a        evaluation of improved regional and national health outcomes, e.g. a 40%\u000d\u000a        reduction in amputation rates [ii] and a 40% reduction in\u000d\u000a        sight-threatening retinopathy 2003-2009 [iii], and has evolved into a\u000d\u000a        powerful nationwide pharmacovigilance tool, allowing safety assessment\u000d\u000a        of diabetes treatments and other therapies [v]. \u000d\u000a    \u000d\u000a    \u000d\u000a      \u000aStrategic Research Impact: SCI-DC is the core of the Scottish\u000d\u000a        Diabetes Research Network (http:\/\/www.sdrn.org.uk\/;\u000d\u000a        Dundee led), that attracts research income (~£500K p.a.) from the Chief\u000d\u000a        Scientist's Office to improve clinical trial performance (300% increase\u000d\u000a        2008-2013). The associated recruitment of individuals to large genomic\u000d\u000a        studies (>40,000 subjects) [7,8], and the linkage of phenotype to\u000d\u000a        genotype, has been of great importance [iv]. Dundee is now a major\u000d\u000a        partner of several international research endeavours including the\u000d\u000a        Wellcome Trust Case Control Consortium 2, the €43M DIRECT study on\u000d\u000a        stratification of diabetes (led from Dundee) and the €32M SUMMIT study\u000d\u000a        on biomarkers for diabetes complications (co-led by Dundee). Dundee\u000d\u000a        leads the Scottish node of the £39M MRC co-ordinated Farr Institute and\u000d\u000a        convenes the UK Health Informatics Research Network. In terms of\u000d\u000a        research policy, this case study has been highlighted as best practice\u000d\u000a        in the UK Life Sciences Strategy 2012, the UKTI \"Business\u000d\u000a          Olympics\" at Lancaster House July 2012, and The House of Lords\u000d\u000a          Report on Genomic Medicine (2009) [7]. The linkage between\u000d\u000a        research, informatics and health care led Sir Mark Walport, Director of\u000d\u000a        the Wellcome Trust to write (The Times 30th May, 2011); \"If you\u000d\u000a        live in Dundee and suffer from diabetes, you have recently been taking\u000d\u000a        part in a medical revolution.\"\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000aCreation of a new business: In 2008 Aridhia Informatics (http:\/\/www.aridhia.com)\u000d\u000a        was co- founded by the University with the aim of creating an\u000d\u000a        international health informatics company based in Scotland. Aridhia is\u000d\u000a        now a small-medium enterprise, based in Dundee and Edinburgh, which\u000d\u000a        employs 82 people. It has attracted >£10M of external investment,\u000d\u000a        including a £1.2M Technology Strategy Board Cancer Informatics programme\u000d\u000a        in Scotland, and venture funding from Scottish Equity Partners and\u000d\u000a        Albion Ventures. Aridhia has cloud-based deployments in Scotland,\u000d\u000a        England, Kuwait, New Zealand and Australia [9].\u000d\u000a      \u000aInternational Impact: We have rolled out the informatics model\u000d\u000a        internationally to the Kuwait-Scotland eHealth innovation network (www.dasmaninstitute.org\/kuwait-scotland).\u000a        The thesis is that we can export the Scottish Health Science \"package\"\u000d\u000a        of informatics, research and quality care delivery to other nations\u000d\u000a        wrestling with the challenge of non-communicable diseases. Following the\u000d\u000a        signing of a Memorandum of Understanding in 2010 between the Ministry of\u000d\u000a        Health in Kuwait, the Dasman Diabetes Institute [10], the University of\u000d\u000a        Dundee, NHS Tayside and Aridhia Informatics, the partners have:\u000d\u000a      \u000d\u000a        installed an electronic health record to the Capital Region of\u000d\u000a          Kuwait City (600,000) with nationwide roll-out anticipated in 2013;\u000d\u000a        enrolled 170 Kuwaiti students on a University of Dundee Masters\u000d\u000a          Course in Diabetes Care, Research and Education;\u000d\u000a        developed the Kuwait clinical skills centre, the first of its kind\u000d\u000a          in the Middle East;\u000d\u000a        established collaborative research programmes in genetics,\u000d\u000a          epidemiology and health services research;\u000d\u000a        secured multi-million pound income to Scotland (>£15M);\u000d\u000a        been shortlisted for the Times Higher Education Supplement\u000d\u000a          International Collaboration of the year 2012.\u000d\u000a      \u000d\u000a    \u000d\u000a    ","ImpactSummary":"\u000d\u000a    A health informatics platform supporting chronic disease management\u000d\u000a      nationally and internationally creating impact upon:\u000d\u000a    \u000d\u000a      \u000aNHS: Implementation in all 1043 general practices, 38\u000d\u000a        hospitals, and 14 Health Boards in Scotland, continuously monitoring\u000d\u000a        care of 271,000 people with diabetes, with evidence of improved clinical\u000d\u000a        outcomes.\u000d\u000a      \u000aGovernment Policy: Embedded in Government policy: Scottish\u000d\u000a        Diabetes Framework, Scottish Diabetes Action Plan; highlighted as \"best\u000d\u000a        practice\" in the 2009 House of Lords Report Genomic Medicine and\u000d\u000a        UK Life Sciences Strategy 2012.\u000d\u000a      \u000aCommercialisation: A start up informatics company, now with 82\u000d\u000a        employees and deployments internationally.\u000d\u000a      \u000aInternationalisation: Implementation of the informatics network\u000d\u000a        through the Kuwait-Scotland eHealth innovation network.\u000d\u000a    \u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Dundee\u000d\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"285787","Name":"Kuwait City"}],"References":"\u000d\u000a    \u000ai. Morris AD, Boyle DIR, MacAlpine R, Emslie Smith A, Jung RT,\u000d\u000a      Newton RW, McDonald TM (1997) The Diabetes Audit and Research in\u000d\u000a      Tayside Scotland (DARTS) Study: electronic record linkage to create a\u000d\u000a      diabetes register. DARTS\/MEMO Collaboration. Brit. Med. J. 315,\u000d\u000a      524 8 DOI: 10.1136\/bmj.315.7107.524).\u000d\u000a    \u000a\u000aii. Schofield CS Yu N, Jain AS, Leese GP (2009) Decreasing Amputation\u000d\u000a      rates in patients with diabetes — a population based study. Diabetic\u000d\u000a        Med. 26, 773 7 ( DOI: 10.1111\/j.1464-5491.2009.02770.x).\u000d\u000a    \u000a\u000aiii. Vallace JH, Wilson, PJ, Leese GP, McAlpine R, MacEwen, CJ, Ellis JD\u000d\u000a      (2008) Diabetic retinopathy: more patients, less laser. Diabetes Care\u000d\u000a      31, 1126 31 (DOI: 10.2337\/dc07-1498).\u000d\u000a    \u000a\u000aiv. Zeggini E,\u000d\u000a\u0009Weedon MN,\u000d\u000a\u0009Lindgren CM,\u000d\u000a\u0009Frayling TM,\u000d\u000a\u0009Elliott KS,\u000d\u000a\u0009Lango H,\u000d\u000a\u0009Timpson NJ,\u000d\u000a\u0009Perry JR,\u000d\u000a\u0009Rayner NW,\u000d\u000a\u0009Freathy RM,\u000d\u000a\u0009Barrett JC,\u000d\u000a\u0009Shields B,\u000d\u000a\u0009Morris AP, \u000d\u000a\u0009Ellard S,\u000d\u000a\u0009Groves CJ,\u000d\u000a\u0009Harries LW,\u000d\u000a\u0009Marchini JL,\u000d\u000a\u0009Owen KR,\u000d\u000a\u0009Knight B,\u000d\u000a\u0009Cardon LR, \u000d\u000a\u0009Walker M,\u000d\u000a\u0009Hitman GA,\u000d\u000a\u0009Morris AD,\u000d\u000a\u0009Doney AS;\u000d\u000a\u0009Wellcome Trust Case Control Consortium (WTCCC),\u000d\u000a\u0009McCarthy MI,\u000d\u000a\u0009Hattersley AT\u000d\u000a\u0009(2007) Replication of genome-wide association signals in UK\u000d\u000a      samples reveals risk loci for type 2 diabetes. Science 316,\u000d\u000a      1336 41 (DOI:10.1126\/science.1142364).\u000d\u000a    \u000a\u000av. Colhoun HM and SDRN Epidemiology Group (2009) Use of insulin glargine\u000d\u000a      and cancer incidence in Scotland: a study from the Scottish Diabetes\u000d\u000a      Research Network Epidemiology Group. Diabetologia 52, 1755\u000d\u000a      65 (DOI:10.1007\/s00125-009-1453-1).\u000d\u000a    \u000aFunding\u000d\u000a    The research underpinning this case study has been funded by substantial\u000d\u000a      research grants from a variety of peer-reviewed sources.\u000d\u000a    • Morris AD, Jung RT, McDonald TM: Does record linkage of\u000d\u000a      drug consumption facilitate complete diabetes registration?; Scottish Home\u000d\u000a      and Health Department (1996 1998) £105,752.\u000d\u000a    • Morris AD, Siann T, Jung RT, Newton RW, McDonald TM,\u000d\u000a      Matthews D, Reith S: Innovative IT to implement the St Vincent Declaration\u000d\u000a      and SIGN guidelines in Scotland; Scottish Office (1999 2001) £214,020.\u000d\u000a    • Morris AD¸ Davey PG, MacEwen CJ, Florey C du V: The\u000d\u000a      epidemiology of diabetic eye disease: a population based study; Wellcome\u000d\u000a      Trust (1998 2001) £177,104.\u000d\u000a    • Morris AD, Hattersley A, McCarthy M, Palmer C, Leese GP: The UK\u000d\u000a      Type 2 Diabetes Genetics consortium Case Control Collection: a resource\u000d\u000a      for the genetic epidemiology of Type 2 diabetes; Wellcome Trust Functional\u000d\u000a      Genomics Grant-(2004 2006) £822,900.\u000d\u000a    • Multiple large International Grants including: Innovative Medicines\u000d\u000a      Initiative (2010 2014, SUMMIT (complications of diabetes); €32M; joint PI\u000d\u000a      Professor H Colhoun, University of — Dundee leading on two work packages;\u000d\u000a      2012-2016 DIRECT Diabetes Research On Patient Stratification; €43M\u000d\u000a      Professor Ewan Pearson Dundee, PI), Wellcome Trust Case Control Consortium\u000d\u000a      2; (Pharmacogenetics Exemplar; Professor C Palmer, PI).\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    Evidence of impact into everyday clinical care across Scotland,\u000d\u000a      and commercialisation can be confirmed from the following websites\u000d\u000a      and individual contacts:\u000d\u000a    \u000d\u000a      The Scottish Government, Edinburgh (2010) Diabetes Action Plan 2010:\u000d\u000a        Quality Care for Diabetes in Scotland. ISBN: 978-0-7559-9379-6;\u000d\u000a        available at: http:\/\/www.diabetesinscotland.org.uk\/Publications\/DAP2010.pdf.\u000d\u000a      Corroboration of statements regarding the roll-out of the SCI-DC\u000d\u000a        across Scotland may be obtained from the former Lead Clinician for\u000d\u000a        Diabetes in Scotland.\u000d\u000a      Corroboration is also available from the Chair of the SCI DC Steering\u000d\u000a        Group.\u000d\u000a      NHS Quality Improvement Scotland (2008) National Overview Follow-up\u000d\u000a        Report ~ March 2008: Diabetes. ISBN 1-84404-499-8; available at: http:\/\/www.healthcareimprovementscotland.org\/previous_resources\/performance_review\/diabetes_follow-up_no.aspx.\u000d\u000a      NHS Scotland Scottish Diabetes Survey Monitoring Group (2009) Scottish\u000d\u000a        Diabetes Survey 2008: http:\/\/www.diabetesinscotland.org.uk\/Publications\/Scottish%20Diabetes%20Survey%202008.pdf\u000a\u000d\u000a      http:\/\/www.sci-diabetes.scot.nhs.uk\/history-2\/\u000d\u000a      House of Lords Science and Technology Committee; 2nd Report of Session\u000d\u000a        2008-09 Genomic Medicine Volume I: Report. Available at: http:\/\/www.publications.parliament.uk\/pa\/ld200809\/ldselect\/ldsctech\/107\/107i.pdf\u000a\u000d\u000a      Further corroboration may be obtained from the Chair of the Office of\u000d\u000a        Strategic Co-ordination of Health Research (OSCHR).\u000d\u000a      Corroboration may be obtained from the Chief Executive Officer of\u000d\u000a        Aridhia Informatics.\u000d\u000a      Corroboration may be obtained from the Director, Dasman Diabetes\u000d\u000a        Institute Kuwait.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Biomedical informatics transforming the care of people with chronic\u000d\u000a        diseases internationally\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Diabetes is a global health problem. In December 1996 the United Nations\u000d\u000a      declared diabetes to be a chronic, debilitating and costly disease\u000d\u000a      associated with severe complications, which poses severe risks for the\u000d\u000a      world. The number of people living with diabetes is estimated to be 500\u000d\u000a      million by 2030.\u000d\u000a    The underpinning research (1996-1998; Chief Scientist Office, Scottish\u000d\u000a      Government-funded) was carried out at the University of Dundee and led by\u000d\u000a      Professor Andrew Morris (Senior Lecturer in Medicine 1996-2000)\u000d\u000a      with Professor Tom McDonald, Director of the Medicines Monitoring\u000d\u000a      Unit who had pioneered record linkage for drug safety. The Diabetes Audit\u000d\u000a      and Research in Tayside, Scotland (DARTS) study tested the hypothesis that\u000d\u000a      record linkage of routinely collected NHS data sources was an efficient\u000d\u000a      and accurate methodology to create a regional diabetes register. The\u000d\u000a      initial study linked information from the community health index (health\u000d\u000a      identity number), hospital clinics, pharmacies, laboratories, and the\u000d\u000a      retinal screening service. The 1997 BMJ publication [i] reported\u000d\u000a      on the sensitivity and specificity of this methodology for diabetes\u000d\u000a      ascertainment and described the prevalence and morbidity of 7,500 people\u000d\u000a      in Tayside Scotland (population 400,000). This initial success was\u000d\u000a      followed by further underpinning research funding (Scottish Government\u000d\u000a      1999-2001) to demonstrate the scalability of the solution to another\u000d\u000a      Health Board, initially NHS Forth Valley (population 350,000) in 2000.\u000d\u000a      This developed and validated the informatics platform for the abstraction,\u000d\u000a      normalisation, integration and provisioning of clinical data. It created a\u000d\u000a      region wide clinical information system that provided value to frontline\u000d\u000a      multi disciplinary clinical teams across two Health Boards in Scotland.\u000d\u000a      From 2002, the Scottish Government adopted the health-informatics\u000d\u000a      platform and implemented it across Scotland. It now supports care of\u000d\u000a      271,000 people with diabetes nationally and represents the most\u000d\u000a      comprehensive clinical information system for the care of people with\u000d\u000a      diabetes internationally.\u000d\u000a    From an academic perspective, the Dundee team not only built on the\u000d\u000a      platform with >150 publications on classical epidemiology studies\u000d\u000a      (Wellcome Trust\/MRC funded [e.g. ii, iii]) but also anticipated the great\u000d\u000a      value of combining routinely collected phenotypic data from electronic\u000d\u000a      patient records with consented biologic materials, including DNA. This\u000d\u000a      additional underpinning research was funded by local charities (£100K\u000d\u000a      Tenovus Tayside; 1999 2002), and gained momentum with funding from the\u000d\u000a      Wellcome Trust Functional Genomics Programme (£790K; 2003-2007) to create\u000d\u000a      the UK Case Control Collection for Type 2 Diabetes. This recruited over\u000d\u000a      20,000 subjects for genetic studies of diabetes, its complications and\u000d\u000a      pharmacogenetics [e.g. iv]. This resource is the cornerstone of large\u000d\u000a      international research collaborations including the Innovative Medicines\u000d\u000a      Initiative and Wellcome Trust Case Control Consortium 2. The roll out to\u000d\u000a      the whole of Scotland has allowed the study of the epidemiology,\u000d\u000a      pharmacovigilance and outcomes research on a national basis, funded by the\u000d\u000a      Wellcome Trust, MRC, ESRC as part of the £3.7M Scottish Health Informatics\u000d\u000a      Programme (2008 2012) [e.g. v], and the recent 2012 award by MRC and nine\u000d\u000a      other funders of a eHealth Informatics Research Centre; Dundee has been\u000d\u000a      invited to lead the £39M UK network of-eHealth Centres, The Farr\u000d\u000a        Institute for Health Informatics Research, based upon this\u000d\u000a      underpinning research.\u000d\u000a    "},{"CaseStudyId":"35839","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000d\u000a    Our BNP research has helped to hasten the diagnosis of heart failure\u000d\u000a    There are considerable clinical difficulties involved in diagnosing heart\u000d\u000a      failure by symptoms alone. Our early work on BNP published in the Lancet\u000d\u000a      1993 and in 1997 lead to intense research into the utility of BNP in the\u000d\u000a      diagnosis of heart failure which has confirmed its accuracy. As a result,\u000d\u000a      all current Guidelines including the European Society of Cardiology 2012\u000d\u000a      Guidelines advocate the measurement of plasma concentrations of BNP in the\u000d\u000a      diagnosis of chronic heart failure, either in combination with, or as an\u000d\u000a      alternative to, an electrocardiogram [1,2]. The availability of BNP as a\u000d\u000a      diagnostic test has important implications. Firstly, when applied early in\u000d\u000a      the diagnostic process in patients with suspected cardiac failure, a\u000d\u000a      negative BNP test can help rule out congestive heart failure and thus\u000d\u000a      avoid unnecessary tests and referral to clinics. Secondly, BNP assessment\u000d\u000a      can hasten the correct diagnosis of heart failure allowing prompt delivery\u000d\u000a      of evidence based treatment and thereby reduce the morbidity and mortality\u000d\u000a      associated with heart failure [3]. The inclusion of BNP testing in the\u000d\u000a      recent 2010 NICE Guidelines [4] will have a major clinical impact [5].\u000d\u000a      These Guidelines was supported by a 2009 Health Technology Assessment\u000d\u000a      which showed that BNP testing is cost-effective and that measuring BNP is\u000d\u000a      the single most useful test to add to the diagnostic process in primary\u000d\u000a      care [3]. A costing report for implementing the 2010 NICE guidance on BNP\u000d\u000a      testing to rule out heart failure estimated that there will be a £3.8\u000d\u000a      million net saving and a 23% reduced risk per patient of being admitted to\u000d\u000a      hospital within the first six months with the implementation of BNP\u000d\u000a      testing [5].\u000d\u000a    Our BNP research has helped to introduce BNP as a biomarker to\u000d\u000a        identify at-risk patients for clinical trials\u000d\u000a    We were the first to utilize BNP as a biomarker to identify patients with\u000d\u000a      left ventricular systolic dysfunction for therapy (angiotensin converting\u000d\u000a      enzyme inhibitors). This concept is currently adopted in clinical trials\u000d\u000a      to identify at risk heart failure patients for study inclusion. Examples\u000d\u000a      of trials that used BNP to select patients are the Eplerenone or Placebo\u000d\u000a      in Addition to Standard Heart Failure Medicines (EMPHASIS-HF) trial and\u000d\u000a      the ongoing PARADIGM study (Efficacy and Safety of LCZ696 Compared to\u000d\u000a      Enalapril on Morbidity and Mortality of Patients With Chronic Heart\u000d\u000a      Failure) [6].\u000d\u000a    Our BNP research has helped to diagnose HFpEF \/ diastolic dysfunction\u000d\u000a    We were also the first to show that BNP was elevated and related to\u000d\u000a      diastolic filling in patients with isolated diastolic dysfunction. Half of\u000d\u000a      patients with heart failure have preserved ejection fraction with similar\u000d\u000a      morbidity and mortality to heart failure with reduced ejection fraction.\u000d\u000a      Diagnosis of HFpEF is challenging, especially in patients with multiple\u000d\u000a      co-morbidities. The diagnosis of heart failure with reduced ejection\u000d\u000a      fraction now requires coupling exertional dyspnoea and a normal left\u000d\u000a      ventricular ejection fraction with objective measures of diastolic\u000d\u000a      dysfunction such as the measurement of plasma BNP. This use of BNP is now\u000d\u000a      recommended by most experts for the diagnosis of HFpEF [7] and as an\u000d\u000a      inclusion criterion in studies of HFpEF such as the TOPCAT study of\u000d\u000a      aldosterone antagonist therapy for adults with heart failure and preserved\u000d\u000a      systolic function [8]. The current NICE Guidelines also recommend BNP\u000d\u000a      testing in heart failure as \"Earlier diagnosis and treatment of associated\u000d\u000a      conditions (such as hypertension) in patients with HFpEF who are found to\u000d\u000a      have raised BNP levels is likely to result in a decrease in the number of\u000d\u000a      these patients needing hospital admission\" [3].\u000d\u000a    Our BNP research has helped in the management of asymptomatic aortic\u000d\u000a        stenosis\u000d\u000a    Identification of subgroups of symptomatic patients with aortic stenosis\u000d\u000a      who may benefit from early surgery is a clinical challenge. We were the\u000d\u000a      first to demonstrate elevated plasma BNP in aortic stenosis and this led\u000d\u000a      to international investigations of the prognostic value of BNP in aortic\u000d\u000a      stenosis which underpin the latest 2012 European Society of Cardiology\u000d\u000a      recommendation for BNP testing in asymptomatic severe aortic stenosis to\u000d\u000a      select patients for aortic valve replacement (Level C, Class IIb\u000d\u000a      recommendation) [9].\u000d\u000a    Our BNP research has prompted the development of commercial assays for\u000d\u000a        BNP\u000d\u000a    The success of BNP testing in routine clinical settings is attested by\u000d\u000a      the fact that BNP tests is available on both mainframe laboratory systems\u000d\u000a      as well as point-of-care analysers. Tests for measuring BNP are now\u000d\u000a      offered by all major in vitro diagnostics players including\u000d\u000a      companies such as Abbott, Alere, Roche, Siemens, OCD and Beckman-Coulter.\u000d\u000a      In a report on point-of-care diagnostic testing world markets, it was\u000d\u000a      stated that in terms of `market drivers ranked in order of impact', BNP\u000d\u000a      testing was placed third out of twelve drivers [10] demonstrating that\u000d\u000a      these commercial BNP assays have a direct economical impact [11].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Our research on brain\/B-type naturietic peptide (BNP) has helped to\u000d\u000a      diagnose both types of heart failure (systolic and diastolic heart\u000d\u000a      failure) and to identify high-risk aortic stenosis patients for surgery.\u000d\u000a      We were first to demonstrate the value of BNP as a biomarker for left\u000d\u000a      ventricular systolic dysfunction, isolated diastolic dysfunction and for\u000d\u000a      aortic stenosis. BNP testing is now recommended in Guidelines as a\u000d\u000a      screening test for patients with suspected heart failure (Class I\u000d\u000a      recommendation) and in the current European Society of Cardiology\u000d\u000a      consensus statement for diagnosis of diastolic heart failure. The European\u000d\u000a      Society of Cardiology Guidelines have also introduced BNP testing in the\u000d\u000a      management of patients with aortic stenosis (Class IIb recommendation).\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Dundee\u000d\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000ai. Motwani JG, McAlpine H, Kennedy N and Struthers AD (1993)\u000d\u000a      Plasma brain natriuretic peptide as an indicator for\u000d\u000a      angiotensin-converting-enzyme inhibition after myocardial infarction. Lancet\u000d\u000a      341, 1109-13 (DOI:10.1016\/0140-6736(93)93126-L).\u000d\u000a    \u000a\u000aii. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG,\u000d\u000a      Poole-Wilson PA and Sutton GC (1997) Value of natriuretic peptides in\u000d\u000a      assessment of patients with possible new heart failure in primary care. Lancet\u000d\u000a      350, 1349-53 (DOI:10.1016\/S0140-6736(97)06031-5).\u000d\u000a    \u000a\u000aiii. Lang CC, Prasad N, McAlpine HM, MacLeod C, Lipworth BJ,\u000d\u000a      MacDonald TM and Struthers AD (1994) Increased levels of brain\u000d\u000a      natriuretic peptide in patients with isolated diastolic dysfunction. Am.\u000d\u000a        Heart J. 127, 1635-636 (DOI:\u000a        10.1016\/0002 8703(94)90401-4).\u000d\u000a    \u000a\u000aiv. Prasad N, Bridges N, Lang CC, Clarkson P, Struthers\u000d\u000a      AD, MacDonald TM (1997) Brain natriuretic peptide plasma concentrations in\u000d\u000a      patients with aortic stenosis. Am. Heart J. 133, 477-479 (DOI:\u000d\u000a        10.1016\/S0002-8703(97)70196-0).\u000d\u000a    \u000a\u000av. Nadir MA, Rekhraj S, Wei L, Lim TK, Davidson J, MacDonald TM, Lang\u000d\u000a      CC, Dow E, Struthers AD (2012) Improving the Primary Prevention of\u000d\u000a      Cardiovascular events by using Biomarkers to identify Individuals with\u000d\u000a      Silent Heart Disease. J. Am. Coll. Cardiology 60, 960-8\u000d\u000a      (DOI: 10.1016\/j.jacc.2012.04.049).\u000d\u000a    \u000aFunding\u000d\u000a    • Struthers AD, Pringle TH, McNeil G: The potential use of\u000d\u000a      natriuretic peptide in clinical cardiology; British Heart Foundation\u000d\u000a      (1993-1995) £65,644.\u000d\u000a    • Cowie M, Coats A, Struthers AD: Sensitivity, specificity and\u000d\u000a      predictive value of natriuretic peptide levels in detecting ventricular\u000d\u000a      dysfunction in those with a new primary care diagnosis of heart failure;\u000d\u000a      British Heart Foundation (1995-1997) £10,205.\u000d\u000a    • Struthers AD, Pringle S, Goudie B, Sullivan F: Improving the\u000d\u000a      diagnosis of heart failure in general practice; British Heart Foundation\u000d\u000a      (2001-2004) £108,206.\u000d\u000a    • Struthers AD, Pringle S, Goudie B, Sullivan, Donnan P: Near\u000d\u000a      patient BNP and portable echocardiography in general practice; British\u000d\u000a      Heart Foundation (2004-2006) £124,670.\u000d\u000a    • Struthers AD, Lang CC, MacDonald T, Houston G: The\u000d\u000a      potential to improve primary prevention by using BNP as an indicator of\u000d\u000a      silent pan-cardiac target organ damage: the 5P study; British Heart\u000d\u000a      Foundation (2007-2013) £323,958.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein\u000d\u000a        K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber\u000d\u000a        L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik\u000d\u000a        PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors\u000d\u000a        AA, Zannad F, Zeiher A; ESC Committee for Practice Guidelines (2012) ESC\u000d\u000a        Guidelines for the diagnosis and treatment of acute and chronic heart\u000d\u000a        failure 2012: The Task Force for the Diagnosis and Treatment of Acute\u000d\u000a        and Chronic Heart Failure 2012 of the European Society of Cardiology.\u000d\u000a        Developed in collaboration with the Heart Failure Association (HFA) of\u000d\u000a        the ESC. Eur. Heart J. 33, 1787-1847\u000d\u000a        (DOI:10.1093\/eurheartj\/ehs104).\u000d\u000a      Letter of Corroboration from the Chairperson, European Society of\u000d\u000a        Cardiology Clinical Practice Guidelines Task Force.\u000d\u000a      National Heart Foundation of Australia (2011) Guidelines for the\u000d\u000a        prevention, detection and management of chronic heart failure in\u000d\u000a        Australia, updated 2011. ISBN 978-1-921748-71-4; available at:\u000d\u000a        http:\/\/www.heartfoundation.org.au\/SiteCollectionDocuments\/Chronic_Heart_Failure_Guidelines_2011.pdf\u000a\u000d\u000a      Letter of Corroboration from the Chair, National Heart Foundation of\u000d\u000a        Australia, Cardiac Society of Australia and New Zealand, Chronic Heart\u000d\u000a        Failure Guidelines Expert Writing Panel.\u000d\u000a      Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, Mant D,\u000d\u000a        McManus RJ, Holder R, Deeks J, Fletcher K, Qume M, Sohanpal S, Sanders\u000d\u000a        S, Hobbs FD (2009) Systematic review and individual patient data\u000d\u000a        meta-analysis of diagnosis of heart failure, with modelling of\u000d\u000a        implications of different diagnostic strategies in primary care. Health.\u000a          Technol. Assess. 13, 1-232. http:\/\/www.journalslibrary.nihr.ac.uk\/hta\/volume-13\/issue-32.\u000d\u000a      Paradigm HF Trial: http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01035255\u000a\u000d\u000a      National Clinical Guideline Centre (2010) Chronic heart failure: the\u000d\u000a        management of chronic heart failure in adults in primary and secondary\u000d\u000a        care London: National Clinical Guideline Centre. Available from: http:\/\/guidance.nice.org.uk\/CG108\/Guidance\/pdf\/English;\u000d\u000a        National Institute for Health and Clinical Excellence (2010) Costing\u000d\u000a        Report — Chronic Heart Failure: Implementing NICE guidance. http:\/\/www.nice.org.uk\/nicemedia\/live\/13099\/51015\/51015.pdf\u000a\u000d\u000a      Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell\u000d\u000a        N, Diaz R, Fleg JL, Gordeev I, McKinlay S, O'Meara E, Shaburishvili T,\u000d\u000a        Pitt B, Pfeffer MA. (2011) Rationale and design of the treatment of\u000d\u000a        preserved cardiac function heart failure with an aldosterone antagonist\u000d\u000a        trial: a randomized, controlled study of spironolactone in patients with\u000d\u000a        symptomatic heart failure and preserved ejection fraction. Am. Heart\u000d\u000a          J. 162, 966-972 (DOI: 10.1016\/j.ahj.2011.09.007).\u000d\u000a      Joint Task Force on the Management of Valvular Heart Disease of the\u000d\u000a        European Society of Cardiology (ESC); European Association for\u000d\u000a        Cardio-Thoracic Surgery (EACTS) (2012) Guidelines on the management of\u000d\u000a        valvular heart disease (version 2012) Eur. Heart J. 33,\u000d\u000a        2451-2496 (DOI: 10.1093\/eurheartj\/ehs109).\u000d\u000a      TriMark Publications, LLC (2013) Point of Care Diagnostic Testing\u000d\u000a        World Markets July 2013. Sample available at:\u000d\u000a        https:\/\/www.trimarkpublications.com\/product_images\/samples\/pocdiagnosticssample.pdf.\u000d\u000a      Letter of Corroboration from the Commercial Director, Axis-Shield\u000d\u000a        \/Alere.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    BNP as a Diagnostic and Risk Stratifying Test in Cardiology\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Around 900,000 people in the UK have heart failure. Both the incidence\u000d\u000a      and prevalence of heart failure increase steeply with age. Heart failure\u000d\u000a      accounts for a total of 1 million inpatient bed days and 5% of all\u000d\u000a      emergency medical admissions to hospital with readmission rates among the\u000d\u000a      highest for any common condition in the UK. Financially, this adds up to\u000d\u000a      some 2% of healthcare costs, about two thirds of which are hospital costs.\u000d\u000a      The costs of GP consultations have been estimated at £45 million per year\u000d\u000a      with an additional £35 million for GP referrals to outpatient clinics.\u000d\u000a      Community based drug therapy for heart failure costs the NHS around £129\u000d\u000a      million per year.\u000d\u000a    The diagnosis of heart failure is difficult because its symptoms are\u000d\u000a      non-specific and the physical signs are often not obvious; however, early\u000d\u000a      and accurate diagnosis is important so that patients can start appropriate\u000d\u000a      life-saving treatment. The British Heart Foundation-funded research and\u000d\u000a      development work underpinning this case study was led by Professor Allan Struthers\u000d\u000a      (Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and\u000d\u000a      Medical School, Dundee) with assistance from Motwani (British Heart\u000d\u000a      Foundation research fellow) and Chim Lang (at the time a Lecturer\u000d\u000a      in the Department) in collaboration with Norman Kennedy (medical\u000d\u000a      physicist, Ninewells Hospital). We were the first to show that plasma\u000d\u000a      levels of BNP could be used in clinical practice to detect left\u000d\u000a      ventricular systolic dysfunction [i]. We followed this with a study of the\u000d\u000a      diagnostic role of BNP in a community population in another Lancet\u000d\u000a      publication [ii]. The latter publication provided the evidence leading to\u000d\u000a      National and International Guidelines recommending BNP testing in patients\u000d\u000a      with suspected heart failure in the community.\u000d\u000a    Our work on BNP as a biomarker of left ventricular wall stress led us to\u000d\u000a      show for the first time that BNP was elevated in patients with the other\u000d\u000a      form of heart failure (isolated diastolic dysfunction) [iii]. The\u000d\u000a      diagnosis of heart failure with preserved ejection fraction (HFpEF) due to\u000d\u000a      diastolic dysfunction is difficult, especially in patients with multiple\u000d\u000a      co-morbidities. To aid diagnosis, the use of plasma BNP as a biomarker\u000d\u000a      which is elevated in elevated left ventricular wall stress has been\u000d\u000a      recommended in Guidelines including the European Society of Cardiology\u000d\u000a      consensus statement on HFpEF. This test and is used as an inclusion\u000d\u000a      criterion in most ongoing studies of HFpEF including the on-going\u000d\u000a      Treatment Of Preserved Cardiac function heart failure with an Aldosterone\u000d\u000a      anTagonist (TOPCAT) study (see section 4).\u000d\u000a    Aortic stenosis is the most common valvular disease in Western countries.\u000d\u000a      Identification of subgroups of symptomatic patients with aortic stenosis\u000d\u000a      who may benefit from early surgery is a clinical challenge. Our 1997\u000d\u000a      American Heart Journal publication was the first study to show elevated\u000d\u000a      plasma BNP in aortic stenosis [iv]. This observation led to international\u000d\u000a      investigations which provided the evidence underpinning the latest\u000d\u000a      European Society of Cardiology recommendation on BNP testing in\u000d\u000a      asymptomatic severe aortic stenosis to select patients for aortic valve\u000d\u000a      replacement.\u000d\u000a    In further recent related work, we have expanded the diagnostic role for\u000d\u000a      BNP into other populations of patients. We have recently described for the\u000d\u000a      first time how BNP could be used in primary prevention to detect patients\u000d\u000a      with silent asymptomatic heart disease such as left ventricular\u000d\u000a      hypertrophy and silent coronary artery disease [v].\u000d\u000a    "},{"CaseStudyId":"35840","Continent":[{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":[],"ImpactDetails":"\u000a    Our underpinning research addressed the challenge of heart failure, which\u000a      is a global health issue. It led to the recognition that aldosterone\u000a      antagonists such as spironolactone have beneficial effects in individuals\u000a      with various kinds of heart failure. It is now widely recognised that\u000a      aldosterone antagonists improve survival among patients with chronic,\u000a      severe systolic heart failure and heart failure after myocardial\u000a      infarction. Consequently, current guidelines recommend the use of an\u000a      aldosterone-receptor antagonist in these patients. This has led to\u000a      significant patient benefit.\u000a    Aldosterone antagonist treatment is now recommended in National Institute\u000a      for Health and Case Excellence (NICE) guidelines, specifically those on\u000a      chronic heart failure ([1]; issued in 2010). In preparing this Guideline,\u000a      NICE gave detailed consideration to our previous work, as follows:\u000a      \"....studies were identified comparing aldosterone antagonists plus\u000a      optimal medical management with placebo plus optimal medical management in\u000a      patients with chronic heart failure. Barr (1995) [i] compared\u000a      spironolactone with placebo in a population with chronic heart failure\u000a      (CHF) secondary to coronary heart disease. Macdonald (2004) [v] compared\u000a      spironolactone with placebo in a population with mild heart failure,\u000a      defined as patients whose CHF had been at least [New York Heart\u000a      Association] NYHA class II at diagnosis, but optimising their treatment\u000a      had improved the patients' condition substantially into a stable and less\u000a      symptomatic one.....\" (Section 5.2.3.2, p96; tabulated on p103). This\u000a      contributed to the following recommendation (R29) for second-line\u000a      treatments: \"....consider adding one of the following if a patient remains\u000a      symptomatic despite optimal therapy with an ACE inhibitor and a\u000a      beta-blocker: an aldosterone antagonist licensed for heart failure\u000a      (especially if the patient has moderate to severe heart failure [NYHA14\u000a      class III-IV], or has had a myocardial infarct within the past\u000a      month)....\".\u000a    In recognition of the influence of his work on heart failure, Prof Struthers\u000a      was appointed as a member of the Steering Group of the NHS Quality\u000a      Improvement Scotland Heart Disease project, which led in 2010 to the\u000a      publication of Clinical Standards for Heart Disease [2]. These apply\u000a      throughout the NHS in Scotland and recommend (Standard Statement 15, p28)\u000a      that \"Patients with heart failure are commenced on medication to reduce\u000a      symptoms and improve prognosis, unless contraindicated....15.5 Patients\u000a      with left ventricular systolic dysfunction and persistent New York Heart\u000a      Association class III heart failure and who have been New York Heart\u000a      Association class IV in the last 6 months receive spironolactone except\u000a      where contraindicated.....\".\u000a    In a further recent development [3], the Eplerenone in Mild Patients\u000a      Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)\u000a      randomised, double-blind trial evaluated the effects of another\u000a      aldosterone antagonist, eplerenone, in patients with chronic systolic\u000a      heart failure and mild symptoms. The decision to undertake this study was\u000a      based upon the outcomes of the RALES and EPHESUS studies, both of which\u000a      were influenced by our work [i-iv]. The results of this Pfizer-funded\u000a      study indicated that eplerenone, as compared with placebo, reduced both\u000a      the risk of death and the risk of hospitalization among patients with\u000a      systolic heart failure and mild symptoms.\u000a    An aldosterone antagonist is now recommended (Level 1 recommendation) for\u000a      use in all patients with systolic heart failure including patients with\u000a      mild NYHA II heart failure. Clinical practice guidelines making this\u000a      recommendation include the 2012 European Society of Cardiology guidelines\u000a      [4,5] and the 2011 National Heart Foundation of Australia and Cardiac\u000a      Society of Australia and New Zealand guidelines [6,7].\u000a    Aldosterone antagonist treatment has been shown to be cost effective: the\u000a      incremental cost-effectiveness ratio for aldosterone antagonist therapy\u000a      when added to standard therapy (ACE inhibitor plus 03b2-blocker) in\u000a      patients with heart failure has been calculated to be ~US$500 per life\u000a      year gained [8].\u000a    Finally, the most recent development (April 2013) has been the addition\u000a      of the use of spironolactone for heart failure to the World Health\u000a      Organization Model List of Essential Medicines, which is updated every two\u000a      years using a transparent evidence-based process endorsed by the WHO\u000a      Expert Committee on Selection and Use and serves as a guide for the\u000a      development of national and institutional essential medicine lists\u000a      throughout the world [9].\u000a    ","ImpactSummary":"\u000a    Our research with spironolactone has advanced treatment in heart failure.\u000a      We conducted the first \"proof of concept\" study to show that\u000a      spironolactone had beneficial cardiac effects in man. In patients with\u000a      heart failure, we demonstrated that it reduced cardiac sympathetic\u000a      activity and arrhythmias. Spironolactone was pioneered in Dundee as a\u000a      treatment to reduce deaths in chronic heart failure. This treatment is now\u000a      recommended (Level A evidence; Class I recommendation) for the treatment\u000a      of symptomatic heart failure in all guidelines including the 2010 NICE\u000a      guidelines. It is also now a standard in the 2010 NHS Quality Improvement\u000a      Scotland standards.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Dundee\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5128638","Name":"New York"}],"References":"\u000a    \u000ai. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers\u000a      AD (1995) Effects of adding spironolactone to an angiotensin-converting\u000a      enzyme inhibitor in chronic congestive heart failure secondary to coronary\u000a      artery disease. Am. J Cardiol. 76, 1259-1265 (DOI:\u000a        10.1016\/S0002-9149(99)80353-1).\u000a    \u000a\u000aii. MacFadyen RJ, Barr CS, Struthers AD (1997) Aldosterone\u000a      blockade reduces vascular collagen turnover, improves heart rate\u000a      variability and reduces early morning rise in heart rate in heart failure\u000a      patients. Cardiovasc. Res. 35, 30-34\u000a      (DOI:10.1016\/S0008-6363(97)00091-6).\u000a    \u000a\u000aiii. MacFadyen RJ, Lee AFC, Morton JJ, Pringle SD, Struthers AD\u000a      (1999) How often are angiotensin II and aldosterone concentrations raised\u000a      during chronic ACE inhibitor treatment in cardiac failure? Heart 82,\u000a      57-61 (DOI:10.1136\/hrt.82.1.57).\u000a    \u000a\u000aiv. Shah NC, Pringle SD, Donnan PT, Struthers AD ( 2007) Spironolactone\u000a        has antiarrhythmic activity in ischaemic cardiac patients without cardiac failure. J.\u000a        Hypertension. 25, 2345-2351 (DOI:\u000a      10.1097\/HJH.0b013e3282e9a72d).\u000a    \u000a\u000av. Macdonald JE, Kennedy N, Struthers AD (2004) Effects of\u000a      spironolactone on endothelial function, vascular angiotensin converting\u000a      enzyme activity, and other prognostic markers in patients with mild heart\u000a      failure already taking optimal treatment. Heart 90,\u000a      765-770 (DOI:10.1136\/hrt.2003.017368).\u000a    \u000aFunding\u000a    The research underpinning this case study was funded by research grants\u000a      from SHERT, British Heart Foundation and the Scottish Office:\u000a    • Struthers AD, Barr CS: Does spironolactone produce beneficial\u000a      effects over and above an ACE inhibitor in chronic heart failure?;\u000a      Scottish Hospitals Endowment Research Trust (1992-1993) £23,190.\u000a    • Struthers AD, Fraser C: Does aldosterone blockade produce\u000a      beneficial effects over and above an ACE inhibitor in chronic heart\u000a      failure?; British Heart Foundation (1992-1994) £21,210.\u000a    • Struthers AD, Pringle S, Morton JJ: The Identification of\u000a      Angiotensin II Reactivation in Heart Failure patients taking ACE\u000a      Inhibitors; Scottish Home & Health Department (1995-1996) £41,526.\u000a    • Struthers AD, MacFadyen RJ, Pringle S: Spironolactone induced\u000a      bradycardia at dawn: what is the mechanism and does it reduce ischaemia?;\u000a      Scottish Home & Health Department (1996-1998) £120,140.\u000a    • Struthers AD, Kennedy N: Will spironolactone reduce cardiac\u000a      deaths in mild chronic heart failure?; Tenovus\/Northwood Trust (2000-2002)\u000a      £109,961.\u000a    • Struthers AD, Pringle S, Donnan P: Does Aldosterone Blockade\u000a      improve endothelial dysfunction in patients with coronary artery disease\u000a      but without heart failure?; British Heart Foundation (2004-2006) £104,071.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"16","Subject":"Medical Physiology"}],"Sources":"\u000a    \u000a      National Clinical Guideline Centre (2010) Chronic heart failure: the\u000a        management of chronic heart failure in adults in primary and secondary\u000a        care London: National Clinical Guideline Centre. Available from: http:\/\/guidance.nice.org.uk\/CG108\/Guidance\/pdf\/English.\u000a      NHS Quality Improvement Scotland (2010) Clinical Standards on Heart\u000a        Disease (ISBN 1-84404-590-0).\u000a      Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H,\u000a        Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group (2011). Eplerenone\u000a        in patients with systolic heart failure and mild symptoms. N. Engl.\u000a        J. Med. 364, 11-21 (DOI: 10.1056\/NEJMoa1009492).\u000a      McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein\u000a        K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber\u000a        L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik\u000a        PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors\u000a        AA, Zannad F and Zeiher A; ESC Committee for Practice Guidelines (2012)\u000a        ESC Guidelines for the diagnosis and treatment of acute and chronic\u000a        heart failure 2012: The Task Force for the Diagnosis and Treatment of\u000a        Acute and Chronic Heart Failure 2012 of the European Society of\u000a        Cardiology. Developed in collaboration with the Heart Failure\u000a        Association (HFA) of the ESC. Eur. Heart J. 33,\u000a        1787-1847 (DOI:10.1093\/eurheartj\/ehs104).\u000a      Letter of Corroboration from the Chairman of the 2012 European Society\u000a        of Cardiology Guideline on Heart Failure.\u000a      Krum, H, Jelinek MV, Stewart S, Sindone A, Atherton JJ. (2011) 2011\u000a        update to National Heart Foundation of Australia and Cardiac Society of\u000a        Australia and New Zealand Guidelines for the prevention, detection and\u000a        management of chronic heart failure in Australia, 2006 Med. J. Aust.\u000a        194, 405-409 (https:\/\/www.mja.com.au\/journal\/2011\/194\/8\/2011-update-national-heart-\u000a          foundation-australia-and-cardiac-society-australia-and).\u000a      Letter of Corroboration from the Chair, National Heart Foundation of\u000a        Australia, Cardiac Society of Australia and New Zealand, Chronic Heart\u000a        Failure Guidelines Expert Writing Panel.\u000a      Banka G, Heidenreich PA, Fonarow GC (2013) Incremental\u000a        cost-effectiveness of guideline-directed medical therapies for heart\u000a        failure. J.\u000a        Am. Coll. Cardiol. 61, 1440-6. (DOI: 10.1016\/j.jacc.2012.12.022).\u000a      WHO Model Lists of Essential Medicines; available at:\u000a        http:\/\/www.who.int\/medicines\/publications\/essentialmedicines\/en\/.\u000a    \u000a    ","Title":"\u000a    Spironolactone as a Treatment to extend life in Heart Failure Patients\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    A major advance in the treatment of heart failure was the development in\u000a      the 1980s of the neurohormonal hypothesis of heart failure (i.e. heart\u000a      failure develops and progresses because endogenous neurohormonal systems\u000a      such as the renin-angiotensin-aldosterone system that are activated by the\u000a      initial injury to the heart exert a deleterious effect on the\u000a      circulation). The success of angiotensin converting enzyme inhibitors (ACE\u000a      inhibitors), which were shown in 1987 to reduce deaths in heart failure,\u000a      provided support for this hypothesis. The expectation thereafter was that\u000a      ACE inhibitors would suppress aldosterone to such an extent that adding\u000a      spironolactone to an ACE inhibitor would not add therapeutic value and\u000a      could be hazardous.\u000a    The underpinning research and development work that challenged this\u000a      contention was funded by the British Heart Foundation and Scottish\u000a      Hospital Endowments Research Trust and carried out at the University of\u000a      Dundee under the leadership of Prof Allan Struthers (Division of\u000a      Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical\u000a      School, Dundee) with assistance from Dr (now Prof) Chim Lang (at\u000a      the time a Lecturer in the Department) in collaboration with Michael\u000a      Arnott and Norman Kennedy (Department of Medical Physics). The original\u000a      impetus for our work was that corticosterone was a known inhibitor of\u000a      uptake for noradrenaline in non-cardiac tissue. This made us wonder\u000a      whether aldosterone (a related steroid hormone) would alter noradrenaline\u000a      kinetics in a different tissue, the myocardium.\u000a    We began by showing this was indeed the case in animals and went on to\u000a      confirm the same effect in man [i]. This was a major finding since cardiac\u000a      noradrenergic\/sympathetic activity is well known to produce arrhythmias\u000a      and hasten death in patients with heart failure. In 1995 we published\u000a      seminal work showing that spironolactone not only reduced cardiac\u000a      adrenergic activity but also reduced ventricular arrhythmias when added to\u000a      ACE inhibitors in patients with heart failure [i]. This was the first\u000a      demonstration of a beneficial cardiac effect of spironolactone in man.\u000a      Hitherto, spironolactone was thought of only as a diuretic and our work\u000a      changed thinking about this familiar drug. These encouraging results,\u000a      along with data from others showing that spironolactone might reduce\u000a      myocardial fibrosis in rats, were a major factor in persuading Searle to\u000a      launch the large, multicentre Randomized ALdactone Evaluation Study\u000a      (RALES) trial. An important contribution of the Dundee paper was based on\u000a      the fact that cardiac arrhythmias are the main cause of sudden cardiac\u000a      death in man; our observation that spironolactone reduced cardiac\u000a      arrhythmias and adrenergic activity suggested for the first time that\u000a      spironolactone might indeed reduce sudden cardiac deaths [i-iv]. This\u000a      hypothesis was subsequently confirmed by the 1999 RALES study and then by\u000a      the 2003 Eplerenone Post-Acute Myocardial Infarction Heart Failure\u000a      Efficacy and Survival Study (EPHESUS).\u000a    The findings of EPHESUS raised the question of whether spironolactone\u000a      would be beneficial in patients with mild or asymptomatic heart failure.\u000a      Our subsequent publication in Heart [v] was the first study to\u000a      show beneficial effects in mild to asymptomatic congestive heart failure\u000a      on a key mechanism underlying its benefits—that is, endothelial function.\u000a      Spironolactone also improved other markers of prognosis (including\u000a      brain\/B-type naturietic peptide) in patients with asymptomatic or mild\u000a      congestive heart failure when added to optimal treatment including 03b2\u000a      blockade.\u000a    "},{"CaseStudyId":"35841","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    This study has delivered an evidence base regarding the use of aspirin in\u000a      diabetes and is now\u000a      embedded at the heart of national and international Guidelines. The 2008 BMJ\u000a      publication [i]\u000a      reported on the results of this trial. The impact of this initial study\u000a      was immediate with much\u000a      publicity worldwide; lay press, radio and television discussions and\u000a      reports were made throughout\u000a      2009-11. Further changes to national and international Guidelines were\u000a      made over the next 3-4\u000a      years taking these data into account (see below). It created a global\u000a      change in prescribing practice\u000a      for patients with diabetes that provided value to frontline clinical teams\u000a      in both primary and\u000a      secondary care. It represents one of the major changes in the care of\u000a      people with diabetes\u000a      internationally over the past 5 years. Further, editorials reviewed this\u000a      article favourably (e.g. [1,2])\u000a      using the evidence from this trial to give advice to readers. The BMJ\u000a      voted the publication second\u000a      most impactive study published by them in 2008. It also received 6 stars\u000a      for clinical impact from the\u000a      American College of Physicians [3], who summarise the best new evidence\u000a      for internal medicine\u000a      from over 130 clinical journals using a worldwide panel of >5000\u000a      physicians to assess the clinical\u000a      relevance and newsworthiness of rigorous studies.\u000a    Government Policy Impact and Guidelines (National and International):\u000a      UK Primary Care\u000a      Guidelines changed as a result of our findings [4], as have those abroad.\u000a      UK and international\u000a      Guidelines for medically-related specialities such as Pharmacy [5] and the\u000a      Drug and Therapeutic\u000a      Bulletin have been influenced, quoting POPADAD as the reason for change.\u000a      The recent SIGN\u000a      Guidelines on the management of diabetes took the trial findings into\u000a      account when making its\u000a      recommendations (http:\/\/www.sign.ac.uk\/pdf\/sign116.pdf).\u000a      In addition the new USA\u000a      recommendations, from a joint statement of the American Diabetes\u000a      Association, the American\u000a      Heart Association, and the American College of Cardiology, essentially\u000a      call for tighter criteria for\u000a      aspirin use in diabetes quoting the trial (http:\/\/circ.ahajournals.org\/content\/115\/1\/114.long).\u000a      Dr Sue\u000a      Kirkman, a member of the writing committee, is quoted: \"The previous\u000a      recommendations had been\u000a      that pretty much anybody with diabetes over the age of 40 should be on\u000a      aspirin, but there...is less\u000a      of a general recommendation for aspirin than there used to be, and this is\u000a      based on some of the\u000a      newer studies that have come out\". Further the respected US Preventative\u000a      Services Task Force [6]\u000a      recommended on aspirin use, based on the trial. The Canadian, New Zealand\u000a      and Australian\u000a      Diabetes Guidelines [7] also changed in response to the trial as did those\u000a      of the European Society\u000a      of Cardiology [8]. The Clinical Guidelines Task Force of the International\u000a      Diabetes Federation\u000a      Global Guideline for the care of people with Type 2 diabetes around the\u000a      world has also\u000a      incorporated the findings from POPADAD [9]. The ATT\u000a      Collaboration updated their\u000a      recommendations for aspirin in primary prevention after considering the\u000a      results from POPADAD\u000a      and two later trials [v,vi]. They concluded that the benefit of aspirin\u000a      appeared to outweigh its risks\u000a      when used for secondary, but not primary, prevention.\u000a    Improved Patient Care and Health Outcomes: The findings have also\u000a      been integrated into UK\u000a      [10] and global [various non-English-language websites] healthcare as an\u000a      exemplar of a clinically\u000a      relevant study. Aspirin has significant side effects associated with its\u000a      use in CVD prevention. Even\u000a      mild adverse events such as dyspepsia can be a major issue, requiring\u000a      additional prescriptions of\u000a      antacids and proton pump inhibitors. In the ATT Collaboration\u000a      meta-analysis [vi], aspirin allocation\u000a      for primary prevention increased major gastrointestinal and extracranial\u000a      bleeds, and this has been\u000a      confirmed by others. Aspirin was associated with a 55% relative risk\u000a      increase in major bleeding.\u000a      Reducing aspirin prescribing reduces these risks and will have impacted on\u000a      the diabetes\u000a      population previously considered for aspirin primary prevention. There is\u000a      also a question regarding\u000a      increased CVD events in patients on proton pump inhibitors and aspirin,\u000a      though this may be due to\u000a      reduced effectiveness of the aspirin produced by the antagonist.\u000a    NHS Cost Impact: Although aspirin is relatively cheap, there are\u000a      251,000 people with diabetes in\u000a      Scotland alone, of which about 50% will have no evidence of CVD. Thus\u000a      there will be potential\u000a      savings to the NHS as aspirin prescribing falls and also for associated\u000a      proton pump inhibitor usage\u000a      which will be substantial over time.\u000a    Impact in other clinical areas: More recently this work has\u000a      underpinned a number of meta-analyses\u000a      including the effect of aspirin on long-term risk of death due to cancer\u000a      and cancer\u000a      metastasis [ii-iv]. This work in cancer has also been the subject of\u000a      editorials in high impact journals\u000a      and produced much interest in the lay press, expressed via radio and TV\u000a      items.\u000a    Pubic Engagement, Media Coverage: The findings have also formed\u000a      the basis for public\u000a      engagement and debate on use of aspirin in diabetes [11]. This debate has\u000a      appeared in tweets,\u000a      blogs and on lay websites, there have been discussions in newspaper\u000a      articles, radio and TV shows\u000a      in all the continents of the world.\u000a    ","ImpactSummary":"\u000a    An eight year MRC-funded clinical trial led by the University of Dundee\u000a      and run throughout\u000a      Scotland (16 hospitals, 188 GP Surgeries) exploring aspirin in diabetes\u000a      for primary cardiovascular\u000a      event prevention, where clinical practice had evolved without evidence.\u000a    \u000a      \u000aNHS: Implementation of results in general practices, hospitals,\u000a        and Health Boards globally,\u000a        by ceasing to prescribe aspirin as primary prevention in diabetes.\u000a      \u000aPolicy: Resulted in major changes to international Guidelines\u000a        globally e.g. American\u000a        Diabetes Association Guidelines, Australian, New Zealand and Canadian\u000a        Guidelines and\u000a        Scottish Intercollegiate Guideline Network (SIGN).\u000a      \u000aImproved Patient Care and Health Outcomes: Reduction in aspirin\u000a        prescribing with\u000a        decrease in adverse events, reduction in concomitant proton pump\u000a        inhibition prescribing.\u000a      \u000aInternationalisation: Implementation worldwide, by doctors and\u000a        pharmacists with reports\u000a        in lay publications, radio programmes, TV interviews and patient\u000a        targeted websites.\u000a    \u000a    ","ImpactType":"Health","Institution":"\u000a    University of Dundee\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000ai. Belch JJF, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott\u000a      R, Lee R, Bancroft J,\u000a      MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, Connacher\u000a      A, Peden N,\u000a      Jamieson A, Matthews D, Leese G, McKnight J, O'Brien I, Semple C, Petrie\u000a      J, Gordon D,\u000a      Pringle S, MacWalter R (2008) Prevention of Progression of Arterial\u000a      Disease and Diabetes\u000a      Study Group, Diabetes Registry Group, Royal College of Physicians\u000a      Edinburgh. The prevention\u000a      of progression of arterial disease and diabetes (POPADAD) trial: factorial\u000a      randomised placebo\u000a      controlled trial of aspirin and antioxidants in patients with diabetes and\u000a      asymptomatic peripheral\u000a      arterial disease. Brit. Med. J. 337, 1030-1033 (DOI:\u000a      10.1136\/bmj.a1840).\u000a    \u000a\u000aii. Rothwell PM, Fowkes FGR, Belch JJF, Ogawa H, Chew E, Warlow\u000a      CP, Peto R, Meade TW\u000a      (2011) Effect of daily aspirin on long-term risk of death due to cancer:\u000a      analysis of individual\u000a      patient data from randomized trials. Lancet 377, 31-41\u000a      (DOI: 10.1016\/S0140-6736(10)62110-1).\u000a    \u000a\u000aiii. Rothwell PM, Wilson M, Price JF, Belch JJF, Meade TW, Mehta\u000a      Z (2012) Effect of daily aspirin\u000a      on risk of cancer metastasis: a study of incident cancers during\u000a      randomised controlled trials.\u000a      Lancet 379, 159-601 (DOI: 10.1016\/S0140-6736(12)60209-8.\u000a    \u000a\u000aiv. Rothwell PM, Price JF, Fowkes GR, Zanchetti A, Roncaglioni MC,\u000a      Tognoni G, Lee R, Belch\u000a      JJF, Wilson M, Mehta Z, Meade TW (2012) Short-term effects of daily\u000a      aspirin on cancer\u000a      incidence, mortality, and non-vascular death: analysis of the time course\u000a      of risks and benefits in\u000a      51 randomised controlled trials. Lancet 379, 1602-1612\u000a      DOI: 10.1016\/S0140-6736(11)61720-0.\u000a    \u000a\u000av. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N,\u000a      Jinnouchi H, Sugiyama S,\u000a      Saito Y; Japanese Primary Prevention of Atherosclerosis With Aspirin for\u000a      Diabetes (JPAD) Trial\u000a      Investigators (2008) Low-dose aspirin for primary prevention of\u000a      atherosclerotic events in\u000a      patients with type 2 diabetes: a randomized controlled trial. JAMA\u000a      300, 2134-41 (DOI:\u000a      10.1001\/jama.2008.623).\u000a    \u000a\u000avi. Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee\u000a      D, Rosenson RS,\u000a      Williams CD, Wilson PW, Kirkman MS; American Diabetes Association;\u000a      American Heart\u000a      Association; American College of Cardiology Foundation (2010) Expert\u000a      Consensus Document:\u000a      Aspirin for Primary Prevention of Cardiovascular Events in People with\u000a      Diabetes. J. Am. Coll.\u000a        Cardiol. 55, 2878-2886 (DOI:10.1016\/j.jacc.2010.04.003).\u000a    \u000aFunding\u000a    • Belch J, Cairns J, Fowles G, Hawthorne V, Jung RT, McEwan S,\u000a      Newton RW and Smith A:\u000a      The Prevention of Progression of Asymptomatic Diabetic Arterial Disease\u000a      (POPADAD) Study:\u000a      A Multicentre study; Medical Research Council, (66 months from August\u000a      1997) £1,065,576.\u000a    • Belch J, Cairns J, Hawthorne V, Jung RT, Newton RW, Smith A,\u000a      McEwan S, and Prescott R:\u000a      The Prevention of Progression of Asymptomatic Diabetic Arterial Disease\u000a      (POPADAD) Study;\u000a      Medical Research Council (12 month extension from February 2003) £268,389.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    Examples of Editorials on the clinical trial findings\u000a    \u000a      Krantz MJ, Berger JS, Hiatt WR (2010) An aspirin a day: are we barking\u000a        up the wrong willow\u000a        tree? Pharmacother. 30, 115-118\u000a        (DOI:10.1592\/phco.30.2.115).\u000a      Nicolucci A (2011) Recommending Aspirin for Primary Prevention in\u000a        Diabetic Patients: What May\u000a        We Conclude? Ther. Adv. Chronic Dis. 2, 157-160 (DOI:\u000a        10.1177\/2040622311400116).\u000a      Farkouh ME (2009) ACP Journal Club. Aspirin and\/or antioxidants did\u000a        not prevent CV events in\u000a        diabetes and peripheral arterial disease. Ann. Int. Med. 150,\u000a        JC1-8 (DOI:10.7326\/0003-4819-150-\u000a        2-200901200-02008).\u000a    \u000a    Examples in Primary Care\u000a    \u000a      \u000aUK: http:\/\/www.gpnotebook.co.uk\/simplepage.cfm?ID=x20081111120515749131;\u000a      Canada: Allan GM, Ivers N and McCorkack J (2010) Type 2 diabetes\u000a      and ASA. Canadian Family\u000a        Physician 56, 664; http:\/\/www.cfp.ca\/content\/56\/7\/664.full;\u000a      USA: Crawford-Faucher A (2009) Secondary Prevention of\u000a      Cardiovascular Events in Diabetes.\u000a      Am. Fam. Physician. 80, 1000; http:\/\/www.aafp.org\/afp\/2009\/1101\/p1000.html.\u000a      \u000a    \u000a    Pharmacy Impact\u000a    \u000a      UK: Burrill, P. (2009) Aspirin and the primary prevention of\u000a        cardiovascular disease. Pharmacy in\u000a        Practice September 2009, 109-111; http:\/\/www.pharmacyinpractice.com\/archive\/2009-volume-19-issue-3\/8-PIP-Cardiovascular-special-section-3-Sept09.pdf;\u000a        USA: http:\/\/dig.pharm.uic.edu\/faq\/ada.aspx.\u000a    \u000a    Additional International Guidelines\/Recommendations influenced by the\u000a        trial\u000a    \u000a      U.S. Preventive Services Task Force recommendation statement (2009)\u000a        Aspirin for the\u000a        prevention of cardiovascular disease Ann. Intern. Med.150,\u000a        396-404 (DOI:10.7326\/0003-4819-\u000a        150-6-200903170-00008).\u000a      Canadian Diabetes Association (2013) Clinical Practice Guidelines for\u000a        the Prevention and\u000a        Management of Diabetes in Canada. Can. J. Diabetes 37:\u000a        s1-212\u000a        (DOI:10.1016\/j.jcjd.2013.01.009) and subsequent articles; PHARMAC and\u000a        the NZ Guidelines\u000a        Group (2011) The Use of Antithrombotic Medicines in General Practice: A\u000a        Consensus Statement.\u000a        Best Practice J. NZ 39:11-2 (http:\/\/www.bpac.org.nz\/BPJ\/2011\/october\/antithrombotic.aspx).\u000a      European Society of Cardiology Task Force on diabetes, pre-diabetes,\u000a        and cardiovascular\u000a        diseases and European Association for the Study of Diabetes (2013) ESC\u000a        Guidelines on\u000a        diabetes, pre-diabetes, and cardiovascular diseases developed in\u000a        collaboration with the EASD.\u000a        Eur. Heart J. 34, 3035-87 (DOI:10.1093\/eurheartj\/eht108).\u000a      IDF Clinical Guidelines Task Force (2006) Global guideline for type 2\u000a        diabetes:\u000a        Recommendations for standard, comprehensive, and minimal care. Diabet.\u000a          Med. 23, 579-93\u000a        (DOI: 10.1111\/j.1464-5491.2006.01918.x).\u000a      Report on changed Guidelines:\u000a        http:\/\/www.eguidelines.co.uk\/eguidelinesmain\/gip\/vol_12\/feb_09\/begg_popadad_feb09.php.\u000a    \u000a    Lay Impact\u000a    \u000a      \u000ahttp:\/\/apvascular.blogspot.co.uk\/2011\/02\/in-popadad-study-bmj-2008-it-was-found.html;\u000a        http:\/\/the-brillo-pad.blogspot.co.uk\/2009\/03\/aspirin-ineffective-for-primary.html;\u000a        http:\/\/www.clotcare.com\/aspirin_and_diabetes.aspx;\u000a        http:\/\/www.ethiopianreview.com\/news\/135701.\u000a    \u000a    ","Title":"\u000a    The use of aspirin as a primary prophylaxis against cardiovascular\u000a        events in patients with Diabetes\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Background: Clinical decision making should, where possible, be\u000a      based on evidence. An example\u000a      of clinical practice reliant on guidelines with an incomplete evidence\u000a      base is the use of low-dose\u000a      aspirin for primary prevention of cardiovascular disease (CVD) events in\u000a      diabetes mellitus.\u000a    Cardiovascular disease is a major global health problem. The website of\u000a      the World Health\u000a      Organisation estimates that 17.3 million people died from CVD in 2008, and\u000a      by 2030 more than 23\u000a      million people will die annually. Vascular disease is the major cause of\u000a      morbidity and mortality in\u000a      diabetes mellitus. Aspirin has a wide publication base of evidence as a\u000a      useful agent for secondary\u000a      prevention of CVD. Antioxidants have little evidence base apart from in\u000a      retrospective population\u000a      studies, but are popular with patients and with alternative therapists.\u000a    Prior to our study, numerous national and international associations\u000a      recommended low-dose\u000a      aspirin for patients with diabetes. Our MRC-funded underpinning research\u000a      work (1998 2007) [i]\u000a      was carried out at the University of Dundee and led by Professor Jill Belch\u000a      (Professor of Vascular-\u000a      Medicine, Ninewells Hospital and Medical School, Dundee 1987 to date). The\u000a      Prevention Of\u000a      Progression of Arterial Disease And Diabetes (POPADAD) trial tested the\u000a      hypothesis that aspirin\u000a      and\/or antioxidants were more effective than placebo in reducing the\u000a      development of CVD events.\u000a      Twenty-seven hospital centres took part in the study, supported by 188 GP\u000a      surgeries. Of 8730\u000a      patients with diabetes mellitus who were screened, 1276 were enrolled into\u000a      the study of aspirin\u000a      versus placebo versus antioxidant. CVD events were the primary outcome.\u000a      The results showed no\u000a      difference between aspirin and placebo or antioxidant and placebo, and the\u000a      finding that aspirin\u000a      does not reduce CVD events in patients with diabetes and no previous CVD\u000a      is now embedded in\u000a      the NHS and also in national and overseas healthcare Guidelines.\u000a    Research Question: Secondary prevention of CVD events and\u000a      mortality can be achieved in\u000a      patients with diabetes by aspirin therapy. What was not known is whether\u000a      primary prevention with\u000a      aspirin was effective, despite recommendations for this treatment in many\u000a      published Guidelines.\u000a    What This Study Adds: This trial provides no evidence to support\u000a      the use of either aspirin or\u000a      antioxidants in primary prevention of CVD events and mortality in the\u000a      diabetes mellitus population\u000a      studied. It thus questions the evidence base for these Guideline\u000a      recommendations.\u000a    Additional Impact in other areas: As well as changing medical\u000a      practice, our data were exploited\u000a      further in later collaborative work with the University of Oxford, whereby\u000a      this study formed part of a\u000a      meta-analysis showing that aspirin reduced both the development and\u000a      metastases of cancer [ii-iv].\u000a    Conclusion: Since the trial's publication two further studies, the\u000a      Japanese Primary Prevention of\u000a      Atherosclerosis With Aspirin for Diabetes (JPAD) study [v] and the\u000a      meta-analysis by the Anti-Thrombotic Trialist (ATT) Collaboration, have validated the results. The\u000a      latter showed that primary\u000a      prevention of vascular events with aspirin is of uncertain value, whereas\u000a      the risk of major episodes\u000a      of haemorrhage may increase. The POPADAD study has been incorporated into\u000a      meta-analyses\u000a      [vi] and, with the JPAD trial and ATT analysis, forms a convincing\u000a      evidence base.\u000a    "},{"CaseStudyId":"35842","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust","Biotechnology and Biological Sciences Research Council","Medical Research Council"],"ImpactDetails":"\u000d\u000a    This research has benefitted the Scottish economy and local population\u000d\u000a      through the establishment of two biotechnology companies, Cypex and CXR\u000d\u000a      which, between them, employ up to 40 staff and generate an average annual\u000d\u000a      turnover of £2.4M. Professor Wolf, a Director of CXR from its\u000d\u000a      formation until August 2012 and a member of the Scientific Advisory Group\u000d\u000a      of the Translational Medicine Research Initiative, received the OBE in\u000d\u000a      2010 for his contribution to life sciences in Scotland.\u000d\u000a    Cypex (www.cypex.co.uk) was formed\u000d\u000a      in 1998 and has, since releasing its first recombinant P450 in 2000,\u000d\u000a      developed a portfolio of >100 products including 19 human P450s, eight\u000d\u000a      sulphotransferases, murine and canine P450s, fine chemicals and\u000d\u000a      antibodies. These are marketed in Europe via Tebu-Bio [1], in the US via\u000d\u000a      XenoTech LLC[2] and in Asia and Africa. Their use helps pharmaceutical\u000d\u000a      companies to eliminate drug candidates which are likely to fail during\u000d\u000a      development or cause drug-drug interactions in patients. Cypex also offers\u000d\u000a      contract services in custom protein expression and the production of drug\u000d\u000a      metabolites. Its products (in the form of cell lines which express human\u000d\u000a      P450s) are used in bioreactors to generate drug metabolites in sufficient\u000d\u000a      quantities for toxicological evaluation, as is now required by the FDA\u000d\u000a      when human-specific metabolites represent more than 10% of the\u000d\u000a      administered dose [3]. This application has been adopted by pharmaceutical\u000d\u000a      companies including Novartis and Hoffmann-La Roche [4]; the intellectual\u000d\u000a      property has been licensed to BTG for further commercialisation and\u000d\u000a      Novartis has licensed the technology (£400K) for further marketing and\u000d\u000a      use.\u000d\u000a    CXR (www.cxrbiosciences.com)\u000d\u000a      was formed in 2002 to provide services in preclinical drug development and\u000d\u000a      chemical safety. It currently has >60 clients worldwide and has\u000d\u000a      pioneered the application of humanised mouse models in drug development.\u000d\u000a      It opened its first international sales office in the USA in May 2012 [5].\u000d\u000a      It also markets a number of cell lines and other reagents derived from\u000d\u000a      University-based research [ii,iii,vi]; these include the Hepatic Reductase\u000d\u000a      Null™ mice and a range of reporter mice, licensed for marketing by CXR via\u000d\u000a      Taconic in the USA and Europe. AstraZeneca, Pfizer and Nestlé have also\u000d\u000a      taken out licenses to these models.\u000d\u000a    The second aspect of the impact of this research has had international\u000d\u000a      reach, benefitting the pharmaceutical industry and regulators. This aspect\u000d\u000a      arose from an ITI Life Sciences-sponsored research and development\u000d\u000a      programme (2005-2009) in which CXR and TaconicArtemis GmbH (Cologne)\u000d\u000a      collaborated in the generation of humanised mouse models to determine the\u000d\u000a      human-specific systemic effects of drugs and chemicals [iv,v]. The\u000d\u000a      generation of these exciting new research tools, which are now marketed\u000d\u000a      via Taconic [6,7], has been welcomed by pharmaceutical companies and\u000d\u000a      regulators because of their applicability in drug regulatory submissions\u000d\u000a      [7].\u000d\u000a    These models have important applications in, for example, allowing the\u000d\u000a      species specificity of non-genotoxic carcinogenesis to be established\u000d\u000a      [8]. This is central to the predictive risk assessment of drugs and\u000d\u000a      consumer products; to that end the use of these humanised and reporter\u000d\u000a      models is embedded in the EU Innovative Medicines Initiative programmes\u000d\u000a      MARCAR (http:\/\/www.imi-marcar.eu\/partners.html)\u000d\u000a      and DILI (http:\/\/www.imi.europa.eu\/content\/mip-dili),\u000a      whose aim is to identify new biomarkers to predict the effects of\u000d\u000a      non-genotoxic carcinogens and predict the potential for drug-induced liver\u000d\u000a      injury. CXR is a key small\/medium enterprise participant in this €25M\u000d\u000a      collaboration, led by Dundee, between academia, the pharmaceutical\u000d\u000a      industry and drug regulators, and the extent of industrial involvement\u000d\u000a      (>€5M) is a direct result of the Dundee team's track record in\u000d\u000a      developing commercially-applicable novel models for assessing chemical\u000d\u000a      safety.\u000d\u000a    In a third aspect of impact, this research has benefitted industry,\u000d\u000a      patients and consumers in Europe and beyond as a result of the development\u000d\u000a      of innovative methods for in vitro toxicity testing. Better in\u000d\u000a        vitro testing methods are urgently needed as a result of the\u000d\u000a      enactment in 2007 of the REACH regulations, which demand toxicity testing\u000d\u000a      of some 30,000 substances using non-animal methods wherever possible, and\u000d\u000a      the staged implementation of the 7th Amendment to the EU Cosmetics\u000d\u000a      Directive, which has prohibited the use of animals for skin irritation,\u000d\u000a      corrosion, and genotoxicity testing since 2009 and for characterising the\u000d\u000a      disposition of cosmetic ingredients since March 2013. The AREc32 cell line\u000d\u000a      [iv], licensed via CXR to Givaudan, has been shown to be useful as part of\u000d\u000a      an integrated testing strategy for the prediction of chemical-induced skin\u000d\u000a      hypersensitivity reactions without the need for animal testing [9,10] and\u000d\u000a      has been adopted for water quality assessment and the evaluation of\u000d\u000a      disinfection by-products by institutions in Australia and Germany [11].\u000d\u000a      The use of this cell line provides the pharmaceutical, cosmetic, consumer\u000d\u000a      product and chemicals industries with a cost-effective,\u000d\u000a      legally-permissible method for assessing potential skin sensitisers and\u000d\u000a      benefits patients and consumers by improving safety assessments.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The development of new paradigms for toxicity testing has benefitted the\u000d\u000a      Scottish economy and population in Tayside through two biotechnology\u000d\u000a      companies which, between them, employ up to 40 staff and have had a\u000d\u000a      combined turnover of some £15M over the last five years. The benefits\u000d\u000a      extend to the international pharmaceutical, cosmetic, chemical and\u000d\u000a      consumer product industries, which have gained access to innovative new\u000d\u000a      methods for safety testing at a time of acute need for more predictive\u000d\u000a      methods to evaluate drug safety and better in vitro tests for\u000d\u000a      consumer products. Patients and consumers in Europe and worldwide have\u000d\u000a      benefitted indirectly from improved risk assessment of drugs, consumer\u000d\u000a      products and environmental contaminants.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    University of Dundee\u000d\u000a    ","Institutions":[{"AlternativeName":"Dundee (University of)","InstitutionName":"University of Dundee","PeerGroup":"B","Region":"Scotland","UKPRN":10007852}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2886242","Name":"Köln"}],"References":"\u000d\u000a    Key Participants\u000d\u000a    • Prof John Hayes, Dr Colin Henderson and Dr Michael Pritchard,\u000d\u000a      Biomedical Research Centre, Ninewells Hospital & Medical School,\u000d\u000a      Dundee.\u000d\u000a    • Prof Bruce Whitelaw, Division of Developmental Biology, The Roslin\u000d\u000a      Institute, University of Edinburgh.\u000d\u000a    • Dr Nico Scheer, TaconicArtemis GmbH, Cologne, Germany.\u000d\u000a    References\u000d\u000a    \u000ai. Pritchard MP, Ossetian R, Li DN, Henderson CJ, Burchell B, Wolf\u000d\u000a      CR and Friedberg T (1997) A general strategy for the expression of\u000d\u000a      recombinant human cytochrome P450s in Escherichia coli using bacterial\u000d\u000a      signal peptides: expression of CYP3A4, CYP2A6 and CYP2E1. Arch.\u000d\u000a        Biochem. Biophys. 345, 342-354 (DOI:\u000a        10.1006\/abbi.1997.0265).\u000d\u000a    \u000a\u000aii. Young R, Wolf CR, Brown K, Hayes JD and Whitelaw CB (2010)\u000d\u000a      Spatial monitoring of toxicity in HMOX-LacZ transgenic mice. Transgenic\u000d\u000a        Res. 19, 897-902 (DOI: 10.1007\/s11248-010-9363-z).\u000d\u000a    \u000a\u000aiii. Henderson CJ, Otto DME, Carrie D, Magnuson MA, McLaren AW, Rosewell\u000d\u000a      I and Wolf CR (2003) Inactivation of the hepatic cytochrome P450\u000d\u000a      system by conditional deletion of hepatic cytochrome P450 reductase. J.\u000d\u000a        Biol. Chem. 278, 13480-13486 (DOI: 10.1074\/jbc.M212087200).\u000d\u000a    \u000a\u000aiv. Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N and Wolf\u000d\u000a      CR (2008) A novel panel of mouse models to evaluate the role of human\u000d\u000a      pregnane X receptor and constitutive androstane receptor in drug response.\u000d\u000a      J. Clin. Invest. 118, 3228-3239 (DOI: 10.1172\/JCI35483).\u000d\u000a    \u000a\u000av. Scheer N, Kapelyukh Y, McEwan J, Beuger V, Stanley LA, Rode A and Wolf\u000d\u000a      CR (2011) Modelling human cytochrome P450 2D6 metabolism and drug-drug\u000d\u000a      interaction by a novel panel of knockout and humanized mouse lines. Mol.\u000d\u000a        Pharm. 81, 63-72 (DOI: 10.1124\/mol.111.075192).\u000d\u000a    \u000a\u000avi. Wang XJ, Hayes JD and Wolf CR (2006) Generation of a stable\u000d\u000a      antioxidant response element-driven reporter gene cell line and its use to\u000d\u000a      show redox-dependent activation of nrf2 by cancer chemotherapeutic agents.\u000d\u000a      Cancer Res. 66, 10983-10994 (DOI:\u000d\u000a      10.1158\/0008-5472.CAN-06-2298).\u000d\u000a    \u000aFunding\u000d\u000a    • Wolf CR et al: MRC\/BBSRC-funded LINK P450 Programme;\u000d\u000a      Industry Sponsors: Astra, Glaxo, Janssen Pharmaceutica, Lilly, Novo\u000d\u000a      Nordisk, Parke-Davis, Pfizer, Roche Products, Sanofi-Winthrop, Servier,\u000d\u000a      SmithKline Beecham, Wellcome, Wyeth (1993-1998) £3.5M.\u000d\u000a    • Wolf CR et al: The Toxicology Consortium; Industry\u000d\u000a      Sponsors: AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer,\u000d\u000a      Roche, Wyeth (1998-2005) £6.0M.\u000d\u000a    • CXR Biosciences and TaconicArtemis: ITI Life Sciences Transgenic\u000d\u000a      Screening and Safety Models (TSM\/TSE); Scottish Enterprise (2005-2009)\u000d\u000a      £8.0M.\u000d\u000a    • Wolf CR et al: MARCAR; EU Innovative Medicines\u000d\u000a      Initiative Award (2010-2015) Total budget €25M; €12M in kind from\u000d\u000a      industrial sponsors; Dundee component £1.1M.\u000d\u000a    • Wolf CR: REDOX; European Research Council Senior Investigator\u000d\u000a      Award (2011-2016) £2.1M.\u000d\u000a    Patents\u000d\u000a    • Wolf CR, Friedberg TH and Pritchard MP: Cytochrome P450\u000d\u000a      expression in enterobacteria; Patent Numbers EP0914446, US6566108,\u000d\u000a      CA22559619; assigned to British Technology Group (BTG).\u000d\u000a    • Wolf CR and Henderson CJ: Transgenic animals for assessing drug\u000d\u000a      metabolism and toxicity in man; Patent Numbers EP1711051, US2009013417.\u000d\u000a      Patents owned by Imperial Cancer Research Technology; licensed to CXR and\u000d\u000a      five pharmaceutical companies which participated in the Toxicology\u000d\u000a      Consortium.\u000d\u000a    • Wolf CR and Henderson CJ: Modulation of cytochrome P450\u000d\u000a      reductase activity; Patent Numbers EP1521827, EP2065464, US7700822,\u000d\u000a      CA2403235, JP005532807, GB2391231. Patents owned by Imperial Cancer\u000d\u000a      Research Technology.\u000d\u000a    • Wolf CR and Clark AJ: Methods and kits for drug screening and\u000d\u000a      toxicity testing using promoter-reporter cells derived from embryonic stem\u000d\u000a      cells; Patent Number EP1893749, US2006292694, US2006292695, US2008152632,\u000d\u000a      CA2613529,JP2008546417. Patents owned by CXR Biosciences\/Geron\u000d\u000a      Corporation.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      Example press release dated 24-Oct-08 at http:\/\/www.prlog.org\/10132610-tebu-bio-and-cypex-ltd-introduce-seven-new-dog-bactosomes.html.\u000d\u000a      Cypex-Xenotech product brochure at http:\/\/204.12.1.74\/uploaded\/documents\/Cypex.pdf.\u000d\u000a      FDA Guidance for Industry Safety Testing of Drug Metabolites (February\u000d\u000a        2008) http:\/\/www.fda.gov\/OHRMS\/DOCKETS\/98fr\/FDA-2008-D-0065-GDL.pdf.\u000d\u000a      Letter of corroboration from PTDCA Biocatalysis Department, F.\u000d\u000a        Hoffmann-La Roche Ltd.\u000d\u000a      Press release dated 17-May-12; http:\/\/www.cxrbiosciences.com\/news_article.php?news_id=43.\u000d\u000a      tADMET™: A unique and evolving portfolio of translational\u000d\u000a        (humanized & knockout) mouse models, in vitro tools and\u000d\u000a        services for an improved prediction of the Absorption, Distribution,\u000a        Metabolism, Excretion and Toxicity\u000d\u000a        characteristics of new compounds in humans.\u000d\u000a        http:\/\/www.taconic.com\/wmspage.cfm?parm1=1792.\u000d\u000a      Letter of corroboration from TaconicArtemis GmbH, Cologne, Germany.\u000d\u000a      Ross J, Plummer SM, Rode A, Scheer N, Bower CC, Vogel O, Henderson CJ,\u000d\u000a        Wolf CR and Elcombe CR (2010) Human constitutive androstane\u000d\u000a        receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic\u000d\u000a        but not the hyperplastic response to the murine nongenotoxic\u000d\u000a        hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol. Sci.\u000d\u000a        116, 452-66 (DOI: 10.1093\/toxsci\/kfq118).\u000d\u000a      Natsch A, Emter R and Ellis G (2009) Filling the Concept with Data:\u000d\u000a        Integrating Data from Different In Vitro and In Silico\u000d\u000a        Assays on Skin Sensitizers to Explore the Battery Approach for\u000d\u000a        Animal-Free Skin Sensitization Testing Toxicol. Sci. 107,\u000d\u000a        106-121 (DOI:10.1093\/toxsci\/kfn204).\u000d\u000a      Presentation by Joanna Matheson, US Consumer Product Safety\u000d\u000a        Commission, \"OECD Dermal Sensitization AOP: Regulatory Perspective\" on\u000d\u000a        the US Environmental Protection Agency website; http:\/\/www.epa.gov\/oppfead1\/cb\/ppdc\/testing\/2013\/july\/workshop\/session2-oecd.pdf.\u000d\u000a      Escher BI, van Daele C, Dutt M, Tang JYM and Altenburger R (2013) Most\u000d\u000a        Oxidative Stress Response In Water Samples Comes From Unknown Chemicals:\u000d\u000a        The Need For Effect-Based Water Quality Trigger Values. Environ.\u000d\u000a          Sci. Technol. 47, 7002 -7011 (DOI:\u000d\u000a        dx.doi.org\/10.1021\/es304793h).\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    New Approaches to Drug and Chemical Safety Assessment\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The research underpinning this impact was led by Prof. C. Roland Wolf\u000d\u000a      (at the time Director, Biomedical Research Centre; now Director, Medical\u000d\u000a      Research Institute; Ninewells Hospital and Medical School Dundee) and used\u000d\u000a      biotechnology approaches to develop better models for the study of\u000d\u000a      xenobiotic disposition and toxicity. Its aim was to address differences\u000d\u000a      between humans and commonly-used rodent models in terms of responses to\u000d\u000a      xenobiotics and to create in vitro systems which can be used to\u000d\u000a      accelerate drug development and reduce candidate attrition in clinical\u000d\u000a      trials.\u000d\u000a    Research published in 1997 developed new technology for the heterologous\u000d\u000a      expression of functional human cytochrome P450s (P450s) in bacteria, yeast\u000d\u000a      and mammalian cells [i]. The proteins thus generated are used to predict\u000d\u000a      pathways of drug disposition and toxicity, making the safety assessment of\u000d\u000a      drug candidates more predictive of likely outcomes in humans. Cell lines\u000d\u000a      expressing P450s can be used in bioreactors to generate human-specific\u000d\u000a      metabolites, with significant cost savings over what are often challenging\u000d\u000a      chemical syntheses. This work resulted in patents granted worldwide and to\u000d\u000a      the establishment in 1998 of the spinout company Cypex.\u000d\u000a    The aim of the second phase of this research was to develop novel in\u000d\u000a        vivo approaches for the assessment of drug and chemical safety by\u000d\u000a      generating transgenic reporter models in which processes such as oxidative\u000d\u000a      stress can be visualised by histochemical staining [ii] and\/or the\u000d\u000a      synthesis of excretable reporter molecules. The results and know-how from\u000d\u000a      this programme were central to the creation in 2002 of the spinout\u000d\u000a      company, CXR Biosciences (CXR).\u000d\u000a    One of the primary aims of the ongoing collaboration between Dundee\u000d\u000a      Medical School and CXR has been to create genetically-engineered models\u000d\u000a      which can be used to improve the predictivity of human risk assessments.\u000d\u000a      Among the first of these was the Hepatic Reductase Null™ mouse [iii] in\u000d\u000a      which the entire hepatic P450 system is ablated in adult mice allowing the\u000d\u000a      dependence of metabolic and toxic processes on P450-dependent hepatic\u000d\u000a      metabolism to be evaluated.\u000d\u000a    Of particular note has been the collaboration between the Medical School,\u000d\u000a      CXR, ITI Life Sciences and TaconicArtemis, Cologne which led to the\u000d\u000a      generation of a unique panel of transgenic mouse models humanised for\u000d\u000a      pathways of drug metabolism [iv,v]. By replicating entire pathways of\u000d\u000a      Phase One human drug metabolism in mice, the profound species differences\u000d\u000a      in these pathways were circumvented, allowing more informed predictions of\u000d\u000a      human drug responses to be obtained, accelerating the process of drug\u000d\u000a      development and benefitting the pharmaceutical industry by reducing the\u000d\u000a      proportion of drug candidates which undergo costly failure late in\u000d\u000a      development.\u000d\u000a    Work in the Medical School has also generated cell-line based reporter\u000d\u000a      systems for the detection of oxidative stress and associated modes of\u000d\u000a      toxicity. These include the human-derived reporter cell line AREc32 [vi],\u000d\u000a      which contains a luciferase gene construct controlled by the antioxidant\u000d\u000a      response element and responds robustly to compounds such as the\u000d\u000a      redox-cycling agent tert-butylhydroquinone which disrupt cellular\u000d\u000a      oxidation status. Such cell lines offer the possibility that the safety of\u000d\u000a      substances such as cosmetic ingredients can, in future, be evaluated\u000d\u000a      without animal testing (http:\/\/ec.europa.eu\/enterprise\/epaa\/3_events\/3_3_workshops\/18-llna-taalman.pdf).\u000d\u000a    "},{"CaseStudyId":"36533","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    After learning of the results of our preliminary analysis of 2009, the\u000d\u000a      Director of the NHS Cancer Screening Programmes asked Halligan to present\u000d\u000a      the data to the next meeting of the National Bowel Cancer Screening\u000d\u000a      Advisory Group. The data were orally presented in April 2010 when Halligan\u000d\u000a      concluded that barium enema should be withdrawn from the NHS immediately\u000d\u000a      (where circumstances allowed) and that CT colonography was a safe,\u000d\u000a      sensitive, and acceptable alternative to colonoscopy for diagnosis of\u000d\u000a      colorectal cancer. Within one month this led to an Interim Guidance Update\u000d\u000a      being issued by the Bowel Cancer Screening Programme (BCSP IGU 007 Apr\u000d\u000a      1010), which was sent to the Director, Lead Nurse, and Lead manager of\u000d\u000a      every NHS bowel screening centre, and to Quality Assurance Reference\u000d\u000a      Centre (QARC) coordinators. This stated that the SIGGAR trials \"show\u000d\u000a        that double contrast barium enema is significantly inferior to CT\u000d\u000a        colonography for detection of colorectal cancer and large polyps. It\u000d\u000a        also shows that the false-negative rate for colorectal cancer is\u000d\u000a        significantly higher for barium enema.\" The screening centres were\u000d\u000a      asked to use \"CTC rather than barium enema wherever local expertise and\u000d\u000a        circumstances permit\" [a].\u000d\u000a    The subsequent \"Guidelines for the use of imaging in the NHS Bowel Cancer\u000d\u000a      Screening Programme\" (NHSBCSP Publication no. 5, July 2010) stated that, \"Where\u000a        imaging is indicated, CTC is the preferred method. Double contrast\u000d\u000a        barium enema is reported to have a fourfold false negative rate; it is\u000d\u000a        therefore not appropriate for screening patients...Where high-quality\u000d\u000a        CTC is not available locally, the patient should be referred elsewhere\u000d\u000a        for examination\" [b].\u000d\u000a    In the light of the trials' findings, Halligan was asked to join the\u000d\u000a      Bowel Cancer Screening Advisory Panel in 2010 to advise on the national\u000d\u000a      implementation of CT colonography in the screening programme.\u000d\u000a      Subsequently, the Programme Director asked that a committee be established\u000d\u000a      with the specific remit to oversee the implementation of CT colonography\u000d\u000a      in the Bowel Cancer Screening programme, and its subsequent quality\u000d\u000a      control. The Bowel Cancer Screening Programme CT Colonography Steering\u000d\u000a      Group was formed in February 2012 and Halligan was asked to sit as\u000d\u000a      advisor. The group updated the Guidelines for the use of imaging in the\u000d\u000a      National Bowel Cancer Screening Programme, published November 2012 [c].\u000d\u000a      The Guidance repeats the statement that barium enema should be\u000d\u000a      discontinued immediately in favour of CT colonography and references the\u000d\u000a      HTA monograph from the SIGGAR trials [d]. The trials are also\u000d\u000a      cited on the \"key research in bowel cancer and bowel cancer screening\"\u000d\u000a      page of the NHS Bowel Cancer Screening Programme website [e].\u000d\u000a    Impact can be proven by analysis of imaging procedure rates within the\u000d\u000a      Bowel Cancer Screening Programme. In 2007 and 2008 the numbers of barium\u000d\u000a      enema and CT colonography studies performed in the Programme were\u000d\u000a      approximately similar (71 vs 99 for 2007 and 210 vs 284 for 2008). In\u000d\u000a      2010, the year the guidelines for imaging were published, the figures were\u000d\u000a      265 barium enema vs 1,291 CT colonography. Figures for 2011 were 128 vs\u000d\u000a      1,833 and for 2012 were 76 vs 1,928 [f].\u000d\u000a    The SIGGAR trials' findings that CTC was more accurate than barium enema\u000d\u000a      and not significantly different to colonoscopy have also impacted on the\u000d\u000a      provision of diagnostic services to symptomatic NHS patients. Firstly,\u000d\u000a      barium enema services are being reduced in the light of the trials'\u000d\u000a      findings and secondly, CT colonography provision is helping alleviate\u000d\u000a      pressure on endoscopy services generated by both the symptomatic service\u000d\u000a      and the screening programme [g]. The British Society of\u000d\u000a      Gastrointestinal and Abdominal Radiology have convened a committee in\u000d\u000a      parallel to the screening programme to oversee the implementation of CT\u000d\u000a      colonography in the symptomatic NHS setting; Halligan also sits on this\u000d\u000a      committee. In May 2013, a meeting of the Royal College of Radiologists\u000d\u000a      Professional Support & Standards Board made the decision to revise its\u000d\u000a      guidelines on the imaging of colorectal cancer in the light of the\u000d\u000a      findings of the SIGGAR trials. Halligan joined the Working Party\u000d\u000a      responsible for revising these guidelines (due December 2013) [h].\u000d\u000a    The impact of the trials reaches beyond the UK: the trial data were used\u000d\u000a      by a US radiologists Working Group on CT colonography in 2010 to justify a\u000d\u000a      higher rating for CT colonography for screening in the American College of\u000d\u000a      Radiology Appropriateness Criteria; they are also currently using the data\u000d\u000a      to evaluate national reimbursement for CT colonography [i]. The\u000d\u000a      trial data were also presented to the National Board of Health &\u000d\u000a      Welfare in Sweden in 2012 during the development of new and updated\u000d\u000a      National Guidelines on colorectal cancer to make the case that barium\u000d\u000a      enema should be withdrawn in Sweden and replaced by CT colonography [j].\u000d\u000a      Reviewing the trials in March 2013, the most-prominent colonoscopist in\u000d\u000a      the USA, Douglas Rex MD, stated, \"these study findings justify widespread\u000d\u000a      incorporation of CTC into U.S. hospitals, with subsequent abandonment of\u000d\u000a      DCBE\" [k].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Work led by researchers at UCL has had a national and international\u000d\u000a      impact on the way that patients with symptoms suggestive of colorectal\u000d\u000a      cancer are investigated. Specifically, investigation of the role of CT\u000d\u000a      colonography (a relatively novel and non-invasive method of investigating\u000d\u000a      the large bowel using an X-ray scanner) has led to this examination\u000d\u000a      replacing the standard alternative of barium enema in the UK National\u000d\u000a      Bowel Cancer Screening Programme and for symptomatic patients in the NHS.\u000d\u000a      The research has also led to easing of pressure on over-subscribed\u000d\u000a      endoscopy services in the NHS because patients can be safely diverted\u000d\u000a      towards CT colonography as an alternative.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Halligan S, Altman DG, Taylor SA, Mallett S, Deeks JJ, Bartram CI,\u000d\u000a      Atkin W. CT colonography in the detection of colorectal polyps and cancer:\u000d\u000a      systematic review, meta-analysis, and proposed minimum data set for study\u000d\u000a      level reporting. Radiology. 2005 Dec;237(3):893-904.\u000d\u000a      http:\/\/dx.doi.org\/10.1148\/radiol.2373050176\u000d\u000a    \u000a\u000a[2] Halligan S, Lilford RJ, Wardle J, Morton D, Rogers P, Wooldrage K,\u000d\u000a      Edwards R, Kanani R, Shah U, Atkin W. Design of a multicentre randomized\u000d\u000a      trial to evaluate CT colonography versus colonoscopy or barium enema for\u000d\u000a      diagnosis of colonic cancer in older symptomatic patients: the SIGGAR\u000d\u000a      study. Trials. 2007 Oct 27;8:32. http:\/\/dx.doi.org\/doi:10.1186\/1745-6215-8-32\u000d\u000a    \u000a\u000a[3] Halligan S, Wooldrage K, Dadswell E, Kralj-Hans I, von Wagner C,\u000d\u000a      Edwards R, Yao G, Kay C, Burling D, Faiz O, Teare J, Lilford RJ, Morton D,\u000d\u000a      Wardle J, Atkin W; SIGGAR investigators. Computed tomographic colonography\u000d\u000a      versus barium enema for diagnosis of colorectal cancer or large polyps in\u000d\u000a      symptomatic patients (SIGGAR): a multicentre randomised trial. Lancet.\u000d\u000a      2013 Apr 6;381(9873):1185-93. http:\/\/dx.doi.org\/10.1016\/S0140-6736(12)62124-2\u000d\u000a    \u000a\u000a[4] Atkin W, Dadswell E, Wooldrage K, Kralj-Hans I, von Wagner C, Edwards\u000d\u000a      R, Yao G, Kay C, Burling D, Faiz O, Teare J, Lilford RJ, Morton D, Wardle\u000d\u000a      J, Halligan S; SIGGAR investigators. Computed tomographic colonography\u000d\u000a      versus colonoscopy for investigation of patients with symptoms suggestive\u000d\u000a      of colorectal cancer (SIGGAR): a multicentre randomised trial. Lancet.\u000d\u000a      2013 Apr 6;381(9873):1194-202. http:\/\/dx.doi.org\/10.1016\/S0140-6736(12)62186-2\u000d\u000a    \u000a\u000a[5] von Wagner C, Ghanouni A, Halligan S, Smith S, Dadswell E, Lilford\u000d\u000a      RJ, Morton D, Atkin W, Wardle J; SIGGAR Investigators. Patient\u000d\u000a      acceptability and psychologic consequences of CT colonography compared\u000d\u000a      with those of colonoscopy: results from a multicenter randomized\u000d\u000a      controlled trial of symptomatic patients. Radiology. 2012\u000d\u000a      Jun;263(3):723-31.\u000d\u000a      http:\/\/dx.doi.org\/10.1148\/radiol.12111523\u000d\u000a    \u000aSelected research grant support:\u000d\u000a    NIHR HTA programme. CT colonography versus colonoscopy or barium enema\u000d\u000a      for diagnosis of colorectal cancer in older symptomatic patients;\u000d\u000a      Multicentre randomised controlled trials (HTA 02\/02\/01). 2004-11. CI: S\u000d\u000a      Halligan, UCL. £1,858,578\u000d\u000a    NIHR. Programme Grant for Applied Research: Imaging diagnosis of\u000d\u000a      colorectal cancer — Interventions for efficient & acceptable diagnosis\u000d\u000a      in asymptomatic & symptomatic populations (RP-PG-0407-10338). 2008-13.\u000d\u000a      CI: S Halligan, UCL. £1,516,044\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    [a] Bowel Cancer Screening Programme. Interim Guidance Update number 007.\u000d\u000a      April 2010. Copy available on request.\u000d\u000a    [b] Guidelines for the use of imaging in the NHS Bowel Cancer Screening\u000d\u000a      Programme, First Edition. NHSBCS Publication no. 5, July 2010. Copy\u000d\u000a      available on request.\u000d\u000a    [c] Guidelines for the use of imaging in the NHS Bowel Cancer Screening\u000d\u000a      Programme, Second Edition. NHSBCS Publication no. 5, November 2012\u000d\u000a      (http:\/\/www.cancerscreening.nhs.uk\/bowel\/publications\/index.html).\u000d\u000a    [d] HTA Programme; Project website: http:\/\/www.hta.ac.uk\/project\/1366.asp\u000d\u000a    [e] Key research in bowel cancer and bowel cancer screening. NHS Bowel\u000d\u000a      Cancer Screening Programme. http:\/\/www.cancerscreening.nhs.uk\/bowel\/research.html\u000d\u000a    [f] Rates for barium enema vs CTC were obtained from the National Bowel\u000d\u000a      Cancer Screening Programme. Contact details provided.\u000d\u000a    [g] The drop in barium enema can be seen from the national diagnostics\u000d\u000a      statistics: https:\/\/www.gov.uk\/government\/news\/nhs-diagnostics-waiting-times-and-activity-data-november-2012\u000d\u000a      Barium enema is down 12.1% in November 2012 compared to 2011.\u000d\u000a    [h] Working Party Terms of Reference and email from the Chair. Copies\u000d\u000a      available on request.\u000d\u000a    [i] Statement from Chair, Colorectal Cancer Committee, American College\u000d\u000a      of Radiology. Available on request.\u000d\u000a    [j] Statement from Professor working on guideline development, Department\u000d\u000a      of Radiology, Sahlgrenska University Hospital. Available on request.\u000d\u000a    [k] http:\/\/www.jwatch.org\/jg201303080000002\/2013\/03\/08\/ctc-vs-barium-enema-ctc-wins\u000d\u000a    ","Title":"\u000d\u000a    CT colonography for diagnosis of colorectal cancer in older symptomatic\u000d\u000a      patients\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The impacts reported here arise from a systematic review of CT\u000d\u000a      colonography and two multicentre clinical trials led by researchers at\u000d\u000a      UCL. Prior to this research, the usual approach to investigating patients\u000d\u000a      with symptoms of bowel cancer was either barium enema examination or\u000d\u000a      colonoscopy of the large bowel (amounting to over 700,000 patients per\u000d\u000a      year in the UK). Both investigations had limitations whereas CT\u000d\u000a      colonography offered theoretical advantages. However, CT was usually\u000d\u000a      advocated to screen asymptomatic patients for pre-malignant polyps but no\u000d\u000a      randomised controlled trials had been undertaken.\u000d\u000a    Professor Steve Halligan (Centre for Medical Imaging, UCL Division of\u000d\u000a      Medicine) realised that most published trials of CT had actually recruited\u000d\u000a      symptomatic patients and believed that existing data showed that CT\u000d\u000a      colonography was likely to have high diagnostic accuracy for detecting\u000d\u000a      established cancer in such patients. In order to confirm this he performed\u000d\u000a      a systematic review with the primary aim of extracting data on cancer\u000d\u000a      detection, from primary studies, with statistical collaborators at Oxford\u000d\u000a      (Altman, Mallett) and cancer epidemiologists at Imperial (Atkin). The\u000d\u000a      systematic review found a pooled sensitivity for cancer by CT colonography\u000d\u000a      of the order of 96% — i.e. equivalent to colonoscopy, the current\u000d\u000a      \"gold-standard\" [1].\u000d\u000a    Aware of CT colonography as a potentially useful diagnostic test and\u000d\u000a      seeing these data abstracted, the NHS's Health Technology Assessment\u000d\u000a      programme commissioned research on the technology in the NHS. An\u000d\u000a      application for funding was led by Professor Halligan as CI. Two\u000d\u000a      multicentre pragmatic randomised controlled trials of CT colonography\u000d\u000a      versus the existing NHS standards of barium enema and colonoscopy in\u000d\u000a      symptomatic patients were proposed. Endpoints included cancer detection,\u000d\u000a      economic modelling within and beyond the trial time-horizon, and\u000d\u000a      health-psychology [2]. A specific focus was how detection of\u000d\u000a      pathology outside the bowel influenced use of the test in the NHS. Key\u000d\u000a      collaborators were Atkin (Imperial, cancer epidemiology), Lilford\u000d\u000a      (Birmingham, health-economics and modelling), and Wardle (UCL, health\u000d\u000a      psychology).\u000d\u000a    The application was successful and 8,484 patients in 21 NHS hospitals\u000d\u000a      were registered and 5,384 randomised and ultimately analysed (BE trial:\u000d\u000a      2527 BE, 1277 CTC. Colonoscopy trial: 1047 colonoscopy, 533 CTC). Known as\u000d\u000a      the \"SIGGAR\" (Special Interest Group in Gastrointestinal & Abdominal\u000d\u000a      Radiology) trial, this was the first RCT of CT colonography worldwide and\u000d\u000a      the largest RCT in gastrointestinal radiology. Procedure detection rates\u000d\u000a      and subsequent tests\/resources were collected and false-negative diagnoses\u000d\u000a      of intra- and extra-colonic cancer identified via NHS Information Centre\u000d\u000a      three years post-randomisation, and trial arms compared. Preliminary data\u000d\u000a      were presented orally in 2009.\u000d\u000a    SIGGAR found that CT colonography was superior to barium enema for\u000d\u000a      diagnosis of colorectal cancer and large polyps [3]. There was no\u000d\u000a      significant difference between CT colonography and colonoscopy [4].\u000d\u000a      CT colonography was significantly better perceived by patients, and was\u000d\u000a      associated with fewer immediate and delayed adverse events [5]. CT\u000d\u000a      colonography was significantly more cost-effective than barium enema (both\u000d\u000a      within trial and extrapolated) and equally cost-effective as colonoscopy [3].\u000d\u000a      Extra-colonic tumours were detected by CT colonography in approximately 4%\u000d\u000a      of recruited patients, of which around half were malignant.\u000d\u000a    "},{"CaseStudyId":"36901","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Canakinumab was licensed for the treatment of CAPS, a new highly\u000d\u000a      effective medicine for a rare\u000d\u000a      orphan disease, in the EU [a] and the US in 2009 and in Japan in\u000d\u000a      2011 [b]. Data for licensing\u000d\u000a      arose principally from the clinical trials led by Hawkins.\u000d\u000a    The NHS CAPS Treatment Service, established in 2010 as a result of\u000d\u000a      Hawkins' research, and\u000d\u000a      funded directly by the Department of Health, provides the national service\u000d\u000a      for patients with\u000d\u000a      autoinflammatory diseases, offering a clinical and genetic diagnostic\u000d\u000a      service, and highly effective\u000d\u000a      treatment with specific cytokine inhibitors [c]. Fifty patients\u000d\u000a      with CAPS are currently receiving\u000d\u000a      canakinumab treatment in the UK centre, at an annual cost of £3.6m, and\u000d\u000a      nearly 300 patients are\u000d\u000a      now being treated world-wide, 234 of whom have CAPS and the remainder\u000d\u000a      having other\u000d\u000a      autoinflammatory diseases [d].\u000d\u000a    An international registry to document the safety and efficacy of\u000d\u000a      canakinumab has been created [e],\u000d\u000a      to which Hawkins contributed design and serves as a member of the steering\u000d\u000a      committee. Among\u000d\u000a      the 241 CAPS patients enrolled on the registry, only two have discontinued\u000d\u000a      treatment due to poor\u000d\u000a      therapeutic response.\u000d\u000a    CAPS-causing mutations result in excessive production of interleukin\u000d\u000a      103b2 (IL-103b2), which causes\u000d\u000a      disabling multi-system inflammation from birth. Patients suffer severe\u000d\u000a      fatigue, fever and muscle\u000d\u000a      pains on a daily basis that mimic influenza, many symptoms of which are\u000d\u000a      also caused by excessive\u000d\u000a      IL-1β clinical features include chronic anaemia and inflammation in the\u000d\u000a      skin, eyes, joints and brain\u000d\u000a      that presents as rashes, conjunctivitis, arthritis, chronic meningitis,\u000d\u000a      blindness, deafness and in\u000d\u000a      some cases cognitive impairment. About 25% of patients develop AA\u000d\u000a      amyloidosis that results in\u000d\u000a      kidney failure and death within 5-10 years. Growth and development are\u000d\u000a      impaired, and puberty is\u000d\u000a      delayed as a result of chronic severe inflammation. Patients with CINCA,\u000d\u000a      the most severe CAPS\u000d\u000a      phenotype, often die before adulthood.\u000d\u000a    Treatment of CAPS with the monoclonal IL-103b2 antibody, canakinumab,\u000d\u000a      results in complete or near-complete\u000d\u000a      remission of the disabling inflammation that affects the skin, eyes,\u000d\u000a      joints and brain and\u000d\u000a      causes the major flu-like symptoms and fevers. The overwhelming fatigue\u000d\u000a      that impedes\u000d\u000a      employment and social activities is abolished, corroborated in clinical\u000d\u000a      studies through normalisation\u000d\u000a      of the SF-36 quality of life and FACIT-F© fatigue scores. In\u000d\u000a      the long term, there is every\u000d\u000a      expectation that continued treatment with canakinumab will prevent the\u000d\u000a      skeletal deformities,\u000d\u000a      blindness, deafness and amyloidosis that commonly occur. Catch-up growth\u000d\u000a      and age-appropriate\u000d\u000a      sexual maturation have been observed in adolescents with CAPS who have\u000d\u000a      been treated with\u000d\u000a      canakinumab.\u000d\u000a    Feedback from patients treated with canakinumab [f] includes:\u000d\u000a    \"I could not have imagined such a change in fortune due to this\u000d\u000a        drug...\"\u000d\u000a    \"My whole body ached, I had difficulty walking and had to be carried\u000d\u000a        to bed. I missed a lot\u000d\u000a        of school with severe headaches, and could not even have a bath due to\u000d\u000a        the rash. I cannot\u000d\u000a        believe the effect of this drug, my symptoms have completely\u000d\u000a        disappeared.\"\u000d\u000a    \"My joints and whole body would swell right up, and I would itch until\u000d\u000a        I would bleed, and had\u000d\u000a        terrible migraines. I am now NORMAL!!!\"\u000d\u000a    \"My joint inflammation and pains have completely disappeared\"\u000d\u000a    \"My daughter had terrible headaches, conjunctivitis, and rashes, and\u000d\u000a        was hardly able to get\u000d\u000a        of bed. She was shunned at school, and put in a remedial class. It got\u000d\u000a        so bad she took an\u000d\u000a        overdose. After the drug all the symptoms vanished; she is happy and\u000d\u000a        alive for the first\u000d\u000a        time, and is now working and has her first boyfriend at 20 years old!\"\u000d\u000a    \"Joints were excruciating, and now the symptoms have disappeared\"\u000d\u000a    \"The effects have been absolutely life changing for me\".\u000d\u000a    \"This is a wonder drug\".\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The UCL Centre for Amyloidosis and Acute Phase Proteins has identified\u000d\u000a      the cause and treatment\u000d\u000a      for the prototypical cryopryin associated periodic syndrome (CAPS), and\u000d\u000a      subsequently for a range\u000d\u000a      of other hereditary and acquired autoinflammatory disorders. As a result\u000d\u000a      of the research,\u000d\u000a      canakinumab was licensed for this condition. In recognition, NHS\u000d\u000a      Specialised Services\u000d\u000a      commissioned the UK CAPS Treatment Service in 2010 to deliver\u000d\u000a      life-changing IL-1 blocking\u000d\u000a      therapy to the national caseload of CAPS patients at UCL.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR,\u000d\u000a      Lachmann HJ, Bybee A,\u000d\u000a      Gaudet R, Woo P, Feighery C, Cotter FE, Thome M, Hitman GA, Tschopp J,\u000d\u000a      McDermott MF.\u000d\u000a      Association of mutations in the NALP3\/CIAS1\/PYPAF1 gene with a broad\u000d\u000a      phenotype including\u000d\u000a      recurrent fever, cold sensitivity, sensorineural deafness, and AA\u000d\u000a      amyloidosis. Arthritis Rheum.\u000d\u000a      2002 Sep;46(9):2445-52. http:\/\/dx.doi.org\/10.1002\/art.10509\u000d\u000a    \u000a\u000a[2] Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor\u000d\u000a      antagonist in the Muckle-\u000d\u000a      Wells syndrome. N Engl J Med. 2003 Jun 19;348(25):2583-4.\u000d\u000a      http:\/\/dx.doi.org\/10.1056\/NEJM200306193482523\u000d\u000a    \u000a\u000a[3] Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical\u000d\u000a      features in\u000d\u000a      Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004\u000d\u000a      Feb;50(2):607-12.\u000d\u000a      http:\/\/dx.doi.org\/10.1002\/art.20033\u000d\u000a    \u000a\u000a[4] Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J.\u000d\u000a      NALP3 forms an IL-\u000d\u000a      1beta-processing inflammasome with increased activity in Muckle-Wells\u000d\u000a      autoinflammatory\u000d\u000a      disorder. Immunity. 2004 Mar;20(3):319-25. http:\/\/dx.doi.org\/10.1016\/S1074-7613(04)00046-9\u000d\u000a    \u000a\u000a[5] Lachmann HJ, Lowe P, Felix SD, Rordorf C, Leslie K, Madhoo S,\u000d\u000a      Wittkowski H, Bek S,\u000d\u000a      Hartmann N, Bosset S, Hawkins PN, Jung T. In vivo regulation of\u000d\u000a      interleukin 1beta in patients\u000d\u000a      with cryopyrin-associated periodic syndromes. J Exp Med. 2009 May\u000d\u000a      11;206(5):1029-36.\u000d\u000a      http:\/\/dx.doi.org\/10.1084\/jem.20082481\u000d\u000a    \u000a\u000a[6] Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla\u000d\u000a      E, Quartier P,\u000d\u000a      Gitton X, Widmer A, Patel N, Hawkins PN; Canakinumab in CAPS Study Group.\u000d\u000a      Use of\u000d\u000a      canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med.\u000d\u000a      2009 Jun\u000d\u000a      4;360(23):2416-25. http:\/\/dx.doi.org\/10.1056\/NEJMoa0810787\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    [a] European Medicines Agency Evaluation of Medicines for Human Use, July\u000d\u000a      2009: CHMP\u000d\u000a      assessment report for canakinumab.\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Public_assessment_report\/human\/001109\/WC500031679.pdf\u000d\u000a    [b] Press releases on approval of canakinumab (tradename Ilaris)\u000d\u000a    \u000d\u000a      In US, 2009: http:\/\/www.drugs.com\/newdrugs\/new-biological-therapy-ilaris-approved-us-children-adults-caps-serious-long-auto-inflammatory-1472.html\u000a\u000d\u000a      In Japan, 2011: http:\/\/www.novartis.com\/newsroom\/media-releases\/en\/2011\/1550036.shtml\u000a\u000d\u000a    \u000d\u000a    [c] National Specialised Commissioning Team Service Specification\u000d\u000a      2012\/13: National treatment\u000d\u000a      service for Cryopyrin Associated Periodic fever Syndromes (CAPS).\u000d\u000a      http:\/\/www.specialisedservices.nhs.uk\/library\/36\/Service_Specification_and_Standards___Cryopyrin_Associated_Periodic_fever_Syndromes_CAPS_2.pdf\u000d\u000a    [d] Patient numbers can be confirmed by Commissioning Support Manager,\u000d\u000a      Royal Free Hospital.\u000d\u000a      Contact details provided.\u000d\u000a    [e] International registry to document the safety and efficacy of\u000d\u000a      canakinumab is at\u000d\u000a      https:\/\/www.bconfidentregistry.com.\u000d\u000a      03b2-Confident is a global, multicentre, prospective,\u000d\u000a      observation registry study of patients diagnosed with CAPS and treated\u000d\u000a      with canakinum A\u000d\u000a      recent publication is: Tilson H, Primatesta P, Kim D, Rauer B, Hawkins PN,\u000d\u000a      Hoffman HM,\u000d\u000a      Kuemmerle-Deschner J, van der Poll T, Walker UA. Methodological challenges\u000d\u000a      in monitoring\u000d\u000a      new treatments for rare diseases: lessons from the cryopyrin-associated\u000d\u000a      periodic syndrome\u000d\u000a      registry. Orphanet J Rare Dis. 2013 Sep 10;8(1):139. http:\/\/dx.doi.org\/10.1186\/1750-1172-8-139\u000d\u000a    [f] Statements from patients with CAPS whose lives have been transformed\u000d\u000a      by treatment with\u000d\u000a      canakinumab. Copies available on request.\u000d\u000a    ","Title":"\u000d\u000a    Hereditary autoinflammatory disease programme: from endogenous pyrogen\u000d\u000a      to the NHS cryopryin associated periodic syndrome (CAPS) Treatment Service\u000d\u000a      at UCL, Royal Free\u000d\u000a      Hospital.\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The notion of autoinflammatory diseases, i.e. chronic multisystem\u000d\u000a      inflammatory disorders without\u000d\u000a      evidence of cell-mediated or humoral autoimmunity, emerged with the\u000d\u000a      molecular characterisation\u000d\u000a      in the late 1990s of two monogenic inherited periodic fever syndromes,\u000d\u000a      familial Mediterranean\u000d\u000a      fever (FMF) and the TNF-associated periodic syndrome (TRAPS), both of\u000d\u000a      which are frequently\u000d\u000a      complicated by the development of reactive systemic (AA) amyloidosis,\u000d\u000a      causing renal failure and\u000d\u000a      early death.\u000d\u000a    Professor Philip Hawkins and Dr Helen Lachmann began to characterise the\u000d\u000a      phenotype of patients\u000d\u000a      referred to the NHS National Amyloidosis Centre with AA amyloidosis of\u000d\u000a      undetermined\u000d\u000a      inflammatory aetiology in the late 1990s. They identified patients in whom\u000d\u000a      there was evidence of\u000d\u000a      familial autoinflammatory disease, notably including those conforming to\u000d\u000a      the description of Muckle-Wells\u000d\u000a      syndrome, a rare disorder characterised by urticarial rash, aching limbs,\u000d\u000a      hearing loss and\u000d\u000a      amyloidosis. In collaboration with Dr Michael McDermott at Bart's and the\u000d\u000a      London, they performed\u000d\u000a      a genome wide genetic linkage study during 2000 in an Indian family with\u000d\u000a      Muckle-Wells syndrome,\u000d\u000a      and identified a defect in the NLRP3 (formerly NALP3) gene, which was\u000d\u000a      reported simultaneously\u000d\u000a      by a US group to be associated with familial cold urticaria, an apparently\u000d\u000a      different, less severe\u000d\u000a      hereditary inflammatory disease [1]. Hawkins and Lachmann\u000d\u000a      undertook a collaborative study with\u000d\u000a      Professor Jurg Tschopp in Lausanne through 2001-03, which demonstrated\u000d\u000a      increased activity of\u000d\u000a      mutated NLRP3 in the interleukin-1 (IL-1) processing inflammasome pathway\u000d\u000a      in myelomonocytic\u000d\u000a      cells, suggesting that excessive IL-1 production may contribute to the\u000d\u000a      pathogenesis of the disease\u000d\u000a      [4]. Hawkins' team firmly validated IL-1 as a therapeutic target in\u000d\u000a      patients with NLRP3 mutations in\u000d\u000a      2003 through the reverse translational approach by demonstrating rapid and\u000d\u000a      complete remission of\u000d\u000a      Muckle-Wells syndrome complicated by advanced amyloidosis following\u000d\u000a      treatment with\u000d\u000a      recombinant IL-1 receptor antagonist [2,3].\u000d\u000a    Further genetic and clinical phenotyping studies by Hawkins and Lachmann\u000d\u000a      confirmed that Muckle-Wells\u000d\u000a      syndrome, familial cold urticaria (now known as familial cold\u000d\u000a      autoinflammatory syndrome)\u000d\u000a      and the apparently sporadic very severe congenital disorder known as\u000d\u000a      chronic infantile\u000d\u000a      neurological, cutaneous and articular syndrome (CINCA) constituted a\u000d\u000a      continuous spectrum of\u000d\u000a      inflammatory disease caused by mutations in NLRP3 (now also known as\u000d\u000a      cyropyrin). They\u000d\u000a      subsequently collaborated with Novartis from 2004 to 2009, resulting in\u000d\u000a      the development of a fully\u000d\u000a      humanised monoclonal anti-IL-103b2 antibody, canakinumab, which they\u000d\u000a      demonstrated produces near\u000d\u000a      complete resolution of inflammatory disease activity in virtually all\u000d\u000a      patients with CAPS, and which\u000d\u000a      they have latterly shown also has high efficacy in other acquitted and\u000d\u000a      hereditary autoinflammatory\u000d\u000a      disorders including TRAPS. Proof of concept clinical studies [5],\u000d\u000a      followed by a pivotal randomised\u000d\u000a      controlled trial of canakinumab in CAPS led by Hawkins, resulted in the\u000d\u000a      approval of this new\u000d\u000a      biologic agent for this orphan indication in the US and EU [6],\u000d\u000a      and Phase II\/III studies are now\u000d\u000a      underway in patients with TRAPS.\u000d\u000a    Further translational studies have shown that inappropriate acute or\u000d\u000a      chronic activation of the innate\u000d\u000a      immune system, mediated substantially by IL-1, contributes to many other\u000d\u000a      acquired chronic\u000d\u000a      disorders, ranging from rare entities such as Schnitzler syndrome, to\u000d\u000a      numerous very common\u000d\u000a      conditions potentially including diabetes mellitus, atherosclerosis and\u000d\u000a      asthma\u000d\u000a    This work was recognised by the NHS National Specialised Services, the\u000d\u000a      national organisation\u000d\u000a      responsible for the commissioning of highly specialised clinical services\u000d\u000a      (formerly the National\u000d\u000a      Commissioning Group), in supporting a national diagnostic and management\u000d\u000a      advisory service for\u000d\u000a      inherited `fever' disorders as part of the NHS National Amyloidosis Centre\u000d\u000a      in 1999, and\u000d\u000a      subsequently the UK CAPS Treatment Service in 2010 to deliver highly\u000d\u000a      effective IL-1 blocking\u000d\u000a      therapy to the national caseload of CAPS patients.\u000d\u000a    "},{"CaseStudyId":"38117","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Over 200 breast cancer teams world-wide now use TARGIT including:\u000a      Cleveland Clinic; University\u000a      of California San Francisco; University of Southern California; Cornell;\u000a      Georgetown University;\u000a      Advocathealth hospitals in Chicago; Moffit cancer centre, Florida; about\u000a      two-thirds of breast\u000a      centres in Germany; several centres in the rest of Europe. The busiest\u000a      centre has treated over 500\u000a      cases and manufacturers Carl Zeiss report that in all, over 8,000 patients\u000a      have been treated with\u000a      TARGIT [a].\u000a    Thus, this idea and resulting research from UCL has revolutionised the\u000a      treatment paradigm from\u000a      radical radiotherapy to localised radiotherapy.\u000a    Impact on patients and their families: improvement in length and\u000a        quality of life, at a reduced cost\u000a    Many women are obliged to choose a mastectomy when they are not able to\u000a      take the prolonged\u000a      postoperative course of radiotherapy because of geography, time or money\u000a      constraints. Many\u000a      receive suboptimal treatment. With TARGIT, such women can have a\u000a      lumpectomy and preserve\u000a      their breast. Even amongst those who have a lumpectomy, TARGIT causes less\u000a      pain, higher level\u000a      of patient satisfaction, and higher quality of life scores than those\u000a      receiving conventional\u000a      radiotherapy [b]. There is a significant improvement in a woman's\u000a      cancer journey when the whole\u000a      of local treatment is completed at the time of the cancer operation,\u000a      rather than a daily 3-6-week\u000a      commute to the cancer hospital. TARGIT patients also have half the risk of\u000a      death from heart\u000a      disease or other cancers by avoiding toxicity. From the numbers in the\u000a      trial (13 fewer deaths\u000a      amongst 1,140 patients who were randomised to receive TARGIT at the time\u000a      of lumpectomy), one\u000a      can extrapolate that out of 8,000 patients, 91 such deaths have already\u000a      been prevented. In\u000a      communities where the patients have to pay for their treatment, TARGIT is\u000a      a fraction of the cost of\u000a      conventional radiotherapy — leading to more equitable availability of\u000a      treatment.\u000a    Impact on the routine treatment guidelines\/recommendations for\u000a        patients in the community\u000a    The TARGIT-A trial was the first proof of principle of `partial breast\u000a      irradiation' and other methods\u000a      of giving partial breast irradiation have proliferated. TARGIT either as a\u000a      tumour bed boost or as\u000a      definitive treatment as well as other methods of partial breast\u000a      irradiation are now included in\u000a      guidelines issued by the European Society of Breast Cancer Specialists [c],\u000a      the European Society\u000a      of Medical Oncology (which are also endorsed by the Japanese Society of\u000a      Medical Oncology) [d]\u000a      and in German national guidelines [e].\u000a    In March 2011, at the biennial international \"St Gallen consensus\"\u000a      conference, 52 world experts\u000a      voted in favour of using intraoperative radiation in selected patients. At\u000a      this time the only level 1\u000a      randomised evidence was from the TARGIT-A trial [f]. In December\u000a      2012, the newsletter at the\u000a      largest breast cancer conference at St Gallen featured our late breaking\u000a      paper [g]. Our research\u000a      has also attracted significant media attention both in scientific\u000a      periodicals as well as lay press [h].\u000a    NICE is currently consulting on the use of TARGIT in routine practice [i].\u000a      The Marmot committee\u000a      on screening has suggested that in patients whose cancers are found only\u000a      on mammographic\u000a      screening, if TARGIT is used rather than EBRT, this would minimise side\u000a      effects due to the over-diagnosis\u000a      and overtreatment that is known to occur with mammographic screening [j].\u000a      We have\u000a      also demonstrated that TARGIT is a method of avoiding cardiac toxicity of\u000a      EBRT [k].\u000a    Impact on the healthcare delivery and budget\u000a    Breast cancer constitutes 1\/3 of the workload of a typical radiotherapy\u000a      department and in many\u000a      areas there can be long waiting lists. When a significant proportion of\u000a      this time is freed up by using\u000a      TARGIT in the operation theatre, it can be used to treat other cancers in\u000a      a timely manner.\u000a    Assuming that each of the 8,000 patients who had TARGIT during their\u000a      lumpectomy would have\u000a      required 30 conventional radiotherapy sessions rather than the single\u000a      session at the time of\u000a      surgery, and that TARGIT takes the time equivalent of 4 routine\u000a      radiotherapy sessions, this is a\u000a      saving of 208,000 radiotherapy sessions to date. Assuming each session\u000a      costs a conservative\u000a      £200, the saving of 208,000 sessions has already saved £41.6m world-wide.\u000a      It is estimated that\u000a      adoption of TARGIT in the UK will save about £60m per year from manpower\u000a      costs alone. A more\u000a      formal model has predicted this amount to be $280m in the US [l].\u000a    ","ImpactSummary":"\u000a    Research from UCL Division of Surgery has transformed the breast cancer\u000a      treatment paradigm so\u000a      women can complete their local treatment intraoperatively (~30 min), with\u000a      reduced toxicity. Our\u000a      work has challenged the dogma of giving several weeks of whole breast\u000a      radiotherapy (EBRT) after\u000a      lumpectomy for breast cancer with our idea of irradiating only the tumour\u000a      bed in selected cases; we\u000a      have developed and evaluated new technology called TARGeted Intraoperative\u000a      radioTherapy\u000a      (TARGIT) within the novel approach of risk-adapted radiotherapy. To date,\u000a      TARGIT has saved\u000a      180,000 hospital visits and could save £60M(UK)\/ $280M(USA)\/year.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University College London\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5391959","Name":"San Francisco"},{"GeoNamesId":"2658822","Name":"Sankt Gallen"},{"GeoNamesId":"5332921","Name":"California"},{"GeoNamesId":"4155751","Name":"Florida"}],"References":"\u000a    \u000a[1] Vaidya JS, Baum M, Tobias JS, D'Souza DP, Naidu SV, Morgan S, Metaxas\u000a      M, Harte KJ,\u000a      Sliski AP, Thomson E. Targeted intra-operative radiotherapy (Targit): an\u000a      innovative method of\u000a      treatment for early breast cancer. Ann Oncol. 2001 Aug;12(8):1075-80.\u000a      http:\/\/annonc.oxfordjournals.org\/content\/12\/8\/1075.long\u000a    \u000a\u000a[2] Vaidya JS, Baum M, Tobias JS, Morgan S, D'Souza D. The novel\u000a      technique of delivering\u000a      targeted intraoperative radiotherapy (Targit) for early breast cancer. Eur\u000a      J Surg Oncol. 2002\u000a      Jun;28(4):447-54. http:\/\/dx.doi.org\/10.1053\/ejso.2002.1275\u000a    \u000a\u000a[3] Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat\u000a      F, Berton S, Perin T,\u000a      Candiani E, Reccanello S, Veronesi A, Canzonieri V, Trovò MG, Zaenker KS,\u000a      Colombatti A,\u000a      Baldassarre G, Massarut S. Targeted intraoperative radiotherapy impairs\u000a      the stimulation of\u000a      breast cancer cell proliferation and invasion caused by surgical wounding.\u000a      Clin Cancer Res.\u000a      2008 Mar 1;14(5):1325-32. http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-07-4453.\u000a    \u000a\u000a[4] Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C,\u000a      Alvarado M, Flyger HL,\u000a      Massarut S, Eiermann W, Keshtgar M, Dewar J, Kraus-Tiefenbacher U,\u000a      Sütterlin M, Esserman\u000a      L, Holtveg HM, Roncadin M, Pigorsch S, Metaxas M, Falzon M, Matthews A,\u000a      Corica T, Williams\u000a      NR, Baum M. Targeted intraoperative radiotherapy versus whole breast\u000a      radiotherapy for breast\u000a      cancer (TARGIT-A trial): an international, prospective, randomised,\u000a      non-inferiority phase 3 trial.\u000a      Lancet. 2010 Jul 10;376(9735):91-102. http:\/\/dx.doi.org\/10.1016\/S0140-6736(10)60837-9.\u000a    \u000aThe Lancet fast-tracked our paper describing the first results of the\u000a      TARGIT-A trial and published it\u000a      with an independent editorial entitled \"Partial breast irradiation: a new\u000a      standard for selected\u000a      patients\". Our conclusion was on their front masthead page: \"For selected\u000a      patients with early\u000a      breast cancer, a single dose of radiotherapy delivered at the time of\u000a      surgery by use of targeted\u000a      intraoperative radiotherapy (TARGIT) should be considered as an\u000a      alternative to external beam\u000a      radiotherapy delivered over several weeks\". It is a `Highly Cited\u000a        Paper' in the ISI database.\u000a    \u000a[5] Vaidya JS, Baum M, Tobias JS, Wenz F, Massarut S, Keshtgar M, Hilaris\u000a      B, Saunders C,\u000a      Williams NR, Brew-Graves C, Corica T, Roncadin M, Kraus-Tiefenbacher U,\u000a      Sütterlin M,\u000a      Bulsara M, Joseph D. Long-term results of targeted intraoperative\u000a      radiotherapy (Targit) boost\u000a      during breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2011 Nov\u000a      15;81(4):1091-7.\u000a      http:\/\/dx.doi.org\/10.1016\/j.ijrobp.2010.07.1996.\u000a    \u000aGrants awarded by the Health Technology Assessment program of the\u000a      National Institutes of\u000a      Health Research:\u000a    • £694,143: TARGIT-A trial: Targeted intraoperative radiotherapy for\u000a      breast cancer (2009)\u000a    • £1,540,174: TARGIT-Boost trial for young \/ high risk breast cancer\u000a      (2012)\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    [a] Correspondence from the Head, Medical and Health Economy, Carl Zeiss\u000a      detailing number of\u000a      patients treated is available on request.\u000a    [b] Welzel G, Boch A, Sperk E, et al. Radiation-related quality of life\u000a      parameters after targeted\u000a      intraoperative radiotherapy versus whole breast radiotherapy in patients\u000a      with breast cancer:\u000a      results from the randomized phase III trial TARGIT-A. Radiat Oncol. 2013\u000a      Jan 7;8(1):9.\u000a      http:\/\/doi.org\/n2v\u000a    [c] Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly\u000a      patients with breast cancer:\u000a      updated recommendations of the International Society of Geriatric Oncology\u000a      (SIOG) and\u000a      European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012\u000a      Apr;13(4):e148-60. http:\/\/doi.org\/n2w. See\u000a        reference 41.\u000a    [d] Senkus E, Kyriakides S, Penault-Llorca F, et al.; on behalf of the\u000a      ESMO Guidelines Working\u000a      Group. Primary breast cancer: ESMO Clinical Practice Guidelines for\u000a      diagnosis, treatment and\u000a      follow-up. Ann Oncol. 2013 Aug 22. http:\/\/doi.org\/n2x.\u000a      See reference 46.\u000a    [e] German National Guidelines, \"Interdis iplin re S3-eitlinie f r die\u000a      iagnostik, Therapie und\u000a      Nachsorge des Mammakar inoms\", 2012. See pages 138\/139\u000a      http:\/\/www.krebsgesellschaft.de\/download\/S3_Brustkrebs_Update_2012_OL_Langversion.pdf\u000a    [f] Goldhirsch A, Wood WC, Coates AS, et al.; Panel members. Strategies\u000a      for subtypes--dealing\u000a      with the diversity of breast cancer: highlights of the St. Gallen\u000a      International Expert Consensus\u000a      on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011\u000a      Aug;22(8):1736-47.\u000a      http:\/\/doi.org\/cpc9t4.\u000a    [g] 2012 San Antonio Breast Cancer Symposium Highlights: TARGIT\u000a      vs Conventional\u000a      Radiotherapy: 10 Years On. 6 December 2012 2012;3:3. Available on request.\u000a    [h] Selected news coverage in scientific periodicals and lay press —\u000a      copies of articles without URLs\u000a      are available on request\u000a    \u000a      Charlie Schmidt Early Breast Cancer: Single Dose of Radiation During\u000a        Surgery Gains\u000a        Support. JNCI Journal of the National Cancer Institute\u000a        2010;102(17):1304-09\u000a      Partial Breast Irradiation safe for some women with invasive breast\u000a        cancer. NCI News\u000a          Bulletin 15 June 2010; 7:12\u000a      Helwick C, Goodman A, Cavallo J. Research Roundup from San Antonio:\u000a        Intraoperative\u000a        Radiotherapy vs. External-beam Radiotherapy. The ASCO Post.\u000a        2013;4(3):41.\u000a      \u000aBBC News, 2010: One-shot radiotherapy 'success against breast\u000a        cancer.'\u000a        http:\/\/bbc.in\/p3SCnh\u000a\u000a      \u000aIndependent, 2010: Dramatic advance in treatment of breast\u000a        cancer. http:\/\/ind.pn\/9teYZP\u000a\u000a      \u000aTimes of India, 2010: Soon, one-shot radiotherapy for breast\u000a        cancer? http:\/\/bit.ly\/15DATUo\u000a\u000a      \u000aNY Times, 2010: Findings may alter care for early breast\u000a        cancer.\u000a      \u000aLA times, 2010: New Treatment for breast cancer.\u000a      \u000aDaily Mail, 2012: Me and my operation: Targeted intraoperative\u000a        radiotherapy blasted my\u000a        breast tumour. http:\/\/dailym.ai\/fqgOaR\u000a\u000a    \u000a    [i] NICE appraisal (in progress) `Intrabeam targeted intraoperative\u000a      radiotherapy for the treatment\u000a      of early or locally advanced breast cancer' [I 618] To appraise the\u000a      clinical and cost\u000a      effectiveness of the INTRABEAM Photon Radiosurgery System for the adjuvant\u000a      treatment of\u000a      early or locally advanced breast cancer during surgical removal of the\u000a      tumour.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/14150\/63573\/63573.pdf\u000a    [j] Marmot M, Altman G, Cameron DA, et al. Independent UK Panel on Breast\u000a      Cancer Screening\u000a      replies to Michael Baum. BMJ. 2013 Feb 13;346:f873. http:\/\/doi.org\/n2z.\u000a      See reference 5.\u000a    [k] Vaidya JS, Bulsara M, Wenz F. Ischemic heart disease after breast\u000a      cancer radiotherapy. N\u000a      Engl J Med. 2013 Jun 27;368(26):2526-7. http:\/\/doi.org\/n22\u000a    [l] Alvarado M, Ozanne E, Mohan A, Esserman L. Cost-effectiveness of\u000a      intraoperative radiation\u000a      therapy for breast conservation. Journal of Clinical Oncology\u000a      2011;29(15_suppl):abstr 6081.\u000a    ","Title":"\u000a    Targeted intraoperative radiotherapy at the time of lumpectomy for\u000a      patients\u000a      with early breast cancer as an alternative to conventional 3-6 weeks of\u000a      postoperative radiotherapy\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Radiotherapy for breast cancer remains an integral part of treatment and\u000a      reduces the risk of local\u000a      recurrence of cancer after breast-conserving surgery. However, many\u000a      patients have limited access\u000a      to radiotherapy and are unable to attend daily for 3-6 weeks for\u000a      post-operative radiotherapy. Such\u000a      patients will choose mastectomy, sacrificing the breast for the\u000a      convenience of avoiding a lengthy\u000a      and expensive course of radiotherapy. This problem is prevalent in many\u000a      parts of the developing\u000a      world, but also affects women in Europe and the USA who live far from a\u000a      radiotherapy centre.\u000a    The initial impetus for \"single-shot\" intra-operative radiotherapy for\u000a      breast cancer arose from\u000a      observations by Professor Jayant S Vaidya at Tata Memorial Hospital,\u000a      Mumbai during the early\u000a      1990s that although two-thirds of mastectomy specimens for small breast\u000a      cancers harbour occult\u000a      cancers distributed throughout the breast, well over 90% of breast\u000a      recurrences in the conserved\u000a      breast appear in the original tumour bed. Professor Vaidya moved to UCL in\u000a      1998 and, in\u000a      collaboration with Professors Michael Baum and Jeff Tobias, developed a\u000a      hypothesis for a novel\u000a      treatment: we proposed that radiotherapy be limited to the tumour bed and\u000a      administered as a \"one-off\"\u000a\u0009  radiation treatment at the time of surgery, avoiding the expensive\u000a      15-to 30-day course of\u000a      EBRT and sparing many an unnecessary mastectomy. This became the TARGeted\u000a      Intraoperative\u000a      radioTherapy (TARGIT) technique [1, 2].\u000a    Through translational research in 2004-8 on the immediate effects of\u000a      radiation on a fresh wound, in\u000a      collaboration with Dr Samuele Massarut and Dr Gustavo Baldassare, we found\u000a      for the first time\u000a      that the fluid that collects in the wound after a lumpectomy is highly\u000a      favourable to cancer cells,\u000a      stimulating them to multiply and invade. This could partly explain the\u000a      propensity of recurrence to\u000a      occur in the tumour bed. We also found that giving TARGIT immediately\u000a      after a lumpectomy\u000a      nullifies such effects and creates a beneficial micro-environment that is\u000a      not conducive to tumour\u000a      growth and invasion [3].\u000a    We conducted an international randomised clinical trial (TARGIT-A trial)\u000a      (2000-2012) comparing\u000a      single-dose TARGIT with standard 3-6 weeks' radiotherapy in 3,451\u000a      patients. We found that\u000a      cancer control rates using TARGIT were similar to EBRT [4].\u000a      Updated results were presented at\u000a      the San Antonio Breast Cancer Conference (6 Dec 2012, General Session 4, http:\/\/goo.gl\/4E10I)\u000a      confirming that, in selected cases, TARGIT given at the time of lumpectomy\u000a      within a risk-adaptive\u000a      approach gives similar cancer control as EBRT. In addition we showed that\u000a      it also results in\u000a      significantly fewer non-breast cancer deaths mainly from cardiovascular\u000a      causes and other cancers.\u000a      Long-term results of our phase 2 studies suggest that if TARGIT is given in\u000a        addition to EBRT as a\u000a      tumour bed boost, the local recurrence of cancer appears to be halved [5].\u000a      We have now launched\u000a      the TARGIT-B randomised trial to test this in young \/ high-risk patients.\u000a    Our discovery that abolition of the tumour stimulating effect of surgical\u000a      wound fluid by\u000a      intraoperative radiotherapy has opened up a new avenue of intervention for\u000a      disease. This effect\u000a      due to significant changes in wound proteins might spill over systemically\u000a      and may explain some of\u000a      the reduced non-breast cancer mortality that we have seen in our\u000a      randomised trial. The HTA\u000a      funded TARGIT-B trial will test this formally and begin a novel strategy\u000a      for drug discovery,\u000a      potentially benefiting future patients.\u000a    "},{"CaseStudyId":"38324","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Biotechnology and Biological Sciences Research Council","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Rima's knowledge of measles and mumps vaccine viruses made him the ideal\u000d\u000a      expert witness in\u000d\u000a      two major court cases in the UK pre 2004 and in the US from 2007 to 2009\u000d\u000a      to deal with claims of\u000d\u000a      adverse reactions to MMR vaccine1. At a Medical Research\u000d\u000a      Council hearing in 1998, Rima and\u000d\u000a      other scientists demonstrated flaws in Wakefield's claimed link between\u000d\u000a      measles vaccine and IBD.\u000d\u000a      Wakefield`s 1998 claim for a causative link between MMR vaccine and autism\u000d\u000a      led to widespread\u000d\u000a      media coverage, public alarm, and a reduction in MMR uptake2\u000d\u000a      with consequences still apparent\u000d\u000a      today as the UK suffers unnecessary outbreaks of measles and mumps .\u000d\u000a    Parents of children with autism in the UK sued three major vaccine\u000d\u000a      manufacturers potentially\u000d\u000a      claiming over £3 Billion in compensation. Seven test cases were selected.\u000d\u000a      Many reports were\u000d\u000a      furnished by a great number of experts in the UK focussing on every aspect\u000d\u000a      of the test cases\u000d\u000a      including the validity of the diagnosis and timings between onset of\u000d\u000a      symptoms and vaccination.\u000d\u000a      However, the only direct and positive evidence was the detection of\u000d\u000a      measles vaccine RNA\u000d\u000a      sequences in gut biopsies from the children by O'Leary's company\u000d\u000a      Unigenetics Ltd in Dublin acting\u000d\u000a      on behalf of the claimants. They claimed to have detected measles vaccine\u000d\u000a      by three techniques;\u000d\u000a      two of which (in situ hybridisation and RT-PCR) are standard\u000d\u000a      techniques with which Rima had\u000d\u000a      experience for measles and mumps and a third test (allelic exclusion\u000d\u000a      technology) developed by\u000d\u000a      O'Leary for distinguishing vaccine from wild-type virus. However, RNA\u000d\u000a      sequence evidence that\u000d\u000a      could have been obtained from the RT-PCR tests and which could\u000d\u000a      unambiguously distinguish\u000d\u000a      vaccine from wild type virus was never presented by the claimant's\u000d\u000a      experts, though requested\u000d\u000a      repeatedly by Rima.\u000d\u000a    Confidential expert reports from Simmonds (Edinburgh) and Rima on the\u000d\u000a      direct evidence for the\u000d\u000a      presence of viral RNA successfully identified flaws in the data and its\u000d\u000a      analysis. An expert report\u000d\u000a      from Professor Bustin, an expert in quantitative RNA detection at\u000d\u000a      University College London also\u000d\u000a      pointed to flaws in the O'Leary application of the technology and the\u000d\u000a      data. Rima also demonstrated\u000d\u000a      that the third test developed by O'Leary was unreliable and that their\u000d\u000a      results were misinterpreted\u000d\u000a      even according to their own flawed criteria3,4.\u000d\u000a    The scientific evidence was not tested in open court in the UK. This\u000d\u000a      allowed the claimants to\u000d\u000a      proclaim a \"cover up\" and allowed Wakefield to start an anti-MMR campaign\u000d\u000a      in the US, again using\u000d\u000a      O'Leary's laboratory data and to claim that measles vaccine RNA had been\u000d\u000a      detected in children\u000d\u000a      with autism. US vaccine manufacturers pay a per-dose-levy to a\u000d\u000a      compensation fund for genuine\u000d\u000a      vaccine-related adverse events. Such cases are adjudicated by the Vaccine\u000d\u000a      Court. Three US test\u000d\u000a      cases were considered in this court and several UK and US experts\u000d\u000a      testified in the three test\u000d\u000a      cases. Only Bustin and Rima's redacted reports3 from the UK\u000d\u000a      litigation were used, as it was clear\u000d\u000a      that the direct \"evidence\" for the presence of measles virus in the\u000d\u000a      children would be decisive in\u000d\u000a      allowing the court to decide the validity of the claims. Bustin's report\u000d\u000a      identified technical flaws in the\u000d\u000a      RNA detection technique used by O'Leary, highlighted potential sources of\u000d\u000a      contamination and\u000d\u000a      pointed to an altered lab book entry (also noted by Rima1,3,4).\u000d\u000a    Rima testified in front of Special Master Denise Vowell, the federal\u000d\u000a      judge in the vaccine court in the\u000d\u000a      Colten Snyder test case. In 2008, affidavits supplied by the claimants to\u000d\u000a      discredit Rima's evidence\u000d\u000a      were successfully answered and rebutted leading to the publication of\u000d\u000a      final judgments in 2009.\u000d\u000a      Judge Vowell and her co-jurists commented that: \"Doctor Rima was a superb\u000d\u000a      expert witness. He\u000d\u000a      was well-qualified in the subject matter of his testimony, testified\u000d\u000a      directly and forthrightly, and made\u000d\u000a      extremely difficult topics understandable. He made his disapproval of\u000d\u000a      certain laboratory practices\u000d\u000a      perfectly plain, without engaging in ad hominem attacks\"5,6,7,8.\u000d\u000a      Her judgement stated5:\u000d\u000a      \"After careful consideration of all of the evidence, it was abundantly\u000d\u000a      clear that petitioners' theories\u000d\u000a      of causation were speculative and unpersuasive. Respondent's\u000d\u000a      experts were far more qualified,\u000d\u000a      better supported by the weight of scientific research and authority, and\u000d\u000a      simply more persuasive on\u000d\u000a      nearly every point in contention. Because of pervasive quality control\u000d\u000a        problems at a now-defunct\u000d\u000a        laboratory that tested a key piece of evidence, petitioners could not\u000d\u000a        reliably demonstrate the\u000d\u000a        presence of a persistent measles virus in Colten Snyder's central\u000d\u000a        nervous system\".\u000d\u000a    This protected the National Vaccine Injury Compensation Program fund from\u000d\u000a      claims that would\u000d\u000a      have exhausted it completely. This judgement as well as many other\u000d\u000a      epidemiological studies and\u000d\u000a      reports renewed confidence in the MMR vaccine leading to a change in\u000d\u000a      uptake in the UK, for\u000d\u000a      example, from below 80% in 2003, to about 85% in 2008 and 91% currently9,10.\u000d\u000a    The recent outbreak in Swansea in 2013 highlights the disastrous impact\u000d\u000a      that Wakefield and\u000d\u000a      O'Leary's MMR claims have had. If the direct evidence for measles genetic\u000d\u000a      material in the affected\u000d\u000a      children had not been refuted, measles fatalities such as the two in the\u000d\u000a      Yorkshire outbreak in 2008\u000d\u000a      and the one fatality in South Wales would have been repeated time and time\u000d\u000a      again. We also would\u000d\u000a      continue to have the large number of hospitalisations for pneumonia in\u000d\u000a      15-20% of the affected\u000d\u000a      children and the spectre of long queues at emergency vaccination clinics\u000d\u000a      of the several hundred\u000d\u000a      thousand children not vaccinated as a result of this affair. Many people\u000d\u000a      played in important roles in\u000d\u000a      showing the false nature of the claimed link between autism and MMR\u000d\u000a      vaccination, but if the direct\u000d\u000a      evidence from Unigenetics Ltd had remained unchallenged it would have been\u000d\u000a      highly unlikely that\u000d\u000a      confidence in the vaccine could have been restored.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Professor Rima's research on measles and mumps viruses over 4 decades at\u000d\u000a      Queen's University\u000d\u000a      allowed him to play an important role in re-establishing public confidence\u000d\u000a      in the safety of the\u000d\u000a      measles-mumps-rubella (MMR) vaccine. Claims that MMR vaccine could cause\u000d\u000a      autism in 1998\u000d\u000a      undermined the vaccine uptake but Rima's expert testimony and that of\u000d\u000a      others established in court\u000d\u000a      that these claims were unfounded. This re-assurance and subsequent\u000d\u000a      promotion of MMR\u000d\u000a      vaccination reduced measles cases in the UK. In the USA, it also reduced\u000d\u000a      the real risk that the\u000d\u000a      Vaccine Court Fund, which compensates vaccinees for genuine vaccine\u000d\u000a      related adverse events,\u000d\u000a      would be bankrupted by over 50,000 claims amounting to between $30-50\u000d\u000a      Billion.\u000d\u000a    ","ImpactType":"Political","Institution":"\u000d\u000a    Queen's University Belfast\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2964574","Name":"Dublin"},{"GeoNamesId":"2634910","Name":"Wakefield"},{"GeoNamesId":"2964574","Name":"Dublin City"},{"GeoNamesId":"2650225","Name":"Edinburgh"}],"References":"\u000d\u000a    \u000a1 Yeo, R.P., Afzal, M.A., Forsey, T. & Rima, B.K. (1993).\u000d\u000a      Identification of a new mumps virus\u000d\u000a      lineage by nucleotide sequence analysis of the SH genes of ten different\u000d\u000a      strains. Archives of\u000d\u000a      Virology 128, 371-377 (47 citations; first identification of genome\u000d\u000a        area that can be used for\u000d\u000a        genotyping of mumps virus strains; still primary area in use).\u000d\u000a    \u000a\u000a2 Rima, B.K., Earle, J.A.P., Yeo, R.P., Herlihy, L., Baczko, K., ter\u000d\u000a      Meulen, V., Carabaña, J.,\u000d\u000a      Caballero, M., Celma, M.L. & Fernandez-Muñoz, R. (1995). Temporal and\u000d\u000a      geographical\u000d\u000a      distribution of measles virus genotypes. Journal of General Virology, 76,\u000d\u000a      1173-1180 (113\u000d\u000a        citations; identification of genome area that can be used for genotyping\u000d\u000a        of strains; still primary\u000d\u000a        area in use; first demonstration of temporal and geographic distribution\u000d\u000a        of measles virus\u000d\u000a        strains).\u000d\u000a    \u000a\u000a3 Stuart H Ralston, Miep H Helfrich, Muhammad Afzal, Jim Gallagher,\u000d\u000a      William D Fraser, Andrew\u000d\u000a      Mee and Bert Rima (2007). Multicenter blinded analysis of RT-PCR detection\u000d\u000a      methods for\u000d\u000a      paramyxoviruses in relation to Paget's disease of bone. J Bone Min Res.\u000d\u000a      22(4), 569-77 (22\u000d\u000a        citations; a multicentre study led by Rima to assess interlaboratory\u000d\u000a        variations in sensitivity of\u000d\u000a        technique, in all but one (US) laboratories that had claimed a role for\u000d\u000a        measles and canine\u000d\u000a        distemper virus in Paget's disease).\u000d\u000a    \u000a\u000a4 Backzo, K., Lampe, J., Liebert, U.G., ter Meulen, V., Pardowitz, I.,\u000d\u000a      Budka, H., Cosby, S.L.,\u000d\u000a      Isserte, S. & Rima, B.K. (1993). Clonal expansion of hypermutated\u000d\u000a      measles virus in an SSPE\u000d\u000a      brain. Virology 197, 188-195 (86 citations; study on the nature of\u000d\u000a      persistent virus in the CNS).\u000d\u000a    \u000a\u000a5 Rima, B.K. and Duprex W.P. (2005). Molecular mechanisms of measles\u000d\u000a      virus persistence.\u000d\u000a      Virus Research 111, 132-147 (47 citations review).\u000d\u000a    \u000a\u000a6 Rima, B.K., Earle, J.A.P., Baczko, K., ter Meulen, V., Liebert, U.G.,\u000d\u000a      Carstens, S.C., Carabaña,\u000d\u000a      J., Caballero, M., Celma, M.L. & Fernandes-Muñoz, R. (1997). Sequence\u000d\u000a      divergence of\u000d\u000a      measles virus haemagglutinin during natural evolution and adaptation to\u000d\u000a      cell culture. Journal\u000d\u000a      of General Virology 78, 97-106 (139 citations; study on the evolution\u000d\u000a        of measles virus).\u000d\u000a    \u000aFunding:\u000d\u000a    1992-1995 Wellcome Trust: Expression of mumps virus polypeptides\u000d\u000a      with the objective of\u000d\u000a      rescuing virus from an infectious cDNA clone (£88,279).\u000d\u000a    1996-1999 Wellcome Trust: Grant in collaboration with Dr S.L.\u000d\u000a      Cosby.\u000d\u000a      Reverse genetic approaches to the study of measles virus neurovirulence\u000d\u000a      and attenuation\u000d\u000a      (£125,296).\u000d\u000a    1997-2000 BBSRC: Grant in collaboration with Dr T. Barrett (IAH,\u000d\u000a      Pirbright). Pathogenesis, cross-species\u000d\u000a      infectivity and immunogenicity of morbilliviruses (£210,000).\u000d\u000a    2000-2002 NARPD: Grant with Prof S Ralston (Aberdeen); scientific\u000d\u000a      co-ordination in Belfast.\u000d\u000a      Paramyxoviruses and Paget's disease; a multicentre comparison of PCR\u000d\u000a      methods for detecting\u000d\u000a      viral transcripts (£19,000).\u000d\u000a    2001-2006 MRC: Programme grant in collaboration with Drs Cosby\u000d\u000a      and Duprex. Linking measles\u000d\u000a      virus genotypes to phenotypes (£549,000).\u000d\u000a    2005-2008 Wellcome Trust: Showcase award with Dr Paul Duprex.\u000d\u000a      Persistently addressing\u000d\u000a      persisting problems: persistent infections as possible solutions\u000d\u000a      (£125,000)\u000d\u000a    2003-2008 Wellcome Trust: Project grant with Drs. Duprex and\u000d\u000a      Cosby. Neurovirulence and\u000d\u000a      attenuation of mumps virus. (£418,000)\u000d\u000a    2006-2010 MRC: Programme grant with Dr Duprex: The role of\u000d\u000a      translational control in the natural\u000d\u000a      history of measles virus (£633,184).\u000d\u000a    2008-2012 MRC: Models grant with Dr Paul Duprex and Rotterdam\u000d\u000a      Erasmus University group. Re:\u000d\u000a      G0801001 — Illuminating childhood respiratory infections: from viral\u000d\u000a      diseases to vaccine delivery\u000d\u000a      (£900,000).\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    1 Lead consultant at Hogan Lovells International LLP, Atlantic House ,\u000d\u000a        Holborn Viaduct,\u000d\u000a        London EC1A 2FG.\u000d\u000a    2 Impact of Wakefield's claims: http:\/\/briandeer.com\/mmr\/uptake-stats.htm\u000d\u000a    3 Rima's expert report: This is a confidential redacted\u000d\u000a        expert report from the UK confidential\u000d\u000a        to the US court and an affidavit for the US cases\u000d\u000a    4 http:\/\/www.uscfc.uscourts.gov\/sites\/default\/files\/autism\/OmnibusTrialsTranscripts\/snyder\/20\u000d\u000a          071108_snyder_pps820-1014.pdf\u000d\u000a    5 http:\/\/www.uscfc.uscourts.gov\/sites\/default\/files\/vaccine_files\/Vowell.Snyder.pdf\u000d\u000a      page 17\u000d\u000a    6 http:\/\/www.uscfc.uscourts.gov\/sites\/default\/files\/vaccine_files\/Hastings-Cedillo.pdf\u000d\u000a          page 52\u000d\u000a    7 http:\/\/www.uscfc.uscourts.gov\/sites\/default\/files\/Hazlehurst.pdf\u000d\u000a      page 17\u000d\u000a    8 Email from US Department of Justice.\u000d\u000a    9 \u000d\u000a        http:\/\/www.hpa.org.uk\/NewsCentre\/NationalPressReleases\/2011PressReleases\/110624Me\u000d\u000a          aslesstatement\/\u000d\u000a    10 https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/192611\/Presentation_by_Mary_Ramsay_-_Measles_in_England_2012___2013.pdf\u000d\u000a    ","Title":"\u000d\u000a    Debunking MMR vaccine associated scares.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2636432","Name":"Swansea"}],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Publications that cast doubt on the safety of the MMR vaccine led to\u000d\u000a      reduced vaccination rates\u000d\u000a      resulting in measles outbreaks with fatal cases in the UK and Ireland.\u000d\u000a      Rima's research on measles\u000d\u000a      and mumps virus has led to over 170 peer reviewed research publications\u000d\u000a      and invited reviews, and\u000d\u000a      has been funded by the major UK funding agencies such as the Wellcome\u000d\u000a      Trust and all relevant\u000d\u000a      UK Research Councils. His work focussed on the application of molecular\u000d\u000a      biology to these viruses.\u000d\u000a      His research on the genetics of these viruses provided the groundwork for\u000d\u000a      the work of relevance to\u000d\u000a      this impact case study. The delineation of genetic differences between\u000d\u000a      vaccine and wild type\u000d\u000a      viruses1,2 was particularly relevant. Wakefield claimed in 1992\u000d\u000a      that measles virus was involved in\u000d\u000a      inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative\u000d\u000a      colitis. After 1992 the\u000d\u000a      claim shifted from an involvement of \"street\" or wild-type measles virus\u000d\u000a      to involvement of \"vaccine\"\u000d\u000a      measles. Rima's research insights in distinguishing the vaccine from\u000d\u000a      circulating wild type virus\u000d\u000a      were crucial in refuting Wakefield's claims. In the case of measles virus,\u000d\u000a      all vaccines are derived\u000d\u000a      from viruses with a specific genetic signature (genotype A), which\u000d\u000a      appeared to be extinct in the\u000d\u000a      wild (i.e. was no longer isolated) with all \"street\" viruses belonging to\u000d\u000a      other genotypes. This allowed\u000d\u000a      for easy distinction between cases apparently derived from vaccine virus\u000d\u000a      or wild type virus. The\u000d\u000a      ability to make this distinction became even more important when Wakefield\u000d\u000a      published his 1998\u000d\u000a      claim that there was a link between the measles component in MMR vaccine\u000d\u000a      and autism. This\u000d\u000a      claim by Wakefield was largely based on the \"findings\" by Dr John\u000d\u000a      O'Leary's laboratory in Dublin of\u000d\u000a      measles vaccine virus genetic material in gut biopsies of children with\u000d\u000a      autism long after\u000d\u000a      vaccination. This brought into play the question of persistence of the\u000d\u000a      virus in human tissue.\u000d\u000a      Rima and colleagues at Queen's University had extensive experience before\u000d\u000a      and after 1992 in\u000d\u000a      dealing with claims of the presence of measles and related canine\u000d\u000a      distemper virus in diseases\u000d\u000a      such as Paget's disease3, otosclerosis and multiple sclerosis.\u000d\u000a      The same applied to mumps virus in\u000d\u000a      inclusion body myositis and other diseases for which claims for\u000d\u000a      paramyxovirus involvement had\u000d\u000a      been made. None of these claims were sustained when sequence analyses of\u000d\u000a      the genetic material\u000d\u000a      of the viruses found in the cases were performed. This demonstrated that\u000d\u000a      the measles genetic\u000d\u000a      material detected was largely due to sample contamination with cloned\u000d\u000a      viral DNA sequences. The\u000d\u000a      difficulty in these cases and in all diseases for which a causative role\u000d\u000a      for a specific virus is claimed\u000d\u000a      is that it is impossible formally to prove the absence of something like a\u000d\u000a      virus. Hence, the\u000d\u000a      question is always decided on the basis of demonstrations of technical\u000d\u000a      flaws in the evidence or\u000d\u000a      direct evidence of contamination of the samples3. Insights\u000d\u000a      gained from Rima's studies on\u000d\u000a      persistent infections by measles virus in vivo and in vitro4,5\u000d\u000a      and the understanding of the evolution\u000d\u000a      of viruses6 during normal circulation and persistent infection\u000d\u000a      was crucial for evaluating the validity\u000d\u000a      of Wakefield's claims about MMR vaccine and autism.\u000d\u000a    In summary, Rima's work was crucial in demonstrating the flawed nature of\u000d\u000a      the only positive\u000d\u000a      \"evidence\" provided by Wakefield and his supporters, which was detection\u000d\u000a      of viral RNA in the\u000d\u000a      children.\u000d\u000a    "},{"CaseStudyId":"38326","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2963597","Name":"Ireland"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The research highlighted above has had a significant economic impact on\u000d\u000a      the local economy in N. Ireland by the development of a company called\u000d\u000a      Almac Diagnostics in 2004. Without the research by Harkin and Johnston\u000d\u000a      this company would not have been established. However, more importantly,\u000d\u000a      it has allowed the development of new diagnostic products, which are\u000d\u000a      likely to improve the management of colon and breast cancer patients.\u000d\u000a      Almac's proprietary microarray technology has been the basis of the\u000d\u000a      company's success both in terms of its internal research and development\u000d\u000a      programme and its external contract research commercial activities. In\u000d\u000a      October of 2012 the Xcel array was licensed by Affymetrix for global\u000d\u000a      distribution based on the realization that this technology platform\u000d\u000a      substantially accelerates the rate at which novel array-based biomarkers\u000d\u000a      can be discovered, validated and commercialized1. This\u000d\u000a      licensing deal involved an upfront technology access fee in addition to\u000d\u000a      volume based milestone payments and royalty payments for the lifetime of\u000d\u000a      the product. To date Almac has chosen to retain exclusive distribution\u000d\u000a      rights to its DSA technology platforms. As stated above Almac has also\u000d\u000a      used its DSA technology to discover and validate two genomic tests in\u000d\u000a      colon and breast cancer.\u000d\u000a    The first of these tests termed, Col-Dx, identifies those patients who\u000d\u000a      are at an increased risk of recurrence following surgery for stage II\u000d\u000a      colon cancer. This information can help clinicians and patients make a\u000d\u000a      more informed decision about the need for additional chemotherapy to\u000d\u000a      optimally manage their disease. The Col-Dx assay was licensed to Precision\u000d\u000a      Therapeutics, a US based diagnostic company for commercialization in the\u000d\u000a      US market. The Col-Dx test (rebranded as GeneFx) has seen Clinical\u000d\u000a      Laboratory Improvements Amendments (CLIA) validated for use in the US and\u000d\u000a      has subsequently been launched 2. Significantly, Almac has\u000d\u000a      carried out a second successful independent validation of the GeneFx assay\u000d\u000a      in collaboration with the Cancer and Leukemia Group B (CALGB) clinical\u000d\u000a      trial group in the US. The results from this study are currently embargoed\u000d\u000a      but will be presented at the American Society for Clinical Oncology\u000d\u000a      meeting in January 2014.\u000d\u000a    Almac's second genomic test termed DDRD-Breast-Dx, identifies early stage\u000d\u000a      node negative and node positive breast cancer patients who are likely to\u000d\u000a      benefit from the addition of chemotherapy following surgery. Existing\u000d\u000a      prognostic tools classify early stage patients into low, intermediate and\u000d\u000a      high risk of recurrence. Low risk patients are not recommended for\u000d\u000a      chemotherapy whilst high risk patients are. However, approximately 40-60%\u000d\u000a      of patients are classified as intermediate risk where the benefit from\u000d\u000a      chemotherapy is unclear. For these patients the DDRD-Breast-Dx test allows\u000d\u000a      clinicians to make an objective decision on likely benefits of\u000d\u000a      chemotherapy. Almac's DDRD-Breast-Dx assay has also been successfully\u000d\u000a      licensed to a major US diagnostic company. The successful\u000d\u000a      commercialization of Almac's core technology platform to Affymetrix and\u000d\u000a      the subsequent licensing of two highly complex genomic cancer assays into\u000d\u000a      the US market has established Almac Diagnostics as a recognised\u000d\u000a      international leader in the cancer diagnostics industry3,4,5,6.\u000d\u000a    In 2012 Almac announced the opening of its CLIA laboratory in Craigavon,\u000d\u000a      N. Ireland7. This laboratory, which has been approved by the\u000d\u000a      College of American Pathologists, was established to facilitate the\u000d\u000a      delivery of novel diagnostic tests to help select patients for enrolment\u000d\u000a      in pharma sponsored biomarker driven clinical trials. Currently Almac is\u000d\u000a      supporting approximately 15 phase I and II global clinical trials from its\u000d\u000a      CLIA laboratory, which further emphasises its prominence with the\u000d\u000a      pharmaceutical industry.\u000d\u000a    The economic importance of Almac Diagnostics is evidenced by its\u000d\u000a      continued growth and expansion of its operations in Europe and the US.\u000d\u000a      Specifically over the last 5 years a total of 50 new positions have been\u000d\u000a      created within Almac Diagnostics across areas such as molecular biology,\u000d\u000a      bioinformatics, project management, business development and marketing.\u000d\u000a      Furthermore approximately 90% of the staff employed are graduates and 50%\u000d\u000a      have PhD qualifications emphasising the contribution research has made to\u000d\u000a      the knowledge-based economy in N. Ireland. In addition, Almac Diagnostics\u000d\u000a      opened an office in Manchester in 2009 as a hub for bioinformatics support\u000d\u000a      and now employs 4 members of staff in that location as well as two\u000d\u000a      business development managers. Finally, Almac Diagnostics have also\u000d\u000a      expanded into the US market and now employ two business development\u000d\u000a      managers there. Almac's reputation in the cancer diagnostics industry has\u000d\u000a      led to substantial new opportunities for the business through strategic\u000d\u000a      partnerships with many of the world's leading pharmaceutical companies. In\u000d\u000a      2009, Almac announced a strategic partnership with Pfizer, the world's\u000d\u000a      largest pharmaceutical company. The agreement provided Pfizer access to\u000d\u000a      Almac's Colon-DSA array to discover and validate new predictive markers of\u000d\u000a      response to chemotherapy in colon cancer5. Similarly in 2009,\u000d\u000a      Almac announced a partnership with Eli-Lilly and the Medical Research\u000d\u000a      Council to help develop new predictive markers for drugs within their\u000d\u000a      pipelines6.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research at Queen's University Belfast has led to the successful\u000d\u000a      development and commercialization of a DNA chip technology platform that\u000d\u000a      facilitates the rapid discovery and validation of new diagnostic tests in\u000d\u000a      cancer. A spin out company has been established called Almac Diagnostics\u000d\u000a      that currently employs 85 staff, thereby significantly contributing to the\u000d\u000a      knowledge based economy in Northern Ireland. Almac has used this\u000d\u000a      technology to develop and validate a number of genomic tests that have\u000d\u000a      been successfully licensed to established US based diagnostic companies,\u000d\u000a      thereby securing long term revenue streams. Almac is now recognised\u000d\u000a      internationally as a worldwide industry leader in this area.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    Queen's University Belfast\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Farragher SM, Tanney A, Kennedy RD, Paul Harkin D. RNA\u000d\u000a      expression analysis from formalin-fixed, paraffin-embedded tissues.\u000d\u000a      Histochem Cell Biol. 2008 Sep;130(3):435-45. doi:\u000d\u000a      10.1007\/s00418-008-0479-7. Epub 2008 Aug 5. Review\u000d\u000a    \u000aThis manuscript highlights Almac's expertise in the analysis of degraded\u000d\u000a      RNA derived from FFPE tissue (cited 99 times).\u000d\u000a    \u000a2. Tanney A, Oliver GR, Farztdinov V, Kennedy RD, Mulligan JM, Fulton CE,\u000d\u000a      Farragher SM, Field JK, Johnston PG, Harkin DP, Proutski V,\u000d\u000a      Mulligan KA. Generation of a non-small cell lung cancer transcriptome\u000d\u000a      microarray. BMC Med Genomics. 2008 May 30;1:20. doi:\u000d\u000a      10.1186\/1755-8794-1-20\u000d\u000a    \u000aThis represents the first publication highlighting the approach taken to\u000d\u000a      develop Almac's Disease Specific Array platforms (cited 14 times).\u000d\u000a    \u000a3. Hosey, A.M., Gorski, J.J., Murray, M.M., Quinn, J.E., Chung, W.Y.,\u000d\u000a      Stewart, G.E., James, C.R., Farragher, S.M., Mulligan, J.M., Scott, A.N.,\u000d\u000a      Dervan, P.A., Johnston, P.G., Couch, F.J., Daly, P.A., Kay, E.,\u000d\u000a      McCann, A., Mullan, P.B. and Harkin, D.P. (2008) \"Molecular Basis\u000d\u000a      for Estrogen Receptor Alpha Deficiency in BRCA1-Linked Breast Cancer.\"\u000d\u000a      Journal of the National Cancer Institute 99(22): 1683-1694. Doi:\u000d\u000a      10.1093\/jnci\/djm207.\u000d\u000a    \u000aThis represents the first manuscript in which the breast cancer DSA was\u000d\u000a      used to translate biology identified using in vitro models in a\u000d\u000a      clinical setting. Impact Factor: 14.3 paper cited 105 times.\u000d\u000a    \u000a4. Tejpar S, Bertagnolli M, Bosman F, Lenz HJ, Garraway L, Waldman F,\u000d\u000a      Warren R, Bild A, Collins-Brennan D, Hahn H, Harkin DP, Kennedy R,\u000d\u000a      Ilyas M, Morreau H, Proutski V, Swanton C, Tomlinson I, Delorenzi M,\u000d\u000a      Fiocca R, Van Cutsem E, Roth A. Prognostic and predictive biomarkers in\u000d\u000a      resected colon cancer: current status and future perspectives for\u000d\u000a      integrating genomics into biomarker discovery. The Oncologist.\u000d\u000a      2010;15(4):390-404. doi: 10.1634\/theoncologist.2009-0233. Epub 2010 Mar\u000d\u000a      29. Review.\u000d\u000a    \u000aThis review was the result of an international collaboration on how to\u000d\u000a      best advance the integration of genomic technologies to aid prognosis and\u000d\u000a      prediction in colorectal cancer (cited 55 times).\u000d\u000a    \u000a5. Kennedy RD, Bylesjo M, Kerr P, Davison T, Black JM, Kay EW, Holt RJ,\u000d\u000a      Proutski V, Ahdesmaki M, Farztdinov V, Goffard N, Hey P, McDyer F,\u000d\u000a      Mulligan K, Mussen J, O'Brien E, Oliver G, Walker SM, Mulligan JM, Wilson\u000d\u000a      C, Winter A, O'Donoghue D, Mulcahy H, O'Sullivan J, Sheahan K, Hyland J,\u000d\u000a      Dhir R, Bathe OF, Winqvist O, Manne U, Shanmugam C, Ramaswamy S, Leon EJ,\u000d\u000a      Smith WI Jr, McDermott U, Wilson RH, Longley D, Marshall J, Cummins R,\u000d\u000a      Sargent DJ, Johnston PG, Harkin DP. Development and independent\u000d\u000a      validation of a prognostic assay for stage II colon cancer using\u000d\u000a      formalin-fixed paraffin-embedded tissue. J Clin Oncol. 2011 Dec\u000d\u000a      10;29(35):4620-6. doi: 10.1200\/JCO.2011.35.4498. Epub 2011 Nov 7\u000d\u000a    \u000aThis manuscript represents the first successful discovery and validation\u000d\u000a      of a colon cancer prognostic assay from historical FFPE samples using\u000d\u000a      microarray technology. The work represented a major collaborative effort\u000d\u000a      across 10 global Cancer Centres in order to ensure a representative\u000d\u000a      patient population for the validation study. Impact Factor: 18; paper\u000d\u000a      cited 30 times.\u000d\u000a    \u000a6. Mulligan JM, Hill LA, Deharo S, Irwin GW, Boyle D, Keating KE, Raji\u000d\u000a      OY, McDyre FA, O'Brien E, Bylesjo M, Quinn JE, Lindor NM, Mullan PB, James\u000d\u000a      CR, Walker SM, Kerr P, Salto-Tellez M, James J, Davison TS, Proutski V,\u000d\u000a        Johnston PG, Couch FJ, Harkin DP, Kennedy DK. Identification and\u000d\u000a      validation of an anthracycline\/cyclophosphamide based chemotherapy\u000d\u000a      response assay in breast cancer. Journal of the National Cancer Institute\u000d\u000a      (In Press).\u000d\u000a    \u000aThis manuscript describes the identification and validation of a\u000d\u000a      microarray based test to predict response to DNA damage based chemotherapy\u000d\u000a      in early stage breast cancer (Journal Impact Factor is 14.3).\u000d\u000a    Grants Awarded:\u000d\u000a      Technology Strategy Board: Awarded a grant of £2.3 Million to Almac\u000d\u000a      Diagnostics in July 2013 to fund the further development of its breast\u000d\u000a      cancer DDRD test for launch into the UK market. This represents one of\u000d\u000a      only four such awards across the UK and highlights the clinical utility of\u000d\u000a      Almac's breast cancer test.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    \u000d\u000a      \u000aAlmac and Affymetrix Announce a Global Distribution Agreement for\u000d\u000a          Almac's Xcel™ Array 29 Mar 2012\u000d\u000a        http:\/\/www.almacgroup.com\/2012\/03\/almac-and-affymetrix-announce-a-global-distribution-agreement-for-almac%E2%80%99s-xcel%E2%84%A2-array\/\u000a\u000d\u000a      \u000aLaunch of GeneFx by Precision Therapeutics\u000d\u000a        http:\/\/www.genefxcolon.com\/\u000a\u000d\u000a      \u000aAlmac Collect Top Recognition for New Ovarian Cancer Research\u000d\u000a          Product, March 10, 2009\u000d\u000a        http:\/\/www.almacgroup.com\/2009\/03\/almac-collect-top-recognition-for-new-ovarian-cancer-research-product\/\u000a\u000d\u000a      \u000aAlmac wins top award at Tech Idol Showcase, December 18, 2007\u000d\u000a        http:\/\/www.almacgroup.com\/2007\/12\/almac-wins-top-award-at-tech-idol-showcase\/\u000a\u000d\u000a      \u000aAlmac Announces Collaboration with Pfizer and the PETACC3\u000d\u000a          Translational Research Working Party May 18, 2009\u000d\u000a        http:\/\/www.almacgroup.com\/2009\/05\/almac-announces-collaboration-with-pfizer-and-the-\u000a          petacc3-translational-research-working-party\/\u000a\u000d\u000a      \u000aAlmac and Lilly Partner on Companion Diagnostic Development, September 15, 2009\u000d\u000a        http:\/\/www.almacgroup.com\/2009\/09\/almac-and-lilly-partner-on-companion-diagnostic-development\/\u000a\u000d\u000a      \u000aAlmac open CLIA laboratory in Craigavon, N. Ireland to support\u000d\u000a          biomarker driven clinical trials.\u000d\u000a          http:\/\/www.almacgroup.com\/2011\/03\/almac-open-clia-lab-for-biomarker-clinical-trials\/\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Development and Commercialization of a Technology Platform to Enable\u000d\u000a      Biomarker Discovery and Validation\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2655984","Name":"Belfast"}],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    A key issue holding back successful gene expression based biomarker\u000d\u000a      discovery and validation projects in oncology is access to well annotated\u000d\u000a      tissue banks with linked clinical information. The majority of high\u000d\u000a      throughput gene expression technologies require high quality fresh frozen\u000d\u000a      tumour samples to obtain good quality RNA for reproducible expression\u000d\u000a      studies. This has created a major bottleneck since very few such tumour\u000d\u000a      banks exist. Professors Harkin (Professor of Molecular Oncology since 2004\u000d\u000a      at Queen's) and Johnston (Professor of Oncology at Queen's since 1996)\u000d\u000a      developed two new array based technology platforms termed DSA and Xcel\u000d\u000a      capable of generating robust gene expression data from partially degraded\u000d\u000a      RNA derived from formalin-fixed, paraffin-embedded (FFPE) material1,2\u000d\u000a      and as a result it is now possible to exploit the many high quality banks\u000d\u000a      of FFPE tumours to both develop and validate new gene expression based\u000d\u000a      tests to improve the management of cancer patients.\u000d\u000a    Two major innovations based on the research by Harkin and Johnston\u000d\u000a      underpin the generation of the DSA and Xcel arrays. The first concerns the\u000d\u000a      content of the arrays. Although it has been established that the human\u000d\u000a      genome encodes approximately 23,000 protein coding genes, it is now clear\u000d\u000a      that many non-coding RNA species that are not well characterized, but have\u000d\u000a      high functional significance are also generated. Harkin and Johnston\u000d\u000a      initiated a high throughput sequencing programme at Queen's to identify\u000d\u000a      the complete transcriptome for the five major cancers: breast, colon,\u000d\u000a      lung, prostate and ovarian cancer. All the sequence information was\u000d\u000a      aligned to identify the unique transcripts from each individual disease\u000d\u000a      type and that information was used to develop a panel of cancer disease\u000d\u000a      specific arrays (DSA's).\u000d\u000a    The second major innovation relates to the design of the probe sets on\u000d\u000a      the arrays to detect transcript expression from degraded RNA derived from\u000d\u000a      FFPE material. Harkin and Johnston observed that the 3-'ends of\u000d\u000a      transcripts extracted from FFPE tumours tended to be protected from\u000d\u000a      degradation by the poly-A tail. As a consequence the arrays were designed\u000d\u000a      to specifically probe the expression of the extreme 3' ends of each\u000d\u000a      transcript resulting in a significant improvement in the ability to detect\u000d\u000a      gene expression from FFPE derived RNA. Through a partnership agreement\u000d\u000a      with Affymetrix, the world leader in microarray manufacture, arrays were\u000d\u000a      generated for lung, colon, breast, prostate and ovarian cancer 1,2,3,4,.\u000d\u000a    Subsequently, the information from the individual DSA's was combined to\u000d\u000a      generate the Xcel array which encodes approximately 92,000 unique\u000d\u000a      transcripts representing the most comprehensive coverage of the cancer\u000d\u000a      transcriptome. Proof of the clinical utility of the technology came from\u000d\u000a      further development of two cancer diagnostic tests. The first of these\u000d\u000a      termed Col-Dx identifies patients at high risk of recurrence following\u000d\u000a      surgery for stage II colon cancer5. A second assay termed\u000d\u000a      DDRD-Breast-Dx predicts the benefit from DNA damage based chemotherapy in\u000d\u000a      node negative and node positive breast cancer and is now in press in the\u000d\u000a      Journal of the National Cancer Institute6.\u000d\u000a    "},{"CaseStudyId":"38327","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2264397","Name":"Portugal"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2017370","Name":"Russia"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    The work of the Queen's group has led to the discovery of rare molecular\u000a      causes of erythrocytosis.\u000a      This has led to changes in the clinical guidelines1,2,3 for\u000a      testing of patients with these diseases as\u000a      well as the establishment of a diagnostic service that screens patients\u000a      for these rare mutations.\u000a      The service investigations generate income for the NHS.\u000a    Around 100 samples per year are received for testing for these rare\u000a      mutations from the UK,\u000a      Ireland, many parts of Europe and the USA in a consolidated service\u000a      framework that has reached\u000a      a steady state. The direct impact on patients of testing is that in some\u000a      of the rare cases a diagnosis\u000a      can now be made. This benefits the individual patient by guiding clinical\u000a      management and\u000a      preventing further futile testing. It reduces health service costs as no\u000a      more investigations need to\u000a      be carried out if the abnormality is identified. This is the case in\u000a      approximately 10% of referrals and\u000a      54 patients with these rare diseases have benefited from an accurate\u000a      diagnosis so far.\u000a    The impact of the research on clinical practice has led to national and\u000a      international guidelines for\u000a      the investigation and management of these blood disorders. Guidelines\u000a      incorporate reference to\u000a      the mutations identified at Queen's and how selected patients should be\u000a      investigated for the\u000a      genetic defects. For example, as one of many, the British Committee for\u000a      Standards in\u000a      Haematology (BCSH) website guidelines state:\u000a    `Patients with an unexplained erythrocytosis and low serum EPO levels\u000a      should be considered\u000a      for investigation of an EPO receptor mutation. The Chuvash form of\u000a      erythrocytosis, an\u000a      autosomal recessive disorder common to a large number of families in\u000a      central Russia, has\u000a      been shown to result from mutations in the VHL gene. These\u000a      patients have inappropriately\u000a      normal or high EPO levels for their Hct'.\u000a    The more recent guidance states:\u000a    `Congenital causes of erythrocytosis include mutations in globin genes\u000a      giving rise to high\u000a      oxygen affinity haemoglobin, BPGM mutation resulting in\u000a      bisphosphoglycerate mutase\u000a      deficiency, mutations in components of the EPO signalling pathway (EPOR)\u000a      and mutations\u000a      within components of oxygen sensing pathways such as in VHL,\u000a        EGLN1 (also termed PHD2)\u000a      and EPAS1 (HIF2A). Especially in younger patients,\u000a      mutations within such genes may identify\u000a      the cause of the erythrocytosis.' 1\u000a    Although these diseases are rare and the cases caused by unusual\u000a      mutations are rarer still, they\u000a      cause ongoing morbidity which is exceedingly costly to health service\u000a      providers and stressful for\u000a      the patients. This has led a European Cooperation in Science and\u000a      Technology action to set up a\u000a      Network of Experts in the molecular diagnosis of myeloproliferative\u000a      neoplasms and related\u000a      diseases. One of the four working groups in this initiative (Working Group\u000a      3 chaired by McMullin),\u000a      is dedicated to the molecular diagnosis of congenital erythrocytosis. This\u000a      working group has been\u000a      inspired by the exciting findings of rare molecular causes for\u000a      erythrocytosis and delivers\u000a      information on which patients should be investigated and where testing can\u000a      be done.\u000a    An international database is now operational to collate information on\u000a      individuals with rare forms of\u000a      erythrocytosis. This provides information on outcomes and a European\u000a      Congenital Erythrocytosis\u000a      Consortium has been formed. Several hundred patients are on this database,\u000a      but an estimated ten\u000a      times more remain undiagnosed. Furthermore, looking at the sources of\u000a      samples that the\u000a      diagnostic service received, makes it clear that many patients in many\u000a      parts of the world remain\u000a      uninvestigated.\u000a    The European Congenital Erythrocytosis Consortium also organises training\u000a      schools for clinical\u000a      scientists on diagnostic methods e.g. the 2nd Training School, in Coimbra,\u000a      Portugal in 2011, to\u000a      which McMullin is a major contributor. Participants in training schools4\u000a      are limited to 15 to allow a\u000a      full interactive hands-on experience and all places are usually taken up.\u000a      This school was rated\u000a      excellent or good by all participants with improvement in knowledge,\u000a      excellent or good rating for\u000a      laboratory work and comments that `interactions with participants were\u000a      very productive'.\u000a    ","ImpactSummary":"\u000a    Diagnostic tests have been successfully developed for identification of\u000a      the cause of erythrocytosis,\u000a      particularly in patients with unexplained forms of this rare disease. A\u000a      diagnostic service with\u000a      worldwide reach was developed for the genetic characterisation of patients\u000a      that carry mutations\u000a      identified by the Queens's group. It deals with approximately 100 samples\u000a      per year referred for\u000a      investigation for this rare disease from the UK, Europe and further\u000a      afield. Proper diagnosis helps in\u000a      management of patients with erythrocytosis where the problem is not\u000a      mutation in one of the\u000a      familiar causative genes. A pan-European web-based database has been\u000a      established to collect\u000a      information on long-term outcomes to inform patient management.\u000a    ","ImpactType":"Technological","Institution":"\u000a    Queen's University Belfast\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5133273","Name":"Borough of Queens"},{"GeoNamesId":"2740636","Name":"Distrito de Coimbra"}],"References":"\u000a    \u000a1. Percy MJ, McMullin MF, Roques AW, Westwood NB, Acharya J,\u000a      Hughes AE, Lappin\u000a        TRJ, Pearson TC. Erythrocytosis due to a mutation in the\u000a      erythropoietin receptor gene. Br.\u000a      J. Haematol. (1998) 100, 407-410. doi: 10.1046\/j.1365-2141.1998.00550.x (Cited\u000a        31 times.\u000a        This paper is the first description of a patient with a mutation in the\u000a        erythropoietin receptor\u000a        arising independently after the original publication by A la Chapelle in\u000a        Finland).\u000a    \u000a\u000a2. Percy MJ, McMullin MF Jowitt SN, Potter M, Treacy M, Watson\u000a      WH, Lappin TRJ.\u000a      Chuvash-type congenital polycythemia in 4 families of Asian and Western\u000a      European\u000a      ancestry. Blood (2003) 102, 1097-1099. doi: 10.1182\/blood-2002-10-3246 (Cited\u000a        58 times.\u000a        This paper describes 4 different kindreds with the same mutation that\u000a        had been discovered\u000a        in a gene in the oxygen sensing pathway. Before this description this\u000a        particular mutation\u000a        had only been seen in the original cohort in the Chuvashia area of\u000a        Russia. This discovery\u000a        provided the justification for analysis of erythrocytosis patients with\u000a        disease of unknown\u000a        origin for mutations in VHL).\u000a    \u000a\u000a3. Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TRJ,\u000a      Maxwell PH, McMullin MF, Lee FS.\u000a      (joint senior author). A family with erythrocytosis establishes a role for\u000a      PHD2 in oxygen\u000a      homeostasis. Proceedings of the National Academy of Science (2006) 103 (3)\u000a      654-659.\u000a      doi: 10.1073\/pnas.0508423103 (Cited 134 times. This paper describes the\u000a        first ever\u000a        mutation found in man in one of the Prolyl Hydroxylase genes PHD2,\u000a        causing\u000a        erythrocytosis).\u000a    \u000a\u000a4. Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF,\u000a      Lee FS. A novel\u000a      erythrocytosis-associated PHD2 mutation suggests the location of a HIF\u000a      binding groove.\u000a      Blood. (2007) 110 (6) 2193-6. doi: 10.1182\/blood-2007-04-084434 (Cited\u000a        64 times. This\u000a        describes further mutations not previously found in man and their\u000a        mechanisms of action).\u000a    \u000a\u000a5. Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin\u000a        MF, Lee FS. A gain of\u000a      function mutation in the HIF2a gene in familial erythrocytosis. New\u000a      England Journal of\u000a      Medicine (2008) 358(2) 162-8. doi: 10.1056\/NEJMoa073123 (Cited 85\u000a        times. This paper\u000a        describes the first mutation found in man in one of the\u000a        Hypoxia-inducible Factor genes, HIF\u000a        2a, which was shown to cause erythrocytosis).\u000a    \u000a\u000a6. Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D,\u000a      Rainey G, van Wijk R,\u000a      Wood M, Lappin TR, McMullin MF, Lee FS. Novel exon 12 mutations in\u000a      the HIF2a gene\u000a      associated with erythrocytosis. Blood (2008) 111 (11) 5400-2. doi:\u000a      10.1182\/blood-2008-02-137703\u000a\u0009  (Cited 30 times. This paper describes further HIF 2a mutations\u000a        accounting for rare\u000a        cases of erythrocytosis).\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    \u000a      Bench AJ, White HE, Foroni L, Godfrey AL, Gerrard G, Akiki S, Awan A,\u000a        Carter I, Goday-Fernandez A,\u000a\u0009\u0009Langerabeer SE, Clench T, Clark J, Evans PA, Grimwade D,\u000a        Schuh A,\u000a        McMullin MF, Green AR, Harrison CN, Cross NC. Molecular diagnosis\u000a        of the\u000a        myeloproliferative neoplasms: UK guidelines for the detection of\u000a        JAK2V617F and other\u000a        relevant mutations. British Journal of Haematology 2013 160:25-34. doi:\u000a        10.1111\/bjh.12075\u000a      Cario H, McMullin MF, Bento C, Pospisilova D, Percy MJ,\u000a        Hussein K, Schwarz J, Astrom\u000a        M, Hermouet S. Congenital and acquired erythrocytosis — classification,\u000a        characterization\u000a        and consensus recommendations for the diagnostic approach to\u000a        erythrocytosis in children\u000a        and adolescents. Pediatr Blood Cancer 2013 June 14. Doi:\u000a          10.1002\/pbc.24625 [Epub\u000a          ahead of print] PMID: 23776154.\u000a\u000a      \u000aMcMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt\u000a        B, Oscier D, Polkey\u000a        MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B. Guidelines\u000a        for the diagnosis,\u000a        investigation and management of polycythaemia\/erythrocytosis. British\u000a        Journal of\u000a        Haematology (2005) 130(2), 174-195. doi: 10.1111\/j1365-2141.05535.x\u000a        (this guideline is\u000a        reviewed annually and is still current).\u000a      Examples are: McMullin, Idiopathic Erythrocytosis: A\u000a        disappearing entity, American Society\u000a        for Hematology, Educational Program New Orleans, USA, December, 2009,\u000a        Diagnosis and\u000a        Management of Erythrocytosis, European Hematology Association, Berlin,\u000a        June, 2009,\u000a        Erythrocytosis, European Hematology Association, Amsterdam, June 2012.\u000a    \u000a    WEBSITES\u000a    http:\/\/mpneuronet.eu and\u000a    http:\/\/impascience.eu\/COSTBM0902_net\/images\/congenital_erythrocytosis.pdf\u000a    http:\/\/www.erythrocytosis.org\/scid\/polycythemias_en\/\u000a    http:\/\/www.bcshguidelines.com\/4_HAEMATOLOGY_GUIDELINES.html?dpage=1&dtype=General+Haematology&sspage=0&ipage=0#g\u000a    ","Title":"\u000a    Identifying Patients with Rare Forms of Erythrocytosis\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    There is a long tradition of haematology research in Queen's, with an\u000a      exciting team of clinicians\u000a      and scientists that has included Professor Bridges (Professor of\u000a      Haematology from 1980 to 1994)\u000a      and currently Professor McMullin (Professor of Clinical Haematology since\u000a      2006), plus scientists\u000a      such as Professor Lappin (Professor of Haematology from 1997 to 2010) and\u000a      Dr Percy (an NHS\u000a      clinical scientist and an Honorary Reader in Queen's since 2009). The\u000a      group has carried out\u000a      extensive investigations focussed on the control of erythropoiesis since\u000a      1980, which resulted in\u000a      many high impact publications1-6.\u000a    An erythrocytosis, where there is an increase in the red cell mass and a\u000a      resulting increase in the\u000a      number of red cells or erythrocytes in the body, is usually due to the\u000a      acquired clonal\u000a      haematological disorder polycythaemia vera (a classical haematological\u000a      disorder with increased\u000a      production of all three types of blood cells) or a secondary cause where\u000a      the hormone erythropoietin\u000a      is up-regulated for some reason, which causes an overproduction of\u000a      specifically only red blood\u000a      cells.\u000a    In rare cases, the cause of the erythrocytosis is not clear. This has\u000a      been a long term focus of the\u000a      Queens's group. Since 1992 the group has explored the causes of the\u000a      myeloproliferative blood\u000a      diseases, in particular polycythaemia vera. They came to recognise that a\u000a      group of patients did not\u000a      have polycythaemia vera but had pure erythrocytosis (where there was an\u000a      increase in red cell\u000a      production only) of unknown cause. These individuals were investigated and\u000a      samples were\u000a      referred from the UK, Ireland and beyond. In 1993 a mutation was\u000a      discovered in the erythropoietin\u000a        receptor gene in an Olympic cross country skier with extreme\u000a      erythrocytosis. Our group described\u000a      the same mutation, arising independently, in 19981.\u000a    In 2002, a group in the United States discovered that a single mutation\u000a      in the von Hippel Lindau\u000a      (VHL) gene was the cause of erythrocytosis in a large cohort of\u000a      individuals from the Chuvash area\u000a      in the Upper Volga region. Investigation of our cohort of erythrocytosis\u000a      patients for this mutation\u000a      demonstrated that a number (not from the Chuvash area) had the same\u000a      variant2. The presence of\u000a      these mutations in a number of families in various parts of the world led\u000a      to the justification for their\u000a      inclusion in the screening programme.\u000a    The group then moved on to investigate genes in the oxygen sensing\u000a      pathway. In 2006, they were\u000a      the first to identify a mutation in the PHD2 gene in one of the\u000a      families who had been referred for\u000a      investigation 3,4. Having identified a potential mutation they\u000a      then demonstrated with collaborators in\u000a      the University of Pennsylvania that the mutation did indeed cause\u000a      erythrocytosis. The Queen's\u000a      group then discovered the first mutation in the HIF2a gene,\u000a      another gene encoding a protein in the\u000a      oxygen sensing pathway 5,6, in a family with erythrocytosis in\u000a      three generations, in 2008. The\u000a      functional effect of the mutations was elucidated with our US\u000a      collaborators and subsequently, it\u000a      was shown that a number of mutations in these genes also cause\u000a      erythrocytosis.\u000a    In summary, this work has established that the mutations identified by\u000a      this and other groups should\u000a      be screened for in rare patients with erythrocytosis who neither fulfil\u000a      the criteria for polycythaemia\u000a      vera nor have an obvious secondary cause. It formed the basis for the\u000a      successful development of\u000a      a diagnostic service.\u000a    "},{"CaseStudyId":"38329","Continent":[{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000a    Shields' research has had three major impacts on the treatment of\u000a      children with asthma and virally induced wheezing as described below.\u000a      First, it generated guidance to separate these two groups for appropriate\u000a      treatment; secondly it reduced the risks associated with high dose inhaled\u000a      corticosteroid treatment and thirdly it helped to advance the development\u000a      of simple hand-held monitoring equipment.\u000a    Impact 1: Improved targeting of inhaled corticosteroids in\u000a        children by modification of the guidelines for practitioners.\u000a    The research work by Shields at Queen's University Belfast showed that it\u000a      was wrong to group children with VIW and chronic non-specific cough as\u000a      having asthma and in need of ICS treatment. Early guidelines defined\u000a      asthma in children as `Cough and\/or wheezing ...' and this emphasis on\u000a      cough as the leading symptom resulted in many children with isolated cough\u000a      being treated for asthma. In Australia ICS was the commonest used\u000a      medication for children with isolated cough and almost 13% had experienced\u000a      steroid side-effects. Shields' research has provided the underpinning\u000a      evidence that children with non-allergic VIW and children with isolated\u000a      chronic coughing would be unresponsive to ICS and hence the steroid side\u000a      effects can be avoided in these children. This has changed the emphasis in\u000a      national and international asthma and cough guidelines for children1,2\u000a      and the chair of the Diagnosis section of the BTS Asthma Guideline stated\u000a      that \"this research brought about a paradigm shift in the approach to\u000a      childhood asthma\"3. It is now recommended that VIW should be\u000a      distinguished from allergic asthma and that both VIW and non-specific\u000a      isolated cough indicate a low probability of an asthma diagnosis. ICS are\u000a      no longer recommended for these conditions. This change in clinical\u000a      practice and the recommendations now means that fewer of these children\u000a      are exposed to unnecessary ICS. Shields now chairs the Pharmacology\u000a      Section of the BTS\/SIGN Asthma Guidelines and the Cough in Children\u000a      Guidelines (BTS).\u000a    Impact 2: High doses of ICS are no longer recommended and used\u000a        for childhood asthma\u000a    In the 1990s ICS therapy was considered safe. Data from the Scottish\u000a      General Practice Research Database show that very high dose ICS (> 800\u000a      mcg\/day) prescriptions for asthmatic children >5 years of age\u000a      quadrupled from 1.1% in 1992 to 4.6% in 2004. Not only were children with\u000a      VIW and isolated coughing inappropriately treated with ICS but the doses\u000a      of ICS had escalated. The pivotal case series published in the Lancet\u000a      identified complete adrenal suppression and growth failure in children on\u000a      very high dose ICS4. In addition it was shown that monitoring\u000a      growth in children (which was done at primary and secondary care clinics)\u000a      did not predict the potentially serious adrenal insufficiency5.\u000a      The previous recommendation for monitoring growth as the tool for\u000a      identifying inhaled steroid side-effects (adrenal insufficiency) was\u000a      clearly inadequate. Following this and the work of others, national and\u000a      international asthma guidelines have reduced the recommended maximal ICS\u000a      dose for children and have added warnings about adrenal suppression. Thus\u000a      while the British Thoracic Society Asthma guidelines in 1997 suggested\u000a      children on Step 3 (poor asthma control despite treatment with 400 mcg\/day\u000a      of ICS) should be treated with 800 to 2000 mcg daily of ICS, this\u000a      recommendation changed and after 2008 clear statements were made\u000a      suggesting Step 3 was up to 400 mcg daily of ICS and those requiring\u000a      greater than 800 mcg per day should be under specialist respiratory\u000a      paediatric care5.\u000a    Impact 3: Simple handheld exhaled nitric oxide devices are now\u000a        available for monitoring airways inflammation in practice\u000a    Shields' research also showed that breath Fractional Exhaled Nitric Oxide\u000a      (FeNO) correlates well with the extent of allergic airways inflammation. A\u000a      high FeNO value of a child attending an asthma clinic may mean the child\u000a      is not adhering to ICS treatment or he\/she needs the ICS treatment\u000a      escalated. Even as late as 2006 FeNO measurement was limited to large\u000a      research centres because the equipment was bulky and expensive.\u000a      Manufacturers had the technology for portable equipment but needed further\u000a      evidence that FeNO measurement was likely to have clinical benefit, and so\u000a      would be widely adopted, before committing to commercially producing\u000a      handheld units.\u000a    Shields and his colleagues provided the underpinning evidence that the\u000a      FeNO breath test correlated closely with bronchoalveolar lavage\u000a      eosinophilia in childhood asthma6. This was used as a key piece\u000a      of evidence by the manufacturer (Aerocrine) supporting the development of\u000a      their product — the handheld NIOX Mino FeNO monitoring device. This key\u000a      reference is also used as supporting the diagnostic accuracy and use of\u000a      FeNO in children in the official American Thoracic Society Clinical\u000a      Practice Guideline. The Co-Chair from the ATS Guideline Committee has\u000a      clearly acknowledged this impact when he comments that \"the work by MD\u000a      Shields has made a major contribution to FeNO monitoring in childhood\u000a      asthma with special emphasis on facilitating moving FeNO from a research\u000a      tool to clinical practice\" (reference letter in box 5).\u000a    ","ImpactSummary":"\u000a    Research led by Professor Shields and colleagues at Queen's University\u000a      Belfast has resulted in changes in the treatment of children with cough\u000a      and wheezing disorders and has been a major contributor to International\u000a      Asthma and Cough Guideline statements.\u000a    Wheezing affects up to one third of children. Research studies that\u000a      demonstrated that viral induced wheezing (VIW) or isolated cough were not\u000a      associated with persistent airway inflammation led to a change in\u000a      recommendations for anti-asthma therapy, such that the use of high dose\u000a      inhaled corticosteroids (ICS) was no longer recommended in such cases.\u000a      Furthermore, the dangers of very high dose ICS were better recognized and\u000a      the upper recommended dose of steroids for use in treatment of classical\u000a      childhood asthma was reduced accordingly.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen's University Belfast\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2655984","Name":"Belfast"}],"References":"\u000a    \u000a1. Clin Exp Allergy 1996, 26; 799-806. Investigating paediatric\u000a      airways by non-bronchoscopic lavage: normal cellular data. LG Heaney, EC\u000a      Stevenson, Gillian Turner, IS Cadden, R Taylor, MD Shields and M Ennis.\u000a    This paper describes sampling methodology to obtain BAL in normal healthy\u000a      children overcoming ethical and safety issues, and for the first time\u000a      allowing true normal data to become available for comparisons with disease\u000a      states.\u000a    \u000a\u000a2. Clin Exp Allergy 1997, 27: 1027-1035. Bronchoalveolar lavage\u000a      findings suggest two different forms of childhood asthma. EC Stevenson,\u000a      Gillian Turner, LG Heaney, B Shock, R Taylor, T Gallagher, M Ennis and MD\u000a      Shields.\u000a    This paper has been cited 274 times and has been described as\u000a        `seminal'. It was the first to show that children with allergic asthma\u000a        had persistent eosinophilic inflammation whereas children with viral\u000a        induced wheeze did not and that lumping the 2 conditions together as\u000a        asthma was wrong.\u000a    \u000a\u000a3. Eur Resp J 2000, 16:1109-1114. Chronic cough in children:\u000a      bronchoalveolar lavage findings. PS Fitch, V Brown, BC Shock, R Taylor, M\u000a      Ennis and MD Shields.\u000a    This paper described that children with chronic non-specific cough and\u000a        no wheezing did not have persistent eosinophilic airways inflammation\u000a        and were different from asthma.\u000a    \u000a\u000a4. Lancet.\u000a      1996 Jul 6;348(9019):27-9.Growth and adrenal suppression in asthmatic\u000a      children treated with high-dose fluticasone propionate. Todd\u000a        G, Dunlop\u000a        K, McNaboe\u000a        J, Ryan\u000a        MF, Carson\u000a        D, Shields\u000a        MD. This paper(cited 146times) was the first to highlight the\u000a        potentially very serious risks of high dose ICS especially with\u000a        Fluticasone Propionate which at the time was considered the safest ICS\u000a        for children.\u000a    \u000a\u000a5. Arch Dis Child 2004; 89: 713-716. Monitoring growth in\u000a      asthmatic children treated with high dose inhaled glucocorticosteroids\u000a      does not predict adrenal suppression. KA Dunlop, DJ Carson, HJ Steen, V\u000a      McGovern, J McNaboe and MD Shields.\u000a    This paper highlighted adrenal suppression occurring in children on\u000a        high dose inhaled corticosteroids and reported that simply measuring\u000a        linear growth at the clinic was not a reassuring monitor for the\u000a        presence of adrenal insufficiency.\u000a    \u000a\u000a6. Thorax 2002,57: 383-7. Exhaled nitric oxide (ENO) correlates\u000a      with airway eosinophils in childhood asthma T J Warke, PS Fitch,V Brown,\u000a      RA Taylor, JDM Lyons, M Ennis, MD Shields.\u000a    This paper was the first to show that the non-invasive measurement ENO\u000a        was diagnostically accurate for the presence of allergic airways\u000a        inflammation in children.\u000a    \u000aResearch grants facilitating this research\u000a    National Asthma Campaign. \"Underlying chronic inflammation in different\u000a      forms of childhood asthma\" 1994\/5, £25,250. MD Shields, M Ennis.\u000a    N Ireland Chest Heart Stroke Association. \"Can a simple blood test\u000a      reflect the airways inflammation in children with asthma\" 1995\/6, £40,350.\u000a      MD Shields, M Ennis.\u000a    National Asthma Campaign. \"Investigation into the role of cytokines. T\u000a      cell subsets and viruses in childhood asthma\". 1997\/9, £131421. M Ennis,\u000a      MD Shields, Johnston.\u000a    R&D Office, DHSS (NI). \"Exhaled nitric oxide for monitoring airways\u000a      inflammation in asthmatic children\". Research Training Fellowship, Dr Tim\u000a      Warke, 1999\/2001 (£84,639)\u000a    R&D Office, DHSS (NI) R&D Office, DHSS(NI).\u000a    A] \"Pathophysiology of childhood asthma\" 2002\/5, circa £800,000. MD\u000a      Shields, L Heaney, M Ennis\u000a    B] \"Genetic signature severe RSV disease\" 2007\/12, circa £1m. U Power, L\u000a      Heaney, MD Shields\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    1] Airways inflammation in children (cough and wheeze)\u000a\u0009\u000a    \u000aDiagnosis and treatment of asthma in childhood: a PRACTALL\u000a        consensus report The European Pediatric Asthma Group, Allergy 2008,\u000a      63(1): 5-34\u000a    \u000aDefinition, assessment and treatment of wheezing disorders in\u000a        pre-school children: an evidence based approach. Eur Resp Society\u000a      Taskforce, Eur Resp J 2008; 32(4): 1096-1110.\u000a    The Chair of `Asthma diagnosis' section — BTS\/SIGN British Guideline\u000a      on the Management of Asthma (Thorax. 2008 to 2013: May;63 Suppl\u000a      4:iv1-121.) makes a pertinent quote regarding the work therein\u000a        `represented a seminal contribution to a paradigm shift in our thinking\u000a        about childhood asthma and one that continues to be relevant to today's\u000a        research agenda'\u000a\u000a    \u000aGuidelines for Evaluating Chronic Cough in Pediatrics,\u000a      American College Chest Physicians Evidence-Based Clinical Practice\u000a      Guidelines\u000a    \u000aBritish Thoracic Society Guidelines \"Recommendations for the\u000a        assessment and management of cough in children\" (Thorax 2008; 63\u000a      Suppl 3: iii1-iii15.). MDShields chaired and wrote the BTS Cough\u000a        guidelines for children that have now been translated into Spanish and\u000a        Polish. They are widely quoted and form the basis of websites for both\u000a        patients and doctors.\u000a\u000a\u0009\u0009\u000a    Examples include:\u000a    a. http:\/\/www.patient.co.uk\/doctor\/Chronic-Cough-in-Children.htm\u000a      for parents\u000a    b. http:\/\/healthguides.mapofmedicine.com\/choices\/map\/cough_in_children1.htm\u000a      for doctors. {This Map of Medicine was published in Apr 2012}\u000a    c. http:\/\/www.uptodate.com\/contents\/approach-to-chronic-cough-in-children\u000a    \u000a\u0009`An Official ATS Clinical Practice Guideline: Interpretation of\u000a        Exhaled Nitric Oxide Levels (FENO) for\u000a        Clinical Applications'.\u000a      http:\/\/www.thoracic.org\/statements\/resources\/respiratory-disease-adults\/feno-document.pdf\u000a\u000a    http:\/\/www.aerocrine.com\/Global\/pdf\/Scientific%20Backgrounder%202007\/SBVI.pdf\u000a\u0009\u000a    2] Problems with high dose ICS\u000a    The publications (Ref 6 and Lancet 1996, 348, 9019; 27-29)\u000a      identifying adrenal suppression with high dose ICS and the finding that\u000a      monitoring linear growth fails to predict adrenal suppression form\u000a      underlying evidence for statements in the BTS asthma guideline and the\u000a      Global Initiative for Asthma (GINA) guidelines, http:\/\/www.ginasthma.org\/guidelines-gina-report-global-strategy-for-asthma.html\u000a    \u000a    ","Title":"\u000a    Improved management of airway disorders in children\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The research programme led by Shields aims to determine the type of\u000a      airways inflammation which underlies childhood wheezing and cough. Shields\u000a      is an academic respiratory paediatrician working at the Royal Belfast\u000a      Hospital for Sick Children and Queen's University Belfast (Professor of\u000a      Child Health). First, Shields and his colleagues developed and reported an\u000a      ethically acceptable, safe and feasible method for obtaining\u000a      bronchoalveolar lavage (BAL) lung samples from children purely for\u000a      research purposes. BAL samples were obtained from children who were\u000a      already subjected to the risks of anaesthesia for elective surgery1.\u000a      This provided the first accurate normal data as a comparator to allow the\u000a      study of airways inflammation in children with stable asthma, viral\u000a      induced wheezing (VIW) and isolated coughing.\u000a    They were then able to demonstrate that children with allergic asthma had\u000a      evidence of persisting inflammation in the bronchi between asthma attacks,\u000a      whereas children with VIW and chronic cough did not. This suggested that\u000a      inhaled corticosteroid treatment, which dampens down allergic airways\u000a      inflammation, was inappropriate in children with VIW and isolated chronic\u000a      cough as these show no airways inflammation2,3. The Tucson\u000a      epidemiology birth cohort study had already in 1988 suggested that\u000a      splitting wheezing children into at least two separate phenotypes should\u000a      be considered. Adult biopsy studies had shown that bronchial inflammation\u000a      persists between exacerbations BUT whether this was the same in asthmatic\u000a      children and\/ or children with VIW could not be determined easily and\u000a      ethically in children.\u000a    When this clinical research work started, children with non-allergic\u000a      Viral Induced Wheezing (VIW) and non-specific cough were treated for\u000a      asthma, often with high doses of inhaled corticosteroids (ICS) and in the\u000a      1990s this was considered safe. However, Shields' research demonstrated\u000a      that the children with VIW did not have persistent airway inflammation and\u000a      thus were being treated inappropriately with ICS. Subsequent randomised\u000a      controlled trials performed by many others have supported the finding that\u000a      ICS were not beneficial in these circumstances. Furthermore, the doses of\u000a      ICS in clinical use had escalated well above those initially recommended.\u000a      In a pivotal case series4, Shields identified potentially very\u000a      serious complete adrenal suppression and growth failure in children on\u000a      very high dose ICS. He then showed that monitoring growth in children\u000a      (which was already done at primary and secondary care clinics) did not\u000a      adequately predict adrenal insufficiency5. This work\u000a      highlighted the problems with the use of high dose inhaled\u000a      corticosteroids. Following this and the work of others (who reported\u000a      similar cases of adrenal suppression), national and international asthma\u000a      guidelines (examples listed in section 5) have reduced the recommended\u000a      maximal ICS dose for children and have added warnings about adrenal\u000a      suppression.\u000a    Shields and his colleagues were also able to demonstrate that in allergic\u000a      asthma the degree of lower airways inflammation correlated closely with a\u000a      simple non-invasive breath test measurement, Fractional Exhaled Nitric\u000a      Oxide (FeNO)6. An elevated FeNO was highly predictive for the\u000a      presence of airways inflammation in children. This finding has been an\u000a      important stimulus for companies (e.g. Aerocrine) to develop handheld FeNO\u000a      monitoring devices for general use. These devices are also important in\u000a      managing asthma and other airways disorders in adult patients as outlined\u000a      in another Impact Case study (Difficult-to-treat Asthma in Adults).\u000a    "},{"CaseStudyId":"38330","Continent":[{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Patients with difficult to control asthma (10% of the asthmatic\u000d\u000a      population, ca 0.5 million in the UK) have significant symptoms\u000d\u000a      and morbidity and are at a high risk of asthma death. This population\u000d\u000a      currently represents a significant economic burden with estimates\u000d\u000a      suggesting that they consume up to 50 - 60% of NHS spend on asthma\u000d\u000a      totalling over £1 billion per annum, indicating that such appropriate\u000d\u000a      management is likely to generate significant cost savings.\u000d\u000a    Several conditions that cause respiratory symptoms might co-exist in\u000d\u000a      asthmatic patients, leading to an apparent failure to respond to asthma\u000d\u000a      therapy and a significant impact of Heaney's work is that systematic\u000d\u000a      evaluation has been shown to identify additional or alternative diagnoses\u000d\u000a      in just over a third of the DA cases. In routine clinical practice, asthma\u000d\u000a      management guidelines advocate escalation of asthma treatment to achieve\u000d\u000a      symptom control. However, if the diagnosis of asthma is incorrect, or more\u000d\u000a      commonly, if one of several other conditions, which frequently co-exist\u000d\u000a      with asthma is present, this escalation in therapy does not improve\u000d\u000a      symptoms. This often leads to treatment side-effects, particularly with\u000d\u000a      systemic steroid treatment. Systematic clinical assessment shifts the\u000d\u000a      focus from asthma therapy escalation and identifies and manages these\u000d\u000a      conditions including smoking and chronic obstructive pulmonary disease\u000d\u000a      (COPD), allergic bronchopulmonary aspergillosis (ABPA) and bronchiectasis,\u000d\u000a      rhinosinusitis, vocal cord dysfunction, gastro- oesophageal reflux,\u000d\u000a      allergen, aspirin, or occupational sensitisation, systemic disease (e.g.,\u000d\u000a      thyroid disease, vasculitis), psychological factors and poor adherence as\u000d\u000a      well as socioeconomic factors. In all of these conditions, identification\u000d\u000a      and explanation or treatment of the condition causing the symptoms, rather\u000d\u000a      than more asthma therapy, is a more appropriate strategy, and in many\u000d\u000a      cases will lead to symptomatic improvement.\u000d\u000a    The non-adherence research programme in DA at Queen's identified for the\u000d\u000a      first time the significant scale of this problem (up to 50% of subjects\u000d\u000a      referred to tertiary care DA services are non-adherent). Non-adherence to\u000d\u000a      asthma treatment is associated with poor healthcare outcomes including\u000d\u000a      recurrent hospital admission, increased risk of ventilation for\u000d\u000a      life-threatening asthma, poor asthma-related quality of life, high symptom\u000d\u000a      scores and excessive use of nebulised reliever medication. The reasons for\u000d\u000a      this pattern of behaviour are complex, and include denial, medication and\u000d\u000a      disease beliefs and secondary gain (secondary gain is where an individual\u000d\u000a      gains a real or perceived benefit from being ill). Thus the precise reason\u000d\u000a      for lack of medication adherence determines how the problem should be\u000d\u000a      addressed. Practical barriers, such as forgetting medication or poor\u000d\u000a      inhaler technique, can largely be solved by practical solutions. With\u000d\u000a      perceptual barriers, such as denial or an erroneous belief that the\u000d\u000a      medication is causing harm, a different approach is required to manage\u000d\u000a      what is essentially a perceptual problem. This illustrates the importance\u000d\u000a      of an individualised `menu-driven' approach to address non-adherence.\u000d\u000a    Heaney is Director of the Northern Ireland Regional Difficult Asthma\u000d\u000a      Service, managing all NI complex tertiary referrals and as a consequence\u000d\u000a      patients in NI have benefited as a result. This ground breaking\u000d\u000a      translational research programme has been implemented in Northern Ireland1\u000d\u000a      and is fully funded by the NHS. A Difficult Asthma programme was included\u000d\u000a      in the Respiratory Framework Standards for Respiratory Care in NI in 20072\u000d\u000a      and in 2013 a similar standard has subsequently been incorporated into the\u000d\u000a      NICE Asthma Standards (NICE Asthma Quality Standard 11 - Difficult Asthma)3.\u000d\u000a      In providing a unique research and clinical infrastructure to move away\u000d\u000a      from the 'one size fits all' approach to treatment in severe asthma there\u000d\u000a      has been a significant paradigm shift away from the more traditional\u000d\u000a      `medical' model of treatments of patients towards a more social and\u000d\u000a      holistic approach.\u000d\u000a    Multi-disciplinary optimised clinical assessment has informed best\u000d\u000a      practice in International Asthma Guidelines (Global INitiative for Asthma\u000d\u000a      [GINA 2009]4, Spanish Asthma Guidelines [SEPAR 2005]5,\u000d\u000a      BTS\/SIGN Asthma Guidelines 2011 which apply to UK, Australia and New\u000d\u000a      Zealand). The major impact of Heaney's work is exemplified in the recent\u000d\u000a      Consultation document for Specialist Centrally Commissioned Severe Asthma\u000d\u000a      Services6 in the NHS in England which builds further on this\u000d\u000a      multi- disciplinary assessment model (4 of the 9 references to underpin\u000d\u000a      this document are from Heaney and the UK Registry). This document supports\u000d\u000a      the development of specialist regional DA services using a systematic\u000d\u000a      multi-disciplinary assessment model and when commissioned, these Centres\u000d\u000a      will be required to input data into the Registry. The National Registry is\u000d\u000a      also hosting the UK Bronchial Thermoplasty Registry for NICE7\u000d\u000a      which will provide long term data capture on the use of this technique\u000d\u000a      within the UK and will provide a unique resource in the future to inform\u000d\u000a      questions about longer term efficacy and safety of this technique.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Heaney's research at Queen's University Belfast on difficult-to-treat\u000d\u000a      asthma (or simply \"difficult asthma\"— DA) patients has led to changes in\u000d\u000a      clinical management guidelines and a drive to co-ordinate and commission\u000d\u000a      specialist services nationally for DA patients. It has also led to the\u000d\u000a      establishment of a UK Multi-centre National Clinical Network and Patient\u000d\u000a      Registry (Centres listed in Section 5). DA patients have persistent\u000d\u000a      symptoms and frequent exacerbations despite being on high dose asthma\u000d\u000a      therapy. DA patients (10% of the asthmatic population) have significant\u000d\u000a      morbidity and carry a high risk of asthma death. Their clinical assessment\u000d\u000a      has been optimised to ensure proper management of both their asthma and\u000d\u000a      non-asthma related conditions.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen's University Belfast\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Heaney LG, Conway E, Kelly C, Johnston BT, English C,\u000d\u000a      Stevenson M, Gamble J. Predictors of therapy resistant asthma: outcome of\u000d\u000a      a systematic evaluation protocol Thorax 2003;58:561-566. Cited 113\u000d\u000a        times.\u000d\u000a      This paper established systematic multi-disciplinary as a clinical\u000d\u000a        model to assess and manage difficult to control asthma.\u000d\u000a    \u000a\u000a2. LG Heaney, DS Robinson. Severe asthma treatment: need for\u000d\u000a      characterising patients. Lancet. 2005 Mar 9;365(9463):974-6. Cited 108\u000d\u000a        times\u000d\u000a        This paper presented data from 2 Centres (Belfast and Royal Brompton)\u000d\u000a        with similar clinical outcomes and emphasised the multi-factorial nature\u000d\u000a        of difficult asthma and the utility of systematic multi-disciplinary\u000d\u000a        assessment.\u000d\u000a    \u000a\u000a3. Gamble J, Stevenson M, McClean E, Heaney LG. The Prevalence of\u000d\u000a      Non-adherence in Difficult Asthma. American Journal Respiratory Critical\u000d\u000a      Care Med. 2009 Nov 1;180(9):817-22.\u000d\u000a      This seminal paper was published in the number 1 ranked respiratory\u000d\u000a        journal (2010 Impact factor 10.2) and has already been cited 114 times\u000d\u000a        in less than 4 years.\u000d\u000a        This paper demonstrated the high prevalence of non-adherence with high\u000d\u000a        dose inhaled therapy in difficult asthma and additionally poor adherence\u000d\u000a        with systemic steroids (prednisolone).\u000d\u000a    \u000a\u000a4. McNicholl D, Stevenson M, McGarvey LPA, Heaney LG. The utility\u000d\u000a      of fractional exhaled nitric oxide suppression in the identification of\u000d\u000a      non-adherence in difficult asthma. Am J Respir Crit Care Med. 2012 Dec\u000d\u000a      1;186(11).\u000d\u000a      This paper presented the first `objective' functional test for\u000d\u000a        non-adherence to inhaled steroids by using the degree of steroid\u000d\u000a        response to an inflammatory biomarker (FeNO).\u000d\u000a    \u000a\u000a5. Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM\u000d\u000a      on behalf of the British Thoracic Society Difficult Asthma Network.\u000d\u000a      Refractory asthma in the UK — cross-sectional findings from a UK\u000d\u000a      Multicentre Registry. Thorax 2010 Sep;65(9):787-94.\u000d\u000a      This paper described detailed clinical phenotypic features in patients\u000d\u000a        with refractory asthma across the UK.\u000d\u000a    \u000a\u000a6. Joan Sweeney, Chris E Brightling, Andrew Menzies-Gow, Rob M Niven,\u000d\u000a      Chris C Patterson, Liam G Heaney, on behalf of the British\u000d\u000a      Thoracic Society Difficult Asthma Network. Clinical management and outcome\u000d\u000a      of refractory asthma in the UK — follow-up data from the British Thoracic\u000d\u000a      Society Difficult Asthma Registry. Thorax 2012\u000d\u000a      This paper described clinical outcomes in patients with refractory\u000d\u000a        asthma managed in Specialist Centres across the UK.\u000d\u000a    \u000aGrant funding supporting clinical assessment and mechanisms of\u000d\u000a        difficult asthma\u000d\u000a    1. 2012 - 2014 - Multi-centre validation of FeNO suppression testing\u000d\u000a        to identify non-adherence in difficult asthma — Glaxo Smith Kline\u000d\u000a      European Clinical Centre of Excellence - £150,000\u000d\u000a    2. 2012 - 2014 - Lebrikizumab in Severe Asthma — Chief\u000d\u000a      Investigator for multi-centre study delivered via British Thoracic Society\u000d\u000a      Network — Roche UK, BTS Network Support funding - £556,875\u000d\u000a    3. 2011 - 2015 - The Regulatory Importance of SOCS molecules in Th2\u000d\u000a        immune responses and disease. Medical Research Council (Johnston,\u000d\u000a      Kissenpfennig, Heaney) - £409,462\u000d\u000a    4. 2012 - 2013 - Biomarkers for steroid resistance in refractory\u000d\u000a        asthma Genentech Inc USA - $150,000\u000d\u000a    5. 2011 - 2014 - Developing and validating a biomarker for\u000d\u000a        non-adherence to inhaled steroid treatment in difficult asthma — NI\u000d\u000a      Chest Heart & Stroke Association £90,281\u000d\u000a    6. 2011 - 2013 - European Framework 7 funded Airway Disease\u000d\u000a        PRedicting Outcomes through Patient Specific Computational Modelling\u000d\u000a        (AirPROM) — Work package 1 co-lead - €72,852\u000d\u000a    7. 2011 - 2013 - Health Economics of Refractory Asthma; a\u000d\u000a        multi-Centre UK analysis — Glaxo Smith Kline - £119,876\u000d\u000a    8. 2011 - 2014 - Take control of asthma: improving stakeholders'\u000d\u000a        understanding of poor medication adherence in difficult asthma and the\u000d\u000a        utility of a targeted management strategy, HSC R&D Office\u000d\u000a      Knowledge Transfer Programme - £99,986\u000d\u000a    9. 2010 - 2011 - Pilot study of treatment of depression in refractory\u000d\u000a        asthma — Asthma UK - £49,258.\u000d\u000a    10. 2010 - 2015 -- AUGOSA — genome wide screen in refractory asthma\u000d\u000a        in the UK — data analysis for National Registry Medimmune UK\u000d\u000a      £50,000.\u000d\u000a    11. 2009 - 2011 - Novel biomarkers of non-adherence in difficult\u000d\u000a        asthma — unrestricted research grant — Glaxo Smith Kline - £100,000\u000d\u000a    12. 2008 - 2011 The use of fractional exhaled nitric oxide (FeNO) and\u000d\u000a        induced sputum in the identification of non-adherence in difficult to\u000d\u000a        control asthma. Asthma UK and NI Chest Heart and Stroke Association\u000d\u000a      £166,282.\u000d\u000a    13. 2007 - 2010 Pilot Funding for British Thoracic Society National\u000d\u000a        Difficult Asthma Registry - £90,000) unrestricted Research Grants\u000d\u000a      from Glaxo Smith Kline, Astra Zeneca and Novartis UK.\u000d\u000a    14. 2004 - 2009 Evaluation of an individualised menu driven nurse led\u000d\u000a        programme to improve adherence in difficult asthma. R&D Office\u000d\u000a      2004, MPhil Fellowship £86,727\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a      Respiratory Framework NI — http:\/\/www.dhsspsni.gov.uk\/rsf_-_asthma_in_adults.pdf\u000a\u000d\u000a      British Thoracic Society \/ Scottish Intercollegiate Guidelines\u000d\u000a        Network: British Guideline on the Management of Asthma: A national\u000d\u000a        clinical guidelne — http:\/\/www.britthoracic.org.uk\/guidelines\/asthma-guidelines.aspx\u000a\u000d\u000a      NICE Asthma Standards — Difficult Asthma — http:\/\/publications.nice.org.uk\/quality-standard-for-asthma-qs25\/quality-statement-11-difficult-asthma#source-guidance-11Uniform\u000d\u000a        definition of asthma severity, control, and exacerbations: document\u000d\u000a        presented for the World Health Organization Consultation on Severe\u000d\u000a        Asthma. J Allergy Clin Immunol. 2010 Nov;126(5):926- 38.\u000d\u000a      Global Initiative for Asthma — Global Strategy for Asthma Management\u000d\u000a        and Prevention —\u000d\u000a        www.ginasthma.org\/uploads\/users\/...\/GINA_Report_2011.pdf\u000a\u000d\u000a      Recommendations of the Spanish Society of Pulmonology and Thoracic\u000d\u000a        Surgery (SEPAR). Guidelines for the Diagnosis and Management of\u000d\u000a        Difficult-to-Control Asthma. Arch Bronconeumol. 2005;41(9):513-23.\u000d\u000a      National Health Service Commissioning Board — Central Commissioning of\u000d\u000a        Severe Asthma\u000d\u000a        https:\/\/www.engage.commissioningboard.nhs.uk\/consultation\/ssc-area-a\/\u000a\u000d\u000a      National Institute for Health and Clinical Excellence — Bronchial\u000d\u000a        thermoplasty for severe asthma (IPG419) — http:\/\/www.nice.org.uk\/nicemedia\/live\/12774\/55435\/55435.pdf\u000a\u000d\u000a    \u000d\u000a    Clinical Centres in the British Thoracic Society Difficult Asthma\u000d\u000a        Network* include:\u000d\u000a      Belfast City Hospital; Wythenshawe Hospital, University Hospital of South\u000d\u000a      Manchester; Glenfield Hospital and Institute for Lung Health, Leicester;\u000d\u000a      Royal Brompton Hospital, London; Birmingham Heartlands Hospital;\u000d\u000a      Southampton General Hospital; Freemans Hospital, Newcastle; Nottingham\u000d\u000a      City Hospital; Gartnavel General Hospital, Glasgow; Stobhill Hospital,\u000d\u000a      Glasgow\u000d\u000a      * Other clinical centres are currently engaging through the thermoplasty\u000d\u000a      programme and central commissioning plan and being established to enter\u000d\u000a      data into the Patient Registry.\u000d\u000a    ","Title":"\u000d\u000a    Improvements in clinical assessment and management of Difficult-to-treat\u000d\u000a      Asthma in Adults\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2655984","Name":"Belfast"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Heaney's research has focused on patients with difficult to control\u000d\u000a      asthma (10% of the asthmatic population, totalling circa 500,000 people),\u000d\u000a      who have significant disease-related morbidity. It is estimated that 50 -\u000d\u000a      80% of asthma deaths occur in this group. In many cases patients are given\u000d\u000a      increasing doses of medication for asthma rather than considering\u000d\u000a      additional underlying factors that may be at play. Heaney's research\u000d\u000a      programme has successfully established multi-disciplinary systematic\u000d\u000a      clinical assessment to characterise patients with difficult-to-treat\u000d\u000a      asthma, providing major benefits in identifying the precise cause for\u000d\u000a      persistent symptoms and the role of non-asthma related co-morbidities in\u000d\u000a      this population1,2. This precise clinical phenotyping of\u000d\u000a      patients prevents the inappropriate escalation of asthma therapy by the\u000d\u000a      targeted management of underlying conditions such as chronic dilation of\u000d\u000a      the bronchi and dysfunctional breathlessness.\u000d\u000a    Of course great strides have been made by others in establishing\u000d\u000a      underlying mechanisms of asthma over the years, but this clinical research\u000d\u000a      importantly demonstrated in 2009 that 35% of patients referred to a\u000d\u000a      Difficult Asthma Service were non-adherent, or inconsistent, in their use\u000d\u000a      of inhaled anti-inflammatory treatment, and that this was associated with\u000d\u000a      poor clinical outcomes for these patients. This has now also been extended\u000d\u000a      to other specialist centres3. Identification of non-adherence\u000d\u000a      is essential in order to prevent the inappropriate escalation of patients\u000d\u000a      onto complex and expensive treatments. In order to deal with this aspect\u000d\u000a      of patient management, the group developed a clinical test which uses\u000d\u000a      directly observed inhaled steroid therapy in parallel with tests that\u000d\u000a      measured to what extent daily exhaled nitric oxide (FeNO suppression test)\u000d\u000a      was suppressed in the patients to identify non-adherence in this\u000d\u000a      population4. As outlined in the Impact Case \"Improved\u000d\u000a      management of airway disorders in children\", this test is useful in\u000d\u000a      managing children with asthma but it also can identify which patients are\u000d\u000a      suitable for the new expensive and complex biological antibody therapies.\u000d\u000a      The tests are currently extended for use in other specialist clinical\u000d\u000a      centres and to include the use of remote telemonitoring technology.\u000d\u000a    A key component of this research has been the development of the National\u000d\u000a      Severe Asthma Patient Registry which was established by Heaney in 2007\u000d\u000a      (British Thoracic Society Severe Asthma Network — see Section 5) centred\u000d\u000a      at Queen's University, which provides a unique research and clinical\u000d\u000a      infrastructure to move away from the 'one size fits all' approach to\u000d\u000a      treatment in severe asthma. Research in the Registry has produced a series\u000d\u000a      of important publications on patients with severe asthma5,6.\u000d\u000a    "},{"CaseStudyId":"38331","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The research led by Elborn which validated CF trial outcome measures, has\u000d\u000a      had very significant impact on the management of people with CF because\u000d\u000a      the early studies from his group made multicentre trials more reliable,\u000d\u000a      effective and efficient. The validation of clinical trial outcome measures\u000d\u000a      has resulted in evidenced based new treatments for people with CF. In 2007\u000d\u000a      the Queen's University Belfast and the Belfast Health and Social Care\u000d\u000a      Trust set up the infrastructure to deliver CF trials. This initiative\u000d\u000a      supported the development of an NHS R&D (equivalent in remit to the\u000d\u000a      National Institute of Health Research in England) clinical trials network\u000d\u000a      (CTN) in Respiratory Health in Northern Ireland. This CTN has now\u000d\u000a      successfully completed 26 phase II\/III investigator-led and pharmaceutical\u000d\u000a      industry supported clinical trials and has become a major hub for delivery\u000d\u000a      and leadership in clinical trials in cystic fibrosis worldwide. The Centre\u000d\u000a      has now led and contributed to 25 clinical trials in people with CF1\u000d\u000a      and is the leading centre in the UK for clinical trials in CF2.\u000d\u000a    These trials have allowed optimisation of current anti-inflammatory and\u000d\u000a      anti-infective treatments and have been a contributor to innovative\u000d\u000a      transformative treatments for the underlying basic defect2, 3\u000d\u000a      The extensive experience with clinical trials and the CTN infrastructure\u000d\u000a      set up by Queen's and the Belfast Trust resulted in Elborn's group being\u000d\u000a      selected by a number of commercial organisations such as Boehringer,\u000d\u000a      Vertex, Novartis, and Pulmatrix to be the international leads for Phase II\u000d\u000a      and Phase III clinical trials and other interventions in CF. For example,\u000d\u000a      Elborn was the co-Chief Investigator for a ground breaking and landmark\u000d\u000a      study using the first corrective therapy for the underlying defect in\u000d\u000a      patients with CF4. Ivacaftor corrects the function of a\u000d\u000a      particular mutation in CF designated as G551D. This mutation in the CF\u000d\u000a      gene affects 5% of people with CF worldwide but 10% of people in Ireland.\u000d\u000a      The drug activates the mutated protein and restores significant function\u000d\u000a      of the defective channel which causes CF in these patients. This Phase III\u000d\u000a      study demonstrated a transformative impact on patients with very\u000d\u000a      significant increases in lung function and quality of life with a\u000d\u000a      concomitant reduction in pulmonary exacerbation6. Ivacaftor\u000d\u000a      represents a paradigm shift since for the first time not just the symptoms\u000d\u000a      of CF are treated in the patients but treatment is aimed directly at the\u000d\u000a      cause of the disease. It has now been approved by FDA5 and EMA6\u000d\u000a      and is licensed and funded in USA, UK, Ireland, France and Germany7.\u000d\u000a      The outstanding results from Kalydeco led Forbes to select this drug as\u000d\u000a      the most important drug licensed in 20129 as it reached sales\u000d\u000a      of $113 million in the first 9 months of the year. This is primarily\u000d\u000a      because Ivacaftor represents a completely new approach to treating people\u000d\u000a      with CF by correcting the basic defect. The very rapid development of this\u000d\u000a      treatment into a prescribed therapy available in the clinic is a\u000d\u000a      consequence of the rapid and efficient execution of the pivotal clinical\u000d\u000a      trial with the appropriate endpoints. Ivacaftor has transformed the\u000d\u000a      quality of life of people with cystic fibrosis who carry the G551D\u000d\u000a      mutation by improving their lung function and nutritional state and\u000d\u000a      reducing the number of exacerbations caused by infection and mucous\u000d\u000a      impaction in the lungs.10 These are all strong surrogates for\u000d\u000a      survival and it is likely that this therapy will also improve length of\u000d\u000a      life. For those patients who have the G551D mutation this is a\u000d\u000a      transformative therapy. This programme is an exemplar of personalised\u000d\u000a      medicine5. The FDA describes the impact of Ivacaftor on people\u000d\u000a      with CF and the exemplar nature of this in the field of personalised\u000d\u000a      medicine as follows: \"Kalydeco represents an excellent example of the\u000d\u000a      future of personalised medicine.....it is part of a revolution in how we\u000d\u000a      will treat patients in the future\". This pivotal trial with Ivacaftor has\u000d\u000a      also for the first time demonstrated that the CFTR protein is a drugable\u000d\u000a      target and correction of function results in transformative clinical\u000d\u000a      benefit. This has very significant societal impact for people with cystic\u000d\u000a      fibrosis demonstrating real future hope that a wide range of mutations may\u000d\u000a      indeed be treatable. This is evidenced by a range of major pharmaceutical\u000d\u000a      companies developing potentiator and corrector programmes as this target\u000d\u000a      is now attractive (Novartis, Pfizer, Bayer). Elborn is an advisor of study\u000d\u000a      designs of the programmes with Novartis and Bayer and a CI on the Novartis\u000d\u000a      and Bayer programmes.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    New therapies supported by clear evidence from clinical trials have\u000d\u000a      resulted in outstanding improvements in survival and quality of life for\u000d\u000a      people living with cystic fibrosis (CF). Elborn's clinical trials group\u000d\u000a      has delivered a programme of crucial clinical trials which has impacted on\u000d\u000a      clinical practice in CF. From 2009-2012 Elborn co-led a pivotal\u000d\u000a      multicentre trial using Ivacaftor (Kalydeco TM), a\u000d\u000a      transformative new drug which represents a paradigm shift as the first\u000d\u000a      approved therapy that corrects the basic defect in CF. This therapy is an\u000d\u000a      exemplar of personalised medicine and is prescribed for patients with the\u000d\u000a      specific gene mutation in which this drug works.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    Queen's University Belfast\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Elborn JS, Prescott RJ, Stack BH, Goodchild MC, Bates J, Pantin\u000d\u000a      C, Ali N, Shale DJ, Crane M. Elective versus symptomatic antibiotic\u000d\u000a      treatment in cystic fibrosis patients with chronic Pseudomonas infection\u000d\u000a      of the lungs. Thorax 2000 May; 55(5): 355-8. PubMed PMID: 10770814; PubMed\u000d\u000a      Central PMCID: PMC1745744.\u000d\u000a      This investigator led study demonstrated that a widely applied practice\u000d\u000a        of giving intravenous antibiotics was not better than treating when\u000d\u000a        symptoms indicated. Exacerbation rate was used as the primary outcome.\u000d\u000a      Funding: British Thoracic Society, £250,000\u000d\u000a    \u000a\u000a2. Balfour-Lynn IM, Lees B, Hall P, Phillips G, Khan M, Flather M, Elborn\u000a        JS; CF WISE (Withdrawal of Inhaled Steroids Evaluation)\u000d\u000a      Investigators. Multicenter randomized controlled trial of withdrawal of\u000d\u000a      inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med.\u000d\u000a      2006 Jun 15; 173(12): 1356-62. Epub 2006 Mar 23. PubMed PMID: 16556691.\u000d\u000a      This study demonstrated that inhaled corticosteroids were ineffective\u000d\u000a        in CF. Exacerbations and lung function were validated as key endpoints.\u000d\u000a        Funding: CF trust, £300,000\u000d\u000a    \u000a\u000a3. Martin SL., Downey D., Bilton D., Keogan MT., Edgar J., Elborn JS.,\u000d\u000a      Recombinant AAT CF study team. Safety and Efficacy of recombinant\u000d\u000a      alpha(1)-antitrypsin therapy in cystic fibrosis. Pediatr. Pulmonol. 2006\u000d\u000a      41(2): 177-183. PubMed PMID: 16372352\u000d\u000a      Pivotal clinical trial for transgenic alpha-1 antitrypsin in CF using\u000d\u000a        novel biomarker and clinical outcome measures.\u000d\u000a    \u000a\u000a4. Downey DG, Brockbank S, Martin SL, Ennis M, Elborn JS. The\u000d\u000a      effect of treatment of cystic fibrosis pulmonary exacerbations on airways\u000d\u000a      and systemic inflammation. Pediatr Pulmonol. 2007 Aug; 42(8): 729-35.\u000d\u000a      PubMed PMID: 17588254.\u000d\u000a      Paper validating the responsiveness of lung function measurements and\u000d\u000a        limitations of inflammatory biomarkers. Funding PPL Therapeutics\u000d\u000a        £250,000.\u000d\u000a    \u000a\u000a5. Döring G, Elborn JS, Johannesson M, de Jonge H, Griese M,\u000d\u000a      Smyth A, Heijerman H; Consensus Study Group. Clinical trials in cystic\u000d\u000a      fibrosis. J Cyst Fibros. 2007 Apr;6(2): 85-99. Review. PubMed PMID:\u000d\u000a      17350898.\u000d\u000a      Key consensus statement from European CF Society on endpoints in\u000d\u000a        clinical trials.\u000d\u000a    \u000a\u000a6. De Boeck K, Bulteel V, Tiddens H, Qagner T, Fajac I, Conway S, Dufour\u000d\u000a      F, Smuth AR, Lee T, Sermet I, Kassai B, Elborn JS; ECFS-CTN\u000d\u000a      network partners. Guideline on the design and conduct of cystic fibrosis\u000d\u000a      clinical trials: the European Cystic Fibrosis Society-Clinical Trials\u000d\u000a      Network (ECFS-CTN). J Cyst Fibros. 2011 Jun;10 Suppl 2:S67-74. Doi: 10.\u000d\u000a      1016\/S1569-1993(11)60010-6. PubMed PMID: 21658\u000d\u000a      Development of 2007 consensus based on a Framework 6 Cost Action,\u000d\u000a        Eurocare CF (€1m). Main output from clinical trials work package.\u000d\u000a    \u000a\u000a7. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P,\u000d\u000a      Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F,\u000d\u000a      Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn\u000a        JS. VX08-770-102 Study Group. A CFTR potentiator in patients with\u000d\u000a      cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov\u000d\u000a      3;365(18):1663-72. Doi: 10.1056\/NEJMoa1105185 PubMed PMID: 22047557;\u000d\u000a      PubMed Central PMCID: PMC3230303.\u000d\u000a      Ground breaking pivotal clinical trial demonstrating the effectiveness\u000d\u000a        of Kalydeco.The primary endpoint was lung function and exacerbations a\u000d\u000a        key secondary endpoint. This agent has now been used to treat 2000 CF\u000d\u000a        patients to date, worldwide.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a      List of Queen's clinical trials and link to clinical trials databases.\u000d\u000a        http:\/\/clinicaltrials.gov\/\u000a\u000d\u000a      Letter from Cystic Fibrosis Trust\u000d\u000a      Letter from European Clinical Trials Network (www.ecfs.eu\/ctn)\u000d\u000a      Letter from European Cystic Fibrosis Society\u000d\u000a      Letter from Vertex\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Summary_of_opinion_-\u000a          Initial_authorisation\/human\/002494\/WC500127780.pdf\u000d\u000a      http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm289633.htm\u000d\u000a      http:\/\/previous.cftrust.org.uk\/pressoffice\/pressofficepo\/kalydeco_updates\/kalydeco_eng_win\u000d\u000a      http:\/\/www.bbc.co.uk\/news\/uk-northern-ireland-21760928\u000d\u000a      http:\/\/www.forbes.com\/sites\/matthewherper\/2012\/12\/27\/the-most-important-new-drug-of-2012\/\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Report\/2012\/12\/WC500136159.pdf\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving outcomes for people with cystic fibrosis through evidence based\u000d\u000a      clinical trials\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2655984","Name":"Belfast"}],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    CF is the most common life limiting autosomal recessive disorder in\u000d\u000a      Caucasian populations. There are over 80,000 people worldwide with the\u000d\u000a      condition, with 10,000 in the UK. Researchers at Queen's University\u000d\u000a      Belfast, led by Elborn, have made major contributions to the understanding\u000d\u000a      of lung disease in cystic fibrosis. This enabled the development of key\u000d\u000a      outcome measures (lung function, exacerbations and nutritional measures)\u000d\u000a      to be used in clinical trials to test new therapies. The group in Queen's,\u000d\u000a      with others, demonstrated in the 2000's that measurements of lung function\u000d\u000a      (FEV1), reductions in pulmonary exacerbations and Quality of Life (QoL)\u000d\u000a      are key outcome measures in clinical trials in order to demonstrate the\u000d\u000a      effectiveness or otherwise of treatments for people with CF1,2,3.\u000d\u000a      The validation of these endpoints by the group at Queen's has been crucial\u000d\u000a      to the subsequent and future success of clinical trials in CF. In order\u000d\u000a      for clinical trials to be successfully carried out, the outcome measures\u000d\u000a      have to be clear and be able to be applied correctly and consistently in\u000d\u000a      the participating centres. Research undertaken from 1995 at Queen's\u000d\u000a      validated the importance of measurement of lung function and pulmonary\u000d\u000a      exacerbations as key endpoints in clinical trials in CF and found that\u000d\u000a      these could be applied consistently. These are widely used in clinical\u000d\u000a      trials and are now regulatory endpoints for proof of efficacy in CF trials\u000d\u000a      both used by the European Medicines Agency (EMA) and the US Federal Drugs\u000d\u000a      Agency (FDA).\u000d\u000a    Elborn's research has made him a world leader in this aspect of CF\u000d\u000a      research. This has been recognised nationally by selection into the NIHR\u000a        Respiratory Translational Research Partnership. The Queen's group is\u000d\u000a      a founder member of this important UK initiative to improve the delivery\u000d\u000a      of early phase clinical trials in lung diseases associated with\u000d\u000a      inflammation and infection. The group is also a founder member of the European\u000a        Cystic Fibrosis Society Clinical Trials Network. This network was\u000d\u000a      initiated and developed by Elborn in his role as President of the European\u000d\u000a      Cystic Fibrosis Society. Both of the above are competitive programmes and\u000d\u000a      success in selection is a mark of excellence and leadership in the area of\u000d\u000a      clinical trials.\u000d\u000a    The Belfast Centre has participated in 14 international clinical trials\u000d\u000a      undertaken in the past five years in cystic fibrosis and Elborn is\u000d\u000a      international chief investigator on three CF clinical trials currently in\u000d\u000a      progress. Further recognition of his leadership in this field has involved\u000d\u000a      senior authorship of two pivotal consensus statements which have set the\u000d\u000a      agenda for the design and conduct of cystic fibrosis clinical trials in\u000d\u000a      Europe4,5,6. Elborn also led a key initiative in European\u000d\u000a      Medicines Agency to provide new guidance for the pharmaceutical industry\u000d\u000a      to develop new therapies in this condition. This has a major emphasis on\u000d\u000a      acceptable and meaningful outcome measures necessary for regulatory\u000d\u000a      approval and application in the clinic7.\u000d\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Report\/2012\/12\/WC500136159.pdf\u000d\u000a    "},{"CaseStudyId":"38334","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    To be on mechanical ventilation in an ICU carries a high risk for\u000a      patients and many succumb to infections and pneumonia. Worldwide, the\u000a      number of patients receiving mechanical ventilation is increasing rapidly,\u000a      and will continue to increase due to improved patient survival and an\u000a      aging population. The cost of providing care to these patients is\u000a      substantial: $3050\/day in the United States (US) and £1400\/day in the\u000a      United Kingdom (UK).\u000a    Getting the research evidence to ICU clinicians\u000a    Blackwood and her collaborators have greatly contributed to expanding the\u000a      knowledge base concerning adoption of weaning strategies, particularly in\u000a      the field of weaning protocols and automated weaning systems. In the UK,\u000a      surveys of adult ICUs show a substantial increase in using weaning\u000a      protocols from 21% in 2002 to 57% in 2010 in the UK [1, 2]. Within Europe,\u000a      the current reported use of weaning protocols in ICUs ranges from 56 to\u000a      69%; and 55% of ICUs reported using one or more automated weaning systems\u000a      [3].\u000a    The research by Blackwood and colleagues has been widely disseminated to,\u000a      and accessed by, practitioners within health care institutions and\u000a      professional organisations, both nationally and internationally. For\u000a      example, within the UK, the importance of the findings from the Cochrane\u000a      review on protocolised weaning was recognised by the National Health\u000a      Service (NHS) by making these findings available to the NHS public health\u000a      and social care sectors on their web portal `NHS Evidence' that provides\u000a      authoritative clinical evidence and best practice to all NHS staff [4].\u000a      Professor Gavin Perkins, Director of Research in the UK Intensive Care\u000a      Society said... \"Weaning from mechanical ventilation is an enduring\u000a      challenge for patients in the intensive care unit. For a number of years\u000a      using clinical protocols to guide practice has been suggested as one way\u000a      to reduce the length of time patients spend on a ventilator. For the first\u000a      time, this review brings together the best current evidence on the use of\u000a      protocols.\"\u000a    In Europe, the major critical care professional organisation, the\u000a      European Society of Intensive Care Medicine (ESICM), published an extended\u000a      summary of the review in the first edition of the Clinical Evidence in\u000a      Intensive Care Handbook. It was distributed to the 5661 delegates from 92\u000a      countries attending the 24th Annual Congress in Berlin, Germany and is\u000a      available to its 6346 members via their web platform [5]. Furthermore, on\u000a      an international level, this review was one of the top 10 accessed reviews\u000a      in full-text format in the on-line Cochrane Library, accessed 1,322 times\u000a      during 2011 [6].\u000a    Translation of evidence into practice\u000a    In 2012, on the basis of the evidence from the protocolized weaning\u000a      review and associated publications, the European federation of Critical\u000a      Care Nursing associations (EfCCNa) issued a Position Paper urging European\u000a      ICU nurses to consider the development and use of weaning protocols in\u000a      their practice [7]. The statement reads, \"As a result of reviewing this\u000a      evidence, the EfCCNa recommends that ICU nurses should actively\u000a      participate in early identification of a patient's readiness to wean. The\u000a      ICU nurse should facilitate early weaning by referring to a protocol that\u000a      lists readiness to wean criteria... and developing and using locally\u000a      agreed weaning protocols based on most recent and updated best evidence\".\u000a    Publication of this statement has prompted national associations to issue\u000a      clinical guidelines for weaning. For example, the Israeli Society for\u000a      Cardiology and Intensive Care Nurses translated the EfCCNa position paper,\u000a      and developed national guidelines for protocolized weaning from mechanical\u000a      ventilation. These have been distributed to all ICU nurses on their\u000a      distribution lists and published in the Israeli nursing journal in Hebrew\u000a      [8]. They are being introduced to all ICUs and currently are being used in\u000a      the 4 main ICUs in Jerusalem.\u000a    In Canada, to reflect the impact of the new evidence from Blackwood and\u000a      colleagues' research findings, guidelines for preventing ventilator\u000a      associated pneumonia were revised [9]. The guidelines are published by\u000a      `Safer Healthcare Now!', the flagship programme of the Canadian Patient\u000a      Safety Institute, that invests in frontline providers and the delivery\u000a      system to improve patient safety by implementing interventions known to\u000a      reduce avoidable harm. The guidelines urge ICU teams to review the\u000a      organisational context in which they wean patients as well as the process\u000a      itself in order to optimise weaning outcomes.\u000a    In summary, the dissemination of comprehensive data on weaning methods\u000a      and their impact on patient outcomes has informed clinical\u000a      decision-making. This is evidenced by the uptake of findings from\u000a      Blackwood and colleagues' work into clinical practice guidelines.\u000a    ","ImpactSummary":"\u000a    In the complex care environment of the ICU, protocols for weaning\u000a      patients from mechanical ventilation optimise the process; reduce\u000a      ventilation duration and ICU length of stay and the risk of ventilator\u000a      associated pneumonia (VAP). This results in cost savings. Blackwood's\u000a      programme of research in the field of mechanical ventilation and its\u000a      weaning has impacted internationally on clinical practice in ICUs. It has\u000a      successfully guided intensive care clinicians to develop context specific\u000a      protocols for weaning and is incorporated into international clinical\u000a      guidelines for preventing VAP. It has informed a recent European position\u000a      paper on protocolised weaning.\u000a    ","ImpactType":"Health","Institution":"\u000a    Queen's University Belfast\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2950159","Name":"Berlin"}],"References":"\u000a    \u000a1. Blackwood B, Wilson-Barnett J, Patterson CC, Trinder TJ,\u000a      Lavery GG. An evaluation of protocolised-weaning on the duration of\u000a      mechanical ventilation. Anaesthesia 2006; 61 (11): 1079-1086\u000a      This first UK clinical trial of protocolised weaning demonstrated no\u000a        effect in the UK context and hypothesised that protocolised weaning is\u000a        influenced by the pre-existing practice and culture into which the\u000a        protocol is introduced. The trial was supported by an All-Ireland\u000a        Nursing Research Fellowship from An Bord Altranis, Ireland.\u000a    \u000a\u000a2. Rose L, Presneill JJ, Johnston L, Cade JF. A randomised, controlled\u000a      trial of conventional versus automated weaning from mechanical ventilation\u000a      using SmartCareTM\/PS. Intensive Care Medicine 2008; 34:1788-1795\u000a      Substantial reductions in weaning duration were not confirmed when\u000a        SmartCare was compared to weaning managed by experienced critical care\u000a        specialty nurses indicating the effect of SmartCare\/PS may be influenced\u000a        by the local clinical organisational context.\u000a    \u000a\u000a3. Blackwood B, Alderdice F, Burns KEA, Cardwell CR, Lavery G,\u000a      O'Halloran P. (2011) Protocolized versus non-protocolized weaning for\u000a      reducing the duration of mechanical ventilation in critically ill adult\u000a      patients: a Cochrane Review. British Medical Journal 2011;\u000a      342:c7237\u000a      Funded review (Health & Social Care, Research & Development\u000a        Division of the Public Health Agency and Health Research Board,\u000a        Ireland). Meta-analysis of 11 trials demonstrating that in comparison\u000a        with usual care protocolised weaning reduced the duration of mechanical\u000a        ventilation by 25% and weaning duration by 78% without adverse effects.\u000a    \u000a\u000a4. Rose L, Schultz MJ, Cardwell CR, Jouvet P, McAuley DF, Blackwood\u000a      B. Automated versus non-automated weaning for reducing the duration of\u000a      mechanical ventilation in critically ill adults & children. Cochrane\u000a        Database of Systematic Reviews, 2013;\u000a      Funded review (Canadian Institute of Health Research, Knowledge\u000a        Transfer). Meta-analysis of 15 trials showing that automated weaning\u000a        reduced duration of mechanical ventilation by 17% and weaning duration\u000a        by 32%.\u000a    \u000a\u000a5. Blackwood B, Wilson-Barnett J. The impact of nurse-directed\u000a      protocolised-weaning from mechanical ventilation on nursing practice: a\u000a      quasi-experimental study. International Journal of Nursing Studies\u000a      2007; 44: 209-226\u000a      Nurses reported protocolised weaning did not impact on practice due to\u000a        the existing level of good communication, collaboration and culture\u000a        within their ICU. Notwithstanding, protocols were particularly\u000a        beneficial in providing safe guidance for junior staff.\u000a    \u000a\u000a6. Rose L, Blackwood B, Burns SM, Frazier SK, Egerod I. The\u000a      influence of structure and process on weaning from mechanical ventilation:\u000a      international perspectives. American Journal of Critical Care\u000a      2011; 20: e10-e18 doi: 10.4037\/ajcc2011430\u000a      This study reports data on context and processes of care that influence\u000a        ventilator weaning across Europe, Canada and the US.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Modernisation Agency. Critical Care Programme: Weaning and long term\u000a        ventilation 2002 http:\/\/www.ics.ac.uk\/professional\/critical_care_programme_-%20weaning_and_long_term_ventilation_\u000a\u000a      Blackwood B, Gregg L, McAuley DF, Rose L. UK survey of doctors' views\u000a        on mechanical ventilation and weaning role responsibilities. Intensive\u000a        Care Society State of the Art Meeting, London 2010 A26; 71\u000a      Rose L, Blackwood B, Ingerod I, Haugdahl H, Hofhuis J, Isfort M, Kelly\u000a        C, McAuley DF, Schubert M, Sperlinga R, Spronk P, Storli S, Schultz M.\u000a        Decisional responsibility for mechanical ventilation and weaning: an\u000a        international survey. Critical Care 2011; 15:R295\u000a        doi:10.1186\/cc10588\u000a        The co-authors on this paper have conducted a national survey of\u000a          weaning in their country that contributed data to this paper. They\u000a          form a European network of researchers and clinicians with a focus on\u000a          ICU research.\u000a\u000a      www.evidence.nhs.uk\/documents\/u-eoe-september-2010.pdf\u000a      \u000ahttp:\/\/www.mwv-berlin.de\/buecher-bestellen\/product_info.php?info=p551_Clinical-Evidence-in-Intensive-Care.html\u000a        Link to book: ESICM Systematic Review Group, Clinical Evidence in\u000a          Intensive Care\u000a\u000a      The Cochrane Anaesthesia Review Group Annual Report 2012 ISSN\u000a        1602-6349) This is an annual report published by the Cochrane\u000a          Collaboration that reports on activity and uptake of Cochrane\u000a          systematic reviews.\u000a\u000a      http:\/\/www.efccna.org\/index.php?option=com_content&view=article&id=164:efccna-position-statement-on-the-nurses-role-in-weaning-from-ventilation-released&catid=3:news&Itemid=2\u000a      Benbenishty J et al. Weaning from mechanical ventilation. Guidelines\u000a        of the Israeli Society of Cardiac and ICU nurses. Israeli Nurse\u000a          Journal 2013; 91: 30-32\u000a      http:\/\/www.saferhealthcarenow.ca\/en\/interventions\/vap\/pages\/default.aspx\u000a    \u000a    ","Title":"\u000a    Protocols that assist clinicians to wean critically ill patients from\u000a      mechanical ventilation in the intensive care unit (ICU)\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Mechanical ventilation is a high-cost and high-risk area of critical care\u000a      practice. Patients requiring prolonged mechanical ventilation account for\u000a      40% of ICU bed days and 50% of ICU costs. To reduce the substantial\u000a      complications and cost associated with protracted mechanical ventilation,\u000a      weaning strategies which enable safe and efficient discontinuation of\u000a      ventilator support are an international research priority and continue to\u000a      present a major clinical challenge.\u000a    Recognition of the importance of strategies for reducing the duration of\u000a      mechanical ventilation and thereby associated morbidity commenced in the\u000a      middle to late 1990s. Many trials investigating weaning strategies\u000a      involving trained multidisciplinary teams, protocols and automated weaning\u000a      systems have reported decreased duration of ventilation time as a result\u000a      of faster clinical decision-making. Delays occur due to inefficient\u000a      processes, clinician shortages, and staff workload. However, the first UK\u000a      trial by Blackwood [1] and her Canadian collaborator, Rose [2] suggest\u000a      that weaning protocols and automated weaning systems may increase, or not\u000a      alter, the duration of ventilation, possibly due to existing efficiencies\u000a      in weaning decision-making. These discordant findings have generated\u000a      uncertainty for intensive care clinicians considering potential\u000a      improvement strategies for weaning. The work of Blackwood with colleagues\u000a      from Queen's University Belfast and international collaborators\u000a      (University of Toronto; University of Amsterdam; Bangor University) has\u000a      focussed on synthesizing existing evidence on a range of weaning\u000a      strategies as well as exploring patient and caregiver perspectives and\u000a      international differences in ICU context relevant to weaning. This work\u000a      identified factors that contribute to weaning success, and to translating\u000a      this information for clinical application.\u000a    Blackwood and colleagues systematically reviewed research evidence for\u000a      protocolised weaning practice versus usual practice. Pooled data from a\u000a      meta-analysis of 11 trials [3] reported that protocolised weaning\u000a      significantly reduced the duration of mechanical ventilation by 25%,\u000a      weaning duration by 78% and length of ICU stay by 10%. Similarly, pooled\u000a      data from a meta-analysis of 15 trials [4] comparing automated weaning\u000a      systems to either usual care or a paper based protocol reported\u000a      significant reductions in the duration of mechanical ventilation (17%) and\u000a      weaning (32%) using an automated system. Despite positive findings for\u000a      written protocols and automated systems, there was significant,\u000a      unexplained inconsistency among study results indicating that protocolised\u000a      weaning may not produce beneficial effects in all ICUs.\u000a    Blackwood and colleagues highlighted the complex reasons why protocols\u000a      may be effective in some settings and not others. They described the\u000a      impact of social organisation and relationships of professional practice\u000a      such as staffing, multidisciplinary team working, professional\u000a      accountability, clinical experience, professional judgment and autonomy on\u000a      the weaning process [5, 6]. In summary, the research has provided a wide\u000a      perspective of factors influencing the weaning process. It has contributed\u000a      to clinical guideline development for the benefit of clinicians in\u000a      promoting early discontinuation from mechanical ventilation.\u000a    "},{"CaseStudyId":"38335","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    This research has had major commercial impact realised through the\u000d\u000a      establishment of PathXL Ltd., a highly successful company that has\u000d\u000a      translated the initial technology and its subsequent developments into\u000d\u000a      products with international appeal that impacts significantly on pathology\u000d\u000a      education, research and diagnostic practice. This is a genuine example of\u000d\u000a      technology transfer from an initial impact in cancer education\u000d\u000a      subsequently extending, through continued collaboration with university\u000d\u000a      researchers, to impact in pharmaceutical research and clinical practice.\u000d\u000a      The company's growth and operations have an important economic impact in\u000d\u000a      the UK. Impacts are therefore evidenced in each of these areas:\u000d\u000a    Successful commercialisation of IP and impact on pathology education\u000d\u000a      PathXL sold its technology to high profile customers such as Royal College\u000d\u000a      of Pathologists of Australasia (RCPA) to support digital educational\u000d\u000a      requirements and so generated significant revenue1. The\u000d\u000a      educational products InView™\/Simulator™ were so unique in their approach\u000d\u000a      that accreditation was granted by both RCPA (2004) for training resident\u000d\u000a      pathologists and the Royal College of Pathologists UK (2006) for continual\u000d\u000a      professional development. The RCPA2 said \"InView has proven\u000d\u000a        to be a cutting edge training tool that can be utilised within large and\u000d\u000a        small training laboratories\". Installation into private and\u000d\u000a      publically funded research laboratories in Australia (2004-5) was to\u000d\u000a      follow. In the UK, a number of pathology training schools adopted the\u000d\u000a      novel approach to pathology training including the Thames Histopathology\u000d\u000a      Training School (2006). Professor Simon Herrington, Secretary of the\u000d\u000a      Pathological Society3 said \"PathXL Simulator is an excellent\u000d\u000a        additional learning resource which complements the traditional methods\u000d\u000a        of teaching\". \"PathXL is an excellent development and provides a\u000d\u000a        very useful educational resource, particularly for pathologists in\u000d\u000a        training\". Professor Hazan Rizvi4 said \"Our main\u000d\u000a        problem was being able to share this programme with collaborators and\u000d\u000a        users. Having a web-based, easy to use interface makes this possible —\u000d\u000a        PathXL Tutor is the perfect solution\" giving the company credibility\u000d\u000a      in a professional marketplace.\u000d\u000a    Queen's developed technology for web-based viewing of large gigapixel\u000d\u000a      medical images transferred across to the company and resulted in\u000d\u000a      subsequent development of a sophisticated web-based image management\u000d\u000a      system for digital pathology — now called PathXL Tutor™. PathXL Tutor™,\u000d\u000a      became a general purpose platform for web based delivery, viewing and\u000d\u000a      reporting of digital slides for educational and research purposes and was\u000d\u000a      subsequently used to underpin undergraduate courses in several UK and\u000d\u000a      European Universities and to support professional organisations such as\u000d\u000a      the RCPA and Pathological Society of Great Britain and Ireland\u000d\u000a      (2006-2007). In addition, since 2008, the company supports the largest\u000d\u000a      pan-European competency test system for pathologists (2008-11) via the\u000d\u000a      European Association of Pathology Chairs. In total, over 6,000 trainee\u000d\u000a      pathologists have used and benefitted from PathXL software over the last\u000d\u000a      five years. Olympus are now distributing the PathXL educational solutions.\u000d\u000a    Expansion of market impact into pharmaceutical research, biomarker\u000d\u000a        imaging and clinical practice\u000d\u000a      In 2011, PathXL focussed increasingly on developing digital pathology\u000d\u000a      software for the R&D Biobank sector. Together with the Queen's\u000d\u000a      Northern Ireland Biobank, a new information management system was\u000d\u000a      developed to support donor recruitment, sample tracking, clinical\u000d\u000a      information handling and digital imaging to support high quality biosample\u000d\u000a      collections. PathXL Biobank software now supports other national\u000d\u000a      biobanking initiatives such as the Mesobank — a UK national multicentre\u000d\u000a      collection of mesothelioma samples. PathXL is also establishing a contract\u000d\u000a      for digital pathology services with a multinational contract research\u000d\u000a      organisation servicing some of the largest biopharmaceutical organisations\u000d\u000a      in the world.\u000d\u000a    Most excitingly during 2008-10, the Queen's group developed new methods\u000d\u000a      for the automated identification of cancer tissue from digital microscope\u000d\u000a      slides, using novel computer vision and image analysis techniques. This IP\u000d\u000a      was subsequently transferred to PathXL in 2011. Now in 2013, PathXL has\u000d\u000a      established a revolutionary new product called TissueMark™ aimed at\u000d\u000a      supporting modern tissue research and molecular pathology laboratories.\u000d\u000a      The methodology involves the automated identification of tumour based on\u000d\u000a      patent pending pattern recognition algorithms for macro-dissection and\u000d\u000a      tumour cell enrichment. This technology underpins the identification of\u000d\u000a      new molecular markers in cancer and can alleviate the current bottleneck\u000d\u000a      that inhibits high throughput molecular analysis of cancer tissue samples.\u000d\u000a      TissueMark™ is now being used by AstraZenica (UK) and Novataris (Boston,\u000d\u000a      USA).\u000d\u000a    Finally, PathXL has developed a Digital Pathology Management System for\u000d\u000a      small hospital laboratories to support increased adoption of digital\u000d\u000a      pathology for frozen section analysis, remote consultations and primary\u000d\u000a      diagnostics. This is now being used pathology laboratories in USA, UK and\u000d\u000a      Ireland. Digital pathology adoption is following the same trend as digital\u000d\u000a      radiology, but is about 10 years behind. They are implementing solutions\u000d\u000a      for a number of clinical laboratories and also partnering with CSC (major\u000d\u000a      provider of IT systems to hospitals) to provide digital pathology software\u000d\u000a      solutions for diagnostic pathology networks in UK. PathXL continues to\u000d\u000a      deliver new solutions to this expanding market.\u000d\u000a    Impact on local economy and international markets\u000d\u000a      PathXL Ltd is now seen as a leader in digital pathology solutions by\u000d\u000a      providing sophisticated web-based digital pathology solutions and Biobank\u000d\u000a      software that support workflows in research and diagnostic laboratories.\u000d\u000a      Unlike other vendors it is independent of scanner and image format and can\u000d\u000a      integrate easily with other third party platforms. PathXL has raised in\u000d\u000a      excess of £1.7m venture capital to grow its business and now employs a\u000d\u000a      strong team of 30 people, a majority of which are based in PathXL's head\u000d\u000a      office in Belfast. It is currently raising further capital to expand its\u000d\u000a      operations globally. The company has just appointed distributors on\u000d\u000a      Australia, Germany and Italy. In 2013, it opened an office in USA and\u000d\u000a      appointed a Head of Sales and Business development for North America. It\u000d\u000a      is selling its digital pathology solutions globally with over 30 key\u000d\u000a      account customers worldwide. Since venture-backed funding, its sales have\u000d\u000a      doubled year on year with expected turn-over in 2015 in excess of £4\u000d\u000a      million.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    PathXL Ltd is a digital pathology software company, founded by Queen's\u000d\u000a      researchers who successfully commercialised a novel technology for\u000d\u000a      objective evaluation of performance in cancer diagnostics and thereby\u000d\u000a      improved cancer pathology training. The company's products initially\u000d\u000a      revolutionized the professional training of young pathologists in the UK\u000d\u000a      and Australia. Now products extend to software for tissue biomarker\u000d\u000a      development, stratified medicine and biobanking. PathXL Ltd has raised\u000d\u000a      significant venture capital funding to expand its business growing from 2\u000d\u000a      to 30 people and is now selling a range of world leading digital pathology\u000d\u000a      products for education, biopharmaceutical and diagnostic research and\u000d\u000a      clinical practice across the world.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    Queen's University Belfast\u000d\u000a    ","Institutions":[{"AlternativeName":"Queen's University Belfast","InstitutionName":"Queen's University Belfast","PeerGroup":"A","Region":"Northern Ireland","UKPRN":10005343}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4930956","Name":"Boston"}],"References":"\u000d\u000a    \u000a1. Hamilton PW, Anderson N, Bartels PH, Thompson D. Expert system\u000d\u000a      support using Bayesian belief networks in the diagnosis of breast fine\u000d\u000a      needle aspiration biopsy specimens of the breast. J Clinical Pathology\u000d\u000a      1994;47:329-336. doi: 10.1136\/jcp.47.4.329\u000d\u000a      This paper showed for the first time how mathematical algorithms\u000d\u000a          could be used to represent breast cancer diagnosis and how software\u000d\u000a          could be developed to support diagnostic decision making in breast\u000d\u000a          cytology\u000d\u000a    \u000a\u000a2. Hamilton PW, Bartels PH, Montironi R, Anderson N, Thompson D.\u000d\u000a      Improved diagnostic decision making in pathology. Do inference networks\u000d\u000a      hold the key? J Pathology 1995;175:1-5. doi: 10.1002\/path.1711750102\u000d\u000a      This paper laid down the principles for developing and adopting the\u000d\u000a          technology in pathology — aimed at demonstrating to practicing\u000d\u000a          pathologists through a mainstream high impact pathology journal the\u000d\u000a          benefits of computer-based systems in pathology\u000d\u000a    \u000a\u000a3. Montironi R, Bartels PH, Thompson D, Scarpelli M, Hamilton PW.\u000d\u000a      Prostatic intraepithelial neoplasia (PIN). Performance of Bayesian belief\u000d\u000a      network for diagnosis and grading. J Pathology 1995;177:153-162. doi:\u000d\u000a      10.1002\/path.1711770209\u000d\u000a      This paper developed previous ideas but applying the technology to\u000d\u000a          tissue histology to support diagnosis and grading of early neoplasia\u000d\u000a          in the prostate.\u000d\u000a    \u000a\u000a4. ML Morrison, WG McCluggage, G Price, J\u000d\u000a        Diamond, MRM. Sheeran, KM Mulholland, MY Walsh, R Montironi, PH\u000d\u000a      Bartels, D Thompson, PW Hamilton. Expert System Support Using A\u000d\u000a      Bayesian Belief Network For The Classification Of Endometrial Hyperplasia.\u000d\u000a      J Pathology 2002;197:403-414. doi: 10.1002\/path.1135\u000d\u000a      This paper further extended our work, showing clear advantages of\u000d\u000a          our technology in difficult diagnostic areas such as endometrial\u000d\u000a          pathology. This paper was awarded the best bioinformatics paper of the\u000d\u000a          year and republished in Int J Medical Informatics\u000d\u000a    \u000a\u000a5. Diamond J, Anderson NH, Thompson D, Bartels PH,\u000d\u000a      Hamilton PW. A computer-based training system for breast fine\u000d\u000a      needle aspiration cytology. J Pathology 2002;196:113-121. doi:\u000d\u000a      10.1002\/path.1012\u000d\u000a      This paper was the first to integrate the novel technology into a\u000d\u000a          virtual training environment for breast cancer cytology\u000d\u000a    \u000a\u000a6. Yinhai Wang, David McCleary, Ching-Wei Wang, Paul Kelly, Jackie\u000d\u000a        James, Dean A. Fennell and Peter Hamilton Ultra-fast Processing of\u000d\u000a      Gigapixel Tissue MicroArray Images using High Performance Computing.\u000d\u000a      Cellular oncology 2010; 32: 181-181.\u000d\u000a      Example of one paper estending digital pathology technology\u000d\u000a          development for high throughput tissue microarray image analysis for\u000d\u000a          biomarker discovery and translational research\u000d\u000a    \u000aGrants supporting the initial research:\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Ulster\u000d\u000a              Cancer Foundation Research Grant 1993-1996\u000d\u000a          £80,000\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Development of Bayesian belief network for decision support in breast\u000d\u000a      fine needle aspiration cytology\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          DENI Smart\u000d\u000a              Award 1998\u000d\u000a          £40,000\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Development of decision support system for breast cancer\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Medical\u000d\u000a              Research Council 1998\u000d\u000a           £170,000\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Automated machine vision for the histopathological diagnosis and grading\u000d\u000a      of prostate neoplasia\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          UK Broadband Fund 2004\u000d\u000a          £60,000\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    e-Learning and decision support for Diagnostic Pathology\u000d\u000a    More recent grants supporting academic\u000d\u000a        development of theme:\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          DEL All\u000d\u000a              Ireland Strengthening Award 2011\u000d\u000a          £1.2m\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Bioinformatics\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Marie Curie\u000d\u000a              FP7 Grant 2012\u000d\u000a          £1.9m\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Fast-Path: Fast-Tracking Pathology via Automated Image Analysis and\u000d\u000a      High-Performance Computing: Application to Prostate Cancer Diagnostics\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          \u000aInvest Northern Ireland R&D Collaborative grant\u000d\u000a            (Queen’s, PathXL, Almac Diagnostics)\u000d\u000a          £2.1m\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Predictive Biomarker Discovery and Development Program\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"8","Level2":"1","Subject":"Artificial Intelligence and Image Processing"},{"Level1":"1","Level2":"4","Subject":"Statistics"},{"Level1":"8","Level2":"6","Subject":"Information Systems"}],"Sources":"\u000d\u000a    \u000d\u000a      http:\/\/www.rcpa.edu.au\/static\/File\/Asset%20library\/PathWay\/Other\/13a.pdf\u000d\u000a      http:\/\/www.pathxl.com\/files\/casestudies\/cs_PathXLsimulator.pdf\u000d\u000a      http:\/\/www.pathxl.com\/files\/casestudies\/cs_PathXLtutor.pdf\u000d\u000a      http:\/\/www.pathxl.com\/files\/casestudies\/cs_tma02.pdf\u000d\u000a      PathXL Website: www.pathxl.com\u000a\u000d\u000a      PathXL investment deal of the month:\u000d\u000a        http:\/\/www.crescentcapital.co.uk\/2013\/01\/03\/pathxl-investment-clinches-deal-of-the-month\/\u000a\u000d\u000a      Seven figure sum investment in PathXL: http:\/\/www.insidermedia.com\/insider\/ireland\/82196-seven-figure-sum-investment-pathxl\u000a\u000d\u000a      Frost & Sullivan Award Enabling Technology Award\u000d\u000a        http:\/\/www.frost.com\/prod\/servlet\/press-release.pag?docid=258395100\u000a\u000d\u000a      PathXL winner in Deloitte Fast50 Companies\u000d\u000a        http:\/\/www.newswiretoday.com\/news\/120815\/PathXL_Shortlisted_for_The_Deloitte_Technology_Fast_50\/\u000a\u000d\u000a      PathXL and Olympus work together\u000d\u000a        http:\/\/www.newswiretoday.com\/news\/113467\/\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Successful Commercial Exploitation of Digital Pathology for Cancer\u000d\u000a      Education, Biomarker Discovery and Clinical Diagnosis\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2655984","Name":"Belfast"}],"UKRegion":[{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Research, led by Peter Hamilton who is Professor of Bioimaging &\u000d\u000a      Informatics at Queen's (since 2002) focused on the development of Bayesian\u000d\u000a      Belief Networks — a mathematical method that can be used to represent\u000d\u000a      knowledge — and its use in decision making in medicine. The work aimed to\u000d\u000a      \"capture\" the expert knowledge and decision making processes used by\u000d\u000a      skilled pathologists in cancer diagnosis, and integrate this with a range\u000d\u000a      of other knowledge management and computer-based representation techniques\u000d\u000a      to establish a computer programme for use in the routine pathological\u000d\u000a      diagnosis of cancer tissue samples. There is a growing trend to use\u000d\u000a      digital image analysis and to capture diagnostic data using algorithms in\u000d\u000a      order to make image interpretation more objective and improve the\u000d\u000a      judgments made by experts. Hamilton and his colleagues established how a\u000d\u000a      simple relational network, the careful representation of diagnostic clues\u000d\u000a      and the definition of the weights associated with these diagnostic clues\u000d\u000a      could be used to represent most diagnostic problems in pathology1,2,3.\u000d\u000a      In addition, they developed a completely novel means by which to\u000d\u000a      objectively map the diagnostic process using cumulative probability\u000d\u000a      calculations, which the team called diagnostic decision maps. This had\u000d\u000a      never before been used in cancer pathology decision making. These new\u000d\u000a      technologies provided the basis for comparing performance and diagnostic\u000d\u000a      precision between different pathologists and allowed subsequent research\u000d\u000a      on performance variation, training modalities and skill acquisition in\u000d\u000a      cancer pathology4,5. This unique approach to studying\u000d\u000a      diagnostic decision making was subsequently enhanced by integrating it\u000d\u000a      with representative digital image libraries and using \"fuzzy logic\" (at\u000d\u000a      that time a novel mathematical approach to representing human language) to\u000d\u000a      transfer the skills used in cancer diagnosis to a computer program3,5.\u000d\u000a      Together with digital whole slide scans of cancer samples, it was used to\u000d\u000a      create a comprehensive virtual computer training environment for\u000d\u000a      pathologists. The management and viewing of whole slide images is common\u000d\u000a      today — but in early 2000 the Queen's team were the first to develop\u000d\u000a      specialist software for viewing virtual slides and integrate them within\u000d\u000a      bespoke educational software to construct comprehensive digital slide sets\u000d\u000a      across a range of diagnostic problems and deliver these as part of a\u000d\u000a      web-based virtual learning environment for training, quality assurance and\u000d\u000a      skill acquisition in cancer pathology5. The virtual learning\u000d\u000a      software was developed and tested across a range of diagnostic problems\u000d\u000a      including breast cytopathology, endometrial hyperplasia and cervical\u000d\u000a      intraepithelial neoplasia, demonstrating distinct benefits and enhancement\u000d\u000a      to decision making and training. This work was published extensively in\u000d\u000a      higher impact pathology-focussed journals 1-5 where the\u000d\u000a      greatest impact would be achieved and was extended to other advanced areas\u000d\u000a      of tissue imaging6. Various aspects of the research were\u000d\u000a      carried out in collaboration with colleagues at Queen's and with Peter\u000d\u000a      Bartels (University of Arizona, USA) and Rodolfo Montironi (University of\u000d\u000a      Ancona, Italy).\u000d\u000a    This research led to the development of a commercial spin-out company\u000d\u000a      from Queen's called originally i-Path Diagnostics Ltd and later after a\u000d\u000a      relaunch and expansion in 2012 named PathXL Ltd. The company quickly\u000d\u000a      generated revenue, seed funding followed by venture capital and now has a\u000d\u000a      team of over 30 people working in non-university purpose-built offices and\u000d\u000a      labs.\u000d\u000a    "},{"CaseStudyId":"38778","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2963597","Name":"Ireland"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Critical congenital heart defects are an extremely serious issue for\u000d\u000a      newborns, affecting around\u000d\u000a      1600 cases annually in the UK alone. Up to one third of these are not\u000d\u000a      detected in basic hospital\u000d\u000a      screening practices, and these babies are at significant risk of serious\u000d\u000a      health complications and\u000d\u000a      death. Through a portfolio of interlinked clinical and theoretical\u000d\u000a      studies, Dr Ewer's work has\u000d\u000a      provided extensive evidence of the clear benefits of pulse oximetry\u000d\u000a      screening, and this has had\u000d\u000a      major impacts on international policy and practice, as well as directly\u000d\u000a      for children and their parents\u000d\u000a      where the test has been implemented as a result. This research was\u000d\u000a      described in a Lancet editorial\u000d\u000a      as 'a new milestone in the history of congenital heart disease' [1].\u000d\u000a    Impact on international policy\u000d\u000a      The Lancet paper (2011) and subsequent HTA report (2012) received\u000d\u000a      considerable international\u000d\u000a      media attention and Dr Ewer has subsequently been invited to advise\u000d\u000a      international policy makers\u000d\u000a      considering the implementation of PulseOx screening.\u000d\u000a    \u000d\u000a      In 2011 Dr Ewer was invited as advisor to a working group of the\u000d\u000a        Secretary's Advisory\u000d\u000a        Committee on Heritable Diseases in Newborns' and Children (SACHDNC) in\u000d\u000a        Washington,\u000d\u000a        USA. Following this meeting the group advocated the introduction of\u000d\u000a        pulse oximetry screening,\u000d\u000a        endorsed by the American Academy of Paediatrics, American Heart\u000d\u000a        Association and American\u000d\u000a        College of Cardiology [2]. As a direct result, the US Secretary for\u000d\u000a        Health and Human Services\u000d\u000a        recommended the addition of pulse oximetry screening for CCHD across the\u000d\u000a        US [3]. Thesenior\u000d\u000a        cardiologist leading the SACHDNC group described Dr Ewer's study as\u000d\u000a        having better design,\u000d\u000a        appropriate reference and clarity of cardiac defect definition which\u000d\u000a        meant that `his data were\u000d\u000a          instrumental in creating [the] recommendations' [4], and that his\u000d\u000a        work \"tipped the balance of\u000d\u000a          evidence towards universal screening in the U.S.A\" [5].\u000d\u000a      Dr Ewer recently advised Michigan State, and 7 states in the US are\u000d\u000a        currently performing\u000d\u000a        routine screening. The majority of states are making progress towards\u000d\u000a        universal screening [6]\u000d\u000a      Following a keynote lecture by Dr Ewer in Sydney, Australia, a\u000d\u000a        state-wide PulseOx screening\u000d\u000a        policy is being developed.\u000d\u000a      Dr Ewer is currently advising Leiden University Medical Centre on a\u000d\u000a        pilot study to assess the\u000d\u000a        feasibility of implementing the pulse oximetry screening in the\u000d\u000a        Netherlands\u000d\u000a      Following a workshop on pulse oximetry screening in Beijing China in\u000d\u000a        April 2013, including key\u000d\u000a        representatives of Chinese national and regional screening committees,\u000d\u000a        the President of the\u000d\u000a        Children's Hospital of Fudan University, wrote to highlight that Dr\u000d\u000a        Ewer's \"own advocacy role\u000d\u000a          has been crucial in convincing my organisation of the importance of\u000d\u000a          this technique in identifying\u000d\u000a          cardiac defects and saving lives\", and that based on his work \"my\u000d\u000a          team has been working on a\u000d\u000a          similar screening project... which is showing encouraging outcome for\u000d\u000a          those newborn babies\u000d\u000a          with severe congenital heart diseases\".[7]\u000d\u000a      The Vice-President of both Union of European Neonatal & Perinatal\u000d\u000a        Societies and the World\u000d\u000a        Association of Perinatal Medicine commented that Dr Ewer's work \"has\u000d\u000a          been fundamental in\u000d\u000a          prompting hospitals and policymakers internationally to consider\u000d\u000a          adoption of this technique into\u000d\u000a          routine clinical practice\". He also noted on behalf of the Spanish\u000d\u000a        Society of Neonatology that Dr\u000d\u000a        Ewer's role has been \"crucial in preparing the proposal of a\u000d\u000a          national neonatal screening\u000d\u000a          recommendation... Our ongoing dialogue has already resulted in\u000d\u000a          preparing a national guideline\u000d\u000a          for Congenital Cardiac Disease Screening programme.\"[8]\u000d\u000a      The research was described in 2012 by the Irish Health Service\u000d\u000a        Executive and Royal College\u000d\u000a        of Physicians in Ireland as seminal research that \"should be\u000d\u000a          undertaken in all Units across the\u000d\u000a          country\", as it was at that time only used in 6 of the 19 units\u000d\u000a        [9]\u000d\u000a    \u000d\u000a    Impact on UK practice and policymakers\u000d\u000a      In 2010 a national survey found that only 7% of UK neonatal units\u000d\u000a      undertook routine pulse oximetry\u000d\u000a      screening. A survey of 204 units in 2012 [10] indicated significant\u000d\u000a      improvement, with almost 20% of\u000d\u000a      units now utilising pulse oximetry routinely. In units which were not\u000d\u000a      screening, 70% were actively\u000d\u000a      considering it, clearly indicating a nationwide shift of opinion among UK\u000d\u000a      neonatologists about pulse\u000d\u000a      oximetry screening in their local units, with a substantial majority now\u000d\u000a      in favour.\u000d\u000a    Birmingham Women's Hospital adopted pulse oximetry screening under the\u000d\u000a      guidance of Dr Ewer.\u000d\u000a      Over a 3 year period (2010-13) there were 187 admissions as a result of an\u000d\u000a      abnormal screening\u000d\u000a      test. This equates to approximately 60\/year, just over one admission per\u000d\u000a      week or 0.8% of all births.\u000d\u000a      Of the 187 babies admitted 7 had a CCHD which had not been previously\u000d\u000a      suspected. In addition, 5\u000d\u000a      other babies had a non-critical congenital heart defect which had not been\u000d\u000a      suspected. Importantly,\u000d\u000a      of the 180 babies which did not have critical congenital heart defects,\u000d\u000a      many other serious health\u000d\u000a      conditions (including congenital pneumonia, sepsis, and pulmonary\u000d\u000a      hypertension) were identified\u000d\u000a      as a result of pulse oximetry screening, and in fact only 36\/180 (20%) of\u000d\u000a      admitted babies had no\u000d\u000a      serious health issues. This highlights important additional benefits for\u000d\u000a      pulse oximetry screening\u000d\u000a      beyond increasing identification of CCHDs.\u000d\u000a    Dr Ewer has also been actively involved in shifting opinion in the\u000d\u000a      central decision-making unit for\u000d\u000a      national screening programmes. The National Screening Committee (NSC)\u000d\u000a      advises Ministers and\u000d\u000a      the NHS in the UK on all aspects of screening, and supports implementation\u000d\u000a      of screening\u000d\u000a      programmes. Using research evidence, pilot programmes and economic\u000d\u000a      evaluation, it assesses\u000d\u000a      evidence for programmes against a set of internationally recognised\u000d\u000a      criteria covering the condition,\u000d\u000a      the test, the treatment options and the effectiveness and acceptability of\u000d\u000a      the screening programme.\u000d\u000a      Dr Ewer has been the key clinician involved in extensive discussions\u000d\u000a      advising the Newborn and\u000d\u000a      Infant Physical Examination (NIPE) programme within the NSC regarding\u000d\u000a      possible implementation\u000d\u000a      of pulse oximetry screening in the UK. This has resulted in a UK public\u000d\u000a      consultation on `Screening\u000d\u000a      for Congenital Heart Defects', which highlights that `There is now\u000d\u000a        considerable research evidence\u000d\u000a        to demonstrate that pulse oximetry... increases the detection rate of\u000d\u000a        critical or life-threatening\u000d\u000a        CHDs at the newborn screening opportunity' and that `Routine\u000d\u000a        pulse oximetry is probably the most\u000d\u000a        promising additional newborn screening modality' under\u000d\u000a      consideration, for which Dr Ewer's work\u000d\u000a      provides the bulk of the underpinning evidence and rationale [11]. The\u000d\u000a      Director, Population Health\u000d\u000a      Science, Public Health England wrote in support of Dr Ewer's role in\u000d\u000a      triggering the NSC debate\u000d\u000a      and further commented \"Without doubt the work that you led and the\u000d\u000a        team research output has\u000d\u000a        already led to considerable debate and change in the whole approach to\u000d\u000a        ante natal and newborn\u000d\u000a        screening, its value, culture and practice.\"[12]\u000d\u000a    International campaign groups\u000d\u000a      A key ongoing impact of this work has been its use by lobbying groups, who\u000d\u000a      have been very quick\u000d\u000a      to recognise the benefits of pulse oximetry for screening newborns and are\u000d\u000a      campaigning for its\u000d\u000a      routine use in national practice. These groups all cite Dr Ewer's PulseOx\u000d\u000a      study as the most\u000d\u000a      important piece of evidence for their campaigns, and many national\u000d\u000a      charities such as the\u000d\u000a      Children's Heart Foundation, Little Hearts Matter, and Tiny Tickers have\u000d\u000a      outlined their gratitude for\u000d\u000a      the credence that Dr Ewer's work has given to their lobbying efforts with\u000d\u000a      NIPE and collaboration\u000d\u000a      with other congenital heart charities. In particular, the Children's Heart\u000d\u000a      Foundation have provided a\u000d\u000a      letter of support stating that:\"The extensive and compelling research\u000d\u000a        from Dr Ewer into the\u000d\u000a        effectiveness of Pulse Oximetry testing in detecting congenital cardiac\u000d\u000a        conditions has been crucial\u000d\u000a        to our understanding and work around the issue. It has allowed us to\u000d\u000a        strongly make the case that\u000d\u000a        this test should be introduced for newborns in the UK.\"[13]\u000d\u000a    Internationally, campaign groups also commonly recognise the value of Dr\u000d\u000a      Ewer's work, including\u000d\u000a      http:\/\/pulseoxadvocacy.com\/research\/,a\u000d\u000a      US site to support parents to lobby for the use of pulse\u000d\u000a      oximetry, which cites the PulseOx study as one of \"the most compelling\u000d\u000a      pieces of evidence\" that\u000d\u000a      \"should be part of any advocacy work\".\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Congenital heart defects are a leading cause of infant death, accounting\u000d\u000a      for more deaths than any\u000d\u000a      other type of malformation and up to 7.5% of all infant deaths. Timely\u000d\u000a      diagnosis is crucial for the\u000d\u000a      best possible outcome for these children. However, the accuracy of current\u000d\u000a      methods for screening\u000d\u000a      for critical congenital heart defects (CCHD) before birth is variable and\u000d\u000a      currently only detects these\u000d\u000a      defects in between 35-50% of cases. Although around a third of remaining\u000d\u000a      cases are picked up\u000d\u000a      after birth, up to a third of children with a CCHD are sent home, where\u000d\u000a      they may become unwell or\u000d\u000a      die. Research led by Dr Andrew Ewer at the University of Birmingham has\u000d\u000a      demonstrated that pulse\u000d\u000a      oximetry is a rapid, safe, non-invasive, painless method of detecting the\u000d\u000a      low blood oxygen levels\u000d\u000a      associated with CCHD, and is also a cost-effective approach. As a result\u000d\u000a      of Dr Ewer's research,\u000d\u000a      Pulse Ox was recommended for adoption across the US in 2011 by the\u000d\u000a      Secretary for Health and\u000d\u000a      Human Services, and Dr Ewer has been instrumental in this screening\u000d\u000a      approach being taken up\u000d\u000a      worldwide. This research prompted a national UK review of screening for\u000d\u000a      these conditions.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2147714","Name":"Sydney"}],"References":"\u000d\u000a    \u000a1. Thangaratinam S, Daniels J, Ewer AK, Zamora J, Khan KS. Accuracy of\u000d\u000a      pulse oximetry in\u000d\u000a      screening for congenital heart disease in asymptomatic newborns: A\u000d\u000a      systematic review.\u000d\u000a      Archives of Disease in Childhood: Fetal and Neonatal Edition\u000d\u000a      2007;92(3):F176-F180.\u000d\u000a      http:\/\/dx.doi.org\/10.1136%2Fadc.2006.107656\u000d\u000a    \u000a\u000a2. Ewer AK, Middleton LJ, Furmston AT, Bhoyar A, Daniels JP,\u000d\u000a      Thangaratinam Set al. Pulse\u000d\u000a      oximetry as a screening test for congenital heart defects in newborn\u000d\u000a      infants (PulseOx): a test\u000d\u000a      accuracy study. Lancet 2011; 378(9793): 785-94. Epub 2011 Aug 4doi:\u000d\u000a        10.1016\/S0140-6736(11)60753-8\u000d\u000a        In REF2\u000d\u000a    \u000a\u000a3. Ewer AK, Furmston AT, Middleton LJ, Deeks JJ, Daniels JP, Pattison HM\u000d\u000a      et al. Pulse oximetry\u000d\u000a      as a screening test for congenital heart defects in newborn infants: a\u000d\u000a      test accuracy study with\u000d\u000a      evaluation of acceptability and cost-effectiveness. Health Technol Assess\u000d\u000a      2012; 16(2):1-184.\u000d\u000a      doi: 10.3310\/hta16020 In REF2\u000d\u000a    \u000a\u000a4. Roberts TE, BartonP, Auguste P, Middleton LJ, Furmston AT, Ewer\u000d\u000a      AK. Pulse oximetry as a\u000d\u000a      screening test for congenital heart disease in newborn infants: a cost\u000d\u000a      effectiveness analysis.\u000d\u000a      Archives of Disease in Childhood 2012 ; 97(3) : 221-226. doi:10.1136\/archdischild-2011-300564\u000d\u000a      In REF2\u000d\u000a    \u000a\u000a5. Thangaratinam S, Brown K, Zamora J, Khan KS, EwerAK. Pulse\u000d\u000a      oximetry screening for critical\u000d\u000a      congenital heart defects (CCHD) in asymptomatic newborns: A systematic\u000d\u000a      review and meta-analysis\u000d\u000a      involving 229 421 babies. Lancet 2012 ; 379 (9835): 2459-2464 DOI\u000d\u000a        10.1016\/S0140-6736(12)60107-X In REF 2\u000d\u000a    \u000a\u000a6. Powell R, Pattison HM, Bhoyar A, Furmston AT, Middleton LJ, Daniels JP\u000d\u000a      et al. Pulse oximetry\u000d\u000a      as a screening test for congenital heart defects in newborn infants: An\u000d\u000a      evaluation of\u000d\u000a      acceptability to mothers. Archives of Disease in Childhood 2013;98:F59-63.\u000d\u000a      DOI\u000d\u000a        10.1136\/fetalneonatal-2011-301225\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000d\u000a    \u000d\u000a      A new milestone in the history of congenital heart disease. Lancet.\u000d\u000a        2012 Jun\u000d\u000a        30;379(9835):2401. doi: 10.1016\/S0140-6736(12)61045-9. PMID: 22748572\u000d\u000a      Kemper AR, et al. Strategies for Implementing Screening for Critical\u000d\u000a        Congenital Heart Disease\u000d\u000a        Pediatrics 2011:128:e1259-e1267 http:\/\/pediatrics.aappublications.org\/content\/128\/5\/e1259.full\u000a\u000d\u000a      U.S.\u000d\u000a          Health & Human Services Makes Critical Congenital Heart Defect\u000d\u000a          Screening Using\u000d\u000a          Motion-Tolerant Pulse Oximetry a Nationwide Newborn Screening\u000d\u000a          Standard. PR Newswire 23\u000d\u000a          September 2011.\u000d\u000a      Sensitivity of pulse oximetry for detection of critical congenital\u000d\u000a        heart defects in newborn infants\u000d\u000a        higher than that of antenatal ultrasound with few false positives.\u000d\u000a        Martin GR, Bradshaw EA.\u000d\u000a        Evid Based Med. 2012 Apr;17(2):57-8. doi: 10.1136\/ebmed-2011-100290.\u000d\u000a        Epub 2011 Nov 28.\u000d\u000a      Letter of support from the Senior Vice President Center for Heart,\u000d\u000a        Lung and Kidney Disease,\u000d\u000a        Children's National Medical Center.\u000d\u000a      Screening Map: http:\/\/cchdscreeningmap.org\/\u000a\u000d\u000a      Letter of support from President of Children's Hospital of Fudan\u000d\u000a        University\u000d\u000a      Letter of support from Vice-President World Association of Perinatal\u000d\u000a        Medicine\u000d\u000a      Health Services Executive, Royal College of Physicians in Ireland.\u000d\u000a        Pulse oximetry testing for\u000d\u000a        newborn congenital heart disease. 2011\u000d\u000a      Singh A, Ewer AK. Pulse oximetry screening for critical congenital\u000d\u000a        heart defects: a UK national\u000d\u000a        survey. Lancet 2013;381:535. doi:10.1016\/S0140-6736(13)60278-0\u000a\u000d\u000a      Screening for Congenital Heart Defects, External review against\u000d\u000a        programme appraisal criteria\u000d\u000a        for the UK NSC. September 2013http:\/\/www.screening.nhs.uk\/congenitalheartdisease\u000a\u000d\u000a      Letter of support from Director of Population Health Science, Public\u000d\u000a        Health England.\u000d\u000a      Letter of support from Children's Heart Foundation\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Pulse Oximetry screening to detect heart disease in newborn babies\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Congenital heart defects (i.e. structural abnormalities existing at birth\u000d\u000a      or during pregnancy) are the\u000d\u000a      most common group of congenital malformations, accounting for 40% of all\u000d\u000a      deaths from congenital\u000d\u000a      malformations. These defects are a leading cause of infant deaths in the\u000d\u000a      developed world, with\u000d\u000a      most deaths occurring in the first year of life. Critical\u000d\u000a      congenital heart defects (CCHD) occur in\u000d\u000a      around 2\/1000 babies, and are most likely to cause death. If they are not\u000d\u000a      detected early, risk of\u000d\u000a      circulatory collapse is increased, and although surgery can greatly\u000d\u000a      improve survival, poor condition\u000d\u000a      at presentation increases surgical mortality — hence timely diagnosis is\u000d\u000a      crucial for the best outcome\u000d\u000a      for these children. However, the accuracy of current methods for detecting\u000d\u000a      CCHD is variable and\u000d\u000a      only 35-50% of affected babies are identified before birth. Defects may be\u000d\u000a      identified after birth,\u000d\u000a      however around a third of babies with these potentially life-threatening\u000d\u000a      defects in their hearts are\u000d\u000a      discharged from hospital before diagnosis.\u000d\u000a    Blood oxygen levels are often low in CCHD. Pulse oximetry is a\u000d\u000a      non-invasive method of measuring\u000d\u000a      blood oxygen levels by placing a sensor on part of the patient's body.\u000d\u000a      Although the technique itself\u000d\u000a      was developed in the 1980s, and explored for CCHD identification in the\u000d\u000a      2000s, the results were\u000d\u000a      inconclusive. Dr Andrew Ewer, Reader in Neonatal Paediatrics and at the\u000d\u000a      University of Birmingham\u000d\u000a      since 1995, led a team which conducted a systematic review (i.e. an\u000d\u000a      exhaustive summary of all\u000d\u000a      available research focusing on the technique) published in 2007 [1] which\u000d\u000a      showed encouraging\u000d\u000a      results but highlighted the difficulties in assessing the accuracy of\u000d\u000a      pulse oximetry because of\u000d\u000a      methodological variations, and importantly the relatively low numbers of\u000d\u000a      patients studied. The\u000d\u000a      systematic review demonstrated a clear need for a larger, robust,\u000d\u000a      well-conducted study to confirm\u000d\u000a      the accuracy, acceptability and cost effectiveness of such a screening\u000d\u000a      test.\u000d\u000a    In 2007, the National Institute for Health Research funded the PulseOx\u000d\u000a      study (NIHR HTA, £947k\u000d\u000a      2007-10, led by Ewer and run by the Birmingham Clinical Trials Unit). This\u000d\u000a      large, multi-centre study\u000d\u000a      assessed the accuracy of pulse oximetry for screening CCHDs in newborn\u000d\u000a      babies. It was the\u000d\u000a      largest UK study in this field, screening 20,055 newborn babies, and the\u000d\u000a      first to assess the added\u000d\u000a      value of pulse oximetry screening in modern healthcare systems where\u000d\u000a      antenatal ultrasound\u000d\u000a      screening was widely available. The study used robust methodology to\u000d\u000a      generate precise estimates\u000d\u000a      of the accuracy [2], cost-effectiveness and acceptability of pulse\u000d\u000a      oximetry and the value added to\u000d\u000a      existing screening [3]. These results demonstrated that the addition of\u000d\u000a      pulse oximetry screening to\u000d\u000a      existing screening tests resulted in 92% of babies with CCHDs being\u000d\u000a      detected prior to discharge.\u000d\u000a      In conclusion, the study found that pulse oximetry is a safe, feasible\u000d\u000a      (i.e. easy to undertake and\u000d\u000a      simple to adopt into routine practice) and acceptable test, complementing\u000d\u000a      and adding value to\u000d\u000a      existing screening where used in addition by identifying more issues at\u000d\u000a      birth. The results of this\u000d\u000a      study significantly enhanced available evidence indicating that pulse\u000d\u000a      oximetry screening could be\u000d\u000a      introduced as a routine procedure.\u000d\u000a    Dr Ewer's team also assessed the cost-effectiveness of utilising pulse\u000d\u000a      oximetry screening in\u000d\u000a      combination with clinical examination in the early detection of\u000d\u000a      potentially life-threatening CCHDs\u000d\u000a      [4]. They demonstrated that the technique would identify 30 additional\u000d\u000a      CCHD cases per 100,000\u000d\u000a      live births compared with routine clinical examination alone, with a very\u000d\u000a      high likelihood (over 90%)\u000d\u000a      that this would be regarded as `cost-effective', i.e. worth the extra\u000d\u000a      investment needed to identify\u000d\u000a      these cases. A further systematic review in 2012 by Dr Ewer's team\u000d\u000a      demonstrated that pulse\u000d\u000a      oximetry met the criteria for routine screening which are set by the\u000d\u000a      National Screening Committee\u000d\u000a      [5,6].\u000d\u000a    "},{"CaseStudyId":"38779","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1733045","Name":"Malaysia"},{"GeoNamesId":"798544","Name":"Poland"},{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"2963597","Name":"Ireland"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"597427","Name":"Lithuania"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d    Ataxia telangiectasia is a devastating disease that affects children from\u000d      a young age. The inherited nature of the disease has meant that advances\u000d      in our understanding of the underlying genetics has played a vital role in\u000d      diagnosis and effective assessment of risk of related conditions in these\u000d      patients, and it is here that the work of Professor Malcolm Taylor's\u000d      laboratory at the University of Birmingham has been vital over the past\u000d      two decades, and notably within the assessment period (when they have\u000d      confirmed 70 new diagnoses of ataxia telangiectasia in the British Isles).\u000d      The Taylor group has consistently worked towards defining how furthering\u000d      knowledge of the specific genetic mutations underlying A-T in each\u000d      individual patient can be put to use in advising the family on prognosis\u000d      and longer term outcomes.\u000d    A-T is not the only recessively inherited ataxia condition, with others\u000d      such as Friedreich's ataxia (a degenerative disease that primarily affects\u000d      the nervous system and the heart), spastic ataxia or abetalipoproteinemia\u000d      (which interferes with the normal absorption of fat and fat-soluble\u000d      vitamins from food) also occurring at a young age. These conditions need\u000d      differential diagnosis so that patients can be treated appropriately as\u000d      quickly as possible. Prof Taylor's team has been involved in identifying\u000d      ATM mutations since its discovery in the mid-1990s, and gained widespread\u000d      credibility as the laboratory that would confirm the increased sensitivity\u000d      of possible A-T patients' chromosomesto ionising radiation, one of the\u000d      hallmarks of the disease. Pediatricians, neurologists and immunologists\u000d      nationally and internationally send blood samples from their patients\u000d      direct to the Taylor laboratories in the University of Birmingham for\u000d      rapid results to help diagnose their patients, as directed by either the\u000d      A-T Society or the documentation relating to the UK NHS National\u000d      Specialised Commissioning Team relating to diagnosis and care in children\u000d      and adults [1-2]. Their laboratory techniques allow them to provide a\u000d      comprehensive cellular analysis of the effects of the ATM mutations in\u000d      each specific A-T patient, all of which is returned directly to the\u000d      patient's consultant to inform treatment. Originally, the gold standard\u000d      for confirmation of diagnosis of A-T had been simply the identification of\u000d      two pathogenic ATM mutations. Building on their research studies, the\u000d      Taylor group demonstrated a key clinical criteria was actually whether\u000d      protein was or was not expressed. The group's innovation in diagnosis was\u000d      to add to this test a cellular investigation when the mutations could be\u000d      classed as `leaky' (producing some normal ATM protein) or `missense'\u000d      mutation (producing some mutant ATM protein), and if protein is expressed\u000d      they also determine whether it has any functional activity. This provides\u000d      further information to the centres caring for these patients on whether\u000d      the clinical phenotype might be milder, which therefore helps inform\u000d        and improve their clinical management.\u000d    Their work in diagnosis informed the establishment and development from\u000d      2009 of a national A-T management service. Together with the AT Society of\u000d      the UK and Clinical Geneticists, Neurologists, Immunologists, Respiratory\u000d      Medicine, practitioners and others they have received National Specialised\u000d      Commissioning Team funding from April 1st 2009 to become the national A-T\u000d      diagnostic service for treatment [1], extended in 2012 to cover adults as\u000d      well as children [2]. This means that the Taylor laboratory is the\u000d        designated laboratory for confirmation of the diagnosis of AT across the\u000d        UK, and as part of differential diagnosis they are also the\u000d      designated laboratory for confirmation of the diagnosis of ataxia\u000d      telangiectasia like disorder (which they themselves had identified) and\u000d      oculomotor apraxia type 1. As outlined by the Consultant Clinical\u000d      Geneticist and Clinical Lead, National Paediatric Ataxia-Telangiectasia\u000d      Clinic \"the services provided by Professor Taylor are pivotal to the\u000d        work of the National Paediatric AT Clinic and the proper management of\u000d        patients with not just AT, but also ATLD and AOA1, as well as their\u000d        families. These services are not available through any NHS Molecular\u000d        Genetics Service Laboratory or through any other Research Group in the\u000d        UK or Ireland.\" [3]. They also offer this diagnostic service\u000d        internationally, and in the last three years have confirmed a total\u000d      of 30 new diagnoses for Belgium, Netherlands, Poland, Germany, Lithuania,\u000d      India, Sri-Lanka, and Malaysia for the genetic diagnosis of A-T. The\u000d      advanced genetic screening tests pioneered by this group are essential for\u000d      diagnosing the milder form of disease, and the genetic diagnosis directly\u000d      influences patient management, since it is only patients suffering from\u000d      A-T rather than the associated conditions who have increased risk of\u000d      cancer, and therefore need to be kept under lifelong surveillance for any\u000d      signs of a tumour, while others can be advised appropriately without the\u000d      added burden of concern.\u000d    The role of Prof Taylor's team as the key UK experts on A-T has driven\u000d      them to play an ongoing role in patient support. As the Chief\u000d      Executive of the Ataxia Telangiectasia Society states in his letter of\u000d      support from Prof Taylor's impact [4], \"Malcolm was responsible for\u000d        the first gathering of families affected by A-T in the UK. Working with\u000d        a parent, ..., they sent a letter to all the families known to Malcolm\u000d        at the time, inviting them to a meeting. From this meeting, the A-T\u000d        Society was born, and without Malcolm's ongoing and active support it\u000d        would not have survived and thrived in the way it has.\" The A-T\u000d      Society represents and looks after over 95% of those diagnosed with the\u000d      condition, currently supporting 152 people with A-T in the UK and also 12\u000d      in the Republic of Ireland. They credit this in large part to Prof\u000d      Taylor's contribution, stating \"The fact that the Society is in active\u000d        contact with so many people reflects both the fact that when carrying\u000d        out laboratory confirmation of diagnoses, Malcolm usually recommends\u000d        contact with the Society\". Furthermore, the supportive information\u000d      distributed to their worldwide audience reached through their website\u000d      (currently visited by over 1500 individual users a month), social media\u000d      and newsletters has relied heavily on significant input from Prof Taylor:\u000d      \"Malcolm was initially the provider of most of the Society's\u000d        information and still acts regularly as consultant on information\u000d        provision, the interpretation of research etc.\" Prof Taylor also\u000d      attends A-T clinics for both adults and children to meet families there\u000d      and discuss their diagnoses, outlook and support available, as well as\u000d      speaking at the A-T family weekend organised by the A-T Society every\u000d      year. This has made a major impact on patient experience of living with\u000d      their disease — as articulated in the letter of support from the A-T\u000d      Society: \"Malcolm's concern for those with or awaiting a diagnosis of\u000d        A-T is such that he goes out of his way to ensure that certainty be\u000d        given as quickly and in as effective a manner as possible. He follows\u000d        the lives of those he has diagnosed with interest and compassion and\u000d        frequently attends funerals. He is loved and admired by many across the\u000d        community of those living with A-T in the UK and Ireland.\"\u000d    Critically, the work of the Taylor group has also had a major role in\u000d        national policy. Their work demonstrated that absence of some\u000d      function in the ATM protein biasesthe development of cancer towards\u000d      non-lymphoid types in A-T patients, specifically toward breast cancer\u000d      development in surviving adults. This also confers an approximately\u000d      doubling of risk of breast cancer in ATM mutation carriers, and a\u000d      five-fold increase risk in ATM carriers under 50 years of age. As a direct\u000d      result of their work on breast cancer in A-T patients, from 2012 annual\u000d      MRI breast cancer screening is now offered to female AT patients from the\u000d      age of 25 years of age or from presentation (in milder cases of A-T). A\u000d      clinical genetics consultant and member of the Advisory Committee for\u000d      Breast Cancer Screening in England (ACBCS) reviewed evidence in 2007 and\u000d      2010 for breast surveillance in these groups to make recommendations that\u000d      fed directly into the decision and current guidance, and states that she \"relied\u000a        heavily on research work undertaken through the National Ataxia\u000d        Telangiectasia Clinic and in Malcolm Taylor's research laboratory\"\u000d      [5], going on to affirm that \"Professor Malcolm Taylor's experimental\u000d        work has provided evidence to explain many observations seen in clinical\u000d        practice. His collaboration with other groups has ensured that\u000d        epidemiological studies have been comprehensively achieved and, as his\u000d        laboratory undertakes ATM mutation testing in the United Kingdom,\u000d        provided the necessary molecular evidence to support these findings...\u000d        His work on Ataxia Telangiectasia is key to the continued progress and\u000d        understanding between the clinic and the laboratory.\"\u000d    As a result of this report, the national Cancer Screening Programme\u000d      recognised in 2012 that A-T heterozygotes (those with only one mutated\u000d      gene) should be included with women who had four times the average risk of\u000d      breast cancer (moderate increased risk), and that A-T homozygotes (those\u000d      with both genes mutated) should be included in the highest risk group for\u000d      breast cancer, and confirmed that both would receive appropriate screening\u000d      [6,7]. This obviously has major ramifications for the support and\u000d      potentially life-saving surveillance available to A-T patients and genetic\u000d      carriers of the mutation.\u000d    ","ImpactSummary":"\u000d    Ataxia telangiectasia (A-T) is an inherited disease affecting multiple\u000d      systems in the body, causing severe disability and death. Work led by\u000d      Professor Malcolm Taylor at the University of Birmingham has been central\u000d      to the biological and clinical understanding of this disease, from the\u000d      identification of the gene responsible to the clarification of related\u000d      conditions with different underlying causes. As a result of this work,\u000d      within the 2008-13 period, his laboratory has been designated the national\u000d      laboratory for clinical diagnosis of A-T — a service also offered\u000d      internationally — and has also changed national screening policy for\u000d      breast cancer, following his confirmation of the increased risks of A-T\u000d      patients and those who carry a single copy of the gene for this type of\u000d      tumour. Furthermore, he has contributed in a major way to patient support\u000d      for this condition.\u000d    ","ImpactType":"Health","Institution":"\u000d    University of Birmingham\u000d    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000d    \u000a1. McConville C M, Stankovic T, Byrd P J, McGuire GM, Yao, Q-Y, Lennox\u000d      GG, Taylor AMR. Mutations associated with variant phenotypes in\u000d      ataxia-telangiectasia. Am J Hum Genet 1996; 59:320-330.\u000d      (Grant, CR-UK Programme Grant 1993-1997) http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1914715\/\u000d    \u000a\u000a2. Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P,\u000d      Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor\u000a        AM. ATM mutations and phenotypes in ataxia-telangiectasia families\u000d      in the British Isles: expression of mutant ATM and the risk of leukemia,\u000d      lymphoma, and breast cancer. Am J Hum Genet 1998;62:\u000d      334-345. (Grant, CR-UK Programme Grant 1998-2002) http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1376883\u000d    \u000a3. Stewart GS, Last JIK, Stankovic T, Haites N, Kidd AMJ, Byrd PJ, Taylor\u000a        AMR. Residual Ataxia Telangiectasia Mutated Protein Function in\u000d      Cells from Ataxia Telangiectasia Patients, with 5762ins137 and 7271T>G\u000d      Mutations, Showing a Less Severe Phenotype J. Biol. Chem. 2001; 276:30133-30141.\u000a      (Grant, CR-UK Programme Grant 1998-2002) http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC11382771\u000d    \u000a4. Reiman A, Srinivasan V, Barone G, Last JI, G. Davies EG, Verhagen MMM,\u000d      WillemsenMAAP, WeemaesCMR, Byrd PJ, Izatt L, Easton DF, Thompson D, Taylor\u000a        AMR. Lymphoid tumours and breast cancer in ataxia telangeictasia;\u000d      substantial protective effect of residual ATM kinase activity against\u000d      childhood tumours. Br. J. Cancer 2011; 105: 586-591. doi:\u000d      10.1038\/bjc.2011.266. (Grant, CR-UK Programme Grant 2008-2012) http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3170966\u000d    \u000a\u000a5. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG,\u000d      Raams A, Byrd PJ, PetriniJH, &Taylor AM The DNA double-strand\u000d      break repair gene hMRE11 is mutated in individuals with an\u000d      ataxia-telangiectasia-like disorder. Cell 1999; 99,\u000d      577-587. (Grant, CR-UK Programme Grant 1998-2002) doi:10.1016\/S0092-8674(00)81547-0\u000d    \u000a\u000a6. Stewart GS, Stankovic T, Byrd PJ, Wechsler T, Miller ES, Huissoon A,\u000d      Drayson MT, West SC, Elledge SJ, Taylor AM. RIDDLE\u000a        immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA\u000d        damage signaling. ProcNatlAcadSci USA 2007 Oct 23;104(43):16910-5.\u000a      Epub 2007 Oct 16. (Grant, CR-UK Programme Grant 2003-2007) doi: 10.1073\/pnas.0708408104\u000d    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000d    \u000d      NHS National Specialised Commissioning Team: National\u000d        Ataxia-Telangiectasia Clinic (http:\/\/www.specialisedservices.nhs.uk\/library\/36\/Service_Specification_and_Standards___Ataxia_Telangiectasia_Service_1.pdf)\u000d      NHS National Specialised Commissioning Team: Multidisciplinary Service\u000d        for diagnosis and management of Ataxia-Telangiectasia in adults (http:\/\/www.specialisedservices.nhs.uk\/library\/36\/Service_Specification_and_Standards___Adult_Ataxia_Telangiectasia_Service.pdf)\u000d      Letter of support from Clinical Lead, National Paediatric\u000d        Ataxia-Telangiectasia Clinic\u000d      Letter of support from the Ataxia telangiectasia Society CEO\u000d      Letter from the Advisory Committee for Breast Cancer Screening in\u000d        England\u000d      Letter from Director of NHS Cancer Screening Programme\u000d      NHSBSP Publication no 74. Protocols for the surveillance of women at\u000d        higher risk of developing breast cancer:\u000d        http:www.cancerscreening.nhs.uk\/breastscreen\/publication\/nhsbsp74.html\u000a\u000d    \u000d    ","Title":"\u000d    Leading diagnosis, patient care and cancer screening policy in ataxia\u000d      telangiectasia\u000d    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    Ataxia telangiectasia (A-T) is a rare disease, inherited from a single\u000d      recessive gene (i.e. two faulty copies — not necessarily with the same\u000d      fault — are needed to cause the disease). It has an incidence of about 1\u000d      in 300,000. Ataxia telangiectasia is usually first noticed in toddlers by\u000d      the appearance of an unsteady gait (ataxia), reflecting brain degeneration\u000d      which typically heralds progressive neuromotor deterioration. This is\u000d      commonly coupled with severe deficiencies in the immune system, premature\u000d      ageing and a cellular sensitivity to ionising radiation. Patients usually\u000d      die during the second or early in the third decade of life.\u000d    A research team led by Professor Malcolm Taylor (Professor of Cancer\u000d      Genetics, at UoB since 1973) at the University of Birmingham has been\u000d      central in advances in understanding of this disease. In the early 1990s,\u000d      Prof Taylor was involved in mapping the location of the gene which causes\u000d      this disease more precisely, culminating with the identification of the\u000d      \"Ataxia Telangiectasia Mutated\" (ATM) gene in 1995. From this point, his\u000d      team were able to quickly start identifying specific ATM mutations in UK\u000d      ataxia telangiectasia patients (1, 2). Quite early on in 1996, his team\u000d      were able to detect an unusual group of more mildly affected patients in\u000d      the UK (1), all of whom expressed a low level of ATM protein with some\u000d      activity. We know now that in the UK ~33% of A-T patients have a milder\u000d      form of disease (3).\u000d    The interest of Prof Taylor's team has always been in the relationship\u000d      between the clinical presentation in A-T, the characteristics of the cells\u000d      in those patients, and the underlying specific mutation in the ATM gene.\u000d      In the case of A-T there is a good correlation between the genetic\u000d      characteristics of the cells (`genotype') and the physical characteristics\u000d      of these cells and the patient (`phenotype'). Prof Taylor's team have\u000d      demonstrated that typically where the protein produced from the mutant ATM\u000d      gene retains some ability to affect other proteins through a process known\u000d      as `phosphorylation' (termed `kinase' activity) then there is a better\u000d      clinical presentation, regardless of whether this is from normal or mutant\u000d      ATM protein (4, 5). This can be seen as a less severe immunodeficiency, a\u000d      later onset and slower progression of neurodegeneration, and at the\u000d      cellular level a smaller increase in sensitivity to ionising radiation, as\u000d      a result of some normal functioning of the ATM protein.\u000d    Importantly, the presence of ATM kinase activity also affects cancer\u000d      risk. This is one of the key areas in which Prof Taylor's team have\u000d      contributed to national and international understanding, demonstrating\u000d      that total loss of ATM protein is associated with an overwhelming\u000d      preponderance of lymphoid tumours in A-T patients under 16 years of age,\u000d      whereas the presence of residual ATM kinase activity protects against\u000d      these childhood lymphomas (3). However, they also showed that longer-lived\u000d      female A-T patients have a 45% risk of breast cancer by the age of 50,\u000d      higher than the equivalent risk in BRCA1 or BRCA2 mutation carriers, the\u000d      main mutant gene typically associated with this type of cancer (3).\u000d    Importantly, not all patients who appear clinically to have A-T have ATM\u000d      mutations. Another major role of Prof Taylor's team, and more recently by\u000d      the team led by Dr Grant Stewart (Reader in Cancer Genetics, at the\u000d      University since 2004), has been to identify the genetic abnormalities in\u000d      these patients which are causing their disease.They have identified some\u000d      \"ataxia telangiectasia-like\" patients that had a mutation in another gene,\u000d      MRE11 (6), known to be part of a group of proteins important in signalling\u000d      the initial response to DNA double strand breaks (Mre11\/Rad50\/Nbn).They\u000d      called this new disorder ataxia telangiectasia like disorder (ATLD). In\u000d      2002-2003 the team noted that a proportion of samples sent to them were\u000d      from patients who had a neurologically similar presentation as A-T and\u000d      ATLD. They identified these as ataxia oculomotor apraxia types 1 and 2,\u000d      with ages of onset in childhood and early teenage respectively. More\u000d      recently they also identified another radiosensitivity disorder, RIDDLE\u000d      syndrome (a primary immunodeficiency disorder), for which they discovered\u000d      the gene responsible, RNF168, in 2009.\u000d    "},{"CaseStudyId":"38780","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000a    The research described above resulted in the development of a real time\u000a      typing method for M. tuberculosis, which has resulted in a\u000a      nationwide change in the methodology used for typing of TB, significant\u000a      improvements to the national TB typing scheme and the management of TB\u000a      infections.\u000a    Delivery of a National Reference Standard\u000a    Prior to the outcomes from this research there was no prospect of\u000a      real-time high volume accurate typing being provided for English isolates\u000a      of M. tuberculosis. The UK National Reference Laboratories used a\u000a      complex, slow and unreliable technique, which only provided results on 75%\u000a      of strains which would then require re-typing using a second method,\u000a      followed by further analysis to identify specific strain types. The\u000a      research conducted by Professor Peter Hawkey at the University of\u000a      Birmingham resulted in a low cost, high volume dHPLC method, with new\u000a      primers and targets that provides real-time typing of M. tuberculosis.\u000a      The new typing method was fully implemented into clinical service at the\u000a      Birmingham National Reference Laboratories for Mycobacterium\u000a        tuberculosis, based at Heart of England NHS Foundation Trust in 2004\u000a      and continues to be used until the present day. As a result of the early\u000a      work completed by the National Reference Laboratory in Birmingham, where\u000a      all isolates were typed and which showed that unsuspected clusters of\u000a      cross-infection were occurring, the universal rapid MIRU-VNTR 24 locus\u000a      typing was recognised as a key component to enable the delivery of the\u000a      Chief Medical Officer's TB action plan [1], which was published in October\u000a      2004 and detailed that \"molecular strain typing of all M. tuberculosis\u000a      isolates and the establishment of a central database linking\u000a      epidemiological data is a key component of TB control\". Whilst the\u000a      publication of document is outside the period of assessment it provided\u000a      the necessary mandate for the other National Reference Laboratories\u000a      (London and Newcastle) to adopt the rapid typing technology developed by\u000a      Professor Peter Hawkey, this occurred fully in 2010.\u000a    Professor Hawkey was a member of the TB Diagnosis and Molecular\u000a      Epidemiology (DAME) Group in the HPA which was responsible for producing a\u000a      national strategy for TB diagnosis. The Chair of DAME, Prof Pete Borriello\u000a      (Chief Executive of the Veterinary Medicines Directorate), detailed in a\u000a      statement to accompany this case study that \"the research undertaken at\u000a      Birmingham to see if the emerging molecular strain differentiation\u000a      techniques could be applied to this problem and turn molecular typing into\u000a      a useful public health tool was very important\" [2]. The DAME Group argued\u000a      successfully for the adoption of the Midlands' TB typing model nationally.\u000a      The service model for M. tuberculosis typing established in\u000a      Birmingham was adopted by the HPA to deliver molecular typing of every\u000a      isolate via the HPA National Strain typing project, which began in January\u000a      2010 and is described in the HPA question and answer sheet published in\u000a      February 2011 [3] and the 2012 HPA report on TB in the UK [4]. Dr P Monk,\u000a      Consultant in Health Protection from the HPA, detailed the following in a\u000a      statement to accompany this case study: \"as a result of the work you\u000a      [Professor Peter Hawkey] have led, there has been a step change in the\u000a      control of TB. The developments of strain typing which came out of the\u000a      research you led have allowed us to introduce a national strain typing\u000a      service\" [5].\u000a    The Birmingham strategy of direct real time reporting on the VNTR targets\u000a      has become the national reference standard and is currently used in the\u000a      other two reference labs (London and Newcastle) for England, Cardiff for\u000a      Wales and Edinburgh for Scotland, as detailed in the National Institute\u000a      for Health and Clinical Excellence guidance on the clinical diagnosis and\u000a      management of tubercuosis [6], which was published in November 2010. A\u000a      compatible variant of the technique is also used in USA, Canada, France,\u000a      Holland and Germany [7].\u000a    Impact on public health\u000a    All M. Tuberculosis isolates in the UK are now typed by the\u000a      National Reference Laboratories which are a critical component of the\u000a      national Public Health England TB typing surveillance tool used by public\u000a      health physicians to delineate and recognise clusters of TB\u000a      cross-infection. The new typing technology has meant that pseudo outbreaks\u000a      can be rapidly identified, i.e. individuals incorrectly thought to have\u000a      acquired TB can be rapidly excluded, thus reducing the time and money\u000a      spent on contact tracing. The use of the rapid typing method in the TB\u000a      typing project has meant that isolates indistinguishable from those in\u000a      previous cases reported to Health Protection Units, regional teams and\u000a      nationally could be linked and controlled as a direct result of the typing\u000a      information. Possible epidemiologically linked cases are investigated to\u000a      ascertain whether an epidemiological cluster or outbreak exists. Any\u000a      ensuing outbreak investigation aims to identify and treat all cases of\u000a      active disease to prevent further transmission.\u000a    The public health community are now provided with detailed information on\u000a      the relationship of different strains of TB. The strain typing data when\u000a      integrated with epidemiological and social information via Origins\u000a      software provides a powerful tool for Health Protection Units to recognise\u000a      and track clusters of TB. Origins is a database which assigns a cultural,\u000a      ethnic and linguistic group based on personal and family name; its\u000a      application to TB epidemiology was developed by Prof Hawkey. Data detailed\u000a      by the HPA through their TB Strain Typing and Cluster Investigation\u000a      Newsletters provides an indication of the level of clusters being\u000a      investigated in the UK. In the period Jan 2011-Dec 2012, of the 144\u000a      clusters being actively investigated by Public Health teams, 40 were from\u000a      London and 41 from the Midlands [8]; this disproportionate use represents\u000a      the early adopter status in the Midlands. This level of investigation has\u000a      only been made possible by the implementation of the rapid typing\u000a      technology and associated epidemiological and social information provided\u000a      via Origins. The method has also enabled the almost complete eradication\u000a      of laboratory contamination being responsible for false positives; prior\u000a      to typing 8% of positive results were contamination.\u000a    Impact on patients\u000a    The early identification of TB patients, which are part of previously\u000a      unidentified clusters of infection, is enabling early treatment and\u000a      avoidance of morbidity and mortality, as detailed in a study from the\u000a      Netherlands and in the report from the HPA on Surveillance of Mycobacterium\u000a        tuberculosis Strain Typing [7, 9].\u000a    Impact on local clinical practice\u000a    In 2006, the University of Birmingham team established a secure website\u000a      (Document Gateway) so that TB teams across East and West Midlands could\u000a      access the data in real-time. This was so successful that from 2008\u000a      onwards Birmingham and Black Country isolates have been managed in monthly\u000a      multidisciplinary meetings with clinicians directly responsible for\u000a      managing the patients, public health clinicians and TB control nurses\u000a      examining typing data. In January 2010, in response to requests from users\u000a      and through the continuing support from the HPA, the service was expanded\u000a      in parallel with nationally agreed guidelines and increased the resolution\u000a      to beyond that of the methodology originally used by the main reference\u000a      lab. This work was done by Dr Evans, Dr Grace Smith (Head of Regional\u000a      Reference Laboratory) and Professor Peter Hawkey working directly with\u000a      clinicians.\u000a    ","ImpactSummary":"\u000a    In 2010, 8,483 cases of tuberculosis (TB) were reported in the UK, mainly\u000a      in urban areas and with London and the West Midlands having the highest\u000a      rates of disease (rate within Heartlands Primary Care Trust 80+ per\u000a      100,000). Research led by Professor Peter Hawkey at the University of\u000a      Birmingham has resulted in the development of novel techniques for real\u000a      time typing of Mycobacterium tuberculosis strains. The new\u000a      cost effective and rapid methodology has been adopted by the three UK\u000a      national reference laboratories and has resulted in significant\u000a      improvements to the national TB typing scheme and TB infection management.\u000a      An associated secure IT system has been developed to enable TB control\u000a      teams to rapidly receive typing data together with an analysis of the\u000a      local cases. This has influenced changes in clinical practice by reducing\u000a      the need for contact tracing. Use of the new techniques developed at\u000a      Birmingham has resulted in faster, more accurate identification of\u000a      outbreaks of TB and this information has been used to significantly\u000a      improve patient management.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hawkey PM, Smith EG, Evans JT, Monk P, Bryan G, Mohamed HH,\u000a      Bardhan M, and Pugh RN. Mycobacterial\u000a        Interspersed Repetitive Unit Typing of Mycobacterium tuberculosis\u000a        Compared to IS6110-Based Restriction Fragment Length Polymorphism\u000a        Analysis for Investigation of Apparently Clustered Cases of Tuberculosis.\u000a      Journal of Clinical Microbiology, Aug. 2003, 41(8): 3514-3520. doi:\u000a        10.1128\/JCM.41.8.3514-3520.2003\u000a    \u000a\u000a2. Evans JT, Hawkey PM, Smith EG, Boese KA, Warren RE, Hong G. Automated\u000a        high-throughput mycobacterial interspersed repetitive unit typing of Mycobacterium\u000a        tuberculosis strains by a combination of PCR and non-denaturing\u000a        high-performance liquid chromatography. J Clin Microbiol. 2004\u000a      Sep;42(9):4175-80. doi: 10.1128\/JCM.42.9.4175-4180.2004\u000a    \u000a\u000a3. Evans JT, Gardiner S, Smith EG, Webber R, Hawkey PM. Global\u000a        Origin of Mycobacterium tuberculosis in the Midlands, UK. Emerg\u000a      Infect Dis. 2010 Mar;16(3):542-5. DOI: 10.3201\/eid1603.090813\u000a    \u000a\u000a4. Menéndez MC, Buxton RS, Evans JT, Gascoyne-Binzi D, Barlow RE,\u000a      Hinds J, Hawkey PM, Colston MJ. Genome\u000a        analysis shows a common evolutionary origin for the dominant strains of\u000a        Mycobacterium tuberculosis in a UK South Asian community.\u000a      Tuberculosis (Edinb). 2007 Sep;87(5):426-36.\u000a        http:\/\/dx.doi.org\/10.1016%2Fj.tube.2007.05.017\u000a    \u000a\u000a5. Evans JT, Smith EG, Banerjee A, Smith RM, Dale J, Innes JA,\u000a      Hunt D, Tweddell A, Wood A, Anderson C, Hewinson RG, Smith NH, Hawkey PM,\u000a      Sonnenberg P. Cluster\u000a        of human tuberculosis caused by Mycobacterium bovis: evidence\u000a        for person-to-person transmission in the UK. Lancet. 2007\u000a      Apr;369(9569):1270-6. http:\/\/dx.doi.org\/10.1016\/S0140-6736(07)60598-4\u000a    \u000a\u000a6. Evans JT, Serafino Wani RL, Anderson L, Gibson AL, Smith EG,\u000a      Wood A, Olowokure B, Abubakar I, Mann JS, Gardiner S, Jones H, Sonnenberg\u000a      P, Hawkey PM. A\u000a        geographically-restricted but prevalent Mycobacterium\u000a        tuberculosis strain identified in the West Midlands Region of the UK\u000a        between 1995 and 2008. PLoS One. 2011 Mar 25;6(3):e17930 doi:10.1371\/journal.pone.0017930\u000a    \u000a\u000a7. Evans et al, Global Origin of Mycobacterium tuberculosis in\u000a      the Midlands, UK. Emerging Infectious Diseases. 2010; 16:3, 542 DOI:\u000a        10.3201\/eid1603.090813\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    \u000a      Chief Medical Officer's TB Action Plan published in 2004\u000a      Letter from the Chief Executive of Defra's Veterinary Medicines\u000a        Directorate (VMD)\u000a      Q & A sheet for HPA National Tuberculosis Strain Typing project,\u000a        published February 2011\u000a      HPA Report: Tuberculosis in the UK, published in 2012\u000a      Letter from the Health Protection Agency, East Midlands South Health\u000a        Protection Unit, County Hall, Glenfield, Leicestershire, LE3 8TB\u000a      NICE Clinical Guideline. Tuberculosis: Clinical diagnosis and\u000a        management of tuberculosis, and measures for its prevention and control.\u000a        Published March 2011\u000a      de Beer et al, Comparative Study of IS6110 Restriction Fragment Length\u000a        Polymorphism and Variable-Number-Tandem-Repeat Typing of Mycobacterium\u000a        tuberculosis Isolates in the Netherlands, Based on a 5-Year Nationwide\u000a        Survey, Journal of Clinical Microbiology. 2013, 51:1193\u000a      HPA TB Strain Typing & Cluster Newsletter published January 2013\u000a      HPA Surveillance of Mycobacterium tuberculosis Strain Typing\u000a    \u000a    ","Title":"\u000a    Enabling faster and more accurate treatment of Tuberculosis\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In the management of suspected outbreaks of TB infection it is critical\u000a      to identify the specific strain of M. tuberculosis for all\u000a      potentially linked isolates, known as typing, so that identical strains in\u000a      apparently unlinked cases can be identified and treatment initiated.\u000a      Previously TB typing used a slow and complex method involving cultivation\u000a      of sputum samples on solid media (3-6 weeks), and a nucleic acid\u000a      restriction digest assay (25% failure rate and takes 5 days). This method\u000a      was expensive and was therefore only applied to a small number of cultured\u000a      isolates.\u000a    An alternative and improved strain typing method was developed at the\u000a      University of Birmingham by Professor Peter Hawkey, Professor of Public\u000a      Health and Clinical Bacteriology with laboratory work undertaken by Dr\u000a      Jason Evans, Clinician Scientist at Heart of England NHS Foundation Trust.\u000a      The method is based on the amplification of previously identified variable\u000a      number tandem repeat (VNTR) DNA sequences in the M. tuberculosis\u000a      genome from liquid cultures and quantification of the number of repeat\u000a      sequences using denaturing high performance chromatography (dHPLC) (≤ 14\u000a      days, first time used for mycobacterial typing) [1]. The team developed\u000a      and validated novel polymerase chain reaction primers to amplify these\u000a      sequences and applied them to collections of known and unknown M.\u000a        tuberculosis strains [2].\u000a    As a result of preliminary work from 2001 to 2003 (funded by Health\u000a      Protection Agency (HPA), a further £175k was secured from the Department\u000a      of Health, which enabled the further development and validation of the use\u000a      of the dHPLC VNTR technique for routine clinical typing of M.\u000a        tuberculosis. The test was first implemented into clinical service\u000a      at the Public Health Laboratories at Heart of England NHS Foundation Trust\u000a      in 2001 and by 2004 all TB isolates going through the Heartlands service\u000a      were being typed using the new technique. Data from the clinical service\u000a      at Heartlands Hospital was used to further understand the worldwide\u000a      evolution of M. tuberculosis, as well as carefully dissecting the\u000a      phylogeny of strains from the Birmingham South Asian community [3, 4].\u000a    In 2007 a cluster of Mycobacterium bovis (normally found in\u000a      cattle) infections was identified in patients in Birmingham. In\u000a      collaboration with Animal Health and Veterinary Laboratories Agency,\u000a      University College London, Health Protection Surveillance Units and the\u000a      Welsh Zoonoses Surveillance Unit, the dHPLC VNTR technique was used to\u000a      identify for the first time M. bovis human to human transmission\u000a      in individuals using recreational steroids [5].\u000a    Using the dHPLC VNTR technique Professor Peter Hawkey's team has also\u000a      been able to identify the world's largest reported cluster (≥ 400\u000a      patients) of cross infection caused by a single M. tuberculosis\u000a      strain (Mercian Strain), which has demonstrated that this strain is\u000a      associated with UK born Caribbean individuals who use recreational drugs\u000a      in a highly restricted geographical location based on epidemiological work\u000a      combined with DNA fingerprinting [6].\u000a    Professor Hawkey and Dr Evans have also led the development of a software\u000a      platform to support the HPA's national TB typing scheme. The OriginsInfo\u000a      software was originally developed by Professor Webber of UCL and utilises\u000a      given and family names to predict cultural, ethnic and linguistic origins\u000a      of patients. The adaptation of the software by Professor Hawkey and Dr\u000a      Evans to the TB setting has enabled the identification of otherwise\u000a      unsuspected social links e.g. a group of Lithuanian immigrant workers in\u000a      illegal accommodation, which when combined with the new typing technique\u000a      controlled this and many other outbreaks [7].\u000a    "},{"CaseStudyId":"38781","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2921044","Name":"Germany"}],"Funders":["Biotechnology and Biological Sciences Research Council"],"ImpactDetails":"\u000a    Antibiotic resistance is a global issue, with the number of pathogenic\u000a      bacteria being resistant to front line,\u000a      therapeutic antibiotics increasing. A recent report by the UK Chief\u000a      Medical Officer (Annual Report March\u000a      2013) detailed that that infections cost the UK economy over £30 billion\u000a      per year in economic cost and\u000a      antibiotic resistance significantly increased mortality rates (to ~30% for\u000a      infections with resistant bacteria\u000a      compared with 15% for infection with drug susceptible strains), over half\u000a      the ~5000 UK deaths from sepsis\u000a      each year caused by E. coli are a result of infection with\u000a      multiply resistant strains. The US Centres for\u000a      Disease Control and Prevention has recently estimated infections with\u000a      resistant organisms to cause over 2\u000a      million illnesses in the US per annum with over 23000 deaths resulting.\u000a      These figures demonstrate the\u000a      global nature of the problem and the impact in developed countries, the\u000a      situation is worse in the developing\u000a      world. With the increasing demand for biocide based antibacterial and\u000a      preservative products, the risk of the\u000a      emergence of new resistant strains has increased. The work described above\u000a      has had an impact on the\u000a      development of European policy and has informed the drafting of new\u000a        legislation governing the licensing\u000a      of biocidal products across the European union.\u000a    The research described above by Professor Laura Piddock and Dr Mark\u000a      Webber at the University of\u000a      Birmingham provided a scientific and mechanistic insight into how biocide\u000a      exposure can select antibiotic\u000a      resistance, proved that common mechanisms of resistance are relevant to\u000a      both biocides and antibiotics and\u000a      that mutants selected after biocide exposure are fit in animal models. The\u000a      research also identified\u000a      significant gaps in the current knowledge base regarding the mechanisms by\u000a      which bacteria respond to\u000a      biocides and commonalities with response to antibiotics, as well as a\u000a      dearth of data on biocide tolerance in\u000a      clinical and environmental isolates of pathogenic species. The impact from\u000a      these findings was the provision\u000a      of significant new information for policy makers and opinion leaders to\u000a      formulate opinions as to the safe use\u000a      of biocides and recommendations for future research priorities at a\u000a      European level (1). This report gave a\u000a      series of recommendations including instigation of research programmes to\u000a      develop surveillance\u000a      programmes to identify levels of biocide tolerance, develop standards for\u000a      testing of the propensity of\u000a      biocides to select for resistance and to monitor biocide production and\u000a      environmental accumulation levels.\u000a    The research was directly and exclusively quoted in 2010 in the EC\u000a      Scientific Committee on Consumer\u000a      Safety `Preliminary opinion on triclosan': `the identification of\u000a        mechanisms of microbial resistance including\u000a        genomic and proteomic aspects, is commendable and should be extended to\u000a        other biocides' (2).\u000a    The research has not only helped to shape EU opinion but also influenced\u000a      changes to the law governing the\u000a      use of biocides. The new `EU biocides regulation (No 528\/2012)' (3) was\u000a      released in 2012 and became\u000a      legally binding across the EU from 2013. This includes requirements for\u000a      any new biocidal product to\u000a      demonstrate that it does not select resistance to itself or target\u000a      organisms before it can be registered and\u000a      used in any formulations. This legislation supersedes the previous\u000a      `Biocidal products directive'. In the UK\u000a      alone 652 biocidal products are currently licensed under the previous\u000a      directive, as detailed on the Health\u000a      and Safety Executive website of licensed biocides (4). The new regulations\u000a      influenced by this work will\u000a      apply to at least this number of products in a growing market. The\u000a      research described was highlighted in a\u000a      report published in October 2013 on antibiotic resistance in the\u000a      environment (5), which was prepared for the\u000a      Houses of Parliament by the Parliamentary Office of Science and\u000a      Technology.\u000a    All biocidal products now submitted for regulatory approval required to\u000a      be allowed to be sold in the\u000a      European Union must now have been demonstrated not to select resistance to\u000a      themselves or other\u000a      antimicrobials, this will prevent biocides being used that provide a\u000a      selective pressure that can drive\u000a      antibiotic resistance. Whilst the new legislation has only been legally\u000a      binding since September 2013 the\u000a      German federal bureau for risk management (BfR) recommended a ban on\u000a      triclosan in 2009 (6) in all non-medical\u000a\u0009  contexts, the BfR ruling relied heavily on the report mentioned\u000a      above from the EC Scientific\u000a      Committee on Consumer Safety `Preliminary opinion on triclosan' to form a\u000a      basis for its decision which in\u000a      turn used research from Birmingham to shape its conclusions. The EU in\u000a      turn imposed a similar ban across\u000a      Europe in 2010 in response to the BfR recommendation and a petition from\u000a      Ciba (the manufacturer of\u000a      triclosan) to remove triclosan from the approved list of biocidal products\u000a      (this ban was over-ruled in 2012\u000a      after appeal from users of triclosan due to procedural problems with the\u000a      original ruling, further legal\u000a      consideration is pending at the time of submission).\u000a    The work was disseminated by publication in international peer reviewed\u000a      journals, conference presentations\u000a      and informal discussion with government agencies e.g. quarterly meetings\u000a      with colleagues at DEFRA.\u000a    ","ImpactSummary":"\u000a    Antibiotic resistance has become one of the great challenges to human\u000a      health in the 21st century with\u000a      increasing numbers of isolates of many pathogenic bacteria being resistant\u000a      to front line, therapeutic\u000a      antibiotics. Recent evidence has suggested that antibiotic resistance can\u000a      be selected by exposure to\u000a      biocides, which are commonly used as disinfectants and preservatives.\u000a    Research at the University of Birmingham has shown the common mechanistic\u000a      links between antibiotic and\u000a      triclosan (a commonly used biocide) resistance. This research was used by\u000a      the European Commission as\u000a      evidence to support two reports published in 2009 and 2010 to inform\u000a      opinions as to the safety of biocide\u000a      use. These reports recommended specific new research avenues be funded and\u000a      that possible selection of\u000a      antibiotic resistance by biocides is a valid concern and were used as part\u000a      of the evidence base in\u000a      preparation of a new law which has come in to force across the European\u000a      Union.\u000a    Biocide use and sales in Europe have been controlled by the Biocidal\u000a      Products Directive since 1998. This\u000a      legislation has been superseded by the EU Biocides Regulation (published\u000a      May 2012, legally binding from\u000a      September 2013). This new legislation now includes a requirement for new\u000a      biocides to be demonstrated\u000a      not to select resistance to themselves or antibiotics in target organisms\u000a      before achieving registration; this\u000a      addition was informed by University of Birmingham research. This will\u000a      prevent biocides entering the\u000a      environment that exert a selective pressure and favour the emergence of\u000a      mutant bacteria with increased\u000a      biocide and antibiotic resistance. Thus the research described has had an\u000a      impact on policy debate and\u000a      the introduction of new legislation.\u000a    ","ImpactType":"Political","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Bailey AM, Constantinidou C Ivens A, Garvey MI, Webber MA\u000a      Coldham, NG Hobman J, Wain J,\u000a      Woodward MJ, Piddock, LJV. Exposure of Escherichia\u000a        coli and Salmonella enterica serovar\u000a      Typhimurium to triclosan induces a species-specific response, including\u000a      drug detoxification. J\u000a        Antimicrob Chemother. 2009 64(5):973-985.  DOI\u000a        10.1093\/jac\/dkp320\u000a    \u000a\u000a2. Webber MA, Randall LP, Cooles S, Woodward MJ, Piddock LJ.\u000a      Triclosan resistance in\u000a      Salmonella enterica serovar Typhimurium. J Antimicrob Chemother.\u000a      2008 62(1):83-91. DOI\u000a        10.1093\/jac\/dkn137\u000a    \u000a\u000a3. Randall LP, Cooles SW, Coldham NG, Penuela EG, Mott AC, Woodward MJ, Piddock\u000a        LJ, Webber\u000a        MA. Commonly used farm disinfectants can select for mutant Salmonella\u000a        enterica serovar\u000a      typhimurium with decreased susceptibility to biocides and antibiotics. J.\u000a        Antimicrob Chemother.\u000a      2007;60(6):1273-80. DOI 10.1093\/jac\/dkm359\u000a    \u000a\u000a4. Karatzas KA, Webber MA, Jorgensen F, Woodward MJ, Piddock\u000a        LJ, Humphrey TJ. Prolonged\u000a      treatment of Salmonella enterica serovar Typhimurium with\u000a      commercial disinfectants selects for\u000a      multiple antibiotic resistance, increased efflux and reduced invasiveness.\u000a      J Antimicrob Chemother.\u000a      2007;60(5):947-55. DOI: 10.1093\/jac\/dkm314\u000a    \u000a\u000a5. Webber MA, Coldham NG, Woodward MJ, Piddock LJ.\u000a      Proteomic analysis of triclosan resistance\u000a      in Salmonella enterica serovar Typhimurium. J Antimicrob\u000a        Chemother. 2008 62(1):92-7. In REF2\u000a    \u000a\u000a6. Karatzas KA, Randall LP, Webber M, Piddock LJ,\u000a      Humphrey TJ, Woodward MJ, Coldham NG.\u000a      Phenotypic and proteomic characterization of multiply antibiotic-resistant\u000a      variants of Salmonella\u000a        enterica serovar Typhimurium selected following exposure to\u000a      disinfectants. Appl Environ Microbiol.\u000a      2008;74(5):1508-16. DOI 10.1128\/AEM.01931-07\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a    \u000a      SCENIHR (Scientific Committee on Emerging and Newly Identified Health\u000a        Risks), Assessment of the\u000a        Antibiotic Resistance Effects of Biocides. European Commission; 19\u000a        January 2009\u000a        http:\/\/ec.europa.eu\/health\/ph_risk\/committees\/04_scenihr\/docs\/scenihr_o_021.pdf\u000a        (cited on p52 and\u000a        on 86)\u000a      SCCS (Scientific Committee on Consumer Safety), Preliminary opinion on\u000a        triclosan (antimicrobial\u000a        resistance). European Commission; 23 March, 2010\u000a        http:\/\/ec.europa.eu\/health\/scientific_committees\/consumer_safety\/docs\/sccs_o_013.pdf\u000a        (cited on p\u000a        50 and 2x on 55)\u000a      Regulation (EU) No 528\/2012 of the European Parliament and of the\u000a        Council of 22 May 2012\u000a        concerning the making available on the market and use of biocidal\u000a        products\u000a        http:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2012:167:FULL:EN:PDF\u000a\u000a      http:\/\/webcommunities.hse.gov.uk\/connect.ti\/pesticides\/viewdatastore?dsid=6020&adv=S\u000a      http:\/\/www.parliament.uk\/documents\/POST\/postpn446_Antibiotic-resistance-in-the-environmentreferences.pdf\u000a      Bfr opinion #031\/2009, 12 June 2009. Bfr supports ban on triclosan in\u000a        food contact materials.\u000a        http:\/\/www.bfr.bund.de\/cm\/349\/bfr_supports_ban_on_triclosan_in_food_contact_materials.pdf\u000a\u000a    \u000a    ","Title":"\u000a    Changing European Commission policy in relation to biocides as agents\u000a        driving\u000a        antibiotic resistance\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In recent years there has been an increase in the use of biocides in\u000a      industrial, clinical and domestic\u000a      applications, this increased usage has prompted concerns that biocide\u000a      exposure may lead to biocide\u000a      resistance, which as a result of common mechanisms of resistance, will\u000a      also select for mutant bacteria\u000a      which are cross-resistant to antibiotics. There is a global reliance on\u000a      the use of antibiotics to treat bacterial\u000a      infections and the emergence of new resistant strains presents a real\u000a      global health concern.\u000a    Research conducted at the University of Birmingham by Professor Laura\u000a      Piddock (at Uob since 1987) and\u000a      Dr Mark Webber (Senior Research Fellow, at UoB since 2001)) aimed to\u000a      investigate the common\u000a      mechanistic links between resistance to the commonly used biocide,\u000a      triclosan and antibiotic resistance.\u000a      The research started in 2003, initially as part of two collaborative\u000a      projects funded by Defra (2003-2007,\u000a      OD2010: £433,925) between the University of Birmingham (Prof Laura\u000a        Piddock), Bristol University (Prof\u000a      Tom Humphrey) and the Animal Health Veterinary Laboratories Agency (Prof\u000a      Martin Woodward) and\u000a      subsequently continuing at Birmingham alone as the focus of a BBSRC David\u000a      Phillips fellowship (2007-2011,\u000a\u0009  BB\/D020476\/1: £451,049) and BBSRC project grant (2009-2012,\u000a      BB\/G012016\/1: £522,284) awarded\u000a      to Dr Mark Webber and continuing to the present.\u000a    Using Salmonella as a model food borne pathogen, the research\u000a      demonstrated that exposure to common\u000a      household biocides does select for mutant bacterial strains, which\u000a      demonstrate cross resistance to\u000a      antibiotics. Novel mechanisms of biocide resistance were identified and\u000a      the mutant strains were found not\u000a      to be severely compromised in their fitness, for example triclosan\u000a      resistant Salmonella were able to survive\u000a      in a chick colonisation model in competition with parent strains\u000a      throughout a 28 day experiment [1-4]. As a\u000a      result such mutants present a credible risk of surviving in the food chain\u000a      once selected and indeed are\u000a      indistinguishable from antibiotic resistant isolates recovered from\u000a      patients. Human infection with resistant\u000a      bacterial strains is known to be associated with higher chances of\u000a      mortality, morbidity and increased lengths\u000a      of time in hospital, with resistant Salmonella strains being associated\u000a      with a three fold higher risk of severe\u000a      illness or death than drug sensitive strains. Proteomic and transcriptomic\u000a      investigations of resistant mutants\u000a      identified novel changes to core metabolism in mutants which are relevant\u000a      to antibiotic resistance, for\u000a      example triclosan resistant mutants were found to have up-regulated a\u000a      network of proteins involved in\u000a      production of fatty acids in order to bypass the metabolic block of the\u000a      drug [5, 6]. This research has already\u000a      resulted in nine publications in internationally recognised microbiology\u000a      journals (an average impact factor of\u000a      4.93 and an average of 25 citations per publication from a total of 221 as\u000a      of March 2013).\u000a    "},{"CaseStudyId":"38782","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3190538","Name":"Slovenia"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2562770","Name":"Malta"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2963597","Name":"Ireland"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    Although individually infrequent, collectively rare diseases are common\u000a      and have a profound effect\u000a      on patients and their families (as around 80% are inherited, family\u000a      members may be affected or at\u000a      risk of having affected children). The need to improve the diagnosis and\u000a      management of rare\u000a      diseases is important not only because of the overall numbers of people\u000a      affected, but also because\u000a      many common clinical syndromes are now believed to comprise subsets of\u000a      rare diseases. An\u000a      investigation by Rare Disease UK found that 46% of patients waited over a\u000a      year for correct\u000a      diagnosis following onset of symptoms (with 19% waiting from 5 to over 20\u000a      years), 46% were\u000a      misdiagnosed initially, and \"the majority of patients' care is poorly\u000a      coordinated\" [1]. This is because\u000a      clinical expertise and resources for such patients can be scarce and\u000a      complex treatments can\u000a      involve several specialists, who may have little or no experience in\u000a      identifying optimal care\u000a      pathways for rare conditions. In 2009, Sir Liam Donaldson (then Chief\u000a      Medical Officer of England)\u000a      highlighted diagnosis and management of rare diseases as one of five key\u000a      areas of public health\u000a      for the NHS to tackle in his Annual Report.\u000a    In Birmingham, Professor Tim Barrett has driven fundamental research into\u000a      the genetic causes and\u000a      molecular mechanisms of rare diabetes syndromes: meticulously mapping real\u000a      patient needs and\u000a      requirements for optimised multi-disciplinary care in these patients by\u000a      detailed genotype-phenotype\u000a      studies. He has successfully translated this work into clinical practice,\u000a      which has transformed the\u000a      care for the affected patients and their families. His initiatives to work\u000a      with patient groups in\u000a      developing services have just been highlighted in a new Rare Disease UK\u000a      report on criteria for\u000a      centres of excellence [2]. Specific impacts include:\u000a    1. The development and implementation in routine clinical practice of a\u000a        national genetic\u000a        diagnostic testing service for Wolfram and Alstrom syndromes,\u000a      facilitated by the\u000a      characterisation of the genes for these conditions by Professor Barrett's\u000a      team. These tests are\u000a      offered through the West Midlands Regional Genetics Laboratory, which has\u000a      now become the\u000a      national reference centre for genetic testing for these two\u000a      diseases, with both tests adopted by\u000a        the UK NHS Diagnostic Testing Network (UKGTN) [3]. The NHS service\u000a      also undertakes\u000a      genetic testing for Spain, Malta, India, Brazil, Slovenia and Iran.\u000a    2. The establishment of nationally commissioned, highly specialised\u000a        multidisciplinary\u000a        services for Wolfram, Alstrom and Bardet-Biedl syndrome patients.\u000a      Molecular and clinical\u000a      research in Birmingham has transformed healthcare in several inherited\u000a      versions of diabetes and\u000a      obesity that are characterised by multi-system involvement; this means\u000a      that affected patients do\u000a      not only suffer from diabetes and obesity but also have other complex\u000a      multisystem problems\u000a      requiring multi-disciplinary care. Professor Barrett's laboratory work in\u000a      this respect has tied in\u000a      closely with his patient care, and through this he has improved quality of\u000a      life for patients through\u000a      integrated multi-disciplinary specialist care established as nationally\u000a      commissioned services.\u000a      Further work from this group has led to the successful application to\u000a      deliver highly specialised\u000a      multidisciplinary services for Wolfram syndrome and Alstrom syndrome\u000a      (University Hospitals\u000a      Birmingham (UHB) and Birmingham Children's Hospital (BCH) are the national\u000a      centres for adults\u000a      and children respectively delivering both of these services), as well as\u000a      Bardet-Biedl syndrome\u000a      (UHB and BCH are two of the four centres delivering this service) [4-6].\u000a      These services are\u000a      commissioned by NHS England and deliver a `one stop shop' service to\u000a      patients from all over the\u000a      UK, Northern Ireland, and abroad. Data from their national audit days\u000a      shows objective and\u000a      measurable improvements in quality of life, earlier ages at diagnosis, and\u000a      children reaching\u000a      adulthood with reduced morbidities compared to children before the\u000a      services were established [7].\u000a      These highly specialised services are regarded by patients and staff alike\u000a      as `the jewel in the\u000a      crown' of the NHS for their patient-centred care, individualised\u000a      appointments and coordination of\u000a      services to maximise efficiency, and their efforts were recognised by an\u000a      award from Alstrom\u000a      syndrome UK at their 10th anniversary conference to celebrate\u000a      the establishment of the world's first\u000a      Alstrom syndrome paediatric clinic at BCH [8].\u000a    Orphanet (www.orpha.net) is the\u000a      European portal for rare diseases and orphan drugs and the\u000a      repository for European services, reports and resources in the field. The\u000a      three services in\u000a      Birmingham for Wolfram, Alstrom, and Bardet-Biedl syndromes are listed as\u000a      Designated European\u000a      centres of expertise for these conditions, and receive referrals from\u000a      other European states\u000a      (including Malta, Spain, Republic of Ireland) who do not have designated\u000a      specialist centres [9].\u000a    Professor Barrett also chairs the NHS England Clinical Reference Group\u000a      for Specialised Diabetes,\u000a      responsible for advising the NHS on rare disease services. Under Professor\u000a      Barrett's leadership\u000a      since April 2013, the impact has been to revise each service\u000a      specification, setting process and\u000a      quality standards, and creating quality dashboards with which NHS England\u000a      will monitor outcomes\u000a      [10].\u000a    3. The creation of a European network of excellence as a platform for\u000a        rapid translation of\u000a        research progress into clinical care, and influencing international\u000a      best practice. Under the\u000a      leadership of Professor Barrett through the EU funded EURO-WABB\u000a      (European Wolfram-Alstrom-\u000a      Bardet-Biedl) project [11], a European reference network for these rare\u000a      diseases has been\u000a      developed, incorporating a network of European genetic testing\u000a      laboratories, a European registry\u000a      with over 300 patients registered from 13 different states, and consensus\u000a      management guidelines\u000a      for health professionals. The network has just been presented at a\u000a      dedicated symposium at the\u000a      European Society for Paediatric Endocrinology international meeting,\u000a      presented at the International\u000a      Society for Paediatric and Adolescent Diabetes meeting, and has been\u000a      selected by the Directorate\u000a      General for Health as an exemplary European public health project.\u000a    This has informed policymakers both within the rare disease community in\u000a      the UK as well as those\u000a      developing plans internationally to support rare diseases. For example,\u000a      Washington University\u000a      wrote a letter of support [12] stating that \"Professor Barrett\u000a        presented details of this initiative to the\u000a      International Wolfram Syndrome meeting in Paris in 2010. After hearing\u000a        Professor Barrett's\u000a        presentation, Professor Alan Permutt at Washington University began\u000a        organizing a Wolfram\u000a        Syndrome Research Clinic in St Louis. This research clinic began with 10\u000a        patients in 2010 and now\u000a        has 23 enrolled patients seen annually. Our research clinic has been\u000a        supported by the American\u000a        Diabetes Association, Washington University and the Jack and J.T. Snow\u000a        Foundation\". Similar\u000a      support was given to colleagues in Almeria, Spain, and their local\u000a      Hospital \"La Inmaculada\" wrote\u000a      to confirm that \"...the meetings on Wolfram's held in Paris within the\u000a        EUROWABB framework\u000a        project, specially, the 2010 meeting, provided me with a quite clear\u000a        idea of how to organise a\u000a        Clinical Unit on Wolfram's syndrome. Based on these ideas, arisen in\u000a        these meetings, I organized\u000a        the clinical unit of Wolfram's syndrome in Almeria, Spain. I discussed\u000a        with Dr Barrett, the setting up\u000a        of our Wolfram clinic. This now includes an expanding multidisciplinary\u000a        team. Children and young\u000a        adults attend over 2 days for a range of investigations.\" [13]\u000a    Children with the rare diabetes syndromes Wolcott-Rallison and Thiamine\u000a      Responsive\u000a      Megaloblastic Anaemia, Diabetes and Deafness (TRMA) are also seen in the\u000a      NHS national\u000a      multidisciplinary rare disease clinics established in Birmingham; and\u000a      included in the international\u000a      EURO-WABB rare diabetes syndromes registry, ensuring that the clinical\u000a      infrastructure established\u000a      by Professor Barrett and colleagues to translate University of Birmingham\u000a      research findings into\u000a      improvements in patient care is used to its full potential.\u000a    ","ImpactSummary":"\u000a    Although individually infrequent, rare diseases collectively are a major\u000a      health burden, particularly\u000a      for individuals who suffer with conditions that are not routinely\u000a      diagnosed or have no effective care\u000a      pathways. Through the work of Professor Tim Barrett, the University of\u000a      Birmingham is\u000a      internationally recognised for translational research in rare inherited\u000a      diabetes and obesity\u000a      syndromes. This has had major impacts on patient care through gene\u000a      identification for devastating\u000a      multi-system syndromes; development of a unique international diagnostic\u000a      testing service\u000a      combining molecular testing with international clinical expertise;\u000a      European reference centre status\u000a      for three NHS highly specialised multidisciplinary services; and\u000a      leadership of the European\u000a      Registry for rare diabetes syndromes. Our national and international\u000a      leadership for these\u000a      previously poorly-served conditions has enabled sharing of best clinical\u000a      practice, including\u000a      development of clinics for Wolfram syndrome across the world.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2521886","Name":"Almeria"},{"GeoNamesId":"4407066","Name":"St. Louis"},{"GeoNamesId":"2988507","Name":"Paris"}],"References":"\u000a    \u000a1. Barrett T, Bundey S, MaCleod A. Neurodegeneration and\u000a      Diabetes; UK Nationwide Study of\u000a      Wolfram (DIDMOAD) Syndrome. Lancet 1995;346:1458-63.doi:10.1016\/S0140-6736(95)92473-6\u000a    \u000a\u000a2. Collier DA, Barrett TG, Curtis D, Macleod A, Arranz MJ,\u000a      Maassen JA, Bundey S. Linkage of\u000a      Wolfram syndrome to Chromosome 4p16.1 and Evidence for Heterogeneity. Am J\u000a      Hum Genet\u000a      1996;59:855-863. PMC1914816\u000a    \u000a\u000a3. Hardy H, Khanim F, Torres R, Scott-Brown M, Sellar A, Poulton J,\u000a      Collier D, Kirk J,\u000a      Polymeropoulos M, Latif F, Barrett T. Clinical and Molecular\u000a      Genetic Analysis of 19 Wolfram\u000a      Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations of WFS1. Am J\u000a      Hum\u000a      Genet 1999;65: 1279-1290. PMC1288280\u000a    \u000a\u000a4. Minton J, Owen K, Ricketts C, Crabtree N, Shaikh G, Ehtisham S, Porter\u000a      J, Carey C, Hodge D,\u000a      Paisey R, Walker M, Barrett T. Syndromic obesity and diabetes;\u000a      changes in body composition\u000a      with age and mutation analysis in 12 UK kindreds with Alstrom syndrome. J\u000a      Clin Endo Metab\u000a      2006;91: 3110-6. DOI 10.1210\/jc.2005-2633\u000a    \u000a\u000a5. Labay V, Raz T, Baron D, Mandel H, Williams H, Barrett T,\u000a      Szargel R, McDonald L, Shalata\u000a      A, Nosaka K, Gregory S, Cohen N. Mutations in SLC19A2 cause\u000a      thiamine-responsive\u000a      megaloblastic anaemia associated with diabetes mellitus and deafness. Nat\u000a      Genet\u000a      1999;22(3):300-4. PMID10391221\u000a    \u000a\u000a6. Delepine M, Nicolino M, Barrett T, Golomaully M, Lathrop G,\u000a      Julier C. E1F2AK3, encoding\u000a      translation initiation factor 2-alpha kinase 3, is mutated in patients\u000a      with Wolcott-Rallison\u000a      syndrome. Nature Genetics 2000;25:406-9. PMID10932183\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    \u000a      Rare Disease UK — Experiences of Rare Diseases: An Insight from\u000a        Patients and Families\u000a        (2010) http:\/\/www.raredisease.org.uk\/documents\/RDUK-Family-Report.pdf\u000a\u000a      Rare Disease UK — Centres of Excellence for Rare Diseases (2013).\u000a        http:\/\/www.raredisease.org.uk\/documents\/Website%20Documents%20\/centres-of-excellence-10-a4.pdf\u000a\u000a      List of tests offered by West Midlands Region Genetics Service through\u000a        UK Genetic Testing\u000a        Network:\u000a        http:\/\/ukgtn.nhs.uk\/fileadmin\/uploads\/ukgtn\/Documents\/Resources\/Library\/Reports_Guidelines\/NHS_Directory_of_Genetic_Testing\/UKGTN%20Directory%20of%20Genetic%20Testing%20version%20v10%20FINAL.pdf\u000a\u000a      NHS England: Specialised diabetes services http:\/\/www.england.nhs.uk\/resources\/spec-\u000a          comm-resources\/npc-crg\/group-a\/a17\/Alstrom Syndrome service (all\u000a        ages) each relates to\u000a        statement about clinical reference group for highly specialised diabetes\u000a      NHS England: Specialised diabetes services http:\/\/www.england.nhs.uk\/resources\/spec-\u000a          comm-resources\/npc-crg\/group-a\/a17\/Bardet-Biedl Syndrome service\u000a        (all ages)\u000a      NHS England: Specialised diabetes services http:\/\/www.england.nhs.uk\/resources\/spec-\u000a          comm-resources\/npc-crg\/group-a\/a17\/ Wolfram Syndrome service (all\u000a        ages)\u000a      Paediatric clinic Alstrom audit day presentation March 8th\u000a        2013\u000a      Spring 2008 Alstrom Syndrome UK Support Group newsletter\u000a      Orphanet directory of specialised services: http:\/\/www.orpha.net\/consor\/cgi-bin\/Clinics_Search_Simple.php?lng=EN\u000a\u000a      Revised 2013 service specifications for Alstrom, Bardet-Biedl and\u000a        Wolfram syndromes\u000a      EURO-WABB website (www.euro-wabb.org)\u000a      Letter of support from Washington University in St Louis\u000a      Letter of support from Hospital \"La Inmaculada\", Almeria, Spain\u000a    \u000a    ","Title":"\u000a    Improving diagnosis and clinical care for rare inherited diabetes\u000a      syndromes\u000a    ","UKLocation":[{"GeoNamesId":"2655603","Name":"Birmingham"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2641364","Name":"Northern Ireland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Rare diseases affect less than 5 people in 10,000. However, there are\u000a      over 6,000 rare diseases,\u000a      and although individually of a low frequency, collectively they account\u000a      for disease in 5-10% of the\u000a      UK population. The vast majority of these diseases are genetic, i.e.\u000a      caused by mutations\u000a      (mistakes) in single genes. We all inherit two copies of all our genes,\u000a      one from each parent. Rare\u000a      diseases most often affect people who have inherited mutations in both\u000a      their copies of a single\u000a      gene. Their parents are healthy because each is a carrier for one healthy\u000a      and one mutated copy.\u000a      This is called autosomal recessive inheritance.\u000a    Through the work of Professor Tim Barrett (Professor of Paediatrics,\u000a      clinical research fellow 1994-\u000a      1996; honorary member of staff 1996-1998 and full member of staff at UoB\u000a      since 1998), Professor\u000a      Eamonn Maher (UoB 1996-April 2013), and Professor Karen Morrison (at UoB\u000a      since 1999), and a\u000a      translational research environment built around strong strategic\u000a      relationships with our local NHS\u000a      Trusts and outstanding scientific research facilities, the University of\u000a      Birmingham has developed an\u000a      international reputation in rare diabetes syndromes.\u000a    Wolfram Syndrome is a rare genetic disorder, causing diabetes\u000a      (usually diagnosed around 6\u000a      years of age), optic atrophy (typically diagnosed around 11, and leading\u000a      to blindness by the age of\u000a      20), and deafness. Life expectancy for children born with this disorder is\u000a      around 30 years. In work\u000a      dating back to 1994, Professor Barrett has been at the forefront of the\u000a      understanding of the genetic\u000a      and cellular mechanisms of Wolfram syndrome in children and adults. This\u000a      work began with a\u000a      clinical characterisation study of UK families (1), then a genetic linkage\u000a      analysis, demonstrating the\u000a      pattern of inheritance (2). Once the gene was identified, he published a\u000a      mutation analysis of UK\u000a      patients (3). Key discoveries include: (i) characterising the progression\u000a      of the syndrome and timing\u000a      of complications; (ii) demonstration that the genetic mechanism is\u000a      autosomal recessive rather than\u000a      mitochondrial inheritance; (iii) narrowing of the candidate gene to a\u000a      region on chromosome 4p\u000a      containing only about 20 genes; (iii) definition of the UK mutational\u000a      spectrum of the wfs1 gene in\u000a      the pathogenesis of Wolfram syndrome, thereby supporting development of\u000a      NHS diagnostic\u000a      services.\u000a    Alstrom Syndrome is a rare genetic recessive disease which leads\u000a      to multi-organ dysfunction,\u000a      characterised by early-onset diabetes, childhood obesity, blindness and\u000a      deafness. Professor\u000a      Barrett's work on this disorder was the first to demonstrate the full\u000a      range of genetic mutations in\u000a      affected UK families; demonstrating severe insulin resistance in affected\u000a      children out of all\u000a      proportion to their degree of obesity (4).\u000a    Other rare diabetes syndromes have also been a related research\u000a      focus. In collaborations with\u000a      partners in Haifa, Israel and Lyon, France, Professor Barrett played a\u000a      crucial role in identifying and\u000a      characterising children with Wolcott-Rallison syndrome and Thiamine\u000a      Responsive Megaloblastic\u000a      Anaemia, Diabetes and Deafness (TRMA), respectively (5,6). The\u000a      characterisation of Birmingham\u000a      and UK families was crucial to the discoveries of the genes responsible\u000a      for these diseases.\u000a      Subsequent characterisation of these and other families has led to the\u000a      recognition of the underlying\u000a      cellular mechanisms responsible for these conditions — endoplasmic\u000a      reticulum stress in Wolcott-\u000a      Rallison syndrome and defective thiamine transport underlying TRMA.\u000a    The work of this team, associated with their ability to test novel\u000a      treatments through the paediatric\u000a      satellite facility of the University's NIHR\/Wellcome Trust Clinical\u000a      Research Facility at Birmingham\u000a      Children's Hospital, has resulted in Professor Barrett being appointed to\u000a      lead the NIHR Rare\u000a      Diseases Translational Research Collaboration Paediatric Cross-cutting\u000a      Theme. This award was\u000a      based largely on internationally recognised research expertise and\u000a      leadership in paediatric rare\u000a      diseases, evidence of leadership of multi-centre research programmes and\u000a      evidence of\u000a      collaboration with industry in rare diseases research.\u000a    "},{"CaseStudyId":"38783","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Fetal therapy is a relatively new subspecialty that allows fetal and\u000a      perinatal morbidity and mortality to be reduced. Such treatment is\u000a      concentrated in specialist centres and there is a strong call amongst\u000a      maternal care specialists and national services for such interventions to\u000a      be evidenced-based [1]. Such interventions have to be targeted at\u000a      congenital conditions which are potentially fatal but have a reversible\u000a      course if treated or the long term consequences of fetal disease can be\u000a      ameliorated by in-utero intervention. The Fetal Medicine Centre led by\u000a      Professor Kilby and affiliated to the University of Birmingham has been\u000a      instrumental in critically appraising evidence for accurate diagnosis of\u000a      fetal conditions and systematically evaluating outcomes of prenatal\u000a      intervention. This is particularly evident in their contribution to\u000a      clinical guidelines and practice in management of monochorionic twins.\u000a    Monochorionic twins have conjoining of the feto-placental circulations\u000a      and `share' a single placenta. This form of twinning is associated with a\u000a      high perinatal mortality (8%). Complications, such as single twin demise\u000a      (death) and twin to twin transfusion syndrome (which complicates 15% of\u000a      monochorionic twin pregnancies) have high fetal mortality rates. Handicap\u000a      and brain development problems in survivors complicate up to 15% of\u000a      survivors, even with treatment.\u000a    Work led by Professor Mark Kilby has been pivotal in critically\u000a      evaluating risks of single twin demise in monochorionic twins and\u000a      outlining optimal investigation and management. In addition, in-utero\u000a      treatment of severe twin to twin transfusion syndrome is complex and has\u000a      been controversial. Critical appraisal of the evidence base informing\u000a      management strategies for this morbid disease have been incorporated by\u000a      the Cochrane Pregnancy and Childbirth Group into guidance on interventions\u000a      to treat twin to twin transfusion syndrome [2].\u000a    Alongside this, Professor Kilby has been instrumental in ensuring that\u000a      his research in monochorionic twins has been incorporated into national\u000a      and international discussion and further peer-reviewed clinical guidance.\u000a      In 2005, Professor Kilby convened an international scientific working\u000a      group that held a week long symposium at the Royal College of\u000a      Obstetricians and Gynaecologists (RCOG) to gather current expertise and\u000a      evidence relating to the management of multiple pregnancies. Expert\u000a      opinion was published as a discussion vignette [3] which then formed the\u000a      basis and stimulus to the creation of a further peer reviewed,\u000a      evidence-based clinical guideline.\u000a    To achieve this, Prof Kilby co-chaired the working group that produced a\u000a      set of RCOG \"Green-top guidelines\" in 2008[4]. This type of guidance has\u000a      been specifically developed by RCOG to provide systematically developed\u000a      recommendations that assist clinicians and patients in making decisions\u000a      about appropriate treatment for specific, specialist conditions. They are\u000a      concise documents, providing specific recommendations on focused areas of\u000a      clinical practice. In this case, the aim of the guidelines was \"to\u000a        describe and, if possible, quantify the problems associated with\u000a        monochorionic placentation and to identify the best evidence to guide\u000a        clinical care, including routine fetal surveillance and treatment of\u000a        complications at secondary and tertiary levels.\"\u000a    It was important to follow this up with official national recommendations\u000a      that would more formally influence practice on a broader scale. Typically\u000a      this is achieved via the National Institute for Health and Care Excellence\u000a      (NICE), which sets accepted practice for patient healthcare, used by\u000a      groups ranging from NHS, Local Authorities, employers, voluntary groups\u000a      and others involved in delivering care or promoting wellbeing.Prof Kilby\u000a      was chairman of the national, multidisciplinary NICE Clinical Guidelines\u000a      Group (within the National Collaborating Centre for Women's and Children's\u000a      Health) which produced the 2011 national guidance for the management of\u000a      twin and triplet pregnancies [5]. This was the first time NICE had\u000a      published detailed recommendations for healthcare professionals on\u000a      managing multiple pregnancy, and therefore remains a crucial set of\u000a      information informing current and future practice. These data were also\u000a      summarised in a vignette for healthcare professionals to help ensure their\u000a      further dissemination and impact on clinical practice [6].\u000a    ","ImpactSummary":"\u000a    Perinatal morbidity and mortality is high in the UK compared to many\u000a      developed countries. Serious congenital diseases may be detected in-utero\u000a      and in some of these diseases fetal therapy may significantly improve\u000a      outcome. The Fetal Research Group in Birmingham led by Professor Mark\u000a      Kilby has made major contributions in improving knowledge of prevalence\u000a      and of best management of major causes of fetal death, especially\u000a      complications arising in monochorionic twins. These are cases where twins\u000a      share the same placenta, in which complications are common and can lead to\u000a      handicap and brain development problems as well as high fetal mortality\u000a      rates. Critical appraisal of the evidence and novel research into these\u000a      disordershasclearly evaluated therapeutic approaches and clinical\u000a      management. This work has ultimately allowed development and\u000a      implementation of evidence-based recommendations on managing multiple\u000a      pregnancies for the first time in the UK.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hillman SC, Morris RK, Kilby MD. Co-twin prognosis after single fetal\u000a      death: a systematic review and meta-analysis. Obstet Gynecol.\u000a      2011;18(4):928-40. doi: 10.1097\/AOG.0b013e31822f129d\u000a    \u000a\u000a2. Fox C, Kilby MD, Khan KS. Contemporary treatments for twin-twin\u000a      transfusion syndrome. Obstet Gynecol. 2005;105(6):1469-77. PMID:15932845\u000a    \u000a\u000a3. Morris RK, Selman TJ, Harbidge A, Martin WI, Kilby MD. Fetoscopic\u000a      laser coagulation for severe twin-to-twin transfusion syndrome: factors\u000a      influencing perinatal outcome, learning curve of the procedure and lessons\u000a      for new centres. BJOG. 2010;117(11):1350-7. doi:\u000a        10.1111\/j.1471-0528.2010.02680.x\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    \u000a      NHS England Standard Contract for Fetal Medicine. 2013. http:\/\/www.england.nhs.uk\/wp-content\/uploads\/2013\/06\/e12-fetal-medi.pdf\u000a\u000a      Roberts D, Neilson JP, Kilby M.D, Gates S. Interventions for\u000a        the treatment of twin-twin transfusion syndrome. Cochrane Database Syst\u000a        Rev. 2008;(1):CD002073. doi: 10.1002\/14651858.CD002073.pub2.\u000a\u000a      RCOG study group statement. Consensus views arising from the 50th\u000a        Study Group: Multiple Pregnancy. 2006. London, RCOG Press.http:\/\/www.rcog.org.uk\/files\/rcog-corp\/uploaded-files\/StudyGroupConsensusViewsMultiplePregnancy.pdf.ISBN-10:\u000a        1904752225.\u000a      RCOG Guidelines for the management of monochorionic twin pregnancies,\u000a        2008\u000a        http:\/\/www.rcog.org.uk\/files\/rcog-corp\/uploaded-files\/T51ManagementMonochorionicTwinPregnancy2008a.pdf.\u000a      Multiple pregnancy: The management of twin and triplet pregnancies in\u000a        the antenatal period Issued: September 2011. NICE clinical guideline\u000a        129.\u000a        www.nice.org.uk\/niceme\u000a\u000a      Visintin C, Mugglestone MA, James D, Kilby MD; Guideline\u000a        Development Group.Antenatal care for twin and triplet pregnancies:\u000a        summary of NICE guidance.BMJ. 2011;343:d5714. doi:\u000a          10.1136\/bmj.d5714.\u000a\u000a    \u000a    ","Title":"\u000a    Establishing evidence-based clinical guidelines for multiple\u000a        pregnancy.\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Fetal disease contributes to perinatal (the period immediately before and\u000a      after birth) morbidity and mortality in the UK and worldwide. A large\u000a      amount of disease is caused by birth defects (normally structural),\u000a      although up to 15% of problems are amenable to prenatal treatment and\u000a      therapy, significantly improving outcome and long-term morbidity. Research\u000a      into the mechanisms underlying conditions that affect fetal health, as\u000a      well as the evaluation of potential fetal therapies, has been led by\u000a      Professor Mark Kilby at the University of Birmingham (at UoB since 1995)\u000a      over the past fifteen years.\u000a    Identical (monozygotic) twins that share the same placenta are known as\u000a      `monochorionic' twins. These pregnancies have high rates of morbidity and\u000a      mortality for the fetus; this is because of a shared placental circulation\u000a      which can cause disproportionate blood supply to one of the twins. This\u000a      may result in `twin-to-twin transfusion syndrome', where one twin has a\u000a      decreased blood volume (potentially leading to restricted growth or brain\u000a      development) and the other has an abnormally high blood volume (which can\u000a      strain their heart and lead to heart failure). In these cases, the risk of\u000a      one or more twins dying is up to 90%. Key systematic reviews delivered by\u000a      Professor Mark Kilby has highlighted the evidence-based risks of co-twin\u000a      demise and brain damage in the survivors of co-twin demise in\u000a      monochorionic twins and have identified the optimal prenatal management in\u000a      such scenarios [1]. Related work over a series of studies led by Professor\u000a      Kilby has demonstrated that fetoscopic laser ablation — ain-utero\u000a      technique involving laser surgery to coagulate and reduce abnormal blood\u000a      vessels — is the superior treatment in these complications [2]. This is in\u000a      comparison with other techniques which simply remove some of the excess\u000a      amniotic fluid with a needle (amniodrainage) to reduce the pressure in the\u000a      womb. Further appraisal of a dataset from Birmingham has also highlighted\u000a      that good outcomes can be achieved using fetoscopic laser ablation even\u000a      where the surgeon is less familiar with the technique but is supported by\u000a      appropriate training [3].\u000a    "},{"CaseStudyId":"38784","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The research conducted by Prof Nick James has had a significant impact on\u000a      clinical practice and\u000a      patients with muscle invasive bladder cancer.\u000a    Impact on patients\u000a    The demonstration by the BC2001 trial that combination chemotherapy and\u000a      radiotherapy can offer\u000a      the potential of disease cure whilst preserving conservation of bladder\u000a      function means that it can\u000a      now be offered as a definitive treatment option compared to the previous\u000a      standard of\u000a      chemotherapy followed by cystectomy. Cystectomy is a major operation and\u000a      is associated with\u000a      considerable morbidity and mortality, and permanent loss of urinary\u000a      function. Patients can now\u000a      make a choice in their treatment to choose a non-surgical option. The new\u000a      options available for\u000a      patients with bladder cancer were detailed in an editorial in the New\u000a      England Journal of Medicine\u000a      2012 (1), which stated that `The development of organ-sparing\u000a          procedures in breast and\u000a          prostate cancer was promoted by vocal patient advocacy groups with the\u000a          use of the\u000a          Internet and social networking. We anticipate that the publication of\u000a          this important study\u000a          will help patients with bladder cancer to find their voice'.\u000a    In addition, cystectomy is unsuitable for many elderly patients and as\u000a      such these patients were\u000a      previously considered suitable only for palliative radiotherapy which\u000a      offered no prospect of cure.\u000a      This was articulated in the NEJM editorial by Shipley (1), who commented\u000a      that `35% of patients\u000a          between the ages of 70 and 80 years received no potentially curative\u000a          therapy at all, a\u000a          proportion that increased to 55% among patients 80 years of age or\u000a          older'. As the number of\u000a      elderly people increases, the importance of this less invasive and\u000a      potentially curative therapy\u000a      becomes even more significant.\u000a    Impact on practice\u000a    There is already clinical evidence that the BC2001 trial has changed\u000a      clinical practice in the UK.\u000a      The number of cystectomies for bladder cancer had shown a relentless\u000a      increase over the last few\u000a      years and peaked at 150 per month in October 2012. Since that time the\u000a      rate has fallen by 23% to\u000a      115 in May 2013, the latest time for which results are available (2). The\u000a      change in clinical practice\u000a      described and associated reduction in the number of cystectomies has and\u000a      will continue to deliver\u000a      economic impact to healthcare providers, as the cost of treatment and the\u000a      number of in patient\u000a      days will be reduced.\u000a    The change in clinical practice has been confirmed by the Chair of the\u000a      National Cancer Research\u000a      Institute Bladder Clinical Studies Group, who detailed in a statement that\u000a      \"it is confirmed that the\u000a          chemotherapy plus radiotherapy regime is now acknowledged as the gold\u000a          standard non-surgical\u000a          treatment schedule for muscle invasive bladder cancer and is now the\u000a          standard\u000a          arm for any future studies in this area\" (3). The outcomes\u000a      from the research have also changed\u000a      clinical practice internationally, with the use of the combined\u000a      chemo-radiotherapy being used as\u000a      the new `standard of care' and the incorporation of the bladder sparing\u000a      regime as a standard arm in\u000a      US trials, this is strong evidence of a change in clinical practice and\u000a      can be evidenced by the trial\u000a      being run by the Radiation Therapy Oncology Group at the US National\u000a      Cancer Institute (4).\u000a    The change in clinical practice is further evidenced by the National\u000a      Cancer Research Institute\u000a      Bladder Clinical Studies Group Annual Report 2013 (5), which states: \"The\u000a          BC2001 trial of\u000a          chemoradiation versus radiation alone (Chief Investigator: Professor\u000a          Nick James) has\u000a          changed standard of care for patients with T2-T4 bladder cancer in the\u000a          UK and\u000a          internationally. The study is the largest ever chemoradiation or\u000a          chemotherapy study in\u000a          bladder cancer, showing improvements in local control equivalent to\u000a          those seen in cervical\u000a          cancer chemoradiation. Many centres both in the UK and internationally\u000a          have adopted its\u000a          treatment schedule as standard practice\".\u000a    The change in clinical practice is now reflected in published guidelines,\u000a      e.g. the Pan Birmingham\u000a      Cancer Network Guideline (6). Point 8.5 details: \"Based on the\u000a          results of the BC2001 trial\u000a          patients receiving radical radiotherapy should be offered synchronous\u000a          chemotherapy with\u000a          continuous infusion 5FU plus a single bolus of mitomycin C on day 1.\u000a          The trial showed a\u000a          50% reduction in invasive recurrence with no increase in late toxicity\u000a          or impact on bladder\u000a          capacity at 1 year. The synchronous regimen toxicity was not adversely\u000a          impacted by prior\u000a          neoadjuvant chemotherapy\".\u000a    Impact on Surgical Education\u000a    Professor James has been an invited speaker at Educational sessions for\u000a      practitioners at nine\u000a      International conferences to date and contributed a chapter to the\u000a      President of American Society of\u000a      Clinical Oncology's `Building Bridges in Oncology' supplement for\u000a      30,000 oncologists at the\u000a      American of Clinical Oncology meeting in 2013 (7). James has been invited\u000a      to author the chapter\u000a      on Bladder Cancer for the highly influential US text Perez & Brady's `Principles\u000a        and Practice of\u000a        Radiation Oncology' (8), one of a very small number of non-US\u000a      authors and as clinical trainees use\u000a      this textbook worldwide this will lead to the work being embedded in\u000a      practice globally.\u000a    This work in bladder preservation has taken a long time to recruit and\u000a      mature. This has been\u000a      driven by a strong sense in the surgical community that cystectomy should\u000a      be offered to as many\u000a      patients as possible, with radiotherapy reserved for palliation or the\u000a      very elderly on unfit. To recruit\u000a      large numbers of patients to a randomised trial thus required substantial\u000a      efforts to convince\u000a      clinicians of the importance of improving non-surgical therapies. To\u000a      achieve this, investigators'\u000a      meetings and workshops were held to emphasise the importance of studying\u000a      alternatives to\u000a      surgery. This was backed up by writing review articles in major journals\u000a      and speaking at meetings\u000a      on the topic. As the trial progressed, the recruitment rate improved as\u000a      clinicians had more\u000a      confidence in the safety and efficacy of the schedules being tested, hence\u000a      just running the trial\u000a      prepared the ground for a change in practice.\u000a    ","ImpactSummary":"\u000a    Muscle invasive bladder cancer is the sixth most common cancer and\u000a      remains a major cause of\u000a      death and suffering worldwide. The standard treatment for advanced bladder\u000a      cancer has been\u000a      surgical removal of the bladder (cystectomy) which is associated with\u000a      considerable morbidity.\u000a      Many (20%) patients are elderly, with significant co-morbidities and hence\u000a      are high risk for a major\u000a      operation. In the past patients who were not able to undergo surgery were\u000a      offered palliative\u000a      radiotherapy. Research at the University of Birmingham has shown that the\u000a      addition of low toxicity\u000a      chemotherapy to radiotherapy is as effective as cystectomy in controlling\u000a      disease progression and\u000a      has minimal impact on bladder function. This new approach is an excellent\u000a      alternative to\u000a      cystectomy and has been adopted as a new standard of care thus\u000a      demonstrating considerable\u000a      impact on clinical practice and patient outcome.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hussain SA, Moffitt DD, Glaholm J, et al: A Phase I\/II Study Of\u000a      Synchronous\u000a      Chemoradiotherapy For Poor Prognosis Locally Advanced Bladder Cancer.\u000a      Annals of\u000a      Oncology 12:929-935, 2001 PMID:11521797\u000a    \u000a\u000a2. Hussain SA, James ND: Organ preservation strategies in bladder\u000a      cancer. [Review] [89\u000a      refs]. Expert Review of Anticancer Therapy 2:641-651, 2002\u000a      doi:10.1586\/14737140.2.6.641\u000a    \u000a\u000a3. Hussain SA, James ND: The systemic treatment of advanced and\u000a      metastatic bladder\u000a      cancer. Lancet Oncol 4:489-497, 2003 doi:10.1016\/S1470-2045(03)01168-9\u000a    \u000a\u000a4. Hussain SA, Stocken DD, Peake DR, et al: Long-term results of a phase\u000a      II study of\u000a      synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.\u000a      Br.J\u000a      Cancer 90:2106-2111, 2004 doi:10.1038\/sj.bjc.6601852\u000a    \u000a\u000a5. James N, Hussain SA: Management of muscle invasive bladder\u000a      cancer--British approaches\u000a      to organ conservation. Semin.Radiat Oncol 15:19-27, 2005 PMID:\u000a        15662603\u000a    \u000a\u000a6. James ND, Hussain SA, Hall E, et al: Radiotherapy with or without\u000a      chemotherapy in\u000a      muscle-invasive bladder cancer. The New England Journal of Medicine\u000a      366:1477-88,\u000a      2012) DOI: 10.1056\/NEJMoa1106106\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Shipley W, Zietman A. Old drugs, new purpose--bladder cancer turning a\u000a        corner. New\u000a        England Journal of Medicine. 2012; 366. Editorial written by two\u000a        Professors of Radiation\u000a        Oncology (Prof Anthony Zietman or Prof William Shipley) from Harvard\u000a        describing the trial\u000a        as a \"landmark study\" and \"practice changing\".\u000a      NHS Hospital Episode Statistics data report\u000a      Letter from the Chair of the National Cancer Research Institute\u000a        Bladder Clinical Studies\u000a        Group.\u000a      http:\/\/www.cancer.gov\/clinicaltrials\/search\/view?cdrid=654727&version=Patient&protocolse\u000a          archid=6312750\u000a      National Institute for Health Research\/National Cancer Research\u000a        Institute\/National Cancer\u000a        Research Network — Bladder Cancer Clinical Studies Group Annual Report\u000a        2012\/2013\u000a        (page 8)\u000a      Pan Birmingham Cancer Network Guideline\u000a      ASCO supplement — Building Bridges to Conquer Cancer, ASCO Educational\u000a        Supplement\u000a        2013\u000a      Website of Perez & Brady's `Principles and Practice of Radiation\u000a        Oncology'.\u000a        http:\/\/www.amazon.co.uk\/Bradys-Principles-Practice-Radiation-Oncology\/dp\/078176369X\u000a\u000a    \u000a    ","Title":"\u000a    The introduction of combination chemo-radiotherapy to reduce the\u000a        need for cystectomy in patients with muscle invasive bladder cancer\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Bladder cancer is one of the most common cancers in the world with an\u000a      estimated 382,000 cases\u000a      annually. Early stage disease is treated with local resection but muscle\u000a      invasive disease carries a\u000a      poor prognosis and has generally been managed by surgical removal of the\u000a      bladder with\u000a      introduction of the ureters into the bowel (cystectomy). This procedure\u000a      carries substantial\u000a      morbidity and is also unsuitable for elderly patients, who are then\u000a      generally offered palliative\u000a      radiotherapy. The aim of the research described here was to provide\u000a      evidence for a new approach\u000a      combining radiotherapy with chemotherapy as an alternative approach to\u000a      cystectomy.\u000a    In 1996 a small randomised study demonstrated the efficacy of cisplatinum\u000a      in bladder cancer, but\u000a      the drug is potentially toxic and patients must have good kidney function\u000a      before being considered\u000a      for treatment. UK experience showed that this approach was not suitable\u000a      for at least 50% of\u000a      patients due to toxicity and the poor general condition of patients. As a\u000a      result, the University of\u000a      Birmingham team undertook a phase I and phase II study which ran from 1997\u000a      to 2000 (Principal\u000a      Investigator Prof Nicholas James, at UoB since 1994) using a regimen of\u000a      mitomycin C and 5-fluorouracil\u000a      which was predicted to be better tolerated. These preliminary studies\u000a      determined the\u000a      doses of chemotherapy and radiotherapy that could be delivered safely to\u000a      patients of 70+ years (1-5).\u000a    In 2001 Professor James obtained funding from the Cancer Research\u000a      Campaign to commence a\u000a      large confirmatory phase III trial called BC2001 which compared\u000a      radiotherapy alone with chemo-radiotherapy\u000a      for the treatment of muscle invasive bladder cancer. The study compared\u000a      different\u000a      radiotherapy techniques and collected detailed data on the effect of\u000a      radiotherapy planning\u000a      techniques on toxicity outcomes. An important observation was that the\u000a      addition of chemotherapy\u000a      did not impact on the delivery rate of the radiotherapy.\u000a    When recruitment closed in 2010, 458 patients had been entered into study\u000a      making this the largest\u000a      ever trial of radiotherapy in bladder cancer. The analysis showed that\u000a      radical radiotherapy\u000a      combined with low dose chemotherapy was very well tolerated, even by\u000a      elderly patients. Indeed\u000a      the median age of the group was 72 years and 15% were aged 80 years or\u000a      more. Moreover the\u000a      treatment was highly effective and led to a 43% reduction in the rate of\u000a      pelvic relapse (6).\u000a    A general perception amongst many urologists around the world has been\u000a      that radiotherapy leads\u000a      inevitably to damage to the bladder such that organ becomes shrunken and\u000a      poorly functioning\u000a      following treatment. It therefore became important for the University of\u000a      Birmingham team to\u000a      demonstrate that the function of the bladder was retained following\u000a      radiotherapy and that the\u000a      addition of chemotherapy did not further adversely affect organ function.\u000a      Remarkably, bladder\u000a      function following radiotherapy and chemotherapy was excellent. Short-term\u000a      side effects during\u000a      treatment were mild to moderate and over 70% of patients reporting no\u000a      long-term side effects at all\u000a      (6).\u000a    Overall these results demonstrate that chemo-radiotherapy is an excellent\u000a      treatment option for\u000a      patients with muscle invasive bladder cancer. Importantly this is\u000a      particularly true for the frail or the\u000a      elderly, and thus considerably extends the population to which potentially\u000a      curative treatment can\u000a      be administered.\u000a    The primary research output of the trial was disseminated through several\u000a      major meetings in 2010\u000a      including plenary sessions at the American Society of Radiation Oncology\u000a      (ASTRO) and the\u000a      National Cancer Research Institute (NCRI) Annual Meeting. Following the\u000a      ASTRO presentation\u000a      Professor James received invitations from the Editors of both the New\u000a        England Journal of Medicine\u000a        (NEJM) and Journal of the American Medical Association to\u000a      submit the full analysis. The paper\u000a      was published in the NEJM in 2012 (6) and was accompanied by an\u000a      editorial that described the\u000a      trial as `indeed remarkable' and a `landmark study' which `is potentially\u000a      practice changing for\u000a      patients with muscle-invasive bladder cancer'. The paper was also featured\u000a      on the US National\u000a      Cancer Institute website.\u000a    "},{"CaseStudyId":"38785","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"3057568","Name":"Slovakia"},{"GeoNamesId":"2960313","Name":"Luxembourg"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"3057568","Name":"Slovakia"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"3077311","Name":"Czech Republic"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    The development of the freelight chain assays by Professors Bradwell and\u000a      Drayson has had\u000a      significant impact on the clinical management of patients with B\u000a      cell lymphoid neoplasias and\u000a      has led to changes in clinical practice and commercial impact\u000a      through the success of the\u000a      Binding Site and the formation of Serascience.\u000a    Clinical impact\u000a      The SFLC test has been adopted into worldwide clinical practice because of\u000a      its importance in the\u000a      diagnosis and management of myeloma, solitary plasmacytoma and light chain\u000a      amyloidosis. This\u000a      is evidenced by numerous review papers, national and international\u000a      guidelines for the diagnosis\u000a      and management of these diseases [1]. These guidelines continue to be\u000a      updated as more\u000a      scientific evidence becomes available about the use of the test. The SFLC\u000a      test has been adopted\u000a      as a prognostic marker for the whole range of B lymphoid cancers and\u000a      premalignant conditions\u000a      including monoclonal gammopathy of undetermined significance which occur\u000a      in 3% of people aged\u000a      >60 years [2]. More recently it has been adopted as a prognostic marker\u000a      for survival in normal\u000a      populations [2]. Use of the SFLC test in the MERIT trial and in the MRC\u000a      Myeloma 11 trial has\u000a      made it clear that the SFLC response to the first few weeks of\u000a      anti-myeloma therapy reliably\u000a      predicts final response [3]; this allows early identification of\u000a      non-responders and change to a\u000a      treatment more likely to be effective in identified individuals.\u000a    Impact on patients\u000a      The ability to measure serum FLC levels has had a major impact on the\u000a      diagnosis and\u000a      management of all patients with plasma cell dycrasias and B lymphoid\u000a      lymphoma and leukaemia\u000a      [4]. In non-secretory and light chain only myeloma and in many\u000a      plasmacytoma and light chain\u000a      amyloid patients SFLC tests allow diagnosis and detection of changes in\u000a      disease activity that could\u000a      not be achieved before. The second generation of these tests\u000a      commercialised by Serascience is\u000a      making these tests more widely available, in particular a point of care\u000a      version, allowing patient\u000a      management decisions to be made more reliably and immediately in the\u000a      outpatient clinic, at the\u000a      bedside or even at home [5].\u000a    Commercial impact\u000a      The Binding Site was formed in 1982 by a group of researchers from the\u000a      University of Birmingham\u000a      Medical School, to manufacture and supply antibodies, alongside developing\u000a      a series of diagnostic\u000a      tests. Following the development of the SFLC test the Binding Site\u000a      incorporated the technology as\u000a      a key part of its product portfolio. In October 2009 the Binding Site sold\u000a      its autoimmune\u000a      diagnostics business to the Werfen Group SA, based in Barcelona, Spain for\u000a      £84 million in order to\u000a      concentrate on Freelite which accounted for most of its other annual\u000a      income and was growing at\u000a      40% per year [6]. The company's annual turnover in 2012 was £55 million\u000a      and the company\u000a      employs in excess of 550 people in the UK and abroad [7]. In 2012, 360,000\u000a      SFLC tests were sold\u000a      each month in 90 countries, directly through offices in UK, USA, Canada,\u000a      Germany, Austria,\u000a      France, Spain, Italy, Czech Republic, Slovak Republic, Belgium,\u000a      Netherlands and Luxembourg;\u000a      and through a network of over 70 distributors [7].\u000a    In 2010, the Binding Site won The Queen's Award for Enterprise in the\u000a      category International\u000a      Trade, for its outstanding achievement in increasing export revenues by\u000a      74% to over £42\u000a      million\/year in 3 years and selling more than 90% of its production\u000a      overseas [8]. Aggregate\u000a      exports over this period totalled £96 million. This growth is primarily\u000a      driven by sales of Freelite®,\u000a      which has grown to £36 million\/year in 2012 [7]. New jobs have been\u000a      created in sales, marketing,\u000a      research and clinical education, both in the UK and internationally, to\u000a      support this trade. In March\u000a      2011, the company moved its headquarters and 380 UK-based staff to larger\u000a      premises in the\u000a      centre of Birmingham. In April 2011 Nordic Capital Fund VII acquired the\u000a      Binding Site for an\u000a      undisclosed sum [9]. City analysts believe that sum to be in the region of\u000a      £200 million [10].\u000a    A new University spinout company, SeraScience, was formed in 2011 to\u000a      commercialise the\u000a      monoclonal based SFLC assay. The company was formed as a result of\u000a      significant investment\u000a      from the University and UK based Healthcare company, Abingdon Health. The\u000a      company has\u000a      successfully developed a new range of \"point of care tests\" for FLC, which\u000a      will mean that the SFLC\u000a      assay can be undertaken within the clinic, providing rapid clinical\u000a      assessment and immediate\u000a      information for the patient and clinical teams. The new range was launched\u000a      at the Biannual\u000a      International Myeloma Conference in Kyoto, Japan in April 2013 [11]. The\u000a      point of care test is\u000a      manufactured by FORSITE in Yorkshire (a spinout company from DEFRA). The\u000a      nephelometric and\u000a      turbidimetric assays are being developed with Spinreact in Gerona, Spain.\u000a    ","ImpactSummary":"\u000a    Research conducted by Professor Jo Bradwell at the University of\u000a      Birmingham provided the basis\u000a      of the commercially available diagnostic test Freelite®, which quantifies\u000a      free immunoglobulin light\u000a      chains in serum and was the first and only assay for the diagnosis and\u000a      monitoring of Multiple\u000a      Myeloma (MM). MM is a cancer of immunoglobulin producing plasma cells in\u000a      the bone marrow.\u000a      Freelite® has markedly improved the diagnosis and management of MM, is\u000a      helpful in the diagnosis\u000a      of all B cell lymphoid neoplasias and provides prognostic information for\u000a      premalignant conditions\u000a      present in over 3% of people over 50 years of age. Freelite was\u000a      commercialised by the University\u000a      of Birmingham spinout company, the Binding Site, which has achieved\u000a      worldwide sales, with over\u000a      360,000 tests being sold per month in 90 countries and an ongoing 25%\u000a      annual growth in sales.\u000a      The company provides annual revenue of £55m and employment for 620 people\u000a      in the UK and\u000a      abroad. An improved second generation of tests has been developed by\u000a      Professor Mark Drayson\u000a      at the University of Birmingham, which has been commercialised by a second\u000a      University spinout\u000a      company Serascience, which started marketing a point of care free light\u000a      chain diagnostic test\u000a      worldwide in April 2013.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3128760","Name":"Barcelona"}],"References":"\u000a    \u000a1. Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ,\u000a      Drayson MT, Drew R. Highly\u000a      sensitive, automated immunoassay for immunoglobulin free light chains in\u000a      serum and urine.\u000a      Clin Chem. 2001 Apr;47(4):673-80. PubMed PMID: 11274017.\u000a    \u000a\u000a2. Mark Drayson, Liang X. Tang, Roger Drew, Graham P. Mead, Hugh\u000a      Carr-Smith, and Arthur\u000a      R. Bradwell. Serum free light-chain measurements for identifying\u000a      and monitoring patients with\u000a      nonsecretory multiple myeloma. Blood 2001;97:9:2900-2902. DOI\u000a        10.1182\/blood.V97.9.2900\u000a    \u000a\u000a3. Arthur R Bradwell, Hugh D Carr-Smith, Graham P Mead, Timothy C\u000a      Harvey, Mark T\u000a        Drayson. Serum test for assessment of patients with Bence Jones\u000a      myeloma. Lancet\u000a      2003;361:489-491. DOI 10.1016\/S0140-6736(03)12457-9\u000a    \u000a\u000a4. Andy C. Rawstron, J. Anthony Child, Ruth M. de Tute, Faith E. Davies,\u000a      Walter M. Gregory,\u000a      Sue E. Bell, Alexander J. Szubert, Nuria Navarro-Coy, Mark T. Drayson,\u000a      Sylvia Feyler, Fiona\u000a      M. Ross, Gordon Cook, Graham H. Jackson, Gareth J. Morgan, and Roger G.\u000a      Owen. Minimal\u000a      Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple\u000a      Myeloma: Impact\u000a      on Outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol.\u000a      2013 Jul\u000a      10;31(20):2540-7. DOI: 10.1200\/JCO.2012.46.2119\u000a    \u000a\u000a5. Fermand\u000a        JP, Bridoux\u000a        F, Kyle\u000a        RA, Kastritis\u000a        E, Weiss\u000a        BM, Cook\u000a        MA, Drayson\u000a          MT, Dispenzieri\u000a        A, Leung\u000a        N. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013\u000a      Oct 9. [Epub ahead of print]. doi: 10.1182\/blood-2013-05-495929\u000a    \u000a\u000a6. Campbell JP, Cobbold M, Wang Y, Goodall M, Bonney SL, Chamba A,\u000a      Birtwistle J, Plant T,\u000a      Afzal Z, Jefferis R, Drayson MT. Development of a highly-sensitive\u000a      multi-plex assay using\u000a      monoclonal antibodies for the simultaneous measurement of kappa and lambda\u000a      immunoglobulin free light chains in serum and urine. J Immunol Methods.\u000a      2013 Feb 3 . doi:\u000a        10.1016\/j.jim.2013.01.014\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    \u000a      International Myeloma Working Group guidelines for serum-free light\u000a        chain analysis in multiple\u000a        myeloma and related disorders, A Dispenzier1, R Kyle, G Merlini, JS\u000a        Miguel, H Ludwig, R\u000a        Hajek, A Palumbo, S Jagannath, J Blade, S Lonial, M Dimopoulos, R\u000a        Comenzo, H Einsele, B\u000a        Barlogie, K Anderson, M Gertz, JL Harousseau, M Attal, P Tosi, P\u000a        Sonneveld, M Boccadoro,\u000a        G Morgan, P Richardson, O Sezer, MV Mateos, M Cavo, D Joshua, I\u000a        Turesson, W Chen, K\u000a        Shimizu, R Powles, SV Rajkumar and BGM Durie on behalf of the\u000a        International Myeloma\u000a        Working Group. Leukemia (2009) 23, 215-224.\u000a      Using Single Protein Biomarkers to Predict Health and Disease in\u000a        Diverse Patient Populations:\u000a        A New Role for Assessment of Immunoglobulin Free Light Chains. Mark T\u000a        Drayson, Mayo\u000a        Clinic Proceedings. Editorial June 2012;87(6):505-507.\u000a      \u000aNovel approaches\u000a          for reducing free light chains in patients with myeloma kidney. Hutchison\u000a        CA, Bladé J, Cockwell P, Cook M, Drayson M, Fermand JP,\u000a        Kastritis E, Kyle R, Leung N,\u000a        Pasquali S, Winearls C; International Kidney and Monoclonal Gammopathy\u000a        Research Group.\u000a        Nat Rev Nephrol. 2012 Feb 21;8(4):234-43. doi:\u000a          10.1038\/nrneph.2012.14. Review.\u000a      \u000awww.myeloma.org.uk\/index.php\/download_file\/view\/2034\/.\u000a        Myeloma Infoguide Series.\u000a        Serum Free Light. Chain Assay. Myeloma UK Serum Free Light\u000a          Chain Infoguide July\u000a        2012:6732 infoguide 25\/07\/2012 09:10 Page 1\u000a      http:\/\/www.myeloma.org.uk\/about-muk\/news\/myeloma-news\/myeloma-uk-welcomes-new-diagnostic-test-for-myeloma\/\u000a      http:\/\/www.bindingsite.it\/corporate-news?story=342\u000a      http:\/\/www.thebindingsite.com\/facts-and-figures\u000a      http:\/\/www.thebindingsite.com\/queens-award\u000a      Nordic Capital Fund VII acquires diagnostics company The Binding Site — Press release, 14th\u000a        April, 2011 (http:\/\/www.nordiccapital.com\/news\/news-listing\/nordic-capital-fund-vii-acquires-diagnostics-company-the-binding-site.aspx)\u000a      Medical technology: Healthcare's third way\u000a        http:\/\/www.unquote.com\/uk\/analysis\/2206565\/medical-technology-healthcares-third-way\u000a\u000a      http:\/\/www.serascience.com\/\u000a    \u000a    ","Title":"\u000a    Global health impact and economic impact from the development of\u000a      Freelite®\u000a    ","UKLocation":[{"GeoNamesId":"2655603","Name":"Birmingham"},{"GeoNamesId":"2657780","Name":"Abingdon"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In the journal Lancet in 1847, Henry Bence Jones described the\u000a      characteristics of the first cancer\u000a      biomarker, a protein in urine from a patient who suffered with mollities\u000a      and fragilitas ossium\u000a      (myeloma). In the 1960s, the Bence Jones protein was identified as\u000a      immunoglobulin free light\u000a      chains (FLC), which when joined with the heavy chain make the whole\u000a      immunoglobulin complex\u000a      (see diagram below). FLCs and whole immunoglobulins are the products of\u000a      normal polyclonal\u000a      plasma cells (polyclonal immunoglobulin) and the neoplastic plasma cell\u000a      clone of myeloma\u000a      (monoclonal immunoglobulin — M-protein). Two forms of FLC are produced:\u000a      kappa and lambda,\u000a      with about twice as much being of the kappa type.\u000a    \u000a\u000a\u000a\u000a    In healthy individuals the total body plasma cell pool produces about\u000a      0.5g\/day of FLC, with a blood\u000a      half-life of 2 to 4 hours. FLCs are removed from the blood by filtration\u000a      into the kidneys and do not\u000a      appear in the urine of healthy individuals because they are metabolised in\u000a      the kidneys. In blood\u000a      cancers such as MM, a single plasma cell gives rise to a greatly expanded\u000a      neoplastic clone, which\u000a      will secrete FLCs of either kappa or lambda type; it is this\u000a      characteristic and the relative ratio of the\u000a      two FLC types, which the diagnostic tests described in this case study are\u000a      based. As a\u000a      consequence of the increased level of FLCs being produced in diseases such\u000a      as MM, the kidneys\u000a      become saturated and FLC become detectable in the urine. A neoplastic\u000a      clone of plasma cells\u000a      must secrete more than 20g of FLC per day (40x the combined secretion of\u000a      all the body's normal\u000a      polyclonal plasma cells) to saturate the kidneys and for FLCs to become\u000a      detectable in urine.\u000a      Accordingly, it is preferable to assess FLC secretion by measurement of\u000a      FLC in blood, not urine. A\u000a      neoplastic clone of plasma cells only has to secrete 1g\/day of monoclonal\u000a      FLC to reveal its\u000a      presence by distorting the normal blood serum FLC (SFLC) kappa to lambda\u000a      ratio. Despite it\u000a      being preferable to measure FLCs in the serum, it was technically\u000a      challenging to develop such a\u000a      test, this is because the level of SFLCs is 1000 fold less than the level\u000a      of FLC in the bound form of\u000a      the whole immunoglobulin. Thus antibodies for the clinical detection of\u000a      SFLC must have a high\u000a      specificity for epitopes (areas which antibodies bind) that are exposed on\u000a      FLC, but are hidden on\u000a      the form bound to the heavy chain in the whole immunoglobulin. Furthermore\u000a      the FLC epitopes\u000a      that the diagnostic antibody recognises must be present on FLC from all\u000a      patients and normal and\u000a      neoplastic plasma cell clones.\u000a    In the late 1990s Professor Jo Bradwell, Senior Lecturer in the School of\u000a      Immunity and Infection at\u000a      the University of Birmingham (until September 2000) led a team to generate\u000a      polyclonal antibodies\u000a      in sheep for the development of laboratory assays to reliably quantitate\u000a      FLCs in serum samples [1].\u000a      The diagnostic test was based on unique sheep polyclonal antibodies\u000a      directed to either kappa or\u000a      lambda FLC, which were conjugated to latex beads. Following the addition\u000a      of FLC containing\u000a      serum sample to these antibody conjugated beads, turbidimetry or\u000a      nephelometry was used to\u000a      measure the amount of cross linked antibody, which was directly correlated\u000a      to the amount of\u000a      SFLC. Professors Bradwell and Drayson (UoB from 1991) used serum samples\u000a      from the national\u000a      MRC myeloma trials to validate the clinical utility of the test from 2000\u000a      onwards. The greater\u000a      sensitivity of measuring FLC in serum rather than urine was demonstrated\u000a      in myeloma patients\u000a      previously classed as non-secretory because the old gold standard methods\u000a      for detecting\u000a      monoclonal Immunoglobulin\/FLC in serum and urine were negative [2].\u000a      Furthermore in myeloma\u000a      patients who secreted large amounts of FLC with no whole monoclonal\u000a      immunoglobulin detectable,\u000a      the new serum FLC test was shown to be greatly more sensitive for\u000a      detecting response to anti-myeloma\u000a      treatment and relapse from remission than the old urine Bence Jones\u000a      Protein test [3].\u000a    Prospective analysis of the SFLC test was made on 1,970 patients enrolled\u000a      into the MRC Myeloma\u000a      9 trial, confirming and furthering the findings of the retrospective\u000a      studies [4]. The results of this and\u000a      use of the SFLC test in the MERIT trial proved for the first time that\u000a      levels of nephrotoxic FLC could\u000a      be lowered quickly resulting in renal recovery and improved patient\u000a      survival and that the SFLC\u000a      tests provide an early and accurate measurement of disease response and of\u000a      relapse [5].\u000a    Despite the success of the original SFLC test, there are problems with\u000a      the reliance on polyclonal\u000a      antibodies which are difficult to produce and are very subject to batch to\u000a      batch variation. In\u000a      addition the sheep polyclonal antibody based tests (FreeliteTM)\u000a      are restricted to use on expensive\u000a      laboratory nephelometers and turbidimeters, have limited sensitivity and\u000a      range of FLC level\u000a      detection, along with antigen excess problems, where patients with\u000a      exceedingly high levels of\u000a      SFLC would be undetectable. The development of a second generation of FLC\u000a      tests based on use\u000a      of mouse monoclonal antibodies addresses the problems described above.\u000a      Professor Mark\u000a      Drayson led the development and clinical validation of the mouse monclonal\u000a      antibody based,\u000a      second generation SFLC tests over the last five years [6]. The use of\u000a      monoclonal rather than\u000a      polyclonal antibodies overcomes the long term problems of antibody\u000a      production and batch to batch\u000a      variation. Using competitive inhibition strategies overcomes the problem\u000a      of antigen excess and\u000a      greatly broadens the range of FLC levels that can be detected. The first\u000a      of these tests to be\u000a      described uses a flowcytometer platform with multiplexed beads enabling\u000a      kappa and lambda FLC\u000a      to be measured simultaneously, along with eight other immunoglobulin based\u000a      analytes. The\u000a      system has been adapted for nephelometry and turbidimetry platforms but\u000a      also ELISAs allowing\u000a      great flexibility on incorporation of the tests into different laboratory\u000a      systems worldwide.\u000a      Importantly the antibodies and the assay described above have been\u000a      integrated into a point of care\u000a      test which has been launched, bringing immediate improvement to patient\u000a      diagnosis and\u000a      management.\u000a    "},{"CaseStudyId":"38786","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"149590","Name":"Tanzania"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"927384","Name":"Malawi"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The United Nations have set out eight Millennium Development Goals\u000d\u000a      (MDGs), international development objectives that were officially\u000d\u000a      established following the Millennium Summit of the United Nations in 2000.\u000d\u000a      All 189 United Nations member states and at least 23 international\u000d\u000a      organisations have agreed to achieve these goals by the year 2015. The\u000d\u000a      fourth and fifth of these goals are `Reducing child mortality rates'\u000d\u000a      and `Improving maternal health'.\u000d\u000a    Scale of the issue\u000d\u000a    \u000d\u000a      Over 700 women die every day from pregnancy-related\u000d\u000a        complications.\u000d\u000a      \u000a99% of maternal deaths occur in developing countries.\u000d\u000a      Over 1,000,000 children are left motherless each year as a\u000d\u000a        result of this.\u000d\u000a      Babies who survive the death of their mother seldom reach their first\u000d\u000a        birthday.\u000d\u000a    \u000d\u000a    Human resource shortages in the health services have been widely\u000d\u000a      acknowledged as a key threat to the attainment of the health-related MDGs,\u000d\u000a      and there is a very clear need to optimise the capacity and capability of\u000d\u000a      the existing workforce in developing nations.The work driven by Prof Arri\u000d\u000a      Coomarasamy and colleagues in the University of Birmingham has made a\u000d\u000a      significant impact on the thinking of policymakers at an international\u000d\u000a      level, reflected both in international guidelines and recommendations, and\u000d\u000a      in local policy and strategy in maternal health units in the developing\u000d\u000a      world. With respect to traditional birth attendants, it is\u000d\u000a      estimated that more than 50% of all births in developing countries are\u000d\u000a      attended by TBAs, with the rate as high as 80-90% in rural parts of some\u000d\u000a      countries. This form of support has proven very popular with women giving\u000d\u000a      birth in these settings, but without suitable training and support they\u000d\u000a      are not knowledgeable or skilled enough in what is required to undertake\u000d\u000a      safe deliveries, nor do they have appropriate materials\/equipment. Despite\u000d\u000a      previous investment in training programmes for TBAs to upskill the group,\u000d\u000a      prior to the research undertaken by Prof Coomarasamy and colleagues, the\u000d\u000a      main international health organisations were heavily promoting skilled\u000d\u000a      birth attendants for all women and correspondingly discontinuing\u000d\u000a      interventions to improve skills and practices of TBAs. However, this\u000d\u000a      discontinuation was not based on high-quality evidence of either benefit\u000d\u000a      or lack of benefit of these traditional workers. While skilled birth\u000d\u000a      attendants are obviously ideal, they are likely to remain in short supply\u000d\u000a      in rural parts of the developing world in the foreseeable future for\u000d\u000a      economic reasons. They therefore do not represent a practical or at least\u000d\u000a      imminent solution.\u000d\u000a    Carers for babies and mothers clearly need to be appropriately trained,\u000d\u000a      equipped and linked to health services to reduce mortality in both groups,\u000d\u000a      and to this end Prof Coomarasamy's team have worked to promote further\u000d\u000a      evaluation of effects of TBAs, not instead of, but alongside increasing\u000d\u000a      coverage of skilled birth attendants.Their work has clearly demonstrated\u000d\u000a      reductions in neonatal, perinatal and maternal deaths where TBAs were\u000d\u000a      appropriately trained and involved, and an editorial review in the British\u000d\u000a      Medical Journal in December 2011 stated that this research `provides\u000d\u000a      compelling evidence that trained and supported traditional birth\u000d\u000a      attendants save babies lives' [1].\u000d\u000a    Similarly, for non-physician clinicians Prof Coomarasamy's team\u000d\u000a      were able to demonstrate that maternal and perinatal mortality was not\u000d\u000a      significantly different following caesarean section, the most common\u000d\u000a      operation to save mothers and their children in sub-Saharan Africa.\u000d\u000a    The evidence around both groups delivered by Prof Coomarasamy's research\u000d\u000a      has been of major importance to international views on the utility of both\u000d\u000a      traditional birth attendants (TBAs) and non-physician clinicians (NPCs) in\u000d\u000a      caring for mothers and children during pregnancy and birth.To ensure that\u000d\u000a      this work truly makes an impact, researchers at the University of\u000d\u000a      Birmingham have been progressing correspondence, meeting and delivering\u000d\u000a      presentations to individuals from relevant national and international\u000d\u000a      bodies. These include:\u000d\u000a    \u000d\u000a      Margaret Chan (Director-General), World Health Organisation (WHO) — 1st\u000d\u000a        March 2012\u000d\u000a      Andrew Mitchell MP (then UK Secretary of State for International\u000d\u000a        Development) and Nina Gora (Gender and Governance Manager), Oxfam — 11th\u000d\u000a\u0009\u0009May 2012\u000d\u000a      Sir Sabaratnam Arulkumaran (then President) International Federation\u000d\u000a        of Gynaecology and Obstetrics (FIGO) — 9th October 2012\u000d\u000a      Rushanara Ali MP, Shadow Minister for International Development — 24th\u000d\u000a        November 2012\u000d\u000a    \u000d\u000a    Organisations such as WHO know where to target training so that NPCs will\u000d\u000a      be better able to perform obstetric surgery safely and effectively, and\u000d\u000a      Prof Coomarasamy, together with other colleagues who contributed to this\u000d\u000a      research, chiefly Profs Christine MacArthur and KK Cheng, provide informal\u000d\u000a      advisory services to WHO as it designs and formulates its own wider global\u000d\u000a      research programme. The team has also facilitated discussions at\u000d\u000a      international conferences such as the annual FIGO congress (October 2012)\u000d\u000a      to promote the further evaluation of the benefits of better training TBAs\u000d\u000a      and NPCs in the developing world. Additional engagements include guidance\u000d\u000a      of the integration of TBAs into practice, given directly to clinicians in\u000d\u000a      Nigeria.\u000d\u000a    Following these discussions, a personal letter was sent from WHO to the\u000d\u000a      team in 2012 [2] noting that \"your letter pointing to the recent\u000d\u000a      evidence on the effects of trained traditional birth attendants came at\u000d\u000a      a time when several WHO departments were involved in developing WHO\u000d\u000a      recommendations on optimizing the delivery of key, effective\u000d\u000a      interventions to improve maternal and newborn health through\u000d\u000a      task-shifting\". This correspondence further confirmed that, in line\u000d\u000a      with the recommendations of their research, the guideline panel\u000d\u000a      was in favour of recommending lay health-workers to deliver health\u000d\u000a      promotion and counselling advice for various interventions, administration\u000d\u000a      of oral misoprostol for the prevention of postpartum haemorrhage, labour\u000d\u000a      companionship and oral supplements (calcium in areas of low calcium\u000d\u000a      intake, iron-folate, intermittent presumptive malaria treatment and\u000d\u000a      vitamin A in areas with deficiency) with targeted monitoring and\u000d\u000a      evaluation activities.\u000d\u000a    Subsequent WHO publications explicitly recommended the use of NPCs for\u000d\u000a      numerous tasks in hospital settings and TBAs \"in settings where serious\u000d\u000a      service gaps exist\" [3]. Prof Coomarasamy was the first author explicitly\u000d\u000a      thanked for his assistance and collaboration in updating the relevant\u000d\u000a      material and providing additional information. This is strong evidence\u000d\u000a      that the team's research has changed international thinking on the\u000d\u000a      importance of these other skilled groups in maternal and infant care, and\u000d\u000a      therefore made a substantial impact in the effort towards the reduction of\u000d\u000a      maternal and perinatal mortality worldwide. For example, the Deputy\u000d\u000a      Director of the Ifakara Health Institute in Tanzania wrote to the team [4]\u000d\u000a      to confirm that:\"The extensive and compelling research from your team\u000d\u000a      at the University of Birmingham into the value of task shifting and the\u000d\u000a      innovative utilisation of alternative health cadres to maximise the\u000d\u000a      opportunities to improve maternal health in less economically developed\u000d\u000a      countries has been crucial to the understanding of this issue within the\u000d\u000a      Ifakara Health Institute in Tanzania, and our subsequent work adapting\u000d\u000a      to the recommendations that it has contributed to in international\u000d\u000a      policy in this area.\"\u000d\u000a    The Head of the Department of Obstetrics and Gynaecology at University of\u000d\u000a      Malawi College of Medicine also wrote to highlight: \"The importance of\u000d\u000a      clear and robust evidence of the beneficial roles of traditional birth\u000d\u000a      attendants and non-physician clinicians in our local context cannot be\u000d\u000a      overstated. Whilst we all recognise that universal access to skill birth\u000d\u000a      attendants and improved coverage of obstetricians would be the ideal,\u000d\u000a      the reality is that there is a continual struggle to deliver care with\u000d\u000a      the limited providers available. The findings of your studies are most\u000d\u000a      helpful to inform not only our strategic priorities for future\u000d\u000a      investment but also our daily operational tasks.\"[5]\u000d\u000a    To support international advocacy around issues relating to maternal and\u000d\u000a      child health, Professor Coomarasamy was instrumental in the establishment\u000d\u000a      of the charity Ammalife, and remains a trustee and the charity's primary\u000d\u000a      contact. The charity run projects, undertakes internationally-valued\u000d\u000a      research, provide specialist advice, education and training & work\u000d\u000a      with others to advance women's health rights. Ammalife has supported much\u000d\u000a      of the work detailed in this case study through funding and support for\u000d\u000a      dissemination, such as work with team member Amie Wilson,who was nominated\u000d\u000a      as one of Oxfam's Most Inspiring Women in the Midlands in March 2011 [6]\u000d\u000a      for her contributions to international charity work (including promoting\u000d\u000a      uptake of the team's research in developing countries). Ammalife have\u000d\u000a      campaigned to support the research outlined here through their links with\u000d\u000a      many of the large international bodies mentioned above, and to raise\u000d\u000a      public and policy-makers awareness of these issues and the validity of the\u000d\u000a      solutions proposed.\u000d\u000a    Through Ammalife, the University of Birmingham research team has\u000d\u000a      collaborated with Made in Europe to produce an evidence-based resource\u000d\u000a      pack of the top 20 interventions to reduce maternal death, including the\u000d\u000a      roles of TBAs and NPCs [7]. The pack has been distributed to numerous\u000d\u000a      charities across the UK (Muslim Charity, Islamic relief, Muslim Hands, Al\u000d\u000a      Muntada Trust, Muslim Charities Forum). This work has raised maternal\u000d\u000a      health issue awarenessand engagement amongst many prominent Muslim\u000d\u000a      scholars (58 have confirmed that they are actively supporting the\u000d\u000a      approaches outlined); supported 776 workshops; and they raised the\u000d\u000a      proportion of Muslim NGOs increasing programme activity on maternal health\u000d\u000a      in their budgets and strategies by 30% [8]. The work was celebrated by\u000d\u000a      Baroness Jenny Tonge (Chair of the UK All Party Parliamentary Group on\u000d\u000a      Population, Development and Reproductive Health) in a House of Commons\u000d\u000a      reception [9].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Maternal health and mortality remains a major concern in the developing\u000d\u000a      world. Research led by Prof Arri Coomarasamy and colleagues at the\u000d\u000a      University of Birmingham has demonstrated the effectiveness of non-typical\u000d\u000a      support for maternal health in low- and middle-income countries worldwide,\u000d\u000a      focused on the benefits of bringing in traditional birth attendants and\u000d\u000a      non-physician clinicians to support the slow process of developing more\u000d\u000a      capacity amongst skilled birth attendants in these regions. Prior to this\u000d\u000a      work, these individuals were considered unsafe and inappropriate to\u000d\u000a      support births, even though they were conducting millions of deliveries in\u000d\u000a      the developing world. Prof Coomarasamy's team's research clearly\u000d\u000a      demonstrated that this is not the case. This has had a major impact on\u000d\u000a      international thinking about the valuable role of non-physician support\u000d\u000a      for maternal health and mortality, reflected in the latest World Health\u000d\u000a      Organisation task-shifting recommendations. In these and other related\u000d\u000a      issues, policy and public awareness has been further supported by Prof\u000d\u000a      Coomarasamy's crucial role in Ammalife, an international maternal health\u000d\u000a      charity focused on the developing world.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"159492","Name":"Ifakara"}],"References":"\u000d\u000a    \u000a1. Jokhio AH, Winter HR, Cheng KK. An intervention involving traditional\u000d\u000a      birth attendants and perinatal and maternal mortality in Pakistan. New\u000d\u000a      England Journal of Medicine. 2005; 352(20): 2091-2099. doi:\u000d\u000a        10.1056\/NEJMsa042830\u000d\u000a    \u000a\u000a2. Wilson A, Gallos I, Planar N, Lissauer D, Khan K, Zamora J, MacArthur\u000d\u000a      C, Coomarasamy A. Effectiveness of strategies incorporating training and\u000d\u000a      support of traditional birth attendants on perinatal and maternal\u000d\u000a      mortality: A meta-analysis. BMJ 2011; 343:d7102. doi: http:\/\/dx.doi.org\/10.1136\/bmj.d7102\u000d\u000a    \u000a\u000a3. Wilson A, Lissauer D, Thangaratinam S, Khan K, MacArthur C,\u000d\u000a      Coomarasamy A. A comparison of clinical officers with medical doctors on\u000d\u000a      outcomes of caesarean section in the developing world: meta-analysis of\u000d\u000a      controlled studies. BMJ 2011; 342:d2600. doi: http:\/\/dx.doi.org\/10.1136\/bmj.d2600\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    \u000d\u000a      Hodnett E. Traditional birth attendants are an effective resource. BMJ\u000d\u000a        2012; 344. doi: http:\/\/dx.doi.org\/10.1136\/bmj.e365\u000a\u000d\u000a      Personal correspondence from WHO\u000d\u000a      WHO recommendations: optimizing health worker roles to improve access\u000d\u000a        to key maternal and newborn health interventions through task shifting.\u000d\u000a        WHO: 2012.\u000d\u000a      Letter of support from Deputy Director, Ifakara Health Institute\u000d\u000a      Letter of support from Head of the Department of Obstetrics and\u000d\u000a        Gynaecology, University of Malawi College of Medicine\u000d\u000a      Oxfam's Most Inspiring Women in the Midlands: http:\/\/suttoncoldfieldlocal.co.uk\/oxfams-birth-\u000a          rights-exhibition-at-good-hope-hospital\/\u000a\u000d\u000a      At Our Mothers' Feet campaign NGO resource pack, MADE in Europe in\u000d\u000a        partnership with Ammalife and support from the UK Department for\u000d\u000a        International Development\u000d\u000a      MADE Partnership annual report 2013\u000d\u000a      House of Commons At Our Mothers' Feet reception invitation\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Promoting non-physician support for maternal health in the developing\u000d\u000a      world\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2655603","Name":"Birmingham"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Traditional birth attendants: Women in developing countries face\u000d\u000a      significant barriers when accessing healthcare; financial, geographical,\u000d\u000a      and cultural. This is why 99% of all maternal deaths worldwide occur in\u000d\u000a      the developing world, and 98% of stillbirths and newborn deaths. 60\u000d\u000a      million births per year take place outside healthcare facilities, more\u000d\u000a      than half without assistance from a skilled birth attendant, i.e.\u000d\u000a      accredited health professionals such as midwives or doctors, trained to\u000d\u000a      manage normal pregnancy and childbirth. Instead most women are supported\u000d\u000a      by local women known as `traditional birth attendants' (TBAs), who rather\u000d\u000a      than regulated training or governance acquired their skills through\u000d\u000a      experience of delivering babies or apprenticeship with other TBAs.\u000d\u000a    Training programmes for TBAs began over 60 years ago and in 1994 more\u000d\u000a      than 85% of developing countries operated some form of TBA training to\u000d\u000a      improve maternal and perinatal outcomes. By 1998, TBA training was a\u000d\u000a      central component of the Safe Motherhood Initiative launched by WHO,\u000d\u000a      United Nations Children's Fund (UNICEF), United Nations Population Fund,\u000d\u000a      World Bank, and other organizations. However there was a lack of evidence\u000d\u000a      from randomised, controlled trials to inform policy-level decision making\u000d\u000a      of effectiveness of such training. In 1998, a team at the University of\u000d\u000a      Birmingham led by Prof KK Cheng collaborated with colleagues in Pakistan\u000d\u000a      to conduct a cluster randomised controlled trial in training TBAs,\u000d\u000a      providing clean delivery kits and linking TBAs with health services. The\u000d\u000a      results, published in New England Journal of Medicine, showed a\u000d\u000a      statistically significant 30% reduction in perinatal (i.e. immediately\u000d\u000a      before,during or after birth) mortality and a similar size reduction in\u000d\u000a      maternal mortality, indicating that substantial improvements in outcomes\u000d\u000a      could be achieved with this intervention [1].\u000d\u000a    Understanding the potential impact of the Pakistan findings, Arri\u000d\u000a      Coomarasamy (Professor of Gynaecology and Reproductive Medicine, at the\u000d\u000a      University of Birmingham since 2008) and colleagues (Dr Heather Winter\u000d\u000a      (deceased), Prof Christine MacArthur, at UoB since 1988; Prof KK Cheng, at\u000d\u000a      UoB since 1993) have worked to promote further evaluation of effects of\u000d\u000a      TBAs, not instead of, but alongside increasing coverage of skilled birth\u000d\u000a      attendants. In 2009 a Cochrane review from another team described the\u000d\u000a      potential of training for TBAs as `promising' (Sibley et al, Cochrane\u000d\u000a      Database Syst Rev 2009;3:CD005460), but at that time the study by\u000d\u000a      researchers in Birmingham was the first and only randomised controlled\u000d\u000a      trial to consider the subject. Therefore evidence to inform and guide any\u000d\u000a      decision-making, policy formulation and investment in training was still\u000d\u000a      lacking. In view of this uncertainty, in 2011 Prof Coomarasamy conducted a\u000d\u000a      systematic review and meta-analysis to investigate the effectiveness of\u000d\u000a      strategies incorporating training and support of TBAs on perinatal and\u000d\u000a      maternal outcomes [2].This review identified six cluster randomised\u000d\u000a      controlled trials and seven non-randomised controlled studies, and\u000d\u000a      meta-analysis (a statistical overview of different primary studies\u000d\u000a      considering the same research question) showed significant reductions in\u000d\u000a      perinatal\/neonatal death and a reduction in maternal death where TBAs\u000d\u000a      provided assistance.\u000d\u000a    Non-physician clinicians: Lack of doctors, particularly specialist\u000d\u000a      trained doctors, greatly affects the availability of care in developing\u000d\u000a      countries, and more specifically the availability of emergency obstetric\u000d\u000a      surgery such as caesarean section. Non-physician clinicians (NPCs) are not\u000d\u000a      doctors; they follow a separate training program, but carry out many tasks\u000d\u000a      performed by doctors such as diagnosis, treatment, surgery and\u000d\u000a      prescribing. Their qualification is not internationally recognised, but\u000d\u000a      they are often significantly (by around five times) less costly than\u000d\u000a      doctors to train and employ. NPCs were initially introduced to fill the\u000d\u000a      coverage gaps within healthcare services in developing countries, but they\u000d\u000a      have now become an integral part of health systems, providing a\u000d\u000a      substantial amount of medical care. NPCs roles within obstetrics vary, yet\u000d\u000a      in less than half of countries in sub-Saharan Africa are they permitted to\u000d\u000a      perform caesarean section.\u000d\u000a    Caesarean section is the most common major operation performed to save\u000d\u000a      the life of a mother or baby in sub-Saharan Africa. The availability of\u000d\u000a      good quality routine and emergency obstetric care has been proven to\u000d\u000a      improve maternal and perinatal outcomes. Aware of the shortage of doctors,\u000d\u000a      Prof Coomarasamy's team recognised the potential beneficial impact of NPCs\u000d\u000a      within obstetric care. However, there was uncertainty around about their\u000d\u000a      role, effectiveness, and their safety, a key need given the central role\u000d\u000a      that NPCs could play in increasing the availability of obstetric surgery.\u000d\u000a    Prof Coomarasamy's team's susbsequent systematic review and meta-analysis\u000d\u000a      of six comparative studies in developing countries [3] compared the\u000d\u000a      outcomes of caesarean section performed by NPCs and doctors. The results\u000d\u000a      of the study showed that there are no significant differences between the\u000d\u000a      rates of maternal and perinatal mortality incurred by NPCs and doctors\u000d\u000a      following caesarean section, but that there are more wound complications\u000d\u000a      following NPC surgery.\u000d\u000a    "},{"CaseStudyId":"38787","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Impact on policy and guidance\u000d\u000a    Since the publication of the research outcomes in 2010, the work has\u000d\u000a      attracted considerable attention across the UK and internationally. The\u000d\u000a      findings from the research described above were used by the DoH in\u000d\u000a      formulating their national policy for MRSA screening in patients\u000d\u000a      (published in 2008), which required all NHS trusts to screen all elective\u000d\u000a      patients on admission and all emergency admissions as soon as practicable\u000d\u000a      possible for MRSA [1, 2]. The letter supplied by the Inspector of\u000d\u000a      Microbiology and Infection Control at the DoH details that \"the work in\u000d\u000a      Birmingham was an important contribution to our [DoH] understanding of the\u000d\u000a      epidemiology of MRSA in hospital patients\" and \"the study on the use of\u000d\u000a      rapid screening methods to identify patients colonised with MRSA on\u000d\u000a      admission was a seminal study that informed and influenced the national\u000d\u000a      guidance on screening from the DoH\" [3]. The importance of the work in\u000d\u000a      influencing NHS policy and practice is further exemplified in the letter\u000d\u000a      supplied by the Director of Infection Prevention and Control at the\u000d\u000a      Hammersmith Hospital, London, who detailed that `the work provided\u000d\u000a      valuable information to the NHS and all NHS trusts about the effectiveness\u000d\u000a      and application of such screening in the NHS environment to tackle the\u000d\u000a      challenge of MRSA\" [4]. The results of this work have been widely used\u000d\u000a      internationally in formulating guidance on the use of screening in USA [5]\u000d\u000a      and Europe [6].\u000d\u000a    Impact on Infection rates and patient outcomes\u000d\u000a    The combination of control measures (including PCR screening) instituted\u000d\u000a      in England has resulted in a 38% decrease in MRSA bacteraemias from\u000d\u000a      April-June 2009 compared to April-June 2011 with substantial improvements\u000d\u000a      in patient outcome, as reported on the Department of Health\/Public Health\u000d\u000a      England website for mandatory reporting [7]. These measures include\u000d\u000a      screening of the patient, followed by prompt decolonisation and isolation,\u000d\u000a      with the advantage of PCR testing being that patients are identified\u000d\u000a      rapidly enabling control measures to be implemented in real time. This has\u000d\u000a      the effect of limiting the transmission of MRSA to other patients on the\u000d\u000a      ward and thereby preventing colonisation and infection.\u000d\u000a    Impact on clinical practice\u000d\u000a    Following the completion of the research, a business plan was written by\u000d\u000a      Professor Peter Hawkey and presented to the Heart of England NHS\u000d\u000a      Foundation Trust recommending the use of PCR based MRSA screening for\u000d\u000a      emergency patients. This strategy was adopted in June 2008 and since the\u000d\u000a      introduction the number of MRSA bacteraemias has continued to decline and\u000d\u000a      the Trust has met the targets that the DoH has set. Annually the Trust\u000d\u000a      screens 71,000 patients for MRSA using the molecular method. Heart of\u000d\u000a      England NHS Foundation Trust published in 2010 that \"by using the latest\u000d\u000a      DNA technology to find patients carrying MRSA within hours of admission\u000d\u000a      and giving them treatment, the chance of those patients passing on MSRA\u000d\u000a      was reduced by 50%\" [8]. Furthermore the Health Protection Agency\u000d\u000a      published in 2009 that \"the use of rapid surveillance testing can further\u000d\u000a      accelerate the reduction in MRSA transmission\", with Professor Hawkey's\u000d\u000a      research being cited directly [9].\u000d\u000a    The proposal for the use of rapid screening form MRSA coupled with\u000d\u000a      decolonisation in a selected setting (high incidence surgical patients)\u000d\u000a      has been modelled for cost effectiveness by a collaboration of\u000d\u000a      international centres and found to be one of the best options [10].\u000d\u000a    At the 2011 General Meeting of the American Society of Microbiology\u000d\u000a      (largest US infection society) Professor Peter Hawkey's work was cited by\u000d\u000a      the Director of Microbiology and Infectious Disease Research at NorthShore\u000d\u000a      University Healthcare System, as one of the most significant studies (as\u000d\u000a      it captured ≥ 80% of missed isolation days) supporting rapid PCR screening\u000d\u000a      of surgical patients [11].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Methicillin-resistant Staphylococcus aureus (MRSA) are strains of\u000d\u000a      bacteria which are resistant to a range of commonly used antibiotics and\u000d\u000a      as a result are difficult to treat and cause significant morbidity and\u000d\u000a      mortality amongst hospitalised patients and individuals with compromised\u000d\u000a      immunity. Research conducted by Professor Peter Hawkey at the University\u000d\u000a      of Birmingham has demonstrated that by rapidly screening patients for MRSA\u000d\u000a      on hospital admission and then using an effective decolonisation\u000d\u000a      treatment, the rate of MRSA acquisition can be significantly reduced. The\u000d\u000a      Department of Health (DoH), who commissioned the research, used the\u000d\u000a      results of the work to formulate guidance, which was published in 2008,\u000d\u000a      for universal MRSA screening in England. This has contributed to the\u000d\u000a      sustained reduction in MRSA infection in England, which is indicated by\u000d\u000a      the fall in MRSA bacteraemia rates from 7,274 in 2002 to 1,185 in 2011\u000d\u000a      (-83.7%).\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    1. Department of Health Grant: A study of the efficacy and\u000d\u000a      cost-effectiveness of MRSA screening and monitoring on surgical wards\u000d\u000a      using a new, rapid molecular test (EMMS), award to: Professor Peter\u000d\u000a      Hawkey. Period of the grant: October 2005 to June 2007. Value of the\u000d\u000a      grant: £575,046\u000d\u000a    \u000a2. Hardy KJ, Szczepura A, Davies R, Bradbury A, Stallard N,\u000d\u000a      Gossain S, Walley P, Hawkey PM. A\u000d\u000a        study of the efficacy and cost-effectiveness of MRSA screening and\u000d\u000a        monitoring on surgical wards using a new, rapid molecular test (EMMS).\u000d\u000a        BMC Health Serv Res. 2007 Oct 3;7:160. DOI 10.1186\/1472-6963-7-160\u000d\u000a    \u000a\u000a3. Hardy K, Price C, Szczepura A, Gossain S, Davies R,\u000d\u000a      Stallard N, Shabir S, McMurray C, Bradbury A, Hawkey PM.\u000d\u000a      Reduction in the\u000d\u000a        rate of methicillin-resistant Staphylococcus aureus acquisition\u000d\u000a        in surgical wards by rapid screening for colonization: a prospective,\u000d\u000a        cross-over study. Clin Microbiol Infect. 2010 Apr;16(4):333-9. DOI\u000d\u000a          10.1111\/j.1469-069.2009.02899x\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    \u000d\u000a      Operational guidance document from DoH detailing screening\u000d\u000a        requirements (31st July 2008), sent to all NHS Chief\u000d\u000a        Executives and other senior NHS officials.\u000d\u000a      Operational document from DoH detailing screening requirements (31st\u000d\u000a        March 2010)\u000d\u000a      Letter of support from the Inspector of Microbiology and Infection\u000d\u000a        Control at the Department of Health\u000d\u000a      Letter of support from the Director of Infection Prevention and\u000d\u000a        Control at the Hammersmith Hospital, London.\u000d\u000a      Marlowe et al, 2011, Conventional and Molecular Methods for the\u000d\u000a        Detection of Methicillin-Resistant Staphylococcus aureus, JCM,\u000d\u000a        49 : S53-6\u000d\u000a      Harbarth et al, 2010, Update on screening and clinical diagnosis of\u000d\u000a        methicillin-resistant Staphylococcus aureus (MRSA), IJAA, 37(2)\u000d\u000a        : 110-7\u000d\u000a      \u000ahttp:\/\/www.hpa.org.uk\/web\/HPAweb&HPAwebStandard\/HPAweb_C\/1233906819629\u000d\u000a        (table 2a)\u000d\u000a      Heart of England NHS Foundation Trust, 2010, Warding off MRSA through\u000d\u000a        rapid screening study drives down super bugs\u000d\u000a      HPA, 2011, Health Protection Report, Study concludes active\u000d\u000a        surveillance testing with molecular methods reduces transmission of MRSA\u000d\u000a        among surgical patients\u000d\u000a      Hubben et al, 2011, Modelling the costs and effects of selective and\u000d\u000a        universal hospital admission screening for methicillin-resistant Staphylococcus\u000a          aureus, PloSOne, 6(3): e14783\u000d\u000a      Petersen, 2011, Molecular vs non-Molecular Testing for MRSA\/MSSA: The\u000d\u000a        Case for Molecular Screening\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Saving lives through universal MRSA Screening\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Staphylococcus aureus is an opportunistic pathogen, with about a third of\u000d\u000a      the population being colonised. It can cause disease if there is an\u000d\u000a      opportunity for it to enter the body through broken skin, or a procedure\u000d\u000a      requiring the use of an invasive medical device. If the bacteria enter the\u000d\u000a      body, mild to life-threatening illnesses may then develop. MRSA strains\u000d\u000a      have emerged which are not only resistant to beta lactam antibiotics,\u000d\u000a      (e.g. flucloxacillin, amoxicillin and cephalosporins), but many other\u000d\u000a      unrelated antibiotics. MRSA is an important health care associated\u000d\u000a      infection as it is difficult to treat and causes a significant degree of\u000d\u000a      morbidity and mortality, with between 1000 and 2000 deaths per year in the\u000d\u000a      UK being attributed to MRSA between 2001 and 2009 (Office of National\u000d\u000a      Statistics Data). Since April 2001 there has been mandatory reporting of\u000d\u000a      all MRSA bacteraemias, which are used as a surrogate marker for the\u000d\u000a      prevalence of MRSA in England. In 2003\/4 the government introduced targets\u000d\u000a      for each NHS Trust and, as a result, multiple infection control measures\u000d\u000a      were introduced. Prior to introducing universal screening for MRSA in\u000d\u000a      England, a controlled trial investigating the impact on MRSA rates of two\u000d\u000a      different screening methodologies was funded by the DoH and undertaken by\u000d\u000a      Professor Hawkey (Professor of Clinical and Public Health Bacteriology, at\u000d\u000a      UoB from 2012) and Dr Hardy (Clinical Scientist) at the University of\u000d\u000a      Birmingham from January 2005 to April 2007 [1].\u000d\u000a    A prospective, cluster, two period cross-over design was used. Seven\u000d\u000a      surgical wards at a large hospital were allocated to two groups, and for\u000d\u000a      the first eight months four wards used rapid MRSA screening by polymerase\u000d\u000a      chain reaction (PCR) and three wards used a standard culture method. The\u000d\u000a      groups were reversed for the second eight months. Regardless of the method\u000d\u000a      of detection, all patients were screened for nasal carriage of MRSA on\u000d\u000a      admission and every four days thereafter. MRSA control measures were the\u000d\u000a      same in both arms and included barrier nursing or isolation of patient,\u000d\u000a      prescribing of decolonisation treatment and alteration of prophylaxis if\u000d\u000a      having surgery [2]. Results were analysed using a log linear Poisson\u000d\u000a      regression model. A total of 12,682\/13,952 patient ward episodes were\u000d\u000a      included in the study.\u000d\u000a    Admission screening identified 453 (3.6%) MRSA positive patient ward\u000d\u000a      episodes, with a further 268 (2.2%) acquiring MRSA post-admission. After\u000d\u000a      adjusting for other variables, rapid PCR screening was shown to\u000d\u000a      statistically reduce MRSA acquisition with patients being 1.49 times\u000d\u000a      (p=0.007) more likely to acquire MRSA in wards where they were screened\u000d\u000a      using the culture method [3]. Screening of surgical patients using rapid\u000d\u000a      PCR testing resulted in a statistically significant reduction in MRSA\u000d\u000a      acquisition [3].\u000d\u000a    "},{"CaseStudyId":"38788","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The outcomes of this research have supported policy makers and opinion\u000d\u000a      leaders to formulate opinions as to the safe use of antibiotics in food\u000d\u000a      producing animals and have been used extensively by the FDA in their\u000d\u000a      proposal to ban the fluoroquinolone antibiotics enrofloxacin and\u000d\u000a      sarafloxacin use in food producing animals, which became law in the USA in\u000d\u000a      September 2005 (1, 2) and which has, therefore, impacted substantially\u000d\u000a        on the use of antibiotics in food producing animals and the presence of\u000d\u000a        antibiotic resistant strains in the food chain since this date and\u000d\u000a        throughout the impact period.\u000d\u000a    The major impact of this work within the period of review relates\u000d\u000a      to the continuing impact of the ban of fluoroquinolone antibiotic use in\u000d\u000a      animals and the consequent impact on human health. The ban on the use of\u000d\u000a      these types of antibiotics has resulted in a reduction in the presence of\u000d\u000a      antibiotic resistant strains in the human food chain. Following the ban on\u000d\u000a      the use of fluoroquinolone antibiotics in food producing animals, studies\u000d\u000a      have been conducted by a variety of groups including US Food Safety\u000d\u000a      Research Organisations (3), the FDA (4) and Academics Food Science\u000d\u000a      Departments (5) to examine the impact of the ban on fluoroquinolone\u000d\u000a      resistance levels in pathogens isolated from food producing animals. These\u000d\u000a      studies have shown varied patterns of resistance for different bacterial\u000d\u000a      strains, with decreases in the proportion of resistant strains of E.\u000d\u000a        coli and Enterococcus being identified in isolates from food\u000d\u000a      producing animals (3-5). In contrast for Campylobacter, no change in the\u000d\u000a      levels of resistant strains were identified in samples taken immediately\u000d\u000a      after the ban, however in more recent studies decreases in the level of\u000d\u000a      resistant strains have been detected (3-5). These data suggest that the\u000d\u000a      ban of fluoroquinolone use has impacted on different species in different\u000d\u000a      ways, but overall there has been a reduction in fluoroquinolone resistance\u000d\u000a      rates of pathogenic species in animal isolates present in the food chain.\u000d\u000a      Latest data from the USA where the fluoroquinolone ban in veterinary\u000d\u000a      medicine was enforced shows very low levels of fluoroquinolone resistance\u000d\u000a      in Salmonella isolated from people, whilst rates of\u000d\u000a      resistant isolates of Campylobacter have remained steady (6).\u000d\u000a    The work was disseminated by publication in international peer reviewed\u000d\u000a      journals, conference presentations and informal discussion with government\u000d\u000a      agencies including the Department for the Environment, Food and Rural\u000d\u000a      Affairs (DEFRA), Veterinary Medicines Directive (VMD) and Advisory\u000d\u000a      Committee on the Microbiological Safety of Food (ACMSF) and continues to\u000d\u000a      this day. In the UK, the VMD reviewed the licences of fluoroquinolone\u000d\u000a      antibiotics but did not withdraw the products from market. Instead they\u000d\u000a      increased awareness of the impact of the use of fluoroquinolone\u000d\u000a      antibiotics in animals, through the publication of advisory material (7)\u000d\u000a      and this has led to a reduction of the amount used by veterinarians. The\u000d\u000a      European Medicines Agency is again reviewing the EU policy on antibiotics\u000d\u000a      used veterinary medicine on a case by case basis and the use of\u000d\u000a      fluoroquinolone antibiotics in animals reared for food production has once\u000d\u000a      again come under close scrutiny (8). Data arising from research carried\u000d\u000a      out by the Piddock team is part of the portfolio of evidence being\u000d\u000a      re-examined.\u000d\u000a    Professor Laura Piddock has also used her international profile in the\u000d\u000a      field of antimicrobial resistance to launch the `Antibiotic Action'\u000d\u000a      campaign — a global initiative designed to inform and educate all about\u000d\u000a      the need for discovery, research and development of new antibiotics as\u000d\u000a      well as appropriate use (http:\/\/antibiotic-action.com\/).\u000a      Professor Piddock has also been awarded a Chair from the British Society\u000d\u000a      in Antimicrobial Chemotherapy in Public Engagement. These activities have\u000d\u000a      resulted in significant recent interactions with politicians, policy\u000d\u000a      makers, industry, the media and general public and allowed her to engage\u000d\u000a      with broad audiences and explain issues including the use of antibiotics\u000d\u000a      in animals (9-10). This activity can be quantified by the number of\u000d\u000a      articles, radio and television programmes and interviews on antibiotics an\u000d\u000a      antibiotic resistance pre November 2011 (when Antibiotic Action was\u000d\u000a      launched) and 2013: using the unique combination of search term words\u000d\u000a      `Professor LJV Piddock, Director of Antibiotic Action' has been quoted in\u000d\u000a      print, broadcast and digital media to the lay and specialist press over\u000d\u000a      7000 times..\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research by Professor Laura Piddock at the University of Birmingham has\u000d\u000a      shown that the use of fluoroquinolone antibiotics in veterinary medicine\u000d\u000a      can select for antibiotic resistance in certain strains of bacteria which\u000d\u000a      then present a potential risk to human health. Fluoroquinolone antibiotics\u000d\u000a      are widely used in human medicine to treat bacterial infections. For those\u000d\u000a      patients with chronic bacterial gastroenteritis and\/or an invasive\u000d\u000a      infection, fluoroquinolone antibiotics are the empiric treatment of choice\u000d\u000a      by GPs; resistance to these agents represents a large public health risk.\u000d\u000a      The outcomes of the research have been used by policy makers to define the\u000d\u000a      human risks of food borne infection from antibiotic resistant strains and\u000d\u000a      have led to the review and amendment of international policy on the use of\u000d\u000a      antibiotics in food producing animals, in particular the World Health\u000d\u000a      Organisation (published outside of the review period) and US Food and Drug\u000d\u000a      Administration (FDA). The research described has had a direct impact on\u000d\u000a      international policy and the ban on the use of certain antibiotics has had\u000d\u000a      an impact on the levels of fluoroquinolone resistance in bacteria isolated\u000d\u000a      from food producing animals, reducing the transmission of resistant\u000d\u000a      strains to humans.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Gaunt PN, Piddock LJ. Ciprofloxacin resistant Campylobacter\u000d\u000a      spp. in humans: an epidemiological and laboratory study. J Antimicrob\u000d\u000a      Chemother. 1996; 37:747-57. PMID: 8722540\u000d\u000a    \u000a\u000a2. Piddock, L.J.V., Ricci, V., Pumbwe, L, Everett, M.J. & Griggs,\u000d\u000a      D.J. (2003) Fluoroquinolone Resistance in Campylobacter species\u000d\u000a      from Man and Animals: detection of mutations in Topoisomerase Genes Journal\u000d\u000a        of Antimicrobial Chemotherapy 51: 19-26. PMID: 12493783\u000d\u000a    \u000a\u000a3. Delsol AA, Sunderland J, Woodward MJ, Pumbwe L, Piddock LJ, Roe\u000d\u000a      JM. Emergence of fluoroquinolone resistance in the native Campylobacter\u000d\u000a      coli population of pigs exposed to enrofloxacin. J Antimicrob Chemother.\u000d\u000a      2004 May;53(5):872-4. Epub 2004 Mar 17. PMID: 15028665.\u000d\u000a    \u000a\u000a4. Humphrey TJ, Jørgensen F, Frost JA, Wadda H, Domingue G, Elviss\u000d\u000a      NC, Griggs DJ, Piddock LJ. Prevalence and subtypes of\u000d\u000a      ciprofloxacin-resistant Campylobacter spp. in commercial poultry flocks\u000d\u000a      before, during, and after treatment with fluoroquinolones. Antimicrob\u000d\u000a      Agents Chemother. 2005 Feb;49(2):690-8. PubMed PMID: 15673753; PMID:\u000d\u000a        547194.\u000d\u000a    \u000a\u000a5. Griggs, D.J., Johnson, M.M., Frost, J.A., Humphrey, T.J,\u000d\u000a      Jorgensen, F., Piddock, L.J.V. (2005). The incidence and mechanism of\u000d\u000a      ciprofloxacin resistance in Campylobacter spp. isolated from\u000d\u000a      commercial poultry flocks in the United Kingdom before, during and after\u000d\u000a      fluoroquinolone treatment. Antimicrobial Agents and Chemotherapy\u000d\u000a      49: 699-707 PMID: 15673754\u000d\u000a    \u000a\u000a6. Randall LP, Eaves DJ, Cooles SW, Ricci V, Buckley A, Woodward MJ,\u000d\u000a      Piddock LJ. Fluoroquinolone treatment of experimental Salmonella enterica\u000d\u000a      serovar Typhimurium DT104 infections in chickens selects for both gyrA\u000d\u000a      mutations and changes in efflux pump gene expression. J Antimicrob\u000d\u000a      Chemother. 2005 Aug;56(2):297-306. Epub 2005 Jun 14. PMID: 15956100.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000d\u000a    \u000d\u000a      http:\/\/www.fda.gov\/AnimalVeterinary\/NewsEvents\/CVMUpdates\/ucm048444.htm\u000d\u000a      http:\/\/www.fda.gov\/AnimalVeterinary\/SafetyHealth\/RecallsWithdrawals\/ucm042004.htm\u000d\u000a      Ciprofloxacin-resistant Campylobacter persists in raw retail chicken\u000d\u000a        after the fluoroquinolone ban. Nannapaneni R, Hanning I, Wiggins KC,\u000d\u000a        Story RP, Ricke SC, Johnson MG. Food Addit Contam Part A Chem Anal\u000d\u000a        Control Expo Risk Assess. 2009 Oct;26(10):1348-53.PMID: 21462579\u000d\u000a      Antimicrobial resistance of Campylobacter isolates from retail meat in\u000d\u000a        the United States between 2002 and 2007. Zhao S, Young SR, Tong E,\u000d\u000a        Abbott JW, Womack N, Friedman SL, McDermott PF. Appl Environ Microbiol.\u000d\u000a        2010 Dec;76(24):7949-56. Epub 2010 Oct 22. PMID:20971875\u000d\u000a      Prevalence and antimicrobial resistance among Campylobacter spp. in\u000d\u000a        Louisiana retail chickens after the enrofloxacin ban. Han F, Lestari SI,\u000d\u000a        Pu S, Ge B. Foodborne Pathog Dis. 2009 Mar;6(2):163-71. doi:\u000d\u000a        10.1089\/fpd.2008.0171.\u000d\u000a      Annual report of the National Antimicrobial Resistance Monitoring\u000d\u000a        System 2011.\u000d\u000a        http:\/\/www.cdc.gov\/narms\/pdf\/2011-annual-report-narms-508c.pdf\u000a\u000d\u000a      VMD guidance material published on the use of fluroquinolone\u000d\u000a        antibiotics — updated June 2011.\u000d\u000a      http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/news_and_events\/news\/2013\/04\/news_detail_001764.jsp&mid=WC0b01ac058004d5c1\u000d\u000a      The world poultry science association and British society for animal\u000d\u000a        science annual conference, Nottingham April 2013. Talk title: Effects of\u000d\u000a        antibiotic resistance in food borne bacteria on human health. http:\/\/www.wpsa-uk.com\/newSite\/meetings\/2013_AnnualMeeting.html\u000a\u000d\u000a      Drug information association conference, Amsterdam, March 2013.\u000d\u000a        Largest European conference in pharmaceutical sciences and which is\u000d\u000a        attended by all major Pharma and SMEs, and pharmacists in industry,\u000d\u000a        academia and the Healthcare sectors. Talk title: Getting the message\u000d\u000a        across - using antibiotics appropriately. http:\/\/www.diahome.org\/en-GB\/Flagship-Meetings\/13101-EuroMeeting.aspx\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Providing an evidence base for the FDA ban of fluoroquinolone\u000d\u000a        antibiotic use in animals\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Non-typhoidal Salmonella and Campylobacter are the top two causes of\u000d\u000a      human bacterial gastroenteritis, generally arising from the consumption of\u000d\u000a      infected meat and poultry. Chronic and invasive infections by these\u000d\u000a      species in people are usually treated with antibiotics, therefore\u000d\u000a      antibiotic resistance arising from the use of antibiotics in food\u000d\u000a      producing animals is a valid concern. The research led by Professor Laura\u000d\u000a      Piddock (at the University of Birmingham since 1987), over a period from\u000d\u000a      1987 to 2009, investigated how exposure of these bacterial species to\u000d\u000a      fluoroquinolone antibiotics resulted in the emergence of antibiotic\u000d\u000a      resistant strains. Resistance was demonstrated in laboratory studies (1,2)\u000d\u000a      and then in the large scale sampling of commercial flocks of chickens and\u000d\u000a      pigs pre, during and post therapeutic application of fluoroquinolone\u000d\u000a      antibiotics. The work documented a rapid emergence of resistant strains in\u000d\u000a      the animals, which were then passed on through the food chain (3-6).\u000d\u000a    The research described above provided a scientific and mechanistic\u000d\u000a      insight into the consequence of use of fluoroquinolone antibiotics in\u000d\u000a      animals reared for food production, particularly poultry, and selection of\u000d\u000a      fluoroquinolone resistant mutants. The work provided quantitative data as\u000d\u000a      to how likely resistance was to emerge, the conditions under which\u000d\u000a      resistance can be selected and the genetic mechanisms of this resistance\u000d\u000a      as well as demonstration for both Salmonella and Campylobacter that the\u000d\u000a      same mechanisms seen in animal isolates are common in human isolates.\u000d\u000a      These seminal studies provided unequivocal evidence of the selection of\u000d\u000a      antibiotic resistant bacteria in animals reared for food production and\u000d\u000a      which were present at slaughter and entry to the food chain.\u000d\u000a    The project team published over 25 manuscripts (cited over 250 times,\u000d\u000a      average journal impact factor of 7.4) describing the selection, mechanisms\u000d\u000a      of resistance, occurrence and evidence of entry into the human food chain\u000d\u000a      of fluoroquinolone resistant non-typhoidal Salmonella and Campylobacter.\u000d\u000a    "},{"CaseStudyId":"38789","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Measurement of disease activity in SLE is central to evaluating the\u000a      severity of the disease and identifying patients at risk of developing\u000a      chronic damage or dying, indicating what type of treatment a patient\u000a      needs, evaluating whether or not they respond to therapy and can be used\u000a      to identify differences in disease manifestations amongst patient groups.\u000a      The BILAG 2004 index has been used increasingly worldwide for the\u000a      assessment of disease activity in lupus patients in clinical trials and\u000a      clinical practice since it was shown to be reliable, valid and sensitive\u000a      to change, as it is the only validated index that shows activity in nine\u000a      individual systems rather than a combined global score. The BILAG 2004\u000a      index has had an impact on clinical practice, patient\u000a        management and the ability of pharmaceutical companies to\u000a      obtain approval for the use of new treatments for lupus.\u000a    Impact on Pharmaceutical Companies and Guidance for Industry\u000a      Until recently the only drugs licensed for lupus were hydroxychloroquine\u000a      and corticosteroids. Other drugs have been used but both steroids and\u000a      other immunosuppressants cause a lot of toxicity. Until the late 1990s\u000a      pharmaceutical companies were not keen to undertake trials in a complex\u000a      multisystem disease like lupus because of uncertainty about how to measure\u000a      appropriate disease end-points. However with increasing need for better\u000a      therapies due to the significant mortality and morbidity of lupus,\u000a      multiple clinical trials of new SLE treatments have been conducted in the\u000a      UK and internationally over the last 10 years, that have incorporated the\u000a      use of the BILAG system of assessing disease activity (1, 2). Many of\u000a      these trials were set up by investigators or companies that were not\u000a      involved in the design and validation of the BILAG 2004 index.\u000a      Recommendations produced in 2009 by international members of the SLE Task\u000a      Force of EULAR included the use of the BILAG system for the assessment of\u000a      activity in clinical trials (3). Furthermore, guidance relating to the use\u000a      of the BILAG 2004 index has also been incorporated into the US Federal\u000a      Food and Drug Administration Guidance for Industry: Systemic Lupus\u000a      Erythematosus — Developing Medical Products for Treatment, which was\u000a      published in 2010. On page 7 of the document (4) it is stated: \"Several\u000a        indices exist that mirror the assessment of experienced clinicians and\u000a        are sensitive to changes in disease activity. The BILAG is the preferred\u000a        index to study reduction in disease activity in clinical trials. The\u000a        BILAG scores patients based on the need for therapy; therefore, the\u000a        clinical interpretation of a change in score is apparent.\" This\u000a      document goes on to discuss how the BILAG indices can be used in clinical\u000a      trials in more detail (4).\u000a    Over the last 5 years there has been increasing use of composite\u000a      end-points in lupus clinical trials using several disease activity\u000a      instruments so that efficacy of treatment is demonstrated as improvement\u000a      without worsening by more than one instrument (2). The BILAG 2004 index\u000a      has been incorporated as the central score to show improvement in the\u000a      BILAG based Combined Lupus Assessment (BICLA) (5). A representative of the\u000a      company UCB wrote (5) \"It was important to have a sensitive efficacy\u000a        assessment instrument, endpoints that are clinically meaningful to the\u000a        treatment of this patient cohort and a placebo response which is limited\u000a        enough to reveal the response of an effective treatment...Composite\u000a        endpoints have greater power than individual tools to identify\u000a        differences between treatment groups, which is particularly useful in\u000a        SLE, where patient populations are heterogeneous and disease progression\u000a        is unpredictable. The BILAG-2004 index was selected as the central score\u000a        on the basis of its comprehensiveness, ability to capture partial\u000a        improvement, incremental changes in disease activity, changes in\u000a        individual involved body systems and the clinical relevance of its\u000a        scoring system...The positive results of EMBLEM™ study proved BICLA as a\u000a        robust, sensitive, composite, endpoint incorporating multiple disease\u000a        activity indices, each of which emphasises different aspects of SLE\u000a        activity.... The BILAG-2004 index, used as the key compartment of BICLA\u000a        in EMBLEM™, is a comprehensive validated tool for assessing disease\u000a        activity in all organ systems, and is capable of measuring incremental\u000a        improvement.\" The BILAG index is also a component of the SLE\u000a      Responder Index (SRI) that was set up by another independent panel of\u000a      lupus investigators. The SRI is based on showing improvement in the SLEDAI\u000a      without worsening by the more comprehensive BILAG index or physician's\u000a      global assessment. Landmark trials with the SRI were published in 2011\u000a      (and tested Belimumab, the first drug licensed for SLE in 50 years) (2).\u000a      The European Medicines Agency (EMA) draft guideline on clinical\u000a      investigations of medicinal products for the treatment of SLE, cutaneous\u000a      lupus and lupus nephritis was published in early 2013 and recommends the\u000a      use of the validated composite indices that incorporate the BILAG indices,\u000a      both the BICLA and the SRI (6). To promote optimal clinical trial data\u000a      collection using the BILAG 2004 index and the SLEDAI, the Lupus Foundation\u000a      of America (a charity supporting lupus research and education) has set up\u000a      a training and testing site which is available for the training of\u000a      investigators worldwide and for pharmaceutical company staff involved in\u000a      clinical trials; reflecting the impact of these instruments on lupus\u000a      research (7). This provides further evidence of impact that BILAG 2004\u000a      index has had on investigators and pharmaceutical companies wanting to\u000a      demonstrate outcome of the disease and efficacy of new drugs for lupus\u000a      which will benefit patients as they gain access to new drug options.\u000a    Impact on Clinical Practice\u000a      In 2010 the European League Against Rheumatism (EULAR), an organisation\u000a      representing patient, healthcare professionals and scientific societies\u000a      across Europe, recommended the use of such a disease activity instrument\u000a      for routine monitoring of lupus patients (8) and in 2011 it was\u000a      recommended as a quality indicator (9). The NHS England Clinical Reference\u000a      Group (CRG)for Specialised Rheumatology has recommended the BILAG 2004\u000a      system specifically in 2013 as a pre-requisite assessment for both\u000a      eligibility and outcome assessment for SLE patients being considered for\u000a      high cost drugs in the UK (10). The Rheumatology CRG Chair wrote \"The\u000a        impact of the BILAG indices also extends directly into improving the\u000a        routine NHS clinical practice and care of our patients. For people\u000a        living with lupus, which can follow an unpredictable course, including\u000a        the risk of major life threatening disease in any organ system, the\u000a        ability to accurately assess disease activity and severity is a\u000a        paramount importance to routine clinical care\" (10). Thus the BILAG\u000a      2004 index is becoming a routine assessment for patients with this\u000a      complex, life-threatening multisystem disease in UK clinical practice and\u000a      abroad, as well as a tool for clinical trials and observational studies on\u000a      disease outcome.\u000a    ","ImpactSummary":"\u000a    Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease\u000a      that is subject to relapses (flares) and remissions. Measuring disease\u000a      activity in multiple systems, some of which may be worsening while others\u000a      are improving, is a challenge in the management of patients with SLE and\u000a      also in the conduct of clinical trials of new drugs for the treatment of\u000a      SLE. The British Isles Lupus Assessment Group (BILAG) disease activity\u000a      index for measuring lupus was developed by Professors Paul Bacon and\u000a      Caroline Gordon at the University of Birmingham and has been validated and\u000a      implemented for clinical trials and routine clinical practice. The\u000a      instrument is able to capture significant improvement or worsening in\u000a      lupus disease activity on a system based approach, leading to improved\u000a      management and treatment of patients. It is the preferred disease activity\u000a      instrument for international SLE trials recommended by the US Food and\u000a      Drug Administration and European Medicines Agency, demonstrating impact on\u000a      health and welfare and public policy and health services.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hay\u000a        EM, Bacon\u000a          PA, Gordon\u000a          C, Isenberg\u000a        DA, Maddison\u000a        P, Snaith\u000a        ML, Symmons\u000a        DP, Viner\u000a        N, Zoma\u000a        A. The BILAG index: a reliable and valid instrument for measuring\u000a      clinical disease activity in systemic lupus erythematosus. Q\u000a        J Med. 1993, Jul;86(7):447-58. PMID: 8210301\u000a    \u000a\u000a2. Yee CS, Farewell V, Isenberg DA, Prabu A, Sokoll K, Teh LS, Rahman A,\u000a      Bruce IN, Griffiths B, Akil M, McHugh N, D'Cruz D, Khamashta MA, Bowman S,\u000a      Maddison P, Zoma A, Allen E, Gordon C. Revised British Isles Lupus\u000a      Assessment Group 2004 index: A reliable tool for assessment of systemic\u000a      lupus erythematosus activity. Arthritis Rheumatism. 2006; 54(10):3300-3305.\u000a      DOI 10.1002\/art.22162\u000a    \u000a\u000a3. Yee CS, Farewell V, Isenberg DA, Rahman A, Teh LS, Griffiths B,\u000a      Bruce IN, Ahmad Y, Prabu A, Akil M, McHugh N, D'Cruz D, Khamashta MA,\u000a      Maddison P, Gordon C. British Isles Lupus Assessment Group 2004\u000a      index is valid for assessment of disease activity in systemic lupus\u000a      erythematosus. Arthritis & Rheumatism. 2007;56:4113-4119.\u000a      DOI 10.1002\/art.23130\u000a    \u000a\u000a4. Yee CS, Isenberg DA, Prabu A, Sokoll K, Teh LS, Rahman A, Bruce IN,\u000a      Griffiths B, Akil M, McHugh N, D'Cruz D, Khamashta MA, Bowman S, Maddison\u000a      P, Zoma A, Gordon C. BILAG-2004 Index captures SLE disease\u000a      activity better than SLEDAI-2000. Annals Rheumatic Diseases. 2008;\u000a      67: 873 - 876 DOI 10.1136\/ard.2007.070847\u000a    \u000a\u000a5. Yee CS, Farewell V, Isenberg DA, Griffiths B, Teh LS, Bruce IN, Ahmad\u000a      Y, Rahman A, Prabu A, Akil M, McHugh N, Edwards C, D'Cruz D, Khamashta MA,\u000a      Maddison P, Gordon C. The BILAG-2004 index is sensitive to change\u000a      for assessment of SLE disease activity. Rheumatology (Oxford)\u000a      2009; 48(6):691-695. DOI 10.1093\/rheumatology\/kep064\u000a    \u000a\u000a6. Isenberg DA, Allen E, Farewell V, D'Cruz D, Alarcon GS, Aranow C,\u000a      Bruce IN, Dooley MA, Fortin PR, Ginzler EM, Gladman DD, Hanly JG, Inanc M,\u000a      Kalunian K, Khamashta M, Merrill JT, Nived O, Petri M, Ramsey-Goldman R,\u000a      Sturfelt G, Urowitz M, Wallace DJ, Gordon C, Rahman A. An\u000a      assessment of disease flare in patients with systemic lupus erythematosus:\u000a      a comparison of BILAG 2004 and the flare version of SELENA. Ann Rheum\u000a        Dis 2011;70:54-59. DOI 10.1136\/ard.2010.132068\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Gayed M, Gordon C. Novel treatments for systemic lupus erythematosus.\u000a        Curr Opin Investig Drugs 2010; 11(11):1256-1264.\u000a      Harvey PR, Gordon C: B-cell targeted therapies in systemic lupus\u000a        erythematosus: successes and challenges. BioDrugs 2013;27:85-95 DOI\u000a          10.1007\/s40259-013-0015-8\u000a\u000a      Gordon C, Bertsias G, Ioannidis JP, Boletis J, Bombardieri S, Cervera\u000a        R, Dostal C, Font J, Gilboe IM, Houssiau F, Huizinga TW, Isenberg D,\u000a        Kallenberg CG, Khamashta MA, Piette JC, Schneider M, Smolen JS, Sturfelt\u000a        G, Tincani A, van Vollenhoven R, Boumpas DT: EULAR points to consider\u000a        for conducting clinical trials in systemic lupus erythematosus. Annals\u000a          Rheumatic Diseases 2009;68:470-476. (published on line 3 Apr 2008)\u000a        DOI 10.1136\/ard.2007.083022\u000a\u000a      \u000a\u000ahttp:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/ucm072063.pdf\u000a        (published 2010)\u000a      Letter from the Medical Director, Lupus and Immunology, UCB, Brussels\u000a      \u000a\u0009  http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2013\/03\/WC500139615.pdf\u000a      \u000ahttps:\/\/www.lfa-point.org\/\u000a        (discussed in\u000a        http:\/\/www.lupus.org\/webmodules\/webarticlesnet\/templates\/new_empty.aspx?articleid=3530\u000a\u000a      Mosca M, Tani C, Aringer M, Bombardieri S, Boumpas D, Brey R, Cervera\u000a        R, Doria A, Jayne D, Khamashta MA, Kuhn A, Gordon C, Petri M, Rekvig OP,\u000a        Schneider M, Sherer Y, Shoenfeld Y, Smolen JS, Talarico R, Tincani A,\u000a        van Vollenhoven RF, Ward MM, Werth VP, Carmona L. EULAR Recommendations\u000a        for monitoring systemic lupus erythematosus patients in clinical\u000a        practice and in observational studies. Ann Rheum Dis 2010;\u000a        69(7):1269-1274 DOI 10.1136\/ard.2009.117200\u000a\u000a      Mosca M, Tani C, Aringer M, Bombardieri S, Boumpas D, Cervera R, Doria\u000a        A, Jayne D, Khamashta MA, Kuhn A, Gordon C, Petri M, Schneider M,\u000a        Shoenfeld Y, Smolen JS, Talarico R, Tincani A, Ward MM, Werth VP,\u000a        Carmona L. Development of quality indicators to evaluate the monitoring\u000a        of SLE patients in routine clinical practice. Autoimmun Rev\u000a        2011; 10(7):383-388 DOI 10.1016\/j.autrev.2010.12.008\u000a\u000a      Letter from the Chair, NHS England Clinical Reference Group,\u000a        Specialised Rheumatology, UK\u000a    \u000a    ","Title":"\u000a    Assessment of disease activity in lupus\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    SLE is an autoimmune disease which can affect any system in the body,\u000a      varies in severity from mild to life-threatening and is more common in\u000a      women. Research conducted at the University of Birmingham in the 1990s (by\u000a      Professors Caroline Gordon, at UoB from 1989 and Paul Bacon, at UoB from\u000a      1981-2003; Honorary Professor thereafter ) showed the incidence is\u000a      3.8\/100,000\/year (6.8\/100,000\/year in women and 0.5\/100,000\/year in men)\u000a      with a median age at diagnosis of 37 years. The prevalence of lupus is 1\u000a      in 2000 in adult women in the UK (actually 49.6\/100,000), but it is about\u000a      tenfold less common in men. It is more common, more severe and presents\u000a      younger in people of Afro-Caribbean and South Asian origin than in those\u000a      of white European origin. The prevalence in adult women is about 1 in 500\u000a      for Afro-Caribbeans and 1 in 1000 in South Asians in Birmingham. The\u000a      average age of death of patients with lupus is 52 years.\u000a    Clinical assessment of this disease is problematic due to the complex\u000a      multi-system nature of the disease, with fluctuating levels of disease\u000a      activity, which may vary between patients and within the same patient over\u000a      time. In the 1980s there were about 40 reports of different ways of\u000a      assessing disease activity in lupus but none had been validated and most\u000a      resulted in a total numerical score. The Birmingham Rheumatology Unit\u000a      (Professors Caroline Gordon and Paul Bacon) and other BILAG collaborators\u000a      were pioneers in developing the BILAG disease activity index. Version 3 of\u000a      this system-based approach to the assessment of lupus disease activity was\u000a      validated and published in 1993 by Professors Gordon and Bacon from the\u000a      University of Birmingham and Professors Hay and Symmons from the\u000a      University of Manchester (1). This system differed from other disease\u000a      activity instruments in being a comprehensive, transitional index that\u000a      assessed how disease activity changes over time with a score for each of\u000a      eight systems and not just a total score based on whether features are\u000a      present or absent. The BILAG disease activity index was adapted for use in\u000a      children and has been used widely for observational studies and clinical\u000a      trials.\u000a    Over time it became apparent that there were still some deficiencies with\u000a      this instrument. In particular it did not capture ophthalmic or\u000a      gastrointestinal systems well and there was need to improve certain\u000a      aspects of the terminology and scoring to reflect current opinion about\u000a      the disease. This led to a complete revision of the instrument in\u000a      2003-2004 which was led by Prof Caroline Gordon at the University of\u000a      Birmingham and Prof David Isenberg from University College London. The\u000a      work was supported by a post-doctoral research fellow, Dr Chee-Seng Yee at\u000a      the University of Birmingham and resulted in many publications (2-5). The\u000a      revised instrument, called the BILAG-2004 index, was designed to have 9\u000a      rather than 8 systems, new terminology and scoring. It was shown to be a\u000a      reliable assessment method with face, content and construct validity, was\u000a      sensitive to change over time and was better than an alternative SLE\u000a      Disease Activity Index (SLEDAI) (2-5).\u000a    The BILAG 2004 system allows for change in severity to be captured and\u000a      incorporated in to the scoring, as well as each system having its own\u000a      score, so that it is possible to see which systems improve on a given\u000a      treatment and which do not. The alternative instrument SLEDAI from Canada\u000a      and other lupus disease activity scores only provide a total score, which\u000a      can be made up by different components. For example, two patients can have\u000a      the same score on the same day or one patient can have the same score on\u000a      different days but the components of the scores include different disease\u000a      manifestations and levels of severity of disease on each occasion. The\u000a      BILAG-2004 index improves the accuracy of reported disease manifestations,\u000a      is sensitive to many types of change in disease activity, distinguishes\u000a      different levels of severity in each system and importantly correlates\u000a      with the simpler index SLEDAI. More recently a revised way of scoring the\u000a      BILAG 2004 index has been proposed to capture lupus flare and was shown to\u000a      perform better than an alternative lupus flare instrument (6).\u000a    "},{"CaseStudyId":"38790","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Birmingham-based research led by Lip and Lane has had international\u000d\u000a      impacts in AF risk assessment, screening and treatment. This has been\u000d\u000a      primarily delivered by their roles with national and international\u000d\u000a      organisations as expert consultants on AF management, positions which have\u000d\u000a      been based on the expertise developed through the research described here.\u000d\u000a      Professor Lip was the previous Clinical Adviser for the current UK NICE\u000d\u000a      guidelines (2006) and is co-authoring the 2014 revision on AF management.\u000d\u000a      He has served as Deputy Editor (\"content expert\") for the 2012 American\u000d\u000a      College of Chest Physicians (ACCP) guidelines on antithrombotic therapy\u000d\u000a      for AF [1] and in similar capacities for various guidelines and\/or\u000d\u000a      position statements from European Heart Rhythm Association (EHRA),\u000d\u000a      including Task Force Chair for a Position Statement on Bleeding Risk in AF\u000d\u000a      Patients [2]. He also served on the writing committee of the European\u000d\u000a      Society of Cardiology (ESC) guidelines on AF (2010) and the 2012 focused\u000d\u000a      update. Dr Lane is also a member of the ACCP and EHRA document writing\u000d\u000a      committees. Both Professor Lip and Dr Lane were part of the BMJ Writing\u000d\u000a      group (2013) for NHS Shared Decision Making in the development of a\u000d\u000a      patient decision aid for stroke prevention for AF or atrial flutter [3]\u000d\u000a      and were recently part of the task force that developed a patient\u000d\u000a      education website for the EHRA (Lip was Chair) [4]. Along with these\u000d\u000a      changes to clinical guidance for patient care, the team have delivered the\u000d\u000a      following impacts in three key areas:\u000d\u000a    Assessing stroke and bleeding risk\u000d\u000a    Professor Lip and Dr Lane have developed and validated two risk\u000d\u000a      stratification scores, CHA2DS2-VASc and HAS-BLED,\u000d\u000a      based on common clinical information that provide well-validated\u000d\u000a      approaches for clinicians to assess their patients' risk of stroke and\u000d\u000a      bleeding, respectively. These scores have helped clinicians to formally\u000d\u000a      assess stroke risk and identify `truly low risk' patients who do not need\u000d\u000a      antithrombotic therapy, and effectively capture those patients who should\u000d\u000a      be considered for oral anticoagulation therapy. CHA2DS2-VASc\u000a      is easily available for use by GPs as part of the Guidance on Risk\u000d\u000a      Assessment and Stroke Prevention for Atrial Fibrillation (GRASP-AF) risk\u000d\u000a      stratification tool for stroke to guide oral anticoagulation treatment,\u000d\u000a      which is freely available and compatible for use with all GP clinical\u000d\u000a      systems in England [5]. The simple, user-friendly HAS-BLED score,\u000d\u000a      comprising risk factors either readily available from the clinical medical\u000d\u000a      history or routinely tested in (new) patients, allows clinicians to\u000d\u000a      formally assess bleeding risk, identifying modifiable risk factors\u000d\u000a      (optimising blood pressure control, removing concomitant anti-platelet,\u000d\u000a      reducing alcohol intake, and optimising time in therapeutic range for\u000d\u000a      those patients receiving warfarin), and those who require regular review\u000d\u000a      (patients at higher bleeding risk).\u000d\u000a    The CHA2DS2-VASc score has become the principal\u000d\u000a      tool to assess stroke risk and decide on anticoagulant therapy in the most\u000d\u000a      recent ESC2010 guidelines on atrial fibrillation [6] and their focused\u000d\u000a      update in 2012[2], both used in Europe and throughout most parts of the\u000d\u000a      world. This score is also used by the Asia Pacific Heart Rhythm Society\u000d\u000a      guideline, which recommends that the CHA2DS2-VASc\u000d\u000a      score should be used to assess the risk of stroke for all patients with\u000d\u000a      nonvalvular AF in the Asia-Pacific region[7]. A narrative form of CHA2DS2-VASc\u000a      is used in the 2012 ACCP guideline [1].The HAS-BLED score is similarly\u000d\u000a      used in international AF treatment guidelines (Europe, Canada) — notably\u000d\u000a      those issued by the ESC in 2010\/12 (noted above) and the 2012 Canadian\u000d\u000a      Cardiovascular Society [8]. Both scores are recommended in the UK\u000d\u000a      Consensus Statement on AF issued by the Royal College of Physicians of\u000d\u000a      Edinburgh [9].The significant worldwide impact of this work with CHA2DS2-VASc\u000d\u000a      and HAS-BLED on the management of AF has recently been acknowledged by two\u000d\u000a      prestigious awards, the Arrhythmia Alliance Team of the Year 2012 and the\u000d\u000a      BMJ Awards Cardiovascular Medicine Team of the Year 2013.\u000d\u000a    AF treatment decisions relating to risk\u000d\u000a    One quarter of all strokes in people aged ≥75 years result from AF, and\u000d\u000a      therefore improving the provision of stroke prevention in elderly people\u000d\u000a      with AF is a critical aspect of management. The BAFTA study clearly led to\u000d\u000a      a change in guidelines and clinical practice by providing clear evidence\u000d\u000a      for health professionals of the benefit of using oral anticoagulation\u000d\u000a      therapy in over 75s. The NHS Quality and Outcomes Framework guidance in\u000d\u000a      2009 and 2013\/14 [10,11] highlighted that \"there is clearly a need to\u000d\u000a        encourage the use of this treatment for AF patients at high risk of\u000d\u000a        stroke\", and both stated \"recent evidence from the BAFTA\u000d\u000a        trial...suggests not only is warfarin much more effective than aspirin,\u000d\u000a        but that it is not as unsafe — in terms of risk of serious haemorrhage —\u000d\u000a        as previously thought\". The 2013\/14 guidelines also noted that \"It\u000a        is advised that patients with stroke associated with AF are reviewed for\u000d\u000a        long-term treatment with warfarin\".\u000d\u000a    Screening in primary care\u000d\u000a    The SAFE study helped to define best practice with respect to AF\u000d\u000a      screening in the elderly population, comparing the effectiveness\u000d\u000a      (including cost-effectiveness, i.e. value for money) of different\u000d\u000a      approaches of systematic or ad-hoc screening to best diagnose AF. Together\u000d\u000a      with the BAFTA trial this has changed the way that AF is now managed at a\u000d\u000a      national and international level: UK clinical guidance: The\u000d\u000a      National Institute for Health and Care Excellence (NICE) sets accepted\u000d\u000a      practice for patient healthcare, used by groups ranging from NHS, Local\u000d\u000a      Authorities, employers, voluntary groups and others involved in delivering\u000d\u000a      care or promoting wellbeing. Results of the BAFTA and SAFE studies were\u000d\u000a      incorporated into the 2006 National Atrial Fibrillation Clinical Guideline\u000d\u000a      for Management in Primary and Secondary Care [12]. These directly\u000d\u000a      reference SAFE, and importantly remain the current guidance informing\u000d\u000a      clinical practice and patient care throughout the assessment period.The\u000d\u000a      British Committee for Standards in Haematology Guidelines on oral\u000d\u000a      anticoagulation published in 2011 also draw on the results of the BAFTA\u000d\u000a      study [13]\u000d\u000aInternational clinical guidelines: The ESC published\u000d\u000a      guidelines in 2010 for AF management [6] referencing the work of Lip, and\u000d\u000a      a 2012 update [2] stating \"\"We therefore recommend that, in patients\u000d\u000a        aged 65 years or over, opportunistic screening for AF by pulse\u000d\u000a        palpation, followed by recording of an ECG to verify diagnosis, should\u000d\u000a        be considered for the early detection of AF\". This work also reached\u000d\u000a      the USA, with the American College of Chest Physicians [1] published\u000d\u000a      evidence-based guidelines on antithrombotic therapy in AFin 2012,\u000d\u000a      incorporating BAFTA results. Utilising this work for primary care was also\u000d\u000a      part of the World Heart Federation\/International Atrial Fibrillation\u000d\u000a      Association 2012 guidelines [15] (Lip part of Steering Committee).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Atrial fibrillation (AF) is the commonest heart rhythm abnormality,\u000d\u000a      affecting around 8.8 million people in the European Union, and confers a\u000d\u000a      substantial risk of stroke and death. It accounts for one third of\u000d\u000a      hospital admissions for cardiac rhythm disturbances, and the rate of\u000d\u000a      AF-related admissions has continued to rise in recent years. The work of\u000d\u000a      Prof Gregory Lip and Dr Deirdre Lane has made Birmingham an\u000d\u000a      internationally-respected centre of excellence for research in AF,\u000d\u000a      delivering crucial impacts in international clinical practice guidelines\u000d\u000a      and improvements in patient care within three main areas: treatment\u000d\u000a      decisions related to stroke and bleeding risk, screening practice in\u000d\u000a      primary care, and stroke and bleeding risk assessment, ultimately reducing\u000d\u000a      morbidity and mortality for a significant proportion of the population,\u000d\u000a      particularly among the elderly.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1: Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining\u000d\u000a      clinical risk stratification for predicting stroke and thromboembolism in\u000d\u000a      atrial fibrillation using a novel risk factor-based approach: the euro\u000d\u000a      heart survey on atrial fibrillation. Chest. 2010;137(2):263-72 doi:\u000a        10.1378\/chest.09-1584\u000d\u000a    \u000a\u000a2: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY.\u000d\u000a      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major\u000d\u000a      bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest.\u000d\u000a      2010;138(5):1093-100. doi: 10.1378\/chest.10-0134\u000d\u000a    \u000a\u000a3: Hobbs FD, Roalfe AK, Lip GY, Fletcher K, Fitzmaurice DA, Mant\u000d\u000a      J; on behalf of the Birmingham Atrial Fibrillation in the Aged (BAFTA)\u000d\u000a      investigators and Midland Research Practices Consortium (MidReC) network.\u000d\u000a      Performance of stroke risk scores in older people with atrial fibrillation\u000d\u000a      not taking warfarin: comparative cohort study from BAFTA trial. BMJ.\u000d\u000a      2011;342:d3653. doi: 10.1136\/bmj.d3653\u000d\u000a    \u000a\u000a4: Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYet\u000d\u000a      al. BAFTA investigators; Midland Research Practices Network (MidReC).\u000d\u000a      Warfarin versus aspirin for stroke prevention in an elderly community\u000d\u000a      population with atrial fibrillation (the Birmingham Atrial Fibrillation\u000d\u000a      Treatment of the Aged Study, BAFTA): a randomised controlled trial.\u000d\u000a        Lancet. 2007;370(9586):493-503. doi:10.1016\/S0140-6736(07)61233-1\u000d\u000a    \u000a\u000a5: Fitzmaurice DA, Hobbs FD, Jowett S, Mant J, Murray ET, Holder\u000d\u000a      Ret al. Screening versus routine practice in detection of atrial\u000d\u000a      fibrillation in patients aged 65 or over: cluster randomised controlled\u000d\u000a      trial. BMJ. 2007;335(7616):383. doi: http:\/\/dx.doi.org\/10.1136\/bmj.39280.660567.55\u000d\u000a    \u000a\u000a6: Mant J, Fitzmaurice DA, Hobbs FD, Jowett S, Murray ET, Holder R\u000d\u000a      et al. Accuracy of diagnosing atrial fibrillation on electrocardiogram by\u000d\u000a      primary care practitioners and interpretative diagnostic software:\u000d\u000a      analysis of data from screening for atrial fibrillation in the elderly\u000d\u000a      (SAFE) trial. BMJ. 2007;335(7616):380. http:\/\/dx.doi.org\/10.1136%2Fbmj.39227.551713.AE\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    \u000d\u000a      You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC et al.\u000d\u000a        Antithrombotic therapy for atrial fibrillation, 9th edition: American\u000d\u000a        College of Chest Physicians evidence-based clinical practice guidelines.\u000d\u000a        Chest 2012; 141(2) (Suppl):e531S-e575S. doi: 10.1378\/chest.11-2304\u000a\u000d\u000a      Lip GYH, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E et al.\u000d\u000a        Bleeding risk assessment and management in atrial fibrillation patients:\u000d\u000a        a position document from the European Heart Rhythm Association, endorsed\u000d\u000a        by the European Society of Cardiology Working Group on Thrombosis.\u000d\u000a        Europace 2011;13: 723-746. doi: 10.1160\/TH11-10-0690\u000a\u000d\u000a      NHS Shared Decision Making. Patient Decision Aid for Stroke Prevention\u000d\u000a        for atrial fibrillation or flutter. http:\/\/sdm.rightcare.nhs.uk\/pda\/stroke-prevention-for-atrial-fibrillation.\u000d\u000a      European Heart Rhythm Association atrial fibrillation patient website.\u000d\u000a        http:\/\/afibmatters.org.\u000d\u000a      Guidance on Risk Assessment and Stroke Prevention for\u000d\u000a        Atrial-Fibrillation (GRASP-AF) .Query and risk stratification\u000d\u000a        toolavailable for use within all GP clinical systems in England.\u000d\u000a        http:\/\/www.improvement.nhs.uk\/graspaf\/documents\/resources\/GRASP-AF_2012_flyer.pdf\u000a\u000d\u000a      Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al.\u000d\u000a        Guidelines for the management of atrial fibrillation. The Task Force for\u000d\u000a        the management of atrial fibrillation of the European Society of\u000d\u000a        Cardiology. European Heart Journal 2010; 31: 2369-2429. doi:10.1093\/eurheartj\/ehq278\u000a\u000d\u000a      APHRS News July 2013: http:\/\/www.aphrs.asia\/news_images\/2013_08\/APHRS-No.8-final.pdf\u000a\u000d\u000a      Canadian Cardiovascular Society Atrial Fibrillation Guidelines\u000d\u000a        Committee. Focused 2012 Update of the CCS Atrial fb01brillation\u000d\u000a        Guidelines: recommendations for stroke prevention and rate\/rhythm\u000d\u000a        control. Can J Cardiol 2012;28:125-136. doi:\u000d\u000a          10.1016\/j.cjca.2012.01.021.\u000a\u000d\u000a      Stott DJ, Dewar RI, Garratt CJ, Griffith KE, Harding NJ, James MA et\u000d\u000a        al. Royal College of Physicians of Edinburgh. RCPE UK Consensus\u000d\u000a        Conference on 'Approaching the comprehensive management of atrial\u000d\u000a        fibrillation: evolution or revolution?'.J R Coll Physicians Edinb.\u000d\u000a        2012;42 Suppl 18:3-4. http:\/\/www.rcpe.ac.uk\/sites\/default\/files\/files\/Final_statement.pdf\u000a\u000d\u000a      BMA\/NHS Employers. Quality and Outcomes Framework guidance for GMS\u000d\u000a        contract 2009\/10. Delivering investment in general practice. March 2009\u000d\u000a        (AF Indicator 3, pp.107-109).\u000d\u000a      2013\/14 general medical services (GMS) contract quality and outcomes\u000d\u000a        framework (QOF) Guidance for GMS contract 2013\/14. (Indicators\u000d\u000a        AF003-004, pp.33-38).\u000d\u000a      National Collaborating Centre for Chronic Conditions. Atrial\u000d\u000a        fibrillation. National Clinical Guideline for management in primary and\u000d\u000a        secondary care. London: Royal College of Physicians; 2006. http:\/\/www.nice.org.uk\/nicemedia\/live\/10982\/30055\/30055.pdf\u000a\u000d\u000a      Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C et al.\u000d\u000a        British Committee for Standards in Haematology Guidelines on oral\u000d\u000a        anticoagulation with warfarin. Fourth edition. British Journal of\u000d\u000a          Haematology 2011; 154(3): 311-324\u000d\u000a        http:\/\/www.bcshguidelines.com\/documents\/warfarin_4th_ed.pdf\u000a\u000d\u000a      Atrial fibrillation in primary care (AFIP). Bringing atrial\u000d\u000a        fibrillation practice closer to guidelines. A Tool for Primary Care\u000d\u000a        Physicians. International Atrial Fibrillation Association. 2012\u000d\u000a        http:\/\/www.world-heart-federation.org\/fileadmin\/user_upload\/documents\/AF-Aware\/GAFA\/AFIPtoolUpdated23July212.pdf\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improving the management of patients with atrial fibrillation\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Atrial fibrillation (AF) is characterised by an irregular, often rapid\u000d\u000a      heartbeat, due to a malfunction in the heart's electrical system. AF is\u000d\u000a      the most common heart rhythm irregularity, or `arrhythmia'. Over the last\u000d\u000a      15 years' research led by Professor Gregory Lip (Professor of\u000d\u000a      Cardiovascular Medicine at the University of Birmingham and consultant\u000d\u000a      cardiologist at City Hospital; Honorary Professor 1999-2009 and returned\u000d\u000a      as Cat C in 2008 RAE; full Professor since 2009) and Dr Deirdre Lane\u000d\u000a      (Lecturer in Cardiovascular Health at the University of Birmingham since\u000d\u000a      2010) into AF has developed and validated new tools for assessing stroke\u000d\u000a      and bleeding risk among patients with AF who are treated with\u000d\u000a      antithrombotic therapy, re-evaluated treatment approaches, and provided\u000d\u000a      crucial insights into the most effective practices in screening for the\u000d\u000a      condition.\u000d\u000a    Assessing stroke risk\u000d\u000a    Due to the irregularity in the beating of the heart in patients with AF,\u000d\u000a      the flow of blood is affected. This can cause blood cells to stick\u000d\u000a      together and increases the risk of a blood clot forming in the upper\u000d\u000a      chambers of the heart (the atria). In people with AF, the most common\u000d\u000a      place for these blood clots to travel to is the brain and this can result\u000d\u000a      in a stroke. AF increases the risk of stroke five-fold.\u000d\u000a    Many risk scoring systems have been developed over the years to predict\u000d\u000a      stroke, thromboembolism and transient ischemic attack (TIA), using various\u000d\u000a      clinical and diagnostic features, typically stratifying patients into\u000d\u000a      high-, intermediate-, or low-risk categories. However, these risk schemas\u000d\u000a      did not clearly take into account many other potential risk factors, and\u000d\u000a      so were not completely predictive or reliable in many cases. A scoring\u000d\u000a      system called CHADS2 (acronym for Congestive heart failure,\u000d\u000a      Hypertension, Age >75 years, Diabetes mellitus, and prior Stroke or\u000d\u000a      TIA), developed in 2001 was widely used internationally to assess stroke\u000d\u000a      risk in AF. Led by Lip, Birmingham's regional AF Clinical Effectiveness\u000d\u000a      Topic Group refined risk stratification specifically for a local primary\u000d\u000a      care population, and in 2006 — after demonstrating its comparable\u000d\u000a      effectiveness to CHADS2 — the Birmingham schema was refined for\u000d\u000a      dissemination in the evidence-based UK National Institute for Health and\u000d\u000a      Clinical Excellence (NICE) guidelines on AF management, which outlined\u000d\u000a      this algorithm-based approach to stroke risk stratification. In 2009, this\u000d\u000a      was then further developed by the Lip team into a risk factor-based\u000d\u000a      approach by reclassifying and incorporating additional new risk factors.\u000d\u000a      The revised schema was then compared with other existing stroke risk\u000d\u000a      stratification schema in a real-world cohort of AF patients from the Euro\u000d\u000a      Heart Survey for AF. This new approach (abbreviated to CHA2DS2-VASc)\u000d\u000a      [1] was able to demonstrate improvement in predictive value for\u000d\u000a      thromboembolism over the CHADS2 schema, with low event rates in\u000d\u000a      low-risk subjects and the classification of only a small proportion of\u000d\u000a      subjects into the intermediate-risk category, offering a clear way to\u000d\u000a      improve stroke risk stratification in AF.\u000d\u000a    Prescription of oral anticoagulation therapy needs to balance the benefit\u000d\u000a      of stroke prevention against the risk of bleeding, but a lack of\u000d\u000a      recommendations on bleeding risk assessment hampered antithrombotic\u000d\u000a      guidelines for AF management. The Birmingham team developed a practical\u000d\u000a      risk score for bleeding, known as HAS-BLED (Hypertension, Abnormal\u000d\u000a      Renal\/Liver Function, Stroke, Bleeding History or Predisposition, Labile\u000d\u000a      INR, Elderly, Drugs\/Alcohol Concomitantly)) [2] to estimate the 1-year\u000d\u000a      risk of major bleeding, and validated it in several independent patient\u000d\u000a      cohorts.\u000d\u000a    AF treatment decisions relating to risk\u000d\u000a    While anticoagulation therapy with warfarin is highly effective in\u000d\u000a      reducing stroke risk in AF, it is associated with high monitoring costs\u000d\u000a      and increased risk of serious haemorrhage. Ongoing uncertainties about\u000d\u000a      whether these benefits and risks were applicable to elderly populations\u000d\u000a      led to work between Lip and colleagues in primary care at the University\u000d\u000a      of Birmingham (Profs David Fitzmaurice, Richard Hobbs (based at Birmingham\u000d\u000a      until 30\/4\/2011), and Jonathan Mant (at Birmingham until 1\/10\/2008)) for\u000d\u000a      the BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) study\u000d\u000a      (£740kMRC, 1999-2004). This compared the efficacy of warfarin with that of\u000d\u000a      aspirin for the prevention of stroke in a primary care population of 973\u000d\u000a      patients with AF aged 75 years or over. The BAFTA study clearly showed the\u000d\u000a      superiority of anticoagulation for stroke prevention, with no increased\u000d\u000a      risk of serious haemorrhage between warfarin versus aspirin in the elderly\u000d\u000a      [3,4].\u000d\u000a    Screening in primary care\u000d\u000a    Again working with colleagues in primary care (Profs Fitzmaurice, Hobbs,\u000d\u000a      Mant), Lip looked at systematic screening (targeted and total population\u000d\u000a      screening) versus routine practice for the detection of AF in the over\u000d\u000a      65s, known as the Screening for Atrial Fibrillation in the Elderly (SAFE)\u000d\u000a      study (£485k NIHR HTA-funded 1999-2003). Evaluating the relative benefits\u000d\u000a      of whole population, targeted, and opportunistic screening for the\u000d\u000a      presence of AF, SAFE showed that opportunistic screening improved on\u000d\u000a      standard practice, and was likely to be cost-effective in terms of the\u000d\u000a      patient benefits of identifying new cases [5]. In addition, SAFE\u000d\u000a      identified that many primary care professionals could not accurately\u000d\u000a      detect AF with standard electrocardiograms, and that additional\u000d\u000a      interpretative software was unable to address this problem even when\u000d\u000a      combined with interpretation by a GP [6]. Their subsequent recommendation\u000d\u000a      was that diagnosis of AF in the community must include reading of\u000d\u000a      electrocardiograms by appropriately trained people.\u000d\u000a    "},{"CaseStudyId":"38791","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    The impact of the application of HLA-peptide tetramers to the study of\u000a      cytomegalovirus infection can be categorized within changing clinical\u000a        practice and commercial development.\u000a    The development of tetramer technology, with which Professor Paul Moss\u000a      was involved, has had an enormous impact on immunology research in\u000a      industry and academia. However, the specific focus of this case study is\u000a      on Professor Paul Moss' development of a clear clinical application for\u000a      these important reagents.\u000a    HLA-peptide tetramers have transformed the ability to interrogate the\u000a      function of the immune system and have had an enormous impact on the\u000a      understanding of CMV infection. A PubMed search for `tetramer' and\u000a      `cytomegalovirus' identifies 148 individual papers which is representation\u000a      of the widespread adoption of this technique since the original paper 12\u000a      years ago. Tetramers have also been used widely in clinical applications\u000a      over this timeframe, specifically in relation to clinical monitoring and\u000a      cellular therapy. As indicated above, in 2001 the Birmingham team were the\u000a      first to use tetramers to monitor the reconstitution of CMV-specific\u000a      immune responses following stem cell transplantation. This work led to a\u000a      plethora of similar publications which correlated such reconstitution with\u000a      factors such as level of T cell depletion and control of viral\u000a      reactivation. This work proved so important that Beckman Coulter went on\u000a      to develop a set of HLA-peptide reagents which are used and sold as a tool\u000a      to monitor T cell reconstitution in order to guide clinical management of\u000a      the risk and clinical significance of viremia in the post-transplant\u000a      period (1). Studies have established the value of this approach which is\u000a      now used in specialist haemopoietic transplantation centres and is also\u000a      finding application in solid organ transplant (2).\u000a    In relation to cellular therapy, the manuscript of Cobbold et al\u000a      (2005) opened the potential for HLA-peptide tetramers, and other forms of\u000a      multimeric reagents, to be used as an approach for accelerating the\u000a      transfer of antigen-specific T cells between patients. This publication\u000a      was followed by similar trials within Europe that demonstrate the value of\u000a      such an approach in the treatment in patients with antiviral-resistant CMV\u000a      reactivation. This approach has proved therapeutically beneficial in\u000a      several reports (3) and is now used as a therapeutic approach in the\u000a      treatment of refractory disease. Indeed, the use of cellular immunotherapy\u000a      as a prophylactic means of suppress the initiation of viremia is also\u000a      appealing and is subject to large scale clinical trials sponsored by\u000a      commercial organisations (see below).\u000a    It is within the area of the clinical application of multimer technology\u000a      that the University of Birmingham's contribution has been most dominant in\u000a      a commercial setting. Specifically, the UK biotechnology company Cell\u000a      Medica was established in London in 2006 with the aim of commercializing\u000a      antigen-specific cellular therapy within the clinical arena (4) and has\u000a      had a range of impacts through the current assessment period. The company\u000a      is pioneering tetramer-based therapy and Professor Paul Moss has served on\u000a      the Scientific Advisory Board of Cell Medica since its foundation. In July\u000a      2012 the company successfully completed series A financing (£17m) and\u000a      expanded its operations to include sites in Texas and Berlin (5). Cell\u000a      Medica is currently sponsoring three multi-centre clinical trials,\u000a      enrolling exclusively within the United Kingdom, which will ascertain the\u000a      value of CMV-specific T cell therapy, performed using multimer selection\u000a      and the prophylaxis or management of CMV reactivation in patients\u000a      undergoing haemopoietic transplantation (6). The first trial started in\u000a      2008 and the second in 2011, with a third treating children launched in\u000a      2013. Over 100 patients within the UK have entered clinical trials to\u000a      assess multimer-based CMV-specific T cell adoptive therapy. The `health\u000a      and wealth' contribution of tetramers to UK medicine has therefore been\u000a      significant. In 2013 the company opened a GMP cell therapy product\u000a      facility in Berlin, its European commercial manufacturing facility,\u000a      initially focusing on adoptive cellular treatments. The commercial launch\u000a      of the product is planned in early 2014.\u000a    In conclusion, the University of Birmingham and in particular Professor\u000a      Paul Moss has made a central contribution to the development of clinical\u000a      and commercial application of HLA-peptide technology, particularly around\u000a      the study of CMV infection and its management. This has been translated to\u000a      considerable scientific, clinical and commercial opportunities within the\u000a      UK and beyond.\u000a    ","ImpactSummary":"\u000a    T lymphocytes recognise antigens in the form of an HLA-peptide complex.\u000a      HLA-peptide tetramers consist of a fluorescent HLA protein and peptide\u000a      which together bind to, and therefore identify, T cells that recognise\u000a      this HLA-peptide complex. As such they have proven to be a revolutionary\u000a      reagent in immunology. Professor Paul Moss at the University of Birmingham\u000a      has played an integral role in the clinical and commercial application of\u000a      tetramers, particularly around the cytomegalovirus (CMV)-specific immune\u000a      response in the context of monitoring immune recovery after\u000a      transplantation and pioneering a new approach for cellular immunotherapy.\u000a        The impact of this research relates to the clinical management of CMV\u000a        infection in immunosuppressed patients and the creation of Cell Medica,\u000a        a UK Biotech company pioneering tetramer-based cell therapy, thus\u000a        demonstrating impact on clinical practice and the UK economy.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2950159","Name":"Berlin"},{"GeoNamesId":"4736286","Name":"Texas"}],"References":"\u000a    Grant Support:\u000a    - Rickinson & Moss — MRC Programme Grant 2000-2005\u000a    - Moss — Leukaemia & Lymphoma Research Programme Grant 2000-2005\u000a    \u000a1. Gillespie GM, Wills MR, Appay V, O'Callaghan C, Murphy M, Smith N,\u000a      Sissons P, Rowland-Jones S, Bell JI, Moss PA. Functional\u000a      heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T\u000a      lymphocytes in healthy seropositive donors. J Virol. 2000\u000a      Sep;74(17):8140-50. (352 citations) DOI\u000a        10.1111\/j.1469-0691.2009.02899.x\u000a    \u000a\u000a2. Cwynarski K, Ainsworth J, Cobbold M, Wagner S, Mahendra P, Apperley J,\u000a      Goldman J, Craddock C, Moss PA. Direct visualization of\u000a      cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell\u000a      transplantation. Blood. 2001 Mar 1;97(5):1232-40. (219 citations) DOI\u000a        10.1182\/blood.V97.5.1232\u000a    \u000a\u000a3. Singhal S, Shaw JC, Ainsworth J, Hathaway M, Gillespie GM, Paris H,\u000a      Ward K, Pillay D, Moss PA, Mutimer DJ. Direct visualization and\u000a      quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in\u000a      liver transplant patients. Transplantation. 2000 Jun 15;69(11):2251-9. (63\u000a      citations) PMID 10868622\u000a    \u000a\u000a4. Keenan RD, Ainsworth J, Khan N, Bruton R, Cobbold M, Assenmacher M,\u000a      Milligan DW, Moss PA. Purification of cytomegalovirus-specific CD8\u000a      T cells from peripheral blood using HLA-peptide tetramers. Br J Haematol.\u000a      2001 Nov;115(2):428-34. (56 citations) DOI\u000a        10.1046\/j.1365-2141.2001.03106.x\u000a    \u000a\u000a5. Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H,\u000a      Assenmacher M, Billingham L, Steward C, Crawley C, Olavarria E, Goldman J,\u000a      Chakraverty R, Mahendra P, Craddock C, Moss PA. Adoptive transfer\u000a      of cytomegalovirus-specific CTL to stem cell transplant patients after\u000a      slection by HLA-peptide tetramers. J Exp Med. 2005 Aug 1;202(3):379-86.\u000a      (280 citations) DOI 10.1084\/jem.20040613\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    \u000a      Gratama JW et al. Immune monitoring with iTAg MHC Tetramers for\u000a        prediction of recurrent or persistent cytomegalovirus infection or\u000a        disease in allogeneic hematopoietic stem cell transplant recipients: a\u000a        prospective multicenter study. Blood. 2010 116(10):1655-62. DOI\u000a        10.1182\/blood-2010-03-273508\u000a      Sund F et al. CMV-specific T-cell immunity, viral load, and clinical\u000a        outcome in seropositive renal transplant recipients: a pilot study. Clin\u000a        Transplant 2010 24 (30 401-9. DOI 10.1111\/j.1399-0012.2009.00976.x\u000a      Schmitt A et al. Adoptive transfer and selective reconstitution of\u000a        streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus\u000a        clearance in patients after allogeneic peripheral blood stem cell\u000a        transplantation. Transfusion. 2011 Mar;51(3):591-9. DOI\u000a        10.1111\/j.1537-2995.2010.02940.x\u000a      http:\/\/www.cellmedica.co.uk\u000a      \u000ahttp:\/\/www.cellmedica.co.uk\/news\/cell-medica-secures-17-million-265-million-equity-investment\/.\u000a      http:\/\/www.cellmedica.co.uk\/news\/cell-medica-announces-completion-patient-recruitment-randomi\/\u000a    \u000a    ","Title":"\u000a    The development of HLA-peptide tetramers and their application as a novel\u000a      form of cell therapy for immune suppressed patients suffering from\u000a      cytomegalovirus infection\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Tetramers are protein based molecules which are used to quantify and\u000a      isolate antigen-specific T\u000a        cells, especially CD8+ T cells. CD8+ T-cells (or T-lymphocytes) are\u000a      a type of lymphocyte that play a central role in cell-mediated immunity,\u000a      to pathogens such as viruses. The first tetramers were developed in the\u000a      1990s, by a team that involved Professor Paul Moss in his previous\u000a      appointment at the University of Oxford. Tetramers are formed from four\u000a      peptide-major histocompatability complex (MHC) molecules that are specific\u000a      for a given population of T cells. These molecules are folded with the\u000a      peptide (antigen) of interest and complexed with fluorescently-labeled streptavidin around\u000a      a biotin core. The tetramer will specifically label T cells that express T\u000a      cell receptors that are specific for a given peptide-MHC complex. The\u000a      strength of antigen-specific responses can be measured as the percentage\u000a      of CD8+ tetramer+ T cells as a fraction of all CD8+ lymphocytes in the\u000a      blood.\u000a    Following his appointment as Chair of Haematology at the University of\u000a      Birmingham in January 1998, Professor Paul Moss used Medical Research\u000a      Council Programme Grant support to investigate the use of tetramers in\u000a      relation to the clinical challenge of CMV infection following bone marrow\u000a      (stem cell) and solid organ transplantation. His group in Birmingham was\u000a      the first to develop a tetramer containing a CMV peptide and used this\u000a      reagent to demonstrate the extraordinary high frequency and phenotypic\u000a      heterogeneity of CMV-specific T cells within peripheral blood of healthy\u000a      donors (1). This work caused a paradigm shift in scientific understanding\u000a      of adaptive immunity. Previously it was understood that the CMV-specific T\u000a      cell immune response was present at a frequency of around 1 in 100,000\u000a      CD8+ T cells. This paper showed that the true frequency was well over 1%\u000a      of the peripheral T cell repertoire, making CMV the most immunodominant\u000a      antigen that is encountered by the human immune system. This work has\u000a      itself had considerable impact, including leading directly to the vaccine\u000a      team in Portland developing the most promising approach for HIV infection\u000a      using CMV as a vaccine vector (Hansen et al, 2011).\u000a    The team in Birmingham, under the continued leadership of Professor Paul\u000a      Moss, then went on to address CMV infection in stem cell and liver\u000a      transplantation. Here, they were the first to use tetramers to demonstrate\u000a      that the CMV-specific immune response was very weak in these patients and\u000a      a direct explanation for the high degree of morbidity and mortality\u000a      related to CMV infection (2, 3). The Moss group then developed a direct\u000a      use for tetramers as a means for antigen-specific T cell therapy, whereby\u000a      tetramers were used to isolate populations of CMV-specific T cells for\u000a      future administration to patients. Following the first publication of\u000a      magnetic separation of these cells in the laboratory (4), they went on to\u000a      complete the first clinical trial using the direct isolation of\u000a      antigen-specific T cells from transplant donors followed by infusion into\u000a      patients. Again, this groundbreaking paper was the first report of the\u000a      direct selection of antigen-specific T cells from human volunteers\u000a      followed by their immediate infusion into patients for any disease\u000a      category (5). This approach has been widely replicated and adopted in many\u000a      clinical protocols.\u000a    "},{"CaseStudyId":"38792","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The work to reduce delays in access to care for patients with RA has had\u000a      impacts in the fields of public policy and services as well as health\u000a        and welfare.\u000a    Public policy and services — policy debate has been stimulated and\u000a        moved forward by research evidence:\u000a    The work, highlighting that patient delay in accessing GPs is a major\u000a      contributor to overall delays in the assessment of patients with a new\u000a      onset of RA, informed the 2009 report by the National Audit Office on\u000a      \"Services for people with RA\", which has highlighted the need to reduce\u000a      delays in help seeking behaviour on the part of patients and the\u000a      subsequent impact on the economy through patients being able to remain in\u000a      the UK workforce. The report highlights the following: \"Too many people\u000a        with rheumatoid arthritis are not presenting, or being diagnosed and\u000a        treated quickly enough. Better value for money could be achieved through\u000a        increasing the number of people diagnosed within three months of onset\u000a        of disease. Our modelling work suggests that increasing from 10 to 20\u000a        per cent the number of people treated within three months would\u000a        initially increase overall NHS costs by £11 million over the first five\u000a        years; but would improve people's quality of life and for the proportion\u000a        that are of working age, earlier treatment would improve their chances\u000a        of remaining in work, generating productivity gains for the economy of\u000a        around £31 million. After around nine years, earlier treatment could\u000a        become cost neutral to the NHS, with ongoing benefits of: improved\u000a        quality of life; and reduced demands on the NHS (for example for\u000a        surgery)\" (1).\u000a    This report was highly influential in informing national policy.\u000a      Following its publication and prior to meeting with the Committee of\u000a      Public accounts, the then Chief Medical Office (David Nicholson) met with\u000a      Prof Karim Raza in Birmingham (18th November 2009) to discuss\u000a      issues related to patient delay. In answer to the following question from\u000a      the Chairman of the Committee of Public accounts \"Presumably you have\u000a        no trouble, Mr Nicholson, with recommendation (a), paragraph 18 on page\u000a        nine: \"The Department of Health should explore the cost-effectiveness of\u000a        options for raising public awareness of the symptoms of inflammatory\u000a        arthritis, including rheumatoid arthritis, to encourage people to\u000a        present to the NHS promptly after symptom onset.\"\" David Nicholson\u000a      replied \"I think it is absolutely the right thing to do ...We are\u000a        considering, I think quite actively at the moment, a bid from\u000a        Birmingham, as it happens, for research into the area of public\u000a        awareness so we can absolutely focus our attention on things that will\u000a        work\" (2).\u000a    The bid referred to by David Nicholson was funded by the NIHR under the\u000a      Research for Patient Benefit Scheme (Chief Investigator Prof Karim Raza;\u000a      Reference number PB-PG-1208-18114) and was supported by Arthritis Research\u000a      UK, the National Rheumatoid Arthritis Society (NRAS) and the Arthritis and\u000a      Musculoskeletal Alliance (ARMA).\u000a    Health and welfare — public awareness of a health risk or benefit has\u000a        been raised:\u000a    The work on understanding the reasons why patients delay in seeking early\u000a      help with their disease has informed the development of a public health\u000a      campaign launched in 2011 by the National Rheumatoid Arthritis Society to\u000a      reduce delays on the part of patients (3). This campaign highlighted that\u000a      the typical symptoms of early RA (stiffness, swelling and tenderness)\u000a      might be an indication of a disease for which urgent treatment was\u000a      necessary. In part, the NIHR funded study, referred to above, will be a\u000a      assessing the impact of this campaign and will look at ways of enhancing\u000a      the effectiveness of future public health messages.\u000a    One of the key issues that this work has identified is that patients of\u000a      South Asian origin are more likely to delay in seeking help compared with\u000a      the general population. Recognising this, the Rheumatology Research group\u000a      has worked with the Birmingham Arthritis Resource Centre (BARC) to develop\u000a      strategies to raise awareness amongst members of ethnic minority groups\u000a      (4). BARC is a voluntary organisation based in Birmingham Central Library\u000a      and supported by the University of Birmingham and Birmingham City Council.\u000a      Strategies developed with BARC have included audio information on a range\u000a      of topics including \"understanding arthritis\", available as a bilingual CD\u000a      and as an audio file (5), running outreach sessions in local community\u000a      venues (e.g. temples), appearing on local South Asian radio stations to\u000a      talk about RA and writing articles about RA for South Asian language\u000a      magazines. The effectiveness of the BARC audio CD has been demonstrated in\u000a      a study published in Musculoskeletal Care in 2011 (6). All patients who\u000a      participated in the study confirmed that the CD had been a useful source\u000a      of information and had addressed some of the language barriers which they\u000a      had previously experienced. In 2011 the University's work with BARC in the\u000a      community was awarded the 2011 Nursing Standard award for Innovations in\u000a      Rheumatology (7). Furthermore the work has attracted considerable media\u000a      attention, which has helped to raise awareness of the disease and the need\u000a      for early diagnosis.\u000a    ","ImpactSummary":"\u000a    Rheumatoid arthritis (RA) is a common destructive joint disease, causing\u000a      pain and swelling, affecting 1 in 100 people. Work conducted by the\u000a      University of Birmingham's Rheumatology Research Group has shown that\u000a      early diagnosis is important, as the first few months represent a critical\u000a      therapeutic window during which treatment can significantly improve health\u000a      outcomes, increasing the chances of achieving disease remission and\u000a      reducing the rate of progressive joint damage. The group have demonstrated\u000a      that there are significant delays in patients making initial contact with\u000a      their GP, which leads to delays in referral to a Rheumatologist and\u000a      starting treatment; this situation has been shown to be worse in patients\u000a      of South Asian origin. The outcome of the work has been incorporated into\u000a      national policy documents and clinical guidance material and has\u000a      underpinned a patient focused campaign to raise awareness of the disease\u000a      and the need for early diagnosis.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    Authors from the University of Birmingham are highlighted in bold:\u000a    \u000a1. van der Linden,M.P., le Cessie,S., Raza,K., van der\u000a      Woude,D., Knevel,R., Huizinga,T.W., and van der Helm-van Mil AH Long-term\u000a      impact of delay in assessment of patients with early arthritis. Arthritis\u000a        Rheum 2010; 62 :3537-3546. DOI 10.1002\/art.27692\u000a    \u000a\u000a2. Kumar,K., Daley,E., Carruthers,D.M., Situnayake,D., Gordon,C.,\u000a      Grindulis,K., Buckley,C.D., Khattak,F., and Raza,K. Delay\u000a      in presentation to primary care physicians is the main reason why patients\u000a      with rheumatoid arthritis are seen late by rheumatologists. Rheumatology\u000a        (Oxford) 2007; 46:1438-1440. DOI 10.1093\/rheumatology\/kem130\u000a    \u000a\u000a3. Raza,K., Stack,R., Kumar,K., Filer,A.,\u000a      Detert,J., Bastian,H., Burmester,G.R., Sidiropoulos,P., Kteniadaki,E.,\u000a      Repa,A., Saxne,T., Turesson,C., Mann,H., Vencovsky,J., Catrina,A.,\u000a      Chatzidionysiou,A., Hensvold,A., Rantapaa-Dahlqvist,S., Binder,A.,\u000a      Machold,K., Kwiakowska,B., Ciurea,A., Tamborrini,G., Kyburz,D., and Buckley,C.D.\u000a      Delays in assessment of patients with rheumatoid arthritis: variations\u000a      across Europe. Ann Rheum Dis 2011; 70 :1822-1825. DOI\u000a        10.1136\/ard.2011.151902 (in REF2)\u000a    \u000a\u000a4. Kumar,K., Daley,E., Khattak,F., Buckley,C.D., and Raza,K.\u000a      The influence of ethnicity on the extent of, and reasons underlying, delay\u000a      in general practitioner consultation in patients with RA. Rheumatology\u000a        (Oxford) 2010; 49 :1005-1012. DOI 10.1093\/rheumatology\/keq011\u000a    \u000a\u000a5. Sheppard,J., Kumar,K., Buckley, C.D., Shaw, K,L,, Raza, K. \"I\u000a      just thought it was normal aches and pains\": A Qualitative Study of\u000a      Decision Making Processes in Patients with Early Rheumatoid Arthritis. Rheumatology\u000a        (Oxford) 2008; 47:1577-82. DOI 10.1002\/art.23681\u000a    \u000a\u000a6. Stack,R.J., Shaw,K., Mallen,C., Herron-Marx,S.,\u000a      Horne,R., and Raza,K. Delays in help seeking at the onset of the\u000a      symptoms of rheumatoid arthritis: a systematic synthesis of qualitative\u000a      literature. Ann Rheum Dis 2012; 71:493-497. DOI\u000a        10.1136\/ard2011.155416\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    \u000a      National Audit Office Report \"Services for people with RA\" published\u000a        15th July 2009:\u000a        http:\/\/www.nao.org.uk\/publications\/0809\/rheumatoid_arthritis.aspx.\u000a      Transcript of the Chief Medical Office answering questions from the\u000a        committee of public accounts published 23rd February 2010: http:\/\/www.publications.parliament.uk\/pa\/cm200910\/cmselect\/cmpubacc\/46\/46.pdf.\u000a      National Rheumatoid Arthritis Society campaign to promote rapid help\u000a        seeking for RA, campaign launched 11th November 2011: http:\/\/nras.org.uk\/about_rheumatoid_arthritis\/what_is_ra\/how_is_it_diagnosed\/have_you_got_s_fact\u000a          or.aspx.\u000a      Birmingham Arthritis Resource Centre: http:\/\/www.barc.org.uk\/.\u000a      Birmingham Arthritis Resource Centre information on \"understanding\u000a        arthritis\" available as an audio file: http:\/\/www.barc.org.uk\/media\/index.html.\u000a      \u000aKumar K, John H, Gordhan C, Situnayake D, Raza K, Bacon PA.\u000a        Breaking communication barriers for RA patients of south Asian origin:\u000a        the use of a bilingual educational audio CD and linguistically\u000a        appropriate peer support and education. Musculoskeletal Care.\u000a        2011;9:11-8. DOI 10.1002\/msc.191\u000a\u000a      2011 Nursing Standard award for Innovations in Rheumatology: adverts\u000a        showing finalists and copy of Nursing Standard confirming award.\u000a      The Financial Times `Early care urged for rheumatoid\u000a        arthritis': http:\/\/www.ft.com\/cms\/s\/2\/1d847d3a-c0d7-11df-94f9-00144feab49a.html#axzz2Kwk6TtHe.\u000a      The Guardian `Failure to act on early signs of rheumatoid\u000a        arthritis could prove fatal':\u000a        http:\/\/www.guardian.co.uk\/science\/2010\/sep\/15\/early-signs-rheumatoid-arthritis.\u000a    \u000a    ","Title":"\u000a    Reducing delays in accessing care for patients with a new onset of\u000a        rheumatoid arthritis\u000a    ","UKLocation":[{"GeoNamesId":"2655603","Name":"Birmingham"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The work described in this case study was conducted by the Rheumatology\u000a      Research Group, in the School of Immunity and Infection at the University\u000a      of Birmingham, within their research strand focussed on management\u000a      pathways for patients with new onset RA. The work was led by Professor\u000a      Karim Raza (Professor of Clinical Rheumatology, at UoB from 2004) with\u000a      support from clinical colleagues: Professor Chris Buckley (Arthritis\u000a      Research UK Professor of Rheumatology, at UoB from 1996) and Dr Andrew\u000a      Filer (Clinical Senior Lecturer in Rheumatology, at UoB from 2006).\u000a      Qualitative aspects were supported by Ms Kanta Kumar (NIHR Doctoral\u000a      Research Fellow, UoB from 2009), Dr Rebecca Stack (Postdoctoral\u000a      Researcher, UoB from 2010) and Dr Karen Shaw (Birmingham Research Fellow,\u000a      UoB from 2005); Kanta Kumar led aspects of the work focussed on access to\u000a      care for patients from South Asian backgrounds. This case study is\u000a      underpinned by primary research in three areas:\u000a    The importance of treating RA early:\u000a    The first few months of clinical disease represent a therapeutic window\u000a      during which intervention leads to significantly improved outcomes,\u000a      increasing the chances of achieving remission and reducing the rate of\u000a      progression of joint damage (1). Work conducted in 2009 and 2010 by the\u000a      Rheumatology Group in Birmingham, in collaboration with the University of\u000a      Leiden, has contributed to a body of international data showing that early\u000a      treatment, within the first 12 weeks of the onset of clinically apparent\u000a      symptoms, is associated with a reduced rate of damage to bone and\u000a      cartilage in the joint, therefore highlighting the benefit of early\u000a      treatment of RA (1).\u000a    Identifying the problem: reasons why many patients with RA are\u000a          treated late in the UK:\u000a    Whilst treatment within the first 12 weeks is associated with optimal\u000a      outcomes, research conducted by the same group in Birmingham between 2004\u000a      and 2010 has shown that the median delay in access to specialist care\u000a      where treatment is initiated is 23 weeks. The work has highlighted that,\u000a      in the UK, the majority of the delay in getting to see a Rheumatologist\u000a      and starting treatment is due to delay on the part of the patient in\u000a      making an initial appointment to see their GP, with the median delay being\u000a      12 weeks. Delays on the part of GPs in referring, and on the part of\u000a      Rheumatologists in seeing patients once a referral has been received, are\u000a      shorter (2-4). Furthermore, the patient delay was significantly longer (24\u000a      weeks) in patients of South Asian origin (4). A parallel international\u000a      study led by Prof Raza at the University of Birmingham within the EU\u000a      funded AutoCure consortium (www.autocure.org),\u000a      showed that delays at the level of the patient were also important\u000a      contributors to total delay in assessment in a number of other European\u000a      countries including Sweden, Switzerland and the Czech Republic (3).\u000a    Informing the solution: approaches to reducing patient delay in the\u000a          UK:\u000a    In order to reduce patient delay, the reasons underlying it need to be\u000a      understood. The same group in Birmingham have carried out primary\u000a      qualitative work to attempt to understand why patients delay in making\u000a      contact with their GP (4). In addition, as part of a National Institute\u000a      for Health Research (NIHR) funded Research for Patient Benefit grant\u000a      (Chief Investigator Prof Karim Raza; Reference number PB-PG-1208-18114\u000a      \"Help seeking behaviour in patients with new onset rheumatoid arthritis:\u000a      understanding the reasons for delay in GP consultation and strategies to\u000a      reduce this delay\". 2010-13) the group has conducted a synthesis of the\u000a      qualitative literature in relation to reasons for delays in help seeking\u000a      in patients with inflammatory arthritis (6). Results showed a lack of\u000a      awareness that symptoms of inflammatory arthritis might indicate a serious\u000a      disease for which effective treatment was available, that most patients\u000a      initially attributed joint symptoms to \"normal wear and tear\", and that\u000a      most patients thought, at symptom onset, that they were too young to\u000a      develop arthritis.\u000a    "},{"CaseStudyId":"38793","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Research led by Prof Franklyn and Dr Boelaert has had a significant\u000d\u000a      impact on clinical management ofthyrotoxicosis (over-activity of the\u000d\u000a      thyroid) and thyroid cancer. This work continues to drive national and\u000d\u000a      international guidance, professional training and clinician decisions, as\u000d\u000a      well as those of patients, in the UK and beyond.\u000d\u000a    Thyrotoxicosis and its treatment with radioiodine\u000d\u000a      Obvious (overt) over-activity of the thyroid affects 5% of the UK\u000d\u000a      population. Untreated, in addition to unpleasant symptoms, it is a\u000d\u000a      significant risk factor for cardiovascular disorders, especially the heart\u000d\u000a      rhythm abnormality atrial fibrillation (AF), as well as for osteoporosis\u000d\u000a      (thin bones). Management is typically with anti-thyroid drugs, radioiodine\u000d\u000a      therapy or occasionally surgery. Radioiodine is used to overcome the\u000d\u000a      hyperactivity of the thyroid gland, but in many cases induces\u000d\u000a      hypothyroidism, i.e. under-activity of the gland, which requires careful\u000d\u000a      management with thyroxine as thyroid hormone replacement. Prof Franklyn\u000d\u000a      and team's research has impacted upon:\u000d\u000a    Clinician awareness and national guidance regarding use of\u000d\u000a          radioiodine:\u000d\u000a    \u000d\u000a      Highlighted and clarified the increased risks of vascular diseases\u000d\u000a        associated with thyrotoxicosis, influencing current guidance in the UK\u000d\u000a        and overseas in terms of recommending and hence driving earlier use of\u000d\u000a        definitive therapy with radioiodine to improve long-term prognosis\u000d\u000a        [1,2].\u000d\u000a      Driven current national guidance for the use of radioiodine in benign\u000d\u000a        thyroid disease (Franklyn co-author and Birmingham work explicitly\u000d\u000a        referenced [3] in guidance published 2007 which has driven practice\u000d\u000a        2008-13), which underpins safe and effective delivery of radioiodine\u000d\u000a        treatment in conjunction with Medical Physics Departments, and\u000d\u000a        subsequent follow-up of patients to promptly identify development of\u000d\u000a        hypothyroidism and to manage it with the correct dose of thyroxine.\u000d\u000a        Franklyn contributed to the 2011 Royal College of Physicians\u000d\u000a        multi-professional guidance statement on diagnosis and treatment of\u000d\u000a        hypothyroidism [4].\u000d\u000a    \u000d\u000a    Training in the administration of radioiodine with associated cost\u000d\u000a          savings and patient benefit:\u000d\u000a      To support clinician training and maximise patient benefit from this work,\u000d\u000a      the team used their expertise to innovate in postgraduate medical\u000d\u000a      education nationally. Franklyn led a team in 2006 that included the Royal\u000d\u000a      College of Radiologists, the Institute of Physics and Engineering in\u000d\u000a      Medicine and ARSAC (the government licensing body) to create the first\u000d\u000a      national curriculum and associated teaching and assessment materials for\u000d\u000a      consultant endocrinologists (specialists who manage patients with thyroid\u000d\u000a      problems) to acquire the knowledge and skills required for licensing by\u000d\u000a      ARSAC to administer radioiodine therapy (guidance issued in 2006 and\u000d\u000a      revised in 2011 [5]). Franklyn and Boelaert developed novel educational\u000d\u000a      materials and have delivered teaching on this national course 2-3 times\u000d\u000a      per year for 264 attendees since 2008. Importantly, over 50 consultant\u000d\u000a      endocrinologists from across the UK have been certified by ARSAC, with\u000d\u000a      support from their NHS Trust medical physics departments, through this new\u000d\u000a      training scheme, representing an increase in licensed endocrinologists of\u000d\u000a      35% since 2008. This has had the specific beneficial impact of reducing\u000d\u000a      patient visits and NHS costs (estimated at £223 per unnecessary oncology\u000d\u000a      clinic appointment) by eliminating the need for cross-referral of patients\u000d\u000a      between endocrinology and either oncology or nuclear medicine specialists\u000d\u000a      for radioiodine treatment, allowing better planning of timing of treatment\u000d\u000a      and follow-up and thus improving and simplifying the care pathway to the\u000d\u000a      benefit of both patients and clinicians [6].\u000d\u000a    Patient access to information about optimal treatment for\u000d\u000a          thyrotoxicosis:\u000d\u000a      The team has worked directly with patient and carer groups to disseminate\u000d\u000a      the findings of their work and to support patient awareness and\u000d\u000a      decision-making. Franklyn was a Trustee (2008-11) of the British Thyroid\u000d\u000a      Foundation (the major UK patient and carer support group), contributing to\u000d\u000a      patient information literature, newsletters, website information (such as\u000d\u000a      the revised patient information on thyrotoxicosis developed by Franklyn\u000d\u000a      and Boelaert [7]). They have also attended meetings of patient support\u000d\u000a      groups, sessions which are \"highly regarded\" and have resulted in\u000d\u000a      excellent patient and carer feedback, as testified by the British Thyroid\u000d\u000a      Foundation [8], who also commented that \"We strongly support the\u000d\u000a        notion that the University of Birmingham Research Portfolio continues to\u000d\u000a        have significant impact on the care of patients with thyroid disorders.\"\u000d\u000a    Mild (subclinical) thyrotoxicosis and its treatment with radioiodine\u000d\u000a    Thyrotoxicosis is described as \"subclinical\" (or mild) when the measurement\u000d\u000a    of thyrotrophin (TSH) from the pituitary in the blood\/serum is low but the\u000d\u000a    blood level of the actual thyroid hormone thyroxine (T4) is normal. This\u000d\u000a    combination of blood test results indicates the earliest stages of\u000d\u000a    thyrotoxicosis which can progress to obvious\/overt disease, but importantly\u000d\u000a    has its own specific associated health risks. Work on subclinical\u000d\u000a    thyrotoxicosis (also termed subclinical hyperthyroidism) led by Franklyn and\u000d\u000a    team has shown how common this disorder is, especially in the elderly and\u000d\u000a    how it is associated with vascular disorders and mortality, and has:\u000d\u000a    \u000d\u000a      Been incorporated into current UK guidance [9],first published in 2006\u000d\u000a        and updated in a Lancet invited review in 2012 [1], which clarifies\u000d\u000a        current best practice in terms the role of treatment of subclinical\u000d\u000a        hyperthyroidism with radioiodine, which is now increasingly undertaken\u000d\u000a        in the UK and abroad;\u000d\u000a      Directly influenced international practice by being incorporated into\u000d\u000a        the American Thyroid Association\/American Association of Clinical\u000d\u000a        Endocrinologists\/US Endocrine Society consensus guidelines in 2004 [10],\u000d\u000a        which remain current and have driven US and international practice\u000d\u000a        2008-13. Franklyn was the only invited overseas expert and consensus\u000d\u000a        guideline panel member;\u000d\u000a      Been incorporated into the most recent US guidance published in\u000d\u000a        2011\/12 [2] directly citing Franklyn and her team's work\u000d\u000a    \u000d\u000a    Thyroid cancer and adjunctive treatment with radioiodine\u000d\u000a      Thyroid nodules are very common, and can be identified by ultrasound\u000d\u000a      scanning in up to 50% of the population, though only around 5% of the\u000d\u000a      population have nodules that are noticed by patients or their doctors. Up\u000d\u000a      to 10% of such nodules may be cancerous, thyroid cancer being the\u000d\u000a      commonest endocrine cancer with more than 2000 new cases each year in the\u000d\u000a      UK.\u000d\u000a    Birmingham work on radioiodine treatment has also extended to thyroid\u000d\u000a      cancer. Surgery (thyroidectomy) is the initial treatment for thyroid\u000d\u000a      cancer, but radioiodine is used subsequently to destroy any remaining\u000d\u000a      thyroid tissue. Much higher doses of radioiodine are used than in\u000d\u000a      treatment of thyrotoxicosis as described above. These high doses require\u000d\u000a      significant hospital stays in isolation because of national radiation\u000d\u000a      protection regulationsfor the general population and high doses are\u000d\u000a      potentially harmful long-term in terms of risk of \"second\"\/later\u000d\u000a      malignancies; high doses of radioiodine were regarded as the best option\u000d\u000a      to ensure ablation of all residual thyroid tissue. Franklyn played a key\u000d\u000a      role in the development and delivery of the `HiLo' trial of \"high\" versus\u000d\u000a      \"low\" doses of radioiodine in thyroid cancer patients at relatively low\u000d\u000a      risk of later recurrence (who represent 40-50% of those diagnosed each\u000d\u000a      year), the trial results showing that low doses were just as effective as\u000d\u000a      high and caused fewer side effects (21% versus 33%), helping with quicker\u000d\u000a      recovery and shorter hospital stays (13% given low dose radioiodine in the\u000d\u000a      HiLo trial hospitalised for at least 3 days versus 36.3% for high dose).\u000d\u000a      These findings have already:\u000d\u000a    \u000d\u000a      Led to reduction in the doses of radioiodine administered to those\u000d\u000a        whose thyroid cancer is at low risk of recurrence, this being a\u000d\u000a        significant proportion of those treated, as evident in our own local\u000d\u000a        tertiary centre guidance and practice. In the year to October 2011 100%\u000d\u000a        of 93 radioiodine doses administered for \"remnant thyroid ablation\" in\u000d\u000a        the Queen Elizabeth Hospital Birmingham were \"high\" (3000 or 5500MBq) in\u000d\u000a        contrast to only 73% of 102 doses in the year to October 2012 and 62% of\u000d\u000a        97 doses in the year to October 2013 [11], a change which was\u000d\u000a        implemented as a result of the HiLo outcomes. These changes represent a\u000d\u000a        saving of approximately 100 days of hospitalisation over a 2 year period\u000d\u000a        in this single centre. More broadly for other centres adopting this\u000d\u000a        recommended change in practice it was estimated within the HiLo study\u000d\u000a        that there was a 24% cost reduction in care of patients treated within\u000d\u000a        the NHS from reduction in hospital days in isolation, as well as\u000d\u000a        associated reduction in days off work.\u000d\u000a      This work has been widely disseminated amongst clinicians and patients\u000d\u000a        through Cancer Research UK [12,13] and hailed as seminal results which\u000d\u000a        are directly changing clinical practice.\u000d\u000a    \u000d\u000a    ","ImpactSummary":"\u000d\u000a    Thyrotoxicosis (over-activity of the thyroid) affects up to 5% of the UK\u000d\u000a      population and causes excess mortality, especially from vascular diseases,\u000d\u000a      even in its mildest form. Thyroid cancer is the commonest endocrine\u000d\u000a      cancer, its treatment being associated with adverse consequences which\u000d\u000a      need to be minimised. A large programme of thyroid research in Birmingham\u000d\u000a      led by Prof Jayne Franklyn has made major contributions to improving the\u000d\u000a      management of thyrotoxicosis, specifically through optimal use of\u000d\u000a      radioiodine treatment. Her group has developed and delivered a national\u000d\u000a      training scheme to allow endocrinologists (hormone specialists) to give\u000d\u000a      this treatment safely and effectively. Radioiodine is also a crucial part\u000d\u000a      of treatment of thyroid cancer; Franklyn helped deliver a major trial\u000d\u000a      showing that lower doses are as effective as higher doses in most cases\u000d\u000a      but with fewer days in hospital and side effects. This research has\u000d\u000a      changed clinical practice regarding more effective and safe use of\u000d\u000a      radioiodine in thyrotoxicosis and thyroid cancer. It has been incorporated\u000d\u000a      in national and international clinical guidance, patient information\u000d\u000a        sources, and has directly affected clinician training and patient care\u000d\u000a        pathways.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Birmingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Franklyn JA, Sheppard MC, Maisonneuve P (2005) Thyroid function and\u000d\u000a      mortality in patients treated for hyperthyroidism. JAMA; 294(1):\u000d\u000a      71-80. DOI 10.1001\/jama.294.1.71\u000d\u000a    \u000a\u000a2. Boelaert K, Maisonneuve P, Torlinska B, Franklyn JA (2013). Comparison\u000d\u000a      of mortality in hyperthyroidism during periods of treatment with\u000d\u000a      thionamides and after radioiodine. Journal of Clinical Endocrinology\u000d\u000a        and Metabolism 98(5):1869-82 In REF2\u000d\u000a    \u000a\u000a3. Franklyn JA, Maisonneuve P, Sheppard MC, Betteridge J, Boyle P. (1999)\u000d\u000a      Cancer incidence and mortality after radioiodine treatment for\u000d\u000a      hyperthyroidism: a population-based cohort study. Lancet ;\u000d\u000a      353(9170): 2111-2115. doi:10.1016\/S0140-6736(98)12295-X\u000d\u000a    \u000a\u000a4. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction\u000d\u000a      of all-cause and cardiovascularmortality in elderly people from one low\u000d\u000a      serum thyrotrophin: a 10-year cohort study. Lancet 2001;\u000d\u000a      358(9285): 861-65. doi:10.1016\/S0140-6736(01)06067-6\u000d\u000a    \u000a\u000a5. Collet TH, Gussekloo J, Bauer DC, den Elzen WPJ, Balmer P, Iervasi G\u000d\u000a      et al.et al. Subclinical hyperthyroidism and risk of coronary heart\u000d\u000a      disease and mortality Archives of Internal Medicine 2012; 172(10):\u000d\u000a      799-809. DOI 10.1001\/jama.2010.1361\u000d\u000a    \u000a\u000a6. Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss Let al. Ablation\u000d\u000a      with low-dose radioiodine and thyrotropinalfa in Thyroid Cancer. New\u000d\u000a        England Journal of Medicine 2012;366: 1674-85. http:\/\/www.nejm.org\/doi\/pdf\/10.1056\/NEJMoa1109589\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    \u000d\u000a      Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 2012\u000d\u000a        379(9821): 1155-66.\u000d\u000a        http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22394559\u000d\u000a        (invited review)\u000d\u000a      \u000aBahn\u000d\u000a          RS, Burch\u000d\u000a          HB, Cooper\u000d\u000a          DS, Garber\u000d\u000a          JR, Greenlee\u000d\u000a          MC, Klein\u000d\u000a          I et al. Hyperthyroidism and other causes of thyrotoxicosis:\u000d\u000a        management guidelines of the American Thyroid Association and American\u000d\u000a        Association of Clinical Endocrinologists. Endocrine Practice\u000d\u000a        2011; 17(3): 456-520.\u000d\u000a        http:\/\/aace.metapress.com\/content\/q707415233782r31\/fulltext.pdf\u000a\u000d\u000a      Royal College of Physicians. Radioiodine in the management of benign\u000d\u000a        thyroid disease. Clinical Guidelines. Report of a Working Party 2007.\u000d\u000a        London: RCP; 2007.\u000d\u000a        http:\/\/bookshop.rcplondon.ac.uk\/contents\/pub208-bdbb4220-3a14-401a-b298-c0d3f20cdd38.pdf\u000a\u000d\u000a      Royal College of Physicians. The Diagnosis and Management of Primary\u000d\u000a        Hypothyroidism. Revised statement June 2011. http:\/\/www.rcplondon.ac.uk\/resources\/clinical-resources\/diagnosis-and-management-primary-hypothyroidism\u000a\u000d\u000a      Notes for Guidance onthe Clinical Administrationof\u000d\u000a        Radiopharmaceuticalsand Use of Sealed Radioactive Sources, 2011 update\u000d\u000a        http:\/\/www.arsac.org.uk\/notes_for_guidance\/documents\/ARSACNFG2006Corrected2011.pdf\u000a\u000d\u000a      Peat I, Franklyn JA. The new era of radioiodine treatment. Clinical\u000a          Medicine 2008; 8(6): 567-8.\u000d\u000a        http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19149274\u000a\u000d\u000a      http:\/\/www.british-thyroid-association.org\/info-for-patients\/\u000d\u000a      British Thyroid Foundation letter of support\u000d\u000a      Association for Clinical Biochemistry. UK Guidelines for the Use of\u000d\u000a        Thyroid Function Tests. British Thyroid Association\/ British Thyroid\u000d\u000a        Foundation; 2006.\u000d\u000a        http:\/\/www.acb.org.uk\/docs\/TFTguidelinefinal.pdf\u000a\u000d\u000a      Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH et\u000d\u000a        al.Subclinical thyroid disease: scientific review and guidelines for\u000d\u000a        diagnosis and management. JAMA 2004; 291(2): 228-38.\u000d\u000a        http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14722150\u000a\u000d\u000a      Radioiodine figures for thyroid cancer, Queen Elizabeth Hospital\u000d\u000a        Birmingham 2010-2013 (personal communication)\u000d\u000a      http:\/\/www.cancerresearchuk.org\/cancer-info\/news\/archive\/pressrelease\/2012-05-02-thyroid-cancer-trial-results\u000d\u000a      Cancer Research UK website — Cancer Help information under Trials and\u000d\u000a        research: A trial looking at radioactive iodine treatment for thyroid\u000d\u000a        cancer (HiLo):\u000d\u000a        http:\/\/www.cancerresearchuk.org\/cancer-help\/trials\/a-trial-looking-at-radioactive-iodine-treatment-for-thyroid-cancer\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Refining the role and optimizing delivery of radioiodine in the treatment\u000d\u000a      of thyrotoxicosis and thyroid cancer\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    A substantial programme of thyroid research of national and international\u000d\u000a      repute has been delivered at the University of Birmingham over the last\u000d\u000a      two decades, led by Prof Jayne Franklyn (at UoB since 1988) and her team,\u000d\u000a      including Dr Kristien Boelaert (Senior Clinical Lecturer, at UoB since\u000d\u000a      2002). Birmingham is regarded as one of the principal centres for this\u000d\u000a      activity in the UK and wider world. Research is underpinned by a uniquely\u000d\u000a      large, detailed and longstanding database that records information about\u000d\u000a      clinical phenotype, test results, treatment given and treatment outcomes\u000d\u000a      for consecutive series of subjects with thyrotoxicosis (hyperthyroidism)\u000d\u000a      and thyroid cancer. In addition, Prof Franklyn and Dr Boelaert manage the\u000d\u000a      regional Birmingham Thyroid Follow-up Register of all subjects in the West\u000d\u000a      Midlands treated with radioiodine for thyrotoxicosis since the 1950s,\u000d\u000a      providing a further unique dataset for examining treatment outcomes. These\u000d\u000a      large datasets of several thousand patients come from a high quality\u000d\u000a      clinical service, forming the basis of important studies (since 1998)\u000d\u000a      defining short- and medium-term treatment outcomes and long-term\u000d\u000a      consequences of thyrotoxicosis and its treatment.\u000d\u000a    Thyrotoxicosis: treatment with radioiodine. Seminal\u000d\u000a      findings from Birmingham have included definition of the long term\u000d\u000a      consequences of obvious\/overt thyrotoxicosis, particularly the finding of\u000d\u000a      increased mortality from vascular disorders [1] and importantly the\u000d\u000a      amelioration of this adverse outcome by treatment specifically with\u000d\u000a      radioiodine [1,2]. Studies have compared the relative efficacy of\u000d\u000a      different treatments (anti-thyroid drugs and radioiodine in different\u000d\u000a      doses) and have shown the long-term safety of radioiodine treatment in\u000d\u000a      terms of any potential later cancer risk [3].\u000d\u000a    Mild\/subclinical thyrotoxicosis: adverse outcome and need for\u000d\u000a          treatment with radioiodine.\u000d\u000a      Collaborations with colleagues in primary care and cardiology have allowed\u000d\u000a      community-based studies in the elderly of mild (subclinical)\u000d\u000a      hyperthyroidism. Major findings published from 2001-2013 include the high\u000d\u000a      prevalence in this age group and strong association of mild\u000d\u000a      hyperthyroidism with risk of atrial fibrillation (AF) and vascular\u000d\u000a      mortality [4].These findings have contributed to meta-analyses of clinical\u000d\u000a      outcomes in mild hyperthyroidism [3] through Franklyn's participation in\u000d\u000a      the International Thyroid Collaboration led by Prof Nicolas Rodondi. These\u000d\u000a      findings have clarified the importance of treating mild hyperthyroidism,\u000d\u000a      radioiodine being the treatment of choice for confirmed cases, a treatment\u000d\u000a      now used increasingly in this condition.\u000d\u000a    Thyroid cancer: ablation of the thyroid remnant with radioiodine:\u000d\u000a      Prof Franklyn's role as Chair of the National Cancer Research\u000d\u000a      Institute Thyroid subgroup (2005-8) facilitated development of the HiLo\u000d\u000a      trial comparing the effectiveness of different doses of radioiodine in\u000d\u000a      destroying residual thyroid tissue after initial surgery (thyroidectomy)\u000d\u000a      for thyroid cancer. This trial was supported by Cancer Research UK\u000d\u000a      funding, Franklyn being a member of the trial management group. HiLo study\u000d\u000a      findings clearly demonstrated that low-dose radioiodine was as effective\u000d\u000a      as high-dose radioiodine in subjects at low risk of cancer recurrence, and\u000d\u000a      with a lower rate of adverse events and shorter hospital stay [6].\u000d\u000a    "},{"CaseStudyId":"38794","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000a    Impact on UK clinical practice and patient care\u000a    The BASIL trial led to a number of recommendations, many of which have\u000a      been actively embraced\u000a      by NICE as part of their recently published (August 2012) Peripheral\u000a      Arterial Disease (PAD)\u000a      Clinical Guidelines [1]. Professor Bradbury was a member of the\u000a      NICE PAD Guidelines\u000a      Development Group. Specifically linked to BASIL findings, the guidelines\u000a      emphasise:\u000a    \u000a      Significant health gains for patients with SLI lie in earlier\u000a        diagnosis and imaging; the\u000a        implementation of evidence-based best medical therapy; appropriate\u000a        imaging; and prompt\u000a        referral to a specialist vascular service\u000a      The best outcomes for SLI are achieved when vascular surgeons and\u000a        interventional\u000a        radiologists work closely together with other professionals as part of a\u000a        multidisciplinary\u000a        team in specialist, high-volume centres\u000a      The decision whether to perform bypass surgery or balloon angioplasty\u000a        first appears to\u000a        depend upon co-morbidities (life expectancy); pattern of disease;\u000a        availability of a vein as a\u000a        bypass conduit; and patient preference\u000a    \u000a    In the context of these guidelines, in terms of clinical practice and\u000a      patient care the BASIL findings\u000a      translate to the following changes:\u000a    \u000a      SLI patients expected to live less than 2 years should usually be\u000a        offered endovascular\u000a        intervention first, as it is associated with less morbidity and cost,\u000a        and such patients are\u000a        unlikely to enjoy the longer-term benefits of surgery\u000a      Those patients expected to live beyond 2 years should usually be\u000a        offered bypass surgery\u000a        first, especially where a vein is available as a conduit\u000a      Many patients who could not undergo a vein bypass would probably have\u000a        been better\u000a        served by a first attempt at balloon angioplasty than prosthetic bypass.\u000a        Surgeons should\u000a        make every effort to use vein and should view prosthetic material as a\u000a        last resort\u000a    \u000a    Impact on international clinical guidelines\u000a    The impact of these findings and their clinical uptake is not limited to\u000a      the UK. Following publication\u000a      of the trial outcomes Professor Bradbury has been invited to present the\u000a      BASIL data in Europe, the\u000a      Middle and Far East, North and South America and Australia. The novel\u000a      insights and\u000a      recommendations emanating from BASIL were consequently adopted into and\u000a      highlighted in a\u000a      number of key international guidelines which are now guiding clinical\u000a      practice in this area:\u000a    \u000a      The 2011 European Society of Cardiology Guidelines on the diagnosis\u000a        and treatment of PAD\u000a        [2], endorsed by the European Stroke Association, reference\u000a        BASIL-1 in their\u000a        recommendations for surgical revascularisation in with respect to\u000a        revascularisation state:\u000a        \"When surgery is considered to revascularise infra-iliac lesions,\u000a          autologous saphenous vein is\u000a          the bypass graft of choice.\"\u000a\u000a      The 2011 American College of Cardiology Foundation\/American Heart\u000a        Association updated\u000a        guidelines for `Management of Patients with Peripheral Artery Disease' [3]\u000a        discuss the BASIL\u000a        trial and how this has led to two new recommendations:\u000a      \u000a        For patients with limb-threatening lower extremity ischemia and\u000a            an estimated life\u000a            expectancy of 2 years or less or in patients in whom an autogenous\u000a            vein conduit is not\u000a            available, balloon angioplasty is reasonable to perform when\u000a            possible as the initial\u000a            procedure to improve distal blood flow.\u000a        For patients with limb-threatening ischemia and an estimated life\u000a            expectancy of more\u000a            than 2 years, bypass surgery, when possible and when an autogenous\u000a            vein conduit is\u000a            available, is reasonable to perform as the initial treatment to\u000a            improve distal blood flow\u000a      \u000a    \u000a    As noted above, BASIL-1 has been endorsed by a number of key\u000a      organisations; most recently, as\u000a      part of the process of applying to the HTA for funds to conduct BASIL-2\u000a      (NIHR HTA, £2,004,572,\u000a      Chief Investigator, Professor Andrew Bradbury):\u000a    \u000a      \u000aCirculation Foundation:\"The original BASIL trial has\u000a          had profound impact worldwide, indeed I\u000a          personally have heard BASIL data referred to and discussed at meetings\u000a          on at least 5\u000a          continents! Trials of such importance have a major effect on clinical\u000a          practice and patient\u000a          care\"[4].\u000a      \u000aEuropean Society of Vascular Surgery: \"The BASIL-1\u000a          trial has had a profound effect on the\u000a          management of lower limb ischaemia at a time when more and more\u000a          clinicians had been\u000a          moving towards an endovascular first approach\" [5]\u000a    \u000a    As a result of this work, the World Federation of Vascular Societies,\u000a      (WFVS) Society for Vascular\u000a      Surgery (SVS) and European Society for Vascular Surgery (ESVS) have agreed\u000a      on the need for\u000a      clear standards for peripheral arterial care, and come together to develop\u000a      standard guidelines.\u000a      Professor Andrew Bradbury was elected as the WFVS Representative to lead\u000a      this initiative by an\u000a      Executive group at which there were representatives from all the\u000a      supporting continental societies:\u000a      ESVS; SVS; Australasian Vascular Society; Asian Vascular Society; Southern\u000a      African Society;\u000a      Indian Vascular Society, Japanese Vascular Society and Society of Vascular\u000a      Surgery and\u000a      Angiology for Latin America. These societies represent almost all vascular\u000a      surgical societies in the\u000a      countries in the world, and Prof Bradbury will now lead the discussions\u000a      and collaborations across\u000a      not only Europe but also Asia, Australasia and Southern Africa that take\u000a      this important area of\u000a      patient care forward.\u000a    ","ImpactSummary":"\u000a    Severe Limb Ischaemia (SLI), in which there is reduced blood flow to the\u000a      leg(s), is the commonest\u000a      cause worldwide of gangrene and limb loss. The BASIL trial, led by\u000a      Professor Andrew Bradbury at\u000a      the University of Birmingham, was the first (and remains the only)\u000a      randomised controlled trial to\u000a      investigate whether surgical bypass or endovascular (`keyhole') treatment\u000a      is best at relieving\u000a      symptoms and preventing amputation and\/or death in patients with SLI. The\u000a      outcomes of the study\u000a      have been of worldwide interest, and the recommendations put forward by\u000a      the team have been\u000a      endorsed by a number of high profile clinical organisations. These\u000a      findings are also\u000a      nowincorporated within a series of national and international guidelines\u000a      on SLI.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Birmingham\u000a    ","Institutions":[{"AlternativeName":"Birmingham (University of)","InstitutionName":"University of Birmingham","PeerGroup":"A","Region":"West Midlands","UKPRN":10006840}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Bypass versus angioplasty in severe ischaemia of the leg\u000a      (BASIL): multicentre, randomised\u000a      controlled trial. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW,\u000a      Forbes JF, Fowkes FG,\u000a      Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants.\u000a      Lancet. 2005 Dec\u000a      3;366(9501):1925-34. PMID: 16325694\u000a    \u000a\u000a2. Multicentre randomised controlled trial of the clinical and\u000a      cost-effectiveness of a bypass-surgery-first\u000a      versus a balloon-angioplasty-first revascularisation strategy for severe\u000a      limb ischaemia\u000a      due to infrainguinal disease. The Bypass versus Angioplasty in Severe\u000a      Ischaemia of the Leg\u000a      (BASIL) trial. Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG,\u000a      Gillespie I, Raab G, Ruckley\u000a      CV. Health Technol Assess. 2010 Mar;14(14):1-210, iii-iv. doi:\u000a        10.3310\/hta14140. PMID: 20307380\u000a    \u000a\u000a3. Bypass versus Angioplasty in Severe Ischaemia of the Leg\u000a      (BASIL) trial: Analysis of amputation\u000a      free and overall survival by treatment received. Bradbury AW, Adam\u000a      DJ, Bell J, Forbes JF,\u000a      Fowkes FG, Gillespie I, Ruckley CV, Raab GM; BASIL trial Participants. J\u000a      Vasc Surg. 2010\u000a      May;51(5 Suppl):18S-31S. doi: 10.1016\/j.jvs.2010.01.074. Erratum\u000a      in: J Vasc Surg. 2010\u000a      Dec;52(6):1751. Bhattachary, V [corrected to Bhattacharya, V]. PMID:\u000a      20435259\u000a    \u000a\u000a4. Bypass versus Angioplasty in Severe Ischaemia of the Leg\u000a      (BASIL) trial: Health-related quality\u000a      of life outcomes, resource utilization, and cost-effectiveness analysis.\u000a      Forbes JF, Adam DJ, Bell J,\u000a      Fowkes FG, Gillespie I, Raab GM, Ruckley CV, Bradbury AW; BASIL\u000a      trial Participants. J Vasc\u000a      Surg. 2010 May;51(5 Suppl):43S-51S. doi: 10.1016\/j.jvs.2010.01.076.\u000a        PMID: 20435261\u000a    \u000a\u000a5. Bypass versus Angioplasty in Severe Ischaemia of the Leg\u000a      (BASIL) trial: A survival prediction\u000a      model to facilitate clinical decision making. Bradbury AW, Adam\u000a      DJ, Bell J, Forbes JF, Fowkes\u000a      FG, Gillespie I, Ruckley CV, Raab GM; BASIL Trial Participants. J Vasc\u000a      Surg. 2010 May;51(5\u000a      Suppl):52S-68S. doi: 10.1016\/j.jvs.2010.01.077. Erratum in: J Vasc Surg.\u000a      2010 Dec;52(6):1751.\u000a      Bhattachary, V [corrected to Battacharya, V]. PMID: 20435262\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    1. `Lower limb peripheral arterial disease: Diagnosis and\u000a      management' NICE Clinical Guideline\u000a      147; Methods, evidence and recommendations August 2012 (http:\/\/guidance.nice.org.uk\/CG147)\u000a    2. `ESC Guidelines on the diagnosis and treatment of peripheral\u000a      artery diseases', European Heart\u000a      Journal (2011) 32, 2851-2906 doi: 10.1093\/eurheartj\/ehr211\u000a    3. 2011 ACCF\/AHA focused update of the guideline for the\u000a      management of patients with\u000a      peripheral artery disease (updating the 2005 guideline). American College\u000a      of Cardiology\u000a      Foundation; American Heart Association Task Force; Society for\u000a      Cardiovascular Angiography and\u000a      Interventions; Society of Interventional Radiology; Society for Vascular\u000a      Medicine; Society for\u000a      Vascular Surgery, Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA,\u000a      Findeiss LK,\u000a      Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley\u000a      JC, White CJ, White\u000a      JV, Zierler RE. Vasc Med. 2011 Dec;16(6):452-76. doi:\u000a      10.1177\/1358863X11424312. PMID:\u000a        22128043\u000a    4. Circulation Foundation letter of support for BASIL-2.\u000a    5. European Society of Vascular Surgery letter of support for\u000a      BASIL-2\u000a    6. E-mail from World Federation of Vascular Societies informing\u000a      Prof Bradbury of his appointment\u000a    ","Title":"\u000a    Improving clinical decision making and patient outcomes in severe limb\u000a      ischaemia\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    SLI, a condition where atherosclerosis (aka `hardening of the\u000a      arteries') leads to a severe lack of\u000a      blood supply to the leg(s), is a common cause of pain, gangrene,\u000a      amputation and death; and\u000a      represents a major health and social care issue in all developed\u000a      and developing economies. The\u000a      numbers of patients requiring lower limb revascularisation for SLI are\u000a      likely to increase significantly\u000a      worldwide as a result of ageing populations, the failure to significantly\u000a      reduce tobacco consumption\u000a      and the increasing global prevalence of diabetes, all of which are closely\u000a      associated with the\u000a      condition.\u000a    Failure to improve the blood supply to the leg(s) (termed`\u000a      revascularisation')in SLI can be\u000a      associated with amputation and death rates as high as 50% at 12 months.\u000a      These risks can be\u000a      dramatically reduced by timely intervention. The two principal treatment\u000a      alternatives for SLI are\u000a      bypass surgery and endovascular (`keyhole') treatment. The latter\u000a      comprises the use of\u000a      angioplasty (the stretching of the narrowed artery from the inside using a\u000a      balloon)and stenting (the\u000a      placing of metal tubes within the narrowed arteries to hold them open).\u000a      Both revascularisation\u000a      strategies have advantages and disadvantages, and for many years there has\u000a      been fierce debate\u000a      within vascular surgery as to which patient is best treated by which\u000a      method.\u000a    The NIHR Health Technology Assessment (HTA)-funded (£1,012,736) Bypass\u000a      versus Angioplasty\u000a      in Severe Ischaemia of the Leg (BASIL) trial led by Chief Investigator\u000a      Professor Andrew Bradbury\u000a      (Sampson Gamgee Professor of Vascular Surgery, at the University of\u000a      Birmingham since 2000)\u000a      was the first (and remains the only) multicentre randomised controlled\u000a      trial (RCT) to investigate\u000a      whether a `surgical bypass first' or an `endovascular (`keyhole')\u000a      treatment first' revascularisation\u000a      strategy is best at relieving symptoms and preventing amputation and\/or\u000a      death in patients with SLI.\u000a    The initial results of the trial were published in the Lancet in 2005 [1]\u000a      and suggested that, up to two\u000a      years after randomisation, amputation-free and overall survival were\u000a      similar following surgical\u000a      bypass and endovascular treatment. However, further analysis of the\u000a      survival curves suggested\u000a      that surgical bypass might be better in the longer term with respect to\u000a      health-related quality of life\u000a      and overall survival of patients. A further application to the HTA to fund\u000a      longer term follow-up was\u000a      successful and the final results of the BASIL trial were published as an\u000a      HTA Monograph [2], and in\u000a      a dedicated supplement of the Journal of Vascular Surgery [3-5] in\u000a      2010.\u000a    These final BASIL trial data have been interpreted internationally as\u000a      supporting an `endovascular\u000a      first' revascularisation strategy for patients with SLI who are expected\u000a      to live for less than 2 years.\u000a      However, for those patients expected live for more than 2 years, surgical\u000a      bypass is preferred in\u000a      most patients as it is associated with a significant improvement in\u000a      overall survival and a better\u000a      quality of revascularisation in the longer term. By implementing\u000a      revascularisation strategies in\u000a      accordance with BASIL data, and paying heed to the BASIL risk prediction\u000a      model, it is anticipated\u000a      that health and social care resources will be utilised in the most\u000a      clinically and cost-effective manner\u000a      in both developed and developing countries.\u000a    The success of the BASIL trial and the resulting widespread support from\u000a      individual clinicians and\u000a      organisations such as the US Society for Vascular Surgery, American Heart\u000a      Association; European\u000a      Society for Vascular Surgery, Vascular Society of Great Britain and\u000a      Ireland (VSGBI), British\u000a      Society of Interventional Radiology (BSIR), UK Circulation Foundation,\u000a      Diabetes UK, and National\u000a      Institute for Health and Care Excellence (NICE) has led to a further RCT\u000a      (BASIL-2) being recently\u000a      funded (NIHR HTA, £2,004,572, Chief Investigator, Professor Andrew\u000a      Bradbury). BASIL-2 will\u000a      focus on diabetic (below the knee) vascular disease and evaluate modern\u000a      endovascular\u000a      interventions such as drug eluting stents and balloons (which were not\u000a      available at the time of the\u000a      original BASIL trial) for the management of SLI. The trial will take place\u000a      in 11 UK regions from the\u000a      south coast of England (Southampton) to the north of Scotland (Aberdeen)\u000a      and is hosted by the\u000a      University of Birmingham Clinical Trials Unit (BCTU).\u000a    "},{"CaseStudyId":"40144","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"357994","Name":"Egypt"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"878675","Name":"Zimbabwe"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2029969","Name":"Mongolia"},{"GeoNamesId":"2186224","Name":"New Zealand"}],"Funders":[],"ImpactDetails":"\u000a    Impacts on health and welfare\u000a    The PROMPT programme has improved outcomes in other units across the\u000a      world as well as the\u000a      UK. For example, a pilot of PROMPT in the state of Victoria in Australia\u000a      demonstrated a reduction\u000a      in low Apgar scores as well as fewer babies born with signs of hypoxia.[e]\u000a      The Royal Australian\u000a      and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) is\u000a      now rolling out the\u000a      training programme to all obstetric units in those two countries.[f].\u000a      These improvements have been\u000a      matched in the other pilot site, Kansas University Medical Center in the\u000a      US.\u000a    Since the introduction of PROMPT in 2008, there has been a 50% reduction\u000a      in infants born with\u000a      hypoxia, a drop of over 90% in infants born with a permanent brachial\u000a      plexus injury and a decrease\u000a      in the caesarean section rate from 32% to 24%.\u000a    A stepped wedge design study has now been funded by the Scottish\u000a      government to roll out the\u000a      training across all the obstetric units in Scotland with a parallel\u000a      process evaluation.[g]\u000a    Commercial impact\u000a    PROMPT is now being used in 85% of maternity units in the UK, and also in\u000a      many other countries\u000a      around the world including Australia, New Zealand, Hong Kong, China, the\u000a      US, Egypt, Mongolia\u000a      and Singapore. Once trained, individual units, institutions and countries\u000a      purchase a licence to roll\u000a      out PROMPT training, to ensure that quality and intellectual property\u000a      rights are maintained.\u000a    The first edition of the PROMPT course manual was the biggest-selling\u000a      text ever published by the\u000a      Royal College of Obstetricians and Gynaecologists (RCOG) Press, with over\u000a      15,000 copies sold\u000a      worldwide. The recently-published second edition is also listed as the\u000a      fastest-selling book ever\u000a      published by the RCOG Press. The manuals are now published by Cambridge\u000a      University Press\u000a      and there are region specific versions for the US, China, Australia and\u000a      New Zealand. Versions for\u000a      India and the Gulf states are being developed.\u000a    Furthermore, research at the University of Bristol has enabled\u000a      collaboration with industry to design\u000a      innovative training products - for example, the PROMPT Birthing Mannequin\u000a      (Limbs & Things), the\u000a      world's best-selling birth simulator, with more than 5,000 units sold at\u000a      over £3,000 each. The\u000a      University is also the main clinical developer of the SimMOM full-body\u000a      Simulator with Laerdal\u000a      Medical.\u000a    Impacts on practitioners and services\u000a    The University of Bristol team's research on defining the effective\u000a      components of obstetric\u000a      emergencies training has directly informed guidance on staff training\u000a      nationally and internationally.\u000a      The RCOG has commissioned members of the research team to write three\u000a      national guidelines for\u000a      the management of shoulder dystocia, cord prolapse and stillbirth.[d]\u000a      Finally, both the RCOG and\u000a      the NHS Litigation Authority have also used Bristol data to recommend\u000a      annual, multi-professional\u000a      skills training (PROMPT) for all maternity staff nationally.\u000a    PROMPT training has transformed the way that healthcare professionals are\u000a      trained worldwide,\u000a      improving the implementation of best practice and outcomes for mothers and\u000a      babies.\u000a    The NHS Litigation Authority has specifically recommended PROMPT training\u000a      in its most recent\u000a      report (`Ten Years of Maternity Claims' — Oct 2012). The RCOG has also\u000a      updated its training\u000a      curriculum to include attendance at a local PROMPT course as an essential\u000a      competency for\u000a      obstetric trainees.\u000a    Impacts on the economy\u000a    The University of Bristol's multi-professional obstetric-emergencies\u000a      training package has been\u000a      associated with savings in litigation costs as a result of improved\u000a      outcomes: comparing five years'\u000a      pre- and ten years' post-training data, there has been a 91% reduction in\u000a      mean annual payouts by\u000a      the NHS Litigation Authority for Southmead Hospital (pre-training\u000a      £2,998,587 per annum to\u000a      £256,820 per annum post-training). The US and Australian pilots have\u000a      demonstrated similar\u000a      reductions in claims costs.\u000a    The team could therefore potentially save the NHS £42 million a year in\u000a      preventable maternity\u000a      damages in its network area and at least £280 million a year across\u000a      England if all units achieved\u000a      the same results as Southmead.\u000a    Impacts on international development\u000a    PROMPT is a low-resource training intervention ideal for supporting\u000a      clinical improvements and\u000a      staff development in resource-poor settings. In partnership with diaspora\u000a      from Zimbabwe, and with\u000a      the support of the Department for International Development and the\u000a      Tropical Health Education\u000a      Trust, a pilot project to roll out PROMPT training was set up in the\u000a      second-largest maternity unit in\u000a      Zimbabwe. Since the introduction of PROMPT in early 2011, local trainers\u000a      have trained over 130\u000a      staff members and improved communication between doctors and midwifery\u000a      staff. Interim data\u000a      have demonstrated a 19% reduction in maternal deaths following the\u000a      implementation of PROMPT.\u000a      The WHO has expressed interest in developing this work to make it\u000a      available in other low-resource\u000a      settings. As a result of the successful implementation of PROMPT in\u000a      Bulawayo, the Deputy Prime\u000a      Minister of Zimbabwe is working with the PROMPT team to develop a roll-out\u000a      strategy for the\u000a      whole country.\u000a    PROMPT training and research centres are also being developed in\u000a      Bangalore, India and\u000a      Chengdu, China following approaches to the Bristol research team from\u000a      national obstetrics and\u000a      gynaecology organisations wanting to implement PROMPT training.\u000a    ","ImpactSummary":"\u000a    As a consequence of a research-based training programme developed at the\u000a      University of Bristol,\u000a      the rates of perinatal hypoxia and intrapartum fetal injury in Bristol and\u000a      two pilot units in Australia\u000a      and the US are now among the lowest in the world. The improvements\u000a      achieved in Bristol, the US\u000a      and Australia have also been successfully achieved in a low resource\u000a      setting in Zimbabwe.\u000a    In response to demand from maternity units across the world, the Bristol\u000a      team has developed\u000a      PROMPT — a PRactical Obstetric Multi-Professional Training package, which\u000a      has been\u000a      successfully implemented in over 20 countries worldwide. PROMPT has had a\u000a      major health and\u000a      welfare impact on more than a million mothers and their babies, as well as\u000a      bringing substantial\u000a      economic benefits and supporting international development.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Bristol\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"1880252","Name":"Singapore"},{"GeoNamesId":"1105843","Name":"Bulawayo Province"},{"GeoNamesId":"1815286","Name":"Chengdu"},{"GeoNamesId":"1277333","Name":"Bangalore"},{"GeoNamesId":"1819729","Name":"Hong Kong"}],"References":"\u000a    \u000a[1] Siassakos, D., et al., The active components of effective\u000a        training in obstetric emergencies.\u000a      British Journal of Obstetrics & Gynaecology, 2009, 116(8),\u000a      1028-1032. PMID: 19438497\u000a    \u000a\u000a[2] Crofts, J.F., et al., Training for shoulder dystocia: a trial of\u000a        simulation using low-fidelity and\u000a        high-fidelity mannequins. Obstetrics & Gynecology, 2006. 108(6),\u000a      1477-1485. PMID: 17138783\u000a    \u000a\u000a[3] Draycott, T., et al., Does training in obstetric emergencies\u000a        improve neonatal outcome? British\u000a      Journal of Obstetrics & Gynaecology, 2006. 113(2), 177-182.\u000a      PMID: 16411995\u000a    \u000a\u000a[4] Draycott, T.J., et al., Improving neonatal outcome through\u000a        practical shoulder dystocia training.\u000a      Obstetrics & Gynecology, 2008. 112(1), 14-20. PMID: 18591302\u000a    \u000a\u000a[5] Siassakos, D., et al., Retrospective cohort study of\u000a        diagnosis-delivery interval with umbilical\u000a        cord prolapse: the effect of team training. British Journal of\u000a      Obstetrics & Gynaecology, 2009.\u000a      116(8), 1089-1096. PMID: 19438496\u000a    \u000a\u000a[6] Siassakos, D., et al., Clinical efficiency in a simulated\u000a        emergency and relationship to team\u000a        behaviours: a multisite cross-sectional study British Journal of\u000a      Obstetrics & Gynaecology,\u000a      2011. 118(5), 596-607. PMID: 21291509\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"10","Subject":"Nursing"}],"Sources":"\u000a    [a] NHS Litigation Authority: Ten Years of Maternity Claims:\u000a      http:\/\/www.nhsla.com\/Pages\/Home.aspx.\u000a      Statement on page 100: \"In recent years PROMPT3\u000a      (PRactical Obstetric Multi-Professional Training) training endorsed\u000a      jointly by the RCOG and\u000a      RCM has been utilised by a number of maternity services to ensure staff\u000a      are trained in this\u000a      topic [CTG interpretation]\".\u000a    [b] e-learning for Health: http:\/\/www.e-lfh.org.uk\/projects\/electronic-fetal-monitoring\/.\u000a      The\u000a      evaluation chapter for this online fetal monitoring programme was\u000a      commissioned from the\u000a      PROMPT research group by the UK Department of Health because of the\u000a      reduction in hypoxic\u000a      infants observed after PROMPT training by units in the UK, Australia and\u000a      United States.\u000a    [c] Testimony available from Karen Hillyer - Chief Executive, Erb's Palsy\u000a      Group Charity. This\u000a      corroborates the reduction in brachial plexus injury (for example, Erb's\u000a      palsy) across the UK\u000a      and now the US.\u000a    [d] Royal College of Obstetricians and Gynaecologists (RCOG) Green Top\u000a      Guidelines, written by\u000a      these UoB researchers and drawing on PROMPT experience in key risk\u000a      situations:\u000a    a. Shoulder dystocia: http:\/\/www.rcog.org.uk\/womens-health\/clinical-guidance\/shoulder-\u000a        dystocia-green-top-42;\u000a    b. Cord prolapse: http:\/\/www.rcog.org.uk\/womens-health\/clinical-guidance\/umbilical-cord-prolapse-green-top-50;\u000a    c. The management of late intrauterine fetal death and stillbirth:\u000a      http:\/\/www.rcog.org.uk\/womens-health\/clinical-guidance\/late-intrauterine-fetal-death-and-stillbirth-green-top-55.\u000a    [e] Victorian Managed Insurance Agency:\u000a      http:\/\/www.vmia.vic.gov.au\/Risk-Management\/Risk-\u000a      partnership-programs\/Projects\/PROMPT.aspx. Indicates the licencing of\u000a      PROMPT by the State\u000a      Government of Victoria via the Victorian Managed Insurance Authority\u000a      (VMIA) to the Royal\u000a      Australian and New Zealand College of Obstetrics and Gynaecology\u000a      (RANZCOG).\u000a    [f] RANZCOG website: http:\/\/www.ranzcog.edu.au\/programs-projects\/prompt.html.\u000a      Contact can\u000a      be provided. Indicates RANZCOG as the executor licencee and plans for\u000a      implementation\u000a      across Australia and New Zealand.\u000a    [g] Catherine Calderwood. Consultant Obstetrician and Gynaecologist,\u000a      Medical Adviser for\u000a      medical and surgical specialties, maternity and women's health, screening\u000a      programmes,\u000a      Scottish Government. National Clinical Director for Women's Health NHS\u000a      England. Dr\u000a      Calderwood approached PROMPT to provide training for all the maternity\u000a      units in Scotland and\u000a      was integral to securing funding for the stepped wedge design study from\u000a      the Chief Scientist\u000a      Office (CSO) and National Education Scotland (NES).\u000a    \u000a    ","Title":"\u000a    Delivering better birthdays: research-based training programme makes\u000a      labour\u000a      and birth safer for babies and mothers across the world.\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Safety in maternity services is a priority for women, their families and\u000a      health services. Obstetric\u000a      emergencies are low-occurrence, high-stakes events that demand a\u000a      coordinated and immediate\u000a      response from expert teams.[1] The SaFE (Simulation and Fire-drill\u000a      Evaluation) Study, funded by\u000a      the UK Department of Health (2003-2005), was a multi-centre randomised\u000a      controlled trial of\u000a      obstetric emergencies training. The research was carried out by Bristol\u000a      researchers (listed at the\u000a      end of this section) in collaboration with maternity staff across the\u000a      South West. This 2×2 factorial\u000a      design randomised trial compared high-technology, simulation-centre\u000a      training with the same\u000a      intervention delivered in a low-technology, in-house hospital setting,\u000a      with or without teamwork\u000a      training.\u000a    The trial identified that the research-based training programme for\u000a      obstetric emergencies\u000a      developed by the Bristol team for the SaFE study improved knowledge,\u000a      skills and attitudes for all\u000a      staff and that these improvements lasted for at least 12 months.[2]\u000a      Additional teamwork training\u000a      and training in a simulation centre did not confer any additional benefit\u000a      compared to training\u000a      locally. These data were encouraging but the improvements were\u000a      demonstrated only in\u000a      simulations. At that time there was no robust research that demonstrated\u000a      improvements in clinical\u000a      outcomes for mothers and their babies associated with training. Indeed,\u000a      there were two studies in\u000a      the US and UK that demonstrated no change, or even deterioration in\u000a      clinical outcomes post-\u000a      training.\u000a    The training programme for the SaFE study was iteratively developed using\u000a      information and data\u000a      from the study. It was then implemented at Southmead Hospital in Bristol\u000a      and its effect evaluated\u000a      using a longitudinal review of clinical outcomes comparing five years'\u000a      post-training with five years'\u000a      pre-training data. Following the introduction of training the Bristol\u000a      research team identified\u000a      significant clinical benefits (published in landmark papers - see section\u000a      3 for six papers that\u000a      collectively have more than 400 citations):\u000a    \u000a      A 50% reduction in babies born in poor condition and a 50% reduction\u000a        in birth-related neonatal\u000a        brain injury.[3], [a, b]\u000a      A 70% reduction in brachial plexus injuries following a common\u000a        complication of birth (shoulder\u000a        dystocia).[4], [c, d]\u000a      A 50% reduction in the time taken to expedite birth in potentially\u000a        life-threatening cases of\u000a        umbilical cord prolapsed.[5]\u000a      Improved composite neonatal outcomes, including a reduction in the\u000a        rates of intensive care\u000a        admission from 38% to 22%.[5]\u000a    \u000a    Further analysis of the simulated team performances recorded in the SaFE\u000a      study has identified\u000a      important lessons for team working.[6] Mixed qualitative and quantitative\u000a      methods of analysis were\u000a      employed by D. Siassakos from Bristol in collaboration with researchers\u000a      from the Department of\u000a      Linguistics and Social Studies at the University of the West of England\u000a      (K. Bristowe and J. Angouri)\u000a      and the Speech and Language Research Unit at Frenchay Hospital, Bristol\u000a      (H. Hambly).\u000a    This research has provided an in-depth understanding of the\u000a      characteristics of effective teams,\u000a      translating them into simple, teachable behaviours and identifying\u000a      suitable training methods.[6]\u000a      These findings are relevant for all healthcare teams, not just those\u000a      providing maternity services.\u000a    The training programme was further developed and made exportable to meet\u000a      a rising demand. The\u000a      programme is called PRactical Obstetric Multi-Professional Training\u000a      (PROMPT) —\u000a      www.promptmaternity.org.\u000a    Positions of key researchers at the University of Bristol\u000a    \u000a      T. Draycott: Honorary Senior Clinical Lecturer (2003-date)\u000a      R. Fox: Honorary Senior Lecturer (2000-date)\u000a      J. Crofts: Postgraduate Research Student (2003-2009); Honorary\u000a        Clinical Lecturer (2009-\u000a        2010); Clinical Lecturer in Obstetrics (2010-date)\u000a      V. Akande: Honorary Senior Clinical Lecturer (2004-date)\u000a      D. Siassakos: Honorary Clinical Lecturer (2008-2010); NIHR Academic\u000a        Clinical Lecturer in\u000a        Obstetrics (2011-date)\u000a    \u000a    "},{"CaseStudyId":"40145","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Impact on clinical guidelines\u000a    By establishing the reliability of mammalian cell systems for drug\u000a      screening and potential cardiac toxicity, the research conducted by\u000a      Professor Hancox and colleagues at the University of Bristol forms a\u000a      cornerstone for the validity of mammalian cell line screens for drug\u000a      certification by pharmaceutical companies (as well as for basic science\u000a      researchers to better understand how hERG gene products work). Their\u000a      research not only showed that mammalian cell lines can be used to identify\u000a      cardiac risk but also revealed some unexpected and clinically important\u000a      interactions of disparate drugs on cardiac repolarization mechanisms (see\u000a      above). For example, the US Food and Drug Administration (FDA) had warned\u000a      about the use of high doses of SSRI antidepressants because of concerns\u000a      over its association with prolonged QT intervals. This prompted the UK's\u000a      regulatory body, the Medicines and Healthcare Products Regulatory Agency\u000a      (MHRA) to amend its dosage guidance so that it no longer recommends high\u000a      doses of SSRIs because of cardiac risk. However, not all SSRIs have the\u000a      same risk and in-vitro hERG bioassays can help identify the less dangerous\u000a      SSRIs (that is, those with least effect on hERG) to allow continued use\u000a      with less risk and avoid unwarranted concerns as to cardiac safety.[a, b,\u000a      c]\u000a    Impact on pre-clinical screening\u000a    For an integrated assessment of cardiac risk in drug discovery\u000a      programmes, both the current European Medicines Agency (EMA) and FDA\u000a      guidelines S7B (2005) recommend the use of mammalian cell line (for\u000a      example, CHO) hERG screens (hERG expression in CHO in physiological\u000a      conditions was pioneered by Professor Hancox and colleagues). These\u000a      guidelines pertained throughout the REF period, and the EMA guidelines\u000a      were updated in December 2009 in ICH guideline M3 (R2).[c] Virtually all\u000a      companies now employ screens against hERG for their lead compounds. Such\u000a      tests are also used to help define structure\/activity relationships for\u000a      lead compounds (these data are commercially sensitive for drug companies\u000a      and thus cannot be documented here). A 2005 survey of 119 pharmaceutical\u000a      companies found that 93% employed hERG assays [d] and approximately 71% of\u000a      test substances have undesired effects on hERG.[e] The hERG screens allows\u000a      companies to:\u000a    \u000a      Develop new antiarrhythmic agents directed toward selective hERG\u000a        channel inhibition. This can be carried out more efficiently with modern\u000a        automated patch clamp screens using stably transfected mammalian cell\u000a        lines.\u000a      Determine cardiac toxicity due to promoting long QT syndrome of all\u000a        other drugs they develop. (It should be noted that there are real\u000a        concerns as to the validity of small animal models for human conditions\u000a        which is reduced by using the human cell line approach.)\u000a      Achieve early rejection of prototype drugs. This creates considerable\u000a        cost savings by preventing progression to expensive animal and clinical\u000a        trials with subsequent rejection due to long QT effects, which represent\u000a        about 70% of the estimated development cost of around $800M per drug\u000a        entity (see http:\/\/content.healthaffairs.org\/content\/25\/2\/420.long).\u000a    \u000a    Impact of new screening technology\u000a    The utility of using hERG assay screens has also led to new spin-offs and\u000a      development of new hERG-based ion channel screens. Just a few examples of\u000a      major pharmaceutical laboratories developing and using hERG-based ion\u000a      channel screens are: Abbot Labs,[f] Pfizer,[g] Millipore,[h] AstraZeneca\u000a      [i] and Johnson and Johnson.[j] The utility of this method has also led to\u000a      the development of companies that carry out confidential screening of\u000a      prototype drugs for the pharmaceutical industry, such as Cytoprotex\u000a      (Macclesfield, UK http:\/\/www.cyprotex.com\/toxicology\/cardiotoxicity\/hergsafety\/),\u000a      which recorded revenues of £8.33m in 2012.\u000a    The ability to use mammalian cell lines (such as CHO cells as\u000a      demonstrated by Professor Hancox) for drug screening is not only\u000a      cost-effective but has also led to the development of automated patch\u000a      clamp machines as an important new industry. Some examples are:\u000a    \u000a      \u000aMultichannel Systems: http:\/\/www.multichannelsystems.com\/products\/automated-patch-clamp\u000a\u000a      \u000aFluxion: http:\/\/www.fluxionbio.com\/\u000a\u000a      \u000aCytocentrics: http:\/\/www.cytocentrics.com\/\u000a\u000a      \u000aMolecular Devices: http:\/\/www.moleculardevices.com\/Products\/Instruments\/Automated-Electrophysiology\/IonWorks-Quattro.html\u000a\u000a    \u000a    Such companies represent a growing $375m industry in the $60-100 billion\u000a      drug screening industry (Global Industry Analysts Inc. \"Top 10 Drug\u000a      discovery technologies\" Market Strategic Analysis and Global Forecasts\u000a      (2010-2015); Ion Channel Trends 2011, HTS Tec Ltd.).\u000a    Impact on drug development legislation\u000a    The development of reproducible and documented drug screens also allows\u000a      regulatory bodies produce guidelines as to how the pharmaceutical industry\u000a      can document the safety of their compounds; this necessary documentation\u000a      must be developed before human trials to minimize risk for patients\u000a      enrolled in the trial.[c]\u000a    Societal impact\u000a    Societal impact arises from increased patient safety; by uncovering\u000a      important interactions between non-cardiac drugs and arrhythmia risk,\u000a      patient mortality is reduced. As one example, during treatment of heroin\u000a      addicts methadone is usually prescribed but it is now known that methadone\u000a      also carries a risk for TdP.[k] Finally, impact also arises from\u000a      replacement of animal models by suitable cell systems that have been\u000a      documented to reproduce native cell behaviour. This not only reduces cost\u000a      and increases speed for drug testing and screening but also reduces\u000a      ethical concerns on animal use, which has important societal impact. It\u000a      also fits with the Research Councils' desire to reduce, refine and replace\u000a      animal use where possible (see also http:\/\/www.nc3rs.org.uk\/\u000a      and http:\/\/www.iacuc.org\/alternate.htm).\u000a    ","ImpactSummary":"\u000a    All new drugs are required to undergo cardiac safety testing to avoid\u000a      dangerous side effects on contractility and excitability. Of particular\u000a      concern is the risk of developing a lethal arrhythmia from inhibition of\u000a      hERG (human Ether-à-go-go-Related Gene) potassium channels. The Bristol\u000a      laboratory of Professor Hancox and colleagues demonstrated the utility of\u000a      hERG-transfected mammalian cell lines for investigation of hERG-related\u000a      effects and risk. Now most drug discovery programmes utilise hERG screens\u000a      as part of an integrated assessment of cardiac risk (as recommended by the\u000a      FDA and MHRA). Second, their work linked hERG inhibition to cardiac risk\u000a      for certain psychotropics (and other agents) that have been either\u000a      withdrawn or now carry warnings as to their cardiac safety.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Bristol\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Hancox, J.C. Levi, A.J. and Witchel, H.J. (1998) Time course and\u000a      voltage dependence of expressed HERG current compared with native \"rapid\"\u000a      delayed rectifier K current during the cardiac ventricular action\u000a      potential. Pflugers Archiv, 436(6), 843-853. PMID: 9799397\u000a    \u000a\u000a[2] Witchel, H.J., Milnes, J.T. Mitcheson, J.S. Hancox, J.C. (2002)\u000a      Troubleshooting problems with in vitro screening of drugs for QT\u000a      interval prolongation using HERG K+ channels expressed in\u000a      mammalian cell lines and Xenopus oocytes. J. Pharm. Toxicol.\u000a        Methods, 48, 65-80. PMID: 14565563\u000a    \u000a\u000a[3] Ridley J.M., Dooley, P.C., Milnes, J.T. Witchel, H.J. Hancox, J.C.\u000a      (2004) Lidoflazine is a high affinity blocker of the HERG K+ channel.\u000a      J. Mol. Cell. Cardiol., 36(5), 701-705. PMID: 15135665\u000a    \u000a\u000a[4] Alexandrou AJ Duncan RS, Sullivan, A, Hancox JC Leishman DJ, Witchel\u000a      HJ, Leaney JL (2006) Mechanism of hERG K channel blockade by the\u000a      fluoroquinolone antibiotic moxifloxacin. Br. J. Pharmacol.,\u000a      147(8), 905-916. PMID: 16474415\u000a    \u000a\u000a[5] Hancox JC, McPate MJ, El Harchi A, Zhang Yh (2008) The hERG potassium\u000a      channel and hERG screening for drug-induced torsades de pointes. Pharm.\u000a        Ther., 119, 118-132. PMID: 18616963\u000a    \u000a\u000a[6] Milnes JT, Witchel HJ, Leaney JL, Leishman DJ, Hancox JC (2010)\u000a      Investigating dynamic protocol dependence of hERG potassium channel\u000a      inhibition at 37oC: cisapride versus dofetilide. J. Pharm.\u000a        Toxicol. Methods, 61, 178-191. PMID: 20172036\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"2","Level2":"99","Subject":"Other Physical Sciences"},{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"}],"Sources":"\u000a    [a] Evidence for linkage of TdP with serotonin uptake inhibitors and\u000a        role of hERG: Kogut, C., Crouse, E.B., Vieweg, W.V.R., Hasnain, M.,\u000a      Baranchuk, A., Digby, G.C., Koneru, J.N., Fernandez, A., Deshmukh, A.,\u000a      Hancox, J.C., Pandurangi, A.K. (2013). Selective serotonin reuptake\u000a      inhibitors and torsade de pointes: new concepts and new directions derived\u000a      from a systematic review of case reports. Therapeutic Advances in Drug\u000a        Safety, 4(5), 189-198. DOI: 10.1177\/2042098613492366\u000a    [b] Evidence for hERG in TdP and linkage of TdP with serotonin uptake\u000a        inhibitors: Witchel, H.J., Hancox, J.C. & Nutt, D.J. (2003).\u000a      Psychotropic drugs, cardiac arrhythmia, and sudden death. Journal of\u000a        Clinical Psychopharmacology, 23(1), 58-77. PMID: 12544377\u000a    [c] Current regulatory guidelines documenting use of bioassays for\u000a        hERG effects for pre-clinical safety studies: EMA ICH M3 (R2)\u000a      guidelines, \"Non-clinical safety studies for the conduct of human clinical\u000a      trials and marketing authorisation for pharmaceuticals\" (2009).\u000a      http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500002720.pdf\u000a    [d] Evidence that pharmaceutical company use of hERG bioassays is\u000a        widespread: Friedrichs G.S., Patmore L., and Bass A. (2005)\u000a      Non-clinical evaluation of ventricular repolarization (ICH S7B): results\u000a      of an interim survey of international pharmaceutical companies. Journal\u000a        of Pharmacological and Toxicological Methods, 52, 6-11. PMID:\u000a      15975833\u000a    [e] MHRA view on the utility of cell-based hERG bioassays: Shah,\u000a      R.R. (2005) Drug-induced QT interval prolongation-regulatory guidance and\u000a      perspectives on hERG channel studies. In hERG Cardiac Potassium Channel:\u000a      Structure, Function and Long QT Syndrome Book Series: Novartis Foundation\u000a      Symposium Volume: 266, 251-285. DOI: 10.1002\/047002142X\u000a    [f] Evidence that Abbot labs uses hERG bioassays: Gintant,\u000a        G (2011) An evaluation of hERG current assay performance:\u000a      Translating preclinical safety studies to clinical QT prolongation. Pharm.\u000a      Thera. 129(2): 109-119 DOI: 10.1016\/j.pharmthera.2010.08.008.\u000a    [g] Evidence that Pfizer uses hERG bioassays: Mo, Z-L, Faxel, T.,\u000a      Yang, Y-S, Gallavan, R., Messing, D., Bahinski, A.B. (2009) Effect of\u000a      compound plate composition on measurement of hERG current IC50 using\u000a      PatchXpress. Journal of Pharmacological and Toxicological Methods\u000a      60(1): 39-44 DOI: 10.1016\/j.vascn.2009.04.198\u000a    [h] Evidence that Millipore uses hERG bioassays: Helliwell,\u000a        Ray M (2008) Recording hERG Potassium Currents and Assessing the\u000a      Effects of Compounds Using the Whole-Cell Patch-Clamp Technique. Methods\u000a      in Molecular Biology Book Series: Methods in Molecular Biology. Ed. Lippiat,\u000a        JD Vol 491:279-295. DOI: 10.1007\/978-1-59745-526-8_22\u000a    [i] Evidence that Astra Zeneca uses hERG bioassays:\u000a      Bridgland-Taylor, M. H., Hargreaves, A. C., Easter, A., Orme, A.,\u000a      Henthorn, D. C., Ding, M., Davis, A. M., Small, B. G., Heapy, C. G.,\u000a      Abi-Gerges, N., Persson, F., Jacobson, I., Sullivan, M., Albertson, N.,\u000a      Hammond, T. G., Sullivan, E., Valentin, J. -P., Pollard, C. E. (2006)\u000a      Optimisation and validation of a medium-throughput electrophysiology-based\u000a      hERG assay using IonWorks(TM) Journal of Pharmacological and\u000a        Toxicological Methods 54(2):189-199. PMID: 16563806\u000a    [j] Evidence that Johnson & Johnson uses hERG bioassays:\u000a      Dubin, AE ; Nasser, N ; Rohrbacher, J ; Hermans, AN ; Marrannes, R ;\u000a      Grantham, C ; Van Rossem, K ; Cik, M ; Chaplan, SR; Gallacher, D ; Xu, J ;\u000a      Guia, A; Byrne, NG ; Mathes, C (2005) Identifying modulators of hERG\u000a      channel activity using the PatchXpress((R)) planar patch clamp. Journal\u000a        of Biomolecular Screening 10(2): 168-181 DOI:\u000a      10.1177\/1087057104272295\u000a    [k] Evidence for the need to employ hERG drug screening to identify\u000a        TdP risk in existing drugs: Methadone-associated Q-T Interval\u000a      Prolongation and Torsades de Pointes. Stringer, J., Welsh, C., Tommaselli,\u000a      A (2009). American Journal of Health-System Pharmacy 66:825-833.\u000a      PMID: 19386945\u000a    ","Title":"\u000a    Expressed hERG potassium channel bioassays in mammalian cell lines to\u000a      evaluate safety and efficacy of new drugs.\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"},{"GeoNamesId":"2643266","Name":"Macclesfield"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The discovery that human-Ether-a-go-go-Related Gene (hERG) is\u000a      responsible for channels mediating the cardiac `rapid' delayed rectifier K+\u000a      current, IKr in 1995 underpins understanding of mechanisms that\u000a      control the length of ventricular action potentials and the QT interval of\u000a      the electrocardiogram. Although it was already known that some drugs\u000a      produce unwanted prolongation of the QT interval of the ECG (acquired Long\u000a      QT syndrome; LQTS) that could lead to a fatal arrhythmia called torsades\u000a        de pointes (TdP), the mechanism was unclear.\u000a    In 1998, Professor Hancox's group showed that native IKr was\u000a      reproduced by hERG protein expression during action potentials at body\u000a      temperature in a mammalian cell line.[1] The close concordance between\u000a      hERG and native IKr under physiological conditions provides an\u000a      underpinning rationale for the use of mammalian cell lines expressing hERG\u000a      channels for drug screening and toxicity tests which are now current (and\u000a      ongoing) pharmaceutical company practice. Between 1998 and 2004, Professor\u000a      Hancox's laboratory also demonstrated pharmacological inhibition of\u000a      recombinant hERG in mammalian cell lines by a range of cardiac and\u000a      non-cardiac drugs, including: tricyclic antidepressants (imipramine and\u000a      amitriptyline), Class Ia and Ic antiarrhythmics (disopyramide,\u000a      procainamide, flecainide, propafenone), selective serotonin reuptake\u000a      inhibitors (SSRIs) (citalopram and fluvoxamine) and antianginals\u000a      (lidoflazine).\u000a    In 2002, they produced an `Appraisal state of the art' article on\u000a      troubleshooting issues associated with screening drugs for QT interval\u000a      prolongation using hERG channels in cell lines and Xenopus\u000a      oocytes. In addition to discussing a number of issues pertaining to the\u000a      use of mammalian cell lines for this kind of screening, this article also\u000a      pointed out that Xenopus oocytes (then widely used for ion channel\u000a      structure function work) are not appropriate for hERG drug potency\u000a      screening. This article has been cited in subsequent work from a range of\u000a      drug companies (including Pfizer, Abbott, Millipore, AstraZeneca,\u000a      Lundbeck, Johnson and Johnson) and by the UK Medical and Healthcare\u000a      Products Regulatory Agency (MHRA).\u000a    From 2004, Professor Hancox and colleagues continued to publish work on\u000a      pharmacological inhibitors of hERG in cell lines, including antiarrhythmic\u000a      drugs (amiodarone and dronedarone) antimicrobials (erythromycin,\u000a      ketaconazole, moxifloxacin), antihistamines (clemastine) and psychotropic\u000a      drugs (TCA - doxepin; antipsychotic - thioridazine) and (recently)\u000a      collaborative work with Pfizer comparing drug potencies obtained with\u000a      different hERG screening protocols. In 2000 and 2008 Professor Hancox and\u000a      colleagues produced substantial reviews\/position papers linking IKr\/hERG\u000a      to acquired LQTS and evaluating hERG based screening assays. To underscore\u000a      the value of this work, some drugs (cisapride, terfenadine) unexpectedly\u000a      caused arrhythmias and the mechanism of that action was subsequently\u000a      traced to hERG (side) effects in cell systems. Also, many other drugs now\u000a      have QT-associated warnings as a result of indicative hERG effects (see: http:\/\/www.azcert.org\/index.cfm).\u000a      This is particularly important for the SSRIs that are widely used to treat\u000a      depression, anxiety and eating disorders, as well as other drugs (for\u000a      example, see Doggrell and Hancox, Expert Opinion on Drug Safety\u000a      2013;12(3):421-431). Furthermore, even after careful drug design to\u000a      minimize depressant cardiac effects, approximately 1-2% of patients still\u000a      exhibit dangerous arrhythmias after overdose (Kerr, Emergency Medicine\u000a      Journal 2001;18(4):236-241) and 8% of psychiatric patients develop ECG\u000a      abnormalities associated with their drug therapy (Reilly et al, Lancet\u000a      2000;355(9209):1048-1052), recapitulating the importance of cardiac\u000a      electrophysiological screening for the development of better and safer\u000a      drugs.[b]\u000a    Jules Hancox was Reader from 1991 to 2002 and Professor of Cardiac\u000a      Electrophysiology from 2002 to date, in the School of Physiology and\u000a      Pharmacology at the University of Bristol.\u000a    "},{"CaseStudyId":"40146","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Biotechnology and Biological Sciences Research Council","Medical Research Council"],"ImpactDetails":"\u000d\u000a    A 30-year-old woman was hospitalised in March 2008 with acute shortness\u000d\u000a      of breath due to\u000d\u000a      marked stenosis of the left main bronchus, rendering her unable to carry\u000d\u000a      out simple domestic\u000d\u000a      duties or care for her children. The only conventional option remaining\u000d\u000a      was removal of her left lung,\u000d\u000a      with an attendant risk of complications and a high mortality rate. Based\u000d\u000a      on successful laboratory\u000d\u000a      work previously performed by the team, and given the urgency of the\u000d\u000a      situation, it was proposed\u000d\u000a      that the lower trachea and the left bronchus should be replaced with a\u000d\u000a      bioengineered airway based\u000d\u000a      on the scaffold of a decellularised cadaver human trachea. Stem cells were\u000d\u000a      obtained from the\u000d\u000a      recipient's own bone marrow, grown into a large population in Bristol, and\u000d\u000a      matured into\u000d\u000a      chondrocytes (cartilage cells) using an adapted method originally devised\u000d\u000a      by Professor Anthony\u000d\u000a      Hollander for treating osteoarthritis. The donor trachea was then seeded\u000d\u000a      with chondrocytes on the\u000d\u000a      outside surface. In order to replicate the inside lining of the trachea,\u000d\u000a      epithelial cells, grown in Bristol\u000d\u000a      by Professor Martin Birchall, were seeded onto the luminal surface. Four\u000d\u000a      days after seeding, the\u000d\u000a      graft was used to replace the patient's left main bronchus. The patient\u000d\u000a      remains alive and healthy\u000d\u000a      with no need for immunosuppression or other health care.\u000d\u000a    4.1 Impact on the patient, Claudia Castillo\u000d\u000a    Without this intervention, the young mother would either have remained\u000d\u000a      seriously ill with very poor\u000d\u000a      life quality and life-long immune-suppression or, more likely, would have\u000d\u000a      died. Instead, she is alive,\u000d\u000a      not under health care and earning a salary. She commented: \"It really is a\u000d\u000a      miracle. The problem\u000d\u000a      has gone... I can go to the park and I can play with my children... I now\u000d\u000a      have a future to look\u000d\u000a      forward to.\" (source [a])\u000d\u000a    4.2 Impact on the field of stem cell research and regenerative\u000d\u000a        medicine\u000d\u000a    4.2.1 This was the first example of a tissue-engineered,\u000d\u000a      three-dimensional organ being created\u000d\u000a      using autologous stem cells and implanted successfully. While the project\u000d\u000a      concerned one patient\u000d\u000a      and a rare disease, it acted as a proof of concept and an exemplar more\u000d\u000a      generally of the possibility\u000d\u000a      of extending this technology to other damaged hollow organs such as the\u000d\u000a      bladder, larynx, intestine\u000d\u000a      and oesophagus. This case also exemplifies the possibility of personalised\u000d\u000a      medicine. While the\u000d\u000a      shape of the implanted organ was provided by a donated cadaveric tracheal\u000d\u000a      segment, the risk of\u000d\u000a      immune rejection was removed by replacement of the donor cells with the\u000d\u000a      patient's own.\u000d\u000a      The Barcelona hospital that had been treating the patient before the\u000d\u000a      operation has made savings\u000d\u000a      by no longer having to admit Castillo to intensive care twice a week at a\u000d\u000a      cost of £3,000 a day, as it\u000d\u000a      had been doing for the previous three years (source [b]).\u000d\u000a    4.2.2 It is clear that the use of this technology in similar operations\u000d\u000a      has the potential to generate\u000d\u000a      huge cost savings. Since the original operation a further 14 patients have\u000d\u000a      been transplanted with a\u000d\u000a      bioengineered trachea as discussed in a critical review in \"Science\"\u000d\u000a      (source [c]). The impact on the\u000d\u000a      wider field of Regenerative Medicine has been summed up by Professor Dame\u000d\u000a      Julia Polak\u000d\u000a      (Imperial College) who has stated to us: \"This work has had a truly\u000d\u000a      galvanizing effect on the field,\u000d\u000a      showing that even very serious diseases can be treated using regenerative\u000d\u000a      medicine approaches\u000d\u000a      and I have been excited by this advance both as a scientist and as a\u000d\u000a      transplant recipient.\"\u000d\u000a    4.3 Impact on national policy\u000d\u000a    4.3.1 In April 2012 the UK MRC published a strategic document \"A strategy\u000d\u000a      for UK Regenerative\u000d\u000a      Medicine\" that formed the basis of subsequent planning for the development\u000d\u000a      of this new branch of\u000d\u000a      medicine. This document refers to \"bone marrow stem cells applied to\u000d\u000a      denuded donated trachea\u000d\u000a      for airway replacement\" as a key example of a therapy using the patient's\u000d\u000a      own cells (source [d]).\u000d\u000a    4.3.2 In 2012 the House of Lords Science and Technology Committee\u000d\u000a      published a call for evidence\u000d\u000a      for their enquiry into Regenerative Medicine. In this call it is stated\u000d\u000a      that \"Examples of such\u000d\u000a      treatments are the transplantation of a new trachea grown using the\u000d\u000a      patient's own stem cells\",\u000d\u000a      directly referring to the tracheal transplant case (source [e]) and\u000d\u000a      Professor Anthony Hollander was\u000d\u000a      called to give evidence to the enquiry (source [f]).\u000d\u000a    4.4 Impact on the public perception of stem cell biology and\u000d\u000a        regenerative medicine\u000d\u000a    This case caught the imagination of the public, as reflected in the\u000d\u000a      worldwide coverage in both\u000d\u000a      electronic and print news media. It has been seen as the first fruit to be\u000d\u000a      borne from the investment\u000d\u000a      in stem cell research. It has also shown how regenerative medicine does\u000d\u000a      not just treat symptoms\u000d\u000a      but can remove a disease from the patient's life altogether.\u000d\u000a    4.4.1 The story received worldwide coverage in newspapers, on television\u000d\u000a      and radio, and on the\u000d\u000a      internet. It was the subject of an article in The New Scientist on\u000d\u000a      19 November 2008 (source [g]),\u000d\u000a      and was picked up across the mainstream media including the BBC (source h)\u000d\u000a      and the Guardian\u000d\u000a      (source [i]).\u000d\u000a    4.4.2 The operation was included in a permanent exhibition entitled \"Who\u000d\u000a      am I?\" at the Science\u000d\u000a      Museum, forming part of a display demonstrating how new technology, from\u000d\u000a      stem cells to gene\u000d\u000a      therapy, can help to repair damage caused by serious illness, with\u000d\u000a      life-changing results (source [j]).\u000d\u000a      The museum receives almost 3 million visitors each year (source [k]), many\u000d\u000a      of whom will have\u000d\u000a      viewed the exhibit.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    In 2008, Professors Martin Birchall and Anthony Hollander (University of\u000d\u000a      Bristol) and a team of\u000d\u000a      scientists and surgeons led from Bristol successfully created and then\u000d\u000a      transplanted the first tissue-engineered\u000d\u000a      trachea (windpipe), using the seriously ill patient's own stem cells. The\u000d\u000a      bioengineered\u000d\u000a      trachea immediately provided the patient with a normally functioning\u000d\u000a      airway, thereby avoiding\u000d\u000a      higher risk surgery or life-long immunosuppression. This sequence of\u000d\u000a      events, which raised public\u000d\u000a      interest and understanding around the world as a result of huge media\u000d\u000a      coverage, acted as proof of\u000d\u000a      concept for this kind of medical intervention. A new clinical technology\u000d\u000a      with far-reaching\u000d\u000a      implications for patients had passed a major test. This development\u000d\u000a      demonstrated the potential of\u000d\u000a      stem cell biology and regenerative medicine to eradicate disease as well\u000d\u000a      as treat symptoms and\u000d\u000a      has already led to the implantation of bioengineered tracheas in at least\u000d\u000a      14 other patients.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Bristol\u000d\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3128760","Name":"Barcelona"}],"References":"\u000d\u000a    \u000a[1] Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA,\u000d\u000a      Dodson A, Martorell\u000d\u000a      J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S,\u000d\u000a      Conconi MT, Birchall\u000d\u000a      MA 2008 Clinical transplantation of a tissue-engineered airway. Lancet 372(9655): 2023-2030.\u000aPMID:\u000d\u000a      19022496\u000d\u000a    \u000a\u000a[2] Kafienah W, Jakob M, Demarteau O, Frazer A, Barker MD, Martin I,\u000d\u000a      Hollander AP 2002\u000d\u000a      Three-dimensional tissue engineering of hyaline cartilage: comparison of\u000d\u000a      adult nasal and\u000d\u000a      articular chondrocytes. Tissue Engineering 8:817-826. PMID:\u000d\u000a      12459060\u000d\u000a    \u000a\u000a[3] Kafienah W, Mistry S, Dickinson S, Sims T, Learmonth I, Hollander A\u000d\u000a      2007 Three-dimensional\u000d\u000a      cartilage tissue engineering using adult stem cells from osteoarthritis\u000d\u000a      patients.\u000d\u000a      Arthritis Rheum. 56:177-187. PMID: 17195220\u000d\u000a    \u000a\u000a[4] Barker E, Macchiarini P, Murison P, Jones A, Haverson K, Bailey M,\u000d\u000a      Birchall M 2005 An ex\u000d\u000a      vivo model for reperfusion of laryngotracheal grafts. Laryngoscope 115(4):699-702.\u000d\u000a      PMID:\u000d\u000a      15805884\u000d\u000a    \u000a\u000a[5] Birchall M, Idowu B, Murison P, Jones A, Burt R, Ayling S, Stokes C,\u000d\u000a      Pope L, Terenghi G\u000d\u000a      2004 Laryngeal abductor muscle reinnervation in a pig model. Acta\u000d\u000a      Otolaryngol 124:839-846.\u000d\u000a      PMID: 15370570\u000d\u000a    \u000a\u000a[6] Rees LE, Gunasekaran S, Sipaul F, Birchall MA, Bailey M 2006 The\u000d\u000a      isolation and\u000d\u000a      characterisation of primary human laryngeal epithelial cells. Mol Immunol\u000d\u000a      43(6):725-730.\u000d\u000a      PMID: 16360018\u000d\u000a    \u000aPeer-reviewed grants:\u000d\u000a    Novel bioresorbable scaffolds and culture methods for cartilage tissue\u000d\u000a      engineering\u000d\u000a      Joint with a consortium of four other European centres\u000d\u000a      European Framework Five\u000d\u000a      €6 million across the consortium; £570,000 to Bristol and Sheffield,\u000d\u000a      2000-2004\u000d\u000a    Regulation of stem cell differentiation for the tissue engineering of\u000d\u000a      cartilage\u000d\u000a      Joint with M Billingham, J Holly, M Perry and WZ Kafienah\u000d\u000a      BBSRC & Smith & Nephew Link grant\u000d\u000a      £460,000, 2002-2005\u000d\u000a    A systems approach to tissue-engineering processes and products\u000d\u000a      (STEPS) EU framework 6\u000d\u000a      Hollander, and many other EU partners\u000d\u000a      €23 million (Bristol, £380,000) 2005-2009\u000d\u000a    The development of a well-vascularised and functional laryngeal\u000d\u000a      transplantation model in the pig\u000d\u000a      Wellcome Trust\u000d\u000a      Birchall, Research Leave Fellowship\u000d\u000a      £1,157,388, 2000-2005\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000d\u000a    [a] A statement from Claudia Castillo, the first tissue-engineering\u000d\u000a      trachea transplant patient,\u000d\u000a      corroborating 4.1, is provided by the report at: http:\/\/www.dailymail.co.uk\/news\/article-1088567\/World-8217-s-stem-cell-transplant-patient-My-murdered-brother-sick-aunt-professors-pigs-gave-strength-live.html\u000d\u000a    [b] A report corroborating 4.2.1 is provided in the newspaper article:\u000d\u000a      \"Transplant first a giant leap\u000d\u000a      for surgery\", The Guardian, 19 November 2008\u000d\u000a      http:\/\/www.guardian.co.uk\/society\/2008\/nov\/19\/stem-cell-transplant-claudio-castillo\u000d\u000a    [c] A scientific review corroborating 4.2.2 is provided at: Trachea\u000d\u000a      Transplants Test the Limits\u000d\u000a      http:\/\/www.sciencemag.org\/content\/340\/6130\/266.long\u000d\u000a    [d] The report referred to as corroborating 4.3.1 is at:\u000d\u000a      http:\/\/www.mrc.ac.uk\/Utilities\/Documentrecord\/index.htm?d=MRC008534\u000d\u000a    [e] The report referred to as corroborating 4.3.2 is at:\u000d\u000a      http:\/\/www.parliament.uk\/business\/committees\/committees-a-z\/lords-select\/science-and-technology-committee\/inquiries\/parliament-2010\/regenerative-medicine\/\u000d\u000a    [f] http:\/\/www.parliamentlive.tv\/Main\/Player.aspx?meetingId=11796\u000d\u000a    [g] A source corroborating 4.4.1 is at: \"Woman receives windpipe built\u000d\u000a      from her stem cells\", The\u000d\u000a        New Scientist, 19 November 2008. http:\/\/www.newscientist.com\/article\/dn16072-woman-receives-windpipe-built-from-her-stem-cells.html\u000d\u000a    [h] A source further corroborating 4.4.1 is at: \"Windpipe transplant\u000d\u000a      breakthrough\", BBC News, 19\u000d\u000a      November 2008 http:\/\/news.bbc.co.uk\/1\/hi\/health\/7735696.stm\u000d\u000a    [i] Another corroboration of 4.4.1 is at: \"Transplant first a giant leap\u000d\u000a      for surgery\", The Guardian, 19\u000d\u000a      November 2008 http:\/\/www.guardian.co.uk\/society\/2008\/nov\/19\/stem-cell-transplant-claudio-castillo\u000d\u000a    [j] Corroboration of 4.4.2 is at: \"Stem cell breakthrough enters\u000d\u000a      permanent national exhibition\",\u000d\u000a      University of Bristol press release http:\/\/www.bris.ac.uk\/news\/2010\/7072.html\u000d\u000a    [k] Further corroboration of 4.4.2 is at: \"Visits made in 2012 to visitor\u000d\u000a      attractions in membership\u000d\u000a      with ALVA\", Association of leading visitor attractions website\u000d\u000a      http:\/\/alva.org.uk\/details.cfm?p=423\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Health benefits, increased public awareness and changes in national\u000d\u000a      policy\u000d\u000a      result from the successful implantation of the first tissue-engineered\u000d\u000a      trachea, created utilising the\u000d\u000a      patient's own stem cells.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Two strands of research at the University of Bristol were brought\u000d\u000a      together from 2000 onwards,\u000d\u000a      leading up to the tracheal tissue engineering project [1]:\u000d\u000a    \u000d\u000a      Professor Anthony Hollander and Dr Wael Kafienah developed a range of\u000d\u000a        techniques for\u000d\u000a        cartilage engineering on 3D scaffolds,[2], the measurement of the\u000d\u000a        quality of cartilage\u000d\u000a        engineering and finally cartilage engineering using autologous (that is,\u000d\u000a        the patient's own) bone\u000d\u000a        marrow-derived mesenchymal stem cells.[3] These techniques were combined\u000d\u000a        for the potential\u000d\u000a        treatment of cartilage lesions in patients with knee osteoarthritis.\u000d\u000a        However, this approach could\u000d\u000a        readily be adapted to the tissue engineering of cartilage outside the\u000d\u000a        articulating joints and was\u000d\u000a        therefore used as the basis for designing the tracheal cartilage\u000d\u000a        engineering methodology. A\u000d\u000a        key component of this method was the use of Parthyroid Hormone Related\u000d\u000a        Peptide (PTHRP) to\u000d\u000a        prevent the differentiation of the stem cells to hypertrophic\u000d\u000a        chondrocytes that are normally\u000d\u000a        found in the developing growth plates of long bones. This type of\u000d\u000a        chondrocyte has the property\u000d\u000a        of calcifying its extracellular matrix and would pose a problem for\u000d\u000a        hyaline cartilage formation.\u000d\u000a        Calcification within articular or tracheal cartilage is likely to impair\u000d\u000a        its function. The Hollander\u000d\u000a        team hypothesised and then demonstrated that PTHRP could inhibit\u000d\u000a        hypertrophy.[3] PTHRP\u000d\u000a        was therefore used for the tracheal transplantation as part of the\u000d\u000a        pre-conditioning of\u000d\u000a        chondrocytes derived from the patient's stem cells.[1] This body of\u000d\u000a        underpinning research was\u000d\u000a        carried out between 2000 and 2007 and was funded by peer-reviewed grants\u000d\u000a        totalling £1.77m\u000d\u000a        from the European Union, the Arthritis Research Campaign and the\u000d\u000a        Biotechnology and\u000d\u000a        Biological Sciences Research Council.\u000d\u000a      Hollander has been Professor of Rheumatology and Tissue Engineering in\u000d\u000a        the School of\u000d\u000a        Cellular and Molecular Medicine at the University of Bristol from\u000d\u000a        September 2000 to the\u000d\u000a        present. Kafienah was a Research Associate in the Department of Clinical\u000d\u000a        Science at North\u000d\u000a        Bristol from February 2001 to January 2006, and subsequently Lecturer in\u000d\u000a        the School of\u000d\u000a        Cellular and Molecular Medicine from February 2006 to the present.\u000d\u000a      Professor Martin Birchall and Professor Mick Bailey (Bristol) have\u000d\u000a        undertaken a programme of\u000d\u000a        research into laryngotrachealeal graft transplantation in pigs.[4,5]\u000d\u000a        This work on upper airway\u000d\u000a        transplantation provided pivotal background information about the need\u000d\u000a        for vascularisation and\u000d\u000a        for the avoidance of immune rejection. This was critical to the\u000d\u000a        subsequent development of the\u000d\u000a        tracheal transplantation methodology. The team's work on culture of\u000d\u000a        airways epithelial cells\u000d\u000a        was also an important part of the tracheal transplantation as the\u000d\u000a        seeding of these cells, derived\u000d\u000a        from an autologous upper airway biopsy, onto the luminal surface was\u000d\u000a        critical to re-establishing\u000d\u000a        the mucosa after transplantation.[6] The laryngotracheal transplantation\u000d\u000a        research was primarily\u000d\u000a        funded by a peer-reviewed, £1.2m Wellcome Trust Clinical Leave\u000d\u000a        Fellowship (2001-2005)\u000d\u000a        awarded to Birchall.\u000d\u000a      Birchall was Professor of Laryngology at the University of Bristol from\u000d\u000a        April 1995 to December\u000d\u000a        2003 before taking up a position at UCL. He has been an Honorary\u000d\u000a        Visiting Professor in the\u000d\u000a        School of Clinical Sciences at the University of Bristol from August\u000d\u000a        2005 to the present. Bailey\u000d\u000a        has been Professor of Comparative Immunology in the School of Veterinary\u000d\u000a        Science from\u000d\u000a        October 1993 to the present.\u000d\u000a    \u000d\u000a    The study was led by Birchall in Bristol and was dependent on the cell\u000d\u000a      biology skills of the\u000d\u000a      Hollander and Birchall teams to design the cell production methodology and\u000d\u000a      to produce the cells\u000d\u000a      for clinical use. The project was a pan-European collaboration and it was\u000d\u000a      Professor Paolo\u000d\u000a      Macchiarini, Professor of Thoracic Surgery at the Hospital Clinic,\u000d\u000a      Barcelona, Spain, who identified\u000d\u000a      the patient, coordinated the final stages of the tissue engineering and\u000d\u000a      performed the surgery in\u000d\u000a      Barcelona. In Milan, Dr Sarah Mantero developed the bioreactor used to\u000d\u000a      culture the cell-scaffold\u000d\u000a      construct. In Verona, Dr Maria-Theresa Conconi developed the\u000d\u000a      detergent-enzyme method for\u000d\u000a      decellularising cadaver tracheal tissue. Combining these skills and\u000d\u000a      expertise with the stem cell\u000d\u000a      biology, epiltheleal cell culture methods and the laryngotracheal\u000d\u000a      transplant experience in pigs was\u000d\u000a      essential to the project's eventual success.\u000d\u000a    A patent was filed to protect the use of PTHRP as a method of inhibiting\u000d\u000a      hypertrophy.\u000d\u000a    "},{"CaseStudyId":"40147","Continent":[{"GeoNamesId":"6255150","Name":"South America"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"3469034","Name":"Brazil"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"248816","Name":"Jordan"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Impact on patients\u000d\u000a    As a result of the trials and cohort studies, the BHI team demonstrated\u000d\u000a      that the technique they developed is as safe as conventional CABG using a\u000d\u000a      cardiopulmonary bypass pump.[1-6] A 2010 study sought to compare off- and\u000d\u000a      on-pump surgery through a systematic review and meta-analysis of\u000d\u000a      propensity score analyses.[a] The estimated overall odds ratio was less\u000d\u000a      than 1 for all outcomes, favouring off-pump surgery. This benefit was\u000d\u000a      statistically significant for mortality (odds ratio, 0.69; 95% confidence\u000d\u000a      interval (CI) 0.60-0.75), stroke, renal failure, red blood cell\u000d\u000a      transfusion, wound infection, prolonged ventilation, inotropic support,\u000d\u000a      and intra-aortic balloon pump support. The study found off-pump surgery\u000d\u000a      superior to on-pump surgery in all of the assessed short-term outcomes.\u000d\u000a      This advantage was statistically significant and clinically important for\u000d\u000a      most outcomes, including mortality. These results agree with previous\u000d\u000a      systematic reviews of randomised and non-randomised trials. A 2009 study\u000d\u000a      analysed the risk reduction of cardiopulmonary bypass complications\u000d\u000a      between on-pump and off-pump coronary artery bypass grafting in high-risk\u000d\u000a      patients. In the intention to treat analysis, the rate of the composite\u000d\u000a      primary end point was significantly lower in the off-pump group (5.8%\u000d\u000a      versus 13.3%). The risk of experiencing the primary end point was\u000d\u000a      significantly greater for the on-pump group (unadjusted odds ratio, 2.51;\u000d\u000a      95% CI, 1.23-5.10; P = 0.011; adjusted odds ratio, 3.07; 95% CI,\u000d\u000a      1.32-7.14; P = 0.009). The study concluded that OPCAB reduces early\u000d\u000a      mortality and morbidity in high-risk patients.[b]\u000d\u000a    A 2013 study queried the Society of Thoracic Surgeons National Cardiac\u000d\u000a      Database for all patients undergoing non-emergency, isolated coronary\u000d\u000a      artery bypass from 2005 to 2010, who had Predicted Risk of Mortality\u000d\u000a      scores and participant\/surgeon identifiers. Of these 876,081 patients\u000d\u000a      (\"all sites\"), 210,469 underwent surgery at participant sites that had\u000d\u000a      performed more than 300 off-pump and 300 on-pump coronary artery bypass\u000d\u000a      operations during the 6-year study period (\"high-volume sites\"). A number\u000d\u000a      of outcomes were analysed with conditional logistic models for all sites\u000d\u000a      and for high-volume sites, stratified by participant centre and surgeon,\u000d\u000a      and adjusted for 30 variables that comprise the Society of Thoracic\u000d\u000a      Surgeons CABG risk models. In this analysis, OPCAB was associated with\u000d\u000a      reduced risk of death, stroke, acute renal failure, mortality or\u000d\u000a      morbidity, and prolonged length of stay after adjustment for 30 patient\u000d\u000a      risk factors and stratifying for both centre and surgeon identity. OPCAB\u000d\u000a      had a significantly greater reduction in these adverse events in patients\u000d\u000a      with higher patient reported outcome scores. The benefit of OPCAB,\u000d\u000a      therefore, may be more apparent in high-risk patients.[c] The European\u000d\u000a      Association for Cardio-Thoracic Surgery (EACTS) Adult Cardiac Surgical\u000d\u000a      Database Report 2010, contains information on over one million patients\u000d\u000a      undergoing adult cardiac surgery in 366 hospitals in 29 countries across\u000d\u000a      Europe and China. It reports an associated mortality rate of 1.4% (OPCAB)\u000d\u000a      versus 2.9%.[d]\u000d\u000a    Impact on international practice\u000d\u000a    Many surgeons had previously been reluctant to take up OPCAB because of\u000d\u000a      concerns that the technique required surgery on the beating heart,\u000d\u000a      potentially causing late blockage of the grafted arteries. The literature\u000d\u000a      on graft patency from randomised controlled trials of OPCAB versus\u000d\u000a      CABG-CPB is inconsistent, and studies conducted in 2005-6 reported\u000d\u000a      findings for only relatively short durations of follow-up [e]. To address\u000d\u000a      these concerns, the BHI has conducted and published in 2009 the longest\u000d\u000a      follow-up study in the world directly comparing the two techniques.\u000d\u000a      Participants in two randomised trials previously undertaken at the BHI\u000d\u000a      comparing OPCAB and CABG-CPB were followed up for six to eight years after\u000d\u000a      surgery. The findings conclusively demonstrated that the likelihood of\u000d\u000a      graft occlusion was no different between OPCAB (10.6%) and CABG-CPB\u000d\u000a      (11.0%) [f].\u000d\u000a    These data were presented and discussed at the 88th Annual Meeting of The\u000d\u000a      American Association for Thoracic Surgery in May 2008 (the world's largest\u000d\u000a      gathering of cardiac surgeons). The discussion clearly demonstrated that\u000d\u000a      in Japan, surgeons have adopted this technique for about 60% of patients\u000d\u000a      undergoing CABG, and in the Japan's National Cardiovascular Centre 98% of\u000d\u000a      CABG procedures have been performed using OPCAB. Currently, it is\u000d\u000a      estimated that 20-25% of CABG operations worldwide are carried out with\u000d\u000a      the OPCAB technique. The National Adult Cardiac Surgery Audit 2010-11 [g]\u000d\u000a      reported that more than 26,000 CABG operations in the UK in 2011 used\u000d\u000a      OPCAB (20% of all such operations). In the US, 18% of CABG operations are\u000d\u000a      carried out with the OPCAB technique as of 2010.[h] The EACTS Adult\u000d\u000a      Cardiac Surgical Database Report 2010 notes that in 29 countries across\u000d\u000a      Europe and China, \"21% of those patients undergoing coronary artery\u000d\u000a      surgery in which the technique is described had off-pump surgery. This\u000d\u000a      varies between countries from 0.8% up to 91.4%.\".[d] The report details\u000d\u000a      that 61% of CABG procedures have been performed using the OPCAB in\u000d\u000a      China.[d] Of the 95,000 CABG performed per year in India, 30% had off-pump\u000d\u000a      surgery.[i] OPCAB surgery is now routine practice for five out of the\u000d\u000a      seven Consultant Cardiac Surgeons at the BHI Hospital, constituting\u000d\u000a      >95% of their coronary surgical practice. The total number of OPCAB\u000d\u000a      cases at the BHI has gone from <5% (25-30 cases per year) in 1995 to\u000d\u000a      >75% (>750 cases per year; >8000 cases in total) in 2011.[j]\u000d\u000a    NICE has recommended the safety and efficacy of OPCAB surgery, through\u000d\u000a      interventional procedure guidance noting that, \"Current evidence on the\u000d\u000a      safety and efficacy of off-pump coronary artery bypass grafting is\u000d\u000a      adequate to support the use of this procedure provided that normal\u000d\u000a      arrangements are in place for clinical governance, consent and audit\".[k]\u000d\u000a      An effective programme of training in OPCAB surgery has been implemented\u000d\u000a      at the BHI.[k] Once surgeons are trained and accustomed to do it, they are\u000d\u000a      reluctant to go back to CABG-CPB because they are more comfortable with\u000d\u000a      the OPCAB technique and its reduction in early post-operative morbidity\u000d\u000a      and use of resources. Consultants trained in beating heart coronary\u000d\u000a      surgery at the BHI and now performing this surgery elsewhere include six\u000d\u000a      in the UK outside of Bristol, and the following consultants\u000d\u000a      internationally: Mr A Gosh, Consultant Cardiac Surgeon, Kolkata, India; Mr\u000d\u000a      P Narayan, Consultant Cardiac Surgeon, Kolkata, India; Professor W Gomes,\u000d\u000a      Professor of Cardiac Surgery, San Paolo, Brazil; Mr A Pitsis, Consultant\u000d\u000a      Cardiac Surgeon, Athens, Greece; Mr W Dihmis, Consultant Cardiac Surgeon,\u000d\u000a      Amman, Jordan; Mr B Izzat, Professor of Cardiac Surgery, Damascus, Syria.\u000d\u000a    Impact on resources\u000d\u000a    The OPCAB technique has had a profound impact on hospital resources and\u000d\u000a      cost, with a 25% saving per patient. A 2003 BHI study recorded a dramatic\u000d\u000a      reduction in intensive care unit and hospital stay [5], as shown in the\u000d\u000a      following table:\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          \u000d\u000a          CABG\u000d\u000a          OPCAB\u000d\u000a        \u000d\u000a        \u000d\u000a          ICU stay (>1 day)\u000d\u000a          22%\u000d\u000a          7%\u000d\u000a        \u000d\u000a        \u000d\u000a          Hospital stay (>7 days)\u000d\u000a          29%\u000d\u000a          15%\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    The reduction in hospital stay was confirmed in 2013 in a study that\u000d\u000a      reported an odds ratio of 0.77 for postoperative length of stay across all\u000d\u000a      of the sites analysed (adjusted by patient).[c] A 2005 meta-analysis\u000d\u000a      examined five studies which have reported on the in-hospital costs and\u000d\u000a      each of them showed OPCAB to be less costly than CABG, with an odds ratio\u000d\u000a      of 0.77 across all of the sites analysed (adjusted by patient).[e] The\u000d\u000a      study included a collation of all the hospital costs from the date of\u000d\u000a      surgery to the date of discharge including all patient services and\u000d\u000a      supplies. The study calculated an average cost per patient of $23,053 for\u000d\u000a      CABG and $17,780 for OPCAB. Across the 26,000 operations in the UK in 2011\u000d\u000a      using OPCAB, this equates to a saving of US$137 million.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    University of Bristol researchers at the Bristol Heart Institute (BHI)\u000d\u000a      have pioneered the development and clinical take-up of the novel technique\u000d\u000a      of off-pump coronary artery bypass (OPCAB) surgery. Over ten clinical\u000d\u000a      trials and several large cohort analyses have assessed the impact of this\u000d\u000a      technique on elective and high-risk patients. The results have shown that\u000d\u000a      it is as safe as the conventional coronary artery bypass grafting (CABG)\u000d\u000a      technique that uses a cardiopulmonary bypass pump and cardioplegic arrest.\u000d\u000a      Most importantly, however, OPCAB significantly reduces the risk of\u000d\u000a      post-operative complications, and reduces morbidity and mortality. It also\u000d\u000a      uses less hospital resources, reducing time in intensive care and length\u000d\u000a      of hospital stay. In 2011 (the last year for which data are available),\u000d\u000a      20% of CABG operations in the UK were carried out with the OPCAB technique\u000d\u000a      and it has had significant take-up overseas (for example, 18% of CABG\u000d\u000a      operations in the US and 21% in the EU in 2010). NICE has recommended the\u000d\u000a      safety and efficacy of OPCAB surgery.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Bristol\u000d\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"170654","Name":"Damascus"},{"GeoNamesId":"264371","Name":"Athens"},{"GeoNamesId":"1275004","Name":"Kolkata"},{"GeoNamesId":"250441","Name":"Amman"}],"References":"\u000d\u000a    Peer-reviewed journal publications\u000d\u000a    \u000a[1] Watters MP, Ascione R, Ryder IG, Ciulli F, Pitsis AA, Angelini GD.\u000d\u000a      Haemodynamic changes during beating heart coronary surgery with the\u000d\u000a      'Bristol Technique'. Eur J Cardiothorac Surg. 2001 Jan;19(1):34-40. DOI:\u000d\u000a      10.1016\/S1010-7940(00)00603-5\u000d\u000a    \u000a\u000a[2] R Ascione, CT Lloyd, WJ Gomes, M Caputo, AJ Bryan, GD Angelini.\u000d\u000a      Beating versus arrested heart revascularization: evaluation of myocardial\u000d\u000a      function in a prospective randomised study. Eur J Cardio-Thoracic Surg;\u000d\u000a      1999;15:685-690. DOI: 10.1016\/S1010-7940(99)00072-X\u000d\u000a    \u000a\u000a[3] Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini GD. On-pump\u000d\u000a      versus off-pump coronary revascularization: evaluation of renal function.\u000d\u000a      Ann Thorac Surg. 1999 Aug;68(2):493-8. DOI: 10.1016\/S0003-4975(99)00566-4\u000d\u000a    \u000a\u000a[4] R Ascione, S Williams, CT Lloyd, T Soondaramorthi, AA Pitsis, GD\u000d\u000a      Angelini. Reduced postoperative blood loss and transfusion requirement\u000d\u000a      after beating-heart coronary operations: a prospective randomised study. J\u000d\u000a      Thorac Cardiovasc Surg 2001;121:689-96. DOI: 10.1067\/mtc.2001.112823\u000d\u000a    \u000a\u000a[5] GD Angelini, FC Taylor, BC Reeves, R Ascione. Early and mid-term\u000d\u000a      outcome after off-pump and on-pump surgery in Beating Heart Against\u000d\u000a      Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two\u000d\u000a      randomised controlled trials. Lancet 2002;359:1194-99. DOI:\u000d\u000a      10.1016\/S0140-6736(02)08216-8\u000d\u000a    \u000a\u000a[6] Ascione R, Reeves BC, Seehra H, Taylor FC, Angelini GD. Beating Heart\u000d\u000a      Against Cardioplegic Arrest Studies (BHACAS 1 and 2): quality of life at\u000d\u000a      mid-term follow-up in two randomised controlled trials. Eur Heart J\u000d\u000a      2004;25:765-70. DOI: 10.1016\/j.ehj.2003.11.015\u000d\u000a    \u000aPeer reviewed grants\u000d\u000a    [7] Angelini GD. Coronary artery revascularisation without\u000d\u000a      cardiopulmonary bypass: a prospective randomised controlled study.\u000d\u000a      1997-1999. Sir Siegmund Warburg Voluntary Settlement £69,876\u000d\u000a    [8] Ascione R, Bryan AJ, Angelini GD. On pump versus off pump coronary\u000d\u000a      surgery: evaluation of small intestinal, pancreatic and liver function.\u000d\u000a      2001-2002. BHF £53,610\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    [a] Kuss O, von Salviati B, Borgermann J. Off-pump versus on-pump\u000d\u000a      coronary artery bypass grafting: a systematic review and meta-analysis of\u000d\u000a      propensity score analyses. J Thorac Cardiovasc Surg 2010;140;829-35. DOI:\u000d\u000a      10.1016\/j.jtcvs.2009.12.022. Corroborates superiority of off-pump to\u000d\u000a      on-pump in short term outcomes including stroke, renal failure and\u000d\u000a      mortality.\u000d\u000a    [b] Puskas JD, Thourani VH, Kilgo P, et al. Off-pump coronary artery\u000d\u000a      bypass disproportionately benefits high-risk patients. Ann Thorac Surg\u000d\u000a      2009;88:1142-7. DOI: 10.1016\/j.athoracsur.2009. 04.135. Corroborates that\u000d\u000a      OPCAB reduces early mortality and morbidity.\u000d\u000a    [c] Polomsky M, He X, O'Brien Sm, Puskas JD. Outcomes of off-pump versus\u000d\u000a      on-pump coronary artery bypass grafting: Impact of preoperative risk. J\u000d\u000a      Thorac Cardiovasc Surg 2013;145;1193-1198. DOI:\u000d\u000a      10.1016\/j.jtcvs.2013.02.002. Corroborates that OPCAB was associated with\u000d\u000a      reduced risk of death, stroke, renal failure, mortality or morbidity, and\u000d\u000a      prolonged length of stay.\u000d\u000a    [d] EACTS Adult Cardiac Surgical Database Report, 2010. Corroborates use\u000d\u000a      of OPCAB across Europe and China.\u000d\u000a    [e] Wijeysundera DN, Beattie WS, Djaiani G, Rao V, Borger MA, Karkouti K,\u000d\u000a      et al. Off pump coronary artery surgery for reducing mortality and\u000d\u000a      morbidity: meta-analysis of randomized and observational studies. J Am\u000d\u000a      Coll Cardiol. 2005;46:872-82. DOI: 10.1016\/j.jacc.2005.05.064.\u000d\u000a      Corroborates reduced costs of OPCAB.\u000d\u000a    [f] GD. Angelini, L Culliford, D Smith, M Hamilton, G Murphy, R Ascione,\u000d\u000a      et al. Effects of on- and off-pump coronary artery surgery on graft\u000d\u000a      patency, survival and quality of life: long term follow-up of two\u000d\u000a      randomised controlled trials. J Thorac Cardiovasc Surg 2009;137:295-303.\u000d\u000a      DOI: 10.1016\/j.jtcvs.2008.09.046. Corroborates that OPCAB does not cause\u000d\u000a      long term blockage of the grafted arteries.\u000d\u000a    [g] 6th National Adult Cardiac Surgical Database Report-Blue Book, http:\/\/www.scts.org\/.\u000d\u000a      Corroborates number of OPCAB surgeries performed in UK.\u000d\u000a    [h] STS Database Registry 2010, http:\/\/www.sts.org\/quality-research-patient-safety\/sts-public-reporting-online.\u000d\u000a      Corroborates number of CABG surgeries performed in US.\u000d\u000a    [i] Senior Vice Chairman, Medica Superspecialty Hospital Kolkata. India.\u000d\u000a      Corroborates number of OPCAB surgeries performed in India.\u000d\u000a    [j] BHI Adult Cardiac Surgery Activity Audit Report 2010-11. Corroborates\u000d\u000a      number of OPCAB surgeries performed at BHI hospital.\u000d\u000a    [k] NICE. `Off-pump Coronary Artery Bypass Grafting'. NICE interventional\u000d\u000a      procedure guidance 377. January 2011. www.nice.org.uk\/nicemedia\/live\/11034\/52580\/52580.pdf.\u000d\u000a      Corroborates NICE recommendation of OPCAB surgery.\u000d\u000a    [l] M Murzi, M Caputo, G Aresu, S Duggan, GD. Angelini. Training\u000d\u000a      residents in off-pump coronary artery bypass surgery: A 14-year\u000d\u000a      experience. J Thorac Cardiovasc Surg 2012;143:1247-53. DOI:\u000d\u000a      10.1016\/j.jtcvs.2011.09.049.\u000d\u000a    ","Title":"\u000d\u000a    Lower risks to patients, advances in international practice and\u000d\u000a      substantial resource savings result from `beating heart' off-pump coronary\u000d\u000a      artery bypass surgery.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Conventional coronary artery bypass grafting (CABG) surgery in an\u000d\u000a      increasingly high-risk population (caused by increasing age, smoking,\u000d\u000a      diabetes, hypertension and high cholesterol) involves stopping the heart\u000d\u000a      (cardioplegic arrest, CA) and the use of a cardiopulmonary bypass pump\u000d\u000a      (CPB). The use of CA and CPB in these patients is associated with\u000d\u000a      significant in-hospital mortality and morbidity due to its\u000d\u000a      non-physiological nature. To overcome these problems, researchers from the\u000d\u000a      University of Bristol at the Bristol Heart Institute (BHI) have pioneered\u000d\u000a      the novel and alternative technique of off-pump coronary artery bypass\u000d\u000a      surgery (OPCAB), avoiding the use of both CA and CPB. The BHI is an\u000d\u000a      internationally recognised centre of excellence for performing\u000d\u000a      translational cardiovascular research that takes basic science discoveries\u000d\u000a      to the clinic.\u000d\u000a    OPCAB has been developed and validated at the BHI since 1997 by a team\u000d\u000a      led by Professor Gianni Angelini, British Heart Foundation Professor of\u000d\u000a      Cardiac Surgery, and Professor Raimondo Ascione, Professor of Cardiac\u000d\u000a      Surgery & Translational Research (Clinical Research Fellow in Cardiac\u000d\u000a      Surgery at the BHI in 1997). Other key research team members include\u000d\u000a      Professor Barnaby Reeves (Professor of Health Services Research and\u000d\u000a      Honorary Senior Lecturer in Epidemiology in 2002 when he joined the BHI)\u000d\u000a      and Mr Alan Bryan (Consultant Cardiac Surgeon and responsible for the BHI\u000d\u000a      data registry since 1998). The development and validation process has\u000d\u000a      involved over ten trials and several large cohort analyses from the BHI\u000d\u000a      data registry.\u000d\u000a    Preliminary work between 1997 and 1998 focused on the development of a\u000d\u000a      reproducible surgical technique with use of locally developed tools. The\u000d\u000a      established technique was reported in 2001.[1] A series of small trials\u000d\u000a      assessed its impact on subsystem organ function in 1997-98, including\u000d\u000a      myocardial,[2] renal,[3] respiratory, cerebral and inflammation. Larger\u000d\u000a      trials followed (Beating Heart Against Cardioplegic Arrest Studies\u000d\u000a      1&2) in 1999-2001,[4, 5] with follow-up in 2003 [6] and 2008,\u000d\u000a      assessing late symptoms and graft patency rate. In addition, case cohort\u000d\u000a      studies (2001-2006) assessed the impact on in-hospital and mid-term\u000d\u000a      clinical end-points, including mortality in elective and high-risk\u000d\u000a      patients. A further trial focused for the first time on cerebral and\u000d\u000a      retinal micro-embolisation.[7] The BHI conducted and published the world's\u000d\u000a      first randomised study on OPCAB surgery.[2] No other centres were\u000d\u000a      rigorously validating the same approach in parallel, as is evident from\u000d\u000a      the absence of concomitant randomised trials published by others. Thus the\u000d\u000a      procedure was validated through rigorous studies from 1997 to 2008,\u000d\u000a      showing that patients benefited directly in terms of reductions in\u000d\u000a      in-hospital morbidity,[5] blood loss, transfusion requirement,[4] chest\u000d\u000a      infection, inotropic support,[5] arrhythmias,[a] cerebral embolisation and\u000d\u000a      renal injury [3] when compared with conventional technique in elective\u000d\u000a      patients, without affecting mid- and long-term benefit.[6] The research\u000d\u000a      has been funded to a total of approximately £3m. The first two funding\u000d\u000a      grants were awarded in 1997 and 2001.[7, 8]\u000d\u000a    "},{"CaseStudyId":"40148","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    4.1 Establishment of methods\/early studies\u000a    By the early 1990s it was apparent that the gene rearrangements present\u000a      in the originating clones sometimes underwent further changes that might\u000a      invalidate MRD detection. Steward et al [5] were the first to publish a\u000a      series investigating this in detail, showing that the problem could be\u000a      overcome by tracking multiple rearrangements detected at diagnosis; this\u000a      approach still underpins MRD analysis to the present day. Collaboration\u000a      was established with three other European groups in order to develop\u000a      uniform systems; this led to the formation of the European Study Group on\u000a      MRD detection in ALL (ESG-MRD-ALL, now EuroMRD; Hancock, Goulden and\u000a      Moppett were founder members) and to the development of agreed testing\u000a      systems in Europe. Euro-MRD now embraces 43 laboratories in Europe,\u000a      Australia, the US, Japan and Israel.\u000a    4.2 Underpinning Modern Clinical Trials in Paediatric and Adult ALL\u000a    Studies of patients in the UK being treated on standard MRC leukaemia\u000a      protocols showed that patients with isolated extramedullary relapses of\u000a      ALL almost invariably had bone marrow disease [1] and that slow early\u000a      clearance of disease was strongly correlated with subsequent relapse ([2]\u000a      and output [a]). The research to demonstrate this had been part-funded by\u000a      the Leukaemia Research Fund (LRF, now Leukaemia & Lymphoma Research)\u000a      and led to the LRF establishing ongoing support of MRD studies in all UK\u000a      trials of ALL therapy. A network of national laboratories was established\u000a      to perform this work on a regional basis, managed and funded via the\u000a      central laboratory in Bristol. In 2007 routine MRD testing was transferred\u000a      to the NHS Pathology Laboratories at Southmead Hospital, Bristol (where it\u000a      is coordinated by Hancock and Moppett), thereby taking the technology to\u000a      fully validated clinical testing.\u000a    MRD assessment is now widely regarded as the most sensitive and specific\u000a      predictor of relapse risk in children with ALL during remission. All\u000a      children and young adults treated in the UK since 2003 for either de\u000a        novo or relapsed ALL have had their MRD measured and used in the\u000a      entry criteria and\/or randomisation procedures of the following trials:\u000a      ALL 2003, UKALL R3 (relapsed and refractory ALL, open until 31\/12\/13,\u000a      output [b]) and Interfant-06 (infant ALL, open until 30\/6\/14).\u000a    The MRC ALL 2003 trial, which ran from 2003 to 2011 and involved 3207\u000a      patients, reported in 2013 ([6] and output [c]); 521 children and young\u000a      adult patients assessed as being at low risk on the basis of MRD assays\u000a      were assigned to receive either one or two delayed intensification (DI)\u000a      chemotherapy courses. There was no significant difference in outcome. The\u000a      importance of this is highlighted by the fact that there were 74 episodes\u000a      of grade 3-4 toxicity affecting 45 patients (17% of the whole cohort) in\u000a      those who received two DI courses. The future use of a single\u000a      intensification course for MRD low-risk patients will therefore avoid much\u000a      unnecessary toxicity and hence patient suffering and cost (output [d]).\u000a      The current ALL trial, UKALL 2011, is built on this finding and again\u000a      utilises MRD as the critical determinant of stratification\/randomisation\u000a      (output [e]).\u000a    4.3 Rationalising use of haematopoietic stem cell transplantation\u000a        (HSCT)\u000a    HSCT has conventionally been applied to those with high-risk features of\u000a      their leukaemia at presentation or with relapsed disease. However, these\u000a      procedures carry high transplant related mortality (20-30%) and an average\u000a      cost of £100-150k per procedure. MRD researchers at Bristol were the first\u000a      to highlight the strong correlation between persistent high level MRD\u000a      going into transplant or re-emergence of MRD soon after transplantation\u000a      with post-transplant relapse.[3,4] In all of the clinical trials mentioned\u000a      above, MRD is used to determine which patients would go onto\u000a      haematopoietic stem cell transplantation. Bader (Frankfurt) learned\u000a      methods of MRD assessment in the Bristol laboratory and subsequently\u000a      conducted a prospective trial using PCR MRD techniques via the European\u000a      ALL-REZ BFM Study Group. In 2009 this study confirmed the strong\u000a      correlation between pre-transplant MRD and outcome in mainland European\u000a      patients treated on BFM protocols (output [f]). Bader and colleagues are\u000a      now giving additional donor T-cells to patients with re-emergent MRD after\u000a      transplantation and have reported successful reversion of incipient\u000a      relapse (output [g]). Many groups around the world have since studied\u000a      peri-transplant MRD and the Bristol research is widely cited (examples\u000a      shown in outputs [a] and [h]).\u000a    4.4 Establishment of national leukaemia cell banking\u000a    Residual DNA samples from UKALL 2003 MRD studies were used to establish\u000a      the LLR\/CCLG Childhood Leukaemia Cell Bank, now being centralised at the\u000a      UK Biobank in Manchester. Since inception over 18,090 samples from 3,175\u000a      leukaemic patients have been collected, comprising DNA and viable cells\u000a      from patients on the ALL2003, ALLR3, ALL97 and ALL2011 interim protocols.\u000a      This collection will play a pivotal role in future UK leukaemia research.\u000a    ","ImpactSummary":"\u000a    Researchers at the University of Bristol have developed tests to track\u000a      low-level leukaemia — `minimal residual disease' (MRD) — in children with\u000a      acute lymphoblastic leukaemia (ALL) down to levels thousands of times\u000a      lower than detectable by light microscopy. These tests have become the\u000a      gold standard for monitoring of leukaemic response in clinical trials. MRD\u000a      testing has been shown in 2013 to allow safe de-intensification of\u000a      treatment for one-fifth of patients treated nationally, with substantial\u000a      savings in toxicity and treatment-related expense. The same techniques\u000a      have also improved worldwide understanding of how disease clearance is\u000a      related to success after haemopoietic stem cell transplantation.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Bristol\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Goulden NJ, Langlands K, Steward CG et al (including Potter). PCR\u000a      assessment of bone marrow status in 'isolated' extramedullary relapse of\u000a      childhood B-precursor acute lymphoblastic leukaemia. Br J Haematol. 1994\u000a      Jun;87(2):282-5. PMID: 7947268\u000a    \u000a\u000a[2] Goulden NJ, Knechtli CJ, Garland RJ et al (including Langlands,\u000a      Hancock, Potter, Steward). Minimal residual disease analysis for the\u000a      prediction of relapse in children with standard-risk acute lymphoblastic\u000a      leukaemia. Br J Haematol. 1998 Jan;100(1):235-44. PubMed PMID: 9450818.\u000a    \u000a\u000a[3] Knechtli CJ, Goulden NJ, Hancock JP et al (including Steward).\u000a      Minimal residual disease status before allogeneic bone marrow\u000a      transplantation is an important determinant of successful outcome for\u000a      children and adolescents with acute lymphoblastic leukemia. Blood. 1998\u000a      Dec 1;92(11):4072-9. PubMed PMID: 9834212.\u000a    \u000a\u000a[4] Knechtli CJ, Goulden NJ, Hancock JP et al (including Potter,\u000a      Steward). Minimal residual disease status as a predictor of relapse after\u000a      allogeneic bone marrow transplantation for children with acute\u000a      lymphoblastic leukaemia. Br J Haematol. 1998 Aug;102(3):860-71. PubMed\u000a      PMID: 9722317.\u000a    \u000a\u000a[5] Steward CG, Goulden NJ, Katz F et al (including Langlands, Potter). A\u000a      polymerase chain reaction study of the stability of Ig heavy-chain and\u000a      T-cell receptor delta gene rearrangements between presentation and relapse\u000a      of childhood B-lineage acute lymphoblastic leukemia. Blood. 1994 Mar\u000a      1;83(5):1355-62. PubMed PMID: 8118037.\u000a    \u000a\u000a[6] Vora A, Goulden N, Wade R (including Hancock). Treatment reduction\u000a      for children and young adults with low-risk acute lymphoblastic leukaemia\u000a      defined by minimal residual disease (UKALL 2003): a randomised controlled\u000a      trial. Lancet Oncol. 2013 Mar;14(3):199-209. PubMed PMID: 23395119.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    [a] The contribution of Bristol MRD clinicians\/scientists in outlining\u000a      the importance of MRD analysis at end of induction and in the pre- and\u000a      post-transplant setting is explained by inclusion of the references 1, 26,\u000a      29 and 39 in the current essay on \"Clinical use of MRD detection in ALL\"\u000a      in UpToDate, written by US clinicians, corroborating 4.2 and 4.4:\u000a      http:\/\/www.uptodate.com\/contents\/clinical-use-of-minimal-residual-disease-detection-in-acute-lymphoblastic-leukemia\u000a    [b] and [c] MRD assessment has been critical to the study design and\u000a      randomisations in the most recent UK trials for de novo and\u000a      relapsed childhood ALL, corroborating 4.2. The role of MRD in these\u000a      protocols is outlined in two trial summaries from www.ClinicalTrials.gov:\u000a      ALLR3 (http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00967057)\u000a      MRC ALL2003 (http:\/\/clinicaltrials.gov\/show\/NCT00222612)\u000a    [d] MRD testing in the ALL2003 trial showed that a low risk group of\u000a      patients could be identified and treated with just one course of\u000a      intensification therapy, reducing costs and side effects. This\u000a      corroborates 4.3 and is described in reference [6].\u000a    [e] The current ALL trial, UKALL 2011, utilises MRD as the critical\u000a      determinant of randomisation, corroborating 4.3: https:\/\/leukaemialymphomaresearch.org.uk\/information\/childhood-leukaemia\/acute-lymphoblastic-leukaemia\/treatment#UKALL%202011\u000a    [f] The Bristol demonstration of the importance of pre-transplant MRD has\u000a      led to wider international study, corroborating 4.4, as shown by this\u000a      reference from the European BFM Group: Bader P, Kreyenberg H, Henze GH et\u000a      al. Prognostic value of MRD quantification before allogeneic stem-cell\u000a      transplantation in relapsed childhood acute lymphoblastic leukemia: the\u000a      ALL-REZ BFM Study Group. J Clin Oncol. 2009 Jan 20;27(3):377-84. PMID:\u000a      19064980.\u000a    [g] Post-transplant MRD analysis has allowed post-graft immune\u000a      manipulation to reduce relapse rates, corroborating 4.4, as detailed here:\u000a      Pulsipher MA, Bader P, Klingebiel T, Cooper LJ. Allogeneic transplantation\u000a      for pediatric acute lymphoblastic leukemia: the emerging role of\u000a      peritransplantation minimal residual disease\/chimerism monitoring and\u000a      novel chemotherapeutic, molecular, and immune approaches aimed at\u000a      preventing relapse. Biol Blood Marrow Transplant. 2009 Jan;15(1\u000a      Suppl):62-71. PMID: 19147081.\u000a    [h] The work on pre- and post-transplant MRD led to inclusion in a major\u000a      textbook on transplantation, corroborating 4.4:\u000a      Clinical Bone Marrow and Blood Stem Cell Transplantation, 3rd\u000a      Edition (ed. K Atkinson) p 1671 references Knechtli et al and an original\u000a      figure is reproduced as figure 105.11. Can be supplied on request.\u000a    ","Title":"\u000a    Minimal residual disease assessment in acute lymphoblastic leukaemia\u000a      allows safe individualisation of chemotherapy and reduction of treatment\u000a      toxicity.\u000a    ","UKLocation":[{"GeoNamesId":"2643123","Name":"Manchester"},{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Acute lymphoblastic leukaemia (ALL) affects approximately 400 children\u000a      per year in the UK and is the commonest childhood leukaemia. It develops\u000a      when a lymphocyte precursor cell undergoes malignant change and copies\u000a      itself uncontrollably to form the leukaemia clone. This usually occurs at\u000a      a stage when the cell is going through the process of rearranging its\u000a      immunoglobulin and\/or T-cell receptor genes, and therefore these provide a\u000a      genetic signature and means of accurate identification. From 1990-2007,\u000a      research by clinicians and scientists at the University of Bristol\u000a      demonstrated that these genetic changes allow extremely sensitive\u000a      detection of low-level leukaemia cells (MRD). The key advances were\u000a      achieved by identifying each child's leukaemic signature and then using\u000a      polymerase chain reaction (PCR) amplification to effectively provide a\u000a      molecular microscope up to 5000 times more powerful than light microscopy.\u000a    The researchers involved in these studies included Potter (1990-1993),\u000a      Steward (1990-2001), Knechtli (1994-98), Goulden (1995-2006), Moppett\u000a      (1999-2003) and Hancock (2002-2007). The research was funded by more than\u000a      £5m of grants, principally from the Leukaemia Research Fund. It also\u000a      attracted conference prizes (British Paediatric Association, British\u000a      Society of Haematology) and led to the award of six PhDs.\u000a    Studies on the fundamentals of leukaemia biology and treatment\u000a        response\u000a    Research on MRD at the University of Bristol elucidated many\u000a      poorly-understood areas of leukaemia behaviour and management. The Bristol\u000a      team were the first to prove that bone marrow disease was almost always\u000a      present at submicroscopic levels in patients who had developed `isolated\u000a      relapse' (in either the central nervous system or testes), thereby\u000a      validating the decision to use powerful systemic chemotherapy rather than\u000a      localised treatment in such patients.[1] In 1998 they showed that poor\u000a      early clearance of MRD identified children with a higher risk of\u000a      subsequent relapse in MRC-funded trials.[2] Bristol researchers were also\u000a      the first to analyse MRD levels before and after bone marrow\u000a      transplantation in order to determine why some patients relapsed so\u000a      quickly after transplantation; these studies have since been widely\u000a      replicated and reported.[3,4]\u000a    Developing a safe system applicable to clinical trials\u000a    The first major contribution to recent trials was via a large study of\u000a      relapsed patients that determined the stability of the genetic signatures\u000a      with time and how to optimise the detection system for maximum\u000a      reliability.[5] With Professor Jacques van Dongen and European colleagues,\u000a      Bristol researchers then founded the EuroMRD group in 2001 to agree the\u000a      genetic targets and technical aspects of MRD detection. These have since\u000a      formed the basis for inter-patient comparison and treatment stratification\u000a      in UK MRC-funded trials for first line treatment, relapsed and infant\u000a      leukaemia (ALL 2003, UKALL R3 and Interfant-06) and BFM group trials in\u000a      mainland Europe. Previous University of Bristol MRD researchers now act as\u000a      the Chief Investigator for UKALL 2011 (Goulden) and the clinical and\u000a      molecular MRD co-ordinators respectively (Moppett, Hancock). MRD\u000a      quantitation has been used successfully to determine the safety and\u000a      efficacy of individualised reduction of intensification chemotherapy in\u000a      patients treated on ALL 2003.[6]\u000a    "},{"CaseStudyId":"40149","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2802361","Name":"Belgium"}],"Funders":[],"ImpactDetails":"\u000a    Creation of new businesses\u000a    Apitope, a University of Bristol spinout company, was established by\u000a      Professor Wraith in 2002.\u000a      Apitope develops peptide therapeutics for a range of autoimmune disorders,\u000a      and currently has five\u000a      product candidates in its pipeline and employs 26 individuals based in\u000a      three key sites across the\u000a      UK and Europe.\u000a    Since the University of Bristol's initial research into ASPI was\u000a      published, a series of patents, start-ups\u000a      and spin-outs have established themselves, each developing peptide\u000a      therapeutics for a variety\u000a      of autoimmune and allergic disorders. Each company listed has made direct\u000a      reference to Professor\u000a      Wraith's laboratory at some stage in their initial research and discovery\u000a      process. Additionally\u000a      Professor Wraith has collaborated or been in direct communication with the\u000a      majority of founding\u000a      researchers listed below.\u000a    Circassia was established by Professor Mark Larché who co-authored with\u000a      Professor Wraith —\u000a      Circassia is a bio-pharmaceutical company specialising in peptide\u000a      therapeutics targeted against a\u000a      range of allergies. Circassia's pipeline currently includes treatments\u000a      for: cat dander, ragweed,\u000a      house dust mite, grass, birch and Japanese birch pollen, Alternaria, and\u000a      dog hair.\u000a    ImmuPharma PLC is European pharmaceutical company founded upon Lupuzor, a\u000a      peptide\u000a      therapeutic for systemic lupus erythematosus (SLE). ImmuPharma has five\u000a      drug candidates in\u000a      development, two platform technologies and approximately 70 patents.\u000a      ImmuPharma has won\u000a      several awards including \"Best Technology 2009\" at the AIM Awards —\u000a      sponsored by\u000a      PricewaterhouseCoopers LLP and \"Best Medical Research & Development\u000a      Company — Europe\" at\u000a      the 2012 New Economy's Healthcare awards.[f]\u000a    Based in Yavne, Israel Andromeda Biotech is currently in phase III\u000a      clinical trials for DiaPep277, a\u000a      peptide therapeutic designed to treat type 1 diabetes.\u000a    Industrial investment\u000a    Work at Apitope has attracted a high level of investment from industry.\u000a      In 2008, Apitope received\u000a      €10 million (~£8.4 million) from an investment consortium based in Belgium\u000a      for continued research\u000a      into peptide therapeutics for multiple sclerosis, type 1 diabetes and type\u000a      A-haemophilia.[a] The\u000a      following year Apitope entered a licensing agreement worth € 154 million\u000a      (~£130 million) with\u000a      pharmaceutical industry leader Merck Serono focused on commercialisation\u000a      of Professor Wraith's\u000a      ATX-MS-1467 compound.[b] In the Spring of 2013 Apitope received €5.925\u000a      million in funding from\u000a      the European commission for their continued research into therapeutics for\u000a      Graves' disease [c].\u000a    Circassia has successfully completed five fundraising rounds, yielding a\u000a      total of approximately\u000a      £105 million.[d] ImmuPharma announced in May 2013 that it has secured a\u000a      £50 million, five year\u000a      Equity Financing Facility to fund their late stage Lupuzor compound.[e] In\u000a      2010 Teva\u000a      Pharmaceuticals Ltd invested in Andromeda at a company to money valuation\u000a      of $170 million\u000a      (~£111 million). This followed a $13.5 million investment by Teva the\u000a      previous year.[f]\u000a    Adoption of new technology\u000a    As a result of its work with Apitope, Merck Serono is continuing\u000a      investigation into ASPI, initiating its\u000a      own clinical trial into the efficacy of ATX-MS-1467 as a treatment for\u000a      multiple sclerosis.[g]\u000a      Additionally GlaxoSmithKline has joined with Apitope in discovering\u000a      peptide therapeutics for\u000a      Graves' disease, an autoimmune condition affecting the thyroid.[c]\u000a    The development of new products\u000a    A number of candidate products have been created using ASPI, several of\u000a      which have entered late\u000a      stage clinical trials. Three of these products are described below:\u000a    DNAJP1\u000a    Developed through research at Utrecht University, the Netherlands, DNAJP1\u000a      is a therapeutic\u000a      peptide created to treat rheumatoid arthritis. DNAJP1 is currently\u000a      licensed by the biotechnology\u000a      company Synthetic Biologics and is undergoing clinical trials to judge its\u000a      efficacy.[h] Early work on\u000a      development of DNAJP1, published in 1997, referred to the ASPI approach\u000a      described by Professor\u000a      Wraith at the University of Cambridge.[i]\u000a    Dirucotide\u000a    Derived from myelin basic protein (MBP) and developed by BioMS, a\u000a      spin-out from the University\u000a      of Alberta, Canada, Dirucotide is currently under licence by Medwell\u000a      Capital Corp, and\u000a      pharmaceutical company Eli Lilly. The therapeutic reached phase III trials\u000a      in 2009 for the treatment\u000a      of multiple sclerosis but is currently under review to determine its\u000a      efficacy.[j] The description of the\u000a      first clinical trial on Dirucotide, published in 2006, refers back to the\u000a      original ASPI work from\u000a      Professor Wraith's laboratory in Cambridge.[k]\u000a    Patent US 7858738 B2 Synthetic human peptides and pharmaceutical\u000a        compositions comprising\u000a        them for the treatment of systemic lupus erythematosus\u000a    A patent was published in 2010 by Yeda Research and Development Co for a\u000a      pair of therapeutic\u000a      peptides aimed at treating the auto-immune disease myasthenia gravis. The\u000a      work preceding this\u000a      patent directly references Professor Wraith's research carried out at the\u000a      University of Bristol.[l]\u000a    ","ImpactSummary":"\u000a    By identifying a novel approach to treat allergy and autoimmune disease\u000a      the University of Bristol\u000a      has created a new field of research into antigen-specific peptide\u000a      immunotherapy. Initial work\u000a      carried out by Professor David Wraith at the University has since 2008 led\u000a      to the creation of new\u000a      businesses, (including the spinout company Apitope), generated 100s of\u000a      millions of pounds of\u000a      investment and underpinned both the adoption of new technology and the\u000a      development of new\u000a      products by the pharmaceutical industry. The commercial impact of this\u000a      research into antigen\u000a      specific immunotherapy is on-going and expanding.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Bristol\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"293222","Name":"Yavne"}],"References":"\u000a    \u000a[1] Anderton, S.M., Burkhart, C., Liu, G.Y., Metzler B. & Wraith,\u000a      D.C. Antigen-specific tolerance\u000a      induction and the immunotherapy of experimental autoimmune disease. Novartis\u000a        Foundation\u000a        Symposium 215, 120-136 (1998) PMID: 9760575\u000a    \u000a\u000a[2] Anderton, S.M. & Wraith, D.C. Hierarchy in the ability of T cell\u000a      epitopes to induce peripheral\u000a      tolerance to antigens from myelin. European Journal of Immunology,\u000a      28, 1251-1261 (1998)\u000a      PMID: 9565365\u000a    \u000a\u000a[3] Anderton, S.M., Viner, N.J., Matharu, P., Lowrey, P.A. & Wraith\u000a      D.C. The influence of a\u000a      dominant cryptic epitope on autoimmune T cell tolerance. Nature\u000a        Immunology 3, 175-181\u000a      (2002) PMID: 11812995\u000a    \u000a\u000a[4] Sundstedt A, O'Neill EJ, Nicolson KS & Wraith DC. Role for IL-10\u000a      in suppression mediated by\u000a      peptide-induced regulatory T cells in vivo. Journal of Immunology,\u000a      170, 1240-1248 (2003)\u000a      PMID: 12538682\u000a    \u000a\u000a[5] Larché, M. & Wraith, D.C. Peptide-based therapeutic vaccines for\u000a      allergic and autoimmune\u000a      diseases. Nature Medicine, 11, pp.S69-S76 (2005) PMID: 15812493\u000a    \u000a\u000a[6] Streeter HB, Pillai S, Scolding NJ & Wraith D.C. ATX-MS1467 a\u000a      therapeutic peptide vaccine for\u000a      treatment of multiple sclerosis (Abstract). Multiple Sclerosis\u000a      14:S185 (2008)\u000a      DOI:10.1177\/1352458508096399\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    [a] Apitope press release 22\/10\/2008: http:\/\/www.apitope.com\/Downloads\/Archive\/221008.pdf\u000a      This press release announces the successful completion of a EUR 10M series\u000a      A financing round\u000a      for Apitope International NV to develop its ASPI approaches.\u000a    [b] Apitope press release 13\/01\/2009: http:\/\/www.apitope.com\/Downloads\/Archive\/130109.pdf\u000a      This press release announces the signing of an agreement between Apitope\u000a      and Merck Serono\u000a      whereby Apitope is eligible to receive up to €154 million in upfront,\u000a      development and milestone\u000a      payments from the development of its ASPI treatment for MS.\u000a    [c] EU Commission CORDIS: http:\/\/cordis.europa.eu\/projects\/rcn\/110669_en.html\u000a      The CORDIS website provides details of the DAVIAD project designed to\u000a      support development of\u000a      ASPI treatments for Graves' disease by Apitope International NV and\u000a      GSK-BIO.\u000a    [d] Circassia web page: http:\/\/www.circassia.co.uk\/company\/investors\/\u000a      This page lists the investors who have provided Circassia with the ~£105\u000a      million in funds required\u000a      to develop ASPI treatments for allergic disorders.\u000a    [e] ImmuPharma web page: http:\/\/www.immupharma.org\/news\/2013\u000a      This page refers to the £50 million facility allowing ImmuPharma to\u000a      complete Phase III\u000a      development of its ASPI approach to the treatment of SLE.\u000a    [f] Andromeda Biotech web page: http:\/\/www.andromedabio.com\/page.php?pageID=67\u000a      This page refers to the $170 million investment into the Diapep ASPI\u000a      treatment for type I diabetes\u000a      by TEVA pharmaceutical industries Ltd.\u000a    [g] Apitope web page: http:\/\/www.apitope.com\/News\/index.html\u000a      This press release announces the phase II development the Apitope approach\u000a      to ASPI for MS by\u000a      Merck Serono (EMD Serono).\u000a    [h] Koffeman, E.C., Genovese, M., Amox, D., Keogh, E., et al.\u000a      Epitope-specific immunotherapy of\u000a      rheumatoid arthritis: Clinical responsiveness occurs with immune deviation\u000a      and relies on the\u000a      expression of a cluster of molecules associated with T cell tolerance in a\u000a      double-blind, placebo-controlled,\u000a      pilot phase II trial. Arthritis & Rheumatism 60, 3207-3216\u000a      (2009) PMID: 19877047\u000a      This paper describes the phase II development of dnaJP1, the ASPI approach\u000a      for the treatment of\u000a      rheumatoid arthritis.\u000a    [i] Prakken, B.J., et al. Peptide-induced nasal tolerance for a\u000a      mycobacterial heat shock protein 60\u000a      T cell epitope in rats suppresses both adjuvant arthritis and\u000a      nonmicrobially induced\u000a      experimental arthritis. Proc Natl Acad Sci U S A 94, 3284-3289\u000a      (1997) PMID: 9096385\u000a      This paper refers to the ASPI work of Professor Wraith's laboratory in\u000a      Cambridge that provided the\u000a      motivation for development of dnaJP1 for the treatment of rheumatoid\u000a      arthritis.\u000a    [j] Markowitz, C. Dirucotide (MBP8298) for the treatment of multiple\u000a      sclerosis. Therapy 5, 605-612\u000a      (2008) DOI: 10.2217\/14750708.5.5.605\u000a      This paper reviews phase I and II data on Dirucotide, an ASPI for MS.\u000a    [k] Warren, K.G., Catz, I., Ferenczi, L.Z. & Krantz, M.J. Intravenous\u000a      synthetic peptide MBP8298\u000a      delayed disease progression in an HLA Class II-defined cohort of patients\u000a      with progressive\u000a      multiple sclerosis: results of a 24-month double-blind placebo-controlled\u000a      clinical trial and 5\u000a      years of follow-up treatment. Eur J Neurol 13, 887-895 (2006)\u000a      PMID: 16879301\u000a      This paper refers to the ASPI work of Professor Wraith's laboratory in\u000a      Cambridge that provided\u000a      support for development of Dirucotide for the treatment of MS.\u000a    [l] Ben-David, H., Sela, M. & Mozes, E. Down-regulation of\u000a      myasthenogenic T cell responses by a\u000a      dual altered peptide ligand via CD4+CD25+-regulated events leading to\u000a      apoptosis. Proc Natl\u000a        Acad Sci U S A 102, 2028-2033 (2005) PMID: 15677327\u000a      This paper refers to the ASPI work of Professor Wraith's laboratory in\u000a      Bristol that provided insight\u000a      into the mechanism of ASPI for the treatment of autoimmune diseases.\u000a    \u000a    ","Title":"\u000a    New businesses, commercial investment and adoption of new technology\u000a      result from antigen-specific peptide immunotherapy development.\u000a    ","UKLocation":[{"GeoNamesId":"2653941","Name":"Cambridge"},{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Developed by the University of Bristol, Antigen-Specific Peptide\u000a      Immunotherapy (ASPI) is a unique\u000a      approach to treating autoimmune diseases and allergies that selectively\u000a      targets and effectively\u000a      neutralises the underlying causes of these conditions. ASPI does not\u000a      appear to have the damaging\u000a      side effects of other treatments for these diseases, making it an\u000a      attractive technology from both a\u000a      commercial and health perspective.\u000a    Autoimmune disease is triggered by our immune system incorrectly\u000a      perceiving one of the proteins\u000a      or tissues that compose our bodies as a threat. For example, multiple\u000a      sclerosis (MS) is primarily\u000a      caused by immune cells attacking myelin, a group of proteins (MBP, PLP and\u000a      MOG) that insulate\u000a      the neurons within our brain and spinal cord. In 1998 Professor David\u000a      Wraith (Professor of\u000a      Experimental Pathology, 1995 to present) and Dr Steven Anderton (Research\u000a      Associate in\u000a      Pathology and Microbiology 1995 to 2000) presented research carried out at\u000a      the University of\u000a      Bristol demonstrating that treatment with select, soluble peptides,\u000a      derived from myelin, inhibited\u000a      disease progression in a mouse model of MS.[1] These peptides were\u000a      identified as being the\u000a      specific (antigenic) regions of myelin that aberrant immune cells react\u000a      against.\u000a    That same year Professor Wraith also identified that treatment with just\u000a      one of these peptides was\u000a      able to protect all the components of myelin from immune attack.[2] This\u000a      cross-protective effect\u000a      suggested these peptides could be a powerful therapeutic agent in the\u000a      treatment of complex, multi-antigen\u000a      immune disorders.\u000a    Further research carried out at the University of Bristol established the\u000a      key requirements for\u000a      identifying and designing these therapeutic peptides. In a 2002 paper,\u000a      Professor Wraith and his\u000a      team revealed that in order for a peptide to suppress disease it must be\u000a      1) able to interact directly\u000a      with immune cell receptors without any additional processing by the body,\u000a      2) in a conformation that\u000a      mimics the form naturally created by cellular breakdown of the original\u000a      target protein.[3]\u000a    In 2003, working with Dr Anette Sundstedt, a research fellow in his\u000a      laboratory at the University of\u000a      Bristol, Professor Wraith discovered that these therapeutic peptides\u000a      generated a unique population\u000a      of immune cells within treated mice.[4] Referred to as T-regulatory cells\u000a      (Tregs) they were able to\u000a      specifically suppress the immune response against myelin. Of key\u000a      commercial interest, it was\u000a      found that this tolerising effect only persisted with succeeding\u000a      administrations of peptide.[4]\u000a    Summarised in a 2005 seminal paper,[5] Professor Wraith's research at the\u000a      University of Bristol\u000a      established the medical potential of ASPI, the means to create these\u000a      therapeutic peptides and the\u000a      mechanism by which they worked.\u000a    In 2008 Apitope, a University of Bristol spinout company founded by\u000a      Professor Wraith, carried out\u000a      a study in which six human MS patients were treated with ATX-MS-1467.\u000a      These preliminary data\u000a      showed the peptides to be safe and well tolerated with preliminary\u000a      evidence of efficacy.[6] A further\u000a      trial in relapsing remitting MS patients (43 subjects) has confirmed that\u000a      the treatment is safe.\u000a      Examination of the MRI results demonstrated a significant decrease in the\u000a      number of contrast-enhancing\u000a      brain lesions in patients with relapsing multiple sclerosis treated by\u000a      intradermal injection\u000a      of ATX-MS-1467 (http:\/\/www.apitope.com\/News\/index.html). These encouraging\u000a      results have\u000a      provided the rationale for continuing Phase II trials in MS.\u000a    "},{"CaseStudyId":"40150","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Annually, over 1 million people worldwide undergo arthroplasty. The use\u000d\u000a      of metal-on-metal bearing surfaces increased rapidly until 2008\/2009, when\u000d\u000a      it represented about 35% of hip replacements in the US and 20% of hip\u000d\u000a      replacements in the UK. Research from the University of Bristol first\u000d\u000a      raised concerns about the biological effects of these implants in 1994 and\u000d\u000a      went on to identify potential local and systemic problems culminating in\u000d\u000a      the largest epidemiological studies of these implants ever published,\u000d\u000a      which showed unequivocally that these implants fail at an unacceptably\u000d\u000a      high rate. These two Lancet publications drew the public's as well as the\u000d\u000a      regulatory bodies' attention to the problem, resulting in extensive\u000d\u000a      worldwide media coverage in print, radio and television, including BBC\u000d\u000a      national news, the cover of the Lancet and Radio 4's Today programme. The\u000d\u000a      University of Bristol research has led to the issuing of guidance from a\u000d\u000a      number of sources worldwide regarding the choice of implants for total hip\u000d\u000a      replacement and the follow-up regime of patients with implants at high\u000d\u000a      risk of failure in situ. The dramatic decrease in use of these prostheses,\u000d\u000a      consequent on our work, will save countless patients from unnecessary\u000d\u000a      suffering, complex revision surgery and vast cost in healthcare resources\u000d\u000a      and societal impact. \u000d\u000a    Chief Medical Officer guidance\u000d\u000a    On the 12 March 2012, in direct response to and quoting our Lancet\u000d\u000a      publication, the Chief Medical Officer and the Medical Director for NHS\u000d\u000a      England wrote to all Chief Executives of NHS Trusts, Strategic Health\u000d\u000a      Authorities and independent hospitals advising them on implant choice[a]\u000d\u000a      This advice, empowered by the research of the University of Bristol, has\u000d\u000a      contributed to a worldwide decline in the use of metal-on-metal hip\u000d\u000a      replacements and they now make up less than 1% of hip replacements\u000d\u000a      performed in England and Wales.[b] The worldwide trend followed the UK\u000d\u000a      lead in the use of these implants and the advice given by the Chief\u000d\u000a      Medical Officer directly cited the research of the University of Bristol.\u000d\u000a    Regulatory Body and Learned Society Advice: UK\u000d\u000a    Various bodies in the UK have issued advice regarding the long-term\u000d\u000a      systemic risks of exposure to metal wear products from Orthopaedic\u000d\u000a      implants and the risk of the early need for revision in metal-on-metal\u000d\u000a      bearings. Partly as a result of research from the University of Bristol,\u000d\u000a      the MHRA issued updated advice to surgeons that patients with\u000d\u000a      metal-on-metal hip replacements should be monitored annually for the life\u000d\u000a      of the hip replacement.[c,d] Similar guidance has been issued by both the\u000d\u000a      British Hip Society [e] and the British Orthopaedic Association.[f].\u000d\u000a      Accordingly, long-term annual follow-up, with monitoring of metal ion\u000d\u000a      levels and cross-sectional imaging as dictated by symptoms and individual\u000d\u000a      patient risk, is now standard practice in the UK. NICE has recently\u000d\u000a      circulated draft recommendations based on our publications. These\u000d\u000a      recommend against using metal-on-metal bearings. The definitive guidance\u000d\u000a      is due in 2014.\u000d\u000a    European Commission\u000d\u000a    The European Commission has asked the Scientific Committee on Emerging\u000d\u000a      and Newly Identified Health Risks (SCENIHR) to assess the safety of\u000d\u000a      metal-on-metal joint replacements with a particular focus on hip implants.\u000d\u000a      Dr Case is an expert adviser. In the light of the above considerations,\u000d\u000a      SCENIHR is requested to provide a scientific opinion on the safety of\u000d\u000a      metal-on-metal joint replacements with a particular focus on hip\u000d\u000a      implants.[g] The Joint Research Centre scientific and policy report for\u000d\u000a      the European commission on hip replacements wrote in their conclusion\u000d\u000a      \"Long term effects are still not fully assessed especially in terms of\u000d\u000a      carcinogenicity, genotoxicity and reproductive toxicity\".[h] They quoted\u000d\u000a      210 papers, of which six were from the University of Bristol (the most\u000d\u000a      quoted research group).\u000d\u000a    US Food and Drug Administration\u000d\u000a    The FDA has issued guidance to patients who have received a\u000d\u000a      metal-on-metal implant. The advice and guidance issued in the UK as well\u000d\u000a      as similar guidance in Canada and Australia is cited in the report. The\u000d\u000a      FDA recommend follow-up every 1 to 2 years to check on the status of the\u000d\u000a      hip replacement and if any symptoms develop, the use of joint aspiration,\u000d\u000a      cross-sectional imaging and blood metal ion level testing to evaluate the\u000d\u000a      function of the joint. They further note that implants may have an effect\u000d\u000a      on general health, including hypersensitivity reactions, cardiomyopathy,\u000d\u000a      neurological and psychological changes, and renal and thyroid function\u000d\u000a      impairment.[i]\u000d\u000a    Other International Regulatory Bodies\u000d\u000a    Citing the research from the University of Bristol regarding the risk of\u000d\u000a      cancer following metal-on-metal joint replacement,[8] as well as the\u000d\u000a      guidance issued by the MHRA, the Therapeutic Goods Administration (TGA) of\u000d\u000a      Australia has recommended a follow-up regime for patients with\u000d\u000a      metal-on-metal joint replacements that includes annual or more frequent\u000d\u000a      follow ups, the use of cross sectional imaging as well as plain\u000d\u000a      radiography and the measurement of blood metal ion levels routinely as\u000d\u000a      part of follow-up.[j] The TGA recommends revision surgery if there are any\u000d\u000a      symptoms, imaging abnormalities or where metal ion levels are rising.\u000d\u000a      Health Canada issued guidance in May 2012 advising annual follow-up of\u000d\u000a      patients and the use of cross-sectional imaging and blood metal ion level\u000d\u000a      analysis where there are any symptoms or physical examination\u000d\u000a      abnormalities.[k]\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research into the field of metal-on-metal (MoM) arthroplasty (joint\u000d\u000a      replacement) conducted at the University of Bristol in conjunction with\u000d\u000a      the National Joint Registry of England and Wales (NJR) has led to a\u000d\u000a      fundamental change in the practice of arthroplasty around the world and in\u000d\u000a      the clinical follow up of patients. High failure rates have been\u000d\u000a      identified nationally in England and Wales for MoM total hip arthroplasty\u000d\u000a      and certain designs of resurfacing arthroplasty in work conducted by our\u000d\u000a      department. Deleterious systemic effects of wear debris produced by these\u000d\u000a      implants have also been identified by our research. The use of these\u000d\u000a      devices has declined from 14% of procedures in 2008 to less than 1% in\u000d\u000a      2012. Citing our research, national bodies including NICE (2014), the MHRA\u000d\u000a      (2011 & 2012), the UK Department of Health (2012), British Orthopaedic\u000d\u000a      Association (2011 & 2012), NJR (2012), British Hip Society (2011 &\u000d\u000a      2012) and the US Food and Drug Administration (FDA) (2013) have issued\u000d\u000a      guidance suggesting the restricted use of such devices or close\u000d\u000a      surveillance of patients in whom these devices have been implanted.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Bristol\u000d\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Case CP, Langkamer VG, James C, Palmer MR, Kemp AJ, Heap PF, et al.\u000d\u000a      Widespread dissemination of metal debris from implants. J Bone Joint Surg\u000d\u000a      Br. 1994 Sep;76(5):701-12. PMID: 8083255\u000d\u000a    \u000a\u000a[2] Case CP, Langkamer VG, Howell RT, Webb J, Standen G, Palmer M, et al.\u000d\u000a      Preliminary observations on possible premalignant changes in bone marrow\u000d\u000a      adjacent to worn total hip arthroplasty implants. Clin Orthop Relat Res.\u000d\u000a      1996 Aug;(329 Suppl):S269-79. PMID: 8769341\u000d\u000a    \u000a\u000a[3] Davies AP, Sood A, Lewis AC, Newson R, Learmonth ID, Case CP.\u000d\u000a      Metal-specific differences in levels of DNA damage caused by synovial\u000d\u000a      fluid recovered at revision arthroplasty. J Bone Joint Surg Br. 2005\u000d\u000a      Oct;87(10):1439-44. PMID: 16189324\u000d\u000a    \u000a\u000a[4] Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, et\u000d\u000a      al. Nanoparticles can cause DNA damage across a cellular barrier. Nat\u000d\u000a      Nanotechnol. 2009 Dec;4(12):876-83. DOI: 10.1038\/nnano.2009.313.\u000d\u000a    \u000a\u000a[5] Sood A, Salih S, Roh D, Lacharme-Lora L, Parry M, Hardiman B, et al.\u000d\u000a      Signalling of DNA damage and cytokines across cell barriers exposed to\u000d\u000a      nanoparticles depends on barrier thickness. Nat Nanotechnol. 2011\u000d\u000a      Dec;6(12):824-33. DOI: 10.1038\/nnano.2011.188.\u000d\u000a    \u000a\u000a[6] Smith AJ, Dieppe PA, Howard PW, Blom AW, National Joint Registry for\u000d\u000a      England and Wales. Failure rates of metal-on-metal hip resurfacings:\u000d\u000a      analysis of data from the National Joint Registry for England and Wales.\u000d\u000a      Lancet. 2012 Nov 17;380(9855):1759-66. DOI: 10.1016\/S0140-6736(12)60989-1\u000d\u000a    \u000a\u000a[7] Smith AJ, Dieppe PA, Vernon K, Porter M, Blom AW, National Joint\u000d\u000a      Registry of England and Wales. Failure rates of stemmed metal-on-metal hip\u000d\u000a      replacements: analysis of data from the National Joint Registry of England\u000d\u000a      and Wales. Lancet. 2012 Mar 31;379(9822):1199-204. DOI:\u000d\u000a      10.1016\/S0140-6736(12)60353-5\u000d\u000a    \u000a\u000a[8] Smith AJ, Dieppe PA, Porter M, Blom AW, National Joint Registry of\u000d\u000a      England and Wales. Risk of cancer in first seven years after\u000d\u000a      metal-on-metal hip replacement compared with other bearings and general\u000d\u000a      population: linkage study between the National Joint Registry of England\u000d\u000a      and Wales and hospital episode statistics. BMJ. 2012;344:e2383. DOI:\u000d\u000a      10.1136\/bmj.e2383\u000d\u000a    \u000aRecent Grants Pertaining to this Work:\u000d\u000a    [9] Medical Research Council, Research Grant. Biological consequences of\u000d\u000a      exposure to prosthetic nanoparticles. PI: Prof Ingham, University of\u000d\u000a      Leeds; Co-applicant: Dr Case. Dates: 1\/6\/2008-31\/5\/2011. Amount: £434,000\u000d\u000a    [10] Arthritis Research UK Project Grant. Is there systemic genotoxicity\u000d\u000a      after hip replacement using resurfacing arthroplasty? PI: Dr Case. Dates:\u000d\u000a      08\/10\/2009 - 05\/2011. Amount: £100,124\u000d\u000a    [11] Furlong Foundation. Could physiologically relevant orthopaedic ions\u000d\u000a      cause indirect DNA and chromosome damage to human embryonic stem cells\u000d\u000a      across a trophoblast cell barrier? PI: Dr Case. Dates: 1\/1\/2011-2014.\u000d\u000a      Amount: £60,000\u000d\u000a    [12] Medical Research Council, Research Grant. Dissecting mechanisms of\u000d\u000a      nanoparticle-mediated foetal toxicity. PI: Dr Case. Dates:\u000d\u000a      1\/10\/2011-1\/10\/2015. Amount: £82,000\u000d\u000a    [13] Medical Research Council, Research Grant. Use of nanoparticles to\u000d\u000a      deliver growth signals to the placenta. PI: Dr Case. Dates:\u000d\u000a      1\/1\/2013-1\/1\/2016. Amount: £590,168.68\u000d\u000a    [14] National Institute of Health Research Programme Grant. Improving\u000d\u000a      patients' experience and outcome of total joint replacement. PI: Prof\u000d\u000a      Blom. Dates: 2008-2011. Amount: £2,059,777\u000d\u000a    [15] Healthcare Quality Improvement\u000d\u000a        Partnership. Contract to run the National Joint Registry statistical\u000d\u000a      support and analysis programme. PI: Prof Blom. Dates: 2011-2014. Amount:\u000d\u000a      £0.6m.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"}],"Sources":"\u000d\u000a    [a] Davies S, Keogh B. Metal on Metal Hip Replacements. Department of\u000d\u000a      Health; 2012 Mar. Major UK Directive citing the research described.\u000d\u000a      Available from: https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/215116\/dh_13\u000a        3035.pdf\u000d\u000a    [b] NJR Steering Committee. National Joint Registry for England and\u000d\u000a      Wales: 9th Annual Report. njrcentre.org.uk. NJR Steering Committee; 2012.\u000d\u000a      Available from: http:\/\/www.njrcentre.org.uk\/njrcentre\/Reports,PublicationsandMinutes\/Annualreports\/tabid\/86\/Default.aspx.\u000d\u000a      Corroborates the major decline in use of metal-on-metal arthroplasty.\u000d\u000a    [c] MHRA Press Release. mhra.gov.uk. London: Medicines and Healthcare\u000d\u000a      Products Regulatory Agency; 2012. Available from: http:\/\/www.mhra.gov.uk\/home\/groups\/comms-po\/documents\/news\/con143785.pdf.\u000d\u000a      MHRA stipulation of need for annual monitoring.\u000d\u000a    [d] Metal-on-Metal Hip Implants [Internet]. Medicines and Healthcare\u000d\u000a      products Regulatory Agency. London; [cited 2013 Aug 19]. Available from: http:\/\/www.mhra.gov.uk\/Safetyinformation\/Generalsafetyinformationandadvice\/Product-\u000aspecificinformationandadvice\/Product-specificinformationandadvice-M-T\/Metal-on-\u000a        metalhipimplants\/. Stipulates need for annual monitoring of\u000d\u000a      metal-on-metal arthroplasty.\u000d\u000a    [e] Large head metal-on-metal hip implants \"should no longer be used,\"\u000d\u000a      surgeons say [Internet]. Arthritis Research UK. 2012 [cited 2013 Aug 19].\u000d\u000a      Available from: http:\/\/www.arthritisresearchuk.org\/news\/general-news\/2012\/march\/06-mar-large-head-\u000a        metalonmetal-hip-implants-should-no-longer-be-used-surgeons-say.aspx\u000d\u000a    [f] Dias J. Metal on Metal Hip Replacements — The Facts [Internet].\u000d\u000a      British Orthopaedic Association. London; [cited 2013 Aug 19]. From: http:\/\/www.boa.ac.uk\/PI\/Pages\/Metal-on-\u000a        Metal.aspx. Professional organisation stipulation for annual\u000d\u000a      monitoring.\u000d\u000a    [g] Scientific Committee on Emerging and Newly Identified Health Risks\u000d\u000a      Request for a scientific opinion on the safety of metal-on-metal joint\u000d\u000a      replacements with a particular focus on hip implants [Internet]. Brussels:\u000d\u000a      European Commission; 2013 Mar. Available from:\u000d\u000a      http:\/\/ec.europa.eu\/health\/scientific_committees\/emerging\/docs\/scenihr_q_033.pdf\u000d\u000a    [h] Holzwarth U, Cotogno G. JRC Scientific and Policy Reports: Total Hip\u000d\u000a      Arthroplasty [Internet]. Luxembourg: European Commission; 2012 pp. 1-60.\u000d\u000a      Report No.: JRC72428. Available from: http:\/\/ihcp.jrc.ec.europa.eu\/our_activities\/public-health\/hip-prostheses-new-jrc-report\/.\u000d\u000a      European Union statement on metal-on-metal arthroplasty ([g] and [h]).\u000d\u000a    [i] Metal-on-Metal Hip Implants. fda.gov. Silver Spring: US Food and Drug\u000d\u000a      Administration; 2013. FDA statement on metal-on-metal arthroplasty.\u000d\u000a      Available from: http:\/\/www.fda.gov\/MedicalDevices\/ProductsandMedicalProcedures\/ImplantsandProsthetics\/\u000a        MetalonMetalHipImplants\/ucm241604.htm\u000d\u000a    [j] Metal-on-Metal Hip Replacement [Internet]. Therapeutic Goods\u000d\u000a      Administration, Department of Health and Aging, Australian Government;\u000d\u000a      2012 Sep. Available from: http:\/\/www.tga.gov.au\/hp\/information-devices-mom-hip-implants.htm\u000d\u000a    [k] Metal-on-Metal Hip Implants — Information for Orthopaedic Surgeons\u000d\u000a      Regarding Patient Management Following Surgery [Internet]. Ottawa: Health\u000d\u000a      Canada, Government of Canada; 2012. Available from: http:\/\/www.healthycanadians.gc.ca\/recall-alert-rappel-avis\/hc-\u000a        sc\/2012\/14120a-eng.php. Australian [j] and Canadian [k] statements.\u000d\u000a    ","Title":"\u000d\u000a    Substantial changes in worldwide healthcare policy and the practice of\u000d\u000a      joint replacement result from research into the failure rates of and\u000d\u000a      systemic effects of metal-on-metal hip replacements.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    University of Bristol research concerning MoM arthroplasty has followed\u000d\u000a      three arms: epidemiology (led by Professor Blom), clinical (led by\u000d\u000a      Professor Blom and Dr Case) and basic science (led by Dr Case). Professor\u000d\u000a      Blom is an orthopaedic surgeon and Head of the group, Dr Case is a\u000d\u000a      Consultant Senior Lecturer; both have been employed at the University\u000d\u000a      throughout the period of the REF.\u000d\u000a\u0009The University's research into the field\u000d\u000a      began in 1994 when we demonstrated widely-disseminated metal wear\u000d\u000a      particles from patients with hip implants post-mortem in the local\u000d\u000a      tissues, lymphatic system, liver, spleen and brain when compared to\u000d\u000a      controls without implants.[1] This raised the possibility of long-term\u000d\u000a      deleterious effects in these patients from exposure to metals, as has been\u000d\u000a      highlighted by the recent concerns of the regulatory bodies in Europe and\u000d\u000a      the US (European Commission and FDA). Our follow-up study published in\u000d\u000a      1996 demonstrated an increase in chromosomal aberrations in local soft\u000d\u000a      tissues for patients with implants in situ when compared with those with\u000d\u000a      no implant in situ and clonal lymphocyte expansion in 2\/21 of these\u000d\u000a      patients with more than 10 years follow-up.[2] Further studies published\u000d\u000a      between 2001 and 2005 demonstrated increased levels of aneuploidy (three\u000d\u000a      fold) and chromosomal translocations (two-fold) in the peripheral blood\u000d\u000a      lymphocytes of patients with hip implants in situ. The level of damage\u000d\u000a      appeared to be influenced by the alloy used (titanium alloys leading to\u000d\u000a      aneuploidy but no translocations, cobalt-chrome (CoCr) leading to both and\u000d\u000a      stainless steel not leading to either). These effects were observed over\u000d\u000a      periods ranging from two years after implantation of a well-fixed device\u000d\u000a      to 11 years after implantation at revision for a loose device. Wear debris\u000d\u000a      collected from such loose implants were observed to cause the same types\u000d\u000a      of chromosomal aberrations in human cells in tissue culture.[3] Recent\u000d\u000a      studies in 2009, 2010 and 2011 have shown that cobalt chrome nanoparticles\u000d\u000a      can cause chromosome damage in human cells including human embryonic stem\u000d\u000a      cells across a placental cell barrier and can cause DNA damage in a foetus\u000d\u000a      in vivo.[4,5] This raises the possibility of teratogenicity in the baby of\u000d\u000a      a woman with a hip replacement in situ. The work described in the period\u000d\u000a      2008-2011 has been led by the University of Bristol and conducted in\u000d\u000a      collaboration with a number of units including Professor Ingham at the\u000d\u000a      University of Leeds.\u000d\u000a    Allied to this basic science approach to researching direct cellular\u000d\u000a      effects of wear debris from total hip replacement, we have studied the\u000d\u000a      epidemiological evidence regarding MoM bearing surfaces in comparison with\u000d\u000a      the alternative bearing surfaces in use. We hold the contract for the\u000d\u000a      analysis of the NJR, the largest joint arthroplasty database in the world.\u000d\u000a      Research on 434,560 primary hip replacements, of which 31,932 were\u000d\u000a      resurfacings, demonstrated that the failure rates of hip replacement were\u000d\u000a      higher for resurfacing than for conventional metal-on-polyethylene (MoP)\u000d\u000a      hip replacement at five years.[6] Failure rates were much higher in women\u000d\u000a      and in smaller bearing sizes for resurfacing (predicted five-year failure\u000d\u000a      rates for women by head size: 8.3% (95% confidence interval 7.2-9.7) with\u000d\u000a      a 42mm head, 6.1% (5.3-7.0) with a 46mm head and 1.5% (0.8-2.6) with a\u000d\u000a      28mm MoP hip replacement). In men with resurfacings, higher failure rates\u000d\u000a      were observed with smaller joint heads (4.1% (3.3-4.9) with a 46mm head,\u000d\u000a      2.6% (2.2-3.1) with a 54mm head and 1.9% (1.5-2.4) with a MoP hip\u000d\u000a      replacement), while rates of failure were similar between larger\u000d\u000a      resurfacings and total hip replacement, only 23% of men had these size\u000d\u000a      implants put in. When total hip replacements with different bearing\u000d\u000a      surfaces were analysed, higher failure rates were observed in larger\u000d\u000a      bearing MoM total hip replacements when compared to the alternatives.\u000d\u000a      Whilst this failure rate increased as head size increased, the opposite\u000d\u000a      pattern was seen in ceramic-on-ceramic total hip replacements.[7] In\u000d\u000a      response to a request from the MHRA, we analysed the risk of developing\u000d\u000a      specific and all cancers after metal hip replacement with MoM bearing\u000d\u000a      surfaces and found no increase in cancers up to 7 years after surgery\u000d\u000a      compared with the general population and alternative bearings.[8]\u000d\u000a    "},{"CaseStudyId":"40151","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    EtxB is a first in class disease-modifying therapy, with potential\u000d\u000a      utility across a range of human\u000d\u000a      diseases in which there is a unmet need: 125 million people suffer from\u000d\u000a      psoriasis worldwide[a];\u000d\u000a      approximately 5.5 million people in the UK are being treated for\u000d\u000a      asthma;[b] and rheumatoid arthritis\u000d\u000a      affects approximately 0.5-1.0% of the population.[c] These and other\u000d\u000a      inflammatory diseases are\u000d\u000a      currently treated with chronically administered non-specific drugs, which\u000d\u000a      primarily control damage\u000d\u000a      rather than impacting on the underlying drivers of disease. In contrast, a\u000d\u000a      short course of EtxB can\u000d\u000a      turn off these processes for long periods,[1,4,6] resetting the balance\u000d\u000a      between inflammation and\u000d\u000a      normal physiology.[4,5] This is a novel and exciting new paradigm for\u000d\u000a      treatment.\u000d\u000a    Williams spun out the EtxB patent portfolio (1999), subsequently rolled\u000d\u000a      into the formation of Trident\u000d\u000a      Pharmaceuticals Inc,[d] established in 2006 to bring EtxB (company code\u000d\u000a      HF1020) through Phase\u000d\u000a      II trials before seeking a large pharmaceutical partner. Williams remains\u000d\u000a      an integral part of the\u000d\u000a      team and KWS (see below) has performed all the preclinical work on EtxB.\u000d\u000a      All 11 substantiating\u000d\u000a      papers cited on the Trident website were published by Williams. Trident\u000d\u000a      generated GMP material\u000d\u000a      (2008-2011) and tested this in formal GLP acute and repeat dose toxicology\u000d\u000a      studies in rodents and\u000d\u000a      primates (completed in 2011). It was found to be safe and in 2011 the MHRA\u000d\u000a      approved a clinical\u000d\u000a      trials application (CTA) for a Phase 1a study in healthy volunteers.\u000d\u000a      Following completion of Phase\u000d\u000a      Ia, in 2013 the MHRA approved a CTA for a Phase II study [text removed\u000d\u000a        for publication]. As with\u000d\u000a      all new drugs, the process of getting them to market takes years, but EtxB\u000d\u000a      has already passed\u000d\u000a      many of the major hurdles. Press coverage of its potential impact included\u000d\u000a      articles in international\u000d\u000a      newspapers, television and radio.[e] Other companies including Hunter\u000d\u000a      Immunology are\u000d\u000a      developing approaches to mimic the effects of EtxB using novel peptides\u000d\u000a      that target the same\u000d\u000a      receptor.[f]\u000d\u000a    The underlying research and the experience gained by Williams of\u000d\u000a      developing EtxB directly gave\u000d\u000a      rise to the formation of KWS BioTest Ltd. Coverage of his work on EtxB\u000d\u000a      established him as a\u000d\u000a      leader in disease efficacy and mechanism of action studies, and repeated\u000d\u000a      requests for work came\u000d\u000a      in from companies wanting to access these models:\u000d\u000a    \u000d\u000a      Williams formed KWS BioTest in 2004,[g] with Professor Day (veterinary\u000d\u000a        pathology).\u000d\u000a      KWS received £200k of investment from a Government Challenge Fund[h]\u000d\u000a        to employ\u000d\u000a        scientists and commercial management and respond to these requests.\u000d\u000a      KWS is now a leading partner for high quality drug discovery and\u000d\u000a        efficacy in Europe, an\u000d\u000a        achievement that was recognised by the award of the 2012 South West\u000d\u000a        Biomedical iNet\u000d\u000a        award for outstanding business achievement.[i] KWS runs validated in\u000d\u000a          vitro and in vivo\u000d\u000a        models of human disease in inflammation, autoimmunity, pain and\u000d\u000a        infection, all of which are\u000d\u000a        founded on the academic work of the Williams laboratory and other groups\u000d\u000a        within Bristol.\u000d\u000a    \u000d\u000a    The success of KWS is based on offering in-depth scientific expertise and\u000d\u000a      analysis of the sort that\u000d\u000a      is lacking in large contract research organisations, while providing\u000d\u000a      service and data quality that are\u000d\u000a      lacking from academia (ISO9001 accredited, GLP led). These activities have\u000d\u000a      generated substantial\u000d\u000a      commercial impact directly within KWS and for partner companies, and have\u000d\u000a      contributed to the\u000d\u000a      discovery of new drugs now in clinical trials and development (details of\u000d\u000a      which are confidential).\u000d\u000a    Since 2004, KWS has carried out experimental studies for more than 75\u000d\u000a      different companies (39%\u000d\u000a      UK, 44% EU, 12% US, 5% rest-of-the-world; 57% small, 24% medium and 19%\u000d\u000a      large pharma).[j]\u000d\u000a      In the case of small companies, this work has been absolutely critical as\u000d\u000a      they typically lack\u000d\u000a      expertise and facilities to carry out pharmacology testing. In the case of\u000d\u000a      medium and large pharma,\u000d\u000a      partners want the expertise that it can offer, recognising that\u000d\u000a      outsourcing is a more cost-effective\u000d\u000a      and ethical approach to drug discovery.[k]\u000d\u000a    Dr Sean Mason (Senior Group Leader at UCB) stated \"KWS have provided\u000d\u000a        excellent, high quality\u000d\u000a        scientific support for several projects, covering a range of diverse\u000d\u000a        activities including complex\u000d\u000a        immune cell-based assays and imaging studies, which together with their\u000d\u000a        prompt and detailed\u000d\u000a        feedback has benefited several of our projects\". The ability of KWS\u000d\u000a      to provide in vivo efficacy\u000d\u000a      models that are validated with control drugs, and which are run regularly,\u000d\u000a      has a clear 3Rs impact.\u000d\u000a    Since its formation, KWS has expanded and grown as evidenced by:\u000d\u000a    \u000d\u000a      Increased turnover from [text removed for publication].[j].\u000d\u000a      Profits have grown from [text removed for publication].\u000d\u000a      KWS employs [text removed for publication], and during 2012\u000d\u000a        contributed [text removed for\u000d\u000a          publication] of income to the University of Bristol.\u000d\u000a      KWS has become a significant exporter (over [text removed for\u000d\u000a          publication] in the last three\u000d\u000a        years).\u000d\u000a      Strategic partnership with Quotient Bioresearch facilitating further\u000d\u000a        exports from these\u000d\u000a        companies.\u000d\u000a    \u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research into novel immunotherapies has given rise to a novel drug\u000d\u000a      (EtxB), which is now in Phase\u000d\u000a      II clinical trials, and to a profitable contract research company\u000d\u000a      partnering with the pharmaceutical\u000d\u000a      industry to develop their compounds. Trident Pharmaceuticals was formed\u000d\u000a      around patents filed by\u000d\u000a      the University of Bristol, has received investment of [text removed\u000d\u000a       for publication], successfully\u000d\u000a      completed Phase I trials (2011) and is in the midst of Phase IIa trials in\u000d\u000a      humans with inflammatory\u000d\u000a      disease (2013). KWS BioTest arose as a result of the underpinning research\u000d\u000a      and experience\u000d\u000a      gained from developing EtxB, and is now a leading contract research\u000d\u000a      organisation working with\u000d\u000a      pharmaceutical and biotechnology companies developing novel treatments for\u000d\u000a      human disease.\u000d\u000a      KWS has directly contributed to the development of therapies at more than\u000d\u000a      75 different companies,\u000d\u000a      employs 28 people, has exported [text removed for publication] and\u000d\u000a      was 2012 winner of a\u000d\u000a      Biomedical iNet Award for outstanding business achievement.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Bristol\u000d\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    Peer reviewed journal publications\u000d\u000a    30 original articles and 7 refereed reviews since 1992 from the\u000d\u000a        Williams lab relating to the use of\u000d\u000a        EtxB as an immune modulating agent, including:\u000d\u000a    \u000a[1] Williams, N.A., Stasuik, L., Nashar, T.O., Richards, C.M., Lang,\u000d\u000a      A.K., Day, M.J. & Hirst, T.R.\u000d\u000a      (1997). Prevention of autoimmune disease due to lymphocyte modulation by\u000d\u000a      the B-subunit of\u000d\u000a      Escherichia coli heat-labile enterotoxin. Proc Natl Acad Sci U\u000d\u000a        S A. 94:5290-5295 [cited 53 times,\u000d\u000a        3.31\/year] PMID: 9144230\u000d\u000a    \u000a\u000a[2] Williams, N.A., Hirst, T.R. & Nashar, T.O. (1999). Immune\u000d\u000a      modulation by the cholera-like\u000d\u000a      enterotoxins: from adjuvant to immunotherapeutic. Immunol Today 20:95-101\u000d\u000a      [cited 172 times,\u000d\u000a        12.29\/year]. PMID: 10098329\u000d\u000a    \u000a\u000a[3] Richards, C.M., Aman, T., Hirst, T.R., Hill, T.J. & Williams,\u000d\u000a      N.A. (2001) Protective mucosal\u000d\u000a      immunity to ocular herpes simplex virus type-1 infection in mice using Escherichia\u000d\u000a        coli heat-labile\u000d\u000a      enterotoxin B-subunit as an adjuvant. J Virol 75:1664-1671\u000d\u000a      PMID: 11160664\u000d\u000a    \u000a\u000a[4] Luross, J.A., Heaton, C.P.E., Hirst, T.R., Day, M.J. & Williams,\u000d\u000a      N.A. (2002) Escherichia coli\u000d\u000a      heat-labile enterotoxin B-subunit prevents autoimmune arthritis through\u000d\u000a      the induction of regulatory\u000d\u000a      CD4+ T cells. Arthritis Rheum 46:1671-1682 PMID: 12115200\u000d\u000a    \u000a\u000a[5] Donaldson DS, Tong KK, Williams NA. (2011) Mucosal administration of\u000d\u000a      the B subunit of E. coli\u000d\u000a      heat-labile enterotoxin promotes the development of Foxp3-expressing\u000d\u000a      regulatory T cells. Mucosal\u000d\u000a        Immunol 4(2):227-238 PMID: 20944556\u000d\u000a    \u000a\u000a[6] Donaldson, DS, Apostolaki M, Bone HK, Richards CM, Williams NA.(2013)\u000d\u000a      The Escherichia coli\u000d\u000a      heat-labile enterotoxin B subunit protects from allergic airway disease\u000d\u000a      development by inducing\u000d\u000a      CD4+ regulatory T cells. Mucosal Immunol 6:535-546. PMID:\u000d\u000a      23032791\u000d\u000a    \u000aPeer reviewed grants\u000d\u000a    £2.66m peer-reviewed and £1.91m industry funding since 1992 to the\u000d\u000a        Williams laboratory relating\u000d\u000a        to investigations into the use of EtxB as an immune modulating agent,\u000d\u000a        including:\u000d\u000a    [7] The Wellcome Trust — £280,492 \"Receptor mediated effects on molecular\u000d\u000a      and cellular\u000d\u000a      mechanisms in antigen presentation, processing and the generation of\u000d\u000a      immunological memory\u000d\u000a      responses by Escherichia coli enterotoxin B-subunits (EtxB)\" March\u000d\u000a      1997-July 2001.\u000d\u000a    [8] The Medical Research Council — £307,544 \"A generic carrier for\u000d\u000a      targeted delivery into both\u000d\u000a      class I and class II processing and presentation pathways\" Jun 1999-May\u000d\u000a      2002.\u000d\u000a    [9] The Wellcome Trust — £275,917 \"Cell signals underlying the\u000d\u000a      immunomodulatory properties of E.\u000d\u000a        coli heat-labile enterotoxin\" January 1999-December 2002.\u000d\u000a    [10] The Wellcome Trust — £275,762 \"Control of ocular HSV-1 infection\u000d\u000a      using mucosal vaccination\u000d\u000a      strategies which stimulate Th1 or Th2 dominated immune responses\" May\u000d\u000a      2000-April 2003.\u000d\u000a    [11] Cancer Research Technology (CRUK) — £236,519 EtxB; a novel approach\u000d\u000a      to cancer\u000d\u000a      vaccinations and therapy July 2007-June 2009.\u000d\u000a    Patents arising, licensed to Trident Pharmaceuticals Inc.\u000d\u000a    [12] Therapeutic agents and autoimmune diseases; Priority date: 5\u000d\u000a      July 1995 (UK)\u000d\u000a      Owner: University of Bristol, PCT Number: PCT\/GB96\/01614\u000d\u000a      Inventors: Williams, N.A., Hirst, T.R. & Nashar, T.O.\u000d\u000a      Status: Granted Australia, Austria, Belgium, Canada, China, Czech\u000d\u000a      Republic, Denmark, European\u000d\u000a      Patent Convention, Finland, France, Germany, Greece, Hungary, Ireland,\u000d\u000a      Italy, Luxembourg,\u000d\u000a      Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Russian\u000d\u000a      Federation, Singapore,\u000d\u000a      Spain, Sweden, Switzerland, United Kingdom, United States\u000d\u000a    [13] Agent for treating allergic and hypersensitivity condition; Priority\u000d\u000a        date: 9 January 1998 (UK)\u000d\u000a      Owner: University of Bristol, PCT Number: PCT\/GB99\/00070\u000d\u000a      Inventors: Williams, N.A., Hirst, T.R. & Bienenstock, J.\u000d\u000a      Status: Granted Australia, Austria, Belgium, Canada, Cyprus,\u000d\u000a      Denmark, European Patent\u000d\u000a      Convention, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg,\u000d\u000a      Monaco, Netherlands,\u000d\u000a      New Zealand, Portugal, Spain, Sweden, Switzerland, United Kingdom\u000d\u000a    [14] Vaccination; Priority date: 8 May 1998 (UK), Owner:\u000d\u000a      University of Bristol\u000d\u000a      PCT Number: PCT\/GB99\/01461\u000d\u000a      Inventors: Williams, N.A. & Hirst, T.R. (Morgan, A.J., Wilson,\u000d\u000a      A.D. & Bird, L.)\u000d\u000a      Status: Granted Czech Republic, Eurasian Patent Organisation,\u000d\u000a      Israel, Japan, Mexico, US.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    [a] National Psoriasis Foundation http:\/\/www.psoriasis.org\/learn_statistics.\u000d\u000a      Corroborates the\u000d\u000a        prevalence of psoriasis worldwide.\u000d\u000a    [b] Asthma UK http:\/\/www.asthma.org.uk\/news-centre\/facts-for-journalists\/.\u000d\u000a      Corroborates the\u000d\u000a        prevalence and health impact of asthma on the UK population.\u000d\u000a    [c] Center for Disease Control (US) http:\/\/www.cdc.gov\/arthritis\/basics\/rheumatoid.htm#5.\u000d\u000a      Corroborates the global prevalence and health impact of arthritis.\u000d\u000a    [d] Trident Pharmaceuticals Inc. http:\/\/www.tridentpharma.com\/index.html.\u000d\u000a      Main company website\u000d\u000a        for Trident highlighting the current status of the therapy underlining\u000d\u000a        the impact case and\u000d\u000a        demonstrating that this is the sole focus for the company.\u000d\u000a    [e] Television and radio: ITN National News (30 November\u000d\u000a      1999); Radio 4 `Science Now' (January\u000d\u000a      2000); Portuguese National Radio (September 2003); Dutch\u000d\u000a        National Radio (Sept 2003); BBC\u000d\u000a        Radio 5 Live (September 2003). Print media: The Daily Mail\u000d\u000a      (1 December 1999); New\u000d\u000a        Scientist (4 December 1999); The Times (4 February 2000); Vogue\u000d\u000a      (March 2000). Provide\u000d\u000a        evidence of impact in raising public awareness of the health issues and\u000d\u000a        of potential new\u000d\u000a        approaches to developing therapies for human disease.\u000d\u000a    [f] Patent licensed by Hunter Immunology, now Bioxyne. Evidence that\u000d\u000a        the technology pioneered in\u000d\u000a        Bristol has led other companies to adopt similar approaches (commercial\u000d\u000a        impact and impact\u000d\u000a        amongst peers).\u000d\u000a    [g] KWS BioTest http:\/\/www.kwsbiotest.co.uk.\u000d\u000a      Evidence of the current scope of the activities of the\u000d\u000a        spin-out arising from the research and vehicle for the impact.\u000d\u000a    [h] Wyvern Investment Fund http:\/\/www.wyvernfund.com\/.\u000d\u000a      Evidence that KWS received investment\u000d\u000a        from and remains part of the portfolio of companies within the Wyvern\u000d\u000a        Government Challenge\u000d\u000a        Fund (economic impact).\u000d\u000a    [i] Outstanding business award (http:\/\/www.inets-sw.co.uk\/;\u000d\u000a      Drug discovery Impact 1.pdf).\u000d\u000a      Evidence of peer recognition of the Economic and Business Impact of KWS\u000d\u000a        BioTest.\u000d\u000a    [j] KWS Operating Plan summary 2012 (Confidential document that can be\u000d\u000a      provided for audit\u000d\u000a      purposes). Evidence of the economic impact of KWS BioTest\u000d\u000a        (CONFIDENTIAL).\u000d\u000a    [k] Clark DE (2011) Outsourcing lead optimisation: the eye of the storm.\u000d\u000a      Drug Discovery Today\u000d\u000a      16:147-157. DOI: 10.1016\/j.drudis.2010.11.012. Evidence of the growing\u000d\u000a        business and\u000d\u000a        economic need for the services of KWS Biotest from Biotech and\u000d\u000a        Pharmaceutical Companies.\u000d\u000a      PMID: 21145413.\u000d\u000a    ","Title":"\u000d\u000a    Translating research into novel immunotherapies delivers scientific and\u000d\u000a      economic gains for the pharmaceutical\/biotechnology sector in drug\u000d\u000a      discovery.\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Research in Infection and Immunology has long been a major strength\u000d\u000a      within Bristol, which was\u000d\u000a      also one of the first Universities in the UK to organise its support for\u000d\u000a      entrepreneurial activities. Neil\u000d\u000a      Williams (appointment at the University of Bristol initially as a Lecturer\u000d\u000a      in 1991, now as a\u000d\u000a      Professor) collaborated with Hirst (then at University of Kent, but\u000d\u000a      subsequently at the University of\u000d\u000a      Bristol 1996-2003) in seeking to understand the unusual ability of a\u000d\u000a      bacterial protein (EtxB) to\u000d\u000a      stimulate mucosal antibodies (Nashar, PNAS 1992; cited 114 times,\u000d\u000a      6.71\/year). This basic\u000d\u000a      immunological finding had little obvious translational value by itself.\u000d\u000a      However, Williams followed\u000d\u000a      these findings up with studies to determine the effects of EtxB on\u000d\u000a      populations of immune cells. He\u000d\u000a      established a range of cellular assays showing that EtxB caused the\u000d\u000a      activation of B lymphocytes,\u000d\u000a      triggered apoptosis in CD8+ T-cells and modulated CD4+ T-cell activation\u000d\u000a      (Nashar, Int Immunol\u000d\u000a      1996; Immunol 1997). Looking at this range of effects, Williams\u000d\u000a      hypothesised that it may be\u000d\u000a      possible to harness this protein as a novel treatment for human\u000d\u000a      inflammatory diseases.\u000d\u000a    A combination of cell biology studies and in vivo experiments\u000d\u000a      validated the hypothesis, culminating\u000d\u000a      in the ground-breaking discovery that EtxB could completely block the\u000d\u000a      development of disease in\u000d\u000a      the gold standard rodent model of rheumatoid arthritis.[1] The potential\u000d\u000a      to use EtxB as a therapy\u000d\u000a      was patented[12] and a key review foresaw its potential in a range of\u000d\u000a      diseases.[2] Peer-reviewed\u000d\u000a      grant funding directly aimed at determining the therapeutic potential of\u000d\u000a      EtxB and to identify its\u000d\u000a      mechanism of action drove the programme forwards over the following ten\u000d\u000a      years (£2.66m from the\u000d\u000a      MRC, Wellcome Trust, Arthritis Research UK, CRUK and others[7-11]).\u000d\u000a      Further patents were\u000d\u000a      subsequently filed covering the use of EtxB as a treatment for allergic\u000d\u000a      disease[13] and as a\u000d\u000a      modulator for use in a vaccine.[14] Peer-reviewed publications\u000d\u000a      corroborated this potential.[3-6]\u000d\u000a    Investigations of the potential of EtxB as a novel therapy led the\u000d\u000a      Williams laboratory to establish\u000d\u000a      key translational models of human diseases, including type 1 diabetes\u000d\u000a      (Ola, Immunol 2006), colitis\u000d\u000a      and asthma,[6] and to use state-of-the-art techniques to characterise the\u000d\u000a      effects of EtxB on a range\u000d\u000a      of immune parameters underlying disease pathogenesis in these conditions\u000d\u000a      (Plant EJI, 2003; [5]).\u000d\u000a      The research established that EtxB was able to modulate the activity of T\u000d\u000a      regulatory cells following\u000d\u000a      its delivery. Demonstrating this required the development of a range of\u000d\u000a      assay systems, enabling\u000d\u000a      the activation and differentiation of T-cells to be tracked in vivo\u000d\u000a      in rodents, and necessitated their\u000d\u000a      application to diseased animals. These tools were not only critical to\u000d\u000a      uncovering the mechanism of\u000d\u000a      action of EtxB, but also established the Williams laboratory as a centre\u000d\u000a      for the study of immune\u000d\u000a      modulating therapies. The data generated from these endeavours and the\u000d\u000a      resulting reputation of\u000d\u000a      the laboratory provided the springboard for the formation by Williams of\u000d\u000a      KWS BioTest Ltd, which\u000d\u000a      offers these and other models developed following its formation to\u000d\u000a      pharmaceutical and\u000d\u000a      biotechnology companies around the world in support of their drug\u000d\u000a      discovery programmes.\u000d\u000a    "},{"CaseStudyId":"40152","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Impact of CRUK publications on committee invitations and development\u000d\u000a        of clinical trials\u000d\u000a    Publications [1-4] and press releases in the 1990s importantly led to\u000d\u000a      Professor Paraskeva being invited onto several UK national research and\u000d\u000a      trials committees and pharmaceutical scientific advisory committees\u000d\u000a      (Merck), which organised clinical trials, including: Medical Research\u000d\u000a      Council (MRC) Molecular and Cellular Medicine Board (1996-1998); MRC\u000d\u000a      Advisory Board (1998-2003); National Translational Cancer Research Network\u000d\u000a      (NTRAC) Clinical Study Group (2002-2005); UK Co-ordinating Committee on\u000d\u000a      Cancer Research (UKCCCR) Sub-Committee on Colorectal Cancer (1996-2001);\u000d\u000a      National Cancer Research Institute (NCRI) Colorectal Clinical Studies\u000d\u000a      Group (2001-2005); the World Cancer Research Fund International Grant\u000d\u000a      Panel (2010-date).\u000d\u000a    Membership of these committees led to Professor Paraskeva's direct\u000d\u000a      involvement in clinical trials such as the CAPP2 study below.\u000d\u000a    Aspirin significantly reduces colorectal cancer incidence in HNPCC\u000d\u000a        hereditary bowel cancer patients (CAPP2 trial) at very high risk of\u000d\u000a        bowel cancer\u000d\u000a    Professor Paraskeva was a collaborator and on the Data Monitoring\u000d\u000a      Committee of an international trial examining aspirin's ability to reduce\u000d\u000a      bowel cancer incidence in high-risk HNPCC patients published in 2011.[a]\u000a      The study involved 861 people and showed that 600mg of aspirin a day for a\u000d\u000a      mean of 25 months significantly reduced bowel cancer incidence in carriers\u000d\u000a      of hereditary bowel cancer.[a] CAPP2 was the first randomised trial of\u000d\u000a      aspirin as a chemopreventive agent with cancer as the primary endpoint. It\u000d\u000a      is of particular importance since HNPCC is the most common form of\u000d\u000a      hereditary bowel cancer, affecting thousands of people worldwide, and\u000d\u000a      provides a basis for recommendation of aspirin chemoprevention in HNPCC\u000d\u000a      patients as standard of care.[a] This Lancet publication received\u000d\u000a      worldwide TV, radio and newspaper exposure.[b] [c] The Bristol work on\u000d\u000a      apoptosis as a plausible mechanism for the chemopreventive action of\u000d\u000a      aspirin,[3] justifying further trials, continues to be cited in journals\u000d\u000a      such as the Lancet (reference [3]; cited in [d]).\u000d\u000a    Impact of high dietary fibre on reducing the risk of bowel cancer in\u000d\u000a        the general population and increasing public awareness\u000d\u000a    Research from Bristol on dietary fibre and apoptosis [1] [2] has been\u000d\u000a      cited as a plausible mechanism to support the chemopreventive properties\u000d\u000a      of fibre and to justify further research (for example, cited in [e]) and\u000d\u000a      there have been a number of high profile publications reporting that high\u000d\u000a      dietary fibre is associated with a reduced risk of colorectal cancer ([f],\u000d\u000a      and papers cited in [f]). Importantly, the research and subsequent\u000d\u000a      publicity has also influenced global policy on cancer prevention and major\u000d\u000a      public health campaigns (five-a-day) and increasing fibre may be\u000d\u000a      influential in reducing other obesity-related cancers, such as breast\u000d\u000a      cancer.[e-j]\u000d\u000a    Impact of aspirin as an adjuvant therapy for colorectal cancer\u000d\u000a    The finding that aspirin induced apoptosis in adenoma and cancer cells\u000d\u000a      led to the proposal that aspirin be used as an adjuvant to treat bowel\u000d\u000a      cancer and not just in prevention;[3-6] (also see BBA Reviews in Cancer,\u000d\u000a      2006, 1766,104-19).Two independent epidemiological studies in 2009\u000d\u000a      and 2012 involving over 2,000 patients have shown that regular\u000d\u000a      aspirin use after diagnosis of colorectal cancer is associated with lower\u000d\u000a      risk of colorectal cancer-specific and overall mortality. Thus aspirin, as\u000d\u000a      originally hypothesized,[5] [6] shows promise as an adjuvant to cancer\u000d\u000a      therapy [k] as well as in chemoprevention,[a] and has saved a large number\u000d\u000a      of lives of patients with bowel cancer.[k]\u000d\u000a    Impact of aspirin on saving lives in several major cancers, not just\u000d\u000a        colorectal cancer\u000d\u000a      Daily aspirin intake was reported in 2011 to reduce deaths in a\u000d\u000a      number of other human cancers including brain, oesophageal, lung, prostate\u000d\u000a      and stomach cancer, as well as colorectal cancer. The paper concerned\u000d\u000a      (Lancet, 2011,377,31-41) cites the Elwood 2009 Lancet paper,[d] which in\u000d\u000a      turn cites the Paraskeva 1996 Cancer Research paper.[3]\u000d\u000a    Impact of Bristol publications on national and international public\u000d\u000a        awareness and public understanding of cancer prevention\u000d\u000a    The four original publications [1-4] not only led to invitations onto\u000d\u000a      influential committees (see section 4) and involvement in clinical trials\u000d\u000a      (as noted above) but also to the Bristol Beating Bowel Cancer (BBBC)\u000d\u000a      Public Fund Raising Campaign in the late 1990s, run jointly between the\u000d\u000a      University of Bristol and the Cancer Research Campaign (CRC). This led to\u000d\u000a      posters of men's and women's bottoms throughout Bristol and a public\u000d\u000a      campaign to increase awareness of bowel cancer. BBBC raised £1.5m of new\u000d\u000a      money for bowel cancer research, and their appeal was debated favourably\u000d\u000a      in the Houses of Parliament: House\u000a        of Commons Hansard Debates for 6 Jul 1999 (pt 4).\u000d\u000a    The importance of diet and dietary fibre in cancer prevention generally,\u000d\u000a      as well as in bowel cancer, was a successful BBBC public awareness\u000d\u000a      campaign. Professor Paraskeva has given 6-10 public talks per year on\u000d\u000a      cancer awareness and cancer prevention for nearly 30 years. For example,\u000d\u000a      in 2012-13 two public talks given at Bristol's M Shed and\u000d\u000a      Watershed both attracted audiences of more than 100. Every year several\u000d\u000a      dozen members of the public have tours and cancer prevention talks at the\u000d\u000a      Bristol Cancer Research UK Laboratories.\u000d\u000a    International impact of Bristol publications and clinical trials on\u000d\u000a        public understanding\u000d\u000a    International and national radio and newspaper coverage was given to the\u000d\u000a      Bristol fibre and aspirin research publications.[1-4] The research has led\u000d\u000a      to a considerable increase in public awareness of the role of diet and\u000d\u000a      fibre in reducing the risk of bowel cancer and other cancers and has led\u000d\u000a      to NHS Direct [g] and prestigious US agencies (Mayo Clinic [h] and NIH) to\u000d\u000a      recommend a high-fibre diet. The famous `five-a-day' slogan is also linked\u000d\u000a      to dietary fibre. The World Cancer Research Fund, a major international\u000d\u000a      cancer prevention charity, has stated from a recent report that they have\u000d\u000a      found strong evidence that foods containing dietary fibre decrease the\u000d\u000a      risk of bowel cancer and they recommend an increase in dietary fibre.[i]\u000d\u000a      [j]\u000d\u000a    Impact of Bristol's Colon Cancer Group publications on clinical trials\u000d\u000a        development\u000d\u000a    The original four research papers published by the Bristol Cancer\u000d\u000a      Research UK Colorectal Cancer Group, showing that butyrate\/fibre\/aspirin\u000d\u000a      induces apoptosis in human colorectal cancer and adenoma cells [1-4], have\u000d\u000a      been cited over 1,000 times and led to more than 60 publications. They\u000d\u000a      continue to be cited as evidence in discussions of the case for using\u000d\u000a      aspirin for bowel cancer prevention (paper 3 cited in Lancet, 2009 [d]),\u000d\u000a      and in the justification for clinical trials reported above and future\u000d\u000a      such studies.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Thousands of people across the world with a genetic predisposition\u000d\u000a      (HNPCC) to bowel cancer, together with the population at large, have\u000d\u000a      benefited from research on aspirin and dietary fibre undertaken at the\u000d\u000a      University of Bristol since 1993. Clinical trials involving the Bristol\u000d\u000a      group show that the incidence of bowel cancer has fallen in HNPCC patients\u000d\u000a      who take aspirin. Moreover, aspirin use after diagnosis of bowel cancer\u000d\u000a      has reduced colorectal cancer mortality. Furthermore, a high fibre diet\u000d\u000a      also lowers the risk of bowel cancer. These studies led to national public\u000d\u000a      health initiatives (such as the `five-a-day' campaign) that have been\u000d\u000a      instrumental in increasing public awareness of the importance of aspirin\u000d\u000a      and dietary fibre in reducing the risk of bowel cancer, and in\u000d\u000a      establishing international guidelines on dietary advice.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Bristol\u000d\u000a    ","Institutions":[{"AlternativeName":"Bristol (University of)","InstitutionName":"University of Bristol","PeerGroup":"A","Region":"South West","UKPRN":10007786}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a[1] Hague, A., Manning, A., Hanlon, K., Huschtscha, L.I., Hart, D.,\u000d\u000a      Paraskeva, C. (1993). Sodium Butyrate induces apoptosis in Human Colonic\u000d\u000a      Tumour cell lines in a p53 independent pathway: Implications for the\u000d\u000a      possible role of dietary fibre in the prevention of Large Bowel Cancer.\u000d\u000a      Int. J. Cancer, 55, 498-505 (cited >430) (All citations are\u000d\u000a        Web of Science) PMID: 8397167\u000d\u000a    \u000a\u000a[2] Hague, A., Elder, D.J.E., Hicks, D.J., Paraskeva, C. (1995).\u000d\u000a      Apoptosis in colorectal tumour cells: induction by the short chain fatty\u000d\u000a      acids butyrate, propionate and acetate and by the bile salt deoxycholate.\u000d\u000a      Int. J. Cancer, 60, 400-406 (cited >265) PMID: 7829251\u000d\u000a    \u000a\u000a[3] Elder, D.J.E., Hague, A., Hicks, D.J., Paraskeva, C. (1996).\u000d\u000a      Differential growth inhibition by the aspirin metabolite salicylate in\u000d\u000a      human colorectal tumor cell lines: Enhanced apoptosis in carcinoma and in\u000d\u000a      vitro-transformed adenoma relative to adenoma cell lines. Cancer Res., 56,\u000d\u000a      2273-2276. (cited >160) PMID: 8625297\u000d\u000a    \u000a\u000a[4] Elder, D.J.E., Halton, D.E., Hague, A., Paraskeva, C. (1997)\u000d\u000a      Induction of apoptotic cell death in human colorectal carcinoma cell lines\u000d\u000a      by a cyclooxygenase-2 selective non-steroidal anti-inflammatory drug:\u000d\u000a      independence from cyclooxygenase-2 protein expression. Clin. Cancer Res.,\u000d\u000a      3, 1679-1683. (c254) (cited >290) PMID: 9815550\u000d\u000a    \u000a\u000a[5] Elder, D.J.E., Paraskeva, C. (1998) COX-2 inhibitors for colorectal\u000d\u000a      cancer. Nature Medicine, 4 (4), 392-393. PMID: 9546780\u000d\u000a    \u000a\u000a[6] Elder, D.J.E., Paraskeva, C. (1996). Are aspirin and other\u000d\u000a      non-steroidal anti-inflammatory drugs effective in the prevention and\u000d\u000a      treatment of colorectal cancer? Lancet, 348, 485 PMID: 8709821\u000d\u000a    \u000aSelected grants which have supported the work (Total of grants\u000d\u000a      (non-selected) >£7m)\u000d\u000a    Cancer Research UK programme grant: Colorectal Tumour Cell Survival\u000d\u000a        and Chemoprevention (2010-2015)\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Total Grant\u000d\u000a          £1,200,000\u000d\u000a        \u000d\u000a        \u000d\u000a          Grant Holders\u000d\u000a          C. Paraskeva (Director) and A.C. Williams\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Research UK programme grant: Regulation of apoptosis and\u000d\u000a        prevention of colorectal cancer (2006-10)\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Total Grant\u000d\u000a          £1,025000\u000d\u000a        \u000d\u000a        \u000d\u000a          Grant Holders\u000d\u000a          C. Paraskeva (Director) and A.C. Williams\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Research UK Programme Grant: Apoptosis as a target for\u000d\u000a        prevention and therapy in colorectal cancer (2001-06)\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Total Grant\u000d\u000a          £800,000\u000d\u000a        \u000d\u000a        \u000d\u000a          Grant Holders\u000d\u000a          C. Paraskeva (Director) and A.C. Williams\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Research Campaign Programme Grant: Cell and Molecular Biology\u000d\u000a        of Colorectal Cancer (1996-2001)\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Total Grant\u000d\u000a          £650,000\u000d\u000a        \u000d\u000a        \u000d\u000a          Grant Holders\u000d\u000a          C. Paraskeva (Director) and A.C. Williams\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    Cancer Research Campaign Programme Grant: Cell and Molecular Biology\u000d\u000a        of Colorectal Cancer (1993-1996)\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          Total Grant\u000d\u000a          £500,000\u000d\u000a        \u000d\u000a        \u000d\u000a          Grant Holders\u000d\u000a          C. Paraskeva (Director) and A.C. Williams\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    [a] Study corroborating Aspirin significantly reduced bowel cancer\u000d\u000a        incidence in carriers of hereditary bowel cancer: Long-term\u000a        effect of aspirin on cancer risk in carriers of hereditary colorectal\u000d\u000a        cancer: an analysis from the CAPP2 randomised controlled trial PMID:\u000d\u000a      22036019\u000d\u000a    [b] National Cancer Institute website publicising above paper (a)\u000d\u000a        showing aspirin reduces bowel cancer incidence: http:\/\/www.cancer.gov\/ncicancerbulletin\/110111\/page4\u000d\u000a    [c] BBC news bulletin publicising above paper (a) showing aspirin\u000d\u000a        reduces bowel cancer incidence: http:\/\/www.bbc.co.uk\/news\/health-15475553\u000d\u000a    [d] Lancet paper citing our research on aspirin preventing bowel\u000d\u000a        cancer and apoptosis: Aspirin, salicylates, and cancer Elwood et al\u000d\u000a      (2009). The Lancet 373,1301-1309 PMID: 19328542\u000d\u000a    [e] Major publication citing our research on fibre and bowel cancer\u000d\u000a        prevention and apoptosis: World Cancer Research Fund, 1997\u000d\u000a      publication. Food, Nutrition and the Prevention of Cancer: a global\u000d\u000a      Perspective. ISBN: 1 899533 05 2. Can be supplied on request.\u000d\u000a    [f] Publication corroborating that fibre reduces bowel cancer risk:\u000d\u000a      Dietary fibre, whole grains, and risk of colorectal cancer: systematic\u000d\u000a      review and dose-response meta-analysis of prospective studies. BMJ\u000d\u000a      2011; 343 doi: 10.1136\/bmj.d6617 (10 November 2011). Cite this as: BMJ\u000d\u000a      2011;343:d6617 PMID: 22074852\u000d\u000a    [g] NHS choices and bulletins and public information on why Fibre and\u000d\u000a        \"5 A Day\" is important:\u000d\u000a    (i) http:\/\/www.nhs.uk\/chq\/pages\/1141.aspx?categoryid=51&subcategoryid=167\u000d\u000a    (ii) http:\/\/www.nhs.uk\/LiveWell\/5ADAY\/Pages\/5ADAYhome.aspx\u000d\u000a    [h] Mayo clinic bulletin: major USA clinic advising high fibre diets\u000d\u000a        prevent bowl cancer: http:\/\/www.mayoclinic.com\/health\/colon-polyps\/DS00511\/DSECTION=prevention\u000d\u000a      World Cancer Research Fund bulletins (i and j) that fibre reduces bowel\u000d\u000a        cancer risk and recommending high fibre diets also for other cancers:\u000d\u000a    [i] http:\/\/www.wcrf-uk.org\/cancer_prevention\/recommendations\/plant_foods_and_cancer.php\u000d\u000a    [j] http:\/\/www.wcrf-uk.org\/cancer_prevention\/types_of_cancer\/bowel_cancer.php\u000d\u000a    [k] Publications corroborating aspirin for the treatment as well as\u000d\u000a        prevention of bowel cancer:\u000d\u000a    (i) Aspirin Use and Survival after Diagnosis of Colorectal Cancer (2009).\u000d\u000a      JAMA, 302, 649-658. PMID: 19671906\u000d\u000a    (ii) Aspirin use PI3CA mutation and Colorectal-Cancer Survival (2012).\u000d\u000a      NEJM 2012, 367, 1596-1606. PMID: 23094721\u000d\u000a    ","Title":"\u000d\u000a    Use of aspirin and high dietary fibre to prevent and reduce deaths from\u000d\u000a      bowel and other cancers, influencing global policy on cancer prevention\u000d\u000a      and major public health campaigns (`five-a-day').\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2654675","Name":"Bristol"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Background to the need for novel preventive and treatment strategies\u000d\u000a        for bowel cancer\u000d\u000a    Bowel cancer is the second most common cause of cancer-related deaths in\u000d\u000a      the UK, with 16,000 deaths a year. Worldwide, 600,000 such deaths occur\u000d\u000a      annually. Hence there is an urgent need to develop novel preventive and\u000d\u000a      therapeutic strategies. It is also vital to increase public awareness of\u000d\u000a      the causes of bowel cancer, since 60-80% of cases are preventable by\u000d\u000a      dietary intervention. The University of Bristol-based Cancer Research UK\u000d\u000a      Colorectal Tumour Biology Research Group was set up in 1993 to focus on\u000d\u000a      new prevention and treatment strategies for bowel cancer. The research has\u000d\u000a      been funded by five consecutive Cancer Research UK programme grants,\u000d\u000a      running until 2015.\u000d\u000a    In the 1980s and early 1990s, epidemiological studies suggested a\u000d\u000a      possible role for aspirin and dietary fibre in the prevention of bowel\u000d\u000a      cancer, but there was very little scientific evidence for a plausible\u000d\u000a      mechanism. Research into cancer prevention, although extremely important,\u000d\u000a      is inherently challenging when dealing with a healthy population.\u000d\u000a      Mechanistic studies on how dietary factors and aspirin prevent cancer,\u000d\u000a      together with proof-of-principle chemoprevention trials in patients at\u000d\u000a      high risk of cancer, such as HNPCC (hereditary nonpolyposis colorectal\u000d\u000a      cancer) patients, are important because they can be extrapolated to the\u000d\u000a      general worldwide population as well as other high cancer risk patients\u000d\u000a      involving other major cancers such as breast, lung and prostate.\u000d\u000a    Dietary fibre\u000d\u000a    Work undertaken between 1993 and 1995 at Bristol was the\u000d\u000a      first to show that the candidate chemopreventive agent, butyrate\u000d\u000a      (bacterial fermentation product of dietary fibre), and other short chain\u000d\u000a      fatty acids, induced apoptosis (programmed cell death) in human colorectal\u000d\u000a      adenoma and carcinoma cells. This was the first report that candidate\u000d\u000a      dietary chemoprevention agents can induce apoptosis and one of the very\u000d\u000a      first cell culture models developed to study apoptosis.[1] [2].\u000d\u000a    Aspirin and other NSAIDs induce apoptosis in colorectal adenoma and\u000d\u000a        carcinoma cells\u000d\u000a    Further studies between 1993 and 1997 showed for the\u000d\u000a      first time that aspirin, a non-selective anti-inflammatory drug,[3] and\u000d\u000a      cyclooxygenase-2 (COX-2) selective NSAIDs,[4] induce apoptosis in human\u000d\u000a      colorectal adenoma and cancer cells. The use of human adenomas as well as\u000d\u000a      cancers was important, from a prevention point of view, in investigating\u000d\u000a      how adenomas regress and how to prevent adenomas becoming cancer.[1-4] The\u000d\u000a      human colorectal adenoma cell lines used in these studies were the first\u000d\u000a      in the world and were developed in the laboratory of Professor Paraskeva.\u000d\u000a      They have been used worldwide ever since (cited in [1] [3]).\u000d\u000a    Aspirin as an adjuvant for treatment as well as in prevention\u000d\u000a    The findings that aspirin and COX-2 selective agents induced apoptosis\u000d\u000a      led to the important hypothesis that these might also be used as adjuvants\u000d\u000a      for bowel cancer as well as for cancer prevention;[5],[6] (also see BBA\u000d\u000a      Reviews in Cancer, 2006, 1766,104-19).\u000d\u000a    Summary\u000d\u000a    These Bristol based discoveries [1-4] showing for the first time\u000d\u000a      that butyrate and aspirin induce apoptosis in colon tumour cells were used\u000d\u000a      as scientific evidence to justify further laboratory-based chemopreventive\u000d\u000a      studies and, importantly, clinical and epidemiological trials to\u000d\u000a      investigate the role of dietary fibre and aspirin in the prevention of\u000d\u000a      bowel cancer.[a,d,e,f,k] Furthermore, trials to investigate whether\u000d\u000a      aspirin can be a novel treatment for bowel cancer were also recommend by\u000d\u000a      the Bristol scientists.[5,6] Since these studies, the Bristol group has\u000d\u000a      published over 60 papers on chemoprevention. More recently in 2012\/13\u000d\u000a      the Bristol group has linked aspirin to inhibiting the survival of adenoma\u000d\u000a      and cancer stem cells (Gut, 61,1306-14, 2012; Carcinogenesis, 34, 1150-7,\u000d\u000a      2013) providing a possible mechanisms of how NSAIDS cause adenoma\u000d\u000a      regression and are chemopreventive as well as of therapeutic interest.\u000d\u000a    The first apoptosis studies [1] [2] published in Bristol were very\u000d\u000a      timely, because they preceded the massive increase in apoptosis research\u000d\u000a      which subsequently followed the realisation that defects in apoptosis\u000d\u000a      regulation were important in carcinogenesis. In the mid-1990s, the\u000d\u000a      publications and subsequent publicity obtained by Bristol through press\u000d\u000a      releases about their research on dietary fibre\/aspirin and apoptosis led\u000d\u000a      Professor Paraskeva to be invited onto national clinical colorectal cancer\u000d\u000a      committees (see section 4). While on these committees, he was involved in\u000d\u000a      setting up subsequent clinical trials. Importantly, the mechanisms studies\u000d\u000a      were used to support both aspirin and dietary fibre laboratory-based\u000d\u000a      experimental studies as well as clinical\/epidemiological trials\u000d\u000a      (a,d,e,f,k, see section 5).\u000d\u000a    Those involved with the Bristol Research (Chemoprevention Grant Income\u000d\u000a        to date >£7m)\u000d\u000a    Professor Chris Paraskeva is chemoprevention group leader (since 1993)\u000d\u000a      and the research was all carried out at Bristol between 1993 and 2013.\u000d\u000a      Other key individuals are: Ann Williams (CRC Fellow and now Professor\u000d\u000a      (1990-date)); Hart was an intercalating medical student (1992-1993); Hicks\u000d\u000a      was a university technician (1994-2012); and Hague (1993-2000), Elder\u000d\u000a      (1993-1999), Qualtrough (2001-2006) and Smartt (2007-2012) were Cancer\u000d\u000a      Research UK-funded scientists.\u000d\u000a    "},{"CaseStudyId":"40410","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The NHS National Amyloidosis Centre (NAC) established by Pepys and\u000d\u000a      Hawkins in 1999 is directly funded by the NHS to provide diagnostic and\u000d\u000a      clinical management services for the national caseload of patients with\u000d\u000a      amyloidosis [a]. Patient flow has increased uninterruptedly from\u000d\u000a      ~40 new patients in 1999-2000. Within the assessment period, annual\u000d\u000a      patient flow and NHS funding have increased from 1877 patient evaluations\u000d\u000a      \/ £2,239,000 in 2008 to 3444 cases \/ £5,356,000 in 2013 [b]. Since\u000d\u000a      2008, 2,950 new and 10,955 completed follow up assessments comprise ~70%\u000d\u000a      of all UK amyloidosis patients, representng the largest, most diverse\u000d\u000a      cohort of amyloidosis patients worldwide. Since 2012, the Centre has\u000d\u000a      provided an online amyloidosis genetic testing service for the UK [c].\u000d\u000a    Improving diagnosis. Our correction of the diagnosis of\u000d\u000a      amyloidosis (see [3,4]) in about 5% of new cases per year\u000d\u000a      underpins steady improvement in mortality and outcome measures. Combining\u000d\u000a      genetic and proteomic testing with refined immunohistochemistry has\u000d\u000a      increased definitive amyloid fibril typing, which is key for appropriate\u000d\u000a      treatment, from ~70% to ~98%.\u000d\u000a    Our development of CT-SPECT 123I-SAP imaging, as part of\u000d\u000a      2,100 total SAP scans p.a., enables evaluation of individual organ amyloid\u000d\u000a      load and localised amyloid deposits in non-visceral sites. We have\u000d\u000a      introduced CT-SPECT with 99mTc-DPD scintigraphy, repurposing\u000d\u000a      this diphosphonate bone tracer for diagnosis, typing and serial evaluation\u000d\u000a      of cardiac ATTR amyloidosis as outlined in [5], leading directly\u000d\u000a      to installation of a new NHS CT-SPECT suite in 2012, and new recurrent NHS\u000d\u000a      funding from April 2012 of £250,000 p.a. Our sophisticated novel cardiac\u000d\u000a      MRI for evaluation of cardiac amyloidosis has won a further £250,000 p.a.\u000d\u000a      of recurrent central NHS funding [b].\u000d\u000a    Improving disease staging and monitoring. Our further refinement\u000d\u000a      and validation of serum biomarkers for staging disease severity have been\u000d\u000a      adopted by pharma and academia in the first industry and academic Phase\u000d\u000a      III clinical trials of chemotherapy in AL amyloidosis [d,e].\u000d\u000a      Recommendations for treatment of AL amyloidosis with the\u000d\u000a      cyclophosphamide-bortezomib-dexamethasone chemotherapy regimen we reported\u000d\u000a      [8], and for the new response criteria we reported in [7]\u000d\u000a      have been adopted in April 2013 guidelines issued by The National\u000d\u000a      Comprehensive Cancer Network (NCCN), an alliance of the world's leading\u000d\u000a      cancer centres [f]. Consensus of experts on a modern framework for\u000d\u000a      clinical trial design and drug development in AL amyloidosis was agreed at\u000d\u000a      the first Roundtable on Clinical Research in Immunoglobulin Light-chain\u000d\u000a      Amyloidosis (AL), a meeting sponsored by the Amyloidosis Foundation\u000d\u000a      (Clarkston, MI, USA) in 2010, and published in 2012 [e].\u000d\u000a    Improving treatment and survival. Refined use of serum free light\u000d\u000a      chain measurements has greatly improved monitoring of responses to\u000d\u000a      chemotherapy in AL amyloidosis [2]. We have also demonstrated the\u000d\u000a      feasibility and limitations of solid organ transplantation in amyloidosis.\u000d\u000a      With careful selection, approximately 2% of patients receive an organ and\u000d\u000a      outcomes match those in general transplant registries; renal\u000d\u000a      transplantation in AL amyloidosis, the most serious type, has doubled\u000d\u000a      during the past 5 years. Almost all patients with AL amyloidosis attending\u000d\u000a      the Centre now benefit from combination chemotherapy regimens that include\u000d\u000a      the novel proteasome inhibitor agent, bortezomib. This and other new high\u000d\u000a      cost, high efficacy drugs, licensed in the past 6 years for treatment of\u000d\u000a      myeloma, are available on the NHS to almost all patients with AL\u000d\u000a      amyloidosis as a direct result of our published clinical research work [g],\u000d\u000a      which completely changed the chemotherapy paradigm. Enforcement of the\u000d\u000a      necessary funding was achieved in association with the British Society of\u000d\u000a      Haematology, the UK Amyloidosis Network (led by us) and crucially the\u000d\u000a      patient support charity, Myeloma UK. Survival of AL amyloidosis patients\u000d\u000a      under the care of the National Amyloidosis Centre has improved\u000d\u000a      substantially during the past 12 years: (NAC figures: 4 yr survival 2001-3\u000d\u000a      was 34%; 2004-7 was 38%; 2008-2012 was 50%).\u000d\u000a    The Centre's advances are rapidly disseminated to specialist centres and\u000d\u000a      collaborations internationally through scientific\/medical publications,\u000d\u000a      international meetings and personal contacts. We established the UK\u000d\u000a      Amyloidosis Network (2009) attracting over 150 participants at the\u000d\u000a      February 2013 annual meeting [h], and the ONS-based epidemiology\u000d\u000a      study of amyloidosis incidence (~5-10 per million p.a. in England),\u000d\u000a      enabling clinical service development in the UK. We lately created the UK\u000d\u000a      Amyloidosis Awareness Group (UKAAG) with whom the NAC has developed a\u000d\u000a      comprehensive website [h, i] patient information literature and a\u000d\u000a      regular newsletter to enable patient and public engagement and promote\u000d\u000a      awareness of this rare disease. Myeloma UK have confirmed: \"The recent\u000d\u000a        creation of UKAAG has been warmly welcomed and has given patients an\u000d\u000a        important platform to formally feed in their views about their treatment\u000d\u000a        and care. In particular the creation of a comprehensive website with\u000d\u000a        high-quality information about amyloidosis, that can be trusted 100%,\u000d\u000a        provides a great deal of comfort.\" [i]\u000d\u000a    The Centre has received charitable donations from patients, relatives,\u000d\u000a      friends and other supporters, as direct gifts and via wide ranging\u000d\u000a      charitable fund raising events organised entirely by donors, enabling\u000d\u000a      flexible support for new research and patient care initiatives in the\u000d\u000a      Centre for Amyloidosis and Acute Phase Proteins and National Amyloidosis\u000d\u000a      Centre; total funds donated are over £1.2 million [j].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The UCL Centre for Amyloidosis and Acute Phase Proteins conducts\u000d\u000a      world-leading research and development that has rapidly fed through to\u000d\u000a      patient care. These include advances in the diagnosis of amyloidosis and\u000d\u000a      clinical characterisation of many new subtypes including genetic forms,\u000d\u000a      development and application of new biomarkers to monitor disease activity\u000d\u000a      and progress, new modalities of imaging and better treatment. The\u000d\u000a      consequences have been new standards of clinical care adopted nationally\u000d\u000a      and internationally, improved and more accurate diagnosis, steady\u000d\u000a      improvements in the outcomes of this disease, major investment by the NHS\u000d\u000a      and adoption of new clinical metrics by the pharmaceutical industry to\u000d\u000a      enable research on specific new therapies currently in development.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University College London\u000d\u000a    ","Institutions":[{"AlternativeName":"University College London","InstitutionName":"University College London","PeerGroup":"A","Region":"London","UKPRN":10007784}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Natural history and outcome in systemic AA amyloidosis. Lachmann HJ,\u000d\u000a      Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, Hawkins\u000d\u000a      PN. N Engl J Med. 2007; 356:2361-71. http:\/\/dx.doi.org\/10.1056\/NEJMoa070265\u000d\u000a    \u000a\u000a2. Outcome in systemic AL amyloidosis in relation to changes in\u000d\u000a      concentration of circulating free immunoglobulin light chains following\u000d\u000a      chemotherapy. Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD,\u000d\u000a      Bradwell AR, Pepys MB, Hawkins PN. Br J Haematol. 2003 122:78-84.\u000d\u000a      http:\/\/dx.doi.org\/10.1046\/j.1365-2141.2003.04433.x\u000d\u000a    \u000a\u000a3. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.\u000d\u000a      Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD,\u000d\u000a      Pepys MB, Hawkins PN. N Engl J Med. 2002 346:1786-91. http:\/\/dx.doi.org\/10.1056\/NEJMoa013354\u000d\u000a    \u000a\u000a4. Diagnosis, pathogenesis, treatment, and prognosis of hereditary\u000d\u000a      fibrinogen A alpha-chain amyloidosis. Gillmore JD, Lachmann HJ, Rowczenio\u000d\u000a      D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN. J Am\u000d\u000a      Soc Nephrol. 2009 20:444-51.\u000d\u000a      http:\/\/dx.doi.org\/10.1681\/ASN.2008060614\u000d\u000a    \u000a\u000a5. Cardiovascular magnetic resonance in cardiac amyloidosis. Maceira AM,\u000d\u000a      Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, Sheppard MN,\u000d\u000a      Poole-Wilson PA, Hawkins PN, Pennell DJ. Circulation. 2005 111:186-93. http:\/\/dx.doi.org\/10.1161\/01.CIR.0000152819.97857.9D\u000d\u000a    \u000a\u000a6. A European collaborative study of treatment outcomes in 346 patients\u000d\u000a      with cardiac stage III AL amyloidosis. Wechalekar AD, Schonland SO,\u000d\u000a      Kastritis E, Gillmore JD, Dimopoulos MA, Lane T, Foli A, Foard D, Milani\u000d\u000a      P, Rannigan L, Hegenbart U, Hawkins PN, Merlini G, Palladini G. Blood.\u000d\u000a      2013. 121:3420-7. http:\/\/dx.doi.org\/10.1182\/blood-2012-12-473066\u000d\u000a    \u000a\u000a7. New criteria for response to treatment in immunoglobulin light chain\u000d\u000a      amyloidosis based on free light chain measurement and cardiac biomarkers:\u000d\u000a      impact on survival outcomes. Palladini G, Dispenzieri A, Gertz MA, Kumar\u000d\u000a      S, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U, Comenzo R,\u000d\u000a      Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G. J Clin Oncol.\u000d\u000a      2012 30:4541-9. http:\/\/dx.doi.org\/10.1200\/JCO.2011.37.7614\u000d\u000a    \u000a\u000a8. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL\u000d\u000a      amyloidosis is associated with high clonal response rates and prolonged\u000d\u000a      progression-free survival. Venner CP, Lane T, Foard D, Rannigan L, Gibbs\u000d\u000a      SD, Pinney JH, Whelan CJ, Lachmann HJ, Gillmore JD, Hawkins PN, Wechalekar\u000d\u000a      AD. Blood. 2012. 119:4387-90. http:\/\/dx.doi.org\/10.1182\/blood-2011-10-388462\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    [a] Details of National Amyloidosis Centre NHS clinical service\u000d\u000a        available: UCL website: www.ucl.ac.uk\/medicine\/amyloidosis\/nac\u000d\u000a      NHS England 2013\/14 NHS Standard Contract For Diagnostic Service For\u000d\u000a      Amyloidosis\u000d\u000a      www.england.nhs.uk\/wp-content\/uploads\/2013\/06\/e13-diag-serv-amyloidosis.pdf\u000d\u000a    [b] National Amyloidosis Centre patient flow and NHS funding\u000d\u000a      Details including awards in 2012 of new recurrent funding of £250,000\/yr\u000d\u000a      for CT-SPECT service and £250,000\/yr for cardiac MRI, and\u000d\u000a      substantial increase in annual patient flow and NHS funding from 1877\u000d\u000a      patient evaluations \/ £2,239,000 in 2008 to 3444 cases \/ £5,356,000 in\u000d\u000a      2013 can be corroborated by Commissioning Support Manager, Royal Free\u000d\u000a      London NHS Foundation Trust, and\/or\u000d\u000a      Operations Manager for Infection and Immunity, Royal Free London NHS\u000d\u000a      Foundation Trust.\u000d\u000a    [c] Genetic testing service\u000d\u000a      http:\/\/www.ucl.ac.uk\/amyloidosis\/nac\/molecular-genetic-testing\u000d\u000a    [d] Adoption of disease staging methods using serum biomarkers by\u000d\u000a      pharma and academia:\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT01659658?term=amyloidosis&recr=Open&rank=10\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01277016?term=BMdex&recr=Open&rank=1\u000d\u000a    [e] Use of new treatment response criteria in clinical trials:\u000d\u000a      Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, Falk\u000d\u000a      R, Wells K, Solomon A, Wechalekar A, Zonder J, Dispenzieri A, Gertz M,\u000d\u000a      Streicher H, Skinner M, Kyle RA, Merlini G. Consensus guidelines for the\u000d\u000a      conduct and reporting of clinical trials in systemic light-chain\u000d\u000a      amyloidosis Leukemia. 2012 Nov;26(11):2317-25 http:\/\/dx.doi.org\/10.1038\/leu.2012.100\u000d\u000a      Examples:\u000d\u000a      http:\/\/www.ukctg.nihr.ac.uk\/trialdetails\/ISRCTN33283585\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT01659658?term=amyloidosis&recr=Open&rank=10\u000d\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01277016?term=BMdex&recr=Open&rank=1\u000d\u000a    [f] International Guidelines on treatment of amyloidosis:\u000d\u000a      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Systemic\u000d\u000a      Light Chain Amyloidosis\u000d\u000a      ®2028 Version 2.2014, 10\/04\/13 © National Comprehensive Cancer Network,\u000d\u000a      Inc. 2013.\u000d\u000a      http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/amyloidosis.pdf\u000d\u000a      (login required; copy avilable on request)\u000d\u000a      Reference to the research [6] is ref 27 therein; the meeting abstract\u000d\u000a      communicating [7] is ref 19 therein; [8] is ref 63 therein.\u000d\u000a    [g] Combination Chemotherapy Regimens\u000d\u000a      Letter from NHS England, confirming the funding for Bortezomib, available\u000d\u000a      on request.\u000d\u000a      Manuscript publication describing improved survival rates available on\u000d\u000a      request.\u000d\u000a    [h] UK Amyloidosis Network (February 2013) annual meeting details:\u000d\u000a      http:\/\/www.ucl.ac.uk\/amyloidosis\/pdfs\/nac_newsletter_2\u000d\u000a    [i] UK Amyloidosis Awareness Group website and patient information\u000d\u000a      resource:\u000d\u000a      www.amyloidosis.org.uk\u000d\u000a      Letter from the Chief Executive. Myeloma UK, available on request.\u000d\u000a    [j] UCL Amyloidosis Research Fund\u000d\u000a      http:\/\/www.ucl.ac.uk\/amyloidosis\/amyloidosis-research-fund\u000d\u000a      Income can be corroborated by the fund administrator: Division of\u000d\u000a      Medicine, UCL. \u000d\u000a    ","Title":"\u000d\u000a    Amyloidosis and acute phase proteins: world leading clinical service\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Amyloidosis is a disorder characterised by organ failure resulting from\u000d\u000a      the accumulation of protein as abnormal fibres. There are various types\u000d\u000a      notably including those arising as a result of long-standing inflammation\u000d\u000a      (AA amyloidosis) or secondary to a haematological malignancy, myeloma (AL\u000d\u000a      amyloidosis) or in association with ageing (ATTR amyloidosis). Highlights\u000d\u000a      of the extensive clinical research programme in amyloidosis at UCL that\u000d\u000a      have led to better management of these patients include:\u000d\u000a    Elucidation of the crucial precursor-product relationship in amyloid\u000d\u000a        fibrillogenesis, which underlies pathogenesis and thus treatment.\u000d\u000a      Seminal studies in unprecedentedly large patient populations with AA [1]\u000d\u000a      and AL [2] amyloidosis have demonstrated for the first time the\u000d\u000a      relationships between production of the amyloid fibril precursor proteins\u000d\u000a      serum amyloid A protein (SAA) and monoclonal immunoglobulin free light\u000d\u000a      chains (FLC) respectively with amyloid load and clinical outcome. These\u000d\u000a      studies not only systematically demonstrated the capacity for regression\u000d\u000a      of amyloid following treatment of underlying disorders, encouraging a\u000d\u000a      proactive approach to treat the underlying cause, but defined monitoring\u000d\u000a      of SAA and FLC concentration as standards of care in AA and AL amyloidosis\u000d\u000a      that enable treatment strategies to be guided by their early effect on\u000d\u000a      these accessible measurements.\u000d\u000a    Understanding of key aspects of hereditary amyloidosis. Until our\u000d\u000a      genetic study [3], hereditary systemic amyloidosis was thought to\u000d\u000a      be incredibly rare and to affect only a few dozen families worldwide. Most\u000d\u000a      affected patients either remained undiagnosed or were incorrectly assumed\u000d\u000a      to have AL amyloidosis resulting in needless and harmful chemotherapy. Our\u000d\u000a      study of 350 patients identified a hereditary cause in 10% of cases,\u000d\u000a      resulting in genetic testing being introduced in the NHS National\u000d\u000a      Amyloidosis Centre as a new standard of care. We have subsequently\u000d\u000a      identified more than 70 patients with hereditary renal amyloidosis, and\u000d\u000a      have characterised the phenotype, diagnostic pathway and role of organ\u000d\u000a      transplantation in this subtype [4].\u000d\u000a    Design and introduction of powerful new diagnostic imaging methods.\u000d\u000a      We invented 123I-serum amyloid P component scintigraphy in\u000d\u000a      1990 to image amyloid deposits in vivo, and during the past 5 years have\u000d\u000a      developed 3D high resolution dual modality CT-SPECT (single-photon\u000d\u000a      emission computed tomography) to enable accurate quantification and\u000d\u000a      characterisation of amyloid in non-visceral sites. We have also developed\u000d\u000a      99mTc-DPD scintigraphy to image cardiac amyloid deposits of\u000d\u000a      transthyretin (ATTR) type, repurposing this diphosphonate radionuclide\u000d\u000a      tracer to enable diagnosis and clinical assessment of elderly patients\u000d\u000a      with this hitherto very difficult to diagnose disorder. We were the first\u000d\u000a      group to systematically demonstrate the utility of cardiac magnetic\u000d\u000a      resonance imaging (CMR) in 2005 [5], and have subsequently\u000d\u000a      developed specific CMR methods to characterise and quantify cardiac\u000d\u000a      amyloid deposits of all types.\u000d\u000a    Major advances in monitoring of disease and therapy. We have led\u000d\u000a      and participated in major international collaborative studies that have\u000d\u000a      evaluated and defined the clinical utility of various biomarkers to stage\u000d\u000a      severity of disease [6] and monitor response to treatment [7]\u000d\u000a      in AL amyloidosis, the most common and serious type of the disease. These\u000d\u000a      findings have now been adopted throughout the world, both for specialist\u000d\u000a      clinical practice and in clinical trials. Our clinical studies of cyclic\u000d\u000a      multiple agent chemotherapy [8] have defined current best practice\u000d\u000a      for the majority of AL amyloidosis patients who are not fit enough to\u000d\u000a      undergo stem cell transplantation.\u000d\u000a    This research was led by Professor Philip Hawkins and Professor Sir Mark\u000d\u000a      Pepys of the UCL Centre for Amyloidosis and Acute Phase Proteins.\u000d\u000a    "},{"CaseStudyId":"40439","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Economic and Social Research Council"],"ImpactDetails":"\u000a    University of Glasgow researchers led pivotal clinical trials in\u000a      collaboration with Roche to show that Xeloda and XELOX were safe and\u000a      effective novel treatments for patients with bowel cancer.a\u000a      This research has enhanced patient care by increasing the therapeutic\u000a      options available and by improving the treatment experience, with more\u000a      convenient dosing schedules and fewer side effects compared with previous\u000a      chemotherapy regimens. This was achieved by substituting oral for\u000a      intravenous chemotherapy, and removing the requirement for either\u000a      in-patient administration or long-term indwelling venous catheters. Xeloda\u000a      and XELOX have been approved by drug regulatory bodies and adopted in US\u000a      and European clinical guidelines for bowel cancer. In the UK, the reduced\u000a      costs offered by these novel treatments have benefitted the NHS, both\u000a      economically and in terms of saving time for patients and healthcare\u000a      staff.\u000a    European licensing extensions granted for Xeloda\u000a    Xeloda was approved as a first-line therapy for metastatic bowel cancer\u000a      in 2001 and as an adjuvant therapy for advanced bowel cancer in 2005 (USA\u000a      and Europe). The European Medicines Agency (EMA) subsequently broadened\u000a      the use of Xeloda to the first-line and second-line treatment of\u000a      metastatic bowel cancer in combination with any other chemotherapy drug\u000a      (February 2008).b The NO16966 phase III clinical trial of XELOX6\u000a      was one of two studies cited as the pivotal clinical evidence to support\u000a      this licence extension.a The phase I study of XELOX4\u000a      was cited to support the safety of combining Xeloda with oxaliplatin,\u000a      whereas the X-ACT phase III trial of Xeloda2 was cited as\u000a      evidence for the beneficial effects of Xeloda on survival and quality of\u000a      life among patients with metastatic bowel cancer. The specific combination\u000a      therapy of XELOX was approved in by the EMA in March 2010.c\u000a      This update cited the NO16968 phase III clinical trial of XELOX as the\u000a      sole evidence.a Both of these EMA approvals were highlighted by\u000a      PharmaTimes, a leading online forum for the pharmaceutical industry and\u000a      healthcare systems (94,280 unique visitors to the website,\u000a      January-February 2013).d\u000a    The Scottish Medicines Consortium (SMC) is responsible for advising NHS\u000a      Scotland on treatment efficacy and costs. In September 2008, the SMC\u000a      stated in their assessment of Xeloda (SMC No. 507\/08e) that it\u000a      was accepted for use alone or as a combination therapy for metastatic\u000a      bowel cancer and directly referenced the 2008 J Clin Oncol paper.6\u000a      This statement was followed by another SMC assessment in July 2011 that\u000a      accepted the use of XELOX as an adjuvant treatment, citing data from\u000a      clinical trial NO16968 (SMC No. 716\/11).f\u000a    Xeloda is currently marketed in over 100 countries. Worldwide sales of\u000a      Xeloda were approximately £1,057 million in 2012, an increase of 9% on the\u000a      previous year, and it ranked fifth in Roche's top 10 best-selling drug\u000a      list.g Xeloda showed sustained growth in sales between 2008 and\u000a      2013 as XELOX gained regulatory approval. For example, Roche saw its\u000a      biggest rise in sales of Xeloda (17%) following EMA approval in 2010,\u000a      demonstrating a substantial economic impact of the research.g\u000a    Changes in clinical guidelines\u000a    The National Comprehensive Cancer Network (NCCN) is a consortium of 23 US\u000a      centres of clinical excellence in cancer care. In 2013, the NCCN published\u000a      clinical guidelines that recommended XELOX (referred to as `CapeOX' by\u000a      this organisation) for use in bowel cancer.h The guidelines on\u000a      colon cancer provide detailed treatment protocols for advanced and\u000a      metastatic cancer that directly cite research by University of Glasgow on\u000a      the basis of evidence and consensus classified as `category 2A' (uniform\u000a      NCCN consensus). In the `Principles of adjuvant therapy (COL-E)' chapter\u000a      it is stated that \"capecitabine appears to be equivalent to bolus\u000a        5-FU\/leucovorin in patients with stage III colon cancer,\" citing the\u000a      2005 NEJM publication.2 The 2008 J Clin Oncol\u000a      publication6 is cited in the chapter `Chemotherapy for advanced\u000a      or metastatic disease (COL-C)'.\u000a    In 2010, the European Society for Medical Oncology (ESMO) published\u000a      clinical guidelines on primary and advanced bowel cancer.i,j\u000a      These guidelines advocated the use of Xeloda in the adjuvant treatment of\u000a      patients with primary colon cancer (class of recommendation A), citing the\u000a      phase III clinical trial X-ACT2 (level of evidence I). XELOX\u000a      (referred to as `CAPOX' by this organisation) was recommended as an\u000a      alternative to FOLFOX for patients with advanced bowel cancer (level of\u000a      evidence I, class of recommendation A). The 2008 J Clin Oncol\u000a      paper6 informed the evidence base for this recommendation.\u000a    Benefits for patients and the NHS\u000a    The XELOX regimen requires only one clinic visit every 3 weeks for the\u000a      2-hour infusion of oxaliplatin, demonstrating a marked advantage over\u000a      treatment with 5-FU. Information on XELOX has been disseminated to\u000a      patients via support groups, including Macmillan Cancer Support.k\u000a      This UK organisation describes what patients with bowel cancer should\u000a      expect in terms of treatment schedule, tumour response and side effects if\u000a      they are prescribed XELOX, citing the 2008 J Clin Oncol paper6\u000a      as the only clinical trial evidence. Similarly, Genentech provides online\u000a      material for US patients.l This resource directly references\u000a      X-ACT2 as the sole evidence base supporting the efficacy of\u000a      XELOX as an adjuvant therapy for bowel cancer.\u000a    The use of Xeloda and XELOX has reduced treatment costs for the NHS. A\u000a      2011 National Institute for Health and Care Excellence (NICE) costing\u000a      report determined that adjuvant treatment with Xeloda cost £3974 per\u000a      patient versus £8736 for 5-FU.m The cost of XELOX was £10,514\u000a      per patient versus £11,461 for FOLFOX. Costs to the NHS will drop further\u000a      when Xeloda comes off patent in December 2013, enabling generic\u000a      formulations to enter clinical practice.\u000a    ","ImpactSummary":"\u000a    Bowel cancer is the third most frequently diagnosed cancer worldwide.\u000a      University of Glasgow researchers have established Xeloda (an oral\u000a      5-fluorouracil precursor) and XELOX (a chemotherapeutic regimen combining\u000a      Xeloda with oxaliplatin) as highly effective, targeted therapies for\u000a      patients with bowel cancer. Since 2008, European regulatory approval of\u000a      these therapies has been incorporated into major international clinical\u000a      guidelines. The research has transformed patient care by improving the\u000a      treatment experience, with more convenient dosing schedules and fewer side\u000a      effects compared with previous chemotherapy procedures. Xeloda and XELOX\u000a      have transformed chemotherapy for bowel cancer and decreased therapeutic\u000a      costs, potentially saving around £4,762 (Xeloda) and £947 (XELOX) per\u000a      patient for the NHS.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Mackean M. et al. Phase\u000a        I and pharmacologic study of intermittent twice-daily oral therapy with\u000a        capecitabine in patients with advanced and\/or metastatic cancer.\u000a        J Clin Oncol 1998; 16: 2977-2985. [pay per view - PDF\u000a      available on request]\u000a    \u000a\u000a2. Twelves C. et al. Capecitabine\u000a        as adjuvant treatment for stage III colon cancer. N Engl J Med\u000a      2005; 352: 2696-2704 doi:10.1056\/NEJMoa043116.\u000a    \u000a\u000a3. Cassidy J.et al. Pharmacoeconomic\u000a        analysis of adjuvant oral capecitabine vs intravenous 5-FU\/LV in\u000a        Dukes' C colon cancer: the X-ACT trial. Br J Cancer 2006; 94:\u000a      1122-1129 doi:10.1038\/sj.bjc.6603059.\u000a    \u000a\u000a4. Díaz-Rubio E. et al. Capecitabine\u000a        (Xeloda®) in combination with oxaliplatin: a phase I, dose-escalation\u000a        study in patients with advanced or metastatic solid tumours. Ann\u000a        Oncol 2002; 13: 558-565 doi:10.1093\/annonc\/mdf065.\u000a    \u000a\u000a5. Cassidy J. et al. XELOX\u000a        (capecitabine plus oxaliplatin): active first-line therapy for patients\u000a        with metastatic colorectal cancer. J Clin Oncol 2004; 22:\u000a      2084-2091 doi:10.1200\/JCO.2004.11.069.\u000a    \u000a\u000a6. Cassidy J. et al. Randomized\u000a        phase III study of capecitabine plus oxaliplatin compared with\u000a        fluorouracil\/folinic acid plus oxaliplatin as first-line therapy for\u000a        metastatic colorectal cancer. J Clin Oncol 2008; 26:\u000a      2006-2012 doi:10.1200\/JCO.2007.14.9898.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    a. Statement from Global Head Oncology\/Immuno-Oncology Partnering,\u000a      F.Hoffmann-La Roche Ltd (available on request)\u000a    b. EMA\u000a        assessment report for Xeloda, February 2008 (sections 1.1 and 1.2,\u000a      pg 2-16)\u000a    c. EMA\u000a        procedural update for Xeloda, March 2010 (No. II\/0044, pg 5)\u000a    d. PharmaTimes coverage of EMA approval, February\u000a        2008 and March\u000a        2010\u000a    e. Scottish Medicines Consortium No.\u000a        507\/08, September 2008 (pg 2-4 and 8)\u000a    f. Scottish Medicines Consortium No.\u000a        716\/11, July 2011 (pg 2-4)\u000a    g. Roche 2012 financial\u000a        summary (pg 5 and 7 of \"Full Media Release\" PDF) and 2010 annualreport\u000a      (pg 34-36, 42, 47)\u000a    h. NCCN\u000a        guidelines version 3.2013 colon cancer, 2013 (Col-E, pg 1-2; Col-C,\u000a      pg 1-9) (log-in required; PDF available on request)\u000a    i. ESMO clinical guidelines for primary\u000a        colon cancer, 2010, doi:10.1093\/annonc\/mdq168 (pg V74)\u000a    j. ESMO clinical guidelines for advanced\u000a        colorectal cancer, 2010, doi:10.1093\/annonc\/mdq222 (pg V94)\u000a    k. Macmillan Cancer Support, cancer\u000a        treatment information for patients\u000a    l. Genentech, Xeloda product information\u000a        for patients\u000a    m. NICE, CG131 colorectal cancer costing\u000a        report, November 2011 (Table 1, pg 16)\u000a    ","Title":"\u000a    Improving tolerability, convenience and cost of bowel cancer chemotherapy\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Over 40,000 people are diagnosed with bowel cancer in the UK each year.\u000a      If diagnosed and treated early enough, up to 93% survive for at least 5\u000a      years after diagnosis. By contrast, the 5-year survival rate for patients\u000a      with advanced disease drops to as little as 7%.\u000a    Until the late 1990s, 5-fluorouracil (5-FU) was the mainstay of\u000a      post-operative chemotherapy (also known as `adjuvant treatment') for\u000a      patients with bowel cancer. This fluoropyrimidine targets tumours by\u000a      inhibiting thymidylate synthase, which is required for cancer-cell growth;\u000a      the effects of 5-FU can be enhanced by the co-administration of leucovorin\u000a      (folinic acid). Patients receive 5-FU directly into the bloodstream either\u000a      by infusion or with an ambulatory in-dwelling pump in repeated lengthy\u000a      sessions. This treatment schedule requires a costly hospital stay and can\u000a      cause complications owing to placement of long-term catheters in blood\u000a      vessels. Thus, the need for a 5-FU-based chemotherapy with improved\u000a      tolerability, efficacy, patient convenience and cost was identified.\u000a    Roche initiates collaborative research programme with the\u000a          University of Glasgow\u000a    In the mid-1990s, a major pharmaceutical company Roche — having\u000a      recognised the University of Glasgow as a world-leader in experimental\u000a      oncology — established a highly productive collaboration with three of the\u000a      institution's medical oncologists, Prof Jim Cassidy, Prof Stan Kaye and Dr\u000a      Chris Twelves. This collaboration marked the beginning of University of\u000a      Glasgow-led clinical studies on novel chemotherapeutic options for bowel\u000a      cancer. In addition to their expertise in both drug development and bowel\u000a      cancer research, the University of Glasgow had a dedicated pharmacology\u000a      research programme at that time researching fluoropyrimidines and\u000a      performing preclinical and early clinical trials, including assessment of\u000a      pharmacokinetics (bodily absorption, distribution, metabolism and\u000a      excretion of a drug) and pharmacodynamics (effects of a drug on the body).\u000a      University of Glasgow researchers identified Roche's drug development\u000a      pipeline as an opportunity to take basic research on novel\u000a      fluoropyrimidines into clinical trials and beyond.\u000a    Xeloda established as a safe and efficient oral targeted therapy\u000a          for bowel cancer\u000a    The oral fluoropyrimidine Xeloda (generic name, capecitabine) was\u000a      synthesised by Roche as an alternative to intravenous 5-FU. Once ingested,\u000a      Xeloda is converted through a three-step process from an inactive\u000a      precursor to active 5-FU. The final step occurs specifically within the\u000a      bowel cancer cells owing to the high local expression of the converting\u000a      enzyme thymidine phosphorylase. This mechanism of activation ensures that\u000a      5-FU accumulates within the tumour but much less so in normal surrounding\u000a      tissues. As such, Xeloda was one of the first targeted therapies for\u000a      cancer.\u000a    University of Glasgow researchers were involved in all three key stages\u000a      of the clinical evaluation of Xeloda (conducted 1995-2006). These trials\u000a      included assessments of safety, tolerability and recommended dose for use\u000a      in subsequent clinical trials (phase I, usually fewer than 100 patients);\u000a      anti-cancer efficacy and safety (phase II, up to several hundred\u000a      patients); and efficacy compared to other standard treatment (phase III,\u000a      several hundred to several thousand patients). The first human phase I\u000a      trial of Xeloda (published in 1998) was led by the University of Glasgow\u000a      and enrolled 34 patients at two centres.1 This trial\u000a      demonstrated that a daily dose of 2,510 mg\/m2 was well-\u000a      tolerated in terms of the number and severity of side effects. Subsequent\u000a      phase II studies established the efficacy of Xeloda and supported its use\u000a      as a first-line option for advanced bowel cancer. In 2005, a phase III\u000a      study (X-ACT, also led by the University of Glasgow) demonstrated that\u000a      Xeloda was effective for adjuvant treatment of bowel cancer to prevent and\u000a      delay recurrence in cancer that had been removed at operation.2\u000a      This study of 1,987 patients reported improved relapse-free survival and\u000a      fewer side effects in patients who received Xeloda compared with those who\u000a      were given infusions of 5-FU. The X-ACT study also examined the economic\u000a      benefits of Xeloda (published in 2006).3 Direct annual\u000a      healthcare costs (chemotherapy drugs, hospital care, managing side\u000a      effects) and societal costs (time and travel per patient) were both\u000a      reduced by £3,608 and £4,925, respectively, when Xeloda was prescribed\u000a      instead of 5-FU.\u000a    XELOX established as a combination therapy for bowel cancer\u000a    In the late 1990s and early 2000s, the chemotherapy drug oxaliplatin was\u000a      developed into a combination therapy with 5-FU (known as `FOLFOX'). Given\u000a      their considerable clinical evidence that Xeloda is superior to 5-FU,\u000a      University of Glasgow researchers led clinical investigation of the novel\u000a      combination of Xeloda plus oxaliplatin (XELOX) and were the first to\u000a      demonstrate that these two compounds are tolerable in combination and had\u000a      a co-operative therapeutic effect.\u000a    In light of the University of Glasgow's pivotal role in the early\u000a      clinical trials of Xeloda, the initial phase I trial of XELOX was led by\u000a      Prof Jeff Evans, in collaboration with Cassidy (at the University of\u000a      Aberdeen from 1994, returning to Glasgow in 2002), Jose Baselga (Hospital\u000a      Vall d'Hebron, Barcelona, Spain) and Eduardo Díaz-Rubio (Hospital Clínico\u000a      Universitario, Madrid, Spain). The findings of this trial helped to\u000a      determine the optimum doses and administration schedule of XELOX (2002).4\u000a      A phase II University of Glasgow led trial that was published in 2004\u000a      confirmed the clinical activity of XELOX as a well-tolerated first-line\u000a      option for metastatic bowel cancer: 55% of patients responded to treatment\u000a      with measurable shrinkage of their tumours.5 A subsequent\u000a      international multicentre phase III trial (NO16966) with leadership from\u000a      the University of Glasgow showed that XELOX had comparable efficacy and\u000a      safety profiles to FOLFOX and established XELOX as a credible therapeutic\u000a      option for patients with bowel cancer (2008).6 Cassidy was the\u000a      joint global lead on this trial (with Prof. Leonard Saltz, Memorial Sloan\u000a      Kettering Cancer Centre, USA) as well as acting as the UK Chief\u000a      Investigator and Principal Investigator for the University of Glasgow,\u000a      which was one of 17 UK study centres. In addition, Cassidy was the\u000a      Principal Investigator for the University of Glasgow in a second\u000a      international multicentre phase III study on XELOX (NO16968), which\u000a      involved 26 UK centres. Cassidy was actively involved in the protocol\u000a      design, conduct, data interpretation and reporting of these two pivotal\u000a      trials.\u000a    Key University of Glasgow researchers: Jim Cassidy,\u000a      Senior Lecturer (1986-1994) and Chair of\u000a    Medical Oncology (2002-2011); Chris Twelves, Senior Lecturer (1994-2003);\u000a      Stan Kaye, Professor of Medical Oncology (1981-2001); Jeff Evans, Senior\u000a      Lecturer (1996-2005).\u000a    "},{"CaseStudyId":"40505","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    CML is classified as an orphan disease—one so rare that it only affects a\u000a      very small number of\u000a      people and might, therefore, be a low priority for pharmaceutical company\u000a      pipelines. However, if\u000a      left untreated, late-stage CML can be fatal within 3-6 months and its\u000a      prevalence is increasing.\u000a      CML is anticipated to become the commonest leukaemia in the future,\u000a      highlighting the urgent need\u000a      for new therapies.\u000a    Bone marrow transplantation was long considered the only realistic\u000a      treatment for CML, but it is a\u000a      toxic procedure that requires suitable donor tissue and is associated with\u000a      serious side effects and\u000a      high death rates. Crucially, bone marrow transplants cannot be performed\u000a      in older patients and the\u000a      average age of CML onset is 55-60 years. Directed therapy with imatinib\u000a      changed the landscape\u000a      of CML care forever: what was once a deadly disease became a persistent\u000a      but manageable\u000a      condition—many patients now live essentially normal lives after diagnosis.\u000a      Consequently, although\u000a      the incidence of CML remains stable, its prevalence has dramatically\u000a      increased since TKIs became\u000a      widely available.\u000a    University of Glasgow researchers have taken a mechanistic approach to\u000a      understanding the\u000a      factors influencing CML stem cells with a view to identifying new\u000a      therapeutic targets. Holyoake's\u000a      team was the first to demonstrate that TKIs are only the initial step\u000a      towards curing CML. A leading\u000a      expert on CMLa and former winner of the highly prestigious\u000a      Lasker prize for the development of\u000a      imatinib states the importance of this finding: \"Holyoake was the first\u000a        to alert the clinical research\u000a        community to the fact that cancer stem cells could not be killed by\u000a        imatinib. Her work on the\u000a        concept of cancer stem cells has since been confirmed in other blood and\u000a        solid cancers.\"\u000a    Impact on industry\u000a    Holyoake has worked closely with key industrial partners, such as\u000a      Novartis and Bristol-Myers\u000a      Squibb (BMS), acting as consultant, opinion leader and international\u000a      advisor, as well as Principal\u000a      Investigator for numerous international clinical trials.b Her\u000a      research has led to a paradigm shift in\u000a      the research and development (R&D) strategy of the pharmaceutical\u000a      industry, refocusing the\u000a      efforts of major companies towards a cure by pursuing the TKI-resistant\u000a      CML stem cell population,\u000a      which in turn has translated into clinical trials of innovative compounds.b,c\u000a    Novartis, the third largest pharmaceutical company worldwide in 2012, has\u000a      developed a 10-year\u000a      strategy to achieve, \"successful TKI discontinuation and potentially\u000a        provide an operational cure for\u000a        CML patients.\" This strategy was developed at a Novartis Advisory\u000a      Board meeting at which\u000a      Holyoake was the sole UK expert.c The pathogenesis-driven\u000a      pathways identified by Holyoake's\u000a      research were incorporated as key targets for the development of novel\u000a      therapies to be given in\u000a      combination with first-generation or second-generation TKIs. According to\u000a      Novartis,c \"Professor\u000a        Holyoake is one of very few clinician-scientists with a long-standing\u000a        interest and expertise in LSC\u000a        [CML stem cell] biology ... her work has led to the current\u000a        understanding of LSC kinetics in CML\u000a        and the development of possible treatment approaches for the management\u000a        of minimal residual\u000a        disease.\" He continues: \"Novartis Oncology has regularly chosen\u000a        Professor Holyoake to participate\u000a        as an expert advisor on stem cell biology for our global Advisory\u000a        Boards. Professor Holyoake has\u000a        participated in several Novartis-sponsored global clinical trials in CML\u000a        as Principal Investigator.\u000a        Only a limited number of global experts with expertise in the conduct of\u000a        CML trials are chosen for\u000a        this role.\"\u000a    Novel compounds enter clinical trials for CML\u000a    Access to the R&D pipelines of pharmaceutical companies has enabled\u000a      Holyoake and her group to\u000a      identify compounds that kill CML stem cells in the laboratory, providing\u000a      the basis for their\u000a      progression into pioneering clinical trials. For example, a pathway called\u000a      hedgehog, which is\u000a      known to regulate stem cell functions such as growth, death and\u000a      development, was shown to be\u000a      highly active in the CML stem cell population. Pharmacological inhibition\u000a      of this pathway is being\u000a      investigated by both BMS and Novartis.b,c\u000a    University of Glasgow researchers Drs Mhairi Copland and David Irvine are\u000a      listed as co-inventors\u000a      (with three Novartis employees) of the hedgehog blocker LDE225 in a patent\u000a      application filed by\u000a      Novartis in the USA (12\/539855) and more than 15 other countries\u000a      (PCT\/US2010\/045133).d A\u000a      phase I trial of LDE225 plus the TKI nilotinib (NCT01456676) was initiated\u000a      by Novartis in January\u000a      2012 to assess toxicity and maximum tolerated dose. This trial is\u000a      currently recruiting 36 CML\u000a      patients from 17 centres in 9 countries in North America, Europe and Asia.\u000a    Copland also led the correlative stem cell assays for patients recruited\u000a      from all participating centres\u000a      worldwide for a phase I trial of the hedgehog blocker BMS-833923 plus the\u000a      TKI dasatinib\u000a      (NCT01218477).e This dose-assessment study was initiated by BMS\u000a      in January 2011 and\u000a      recruited 27 CML patients from 12 centres in 7 countries in North America\u000a      and Europe (analysis is\u000a      currently underway). The University of Glasgow was the sole UK centre for\u000a      this trial.\u000a    Established drugs offer a fresh approach to treating CML\u000a    Hydroxychloroquine—an antimalarial drug also used to treat inflammatory\u000a      diseases—was shown\u000a      by Holyoake's team to kill CML stem cells by blocking autophagy. Holyoake\u000a      is leading the phase II\u000a      CHOICES study (NCT01227135), the first clinical trial to investigate\u000a      treatment responses to the\u000a      combination of hydroxychloroquine and imatinib. CHOICES began in March\u000a      2010 with the target to\u000a      recruit 66 CML patients from ten centres in the UK, Germany and France. As\u000a      of July 31st 2013, 36\u000a      CML patients have been recruited, 18 of whom have received this\u000a      combination therapy.\u000a    Public engagement\u000a    Holyoake instigated and led the establishment of the Paul O'Gorman\u000a      Leukaemia Research Centre\u000a      (POGLRC), an enterprise funded by more than 1,800 charitable donations\u000a      totalling in excess of\u000a      £2.6 million, many of which were made by CML patients, their families and\u000a      friends. POGLRC\u000a      benefits patients with CML throughout the UK by giving them unprecedented\u000a      access to the latest\u000a      clinical trials. The centre was officially opened on 22nd May 2008 by Dr\u000a      Richard Rockefeller,f,g a\u000a      practicing clinician who himself has CML. Rockefeller donated $200,000\u000a      (approximately £124,000)\u000a      to help launch POGLRC and at the opening ceremony said \"I have chosen\u000a        to support POGLRC\u000a        because among all the world's researchers, Dr Tessa Holyoake and her\u000a        extraordinary staff stand\u000a        out as offering the greatest promise of a medical cure for the leukaemia\u000a        from which I have\u000a        suffered.\"\u000a    Established in 2009, the \"Friends of POGLRC\" is a committee of patients,\u000a      volunteers and donors,\u000a      chaired by Holyoake and administered by University of Glasgow, who raise\u000a      awareness of, and\u000a      conduct fundraising and educational activities for, the centre via social\u000a      media.h The importance of\u000a      cancer stem cells in driving drug resistance of leukaemia is the key\u000a      message conferred through\u000a      laboratory open days and regular newsletters. Over the past 5 years, more\u000a      than 2,000 people have\u000a      taken part in Cycle Glasgow, raising approximately £160,000 for POGLRC.i\u000a      The event is supported\u000a      by local and national companies (including Tunnock's, Costco, Grease\u000a      Monkey Bicycles and\u000a      Overton Farm Shop) who supply food and water for the participants. In\u000a      addition, Tunnock's fields a\u000a      team of fundraisers who to date have raised around £10,000.i In\u000a      August 2008, the profile of this\u000a      event was raised by the participation of record-breaking cyclist and\u000a      broadcaster Mark Beaumont.\u000a      Further events promoted by the Friends of POGLRC have included\u000a      international treks (Vietnam,\u000a      China and Africa, 2010), a zip slide across the river Clyde (2012), gala\u000a      lunches (2012) and a\u000a      fashion show (2013).i\u000a    In November 2009, Holyoake received a Scottish Health Award for her work\u000a      in clinical cancer care\u000a      at a ceremony hosted by the Scottish Government and the Daily Record\u000a      newspaper.j She later\u000a      received an award from the Lord Provost of Glasgow for services to health\u000a      (May 2011). These\u000a      awards honour people who have dedicated their professional lives to public\u000a      service or worked\u000a      selflessly for their communities. In 2013, Holyoake was one of 44 new\u000a      Fellows elected to the\u000a      Academy of Medical Sciences, which \"promotes the best of medical\u000a        science for the benefit of\u000a        society.\"\u000a    ","ImpactSummary":"\u000a    Chronic myeloid leukaemia (CML) is a rare blood cancer, with around 560\u000a      new cases diagnosed in\u000a      the UK each year. Research conducted by Professor Tessa Holyoake's team at\u000a      the University of\u000a      Glasgow has led drug development and stimulated clinical trials of\u000a      therapies targeting CML stem\u000a      cells at two major pharmaceutical companies (Novartis and Bristol-Myers\u000a      Squibb). The researchers\u000a      are listed as co-inventors of a novel compound (LDE225) and have promoted\u000a      two further therapies\u000a      targeting CML stem cells (BMS-833923 and hydroxychloroquine) into clinical\u000a      trials as treatments\u000a      for CML. Holyoake also had a key role in establishing the Paul O'Gorman\u000a      Leukaemia Research\u000a      Centre in May 2008, funded by more than 1,800 charitable donations\u000a      totalling around £2.6 million\u000a      and giving patients unprecedented access to the latest clinical trials.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Holyoake, T.L. et al. Primitive\u000a        quiescent leukemic cells from patients with chronic myeloid\u000a        leukemia spontaneously initiate factor-independent growth in vitro in\u000a        association with up-\u000a        regulation of expression of interleukin-3. Blood 97,\u000a      720-728 (2001) doi:10.1182\/blood.V97.3.720.\u000a    \u000a\u000a2. Graham, S.M. et al. Primitive,\u000a        quiescent Philadelphia-positive stem cells from patients with\u000a        chronic myeloid leukemia are insensitive to STI571 in vitro. Blood\u000a      99, 319-325 (2002)\u000a      doi:10.1182\/blood.V99.1.319.\u000a    \u000a\u000a3. Copland, M. et al. Dasatinib\u000a        (BMS-354825) targets an earlier progenitor population than\u000a        imatinib in primary CML but does not eliminate the quiescent fraction.\u000a      Blood 107, 4532-4539\u000a      (2006) doi:10.1182\/blood-2005-07-2947.\u000a    \u000a\u000a4. Jørgensen, H.G. et al. Intermittent\u000a        exposure of primitive quiescent chronic myeloid leukemia\u000a        cells to granulocyte-colony stimulating factor in vitro promotes their\u000a        elimination by imatinib\u000a        mesylate. Clin. Cancer. Res. 12, 626-633 (2006)\u000a      doi:10.1158\/1078-0432.CCR-05-0429.\u000a    \u000a\u000a5. Bellodi, C. et al. Targeting\u000a        autophagy potentiates tyrosine kinase inhibitor-induced cell death in\u000a        Philadelphia chromosome-positive cells, including primary CML stem\u000a        cells. J. Clin. Invest. 119,\u000a      1109-1123 (2009) doi:10.1172\/JCI35660. [A Hamilton, joint first author]\u000a    \u000a\u000a6. Hamilton, A. et al. Chronic\u000a        myeloid leukemia stem cells are not dependent on Bcr-Abl kinase\u000a        activity for their survival. Blood 119, 1501-1510\u000a      (2012) doi:10.1182\/blood-2010-12-326843.\u000a    \u000aGrant funding\u000a    Medical Research Council. Is the induction of autophagy by tyrosine\u000a        kinase inhibitors a key\u000a        survival mechanism for chronic myeloid leukaemia stem cells? (Feb\u000a      2010-Jan 2013, £1,041,000; T\u000a      Holyoake, principal investigator).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000a    a. Statement from Director, Knight Cancer Institute (available on\u000a      request).\u000a    b. [Text removed for publication]\u000a    c. Statement from Head of Hematology, Novartis Oncology (available on\u000a      request)\u000a    d. LDE225 US (12\/539855)\u000a      and international (PCT\/US2010\/045133)\u000a      patent application (available\u000a      on request)\u000a    e. BMS-833923 clinical trial contract (available on request)\u000a    f. Statement from Dr Richard Rockefeller (available on request)\u000a    g. Opening of POGLRC media coverage, May 2008 in the Herald\u000a      and University\u000a        of Glasgow pressrelease\u000a    h. Friends of Paul O'Gorman\u000a        Facebook page\u000a    i. Fundraising for POGLRC, 2008-2013 (available on request)\u000a    j. Awards media coverage:\u000a    \u000a      \u000aScottish\u000a          Health Awards, Cancer Care Team award presented to Prof Holyoake,\u000a        November\u000a        2009\u000a      \u000a      \u000aLord\u000a          Provost's Awards — Health Award presented to Prof Holyoake, May\u000a        2011\u000a      \u000aFellowship\u000a          of the Academy of Medical Sciences awarded to Prof Holyoake, May\u000a        2013\u000a    \u000a    ","Title":"\u000a    Transforming the treatment of chronic myeloid leukaemia\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Since 1999, a team of University of Glasgow investigators led by\u000a      experimental haematologist\u000a      Professor Tessa Holyoake has conducted research into chronic myeloid\u000a      leukaemia (CML). The\u000a      hallmark of CML is a genetic rearrangement that produces BCR-ABL, a\u000a      chimeric protein\u000a      instrumental in cancer development. BCR-ABL is a tyrosine kinase that\u000a      modulates the functions of\u000a      other proteins and is permanently active in the cancer cells of patients\u000a      with CML. These properties\u000a      of BCR-ABL were exploited by the pharmaceutical industry to create the\u000a      first targeted therapy for\u000a      CML—the tyrosine-kinase inhibitor (TKI) imatinib.\u000a    Holyoake was the first scientist worldwide to demonstrate that all CML\u000a      patients have a pool of\u000a      cancer-forming stem cells (`CML stem cells') that lead to leukaemia in\u000a      experimental animal models\u000a      (1999; work conducted at the Terry Fox Laboratory, Canada). This discovery\u000a      provided the\u000a      cornerstone for her subsequent world-leading research at the University of\u000a      Glasgow.\u000a    In 2001, Holyoake's group demonstrated that CML stem cells from newly\u000a      diagnosed patients\u000a      produced specific factors (cytokines) that switch on key signalling\u000a      pathways to facilitate their\u000a      survival and expansion,1 thereby suggesting a mechanism for the\u000a      growth advantage that CML\u000a      stem cells have over normal cells (which do not produce these cytokines).\u000a      In 2002, the University\u000a      of Glasgow research group published the first study to show that CML stem\u000a      cells are resistant to\u000a      treatment with imatinib because they can survive in a dormant state.2\u000a      This observation highlighted\u000a      a major limitation of imatinib—patients with CML are unlikely to be cured\u000a      by treatment with imatinib\u000a      alone, despite the drug lengthening their lives, because of the persisting\u000a      CML stem cell population.\u000a      In response, pharmaceutical companies developed more-potent TKIs such as\u000a      dasatinib, nilotinib\u000a      and bosutinib. However, research conducted in the Holyoake laboratory\u000a      demonstrated that CML\u000a      stem cells were also resistant to these new compounds,3 leading\u000a      the team to focus on identifying\u000a      novel methods of enhancing the effects of TKIs.\u000a    Holyoake's group discovered that intermittent exposure to granulocyte\u000a      colony-stimulating factor\u000a      forced CML stem cells out of their dormant state, thereby enhancing the\u000a      ability of imatinib to kill\u000a      them (published in 2006).4 Furthermore, the University of\u000a      Glasgow team showed that CML stem\u000a      cells can be killed by compounds that target pathways other than that\u000a      involving BCR-ABL, such as\u000a      those active during cellular responses to environmental signals (e.g.\u000a      stress) and mechanisms that\u000a      prevent cell death. For example, Holyoake's team and their international\u000a      research collaborators\u000a      (see below) showed that treatment with imatinib induced metabolic stress\u000a      and provoked an\u000a      autophagy response in CML stem cells that, by promoting the degradation of\u000a      damaged intracellular\u000a      organelles and cytosolic proteins as an alternative source of energy,\u000a      allowed them to survive the\u000a      toxic effects of the drug.5 By contrast, suppressing autophagy,\u000a      either by knockdown of essential\u000a      autophagy genes or by pharmacological agents such as chloroquine, allowed\u000a      imatinib to more\u000a      effectively kill CML stem cells. The validity of this approach was\u000a      confirmed by the discovery in 2012\u000a      that CML stem cells do not depend on the activity of BCR-ABL to stay\u000a      alive.6 This study showed\u000a      that inhibiting BCR-ABL in a laboratory setting did not affect the ability\u000a      of CML stem cells to survive\u000a      in sub-optimal conditions. Taken together, this body of research\u000a      demonstrates that treatment with a\u000a      TKI alone cannot cure CML because of the residual population of\u000a      TKI-resistant CML stem cells.\u000a    Key University of Glasgow researchers: Tessa\u000a      Holyoake (Professor of Experimental\u000a      Haematology, 1992-present); Mhairi Copland (Clinical Research Fellow,\u000a      2003-2008; Clinical\u000a      Senior Lecturer, 2008-2013; Professor of Translational Haematology,\u000a      2013-present); Heather\u000a      Jørgensen (Research Fellow, 2006-present); Ashley Hamilton (Research\u000a      Assistant, 2004-2010);\u000a      David Irvine (Clinical Research Fellow, 2008-2012, Clinical Lecturer,\u000a      2008-present); G Vignir\u000a      Helgason (Postdoctoral Fellow, 2007-present); Susan Graham (Research\u000a      Assistant, 1999-2006;\u000a      now at Novartis).\u000a    Key external research collaborators: Connie Eaves and\u000a      Xiaoyan Jiang (Terry Fox Laboratory,\u000a      Canada); Paolo Salomoni (University College London, UK); Bruno Calabretta\u000a      (Thomas Jefferson\u000a      University, USA).\u000a    "},{"CaseStudyId":"40939","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The concept of stroke units was first put forward in the 1960s; however,\u000a      they were not widely\u000a      implemented owing to lack of robust evaluation of the benefits and costs.\u000a      University of Glasgow\u000a      research demonstrated conclusively that implementation of specialist\u000a      stroke units can reduce the\u000a      chances of death or serious disability after experiencing a stroke. This\u000a      work also identified key\u000a      factors required for optimum patient care.\u000a    The body of research produced by the University of Glasgow on specialist\u000a      stroke units has\u000a      influenced healthcare provision and policy on an international scale,\u000a      benefiting end-users such as\u000a      clinical and social care staff involved in stroke management, as well as\u000a      patients with stroke. This\u000a      work has raised awareness about the advantages of coherent stroke care and\u000a      driven development\u000a      of clinical guidelines that have been translated into national standards.\u000a    International and national clinical guidelines\u000a    Langhorne was co-chair of the Stroke Units and General Treatments\u000a      subcommittees of the ESO\u000a      from 2006 to 2008. The ESO developed guidelines for management of\u000a      ischaemic stroke and\u000a      transient ischaemic attack that recommended all stroke patients should be\u000a      treated in a stroke unit.a\u000a      These guidelines (published in 2008) directly reference the 2007 edition\u000a      of the Cochrane\u000a      Systematic Review,2 stating \"All types of patients,\u000a        irrespective of gender, age, stroke subtype and\u000a        stroke severity, appear to benefit from treatment in stroke units.\"\u000a      In addition, the 2002 Age and\u000a        Ageing paper4 is cited in the evidence base for\u000a      components of care. The ESO guidelines have\u000a      been translated into 14 languages, including Spanish, Russian and Chinese,\u000a      reflecting the\u000a      authority they possess for improving healthcare standards internationally.\u000a      University of Glasgow\u000a      findings have also helped shape clinical guidelines outside Europe. For\u000a      example, the Australian\u000a      National Stroke Foundation published clinical guidelines in 2010,b\u000a      which explicitly recommend\u000a      improving access to stroke units across the country (Chapter 1\u000a      recommendations, \"organisation of\u000a      services\"), citing research conducted at the University of Glasgow as\u000a      evidence for this approach.2,4\u000a    Since 2004, Langhorne has been a member of the UK Royal College of\u000a      Physicians (RCP)\u000a      Intercollegiate Stroke Working Party tasked with developing the National\u000a        Clinical Guideline for\u000a        Stroke (3rd edition published 2008; revised 2012), which was refined\u000a      in response to the ESO\u000a      guidelines.c The RCP guidelines advocate on-going inpatient\u000a      rehabilitation (recommendation\u000a      3.2.1F), citing the 2007 Cochrane Systematic Review2 in support\u000a      of this recommendation. The\u000a      National Institute for Health and Care Excellence (NICE) guidelines,\u000a      published in 2008,\u000a      acknowledge the contribution of the Cochrane Systematic Review2\u000a      as a \"catalyst for marked\u000a        change in stroke service organisation across the NHS\" (section\u000a      7.1.1).d These guidelines\u000a      recognise specialist care as a key priority for implementation among\u000a      patients with stroke. The\u000a      Scottish Intercollegiate Guidelines Network (SIGN) develops evidence-based\u000a      clinical guidelines for\u000a      NHS Scotland. From 2006 to 2009, Langhorne was vice-chair of the SIGN\u000a      stroke guidelines; these\u000a      guidelines (published in 2008) highlight the need for multidisciplinary\u000a      hospital care\u000a      (recommendation 2.2).e\u000a    National standards and audit\u000a    In order for guidelines to make meaningful changes to clinical practice,\u000a      it is essential that clear\u000a      standards and targets are established and outcomes audited. Langhorne is\u000a      President of the British\u000a      Association of Stroke Physicians (BASP), a UK-wide professional\u000a      organisation that has been\u000a      active in lobbying for national standards of stroke care. BASP has worked\u000a      with both NICE and\u000a      SIGN to achieve this goal.\u000a    The UK government launched a 10-year National Strategy for Stroke\u000a      in 2007 that specifically\u000a      highlighted the requirement for immediate referral of suspected cases for\u000a      specialist assessment.f\u000a      University of Glasgow research, particularly the Cochrane Systematic\u000a      Review, provided the\u000a      evidence base and rationale for specialist stroke units, including\u000a      rehabilitation and leadership in\u000a      stroke care. In 2010, NICE published a stroke quality standard covering\u000a      all phases of the\u000a      integrated care process for adult stroke patients.g This\u000a      document set out \"aspirational but\u000a        achievable\" standards and outcome measures for healthcare\u000a      professionals. These include the\u000a      need to provide evidence of local arrangements to ensure patients with\u000a      suspected stroke are\u000a      admitted directly to a specialist stroke unit (quality statement 3).\u000a    Langhorne is a member of the RCP Intercollegiate Stroke Working Party\u000a      that established and\u000a      oversaw the Sentinel audit of stroke services in NHS England, Wales and\u000a      Northern Ireland.h\u000a      Sentinel evaluated nine key indicators of stroke care among 11,353\u000a      patients and was published in\u000a      2010. Improvements were recorded in 2010 for stroke-related death (17% vs.\u000a      24% in 2004),\u000a      admission to a specialist stroke unit (88% vs. 46% in 2004), length of\u000a      hospital stay (10 days vs. 18\u000a      days in 2004) and institutionalisation (10% vs. 13% in 2006). In all, 88%\u000a      of patients were admitted\u000a      to a stroke unit at some point during their hospital stay (vs. 74% in\u000a      2008) and 60% of patients\u000a      spent the majority of their stay in a stroke unit (vs. 51% in 2006).\u000a      High-quality care (defined as an\u000a      average score of at least 80%) was more likely to be delivered in a stroke\u000a      unit than a general ward.\u000a      In 2010, the National Audit Office reported that all hospitals in England\u000a      now have a stroke unit and\u000a      that they are working to standardise care across these units. The Sentinel\u000a      audit data for NHS\u000a      England showed that the average score for the nine key indicators of\u000a      stroke care had improved\u000a      from 60% in 2006 to 83% in 2010.h The intellectual\u000a      underpinning of these changes has been the\u000a      SUTC Cochrane Systematic Review.2\u000a    Within NHS Scotland, the number of stroke units now exceeds 30 across all\u000a      14 health boards.\u000a      Langhorne and colleagues on the National Advisory Committee for Stroke\u000a      successfully lobbied the\u000a      Scottish Government to establish and implement national standards for\u000a      stroke services. This effort\u000a      culminated in the establishment of `HEAT' targets for rapid access to a\u000a      stroke unit (April 2011).\u000a      Current HEAT targets require local NHS Scotland authorities to achieve a\u000a      rate of 90% of stroke\u000a      patients to be admitted to a stroke unit within 1 day. By March 2013, 80%\u000a      of all Scottish stroke\u000a      patients were admitted within this timeframe, compared with just 49% in\u000a      2005. In all, five NHS\u000a      Scotland health boards exceeded the 2012\/2013 HEAT target.i,j\u000a      Langhorne is also a member of the\u000a      Scottish Stroke Care Audit report writing team, an exercise endorsed by\u000a      the Scottish Cabinet\u000a      Secretary for Health and Wellbeing. The 2013 audit of stroke services\u000a      across Scotland revealed\u000a      that patients admitted quickly to a stroke unit were more likely to be\u000a      treated in line with other quality\u000a      standards (e.g. diagnostic tests, administration of aspirin and brain\u000a      imaging).j\u000a    Accreditation\u000a    Inconsistencies in infrastructure and excellence of stroke care have been\u000a      identified among various\u000a      European countries following conduct of hospital surveys. Langhorne was a\u000a      founding member of\u000a      the ESO Stroke Unit Committee that from 2010 to 2013 worked to establish\u000a      standards and\u000a      accreditations that categorise stroke services into two tiers (unit and\u000a      centre) reflecting the level of\u000a      care available.k The ESO used the SUTC definition of a stroke\u000a      unit — namely, a discrete ward or\u000a      area with specialist stroke staff working as part of a multidisciplinary\u000a      team. By contrast, a stroke\u000a      centre was characterised by a wider infrastructure that also involved\u000a      stroke prevention (raising\u000a      public awareness), emergency services and subsequent rehabilitation. Under\u000a      the ESO scheme,\u000a      which was published in 2013,k hospitals are encouraged to apply\u000a      for certification that ensures\u000a      defined evidence-based organisation and procedural benchmarks are met. The\u000a      aim of these\u000a      accreditations is to help governments recognise differences in stroke care\u000a      between hospitals and\u000a      assist in the standardisation of treatment. The accreditation process is\u000a      currently being piloted\u000a      across Europe.\u000a    Global awareness raising\u000a    Highlighting the benefits of organised stroke care continues to be an\u000a      important goal. In contrast to\u000a      high-income countries, the incidence of stroke is rapidly rising in the\u000a      developing world. Estimates\u000a      suggest that stroke burden in low-income and middle-income countries is\u000a      likely to exceed that of\u000a      malaria and tuberculosis by 2030. The World Stroke Organization (WSO) is\u000a      an umbrella\u000a      organisation of more than 60 societies across 85 countries providing \"one\u000a        world voice\" for stroke\u000a      care. WSO initiatives include the World Stroke Academy (WSA), an online\u000a      educational resource for\u000a      continuing professional development (CPD). In May 2013, Langhorne was\u000a      commissioned by the\u000a      WSA as the sole UK representative on a panel of three experts who created\u000a      the \"Essential stroke\u000a      services\" CPD module to support the international initiative to widen\u000a      access to stroke unit care\u000a      (available online May 2013).l To date, more than 400\u000a      individuals have read the module content,\u000a      and 35 have completed the accompanying CPD assessment.\u000a    ","ImpactSummary":"\u000a    Worldwide, around 5 million stroke-related deaths occur annually, while\u000a      another 5 million people\u000a      are left with chronic disabilities following strokes. University of\u000a      Glasgow research demonstrated\u000a      that admission to a specialist stroke unit significantly improves\u000a      patients' chances of survival and\u000a      recovery. This discovery transformed the culture of stroke service\u000a      delivery in the UK. These studies\u000a      drove the development of new advice in national and international clinical\u000a      practice guidelines and\u000a      promoted the implementation of NHS healthcare targets and audit activities\u000a      to standardise and\u000a      evaluate the quality of stroke care. In the UK, the early death rate after\u000a      stroke has fallen from over\u000a      45% to under 30% in the past 20 years; at least one-fifth of that decline\u000a      is attributed to the\u000a      introduction of stroke units.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Langhorne P, Williams BO, Gilchrist W, Howie K Do\u000a        stroke units save lives? Lancet, 1993; 342:\u000a      395-398 doi:10.1016\/0140-6736(93)92813-9.\u000a    \u000a\u000a2. Stroke Unit Trialists' Collaboration. Organised\u000a        inpatient (stroke unit) care for stroke. Cochrane\u000a        Database of Systematic Reviews 2013, Issue 9. Art. No.: CD000197\u000a      doi:10.1002\/14651858.CD000197.pub3. [Langhorne is the corresponding\u000a      author]\u000a    \u000a\u000a3. Stroke Unit Trialists' Collaboration. Collaborative\u000a        systematic review of the randomised trials of\u000a        organised inpatient (stroke unit) care after stroke. BMJ,\u000a      1997; 314: 1151-1159 doi:\u000a      10.1136\/bmj.314.7088.1151. [Langhorne is the corresponding author]\u000a    \u000a\u000a4. Langhorne P, in conjunction with the Stroke Unit Trialists'\u000a      Collaboration. What\u000a        are the\u000a        components of effective stroke unit care? Age Ageing, 2002;\u000a      31: 365-371 doi:\u000a      10.1093\/ageing\/31.5.365.\u000a    \u000a\u000a5. Govan L, for the Stroke Unit Trialists' Collaboration. Does\u000a        the prevention of complications\u000a        explain the survival benefit of organised inpatient (stroke unit) care?\u000a        Further analysis of a\u000a        systematic review. Stroke, 2007; 38: 2536-2540\u000a      doi:10.1161\/STROKEAHA.106.478842.\u000a      [Langhorne is the corresponding author]\u000a    \u000a\u000a6. Langhorne P et al. Estimating\u000a        the impact of stroke unit care in a whole population: an\u000a        epidemiological study using routine data. J Neurol Neurosurg\u000a        Psychiatry, 2010; 81: 1301-1305\u000a      doi:10.1136\/jnnp.2009.195131.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000a    a. ESO\u000a        guidelines, 2008 (ref 61: p463, 464 and 484; ref 119: p464, 477 and\u000a      478)\u000a    b. National\u000a        Stroke Foundation - Australia guidelines, 2010 (ref 5: p4, 5 and 7;\u000a      ref 41: p4 and 8)\u000a    c. RCP\u000a        guidelines, 2012 (p21)\u000a    d. NICE CG68\u000a        guidelines, 2008 (ref 51: p51, 52, 56 and Table 7.1)\u000a    e. SIGN 108 guidelines,\u000a      2008 (p4).\u000a    f. UK\u000a        Department of Health National Stroke Strategy, 2007 (p30, 36, 52 and\u000a      56)\u000a    g. NICE\u000a        QS2 quality standard, 2010 (p14-16 and 42)\u000a    h. National\u000a        Sentinel Stroke Audit, 2010 (p16-52)\u000a    i. NHS Scotland HEAT\u000a        targets for stroke, 2012-2013\u000a    j. Scottish\u000a        Stroke Care Audit, 2013 (p1-11)\u000a    k. ESO\u000a        accreditation scheme, 2013 doi:10.1161\/STROKEAHA.112.670430\u000a    l. WSA \"Essential\u000a        stroke services\" module, 2013, and usage metrics (available on\u000a      request)\u000a      \u000a    ","Title":"\u000a    Specialist stroke services become the national standard of care\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Stroke is an acute medical emergency with potentially lifelong effects.\u000a      This condition occurs when\u000a      a clot blocks the blood supply to the brain (ischaemic stroke) or when a\u000a      blood vessel in the brain\u000a      bursts (haemorrhagic stroke). Global estimates from the World Health\u000a      Organization (WHO)\u000a      suggest that one in six people will experience a stroke in their lifetime\u000a      and approximately 15 million\u000a      people will have a stroke each year. Research led by University of Glasgow\u000a      researcher Prof Peter\u000a      Langhorne has a long-standing and distinguished reputation in the field of\u000a      clinical stroke care.\u000a    Proof-of-concept for specialist stroke units\u000a    Up until the early 1990s, cohesive clinical approaches to the management\u000a      of stroke patients were\u000a      not routinely adopted. In 1993, clinical researchers at the University of\u000a      Glasgow (Profs Brian\u000a      Williams and William Gilchrist) published a meta-analysis championing the\u000a      role for specialist stroke\u000a      units.1 A stroke unit is a system of organised hospital care\u000a      that allows patients to be managed in a\u000a      dedicated ward by a specialist multidisciplinary team. This integrated\u000a      approach provides access to\u000a      emergency care; diagnostic and imaging tests; clot-busting therapy;\u000a      rehabilitation; supported\u000a      discharge; and a programme of aftercare. The meta-analysis evaluated 1,586\u000a      patients enrolled in\u000a      10 different studies; treatment in a stroke unit rather than a general\u000a      ward led to a 28% reduction in\u000a      mortality. This proof-of-concept study paved the way for grant funding\u000a      from Chest, Heart & Stroke\u000a      Scotland and was used as a framework to campaign for change in stroke\u000a      care.\u000a    Stroke Unit Trialists' Collaboration establishes benefits of\u000a          organised stroke unit care\u000a    Based on the results of this initial study, Langhorne established the\u000a      Stroke Unit Trialists'\u000a      Collaboration (SUTC) in 1994 to take this work forward in an international\u000a      setting. This forward-\u000a      thinking and innovative initiative comprises the co-ordinators of all\u000a      stroke unit trials conducted\u000a      worldwide. Under Langhorne's direction and coordinated by the University\u000a      of Glasgow, the SUTC\u000a      conducts extensive meta-analysis and systematic review of clinical\u000a      outcomes from multiple studies\u000a      to provide reliable estimates of the content, effectiveness and health\u000a      economic impact of stroke\u000a      unit-based care. The first phase of this work was carried out between 1994\u000a      and 1997 and led to\u000a      several publications, including a Cochrane Systematic Review. These\u000a      reviews evaluate primary\u000a      clinical research, and are recognised internationally as the gold standard\u000a      in evidence-based health\u000a      care. First published in 1995, the SUTC Cochrane Systematic Review has\u000a      been regularly revised\u000a      to provide the most up-to-date information on stroke care; the most recent\u000a      edition was published in\u000a      September 2013.2\u000a    Taken together, the University of Glasgow-led SUTC publications\u000a      established that:\u000a    \u000a      Stroke units have characteristic features, such as multidisciplinary\u000a        team-based care and\u000a        defined management pathways, which can be quantified and replicated3,4\u000a\u000a      Patients cared for in a stroke unit are more likely to survive, return\u000a        home and regain\u000a        independence than those placed on a general medical ward; for every 100\u000a        patients treated\u000a        in a stroke unit, there are 4 extra survivors and 6 additional patients\u000a        who return home and\u000a        regain independence2,3\u000a\u000a      The observed benefits are widely applicable since they are independent\u000a        of the clinical\u000a        specialty or patient age, sex, stroke type and severity2,3\u000a\u000a      The benefits of stroke unit care are partly explained through a\u000a        reduction in common\u000a        complications of stroke5\u000a\u000a      Stroke units are likely to be cost effective2\u000a\u000a    \u000a    Ongoing research at the University of Glasgow has demonstrated the\u000a      successful implementation of\u000a      the SUTC evidence in terms of the impact of stroke unit care among\u000a      patients in Scotland during the\u000a      period 1986-2005.6 Admissions to a stroke unit increased from\u000a      0% to 87%; mortality decreased\u000a      from 45% to 29%; and discharges home increased from 46% to 59%.\u000a    Key University of Glasgow researchers: Peter Langhorne\u000a      (Professor of Stroke Care, 1994-\u000a      present); Brian Williams (Honorary Lecturer in Geriatric Medicine,\u000a      1976-2010); William Gilchrist\u000a      (Honorary Lecturer in Geriatric Medicine, 1988-present).\u000a    Key external SUTC collaborators: Martin Dennis (Western\u000a      General Hospital, Edinburgh) and\u000a      Graeme Hankey (University of Western Australia, Australia).\u000a    "},{"CaseStudyId":"40998","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2623032","Name":"Denmark"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Establishment of Bower Cancer Screening Programmes across the world\u000a    The Nottingham trial is one of four randomised trials of population-based\u000a      screening worldwide in support of bowel cancer screening with the Faecal\u000a      Occult Blood (FOB) test [a]. Professor Hardcastle was also instrumental in\u000a      setting up the Danish study that constitutes another of these four trials\u000a      [a].\u000a    The results from the Nottingham Bowel Cancer Screening trial [1] led to\u000a      the development of NHS screening pilots for bowel cancer in Coventry and\u000a      Tayside in 1998. Professors Hardcastle and Scholefield advised the\u000a      Department of Health, and thereby influenced the design and operation of\u000a      the pilots and, through these, the National Bowel Cancer Screening\u000a      Programme itself [a]. Professor Scholefield served on the National Bowel\u000a      Cancer Screening Advisory Board from its inception in 2007 to present and,\u000a      in 2012, became Chair of this Advisory Board. Professor Scholefield is\u000a      also Chair of the Research and Audit Committee for the National Bowel\u000a      Cancer Screening Programme (2008 to present).\u000a    The results of the screening pilots were similar to the Nottingham trial,\u000a      showing a 16% reduction in bowel cancer mortality compared with no\u000a      intervention, and a doubling in the proportion of early-stage cancers\u000a      detected. This led to the introduction of a National Bowel Cancer\u000a      Screening Programme, modelled on the Nottingham criteria for population\u000a      screening [b]. Roll out of the Programme achieved national coverage in\u000a      2010. This involved establishing 5 dedicated screening hubs (one of which\u000a      is in Nottingham), based in secondary care, serving a potential population\u000a      of 10 million people. The hubs send out, process and arrange colonoscopies\u000a      in over 70 national endoscopy units.\u000a    The Nottingham work on FOB screening influenced the introduction of bowel\u000a      cancer screening programmes not only in the UK, but also around the world\u000a      [a]. Since 2008, similar programmes of bowel cancer screening using FOB\u000a      tests have either been rolled out or achieved national coverage in\u000a      Northern Ireland, Scotland and Wales [c]. National bowel cancer screening\u000a      programmes modelled on the UK system using FOB tests are also being\u000a      developed and implemented in Canada [d], Denmark (committed in 2013 to\u000a      introducing a programme in 2014) [e] and Australia [f]. Some of this\u000a      commitment will undoubtedly have been influenced by the `European\u000a      Guidelines for Quality Assurance in Colorectal Cancer Screening and\u000a      Diagnosis', the first edition of which was published in 2010 [g]. This\u000a      publication aims to ensure appropriate quality assurance at all levels\u000a      when performing bowel cancer screening. Our Nottingham research is\u000a      repeatedly cited in these guidelines as evidence for the effectiveness of\u000a      FOB screening.\u000a    Prevention and early detection of bowel cancers\u000a    Since 2008, the National Bowel Cancer Screening Programme in England has\u000a      sent out almost 18 million invitations and detected 16,000 early cancers\u000a      [h]; around 2,000 per annum. Of these, 21.6% were Dukes stage A — early\u000a      cancers with a 95% cure rate by surgical resection alone. Before FOB\u000a      screening became available, only 10-14% of bowel cancers detected in\u000a      symptomatic populations were Dukes stage A [The Lancet\u000a      1993;342(8865),241]. Regular bowel screening thereby increases the\u000a      detection of early-stage cancers and also reduces the risk of dying from\u000a      bowel cancer by 16% [1,b], equating to around 3,500 lives saved in the UK\u000a      per annum.\u000a    Follow up of the Nottingham cohort has also shown that there is a small\u000a      reduction in incidence of bowel cancer (due to removal of large\u000a      precancerous polyps after positive FOB tests), although the sample size\u000a      was too small to enable extrapolation to numbers of cancers prevented [3].\u000a    Health economic benefits\u000a    The health economic benefits of FOB screening for bowel cancer are around\u000a      £1,600 per QALY (quality-adjusted life year) gained [i], much lower than\u000a      the cost per QALY gained for breast cancer screening (£20,800) [BMJ 2013;\u000a      346:f2618]. This means that compared with no screening, FOB-based\u000a      population screening would cost the NHS £1,600 for every extra year of\u000a      perfect health provided.\u000a    Impact on other bowel screening methods\u000a    Through proving the suitability of bowel cancer for a national screening\u000a      programme, and showing that lives would be saved through such a programme,\u000a      our work has paved the way for the development of new screening\u000a      techniques, such as flexible sigmoidoscopy. The current pilot of flexible\u000a      sigmoidoscopy is also dependent on the infrastructure that has been\u000a      established for FOB screening; it is being run from the same five\u000a      screening hubs and is using the same call and recall systems. Incremental\u000a      cost effectiveness analysis [j] has reported that the most cost effective\u000a      strategy is to give flexible sigmoidoscopy at age 55, followed by biennial\u000a      iFOB screening for ages 56-74 year olds. This approach requires six times\u000a      as many screening colonoscopies as the current programme, and the NHS does\u000a      not yet have the skilled personnel nor endoscopic facilities required to\u000a      provide population screening by flexible sigmoidoscopy. In the meantime,\u000a      the current programme of biennial FOB screening for ages 60-74 will remain\u000a      the sole method used in the National Bowel Cancer Screening Programme.\u000a    ","ImpactSummary":"\u000a    The Nottingham Bowel Cancer Screening trial showed that biennial Faecal\u000a      Occult Blood testing reduced bowel cancer mortality by 16%. As a\u000a      consequence of this trial, the Department of Health launched two screening\u000a      pilots and introduced a National Bowel Cancer Screening Programme (NBCSP),\u000a      achieving national coverage in 2010. Since 2008, this has sent out almost\u000a      18 million invitations and detected 16,000 bowel cancers, of which 21.6%\u000a      were early cancers with a 95% chance of cure. It is estimated that the\u000a      NBCSP saves around 3,500 lives each year in the UK. International\u000a      screening programmes modelled on the UK system will save many more.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Hardcastle JD, Chamberlain JO, Robinson MH, Moss Sm, Amar SS,\u000a      Balfour TW, James PD, Mangham CM. Randomised controlled trial of faecal\u000a      occult blood screening for colorectal cancer. Lancet 1996;348:1472-1477\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(96)03386-7\u000a    \u000a\u000a2. Whynes DK, Mangham CM, Balfour TW, Scholefield JH. Analysis\u000a        of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer.\u000a      Gut 2010 Aug;59(8):1088-1093\u000a      http:\/\/dx.doi.org\/10.1136\/gut.2009.192971\u000a    \u000a\u000a3. Scholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle\u000a        JD. Nottingham trial of faecal occult blood testing for colorectal\u000a      cancer: a 20-year follow-up. Gut 2012;61(7);1036-1040\u000a      http:\/\/dx.doi.org\/10.1136\/gutjnl-2011-300774\u000a    \u000a\u000a4. Whynes DK, Neilson AR, Walker AR, Hardcastle JD. Faecal occult\u000a      blood screening for colorectal cancer: is it cost-effective? Health\u000a      Economics 1998, 7: 21-29\u000a      http:\/\/dx.doi.org\/10.1002\/(SICI)1099-1050(199802)7:1<21::AID-HEC306>3.0.CO;2-9\u000a    \u000a\u000a5. Scholefield JH. Immunochemical testing for colorectal cancer.\u000a      Lancet Oncol. 2006 Feb;7(2):101-103\u000a      http:\/\/dx.doi.org\/10.1016\/S1470-2045(06)70549-6\u000a    \u000aGrants\u000a    The Nottingham Bowel Cancer Screening Trial has been funded by the MRC\u000a      over a period of 24 years. Grants covering research from 1993 include:\u000a    • 1989-1995: £186,000 (MRC) to JD Hardcastle `Population screening for\u000a      colorectal cancer — a randomised trial'\u000a    • 1995-1999: £142,000 (MRC) to JD Hardcastle `A randomised trial of\u000a      population screening for colorectal cancer'\u000a    • 1999-2005: £237,000 (MRC) to JH Scholefield `Follow up of the\u000a      Nottingham Screening trial'\u000a    • 2006-2012: 135,000 (MRC) to JH Scholefield `Follow up of the Nottingham\u000a      Screening trial'\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    [a] Letter from Professor J Patnick CBE, Director of NHS Cancer Screening\u000a      Programmes.\u000a    [b] National Bowel Cancer Screening Programme (England):\u000a      http:\/\/cancerscreening.nhs.uk\/bowel\/index.html\u000a    [c] FOB screening programmes in the UK:\u000a      Northern Ireland: http:\/\/www.cancerscreening.hscni.net\/1995.htm\u000a      Scotland: http:\/\/www.nsd.scot.nhs.uk\/documents\/annreports09-10\/bowelsc09-10.pdf\u000a      Wales: http:\/\/www.wales.nhs.uk\/sites3\/docopen.cfm?orgid=747&id=182730\u000a    [d] Bowel Cancer Screening Programme in Canada:\u000a      http:\/\/www.cancerview.ca\/idc\/groups\/public\/documents\/webcontent\/cancer_snapshot_10.pdf\u000a    [e] Bowel Cancer Screening Programme in Denmark (page last modified\u000a      February 2013):\u000a      http:\/\/www.cancer.dk\/international\/english\/Screening+colon+cancer+english\/\u000a    [f] Bowel Cancer Screening Programme in Australia:\u000a      http:\/\/www.cancerscreening.gov.au\/internet\/screening\/publishing.nsf\/Content\/bowel-about\u000a    [g] Segnan N, Patnick J and von Karsa L (eds.) (2010) European\u000a        Guidelines for Quality Assurance in Colorectal Cancer Screening and\u000a        Diagnosis, 1st edition, Luxembourg: Publications Office\u000a      of the European Union. Available on request.\u000a    [h] Email correspondence from Claire Nickerson, Project Manager, NHS\u000a      Cancer Screening Programmes.\u000a    [i] Macafee DA, Waller M, Whynes DK, Moss S, Scholefield JH.\u000a      Population screening for colorectal cancer: the implications of an ageing\u000a      population. Br J Cancer. 2008 Dec 16;99(12):1991 - 2000.\u000a      http:\/\/dx.doi.org\/10.1038\/sj.bjc.6604788\u000a    [j] ScHARR report (see pages 40-42):\u000a      http:\/\/www.cancerscreening.nhs.uk\/bowel\/scharr-full-report-summary-201202.pdf\u000a    ","Title":"\u000a    Saving lives through faecal occult blood screening for bowel cancer\u000a    ","UKLocation":[{"GeoNamesId":"2652221","Name":"Coventry"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Around one in 20 people in the UK will develop bowel cancer during their\u000a      lifetime. The disease kills around 16,000 people each year in the UK, and\u000a      around 608,000 worldwide — mainly because it has non-specific symptoms and\u000a      thus presents at a late stage. Bowel cancers tend to develop slowly from\u000a      colonic polyps over a period of 10-15 years. Removal of these polyps at\u000a      colonoscopy can prevent the polyp from becoming a cancer. Furthermore, the\u000a      slow development of bowel cancers means they can often be detected at an\u000a      early stage, when they are easier to treat. These characteristics make\u000a      bowel cancer an excellent candidate for a population screening programme.\u000a      Faecal Occult Blood (FOB) testing can detect polyps on the lining of the\u000a      bowel, and also early-stage bowel cancers.\u000a    Professor Jack Hardcastle (University of Nottingham) designed and ran the\u000a      Nottingham Bowel Cancer Screening Trial until his retirement in 1996, when\u000a      Professor John Scholefield (also University of Nottingham) took over. The\u000a      trial stopped recruiting in 1995, and follow up of the trial populations\u000a      continued until 2009.\u000a    The Nottingham trial randomised over 150,000 individuals (aged over 60)\u000a      in the Nottingham area, by household, to receive either biennial FOB tests\u000a      or no intervention. It showed a 16% reduction in bowel cancer mortality\u000a      [1,2], which was maintained in follow up to 2009 [3]. The proportion of\u000a      early-stage cancers (Dukes Stage A) detected in the screened groups was\u000a      26%, compared with 13% in the control population. Follow up of the\u000a      Nottingham cohort also showed that there is a small reduction in incidence\u000a      of bowel cancer (due to removal of large polyps after positive FOB tests)\u000a      after a median of 18 years of follow up [3], although the sample size was\u000a      too small to enable extrapolation to numbers of cancers prevented.\u000a    Our group has shown that the health economic benefits (cost per\u000a      quality-adjusted life year [QALY]) of FOB screening for bowel cancer are\u000a      similar to those for breast cancer screening in the short term [4]. Over\u000a      the longer term, the estimates for bowel cancer screening were superior to\u000a      those for breast cancer screening [4]. QALYs are a measure of disease\u000a      burden used to assess the value of a medical intervention. They are based\u000a      on the number of years of life, and the quality of these years, that would\u000a      be added by the intervention. One QALY is one year spent in perfect\u000a      health.\u000a    Population screening with FOB tests is simple, cheap and effective,\u000a      usually detecting bowel cancers before they would present symptomatically.\u000a      A guaiac-based test can be used in conjunction with an immunochemical test\u000a      to help increase sensitivity of FOB screening. Furthermore, automation of\u000a      the test allows manipulation of sensitivity and increased throughput [5].\u000a    "},{"CaseStudyId":"40999","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    Fulvestrant: Development and introduction into worldwide use\u000a      [text removed for publication] [a] [b] [c]. Since registration in 2010,\u000a      fulvestrant 500mg has become the treatment of choice for second-line\u000a      endocrine therapy in\u000a      post-menopausal women, and it is now used as the standard arm in new,\u000a      on-going Phase III registration studies (e.g. FGFR inhibitor [AZD4547\u000a      AstraZeneca], Pi3K inhibitor [BKM120, Novartis], CDK4\/6 inhibitor\u000a      [Palbociclib, Pfizer]) [d].\u000a    [text removed for publication] [a].\u000a    Improving treatment for breast cancer patients: [text removed for\u000a      publication] [b]. Fulvestrant has not only provided another therapeutic\u000a      option to keep BC controlled for longer, but the 500mg dose is also better\u000a      than current options, providing improved treatment outcomes in the second\u000a      line setting — both in terms of disease progression (HR=0.80; P=0.006) and\u000a      overall survival (HR=0.81; p=0.016) [e]. [text removed for publication]\u000a      [a] [f] [g]\u000a    [text removed for publication] [a] [b] [g]\u000a    In summary, translational research at the University of Nottingham,\u000a      combined with a long-term commercial partnership, has changed clinical\u000a      practice and the standard of care and is improving outcomes for hundreds\u000a      of thousands of breast cancer patients worldwide. The impact is also\u000a      increasing year on year (shown by commercial sales) and is expected to\u000a      further increase based on the FALCON trial.\u000a    ","ImpactSummary":"\u000a    As part of a 20 year partnership with AstraZeneca, Professor John\u000a      Robertson, University of Nottingham, has made the largest and most\u000a      consistent contribution by a clinical academic to the development of the\u000a      most recent endocrine agent licensed for breast cancer, fulvestrant\u000a      (Faslodex®). [text removed for publication]. Since 2008, fulvestrant 250mg\u000a      has continued to be registered and launched in a number of countries based\u000a      on Robertson's work, and Robertson has enhanced the clinical uptake of\u000a      fulvestrant 250mg through training. His research has also been\u000a      instrumental in the development and uptake of the more efficacious\u000a      fulvestrant 500mg, including registration in 2010.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Response to a specific antioestrogen (ICI 182,780) in\u000a      tamoxifen-resistant breast cancer. Howell A, DeFriend D, Robertson\u000a          JFR, et al. Lancet 1995;345: 29-30 [IF: 39.06]\u000a      (Scopus citations = 274)\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(95)91156-1\u000a    \u000a\u000a2) Comparison of the short-term biological effects of\u000a      7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5,(10)-triene-3,17beta-diol\u000a     (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Robertson\u000a          JFR, Nicholson RI, Bundred NJ, et al. Cancer Res. 2001; 61:\u000a      6739-6746 [IF:8.65] (SC = 121) (pdf available on request).\u000a    \u000a\u000a3) Fulvestrant, formerly ICI 182,780, is as effective as\u000a      anastrozole in postmenopausal women with advanced breast cancer\u000a      progressing after prior endocrine treatment. Howell A, Robertson\u000a          JFR, Quaresma Albano J, et al. J Clin Oncol. 2002; 20:\u000a      3396-3403 [IF: 18.04] (SC = 356)\u000a      http:\/\/dx.doi.org\/10.1200\/JCO.2002.10.057\u000a    \u000a\u000a4) Fulvestrant versus anastrozole for the treatment of advanced\u000a      breast carcinoma in postmenopausal women: a prospective combined analysis\u000a      of two multicenter trials. Robertson JFR, Osborne\u000a      CK, Howell A, et al. Cancer. 2003; 98: 229-238 [IF: 5.20] (SC = 189)\u000a      http:\/\/dx.doi.org\/10.1002\/cncr.11468\u000a    \u000a\u000a5) Comparison of fulvestrant versus tamoxifen for the treatment of\u000a      advanced breast cancer in postmenopausal women previously untreated with\u000a      endocrine therapy: a multinational, double-blind, randomized trial Howell\u000a      A, Robertson JFR, Abram P, et al. J Clin Oncol. 2004;\u000a      22:1605-1613 [IF: 18.04] (SC=191)\u000a      http:\/\/dx.doi.org\/10.1200\/JCO.2004.02.112\u000a    \u000a\u000a6) Activity of fulvestrant 500 mg versus anastrozole 1 mg as\u000a      first-line treatment for advanced cancer: the results from the FIRST study\u000a      Robertson JFR, Llombart-Cussac A, Rolski J, et al. J Clin\u000a      Oncol. 2009: 27:4530-4535. [IF: 18.04] (SC=69)\u000a      http:\/\/dx.doi.org\/10.1200\/JCO.2008.21.1136\u000a    \u000a\u000a7) Ganitumab with either exemestane or fulvestrant for\u000a      postmenopausal women with advanced, hormone receptor-positive breast\u000a      cancer: a randomised, controlled, double-blind, phase 2 trial Robertson\u000a          JFR, Ferrero J-M, Bourgeois H, et al. Lancet Oncology 2013;\u000a      14: 228-235 [IF: 25.11] http:\/\/dx.doi.org\/10.1016\/S1470-2045(13)70026-3\u000a    \u000aFunding sources include:\u000a    Since 1993, Robertson's research on fulvestrant has been funded primarily\u000a      by AZ, but also by AMGEN and Novartis looking at fulvestrant in\u000a      combination with their drugs. The funding support has been for clinical,\u000a      translational and basic biological studies. Some of the clinical studies\u000a      have been Investigator Initiated Studies and others RCTs by the companies.\u000a      Total funding was £1.2 - £1.5 million.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    [a] Letter from Dr Elizabeth Stott, Vice President, Global Medicines\u000a      Development, AstraZeneca.\u000a    [b] Letter from Larry Norton, Professor of Medicine, Weill Medical\u000a      College of Cornell University and Deputy Physician-in-Chief, for Breast\u000a      Cancer Programs, Medical Director, Evelyn Lauder Breast Cancer Center,\u000a      Memorial Sloan Kettering Cancer Center, New York (Past President of ASCO).\u000a    [c] Email correspondence from Gary Nunn, Global Products Manager,\u000a      AstraZeneca.\u000a    [d] Trials in which fulvestrant 500mg is the standard arm:\u000a      http:\/\/clinicaltrials.gov\/show\/NCT01202591\u000a      http:\/\/clinicaltrials.gov\/show\/NCT01610284\u000a      http:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT01437566\u000a    [e] Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM\u000a      Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in\u000a      Postmenopausal Women With Estrogen Receptor-Positive Advanced Breast\u000a      Cancer. J Clin Oncol 2010; 28:4594-4600.\u000a      http:\/\/dx.doi.org\/10.1200\/JCO.2010.28.8415\u000a    [f] Letter from Sandra Swain, Professor of Medicine, Georgetown\u000a      University and Medical Director, Washington Cancer Institute, MedStar\u000a      Washington Hospital Center (Immediate Past President of ASCO).\u000a    [g] Letter from John Forbes, Professor of Surgical Oncology, University\u000a      of Newcastle, Director, Department of Surgical Oncology, Calvary Mater\u000a      Newcastle Hospital, Newcastle, Australia and Director of Research and a\u000a      member of Board of the Australia and New Zealand Breast Cancer Trials\u000a      Group (ANZBCTG).\u000a    ","Title":"\u000a    The development and introduction to worldwide clinical use of a new\u000a        anti-oestrogen, fulvestrant, in the treatment of breast cancer\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Breast cancer (BC) is the most common female cancer in the world. Between\u000a      650,000 and 780,000 cases of hormone receptor positive tumours in\u000a      postmenopausal women account for 50-60% of all new breast cancer cases\u000a      diagnosed each year. Professor John Robertson has been involved in 13\u000a      clinical trials of fulvestrant since 1992 to present day: 9 as Chief\u000a      Investigator (CI), of which 7 were multi-centre RCTs (3\/7 UK and 4\/7\u000a      international).\u000a    Development of 250mg dose: The first Phase II clinical\u000a      study (performed at Manchester and Nottingham) demonstrated in 1995 that\u000a      fulvestrant 250mg had substantial activity against tumours resistant to\u000a      prior endocrine therapy1. A translational biology study\u000a      confirmed AstraZeneca's initial laboratory findings on fulvestrant's\u000a      distinct mode of action in BC patients (Robertson; CI). It also provided\u000a      pharmacokinetic (PK) data showing dose response up to the highest (250mg)\u000a      dose studied2. In the subsequent clinical programme in\u000a      postmenopausal patients with advanced BC, Robertson was an Investigator in\u000a      one of the two pivotal Phase III trials3 and primary author of\u000a      the published combined analysis4. Of five PK studies, Robertson\u000a      was involved in four (two as CI). These included the study which confirmed\u000a      the unique mechanism of action of fulvestrant2, the two pivotal\u000a      Phase III trials4 and a study on a split dose (2x125mg) for\u000a      data required to meet USA guidelines. The latter study bridged the two\u000a      Phase III clinical trials. Robertson's study showed that a 2 x 2.5mls\u000a      (125mg) injection regimen (USA schedule) was equivalent\u000a      pharmacokinetically to the single 5ml (250mg) dose used in the rest of the\u000a      world [Cancer Chemother Pharmacol. 2003; 52: 346-348]. This facilitated\u000a      registration of the 250mg dose by showing the bioavailability equivalence\u000a      of the two regimens.\u000a    Development of 500mg dose: In 2004, Robertson was an\u000a      investigator in a Phase III study concluding that fulvestrant 250mg was as\u000a      effective as tamoxifen (but not superior) in the first line endocrine\u000a      therapy setting5. Collaboration with Professor Robert Nicholson\u000a      and Dr Julie Gee (both at the Tenovus Institute, Cardiff) had shown\u000a      previously that, while 250mg down-regulated oestrogen receptor (ER)\u000a      significantly more than tamoxifen in the short term, it did not deplete ER\u000a      completely2. In 2004, this collaboration showed that even after\u000a      long-term treatment with 250mg in tumours which showed objective response,\u000a      a reduced level of ER was still detectable. Subsequently, 500mg\u000a      fulvestrant showed greater down-regulation of ER in independent\u000a      translational studies, one from Nottingham, in collaboration with\u000a      Professor Ian Ellis (Oncology, University of Nottingham), and the other by\u000a      Dr Irene Kutter (Massachusetts General Hospital). The CONFIRM RCT\u000a      (Robertson adviser) showed that 500mg was superior to 250mg in second line\u000a      endocrine therapy, and the FIRST RCT (Robertson CI) showed that 500mg was\u000a      superior to an aromatase inhibitor (AI) in the first line endocrine\u000a      setting6. Both trials reported no increase in side-effects\u000a      using the 500mg dose.\u000a    Combination of fulvestrant and other targeted therapies:\u000a      Other research has investigated targeted therapies that might prevent or\u000a      delay the onset of resistance to fulvestrant. An international RCT\u000a      (Robertson, CI) demonstrated that anti-IGFR therapy produced by AMGEN did\u000a      not delay onset of resistance to fulvestrant and, unexpectedly, was\u000a      detrimental to patient outcome7. Critically, this work\u000a      highlighted the importance to patient care of biologically based and\u000a      statistically robust clinical trials.\u000a    Fulvestrant in premenopausal patients: Robertson was also\u000a      CI of a pivotal study concluding that fulvestrant 250mg had no biological\u000a      activity on markers of the ER pathway in premenopausal BC [Eur J Cancer\u000a      2007; 43: 64-70].\u000a    "},{"CaseStudyId":"41000","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Beneficiaries of this research have been: 1) the patients who have\u000a      benefited from earlier detection and therefore improved treatment options\u000a      and outcomes, 2) clinicians who are able to offer their high-risk patients\u000a      improved early detection, 3) shareholders in the spin-out company, and 4)\u000a      the US and UK economies through taxation, legal fees and patent attorney\u000a      and other services.\u000a    Clinical Impact\u000a    Treatment for lung cancer is more successful when the disease is\u000a      diagnosed at an earlier stage. But, currently, 85% of patients with lung\u000a      cancer remain undiagnosed until the disease has reached an advanced stagea.\u000a    EarlyCDT-Lung detects all types and all stages of lung cancer,\u000a      including Stage I and II, and is non-invasive, with no radiation risk for\u000a      the patient. The test is currently marketed for use as `a diagnostic test\u000a      to aid in the early detection of lung cancer in your high-risk patients;\u000a      most notably long-term smokers and ex-smokers'b (ie smokers\u000a      and ex-smokers who quit <15 years previously). It is already\u000a      influencing treatment decisions and saving lives in clinical practice. For\u000a      example, in US pilot studies on smokers, the test `either confirmed\u000a      suspicions of a cancer, or prompted surgical intervention on a cancerous\u000a      nodule previously thought to be benign'c.\u000a    Our team have helped to develop EarlyCDT-Lung as an aid to\u000a      diagnosis in the assessment of pulmonary lung nodules. Around 35-50% of\u000a      individuals undergoing computerised tomography (CT) scanning have lung\u000a      nodules, 96% of which are not malignant. CT scanning detects all of these\u000a      nodules, whether malignant or benign. An EarlyCDT-Lung test\u000a      significant improves the assessment of risk of malignancy of lung nodules,\u000a      thereby impacting on the clinician's decision, and changing patient care.\u000a      When used with CT, a positive EarlyCDT-Lung result can mean\u000a      between a two-fold and five-fold increase in risk of cancer depending on\u000a      the lung nodule size. Because of this, EarlyCDT-Lung is also now\u000a      marketed as `a new tool to stratify pulmonary nodules' for malignancyb,\u000a      especially in the indeterminate nodule (8-20mm) and\/or where PET is not\u000a      indicated or is inconclusive. According to a US clinician `You see these\u000a      indeterminate nodules, and they could be totally harmless and irrelevant\u000a      to health and best left alone. But other patients will have ones that are\u000a      small lung cancers. [The test] has dramatically changed our management of\u000a      things, of how we make our decisions. For some of those patients who we\u000a      had not planned to operate, we have then taken a different approach. When\u000a      the nodules are studied afterwards it has confirmed that it was malignant'c.\u000a    In 2011, the US National Lung Screening Trial (NLST) demonstrated that\u000a      early detection with CT, followed by appropriate treatment, significantly\u000a      reduces deaths from lung cancer by 20% [NEJM 2011; 365, 395-409]. But, CT\u000a      screening has a high false positive rate, is expensive, and `is unlikely\u000a      to achieve a cost effective position to justify national screening'a.\u000a      Commercialisation of the EarlyCDT-Lung test has therefore\u000a      addressed an urgent and unmet clinical need for a pre-CT screening blood\u000a      test — both to widen the entry criteria for CT, and to reduce the number\u000a      of unnecessary CTs performed. `EarlyCDT-Lung will detect\u000a      approximately half the cancers in the screened population and reduce the\u000a      overall number to be followed up with CT to 7%. Having up to half the\u000a      cancers in only 7% of the screening population should make the combination\u000a      of EarlyCDT-Lung followed by CT highly cost effective'a.\u000a    The patient benefits brought by EarlyCDT-Lung have led to the\u000a      NHS-Scotland supported Early Cancer Detection — Lung Cancer Scotland\u000a      (ECLS) studyd, which is assessing the test's feasibility as the\u000a      basis for a national screening programme for lung cancer, as opposed to\u000a      individuals having to request the test themselves. A health economic\u000a      assessment from the US has shown that, on a population basis, use of the\u000a      test as proposed in ECLS should save lives and money: the cost per life\u000a      year gained of CT plus EarlyCDT-Lung was $20,044 (compared with no\u000a      screening) and $19,293 (compared with CT alone)e. The group\u000a      predicted that screening with CT plus EarlyCDT-Lung, or with CT\u000a      alone, would lead to a gain of 6.3 and 5.7 life years, respectivelye.\u000a      [text removed for publication]f.\u000a    Commercial Impact\u000a    The Lachesis regional investment fund initially provided funding [text\u000a      removed for publication] to support the company's goal of `developing\u000a      medical diagnostics for cancer screening, recurrence and therapeutic\u000a      guidance through a patent protected `autoantibody panel' of immunoassays'.\u000a      [text removed for publication]g. In 2006, a US subsidiary\u000a      (Oncimmune LLC) was established to facilitate the FDA oversight and\u000a      Clinical Laboratory Improvement Amendments lab approvals necessary to\u000a      market the test in US federal health program Medicare\/Medicaid cases.\u000a      [text removed for publication]. On the basis of these sales, Health\u000a      Diagnostics Laboratory inc. has acquired the rights to commercialise this\u000a      test in the USh. Commercial utility is evidenced by the cost of\u000a      the test being reimbursed by some private insurance companies and approval\u000a      for reimbursement by Medicare. The test has now also been launched in\u000a      Canada, South America and UKi, with samples being sent to\u000a      Oncimmune LLC for processing. [text removed for publication]h.\u000a    The key drivers for commercial success are:\u000a    i) UoN patentsj which provide Oncimmune with a strong\u000a      position particularly in the USA and Europe, the two largest oncology\u000a      markets in the world. 169 patents are currently enforceable in 12\u000a      Territories, 73% of which have been granted since 2008, with 49 pending.\u000a      These patents cover autoantibody assays to any cancer associated antigen.\u000a      This width of patent protection provided a strong basis for securing the\u000a      investment required to develop the test commercially.\u000a    ii) A solid reproducibility and precise EarlyCDT-Lung assay with\u000a      a sustainable calibration and control system (which also has IP\u000a      protection).\u000a    Professor Robertson has played a central role in bringing a new\u000a      diagnostic test for lung cancer (EarlyCDT-Lung) to market. The\u000a      technology behind EarlyCDT-Lung is applicable to all solid\u000a      cancers. These relatively inexpensive blood tests could be taken up\u000a      readily worldwide, even in resource poor\/developing countries, in which\u000a      around half of all cancers are diagnosed each year.\u000a    ","ImpactSummary":"\u000a    Research directed by Professor John Robertson at The University of\u000a      Nottingham led to the launch, in 2009, of the world's first autoantibody\u000a      blood test for the detection of early-stage lung cancer. The EarlyCDT-Lung\u000a      test has been commercialised through the spin-out company Oncimmune. [text\u000a      removed for publication]. EarlyCDT-Lung is now used clinically in\u000a      North and South America, the UK and the Middle East, generating revenue\u000a      and saving lives.\u000a    ","ImpactType":"Technological","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Robertson JFR, Graves CRL, Price MR. Tumour Markers US\u000a      7,402,403,B1. 1999.\u000a      http:\/\/patft.uspto.gov\/netacgi\/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7402403.PN.&OS=PN\/7402403&RS=PN\/7402403\u000a    \u000a\u000a2) Chapman C, Murray A, Chakrabarti J, Thorpe A, Woolston C, Sahin\u000a      U, Barnes A, Robertson JFR. Autoantibodies in breast\u000a      cancer: their use as an aid to early diagnosis. Ann. Oncol. 2007\u000a      May;18:868-873 [IF: 7.38] http:\/\/dx.doi.org\/10.1093\/annonc\/mdm007\u000a    \u000a\u000a3) Chapman CJ, Murray A, McElveen JE, Sahin U, Luxemburger U,\u000a      Türeci O, Wiewrodt R, Barnes AC, Robertson JFR.\u000a      Autoantibodies in Lung Cancer — possibilities for early detection and\u000a      subsequent cure. Thorax. 2007;63:228-233 [IF: 8.37] http:\/\/dx.doi.org\/10.1136\/thx.2007.083592\u000a    \u000a\u000a4) Murray A, Chapman CJ, Healey G, Peek LJ, Parsons G, Baldwin D,\u000a      Barnes A, Sewell HF, Fritsche HA, Robertson JFR. Technical\u000a      validation of an autoantibody test for lung cancer. Ann Oncol. 2010;\u000a      21:1687-1693 [IF: 7.38] http:\/\/dx.doi.org\/10.1093%2Fannonc%2Fmdp606\u000a    \u000a\u000a5) Boyle P, Chapman CJ, Holdenrieder S, Murray A, Robertson C,\u000a      Wood WC, Maddison P, Healey G, Fairley GH, Barnes AC, Robertson JF.\u000a      Clinical Validation of an Autoantibody Test for Lung Cancer. Ann Oncol.\u000a      2011 22:383-389 [IF: 7.38] http:\/\/dx.doi.org\/10.1093%2Fannonc%2Fmdq361\u000a    \u000a\u000a6) Lam S, Boyle P, Healey GG, Maddison P, Peek L, Murray A,\u000a      Chapman CJ, Allen J, Wood WC, Sewell HF, Robertson JFR.\u000a      2011. EarlyCDT-Lung: an Immuno-biomarker Test as an Aid to Early Detection\u000a      of Lung Cancer. Cancer Prev Res 4;1126-1134 [IF 4.9] http:\/\/dx.doi.org\/10.1158\/1940-6207.CAPR-10-0328\u000a    \u000a\u000a7) Chapman CJ, Thorpe AJ, Murray A, Parsy-Kowalska CB, Allen J,\u000a      Stafford KM, Chauhan AS, Kite TA, Maddison P, Robertson JFR.\u000a      2011. Immuno-biomarkers in small cell lung cancer: Potential early\u000a      clinical signals. Clin. Cancer Res. 17:1474-1480 [IF: 7.84]\u000a        http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-10-1363\u000a    \u000a\u000a8) Jett J, Peek LJ, Fredericks L, Jewell W, Pingleton WW, Robertson\u000a          JFR. Audit of the autoantibody test, EarlyCDT®-Lung, in 1600\u000a      patients: an evaluation of its performance in routine clinical practice.\u000a      Lung Cancer (in press).\u000a    \u000aFunding sources include: Funding for this work from 1993 to 2013\u000a      was awarded to Professor Robertson from a number of sources (e.g. Susan\u000a      Komen, Bayer Diagnostics, Cis Bio International, Nottingham University\u000a      Hospitals [NUHs] Charity, AstraZeneca, Whitaker Charitable Fund,\u000a      Oncimmune, European Union FP5, MRC) and has totalled over £4M.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    a. News article: http:\/\/www.obn.org.uk\/obn_\/news_item.php?r=PD4LIH840341\u000a    b. OncImmune: http:\/\/www.oncimmune.com\/\u000a    c. `New blood test detects cancer before it grows' and `US lung patients\u000a      already feeling the benefits'. The Times, 2010. (Articles available as a\u000a      pdf on request.)\u000a    d. ECLS brochure (pdf available on request).\u000a    e. Weycker D, Jett JR, Detterbeck FC, et al. Cost-effectiveness of an\u000a      autoantibody test (AABT) as an aid to diagnosis of lung cancer. J Clin\u000a      Oncol (2010) 28(15) May 20 Supplement, 7030 http:\/\/meeting.ascopubs.org\/cgi\/content\/abstract\/28\/15_suppl\/7030?sid=91dc6c3d-b385-4e42-aa8a-c2ad35c3324c\u000a    f. Letter from Professor Frank Sullivan, Clinical Director, University of\u000a      Dundee.\u000a    g. OncImmune factsheet and OncImmune accounts 2011\/2012.\u000a    h. HDL press release.\u000a    i. EarlyCDT-Lung launch:\u000a      Canada: http:\/\/www.marketwired.com\/press-release\/oncimmuner-earlycdt-lung-simple-blood-test-aid-early-detection-lung-cancer-now-available-1283347.htm\u000a      UK: http:\/\/www.earlycdt-lung.co.uk\/learn-more\/test_providers-0\/\u000a      South America: http:\/\/www.auroramdx.com\/index.php?country=CL&lang=en\u000a    j. 7 patent families giving rise to 169 granted patents in 12 Territories\u000a      (36 countries) can be identified using: \u000a        http:\/\/patentscope.wipo.int\/search\/en\/search.jsf by entering the\u000a      patent numbers:\u000a    1. WO1999\/58978 2. WO2000\/34787 3.\u000a      WO2004\/044590 4. US20110086061 5. WO2006\/126008 6.\u000a      WO2008\/032084 7. WO2009\/081165\u000a    ","Title":"\u000a    Development and commercial exploitation of a novel diagnostic for\u000a        early detection of lung cancers\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    In the 1990s, established assays for tumour-secreted markers in bodily\u000a      fluids focused on the detection of single proteins that reflected tumour\u000a      bulk and were of value only late in the disease process. In the same\u000a      period, circulating autoantibodies (AABs) were shown to be present before\u000a      tumour-associated antigens (TAAs) could be detected. A research programme\u000a      directed (since 1996) by Professor John Robertson in the Division of\u000a      Surgery, University of Nottingham, identified that AAB response to\u000a      specific panels of TAAs provides an indicator of disease at an early\u000a      stage. Initial research in breast cancer showed that measurement of AABs\u000a      in patient serum to a panel of TAAs, rather than to individual antigens\u000a      per se, increased the sensitivity of detection such that it was possible\u000a      to discriminate normal control individuals, primary breast cancer cases,\u000a      metastatic cancers and asymptomatic BRCA1 mutation (at-risk) carriers with\u000a      95-100% confidence. Measurement of AABs provided enhanced sensitivity of\u000a      detection compared with low levels of antigens. The technology also\u000a      increased specificity compared with other methods since AABs distinguish\u000a      normal and tumour isoforms of antigens. This research was disclosed in a\u000a      patent filed by The University of Nottingham (Inventors: Professors\u000a      Robertson and Mike Price, and Dr Ros Graves) in 19991. The\u000a      patent also included the observation that use of biotinylated TAAs\u000a      expressed in bacteria could form the basis of a high throughput screening\u000a      test. The diagnostic potential of this approach was further supported by\u000a      evaluation of an appropriate TAA marker panel and insight into the type of\u000a      TAA sequences required for efficient AAB detection2.\u000a    The above research and four associated patent families (see section 5)\u000a      from the group led the University to form the spin-out company, Oncimmune,\u000a      in 2003. Oncimmune and University of Nottingham staff were co-located, and\u000a      recruitment to the joint team of Dr Caroline Chapman (postdoctoral\u000a      biochemist) in 2003 and Professor Herb Sewell (Professor of Immunology and\u000a      Consultant Immunologist) in 2005, added significant expertise. Professor\u000a      Robertson has been the Chief Scientific Officer of Oncimmune since the\u000a      formation of the company, and both he and Dr Chapman are University of\u000a      Nottingham inventors on three further patent families generated by\u000a      Oncimmune.\u000a    The primary goal of Oncimmune was to develop a commercial AAB test for\u000a      the early detection of lung cancer; much of the research to achieve this\u000a      was done in collaboration with University of Nottingham researchers. Lung\u000a      cancer is the largest cause of death from cancer worldwide (1.4 million\u000a      deaths per year), and less than 13% of lung cancers in the UK are\u000a      diagnosed at the earliest stages [National Lung Cancer Audit Report 2012].\u000a      This created a substantial market for an early detection test and\u000a      facilitated Oncimmune raising investment that has funded £4.88M research\u000a      in the University team.\u000a    Through European Union 5th Framework funding to Professor\u000a      Robertson, the team demonstrated the potential value of an optimised panel\u000a      of AABs as a means of early detection of lung cancer3. The\u000a      technical validation of the lung cancer assay4 and the first\u000a      clinical evaluation of 655 patients to validate the lung cancer panel5\u000a      was in collaboration with others, including Centres in the US (WC Wood,\u000a      Emory School of Medicine) and Germany (S Holdenrieder, University Hospital\u000a      Munich), and the University of Strathclyde (C Robertson: Statistics).\u000a      These studies demonstrated the sensitivity and specificity of the\u000a      technology in a high risk population. Further datasets including 574\u000a      patients from US, Canada and UK confirmed that 40% of all newly diagnosed\u000a      lung cancer types could be detected reproducibly with very high\u000a      specificity using EarlyCDT-Lung6. In the largest\u000a      prospective cohort study of small cell lung cancer, the sensitivity of the\u000a      test increased to 55% of patients, irrespective of stage of disease7.\u000a      These clinical studies were enabled through collaborations with Nottingham\u000a      University Hospital NHS Trust (P Maddison, D Baldwin), British Columbia\u000a      Cancer Agency (S Lam), International Prevention Research Institute, Lyon\u000a      (P Boyle) and others. A prospective audit of the first 1,600 individuals\u000a      in the USA to buy the test has shown that the test characteristics (i.e.\u000a      sensitivity and specificity) in routine clinical practice8 were\u000a      precisely as predicted from the validation and further (post-validation)\u000a      results. Similarly, an audit of 443 patients with lung nodules has shown\u000a      that whatever the lung nodule size, a positive EarlyCDT-Lung test\u000a      conveys an increased risk that the nodule is malignant (manuscript in\u000a      preparation).\u000a    In 2008, The University of Nottingham and Professor Robertson established\u000a      the UK's first academic Centre of Excellence for Autoimmunity in Cancer\u000a      (CEAC). CEAC and Oncimmune R&D scientists have worked since 2008 to\u000a      develop new AAB tests for hepatocellular and colon cancers that are in\u000a      different stages of development. Their research has also identified that\u000a      AABs provide an individual immune-profile which, when measured in a\u000a      sequential manner, provides improved sensitivity and personalised risk\u000a      assessment. Oncimmune's IP portfolio now has 169 patents currently\u000a      enforceable in 12 Territories (Europe counted as a single Territory), with\u000a      49 pending applications in 12 Territories (Europe counted as one). This\u000a      will help to guarantee investment for the second generation of EarlyCDT\u000a      tests, with the launch for hepatocellular cancer on track for 2014.\u000a    "},{"CaseStudyId":"41001","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000a    Epidemiology and diagnostic criteria tools: Our International\u000a      Study of Asthma and Allergies in\u000a      Childhood (ISAAC: 1.96 million children, 306 research centres in 105\u000a      countries, 53 languages,\u000a      >500 publications) has increased global awareness of the importance of\u000a      eczema as a significant\u000a      childhood disease to policy makers by demonstrating that it is increasing\u000a      and common in\u000a      developing as well as developed countries. The work influenced the\u000a      formation of a National Child &\u000a      Youth Eczema Clinical Network funded by the Ministry of Health and\u000a      Paediatric Society of New\u000a      Zealand in 2012 [a]. This has provided information and training in patient\u000a      education and eczema\u000a      management to nurse specialists, general practitioners and paediatricians,\u000a      and has developed a\u000a      system for monitoring services to inform continuous quality\u000a      improvement.The diagnostic criteria for\u000a      eczema that we developed for ISAAC and other epidemiological studies were\u000a      found to be the best\u000a      validated and widely used criteria worldwide in an independent systematic\u000a      review in 2008 [b]. They\u000a      continue to be the most widely used diagnostic criteria for eczema for\u000a      epidemiological studies\u000a      [PLoS One.2012;7(7):e39803].\u000a    Systematic reviews influencing clinical practice: Our systematic\u000a      review of eczema treatments\u000a      was the major evidence source for the UK NICE guidance on eczema in\u000a      children 2007,\u000a      recommendations of which were taken up from 2008 onwards as in the NICE\u000a      update in 2011 [c],\u000a      SIGN guidance on eczema of all ages in 2011 [d], and international eczema\u000a      guidelines for\u000a      dermatologists, paediatricians and general practitioners in South Africa,\u000a      Europe, New Zealand and\u000a      Japan [e]. The Japanese guidance required a full translation into\u000a      Japanese. As a result of another\u000a      key finding from our review, picked up by our BMJ change page [Br Med J\u000a      2007;334:1272] and\u000a      2011 SIGN Guidance [d], it was recommended that doctors prescribe\u000a      once-daily topical steroids\u000a      rather than more frequent application. This benefits patients and their\u000a      carers by reducing the\u000a      treatment palaver for busy parents, and reducing the risk of side-effects\u000a      like skin thinning. It also\u000a      benefits the NHS by reducing treatment costs from £3.25million to\u000a      £2.44million (2012 prices) [f].\u000a    Clinical Trials — introducing cost-effective treatments and discarding\u000a        ineffective ones:\u000a      Following on from our pioneering research into nurse-led clinics,\u000a      dermatologists in the UK,\u000a      Germany and the Netherlands set up similar clinics from 2005 to 2012,\u000a      which have been shown to\u000a      be cost saving. NICE Guidance including an analysis of the\u000a      cost-effectiveness of nurse-led\u000a      educational interventions for eczema in children concluded that it\u000a      \"appears to be both effective and\u000a      good value for money for children with atopic eczema in secondary care\"\u000a      [c], which has been borne\u000a      out by a subsequent analysis of a large trial of nurse education conducted\u000a      in the Netherlands in\u000a      2010 [Br J Dermatol 2011;165:600-611].\u000a    Our topical corticosteroids trial has been cited 111 times and was used\u000a      to inform the NICE\u000a      guidance updated in 2011 [c]. It was the first trial to evaluate disease\u000a      flares in eczema research\u000a      and has led to a series of trials of \"proactive\" (twice weekly) therapy\u000a      which has reduced eczema\u000a      flares in children and adults by around 50% [g].\u000a    Our trial of water softeners provided clear guidance, showing for the\u000a      first time that these do not\u000a        work for children with eczema. If our work prevented just 10% of the\u000a      estimated 400,000 UK\u000a      families with a child with moderate to severe eczema buying a device over\u000a      the 3-year period\u000a      2011-2013, this would save around £4 million (based on an average cost of\u000a      £750 per unit, plus\u000a      salt and servicing costs).\u000a    Outcomes research: Patient Reported Outcome Measures (PROMs) are\u000a      recommended by the\u000a      Department of Health as critical aspects of measuring clinical care\u000a      outcomes. Our eczema-specific\u000a      PROM, called the Patient-Reported Eczema Measure (POEM), one of three\u000a      eczema severity\u000a      scales that have been appropriately validated and recommended for use, is\u000a      recommended as a\u000a      tool for capturing treatment response in consultations with eczema\u000a      patients by NICE [c] and Map of\u000a      Medicine [h]. POEM is being used in clinical practice to assess the\u000a      severity of eczema and monitor\u000a      treatment outcomes. Quotes describing its impact include `especially good\u000a      as makes assessment\u000a      less subjective' and `very useful resources in a busy clinical setting'\u000a      [i]. Beneficiaries have included\u000a      paediatric dermatology teams at Nottingham, Birmingham, Dewsbury, Oxford,\u000a      Gloucester and\u000a      London, and US care organizations including the Boston Children's Hospital\u000a      and Mayo clinic [i].\u000a    Public engagement in research: Our James Lind Alliance research\u000a      priority setting partnership\u000a      has benefitted NHS funders including the NIHR Efficiency and Mechanism\u000a      Evaluation (EME)\u000a      Programme who, in 2013, issued a special call on skin diseases\u000a      [http:\/\/www.nets.nihr.ac.uk\/funding\/eme-commissioned\/briefs\/13-50-com-brief.pdf].\u000a      The Nottingham Support Group for Carers of Children with Eczema\u000a      (http:\/\/www.nottinghameczema.org.uk),\u000a      which we established in partnership with patients, has\u000a      developed twenty two information sources for patients' benefit covering\u000a      all aspects of eczema, and\u000a      has won several awards. Our University now hosts this website, the value\u000a      and impact of which is\u000a      evidenced by numerous quotes from patients, carers and healthcare\u000a      professionals [j]. Our\u000a      engagement with the public has benefitted outstanding patient volunteers\u000a      such as Amanda\u000a      Roberts [j] who became part of the NICE 2007 and RCPCH 2011 guidelines\u000a      groups. Amanda runs\u000a      a Twitter account on the group's eczema work (@eczemasupport), and has\u000a      over 4,200 followers.\u000a    ","ImpactSummary":"\u000a    Research in the Centre of Evidence Based Dermatology at the University of\u000a      Nottingham has\u000a      improved the lives of children with eczema throughout the world. This has\u000a      been achieved by\u000a      improving the evidence base for clinical care through identifying\u000a      treatments that work and those\u000a      that do not, thus reducing the burden of disease for patients and reducing\u000a      costs for patients and\u000a      the NHS. Clinical care has been improved, economic benefits have been\u000a      realised and Government\u000a      policy informed.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"4930956","Name":"Boston"}],"References":"\u000a    \u000a1. Asher MI, Bjorksten B, Lai CKW, Strachan DP, Weiland SK, Williams\u000a          HC and the ISAAC\u000a      Phase Three Study Group. Worldwide time trends in the prevalence of\u000a      symptoms of asthma,\u000a      allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phase Three\u000a      multicountry cross-sectional\u000a      survey. Lancet 2006:368:733-743. http:\/\/dx.doi.org\/10.1016\/S0140-6736(06)69283-0\u000a    \u000a\u000a2. Hoare C, Li Wan Po A, Williams HC. Systematic review of\u000a      treatments for atopic eczema,\u000a      Health Technol Assess 2000; 4(37):1-191. (cited 333 times) http:\/\/dx.doi.org\/10.3310\/hta4370\u000a      (PDF available on request.)\u000a    \u000a\u000a3. Gradwell C, Thomas KS, English JSC, Williams HC\u000a      An RCT of nurse follow-up clinics: do\u000a      they help patients and do they free up consultants' time? Br J\u000a        Dermatol 2002; 147: 513-517.\u000a      http:\/\/dx.doi.org\/10.1046\/j.1365-2133.2002.04901.x\u000a    \u000a\u000a4. Thomas KS, Armstrong S, Avery A, Li Wan Po A, O'Neill\u000a      C, Williams HC. Randomised\u000a      controlled trial of short bursts of a potent topical corticosteroid versus\u000a      more prolonged use of a\u000a      mild preparation, for children with mild or moderate atopic eczema. BMJ\u000a      2002; 324:768-775.\u000a      http:\/\/dx.doi.org\/10.1136\/bmj.324.7340.768\u000a    \u000a\u000a5. Thomas KS, Dean T, O'Leary C, Sach TH, Koller K, Frost\u000a      A, Williams HC and the SWET\u000a      Trial Team. A randomised controlled trial of ion-exchange water softeners\u000a      for the treatment of\u000a      eczema in children. PLOS Medicine 2011; 8 (2): e1000395\u000a      http:\/\/dx.doi.org\/10.1371\/journal.pmed.1000395\u000a    \u000a\u000a6. Charman CR, Venn AJ, Williams HC. The Patient-Orientated\u000a      Eczema Measure (POEM) — development\u000a      and initial validation of a new tool for measuring atopic eczema severity\u000a      from the\u000a      patients' perspective. Arch Dermatol 2004;140:1513-1519.\u000a      http:\/\/dx.doi.org\/10.1001\/archderm.140.12.1513\u000a    \u000aAttribution and income: Grants to Williams and Thomas that\u000a      underpinned the above research\u000a      included: Department of Health, Meta-analysis of Epogam Trials, 1995-6,\u000a      £10k; NHS R&D Trent\u000a      Region, Outcome measures for atopic eczema, 1998-2001, £105k and Trial of\u000a      topical\u000a      corticosteroids in eczema, 2000-2, £123k; NIHR HTA Programme, Systematic\u000a      review of eczema\u000a      treatments, 1999-2000, £50k and RCT of water softeners for atopic eczema,\u000a      2006-10, £905k;\u000a      NIHR Applied Research Programme Grant, Setting priorities and reducing\u000a      uncertainties in the\u000a      prevention and treatment of people with skin diseases, 2008-13,\u000a      £1,930,000; BUPA Foundation,\u000a      International Study of Asthma and Allergies in Childhood, 2008-11, £179k.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. Email correspondence from Mollie Wilson, Chief Executive Officer,\u000a      Paediatric Society of New\u000a      Zealand.\u000a    b. Brenninkmeijer EE, Schram ME, Leeflang MM, Bos JD, Spuls PI.\u000a      Diagnostic criteria for atopic\u000a      dermatitis: a systematic review. Br J Dermatol. 2008;158:754-765.\u000a      http:\/\/dx.doi.org\/10.1111\/j.1365-2133.2007.08412.x\u000a    c. NICE Guidelines on Management of AE in children (2007): CG57\u000a      http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG057FullGuideline.pdf\u000a      (Although published in Dec 2007,\u000a      this guidance has not been updated since. The findings which relied on our\u000a      systematic review\u000a      (2000) are still relevant and not deemed to require revision despite\u000a      consideration in 2011.\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/11901\/55943\/55943.pdf\u000a      This policy document forms the\u000a      major sole source for many other evidence-based guidelines and patient\u000a      information resources.\u000a    d. Management of atopic eczema in primary care (Number 125, March 2011)\u000a      http:\/\/www.sign.ac.uk\/pdf\/sign125.pdf\u000a    e. Saeki H, Furue M, Furukawa F, et al. Guidelines for management of\u000a      atopic dermatitis. J\u000a        Dermatol. 2009;36:563-577. (PDF available on request.)\u000a      http:\/\/dx.doi.org\/10.1111\/j.1346-8138.2009.00706.x\u000a    f. Economic analysis by Professor R Elliott, Lord Trent Professor of\u000a      Medicines and Health, The\u000a      University of Nottingham.\u000a    g. Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy and\u000a      tolerability of proactive\u000a      treatment with topical corticosteroids and calcineurin inhibitors for\u000a      atopic eczema: systematic\u000a      review and meta-analysis of randomized controlled trials. Br J Dermatol.\u000a      2011;164:415-428.\u000a      http:\/\/dx.doi.org\/10.1111\/j.1365-2133.2010.10030.x\u000a    h. Map of Medicine eczema care pathway (published Nov 2012):\u000a      http:\/\/healthguides.mapofmedicine.com\/choices\/map\/eczema1.html\u000a    i. Table of quotes demonstrating impacts of POEM (see pdf).\u000a    j. Letter from Amanda Roberts, Carer.\u000a    ","Title":"\u000a    Reducing treatment uncertainties for childhood eczema\u000a    ","UKLocation":[{"GeoNamesId":"2648404","Name":"Gloucester"},{"GeoNamesId":"2651286","Name":"Dewsbury"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The Centre of Evidence Based Dermatology at the University of Nottingham\u000a      is internationally\u000a      recognised for the way it has developed evidence-based treatment pathways\u000a      for children with\u000a      eczema by first systematically reviewing all existing evidence to identify\u000a      research gaps, prioritising\u000a      those gaps with patients, and then addressing them through national\u000a      randomised controlled trials.\u000a      Led by Professors Hywel Williams and Kim Thomas (since 1994 and 1999\u000a      respectively), the\u000a      eczema theme is underpinned by relevant international epidemiological and\u000a      outcome measure\u000a      research, and disseminated to a community of over 700 research users and\u000a      its own patient support\u000a      group.\u000a    Epidemiology: The International Study of Asthma and Allergies in\u000a      Childhood (ISAAC), for which\u000a      Williams was eczema lead from 1994 to 2013, has shown that childhood\u000a      eczema affects up to 20%\u000a      of children worldwide [1] and its prevalence is increasing, raising\u000a      awareness of the global\u000a      importance of the disease. ISAAC holds the Guinness World Record for the\u000a      largest epidemiological\u000a      study that has ever been conducted http:\/\/www.guinnessworldrecords.com\/records-3000\/largest-epidemiological-study\u000a    Systematic reviews: In 2000, Williams conducted an over-arching\u000a      systematic review of eczema\u000a      treatments [2], which included 272 trials in 47 treatment categories. The\u000a      review was updated in\u000a      2013 and a further 259 trials were identified. This body of over 500\u000a      eczema trials has helped us to\u000a      identify treatments that work (such as twice-weekly topical\u000a      corticosteroids and ultraviolet light),\u000a      treatments that do not work (such as evening primrose oil) and treatments\u000a      where further research\u000a      is desperately needed (such as the evaluation of commonly used treatments\u000a      including bath\u000a      emollients and antimicrobials). The review also identified for the first\u000a      time that once daily\u000a      application of topical steroids was as effective as more frequent\u000a      application. We have extracted\u000a      key information from the 500+ published trials (including trial design,\u000a      treatments compared, and\u000a      health outcomes collected), and summarised this in a freely accessible\u000a      online database (GREAT\u000a      Database http:\/\/www.greatdatabase.org.uk\/)\u000a      designed to prevent unnecessary international\u000a      duplication of effort in searching and appraising eczema trials for the\u000a      development of systematic\u000a      reviews and guidelines. Our eczema review led us to publish five detailed\u000a      Cochrane reviews and\u000a      an overview of eczema prevention systematic reviews.\u000a    Clinical Trials: Williams and Thomas have conducted five\u000a      randomised controlled trials on the\u000a      prevention or treatment of eczema since 2002 (and a further three are\u000a      ongoing) that focus on\u000a      questions of importance to patients and health professionals. Here, we\u000a      highlight three that have\u000a      contributed to changes in clinical practice or to cost savings for\u000a      families and the NHS:\u000a    (i) Nurse-led clinics and patient education [3] — this was the\u000a      first randomised controlled trial to\u000a      evaluate the role of nurse-led educational clinics alongside dermatology\u000a      consultations in the\u000a      management of patients with chronic skin disease including eczema. It\u000a      showed that patients\u000a      receiving a consultation with the dermatology nurse had enhanced\u000a      understanding of the disease\u000a      and were better able to apply treatments appropriately.\u000a    (ii) Optimal ways of using topical corticosteroids [4] — this\u000a      trial was groundbreaking because it\u000a      studied overall control of disease over a period of months, rather than\u000a      the usual eczema trial of\u000a      6 weeks duration. The study showed that short bursts of stronger\u000a      corticosteroids were as good as\u000a      longer term use of milder preparations, and its novel design set down a\u000a      marker for longer term\u000a      trials on flare prevention in eczema.\u000a    (iii) Water softeners for eczema treatment [5] — this trial\u000a      showed that installing an ion-exchange\u000a      water softener in the home of eczema patients did not result in\u000a      improvements in eczema control.\u000a      Although water softeners are not prescribed via the NHS, our NIHR-funded\u000a      trial was important as\u000a      parents often ask about the role of hard water in exacerbating eczema and\u000a      also whether\u000a      purchasing a water softener would help.\u000a    Diagnostic criteria and outcomes research: In 1993\/1994, Williams\u000a      led the development and\u000a      validation of international diagnostic criteria for eczema used in ISAAC\u000a      [1] and other international\u000a      studies for the following 20 years. Williams and Dr Carolyn Charman (also\u000a      University of\u000a      Nottingham) developed a Patient Reported Outcome Measure (PROM) for eczema\u000a      in 2004 [6] and\u000a      harmonised the 21 named scales for measuring eczema in clinical trials\u000a      into one core set with\u000a      Thomas and an international group of dermatologists, regulators, industry\u000a      and patients in 2012.\u000a    Public engagement in research: In 2011, Thomas and Williams ran a\u000a      James Lind Alliance\u000a      research Priority Setting Partnership on eczema, involving 341 patients\u000a      and 152 clinicians. This\u000a      used consensus methodology to identify 14 priority topics for future\u000a      research. Williams (and other\u000a      clinical colleagues from the award-winning special eczema clinic at\u000a      Nottingham) also helped to\u000a      establish the Nottingham Support Group for Carers of Children with Eczema\u000a      in 2005\u000a      (http:\/\/www.nottinghameczema.org.uk\/).\u000a      This patient support group works with our Centre to\u000a      ensure accurate and up to date patient information on eczema.\u000a    "},{"CaseStudyId":"41002","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2623032","Name":"Denmark"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    The clinical guideline\u000a    The new Clinical Guideline was published by the Royal College of\u000a      Paediatrics and Child Health (RCPCH), with endorsements from additional\u000a      relevant colleges in 2008. It was awarded NHS Evidence\u000a      accreditation in 2010 [a].\u000a    The awareness campaign\u000a    In line with recommended practice, we planned a dissemination strategy\u000a      and acquired funding through a collaborative application involving the\u000a      Children's Brain Tumour Research Centre (CBTRC), RCPCH and The Brain\u000a      Tumour Charity (formerly the Samantha Dickson Brain Tumour Trust) to the\u000a      Closing the Gaps scheme of the Health Foundation. The strategy was\u000a      designed to reduce multiple referrals by highlighting symptom clusters in\u000a      a handy symptom card for the public and profession, and by signposting to\u000a      a decision-support website (www.headsmart.org.uk\/home\/).\u000aThese\u000a      use evidence-based criteria for reassurance, timed review\u000a      and urgent referral for imaging. The information support website\u000a      is linked to relevant NHS websites. Training modules have been developed\u000a      within the HeadSmart website as well as an additional module [b] developed\u000a      in conjunction with the Royal College of General Practitioners (RCGP),\u000a      called `Brain Tumours in Children' (launched from their e-learning\u000a      website). There are also Facebook (facebook.com\/headsmartcampaign)\u000a      and Twitter\u000a      (https:\/\/twitter.com\/HeadSmartUK)\u000a      profiles, and a smartphone app (Text SMART to 81400).\u000a\u000a\u000a\u0009  \u000a    The dissemination campaign, consisting of symptom cards, website and\u000a      media programme, was launched on 11th June 2011 to the\u000a      profession and the public, with political, professional, charity and\u000a      Department of Health support. Watch: HeadSmart\u000a        Launch video.\u000a    Was awareness and confidence raised?\u000a    `The awareness of the signs and symptoms of a childhood brain tumours\u000a      have dramatically increased since the HeadSmart campaign was launched'\u000a      [c]. Around 14 million people were made aware of HeadSmart, equating to\u000a      11% of the UK population [d]. Over 650,000 symptom checklist cards have\u000a      now been distributed, the website has had over 117,000 visits from\u000a      >98,000 unique visitors and is currently (July 2013) experiencing\u000a      >12,000 visits from >11,000 unique visitors per month, the Facebook\u000a      site has >12,000 likes and Twitter has >1,250 followers [e].\u000a      Professional surveys identified that 73% of paediatricians but only 26% of\u000a      GPs were aware of HeadSmart after the launch in 2011 [f]. Amongst\u000a      paediatricians, confidence in making a brain tumour diagnosis rose from\u000a      32% to 54% [f]. In July 2013, the RCGP agreed to disseminate campaign\u000a      materials to its 46,000 membership throughout 2013\/14 [g].\u000a    Were cases diagnosed more quickly?\u000a    Through our clinical guideline and HeadSmart campaign, we `effectively\u000a      decreased the risk of serious consequences associated with delay through\u000a      significantly reducing the time taken to diagnose brain tumours in\u000a      children from 13 weeks to 6 weeks' [g].\u000a    Comparing total diagnostic interval (TDI) data at 3 time points:\u000a    1) In 2006 in 4 centres for one year,\u000a    2) In Jan-June 2011 after Guideline publication in 2008\u000a      and prior to HeadSmart launch;\u000a    3) Post HeadSmart launch until May 2013.\u000a    There was a 52% decrease (p=0.001) in median TDI across these three time\u000a      points, with a 65% decrease (3 weeks to 1 week) in median time from first\u000a      doctor contact to brain scanning. These decreases in median TDI had the\u000a      greatest impact in low grade tumours, compared with high grade tumours,\u000a      and a trend for centrally placed tumours involving optic pathways compared\u000a      with other anatomical sites. The fall in TDI began with the publication of\u000a      our clinical guideline in 2008 [g,h], and HeadSmart built on this, `the\u000a      time to diagnosis being dramatically reduced from 9.2 to 6.9 weeks in just\u000a      two years, summing up the remarkable impact of this campaign' [c].\u000a\u000a\u0009Figure: Time from symptom onset to brain tumour diagnosis has been reduced from a median\/mean of 14.4\/35.4 weeks (2006) to 6.9\/20.4 weeks (2011-2013).\u000a\u0009  \u000a    Our preliminary findings on 1 year survival, disability rates, visual\u000a      impairment rates, public and professional awareness and website usage, are\u000a      the focus of on-going evaluation until 2016, whilst the awareness campaign\u000a      is sustained and augmented. As a result of our lobbying, the National\u000a      Cancer Intelligence Network announced in 2012 that it will collect TDI\u000a      data from children with a brain tumour as part of the cancer registry\u000a      dataset from August 2013 [i]. This will benefit researchers and clinicians\u000a      nationally, and also facilitate our ongoing evaluation of the impacts of\u000a      HeadSmart.\u000a    This strategy is a `world first' in paediatric brain tumour, now being\u000a      emulated in Germany, Denmark, Sweden, Italy and Iran [g,j]. Its excellence\u000a      was acknowledged by an NHS Innovation Award in 2013, worth\u000a      £100,000. As summarised by the RCPCH `Overall, this is an excellent piece\u000a      of work with wide professional and societal impact and has helped ensure\u000a      speedier diagnosis for children with complex conditions as part of\u000a      optimising clinical practice' [h].\u000a    ","ImpactSummary":"\u000a    The University of Nottingham's Children's Brain Tumour Research Centre\u000a      developed new NHS evidence-accredited referral guidelines, published in\u000a      2008, to reduce diagnostic delays for children with brain tumours. Their\u000a      messages were disseminated through an awareness campaign, `HeadSmart — Be\u000a      Brain Tumour Aware', launched in 2011. Three months post-launch, 11% of\u000a      the UK population (over 14 million people) and 73% of paediatricians were\u000a      aware of HeadSmart, and diagnostic confidence among paediatricians had\u000a      risen from 32% to 54%. The time from symptom onset to brain tumour\u000a      diagnosis reduced from 14.4 weeks in 2006 to 6.9 weeks in 2013. This\u000a      strategy is a `world first' in paediatric brain tumour, now being emulated\u000a      internationally.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1) Wilne\u000a      SH, Ferris\u000a      RC, Nathwani\u000a      A and Kennedy\u000a      CR. The presenting features of brain tumours: a review of 200 cases. Arch\u000a      Dis Child. 2006 June;91(6):502-506. (Scopus citation 52) http:\/\/dx.doi.org\/10.1136%2Fadc.2005.090266\u000a    \u000a\u000a2) Wilne S, Collier J, Grundy R and Walker\u000a          D et al, 2012. Progression from first symptom to diagnosis in\u000a      childhood brain tumours. European Journal of Pediatrics. 171(1), 87-93.\u000a      (SC 6) http:\/\/dx.doi.org\/10.1007%2Fs00431-011-1485-7\u000a    \u000a\u000a3) Wilne S, Collier J, Kennedy C, Koller K, Grundy\u000a          R and Walker D. 2007. Presentation of childhood\u000a      CNS tumours: a systematic review and meta-analysis The Lancet Oncology.\u000a      8(8), 685-695 (SC 71)\u000a      http:\/\/dx.doi.org\/10.1016%2FS1470-2045%2807%2970207-3\u000a    \u000aGrants\u000a    • 09\/2003-02\/2006 Walker et al `Tracking delays in diagnosis of brain\u000a      tumours in childhood'. Samantha Dickson Brain Tumour Trust \/ Community\u000a      Fund (Lottery) £105k\u000a    • 09\/2006-08\/2007 Walker et al `Pathways II Introduction of guidance to\u000a      shorten symptom interval' Samantha Dickson Brain Tumour Trust £44,479\u000a    • 11\/2009 - 10\/2011 Walker et al `Brain Pathways: Promoting an earlier\u000a      diagnosis of brain tumours in children'. Health Foundation £409k\u000a    • 2013-2018 David Walker and Richard Grundy, CBTRC Programme Grant, The\u000a      Brain Tumour Charity £1.5m (within this, a programme grant £200k awarded\u000a      for HeadSmart post-doctoral fellowship).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. Sophie Wilne, Karin Koller, Jacqueline Collier, Colin Kennedy, Richard\u000a      Grundy and David Walker (2010) The diagnosis of brain tumours in children:\u000a      a guideline to assist healthcare professionals in the assessment of\u000a      children who may have a brain tumour. Archives of Disease in Childhood.\u000a      95, 534-539. (SC 18): http:\/\/dx.doi.org\/10.1136\/adc.2009.162057\u000a    b. RCGP Training: http:\/\/www.elearning.rcg.org.uk\/course\/info.php?id=99\u000a    c. Letter from Neil Dickson, Founder and Vice-Chair, The Brain Tumour\u000a      Charity.\u000a    d. Media impact report: http:\/\/www.cbtrc.org\/cbtrc\/headsmart\/index.aspx\u000a    e. HeadSmart dissemination summary. Google analytics: HeadSmart website\u000a      traffic data. Provided by Peter Dickens, Head of Communications, The Brain\u000a      Tumour Charity.\u000a    f. The Health Foundation report (also available as a pdf on\u000a      request): http:\/\/www.health.org.uk\/public\/cms\/75\/76\/6270\/3930\/CtGtCC%20HeadSmart%20final%20report.pdf?realName=UT94qs.pdf\u000a    g. Letter from Dr Jane Jones, Assistant Director, The Health Foundation.\u000a    h. Letter from Dr Chris Hanvey, Chief Executive, Royal College of\u000a      Paediatrics and Child Health.\u000a    i. NCIN evidence of NCIN changing strategy to collect TDI data:\u000a      http:\/\/www.ncin.org.uk\/view?rid=1761\u000a      (see first 2 bullet points on slide 9)\u000a    j. Letter from Kathy Oliver, Co-Director, The International Brain Tumour\u000a      Alliance. \u000a    ","Title":"\u000a    Accelerating diagnosis of the UK's biggest childhood cancer killer\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Why children's brain cancer? Brain cancers are the commonest solid\u000a      tumours for children under 16 years, with around 500 being diagnosed in\u000a      the UK annually. Delays in diagnosis are common, risking premature death\u000a      in a few and disability in over 60%, mainly due to brain damage occurring\u000a      around the time of diagnosis. The risk of disability is greatest for the\u000a      youngest, due to their brain's immaturity, and can impair a child's\u000a      acquisition of critical skills, thereby impairing their education. Watch:\u000a      Jake's Video; Sarah's\u000a        Video; All\u000a        they need is a scan\u000a    Why try to accelerate diagnosis? For patients and families,\u000a      reducing unnecessary delays at the critical moment of diagnosis is\u000a      important to boost their confidence in health care, and to improve\u000a      survival and reduce disability of survivors. As tumours detected earlier\u000a      are usually smaller, there is less raised intra-cranial pressure, tumour\u000a      invasion and compression of vital structures, and therefore less brain\u000a      damage. Symptoms that progress during the pre-diagnostic interval are\u000a      consequently less advanced, reducing damage to vision, dexterity,\u000a      mobility, cognition and the brain's control of growth and development.\u000a    Why did this project happen? The University of Nottingham's\u000a      Children's Brain Tumour Research Centre (CBTRC) was established in 1997 to\u000a      initiate research focused upon issues prioritised by children with brain\u000a      tumours and their families. Public concerns about diagnostic delays,\u000a      expressed in the media, in the courts and in Parliament, were very\u000a      prominent and resonated with professional concerns. The median total\u000a      diagnostic interval (TDI) from symptom onset to diagnosis were reported to\u000a      be 12.0-14.4 weeks in the UK, whilst comparable figures in the US and\u000a      Poland were 5 weeks, and Canada, Switzerland and Israel were less than 8\u000a      weeks.\u000a    What research did we do? Professor David Walker, Dr Sophie Wilne,\u000a      Ms JoFen Liu, Professor Richard Grundy, Ms Maya Sussman (all University of\u000a      Nottingham, 1993-2013), and Professor Colin Kennedy (University of\u000a      Southampton), conducted evaluations of regional referral practice in four\u000a      English centres (1981-2006) and a regional audit of referral practice. Dr\u000a      Thomas Chu and Professor Michel Coleman (both London School of Hygiene and\u000a      Tropical Medicine), working with Professor David Walker at the CBTRC,\u000a      studied referral practice across the primary : secondary care interface\u000a      using linked data sets from the National Cancer Registry, primary (CPRD,\u000a      Clinical Practice Research Datalink) and secondary care (HES, Hospital\u000a      Episodes Statistics) electronic records from 1997-2007 in under 24 year\u000a      olds. Together, these studies showed that the current median TDI in four\u000a      English regional units was 14.4 weeks and had not changed over the\u000a      previous 25 years [1,2]. We found that multiple ineffective referrals\u000a      between home, primary and secondary care were occurring prior to\u000a      diagnosis, particularly in patients with the slowest growing tumours. The\u000a      symptom groups that progressed most during the interval from symptom onset\u000a      to diagnosis were those involving visual and motor functions. We decided\u000a      to produce a new clinical referral guideline for the UK, and to develop\u000a      and run an awareness campaign.\u000a    How did we produce the guideline? We conducted a systematic\u000a      literature review and meta-analysis of previous studies describing\u000a      symptomatology [3], which, together with information from referral\u000a      studies, supported a Delphi consensus process with over 150 experienced\u000a      health professionals and parents. 77 consensus statements were accepted,\u000a      and supported the AGREE process which was used to draft a new Clinical\u000a      Guideline.\u000a    What methodology underpinned the awareness campaign?\u000a    The awareness campaign was managed according to Quality Improvement (QI)\u000a      methodology, and included:\u000a    \u000a      Rapid resource development using Plan Do Study Act (PDSA) cycles.\u000a      The selection and application of a QI driver target, a median of 5\u000a        weeks which equals the best reported TDI data in the USA, for service\u000a        change.\u000a      Development of a UK network of Clinical Champions in each of\u000a        the children's cancer treatment centres to communicate the aims and\u000a        methods of the project with their regional paediatric and primary care\u000a        colleagues and collect TDI data from each new case of brain tumour prior\u000a        to and after the Campaign launch.\u000a      A developing network of Community Champions, recruited to\u000a        disseminate the campaign within local communities and media.\u000a    \u000a    "},{"CaseStudyId":"41003","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    Change in practice\u000a      Since 2008, our findings have informed clinical practice guidelines\u000a      nationally [a] and internationally [b]. Both sets of guidelines recommend\u000a      the use of once daily aminoglycosides. The UK guidelines also advise that\u000a      intravenous gentamicin should not be used. Our national survey, conducted\u000a      in the UK in 2002, showed that once daily aminoglycosides were used by\u000a      only 17% of UK CF centres [c]. By 2013, once daily aminoglycoside usage\u000a      had risen to 86% [d]. Out of 22 CF Centres reporting a change in\u000a      aminoglycoside dosing interval, 20 cited our work as a reason for changing\u000a      from three times daily to once daily, and 9 cited the 2009 UK guidelines\u000a      [d]. Similar studies in Australia have shown an increase in once daily\u000a      dosing from 54% in 1999 [e] to 88% in 2009 [f]. The Director of the Adult\u000a      CF Centre in Queensland (also a senior author on references [e] and [f]),\u000a      has stated that the majority of the increase seen in Australia is\u000a      attributable to our work [g]. There are no recent surveys from the US, but\u000a      a once daily regimen is recommended in US guidelines [b]. In 2006, 30% of\u000a      UK CF centres were still using gentamicin. Following the publication of\u000a      our case control study in 2008, and the resulting recommendation in UK\u000a      guidelines against gentamicin in 2009, gentamicin is no longer used as a\u000a      first line aminoglycoside in any UK CF centre [d]. Of 12 centres who have\u000a      stopped using gentamicin, 10 have cited our work as the reason for\u000a      changing their practice [d]. Similarly, our work has been instrumental in\u000a      the switch from gentamicin to tobramycin in Australian CF Centres [g].\u000a    Beneficiaries\u000a    The beneficiaries of this impact are:\u000a    \u000a      People with CF — who, because of the switch from gentamicin to\u000a        tobramycin, are now at reduced risk of acute kidney injury (AKI) — a\u000a        serious treatment related complication.\u000a      People with CF having lung transplantation — who may avoid chronic\u000a        kidney disease, which confers a much worse outcome from lung\u000a        transplantation and greater costs [h].\u000a      Clinicians who care for CF patients — who can deliver effective care\u000a        without compromising safety.\u000a      Those who commission health care — who can pay for an intervention\u000a        which is no more expensive but which has a lower risk of AKI. This\u000a        complication requires expensive and resource intensive management\u000a        (dialysis). The cost of dialysis for AKI in CF is around £3,500 per\u000a        patient and over half of patients with AKI require dialysis.\u000a    \u000a    The cost savings of preventing AKI with a simple strategy of once daily\u000a      aminoglycoside dosing and avoidance of gentamicin are therefore\u000a      considerable.\u000a    Dissemination\u000a      We have disseminated these findings beyond conventional pathways, such as\u000a      presentations at international conferences, publication in the peer\u000a      reviewed literature and incorporation into guidelines. Our group have\u000a      pioneered an innovative approach of engaging with the patient community,\u000a      to share the findings of research in the CF field. Dr Matt Hurley\u000a      (University of Nottingham, School of Medicine) has set up CF Unite [i] — a\u000a      web based public engagement programme (Wellcome Trust People Award 2012,\u000a      £29,624). CF Unite allows patients to have a dialogue with researchers.\u000a      This is achieved without the need for people with CF to meet in person\u000a      (with a risk of cross infection). Dialogue is through:\u000a    \u000a      lay summaries of research published on the website\u000a      webcasts (and archived recordings) of conventional scientific meetings\u000a      bespoke web conferences for patients and their families\u000a      real-time online dialogue between patients, scientists and clinicians.\u000a    \u000a    Lay summaries of the research described in Section 2 have been uploaded\u000a      to the CF Unite website. Feedback from users of CF Unite has been very\u000a      positive; for instance, `I am very grateful for the opportunity to\u000a        hear from these experts. Something that would otherwise be unavailable\u000a        to me' [j]. Since set-up in 2012, CF Unite has had around 10,700\u000a      visits from over 6,500 individuals (one third using mobile devices) [j].\u000a    Through our research on aminoglycosides, and our drive to set up CF\u000a      Unite, we have changed clinical practice, improved the treatment of cystic\u000a      fibrosis and empowered the CF community to become more informed about\u000a      their condition. We plan to use CF Unite to actively seek the advice of\u000a      patients in the design of clinical research and to encourage research\u000a      participation.\u000a    ","ImpactSummary":"\u000a    Research from the University of Nottingham on aminoglycoside antibiotics\u000a      in cystic fibrosis (CF) has changed clinical practice and improved patient\u000a      safety internationally. There are over 70,000 people with CF worldwide.\u000a      Most require frequent and prolonged intravenous courses of aminoglycoside\u000a      antibiotics (which can cause kidney damage) to treat chronic lung\u000a      infection with Pseudomonas aeruginosa. This infection may lead to\u000a      respiratory failure and death. Our research has influenced national and\u000a      international guidelines, and changed practice, such that once-daily\u000a      aminoglycosides (less toxic to the kidneys) are now used. We have also\u000a      stopped the use of gentamicin, in favour of less toxic aminoglycosides.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a[1] Smyth AR, Bhatt J. Once-daily versus multiple-daily\u000a      dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane\u000a      Database Syst Rev. 2012:Issue 2. Art. No.: CD002009. [Update of Cochrane\u000a      Review 1st published in 2000].\u000a      http:\/\/dx.doi.org\/10.1002\/14651858.CD002009.pub4\u000a    \u000a\u000a[2] Smyth A, Tan KHV, Hyman-Taylor P, Mulheran M, Lewis S,\u000a      Stableforth D, et al. Once versus three-times daily regimens of tobramycin\u000a      treatment for pulmonary exacerbations of cystic fibrosis — the TOPIC\u000a      study: a randomised controlled trial. Lancet. 2005;365:573-578.\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(05)17906-9\u000a    \u000a\u000a[3] Bertenshaw C, Watson AR, Lewis S, Smyth A. Survey of\u000a      acute renal failure in patients with cystic fibrosis in the UK. Thorax.\u000a      2007;62:541-545.\u000a      http:\/\/dx.doi.org\/doi:10.1136\/thx.2006.067595\u000a    \u000a\u000a[4] Smyth A, Lewis S, Bertenshaw C, Choonara I, McGaw J,\u000a      Watson A. Case-control study of acute renal failure in patients with\u000a      cystic fibrosis in the UK. Thorax. 2008;63:532-535.\u000a      http:\/\/dx.doi.org\/doi:10.1136\/thx.2007.088757\u000a    \u000a\u000a[5] Quon BS, Mayer-Hamblett N, Aitken ML, Smyth AR, Goss\u000a      CH. Risk Factors for Chronic Kidney Disease in Adults with Cystic\u000a      Fibrosis. Am J Respir Crit Care Med. 2011;184:1147-1152.\u000a      http:\/\/dx.doi.org\/doi:10.1164\/rccm.201105-0932OC\u000a    \u000aGrants\u000a    £404,464 Smyth A. Tobramycin Once-daily Prescribing\u000a      In Cystic fibrosis (TOPIC trial). Cystic Fibrosis\u000a      Trust (project number: PJ467) 1999-2004.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    [a] Antibiotic Treatment for Cystic Fibrosis. Report of the UK Cystic\u000a      Fibrosis Trust Antibiotic Group. London: UK Cystic Fibrosis Trust; 2009.\u000a      (See Section 6.7 `Recommendations'.)\u000a      https:\/\/www.cysticfibrosis.org.uk\/media\/82010\/CD_Antibiotic_treatment_for_CF_May_09.pdf\u000a    [b] Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ,\u000a      et al. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary\u000a      Exacerbations. Am J Respir Crit Care Med. 2009;180:802-808. (See page\u000a      805.)\u000a      http:\/\/www.atsjournals.org\/doi\/pdf\/10.1164\/rccm.200812-1845PP\u000a    [c] Tan KHV, Hyman-Taylor P, Mulheran M, Knox A, Smyth A.\u000a      To the editor: Lack of concordance in the use and monitoring of\u000a      intravenous aminoglycosides in UK cystic fibrosis centers. Pediatr\u000a      Pulmonol. 2002;33:165.\u000a      http:\/\/dx.doi.org\/10.1002\/ppul.10036\u000a    [d] Smyth AR, Campbell EL. Prescribing practices for intravenous\u000a      aminoglycosides in UK Cystic Fibrosis Clinics: a questionnaire survey. J\u000a      Cyst Fibros. 2013:Submitted.\u000a    [e] Phillips JA, Bell SC. Aminoglycosides in cystic fibrosis: a\u000a      descriptive study of current practice in Australia. Intern Med J.\u000a      2001;31:23-26.\u000a      http:\/\/dx.doi.org\/10.1046\/j.1445-5994.2001.00010.x\u000a    [f] Soulsby N, Bell S, Greville H, Doecke C. Intravenous aminoglycoside\u000a      usage and monitoring of patients with cystic fibrosis in Australia. What's\u000a      new? Intern Med J. 2009;39:527-531.\u000a      http:\/\/dx.doi.org\/10.1111\/j.1445-5994.2008.01787.x\u000a    [g] Letter of support from Professor Scott Bell, Director of the Adult\u000a      Cystic Fibrosis Centre Team, The Prince Charles Hospital, Brisbane; and\u000a      also Professor at the University of Queensland.\u000a    [h] Arnaoutakis GJ, George TJ, Robinson CW, Gibbs KW, Orens JB, Merlo CA,\u000a      et al. Severe acute kidney injury according to the RIFLE (risk, injury,\u000a      failure, loss, end stage) criteria affects mortality in lung\u000a      transplantation. J Heart Lung Transplant. 2011;30:1161-1168.\u000a      http:\/\/dx.doi.org\/10.1016\/j.healun.2011.04.013\u000a    [i] CF Unite website: http:\/\/cfunite.org\u000a    [j] Email correspondence from Dr Matthew Hurley, Clinical Research\u000a      Fellow, The University of Nottingham.\u000a    ","Title":"\u000a    Improving the safety of aminoglycoside antibiotics in cystic fibrosis\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Professor Alan Smyth was awarded an honorary appointment with the\u000a      University of Nottingham in 1996 and became a full time university\u000a      employee (Senior Lecturer) in 2004. He is based in the School of Medicine\u000a      and is the co-ordinating editor of the Cochrane Cystic Fibrosis and\u000a      Genetic Disorders Group (http:\/\/cfgd.cochrane.org\/our-contributors).\u000a      This role has been supported by the School and has allowed Professor Smyth\u000a      to publish a number of systematic reviews (six published and one in\u000a      progress).\u000a    The publication of the initial systematic review [1] of once versus\u000a      multiple daily dosing with aminoglycosides in cystic fibrosis (CF) showed\u000a      that there were few trials looking at the optimal dosing regimen and\u000a      insufficient statistical power to say if one regimen is better. This\u000a      Cochrane Review was a key factor in Professor Smyth obtaining a grant\u000a      (£404,464 from the UK CF Trust, awarded 1999) for the definitive clinical\u000a      trial — the TOPIC trial.\u000a    This UK multicentre trial was conducted between 1999 and 2004, and was\u000a      the largest clinical trial in CF ever conducted in the UK, with 244\u000a      participants. Professor Smyth and Professor Alan Knox (also School of\u000a      Medicine, University of Nottingham) were co-principal investigators. The\u000a      trial showed that a once daily regimen in CF patients, using the\u000a      aminoglycoside antibiotic tobramycin, was equally effective and less toxic\u000a      to the kidneys than traditional three times daily dosing [2].\u000a    Professor Smyth went on to undertake a national survey of cases of acute\u000a      kidney injury (AKI) in patients with CF [3]. This showed that the\u000a      incidence risk of AKI was between 5 and 11 cases \/ 10,000 CF patients \/\u000a      year. The median age of presentation was 10 years and the incidence of AKI\u000a      in children with CF was found to be 100 times greater than in the general\u000a      population. The genetic defect of CF is not thought to affect the kidneys\u000a      and so the cause of this increased incidence is likely to be treatment.\u000a      Indeed, 88% of individuals who developed AKI had received an\u000a      aminoglycoside shortly beforehand. These episodes were not trivial — over\u000a      half of the patients required dialysis, for an average of 8 days [3].\u000a    To investigate this link further, Professor Smyth's group performed a\u000a      case control study of AKI in CF [4]. The team collected data from 55 of 56\u000a      CF centres in the UK. This showed that the use of gentamicin, but not\u000a      tobramycin, was associated with a significantly increased risk of acute\u000a      kidney injury.\u000a    Finally, Professor Smyth has collaborated with colleagues in the US to\u000a      conduct a registry-based study of chronic kidney disease [5]. This study\u000a      showed that every year, on average, 2.3% of people with CF develop chronic\u000a      kidney disease, and that the risk doubles with every decade increase in\u000a      age. This is a particular problem for patients with severe lung disease\u000a      who may require a lung transplant, where kidney damage greatly reduces the\u000a      rate of successful transplant.\u000a    "},{"CaseStudyId":"41004","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Our work has led to a paradigm shift in the thinking about and management\u000d\u000a      of perioperative fluid therapy. Initially raising awareness within the\u000d\u000a      professional community, it also informed the development and adoption of\u000d\u000a      clinical guidelines to change clinical practice, resulting in improved\u000d\u000a      surgical outcomes, both nationally and internationally.\u000d\u000a    Increasing awareness\u000d\u000a      Our surveys of junior doctors and consultant surgeons led to an increased\u000d\u000a      awareness of the importance of handling fluid prescriptions. Since 2003,\u000d\u000a      as a result of our surveys, there have been several conferences debating\u000d\u000a      this subject and Professor Lobo has been invited to give over 70 lectures\u000d\u000a      (45 since 2008) at prestigious international meetings and to international\u000d\u000a      societies in six continents. He has also written 4 book chapters on the\u000d\u000a      subject (2 since 2008), as well as a complete book which is now\u000d\u000a      recommended reading for science and medical students in several\u000d\u000a      Universities in the UK and worldwide (e.g. University of Nottingham,\u000d\u000a      University of Leeds and University College, London; and Universities in\u000d\u000a      Sweden, Madrid and New Zealand) [a,b]. It is also recommended reading for\u000d\u000a      members of the European Society for Clinical Nutrition and Metabolism\u000d\u000a      (ESPEN), and was distributed to all 2,500 delegates at the 2013 Conference\u000d\u000a      of the Society. The book has been made freely available with the help of\u000d\u000a      an educational grant from BBraun.\u000d\u000a    Universities have now included a fluid therapy module in undergraduate\u000d\u000a      courses, and fluid therapy forms an important part of postgraduate\u000d\u000a      surgical examinations [c]. In 2008, Professor Lobo developed an\u000d\u000a      international educational course on fluid prescription for health care\u000d\u000a      professionals, with the help of Baxter Healthcare [d]. To date, the course\u000d\u000a      has trained over 1,000 surgeons, anaesthetists, nurses and Operating\u000d\u000a      Department Personnel in the UK and Europe, and has received excellent\u000d\u000a      feedback [d]. Professor Lobo also teaches the fluid therapy module of the\u000d\u000a      Perioperative Care section of the Life Long Learning Course run by ESPEN,\u000d\u000a      for which the book is also recommended reading.\u000d\u000a    Informing clinical guidelines\u000d\u000a      Our findings have been incorporated into national and international\u000d\u000a      guidelines [e-h] that serve to inform optimal perioperative fluid therapy.\u000d\u000a      Our work was instrumental in the set-up of the GIFTASUP and NICE fluid\u000d\u000a      therapy guideline groups, and also in the formulation of the resultant\u000d\u000a      guidelines [e,f]. Our research is also quoted extensively in four sets of\u000d\u000a      clinical guidelines from the Enhanced Recovery After Surgery (ERAS) Group\u000d\u000a      [g] and in the NHS Diabetes guidelines [h]. Guidelines incorporating the\u000d\u000a      findings of our research have been endorsed and publicised by major\u000d\u000a      professional bodies (e.g. BAPEN, ESPEN, AAGBI, ASGBI, Renal Association),\u000d\u000a      nationally and internationally. Professor Lobo has also advised the Renal\u000d\u000a      Association and the Royal College of Physicians of Edinburgh regarding\u000d\u000a      fluid therapy in acute kidney injury.\u000d\u000a    Changing clinical practice\u000d\u000a      Demonstration of the adverse effects of large volumes of 0.9% saline has\u000d\u000a      led to balanced crystalloids being preferred to 0.9% saline [e]. This is a\u000d\u000a      major achievement, considering that until recently the yearly consumption\u000d\u000a      of 0.9% saline was 10 million litres in the UK and 200 million litres in\u000d\u000a      the USA [Clin Nutr 2008,27:179-88; Ann Surg 2012,256:18-24]. Now, largely\u000d\u000a      because of the increased awareness of saline-induced hyperchloraemic\u000d\u000a      acidosis, as demonstrated by our research and subsequent incorporation\u000d\u000a      into guidelines, balanced fluids rather than 0.9% saline are the\u000d\u000a      crystalloids of choice in most hospitals in the UK and Europe.\u000d\u000a    Patients are less likely to be fluid overloaded now than they were at the\u000d\u000a      beginning of the 21st century. Patients who are now maintained\u000d\u000a      in a state of fluid balance have an average of a 3.4 day shorter stay in\u000d\u000a      hospital, and a 41% reduction in relative risk of postoperative\u000d\u000a      complications. This has led to improved quality of life for patients and\u000d\u000a      projected financial benefits to healthcare systems in the UK, Europe and\u000d\u000a      Worldwide. Based on the fact that each year around 182,000 major abdominal\u000d\u000a      operations are performed in England, it has been calculated that this\u000d\u000a      would equate to a total annual saving of £122 million for NHS England [i].\u000d\u000a    Impact on industry\u000d\u000a      Professor Lobo has advised industry (Baxter Healthcare and BBraun) on\u000d\u000a      intravenous fluids and subsequently established research collaborations\u000d\u000a      with these companies [d]. This collaboration has led to both companies\u000d\u000a      investing more in research on balanced crystalloids and how optimal fluid\u000d\u000a      therapy can influence patient outcomes [d]. We are currently collaborating\u000d\u000a      with BBraun on work on fluid physiology in healthy volunteers, and\u000d\u000a      planning a 3 year programme grant on fluid therapy in surgical patients\u000d\u000a      with Baxter Healthcare.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Original research carried out by The University of Nottingham has shown\u000d\u000a      that both knowledge and practice related to perioperative fluid\u000d\u000a      prescribing was poor, resulting in significant and avoidable postoperative\u000d\u000a      morbidity. We have shown that maintaining patients in as near a state of\u000d\u000a      zero fluid balance as possible reduces hospital stay by 3.4 days and\u000d\u000a      complication rate by 41%. Our work guided the formulation of the British\u000d\u000a      Consensus Guidelines and NICE Guidelines on intravenous fluid therapy for\u000d\u000a      adult surgical patients. It has also reduced the frequency of\u000d\u000a      postoperative fluid overload, and led to improved patient outcome and\u000d\u000a      potential financial benefits of £122m per year for NHS England.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Nottingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3117735","Name":"Madrid"}],"References":"\u000d\u000a    \u000a1. Lobo DN, Bostock KA, Neal KR, et al. Effect of salt and\u000d\u000a      water balance on recovery of gastrointestinal function after elective\u000d\u000a      colonic resection: a randomised controlled trial. Lancet. 2002 May\u000d\u000a      25;359(9320):1812-1818.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(02)08711-1\u000d\u000a    \u000a\u000a2. Varadhan KK, Lobo DN. A meta-analysis of randomised\u000d\u000a      controlled trials of intravenous fluid therapy in major elective open\u000d\u000a      abdominal surgery: getting the balance right. Proc Nutr Soc. 2010\u000d\u000a      Nov;69(4):488-498.\u000d\u000a      http:\/\/dx.doi.org\/10.1017\/S0029665110001734\u000d\u000a      Epub 2010 Jun 2. Erratum in: Proc Nutr Soc. 2010 Nov;69(4):660.\u000d\u000a      http:\/\/dx.doi.org\/10.1017\/S0029665110002028\u000d\u000a    \u000a\u000a3. Lobo DN, Dube MG, Neal KR, et al. Problems with\u000d\u000a      solutions: drowning in the brine of an inadequate knowledge base. Clin\u000d\u000a      Nutr. 2001 Apr;20(2):125-130.\u000d\u000a      http:\/\/dx.doi.org\/10.1054\/clnu.2000.0154\u000d\u000a    \u000a\u000a4. Reid F, Lobo DN, Williams RN, et al. (Ab)normal saline\u000d\u000a      and physiological Hartmann's solution: a randomized double-blind crossover\u000d\u000a      study. Clin Sci (Lond). 2003 Jan;104(1):17-24.\u000d\u000a      http:\/\/www.clinsci.org\/cs\/104\/0017\/1040017.pdf\u000d\u000a    \u000a\u000a5. Lobo DN, Stanga Z, Aloysius MM, et al. Effect of volume\u000d\u000a      loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated\u000d\u000a      gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume\u000d\u000a      and endocrine responses: a randomized, three-way crossover study in\u000d\u000a      healthy volunteers. Crit Care Med. 2010 Feb;38(2):464-470. (PDF available\u000d\u000a      on request.)\u000d\u000a      http:\/\/dx.doi.org\/10.1097\/CCM.0b013e3181bc80f1\u000d\u000a    \u000a\u000a6. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A\u000d\u000a      randomized, controlled, double-blind crossover study on the effects of 2-L\u000d\u000a      infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity\u000d\u000a      and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012\u000d\u000a      Jul;256(1):18-24. (PDF available on request.)\u000d\u000a      http:\/\/dx.doi.org\/10.1097\/SLA.0b013e318256be72\u000d\u000a    \u000aGrants (all awarded to Dileep N Lobo):\u000d\u000a    • 1999-2001. £76,000 from the Special Trustees of Nottingham University\u000d\u000a      Hospitals: Physiological aspects of fluid and electrolyte balance.\u000d\u000a    • 1999. €15,000 from ESPEN (European Society for Enteral and Parenteral\u000d\u000a      Nutrition): The effects of salt and water overload on gastrointestinal\u000d\u000a      function in the postoperative period.\u000d\u000a    • 1999. £2,000 from Nutricia Clinical Care: Mechanisms of\u000d\u000a      hypoalbuminaemia.\u000d\u000a    • 2010. £48,000 from Baxter Health Care: The effects of crystalloid and\u000d\u000a      colloid infusions on renal and superior mesenteric blood flow.\u000d\u000a    • 2012-2013. £78,000 from the European Hydration Institute: The effect of\u000d\u000a      hydration status at admission on clinical outcomes.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000d\u000a    [a] Letter from Dr G Grimble, Prinicipal Teaching Fellow, University\u000d\u000a      College London.\u000d\u000a    [b] Letter from Professor O Ljungqvist, Professor of Surgery, Orebro\u000d\u000a      University Hospital, Sweden.\u000d\u000a    [c] Intercollegiate surgical curriculum programme; Module 5\u000d\u000a      `Peri-operative care of the surgical patient' — `To assess, plan and\u000d\u000a      manage post-operative fluid balance':\u000d\u000a      https:\/\/www.iscp.ac.uk\/surgical\/SpecialtySyllabus.aspx?enc=j4VfyFXq6Hwh0loAlHujtkC075cafAX8g\/MdvMtfyBw\u000d\u000a    [d] Letter from Carol R. Schermer, Medical Director, Baxter Healthcare.\u000d\u000a    [e] Powell-Tuck J, Gosling P, Lobo DN, et al.\u000d\u000a      British consensus guidelines on intravenous fluid therapy for adult\u000d\u000a      surgical patients. GIFTASUP. 2008 British Association for Parenteral and\u000d\u000a      Enteral Nutrition: http:\/\/www.bapen.org.uk\/pdfs\/bapen_pubs\/giftasup.pdf\u000d\u000a    [f] National Clinical Guidance Centre. Intravenous fluid therapy:\u000d\u000a      Intravenous fluid therapy in adults in hospital. Draft for consultation.\u000d\u000a      Commissioned by the National Institute for Health and Care Excellence. May\u000d\u000a      2013: http:\/\/www.nice.org.uk\/nicemedia\/live\/13298\/63879\/63879.pdf\u000d\u000a      (see section 7)\u000d\u000a    [g] Enhanced Recovery After Surgery (ERAS®) Society recommendations:\u000d\u000a      Lassen K, Soop M, Nygren J, et al; Enhanced Recovery After Surgery (ERAS)\u000d\u000a      Group. Consensus review of optimal perioperative care in colorectal\u000d\u000a      surgery. Arch Surg. 2009 Oct;144(10):961-969: http:\/\/dx.doi.org\/10.1001\/archsurg.2009.170\u000d\u000a    Other ERAS guidelines for:\u000d\u000a      - pancreaticoduodenectomy: http:\/\/dx.doi.org\/10.1007\/s00268-012-1771-1\u000d\u000a      - elective rectal\/pelvic surgery: http:\/\/dx.doi.org\/10.1007\/s00268-012-1787-6\u000d\u000a      - elective colonic surgery: http:\/\/dx.doi.org\/10.1007\/s00268-012-1772-0\u000d\u000a    [h] Dhatariya K, Levy N, Kilvert A, Watson B, Cousins D, Flanagan D,\u000d\u000a      Hilton L, Jairam C, Leyden K, Lipp A, Lobo D,\u000d\u000a      Sinclair-Hammersley M, Rayman G; Joint British Diabetes Societies. NHS\u000d\u000a      Diabetes guideline for the perioperative management of the adult patient\u000d\u000a      with diabetes. Diabet Med 2012; 29: 420-433: http:\/\/dx.doi.org\/10.1111\/j.1464-5491.2012.03582.x\u000d\u000a    [i] Economic analysis by Professor R Elliott, Lord Trent Professor of\u000d\u000a      Medicines and Health, The University of Nottingham.\u000d\u000a    ","Title":"\u000d\u000a    Improving patient outcome by optimising perioperative fluid therapy\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Although fluid and electrolytes are the most frequently prescribed drug\u000d\u000a      in hospitals, prescribing practices were often suboptimal (and still are\u000d\u000a      in a few cases), resulting in avoidable perioperative morbidity and\u000d\u000a      mortality. The work carried out in this field in The University of\u000d\u000a      Nottingham since 1999 (undertaken mainly by Professor Dileep N Lobo, and\u000d\u000a      Professors Simon Allison and Brian Rowlands, who retired in 2004 and 2009,\u000d\u000a      respectively) has influenced national and international guidance, thereby\u000d\u000a      improving care and saving money.\u000d\u000a    In 1999, the UK National Confidential Enquiry into Perioperative Deaths\u000d\u000a      estimated that 20% of patients had either poor documentation of fluid\u000d\u000a      balance or unrecognised \/ untreated fluid imbalance [http:\/\/www.ncepod.org.uk\/pdf\/1999\/99full.pdf;\u000d\u000a      page 68]. It also reported that a significant number of patients were\u000d\u000a      dying as a result of the infusion of too much or too little fluid by\u000d\u000a      doctors and practitioners who had little knowledge and training on the\u000d\u000a      subject. Furthermore, in 2005, a small study in the Wirral estimated that\u000d\u000a      each year in the UK, around 17% of surgical patients (approximately 42,500\u000d\u000a      individuals) have complications that can be directly related to\u000d\u000a      mismanagement of fluid therapy [Ann R Coll Surg Engl 2005;87:126-130].\u000d\u000a      Based on these data, we undertook telephone and postal surveys of junior\u000d\u000a      doctors [Clin Nutr 2001;20:125-30] and consultant surgeons [Ann R Coll\u000d\u000a      Surg Engl 2002;84:156-60]. We found that over 90% of fluid prescription\u000d\u000a      was done by the most junior member of the surgical team, who often\u000d\u000a      prescribed too much fluid and sodium to their patients, and that the\u000d\u000a      seniors did not pay much attention to these prescriptions. The knowledge\u000d\u000a      base was poor and there was a lot of confusion between maintenance,\u000d\u000a      replacement and resuscitation requirements. Both knowledge and practice\u000d\u000a      related to fluid and electrolyte prescribing in the UK was suboptimal and\u000d\u000a      it was clear that a paradigm shift was necessary to improve clinical\u000d\u000a      practice and patient outcomes.\u000d\u000a    We published a landmark clinical trial in the Lancet [1] (cited >290\u000d\u000a      times as of July 2013), demonstrating that a cumulative fluid overload of\u000d\u000a      as little as 3 litres in the first 4 postoperative days led to intestinal\u000d\u000a      failure and increased complications when compared with patients in zero\u000d\u000a      fluid balance. These results have since been corroborated by others in\u000d\u000a      several randomised trials (e.g. Ann Surg 2003,238:641-8; Anesthesiol\u000d\u000a      2005,103:25-32; Ann Surg 2009,250:28-34). Our meta-analysis [2] of these\u000d\u000a      confirmed that patients in a state of fluid imbalance have a 3.4 day\u000d\u000a      longer hospital stay and a 41% greater complication rate than those\u000d\u000a      maintained in a state of fluid balance.\u000d\u000a    We corroborated these findings in numerous physiological studies, which\u000d\u000a      demonstrated how healthy volunteers handle intravenous fluid loads. These\u000d\u000a      showed that compared with balanced crystalloids, 0.9% saline, even in\u000d\u000a      modest doses, causes a hyperchloraemic acidosis that persists for more\u000d\u000a      than six hours after the infusion [3,4]. We also showed that saline causes\u000d\u000a      increased interstitial fluid overload and oedema compared with balanced\u000d\u000a      crystalloids [5,6], and this finding has been corroborated by others.\u000d\u000a    This work enabled us to confirm that the hyperchloraemia caused by saline\u000d\u000a      overload can lead to a decrease in renal arterial blood flow and cortical\u000d\u000a      tissue perfusion, a phenomenon we demonstrated in humans for the first\u000d\u000a      time [6]. Subsequently, others have shown that chloride excess can lead to\u000d\u000a      more patients developing acute kidney injury and needing renal replacement\u000d\u000a      therapy [Ann Surg 2012,255:821-9; JAMA 2012,308:1566-72]. We have also\u000d\u000a      analysed differences in the way the body handles crystalloid and colloid\u000d\u000a      infusions, and have developed a reproducible human model for the study of\u000d\u000a      the responses to fluid infusions.\u000d\u000a    "},{"CaseStudyId":"41005","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    In the early 1990s, little research on lymphangioleiomyomatosis (LAM) had\u000a      been performed, no effective treatments were available and patients with\u000a      LAM were told they would die within 5-10 years. Following on from\u000a      Professor Johnson's two key papers1,2, his group's subsequent\u000a      research papers and widely cited reviews continued to increase the profile\u000a      of LAM, as shown by an approximately five-fold increase in research papers\u000a      on LAM from the 1990s to 2010, and by the setting up of a European\u000a      Respiratory Society Task Force (in 2005) and a European LAM Organisation\u000a      (in 2009) that has regular research and patient meetings.\u000a    The group's work has been instrumental in showing that widely used\u000a      treatments are ineffective, and in identifying a treatment that does work.\u000a      This, and their role in establishing a patient support group and the\u000a      National Centre for LAM, has transformed the outlook for patients with\u000a      this disease, and vastly improved the patient experience. This program of\u000a      work at the University of Nottingham has resulted in benefits for patients\u000a      with LAM, the pharmaceutical industry and, more recently, patients with\u000a      other cancers for which mTOR inhibitors are being trialled.\u000a    Informing clinical guidelines\u000a    Professor Johnson led a European Task Force, funded by the European\u000a    Respiratory Society, to form an evidence synthesis which, in 2010, published\u000a    the first international diagnostic and clinical management guidelines for\u000a    LAMa. These incorporated data from Nottingham's clinical research\u000a    papers in eight of 112 cited references, including their 2008 study showing\u000a    effective treatment of LAM with the mTOR inhibitor Sirolimus. Sirolimus was\u000a    recommended in these guidelines for treatment of patients with progressive\u000a    lung, kidney and lymphatic disease, and has been funded by National\u000a    Specialised Commissioning since 2011. Their work has also been cited in US\u000a    guideline statements for treatment of LAM (American Thoracic Society LAM\u000a    guidelines group) and TSC (Tuberous Sclerosis Alliance guideline group)b.\u000a    Johnson represents Europe on both of these groups.\u000a    The group's findings that commonly used, anti-oestrogen treatments were\u000a      ineffective in the treatment of LAM have also been picked up by\u000a      guidelines, such that anti-oestrogen therapy is advised against in the\u000a      Europeana and North Americanb guidelines.\u000a    Following on from their work highlighting that a definite diagnosis can\u000a      usually be made using imaging alone without need for invasive\u000a      investigations6, this strategy is now used at the UK LAM Centrec\u000a      and other units. This, and their finding that early surgical management of\u000a      pneumothorax can reduce morbidity2, were adopted in 2011 as\u000a      quality indicators of patient outcomec, highlighting their\u000a      importance in clinical care at the National Centre for LAM.\u000a    Changing clinical practice\u000a      In the 1990s, two-thirds of UK patients were given ineffective hormone\u000a      therapy which caused frequent side effects including osteoporosis. Johnson\u000a      and Tattersfield performed the first clinical trials on mTOR inhibitors in\u000a      patients with LAM and TSC, and, in so doing, the group were instrumental\u000a      in the development of these drugs as an effective treatment for LAM and\u000a      TSC. In 2008, mTOR inhibitors were not an option for patients with LAM or\u000a      TSC. Following publication of the 2010 guidelines, mTOR inhibitors became\u000a      the standard of care for LAM patients with progressive lung and renal\u000a      disease in the UK and the USAa,b. Now, the majority of patients\u000a      are considered for mTOR inhibitor therapy, and around 20% of patients with\u000a      LAM at the UK LAM Centre, and in other developed countries, are now\u000a      treated with these drugs.\u000a    As a result of the group's studies, the use of anti-oestrogens in LAM has\u000a      fallen from 53% of patientsd to a small minority of patients,\u000a      outside of specialist centres.\u000a    Improving patient care\u000a      Professor Johnson's work has led to a number of improvements for patients.\u000a      Rather than being told they have only 5-10 years to live, LAM patients now\u000a      have access to an effective treatment. They are also now spared the side\u000a      effects of an ineffective anti-oestrogen treatment, and a definitive\u000a      diagnosis can usually be made without invasive investigations.\u000a      Complications including pneumothorax are now treated earlierc,\u000a      thereby reducing patient morbidity. In addition, because the group\u000a      described the effect of LAM on pregnancy, physicians are now able to\u000a      advise more women on the true risks of childbirth in LAM where previously\u000a      all patients were discouraged from pregnancy.\u000a    The recognition by the advisory group for National Specialised\u000a      Commissioning, that LAM is a complex multisystem disease with a variable\u000a      prognosis and specific treatments, led to the Nottingham group's\u000a      successful tender to establish a National Clinical Centree to\u000a      serve the national caseload of patients under National Specialist\u000a      Commissioning from 2011. This resulted in an initial £1 million of\u000a      dedicated funding for specialist care for LAM patients. As a result, the\u000a      service now offers clinical care to all UK patients and sees over half of\u000a      these patients, and increasingly those with TSCe. This has\u000a      allowed the group to incorporate their research and evidence-based care\u000a      into treatment of all patients with LAM in the UK. The service also\u000a      receives referrals of LAM patients from some European countries.\u000a    LAM patients also now have the option of participating in clinical\u000a      trials, and access to a patient support group (LAM Action), which was\u000a      established by Tattersfield and Johnson in 1999. LAM Actionf is\u000a      a registered National Charity that provides peer support to newly\u000a      diagnosed patients and is part of the UK Respiratory Alliance, a Pressure\u000a      group of respiratory organisations lobbying for improved funding for\u000a      respiratory care and research. LAM Action has raised ~£400,000 since 2008.\u000a    LAM research in Nottingham has also extended to patients with TSC-related\u000a      conditions. As mTOR is overactive in all TSC-related lesions, mTOR\u000a      inhibitors have widespread application and are being tested across other\u000a      TSC hamartomas. The group's work has been cited in these publications as\u000a      part of the rationale for clinical trials of mTOR inhibitors in\u000a      TSC-related brain tumours, cognitive dysfunction, angiomyolipoma and\u000a      sporadic renal carcinoma. Acting as a consultant on LAM and TSC biology to\u000a      Novartis pharmaceuticals on several occasions since 2008, Johnson has been\u000a      involved in designing and performing these studies.\u000a    A model for rare diseases\u000a      Professor Johnson has led initiatives essential to working in rare\u000a      diseases; including establishing a database of patients with LAM willing\u000a      to participate in research, and collecting blood and tissue samples from\u000a      around half of UK patients. He ran a work-package of the European Network\u000a      Centres of Expertise (ENCE) programme established in 2009 under FP7, which\u000a      outlined clinical and research frameworks for the care of rare diseasesg,\u000a      and Johnson was also responsible for the use of LAM as a model for\u000a      European rare disease care. This has resulted in discussions with other\u000a      rare lung disease groups, including alpha-1 anti-trypsin deficiency and\u000a      hereditary haemorrhagic telangiectasia, both of whom wish to adopt this\u000a      strategy.\u000a    In summary, LAM research at the University of Nottingham has increased\u000a      awareness of LAM, and significantly changed clinical practice such that\u000a      the majority of patients now receive multidisciplinary care at a National\u000a      Specialist Centre. We have improved patient care with better understanding\u000a      of the disease phenotype and demonstration of the efficacy of mTOR\u000a      inhibitors, and reduced the use of invasive investigations to make a firm\u000a      diagnosis. Clinical trials have become the standard of care for patients\u000a      with progressive disease, with clinical trials running in the USA and\u000a      Europe, giving most UK patients the opportunity to participate in clinical\u000a      trials if they wish.\u000a    ","ImpactSummary":"\u000a    Research at the University of Nottingham has defined the clinical\u000a      phenotype and management of lymphangioleiomyomatosis, a rare and often\u000a      fatal multisystem disease affecting 1 in 200,000 women worldwide. The\u000a      group has led the development and evaluation of new therapies and\u000a      diagnostic strategies which are now part of routine clinical care. The\u000a      research has underpinned the transformation of this previously under\u000a      recognised and untreatable disease into a condition recognised by\u000a      respiratory physicians, with international clinical guidelines, patient\u000a      registries, clinical trials, specific treatments and a UK specialist\u000a      clinical service.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Nottingham\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Johnson SR, Tattersfield AE. Decline in\u000a      lung function in lymphangioleiomyomatosis: relation to menopause and\u000a      progesterone treatment. Am J Respir Crit Care Med.\u000a      1999;160:628-633.\u000a      http:\/\/dx.doi.org\/10.1164\/ajrccm.160.2.9901027\u000a    \u000a\u000a2. Johnson SR, Tattersfield AE. Clinical\u000a      experience of lymphangioleiomyomatosis in the UK. Thorax\u000a      2000:55:1052-1057 http:\/\/dx.doi.org\/10.1136\/thorax.55.12.1052\u000a    \u000a\u000a3. Davies DM, Johnson SR, Tattersfield A, Kingswood JC,\u000a      Cox JA, McCartney DL, Doyle T, Elmslie F, Saggar A, de Vries P, Sampson\u000a      JR. Sirolimus therapy in tuberous sclerosis or sporadic\u000a      lymphangioleiomyomatosis. New England Journal of Medicine\u000a      2008;358:200-203\u000a      http:\/\/dx.doi.org\/10.1056\/NEJMc072500\u000a    \u000a\u000a4. Davies DM, de Vries PJ, Johnson SR, McCartney D, Cox\u000a      JA, Serra AL, Watson P, Howe CJ, Doyle T, Pointon K, Cross J, Tattersfield\u000a          AE, et al. Sirolimus Therapy for Angiomyolipoma in Tuberous\u000a      Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 Study. Clin\u000a        Cancer Research 2011;17:4071-4081. http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-11-0445\u000a    \u000a\u000a5. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U,\u000a      Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, Popper H. Bonetti F,\u000a      Kingswood C, and the Review panel of the ERS LAM Task Force. European\u000a      Respiratory Society Guidelines for the diagnosis and management of\u000a      lymphangioleiomyomatosis (LAM). Eur Resp J 2010;35:14-26.\u000a      http:\/\/dx.doi.org\/10.1183\/09031936.00076209\u000a    \u000a\u000a6. Chang WYC, Cane J, Kumaran M, Pointon KS, Blakey J, Johnson SR.\u000a      Application of diagnostic guidelines and putative biomarkers in\u000a      lymphangioleiomyomatosis. Respiratory Research 2012. 13:34. http:\/\/dx.doi.org\/10.1186\/1465-9921-13-34\u000a    \u000aGrant funding for these studies includes:\u000a    •2005-2006: LAM Foundation ($40,000) to SR Johnson (PI) `Development of\u000a      an in vivo model of lymphangioleiomyomatosis'.\u000a    • 2005-2007: European Respiratory Society Task Force on\u000a      Lymphangioleiomyomatosis (€19 300) to SR Johnson and J-F Cordier\u000a      `Co-Chair'.\u000a    • 2007: British Lung Foundation (£100,000) and LAM Action (£50,000) to SR\u000a      Johnson (PI) `A randomised, double blind, placebo controlled trial of\u000a      doxycycline in LAM'.\u000a    • 2009: European Networks of Centres of Expertise for CF, LAM and Lung\u000a      Transplantation (€999,472). EU, FP7-HEALTH-2007-B. Coordinator Prof T.O.F.\u000a      Wagner, University of Frankfurt.\u000a    • 2001-2013: LAM Action (£250,000) to SR Johnson `Molecular Pathology of\u000a      Lymphangioleiomyomatosis'.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    a) European Respiratory Society LAM Guidelines:\u000a      http:\/\/www.ers-education.org\/guidelines.aspx\u000a      (scroll down to 2010 guidelines — `European Respiratory Society Guidelines\u000a      for the diagnosis and management of\u000a      lymphangioleiomyomatosis (LAM)'. (Alternatively, PDF is available on\u000a      request).\u000a      See p20-21 (anti-oestrogens), p21 (pneumothorax), p23 (references).\u000a    b) Krueger DA, Northrup H, on behalf of the International Tuberous\u000a      Sclerosis Complex Consensus Group. Tuberous Sclerosis Complex Surveillance\u000a      and Management: Recommendations of the 2012 International Tuberous\u000a      Sclerosis Complex Consensus Conference. Pediatr Neurol\u000a      2013;49(255)255-265. http:\/\/dx.doi.org\/10.1016\/j.pediatrneurol.2013.08.002\u000a    c) Clinical protocols for diagnostic workup, angiomyolipoma management,\u000a      pneumothorax and Sirolimus at the National LAM Centre (pdf available on\u000a      request).\u000a    d) The NHLBI Lymphangioleiomyomatosis Registry: Characteristics of 230\u000a      Patients at Enrollment (2006) Am J Respir Crit Care Med; 173,105-111\u000a      http:\/\/dx.doi.org\/10.1164\/rccm.200409-1298OC\u000a    e) The National Centre for Lymphangioleiomyomatosis\u000a      http:\/\/www.specialisedservices.nhs.uk\/service\/lymphangioleiomyomatosis\/search:true\u000a    f) LAM Action: http:\/\/lamaction.org\/\u000a    g) European Network of Centres of Expertise (ENCE) http:\/\/pneumo-frankfurt.de\/297.0.html\u000a    ","Title":"\u000a    Improving clinical care for lymphangioleiomyomatosis\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Lymphangioleiomyomatosis (LAM) is a rare disease which almost exclusively\u000a      affects women. With a prevalence of 1 in 200,000 individuals globally,\u000a      there are over 200 affected patients in the UK and 17,500 worldwide.\u000a      Patients with LAM develop lung cysts and recurrent pneumothorax, and have\u000a      kidney tumours. The disease is progressive and, in the majority of cases,\u000a      leads to death or lung transplant due to respiratory failure. LAM can\u000a      occur sporadically or as part of the genetic disease tuberous sclerosis\u000a      complex (TSC). Increasing recognition of LAM as a clinical problem for\u000a      adults with TSC has increased our reach to a wider group of patients, with\u000a      a prevalence of 1 in 6,000; approaching 1 million patients worldwide.\u000a      Until recently, little research on LAM had been performed, no treatments\u000a      were available and patients with LAM were told they would die within 5-10\u000a      years.\u000a    Professor Simon Johnson's work on LAM began in 1995, initially under the\u000a      guidance of Professor Anne Tattersfield in the Division of Respiratory\u000a      Medicine, University of Nottingham. They published two clinical papers1,2\u000a      in 1999 and 2000 based around the first comprehensive national cohort to\u000a      be studied, which helped to redefine understanding of the natural history\u000a      and clinical phenotype of the disease, showing for the first time the rate\u000a      of progression of LAM. The first study on the natural history of lung\u000a      function change in LAM, published in the world's leading respiratory\u000a      journal, showed that commonly used, anti-oestrogen treatments were\u000a      ineffective1. The second paper showed that early surgical\u000a      management of pneumothorax could reduce morbidity, and described the risks\u000a      of pregnancy and pneumothorax in LAM2. These papers highlighted\u000a      the need for a change in management for these patients.\u000a    Since appointment to Clinical Senior Lecturer in 2000, Johnson has\u000a      established a translational research program comprising patients and staff\u000a      at the National LAM Centre in Nottingham, and a laboratory group within\u000a      the Division of Respiratory Medicine, University of Nottingham. In 2007,\u000a      they jointly performed the first clinical trials of mTOR inhibitors in\u000a      patients with LAM and the related disease TSC3,4. These studies\u000a      showed that mTOR inhibitors could reduce kidney tumour volume in patients\u000a      with LAM and TSC, and were safe over a sustained period of time for these\u000a      patients.\u000a    After publishing evidence-based European guidelines for the diagnosis and\u000a      management of LAM5, the team critically evaluated this\u000a      evidence-based approach in their National clinical cohort and, in 2012,\u000a      published a diagnostic strategy to improve diagnostic accuracy using\u000a      non-invasive means6. This study showed that by using the\u000a      guidelines they had formulated in conjunction with serum biomarkers, a\u000a      firm diagnosis could be made in most cases using imaging alone. An\u000a      invasive lung biopsy could be avoided in 70% of patients with suspected\u000a      LAM6.\u000a    Their laboratory program continues to study new targets for LAM to\u000a      generate future targets for therapy.\u000a    "},{"CaseStudyId":"41006","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    Our research has had an impact in six main areas: patient safety, quality\u000d\u000a      of life, healthcare costs, management guidelines, prescribing practice and\u000d\u000a      opportunities for the pharmaceutical industry.\u000d\u000a    Patient safety:\u000d\u000a    Before our research, the only way to reduce the risk of a non-steroidal\u000d\u000a      anti-inflammatory drug (NSAID)-associated ulcer complication was to avoid\u000d\u000a      using NSAIDs or to use low doses. Previously recommended measures such as\u000d\u000a      the use of slow release or effervescent preparations or enteric coating\u000d\u000a      were at best ineffective. NSAIDs were regarded as the biggest iatrogenic\u000d\u000a      cause of hospitalisation and death worldwide. The most conservative\u000d\u000a      estimates (UK) were that 1 in every 250-370 people being treated with\u000d\u000a      NSAIDs would be hospitalised for ulcer complications each year\u000d\u000a      [Pharmacoepidemiol Drug Saf, 2001;10:13-19]. With at least a 10% death\u000d\u000a      rate, this resulted in an estimated societal burden of 3,500-4,000\u000d\u000a      admissions and 400-1,000 deaths per annum. Estimates from other societies\u000d\u000a      and meta-analyses of clinical trials suggested greater harm, with annual\u000d\u000a      ulcer complication rates of 1 in 67 users, with two estimates of death\u000d\u000a      rates in the USA of 7,000-10,000 [Clin Ther 2010;32:667-677] and 16,500\u000d\u000a      [Gastroenterol, 1985;96,647-655].\u000d\u000a    Based on a Health Technology Appraisal (HTA) meta-analysis drawing on our\u000d\u000a      work [HTA 2006, 10(38); Am J Gastroenterol 2006,101:701-710] and studies\u000d\u000a      by others with other proton pump inhibitors (PPIs), the NICE\u000d\u000a      Osteoarthritis Development Group reported in 2009 that use of PPIs in\u000d\u000a      patients aged 55 or over reduced the risk of hospitalisation for\u000d\u000a      gastrointestinal bleeding by 54% and symptomatic ulcer by 63%, and was the\u000d\u000a      most cost effective prophylactic strategya,b. A pro rata\u000d\u000a      reduction in death could prevent between 216 and 540 deaths per annum in\u000d\u000a      the UK, with higher values if estimates from other countries are used.\u000d\u000a      Worldwide, NSAID use is extensive [PLoS Med 2013;10(2):e1001388]. Using\u000d\u000a      even the most conservative estimate above (1 hospitalisation per 370 users\u000d\u000a      per annum), several hundred thousand life-threatening ulcer complications\u000d\u000a      could be prevented annually, worldwide, by use of proton pump inhibitors.\u000d\u000a    Quality of Life:\u000d\u000a    As well as preventing ulcer complications, PPIs improve quality of life\u000d\u000a      by reducing dyspepsia and allowing continuation of treatment that would\u000d\u000a      otherwise be stopped. NICE estimate dyspepsia rates between 5.4% and 9.6%\u000d\u000a      per annum in NSAID users and a 57% reduction with PPI co-prescriptiona,b.\u000d\u000a      Another meta analysis reported higher rates (13.5%-31%) with the 66%\u000d\u000a      reduction by PPIs being identified as the most effective available\u000d\u000a      treatment or preventative measure for NSAID dyspepsia [Am J Med;\u000d\u000a      2006:119(5):448.e27-36]. NICE estimate that the combined effect of reduced\u000d\u000a      mortality and improved quality of life results in a gain of 5-10 QALYs\u000d\u000a      (quality adjusted life years) per thousand people treateda,b.\u000d\u000a      [QALYs are a measure of disease burden used to assess the value of a\u000d\u000a      medical intervention. They are based on the number and quality of years of\u000d\u000a      life that would be added by the intervention. One QALY is one year spent\u000d\u000a      in perfect health.]\u000d\u000a    Healthcare costs:\u000d\u000a    NICE report that the ability of PPIs to prevent hospitalisation and other\u000d\u000a      adverse events reduces healthcare costs to the extent that their use\u000d\u000a      `increases the estimated gain in quality adjusted life years at little or\u000d\u000a      no additional cost\" with \"savings from not having to treat adverse\u000d\u000a      effects'.a\u000d\u000a    Guidelines:\u000d\u000a    These observations led NICE to recommend that PPIs are considered for use\u000d\u000a      in all patients taking NSAIDsa. All other major guidelines\u000d\u000a      produced or updated in the past five years (Osteoarthritis Research\u000d\u000a      Society International [OARSI] 2008c, Cardiology 2008d,\u000d\u000a      American Colleges of Gastroenterology 2009e, and Rheumatology\u000d\u000a      2012f, place the PPI co-prescription strategy that we developed\u000d\u000a      at the heart of their guidelines, particularly for patients at increased\u000d\u000a      risk of ulcer complications. An updated Cochrane analysisg\u000d\u000a      supports the strategy, as do other national and international\u000d\u000a      recommendations.\u000d\u000a    Prescribing practice:\u000d\u000a\u0009  To be effective, guidelines must be implemented.\u000d\u000a      Current data show progressive adoption of PPI co-prescription in UK (see\u000d\u000a      figure) and internationally [Am J Gastroenterol. 2008;103:1097-1103].\u000d\u000a      Clinical Practice Research Database Statisticsh show a rise in\u000d\u000a      co-prescription of a PPI in the UK from 27.6% in 2008 to 44.1% in 2012 in\u000d\u000a      patients aged >45 using non-aspirin NSAIDs, resulting in safer symptom\u000d\u000a      relief. During this time, aspirin use has doubled in the UK with a\u000d\u000a      concurrent rise in the proportion of patients receiving PPI protectionh\u000d\u000a      from 25.5% in 2008 to 34.8% in 2012, allowing patients to access the\u000d\u000a      cardiovascular and anti-cancer benefits of aspirin more safely.\u000d\u000a\u000d\u000aFigure: Rates of UK co-prescription of PPIs in patients using NSAIDs and aspirin by year, based on data routinely collected from general practices with electronic systems that feed into the Clinical Practice Research Database.\u000d\u000a\u0009  \u000d\u000a    Commercial Opportunities:\u000d\u000a    Esomeprazole is one of AstraZeneca's 10 leading medicines by sales.\u000d\u000a      Worldwide sales of this drug generated £3.9 billioni in revenue\u000d\u000a      for AstraZeneca in 2012, with an increasingly significant contribution\u000d\u000a      from NSAID ulcer prophylaxis. The effectiveness of PPI prescription has\u000d\u000a      also led to development of combination preparations, of which several have\u000d\u000a      so far been approved and launched internationally (Axorid: ketoprofen +\u000d\u000a      omeprazole 2009, Vimovo: naproxen + esomeprazole 2010, and Axanum: Aspirin\u000d\u000a      + esomeprazole:2011)j.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Non-steroidal anti-inflammatory drugs (NSAIDs) are valuable analgesics,\u000d\u000a      but cause dyspepsia, ulcers and hospitalisation (UK: 3,500pa, USA:\u000d\u000a      100,000pa) for complications that can lead to death (UK: 400-1,000pa, USA:\u000d\u000a      16,500pa). Acid inhibition by proton pump inhibitors (PPIs), the only\u000d\u000a      widely accepted preventative strategy, was proposed and systematically\u000d\u000a      proved by studies from Nottingham. NICE now recommends PPIs for all\u000d\u000a      patients using NSAIDs and PPIs are central to all major international\u000d\u000a      guidelines. PPI co-prescription has increased worldwide (from 27.6% in\u000d\u000a      2008 to 44.1% in 2012, in the UK); and reduces the risk of hospitalisation\u000d\u000a      for gastrointestinal bleeding by 54% and symptomatic ulcer by 63%, thereby\u000d\u000a      preventing up to 540 deaths per annum in the UK.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Nottingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine\u000d\u000a      for the prevention of gastric and duodenal ulcers caused by non-steroidal\u000d\u000a      anti-inflammatory drugs. N Engl J Med 1996; 334(22):1435-1439. http:\/\/dx.doi.org\/10.1056\/NEJM199605303342204\u000d\u000a    \u000a\u000a2. Hawkey CJ, Karrasch JA, Szczepanski L, et al.\u000d\u000a      Omeprazole compared with misoprostol for ulcers associated with\u000d\u000a      nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for\u000d\u000a      NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998;\u000d\u000a      338(11):727-734\u000d\u000a      http:\/\/dx.doi.org\/10.1056\/NEJM199803123381105\u000d\u000a    \u000a\u000a3. Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard JM, van Rensburg CJ,\u000d\u000a      Swannell AJ, Hawkey CJ for the ASTRONAUT Study Group. A\u000d\u000a      comparison of omeprazole and ranitidine for treating and preventing ulcers\u000d\u000a      associated with non-steroidal anti-inflammatory drugs. N Eng J Med 1998;\u000d\u000a      338(11):719-726.\u000d\u000a      http:\/\/dx.doi.org\/10.1056\/NEJM199803123381104\u000d\u000a    \u000a\u000a4. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised\u000d\u000a      controlled trial of Helicobacter pylori eradication in patients\u000d\u000a      taking non-steroidal, anti-inflammatory drugs: The HELP NSAIDs Study.\u000d\u000a      Lancet 1998; 352(9133):1016-1021.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/S0140-6736(98)04206-8\u000d\u000a    \u000a\u000a5. Hawkey CJ, Talley NJ, Yeomans ND, et al. Improvements\u000d\u000a      with esomeprazole in upper gastrointestinal symptoms in patients taking\u000d\u000a      non-steroidal anti-inflammatory drugs including selective COX-2 inhibitors\u000d\u000a      (NASA1 — SPACE1). Am J Gastroenterol 2005,100(5):1028-1036.\u000d\u000a      http:\/\/dx.doi.org\/10.1111\/j.1572-0241.2005.41465.x\u000d\u000a    \u000a\u000a6. Yeomans N, Lanas A, Labenz J, van Zanten SV, van Rensburg C, Racz I,\u000d\u000a      Tchernev K, Karamanolis D, Roda E, Hawkey C, Naucler E,\u000d\u000a      Svedberg LE. Efficacy\u000a        of esomeprazole (20 mg once daily) for reducing the risk of\u000d\u000a        gastroduodenal ulcers associated with continuous use of low-dose\u000d\u000a        aspirin. Am J Gastroenterol. 2008,103(10):2465-2473. http:\/\/dx.doi.org\/10.1111\/j.1572-0241.2008.01995.x\u000d\u000a    \u000aRelevant grants total over £2m, from Astra, Astra Zeneca, Merck\u000d\u000a      Sharpe & Dohme, MRC ROPA, Novartis and University of Dundee\/EMEA (via\u000d\u000a      unrestricted grant from Pfizer). All awarded to CJ Hawkey for work between\u000d\u000a      1993 and 2013 for research on NSAID complications and their prevention,\u000d\u000a      including co-prescription of NSAIDs and PPIs.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"15","Subject":"Pharmacology and Pharmaceutical Sciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    a) Latimer N. Lord J. Grant RL. et al. National Institute for Health and\u000d\u000a      Clinical Excellence Osteoarthritis Guideline Development Group. Cost\u000a        effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone\u000d\u000a        or in combination with a proton pump inhibitor for people with\u000d\u000a        osteoarthritis. BMJ. 339:b2538, 2009 http:\/\/dx.doi.org\/10.1136\/bmj.b2538\u000d\u000a    b) National Institute for Health and Clinical Excellence. Osteoarthritis:\u000d\u000a      The care and management of osteoarthritis in adults. http:\/\/www.nice.org.uk\/nicemedia\/pdf\/CG59NICEguideline.pdf\u000d\u000a    c) Zhang W, Moskowitz RW, Nuki G, et al. OARSI Recommendations for the\u000d\u000a      Management of Hip and Knee Osteoarthritis, Part II: OARSI evidence-based,\u000d\u000a      expert consensus guidelines. Osteoarthritis & Cartilage 2008; 16:\u000d\u000a      137-162.\u000d\u000a      http:\/\/dx.doi.org\/10.1016%2Fj.joca.2007.12.013\u000d\u000a    d) American College of Cardiology Expert Consensus Document on Reducing\u000d\u000a      the GI risks of Antiplatelet Therapy and NSAID Use 2008:\u000d\u000a      http:\/\/cardiocompass.cardiosource.org\/cc2\/openCont2?objID=108\u000d\u000a    e) Lanza FL, Chan FKL, Quigley EMM and the Practice Parameters Committee\u000d\u000a      of the American College of Gastroenterology. Guidelines for prevention of\u000d\u000a      NSAID-related Ulcer Complications. Am J Gastroenterol 2009; 104: 728-738.\u000d\u000a      http:\/\/dx.doi.org\/10.1038%2Fajg.2009.115\u000d\u000a    f) Hochberg MC, Altman RD, April T, et al, American College of\u000d\u000a      Rheumatology 2012 Recommendations for the use of Nonpharmacologic and\u000d\u000a      Pharmacologic Therapies in Osteoarthritis of the Hand, Hip and Knee.\u000d\u000a      Arthritis Care & Research 2012; 64(4): 465-474.\u000d\u000a      http:\/\/dx.doi.org\/10.1002%2Facr.21596\u000d\u000a    g) Rostom A. Dube C. Wells G. et al. Prevention\u000a        of NSAID-induced gastroduodenal ulcers. Cochrane Database of\u000d\u000a      Systematic Reviews http:\/\/dx.doi.org\/10.1002\/14651858.CD002296\u000d\u000a    h) Scrutiny of CPRD database. Corroborated by Dr Yana Vinogradova (pdf\u000d\u000a      available on request).\u000d\u000a    i) AstraZeneca 2012 annual report: http:\/\/www.astrazeneca-\u000a        annualreports.com\/2012\/documents\/eng_download_centre\/annual_report.pdf\u000d\u000a    j) Vimovo: http:\/\/www.medicines.ie\/medicine\/14981\/SPC\/VIMOVO+500+mg+20+mg+modified-release+tablets\/#ORIGINAL\u000d\u000a    ","Title":"\u000d\u000a    Preventing the gastroduodenal hazards of non-steroidal\u000d\u000a        anti-inflammatory drugs and aspirin through widespread adoption of\u000d\u000a        proton pump inhibitors\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Scale of the problem: Non-steroidal anti-inflammatory drugs\u000d\u000a      (NSAIDs) cause two clinically important gastroenterological problems —\u000d\u000a      ulcer complications (largely bleeding) which are relatively rare but\u000d\u000a      dangerous, and dyspepsia which is common, impairs quality of life and\u000d\u000a      restricts NSAID use. NSAIDs have an attributable rate of hospitalisation\u000d\u000a      of approximately 2.7-4.0 per 1,000 patient years in patients aged >60.\u000d\u000a      On the basis of this, prior to widespread adoption of proton pump\u000d\u000a      inhibitor (PPI) co-prescription, NSAIDs were conservatively calculated to\u000d\u000a      cause 3,500-4,000 hospitalisations and 400-1,000 deaths pa in the UK\u000d\u000a      [Pharmacoepidemiol Drug Saf, 2001;10:13-19]. In trials, between 13 and 31%\u000d\u000a      of patients report dyspepsia [Clin Ther 2010;32:667-677; BMJ\u000d\u000a      2009;339:b2538].\u000d\u000a    Nottingham's contribution: Much of the most reliable\u000d\u000a      epidemiological data that identified and quantified the GI risks of NSAIDs\u000d\u000a      emanated from the Department of Therapeutics under Professor Michael\u000d\u000a      Langman (1971-1987). Professor Chris Hawkey (Nottingham Digestive Diseases\u000d\u000a      Centre, 1983-present) then developed the translational models described\u000d\u000a      here, becoming a UK leader in this field. Hawkey also developed the\u000d\u000a      therapeutic interventions discussed, before their evaluation in clinical\u000d\u000a      trials.\u000d\u000a    Translational basis: Our translational facility enabled strategies\u000d\u000a      for mucosal protection and underlying mechanisms to be investigated.\u000d\u000a      Investigations were based on ex vivo pharmacology, mucosal injury,\u000d\u000a      spontaneous and induced bleeding and healing of mucosal breaches. Of more\u000d\u000a      than twenty strategies evaluated, use of omeprazole (first of the then\u000d\u000a      novel PPI class of drugs) appeared to be most effective. Omeprazole was\u000d\u000a      potent and reliable in its ability to virtually abolish mucosal injury,\u000d\u000a      measured as acute microbleeding.\u000d\u000a    Initial trials: This caused us to suggest to Astra that they\u000d\u000a      conduct trials with omeprazole in NSAID users, but these suggestions were\u000d\u000a      not taken up. Our team therefore collaborated with rheumatological and\u000d\u000a      gastroenterological colleagues in Nottingham and Glasgow to do a proof of\u000d\u000a      principle investigator-initiated study with the H2 antagonist famotidine.\u000d\u000a      This study showed that acid inhibition with high, but not standard, doses\u000d\u000a      of famotidine was effective in preventing and healing ulcers and treating\u000d\u000a      the dyspepsia caused by NSAIDs1.\u000d\u000a    Definitive omeprazole trials: This work provoked renewed interest\u000d\u000a      by Astra. As co-Chief Investigators, Professors Hawkey and Neville Yeomans\u000d\u000a      (Melbourne, Australia) developed and coordinated a large international\u000d\u000a      programme of three linked studies of primary and secondary prevention, and\u000d\u000a      ulcer healing, which the company funded2,3. These studies\u000d\u000a      showed that omeprazole had clear efficacy and tolerability advantages over\u000d\u000a      the H2 antagonist ranitidine and the prostaglandin analogue misoprostol,\u000d\u000a      which were used as comparators. This work authoritatively established the\u000d\u000a      effectiveness of PPIs for ulcer prevention, healing and maintenance, and\u000d\u000a      for symptom control, and this was reflected in the ensuing licensed\u000d\u000a      indications for omeprazole and, later, other PPIs. The nature and quality\u000d\u000a      of the team's academic relationship led Astra to support a pivotal\u000d\u000a      investigator-initiated trial of little commercial interest which was\u000d\u000a      important in showing H.pylori eradication to be insufficient as an\u000d\u000a      alternative strategy4.\u000d\u000a    Broadening the evidence: As co-Chief Investigators, Professors\u000d\u000a      Hawkey and Yeomans later reported similar finding with esomeprazole5,\u000d\u000a      and effectiveness was shown for other PPIs. Because the GI hazards of\u000d\u000a      aspirin were an important unmet need, Hawkey and Yeomans persuaded\u000d\u000a      AstraZeneca to support investigator-initiated studies that established\u000d\u000a      efficacy of PPI prophylaxis here too6, leading to a successful\u000d\u000a      regulatory claim for a combination preparation.\u000d\u000a    "},{"CaseStudyId":"41007","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1835841","Name":"South Korea"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1861060","Name":"Japan"}],"Funders":[],"ImpactDetails":"\u000d    Scancell Holdings Plc (a) has legitimised an exciting new model for\u000d      Biotechnology investment; demonstrating that floating on the stock market\u000d      at an early stage can realise good returns for private investors. This\u000d      unlocks greater potential for the private sector to invest in a wide range\u000d      of research and development. In line with the Government's plan to promote\u000d      the Biotechnology Industry, this provided a good opportunity to translate\u000d      more novel products into the clinic and onto the market. Scancell out\u000d      performed shares in the biotechnology industry as indicated by the FTSE\u000d      All-share index for Pharmaceutical and Biotechnology and all shares in AIM\u000d      (see graph). Cancer immunotherapeutics, such as those developed by\u000d      Scancell, are predicted to bring in $35 billion in annual sales for the\u000d      Pharmaceutical industry (b) and, by 2018, 4 of the top 5 cancer products\u000d      are expected to be immunotherapies.\u000d    \u000d      Figure showing the % increase in share price from Jan 2009\u000d          until Jan 2013.\u000d    \u000d    Scancell has generated licensing income of £6million from\u000d      US\/Japanese\/Korean companies from its patent portfolio (c). It filed\u000d      patents on the three most promising mabs, SC100, SC101 and SC104. SC100\u000d      was then licensed to a Korean company ISU. Scancell sold its cancer\u000d      killing mabs including SC101 and SC104 to the Australian biotechnology\u000d      company, Peptech Therapeutics (now part of Teva). The lead candidate\u000d      antibody, SC104 (CEP-37250\/KHK2804), was humanised by Peptech and\u000d      defucosylated by Kyowa Hakko Kirin in Japan and both these companies are\u000d      co-developing it. It entered phase I clinical trials in the US in December\u000d      2011 (d). These international deals have all helped to increase the\u000d      profile of UK Biotechnology around the globe. Scancell continues to\u000d      develop its vaccine platforms and currently holds four patent families\u000d      protecting cancer vaccine platforms targeting solid tumours and infectious\u000d      diseases (e). It filed its initial protein vaccine platform in 2006 and\u000d      this was awarded in Europe in 2007 and in the US in 2012. In 2008, it\u000d      filed its DNA patent portfolio. The first patent on its lead vaccine\u000d      SCIB1, which is currently in clinical trial (f), was awarded in Europe in\u000d      2012. In 2012 it developed a novel platform on modified peptides and filed\u000d      a patent in August 2012.\u000d    Scancell financed its expansion with an innovative approach, which has\u000d      legitimised a new model for Biotechnology investment. After spinning out\u000d      and raising private equity funding (£4 million) it acquired a PLUS listing\u000d      in 2008 and an AIM listing on the London Stock exchange in 2010 (g). In\u000d      2012, in response to the successful clinical results for SCIB1, Scancell\u000d      holdings plc shares increased by the highest percentage on the London\u000d      stock exchange, generating significant press coverage for both the company\u000d      and the University. From its initial market capitalisation of £10m it\u000d      reached a value of £98 million which provided a tenfold return for\u000d      investors (h). As indicated in the PraxisUnico annual report 2013 (i),\u000d      Scancell is one of the few University start-up companies to provide not\u000d      only reward for early investors but also a vehicle for further investment\u000d      and profit.\u000d    As a result Scancell has clearly demonstrated the potential for private\u000d      sector investors in small scale Biotech to realise strong returns within\u000d      reasonable time scales. This provided a new successful model for\u000d      Biotechnology investments whereby individuals can invest at different\u000d      stages of a product's life history and still get value on their\u000d      investment. Additionally, as the companies mature, there remains a large\u000d      upside for new investors as the products are licensed\/sold to the\u000d      pharmaceutical industry. In July 2013, Scancell raised a further £6.5\u000d      million and although the share price dipped it has come back strongly and\u000d      its market capitalisation has remained stable at around £80 million during\u000d      2013 (g).\u000d    Scancell has thus created significant value from modest investments of\u000d      £10.5 million. It has done this through innovative science, a novel\u000d      business model and by keeping overheads low. By listing on the stock\u000d      market it has released significant value for its initial investors. Along\u000d      the way Scancell has contributed to the local economy, employing 9-10\u000d      highly skilled people during the period 2008-2013 and supporting other UK\u000d      businesses through its outsourcing of manufacturing, development and\u000d      clinical work.\u000d    In line with the Government's plan to promote Biotechnology Industry,\u000d      Scancell's model provides an example of how to promote investment in this\u000d      sector.\u000d    ","ImpactSummary":"\u000d    The University of Nottingham spin out company Scancell Holdings plc is\u000d      developing novel immunotherapies for the treatment of cancer. By licensing\u000d      products (£6million) and listing and raising money (£4million) on the\u000d      stock exchange, it has provided an excellent return for investors. In\u000d      2012, in response to good clinical trial results, Scancell's shares showed\u000d      the greatest percentage increase (10fold) on London's AIM stock exchange,\u000d      reaching a market capitalisation of £98million. This has encouraged\u000d      further investment (£6.5million) which is in line with the Government's\u000d      plan to promote the Biotechnology Industry. As the products progress to\u000d      market it will save further lives and continue to increase in value\u000d      providing further profit for investors.\u000d    ","ImpactType":"Technological","Institution":"\u000d    University of Nottingham\u000d    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[],"References":"\u000d    \u000a1. LG Durrant, SJ Harding, NH Green, LD Buckberry, and T\u000d      Parsons (2006). A new anti-cancer glycolipid monoclonal antibody, SC104,\u000d      which directly induces tumour cell death without immune effector cells.\u000d      Cancer Res. 66(11) 1-9. http:\/\/dx.doi.org\/10.1158\/0008-5472.CAN-05-3812\u000d    \u000a\u000a2. S Amin, RA Robins, CA Maxwell-Armstrong, JH Scholefield and LG\u000d          Durrant (2000). Vaccine induced apoptosis: a novel clinical\u000d      trial endpoint? Cancer Res., 60; 3132-3136.\u000d      http:\/\/cancerres.aacrjournals.org\/content\/60\/12\/3132\u000d    \u000a\u000a3. GJ Ullenhag, I Spendlove, NF Watson, AA Indar, M Dube, RA\u000d      Robins, C Maxwell-Armstrong, JH Scholefield, and LG Durrant.\u000d      A neoadjuvant\/adjuvant randomized trial of colorectal cancer patients\u000d      vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55 (2006).\u000d      Clin Cancer Res. 12: 7389-7396. http:\/\/dx.doi.org\/10.1158\/1078-0432.CCR-06-1003\u000d    \u000a\u000a4. K Pritchard-Jones, I Spendlove, C Wilton, J Whelan, S Weeden, I\u000d      Lewis, J Hale, C Douglas, C Pagonis, B Campbell, P Alvarez, G Halbert, and\u000d      LG Durrant. Immune responses to the 105AD7 human\u000d      anti-idiotypic vaccine after intensive chemotherapy, for osteosarcoma\u000d      (2005). Br J Cancer . 92: 1358-1365. http:\/\/dx.doi.org\/10.1038\/sj.bjc.6602500\u000d    \u000a\u000a5. VA Pudney, RL Metheringham, B Gunn, I Spendlove, JM Ramage and LG\u000a          Durrant (2010). DNA vaccination with T cell epitopes encoded\u000d      within antibody molecules induces high avidity CD8 T cells which are\u000d      capable of efficient anti-tumor activity. Eur J Immunol 40(3) 899-910.\u000d      http:\/\/dx.doi.org\/10.1002\/eji.200939857\u000d    \u000a\u000a6. VA Brentville, RL Metheringham, B Gunn and LG Durrant\u000d      (2012). High avidity CTL to tumor associated antigens can be selected into\u000d      the memory pool but they are exquisitely sensitive to functional\u000d      impairment. Plos one 7(7):e41112 http:\/\/dx.doi.org\/10.1371\/journal.pone.0041112\u000d    \u000aGrants underpinning this research and awarded to Professor Durrant:\u000d    • Cancer Research UK programme grant — £400K; 1993-1997\u000d    • Cancer Research UK funding for antibody development — £500K; 2008-2015\u000d    • Lewis Trust funding for anti-Lewis y mabs — £250K; 2008-2016\u000d    • Pancreatic Cancer Research Trust funding for anti-pancreatic mabs —\u000d      £250K; 2010-2014.\u000d    Patents:\u000d    • Specific binding members; patent awarded in Europe (EP1745077;2012),\u000d      Japan\u000d      (JP4944016;2012), US (US8343490;2013:US7915387;2011), Australia\u000d      (AU2005240837;2011: AU2011200487;2013), China (CN1961004;2012), India\u000d      (6191\/DELNP\/2006;2011), Korea (KR2007008511;2012), New Zealand\u000d      (550738;2011).\u000d    • A human anti-idiotypic antibody 105AD7; patent awarded in Europe\u000d      (EP0440689;1995), Japan (JP3095169) and USA (US6042827).\u000d    • Binding member which binds to both lewis-y and lewis-b haptens, and its\u000d      use for treating cancer. Patent awarded in Europe (EP1385547;2009),\u000d      Australia (AU2002307934;2007), Japan (JP4559030;2010), USA\u000d      (US7267821;2007: US7879983;2011; US8273349;2012).\u000d    • Humanised antibodies to the epidermal growth factor receptor. Patent\u000d      awarded in Europe (EP1278851; 2006), China (CN1239701), Korea\u000d      (KR100480985;2005).\u000d    • Polypeptides stimulating T cell responses; WO02058728\u000a        (A2). Patent awarded in Europe (2005), US (2012), Australia (2007).\u000d    • Denatured antigen DNA vaccine; PCT 08735583; awarded in Europe in 2013.\u000d    • DCIB68 DNA vaccine; PCT10152624.2; patent awarded in Europe in 2011.\u000d    • Anti-tumour responses against modified tumour antigens;\u000d      PCT\/GB2013\/052109.\u000d    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d    (a) All financial and corporate governance details are corroborated by\u000d      accounts filed by Scancell holdings plc at companies house and on the\u000d      company website http:\/\/www.scancell.co.uk\u000d      (also available as a pdf on request).\u000d    (b) News article: http:\/\/www.cnbc.com\/id\/100757009\u000d      (PDF available on request.)\u000d    (c) The licensing deals and revenues are all publicised in press\u000d      releases, copies of which are found on the company website http:\/\/www.scancell.co.uk.\u000d      Examples (in pdf format) are available on request.\u000d    (d) Clinical trials of SC104\/CEP-37250\/KHK2804: http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01447732\u000d    (e) Patents. See:\u000d      http:\/\/worldwide.espacenet.com\/searchResults?compact=false&ST=advanced&IN=Durrant&locale=en_EP&DB=EPODOC&PA=Scancell\u000d      (a pdf of patents is also available on request).\u000d    (f) Clinical trials of SCIB1: http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01138410?term=SCIB1&rank=1\u000d    (g) Its current share price and market capitalisation can be verified at\u000d      the London Stock exchange linked via the website: http:\/\/www.scancell.co.uk\/Apps\/Content\/HTML\/?id=133\u000d    (h) News articles: http:\/\/www.thisismoney.co.uk\/money\/investing\/article-2254089\/Stock-market-winners-losers-2012-Small-proved-beautiful-energy-firms-helped-shares-shine.html\u000d      http:\/\/www.thetimes.co.uk\/tto\/business\/markets\/article3644511.ece\u000d      (PDF available on request.)\u000d    (i) PraxisUnico Spinouts UK Survey: Annual Report 2013 (PDF available on\u000d      request).\u000d    ","Title":"\u000d    Scancell — a successful cancer immunotherapy company\u000d    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d    Cancer is the second leading cause of death in the Western world.\u000d      Worldwide, around 12.7 million cancer cases are diagnosed every year, and\u000d      this is expected to increase to 21 million by 2030. The drive behind the\u000d      Cancer Immunotherapy group at The University of Nottingham (UoN) was\u000d      therefore to improve treatment for cancer patients worldwide. In order to\u000d      fund the development of these products, Professor Lindy Durrant (Professor\u000d      of Cancer Immunotherapy, UoN, 2003-2013) spun out Scancell and, in 2008,\u000d      listed on the Plus and then AIM London stock market. Durrant is the joint\u000d      CEO of Scancell.\u000d    Durrant developed both novel oncolytic monoclonal antibodies (mabs) which\u000d      recognised unique glycolipids, and pioneered novel cancer vaccines\u000d      targeting dendritic cells in vivo. All of these immunotherapies\u000d      were licensed to Scancell. The company prioritised three mabs — SC100,\u000d      SC101 and SC104 — for further development and patenting. SC100 recognised\u000d      epidermal growth factor receptor and inhibited binding of its growth\u000d      factor, resulting in significant inhibition of tumour growth. SC101\u000d      recognises a glycan, Lewis y-b, and shows direct tumour\u000d      killing. SC104 showed good in vivo anti-tumour responses,\u000d      recognised a unique glycolipid antigen sialyltetraosylceramide and\u000d      mediated apoptosis (1). In collaboration with Peptech\/Kyowa Hakko Kirin,\u000d      SC104 was therefore humanised, defucosylated and further patent protected.\u000d      SC104 subsequently entered Phase I clinical trials in the US in December\u000d      2011 for the treatment of gastrointestinal tumours. The Cancer\u000d      Immunotherapy group has recently been awarded £500k in grants from the UoN\u000d      with matched funding from Cancer Research UK, Pancreatic Cancer Research\u000d      fund and Lewis Trust to set up a Centre of Excellence in Therapeutic\u000d      Antibodies. The aim is to produce and license further anti-tumour\u000d      antibodies to the Pharmaceutical industry to promote rapid clinical trials\u000d      and to allow the centre to become self-financing.\u000d    As part of the research, Durrant also developed cancer vaccines. The lead\u000d      product, 105AD7 was produced in collaboration with Professor John\u000d      Scholefield (Professor of Surgery, UoN 1998-2013) and was shown to\u000d      stimulate T cell responses in over 300 colorectal cancer patients with no\u000d      associated toxicity (2,3). In collaboration with Professor Kathy\u000d      Pritchard-Jones (UCL) a similar trial was performed in osteosarcoma\u000d      patients. Two of the 28 patients were cured of their disease and survived\u000d      for at least 10 years post treatment (4).\u000d    Scancell have now shown that it is possible to replace the T cell\u000d      epitopes within 105AD7 with a range of different epitopes and stimulate\u000d      high avidity T cell responses targeting other cancers (5,6). This vaccine\u000d      worked as a protein but is more effective in DNA form. The vaccine is\u000d      superior to traditional DNA vaccines, peptide vaccines and peptide pulsed\u000d      dendritic cell vaccines, as it directly targets antigen-presenting cells\u000d      and cross presents the antibody via the high affinity Fc receptor, CD64\u000d      (5,6). This approach, termed \"ImmunoBody®\", has been patent\u000d      protected.\u000d    The lead product emerging from this research, SCIB1, is a DNA vaccine for\u000d      melanoma. In collaboration with Professor Poulam Patel (Professor of\u000d      Oncology, UoN, 2003-2013), SCIB1 successfully completed Phase I (2012),\u000d      and has just completed recruitment for Phase II, clinical trials. Phase I\u000d      results showed no toxicity and at the highest dose one of four advanced\u000d      melanoma patients showed tumour regression of most lesions, including\u000d      complete regression of lung lesions in one patient. Scancell is continuing\u000d      to develop a range of ImmunoBody® vaccines for treatment of\u000d      other cancers. They have recently developed a new vaccine platform based\u000d      upon modified self-peptides with the patent filed in August 2012.\u000d    "},{"CaseStudyId":"41008","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"3996063","Name":"Mexico"},{"GeoNamesId":"2017370","Name":"Russia"},{"GeoNamesId":"1835841","Name":"South Korea"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Clinical and patient benefits\u000d\u000a    [text removed for publication] shunts and External Ventricular Drain\u000d\u000a        (EVD)\u000d\u000a    The initial application of our novel approach to anti-infective catheters\u000d\u000a      (USA Patent 4917686) was licensed in 1995 to a major USA company [text\u000d\u000a      removed for publication]. Since launch (1998 in EU, 2001 in USA), about\u000d\u000a      97,000 children and adults in 47 countries have received the antimicrobial\u000d\u000a      shunt, and since 2008 there has been a 22% growth in usage in the UK [a].\u000d\u000a      Almost 70% of shunts used annually in England now comprise our [text\u000d\u000a      removed for publication] shunt [a] and the technology prevents around 370\u000d\u000a      brain infections and 38 deaths in England each year [b]. Eleven\u000d\u000a      international clinical trials involving 5,613 patients [c] (2,180 since\u000d\u000a      2008) have all shown a reduction in infection (control rate 8.75%, [text\u000d\u000a      removed for publication] rate 3.6%, extracted from those studies after\u000d\u000a      2008), and data from the UK Shunt Registry [J Neurosurg Pediatr 2009;\u000d\u000a      4(4): 389-393] has confirmed this. In the same analysis, infection rates\u000d\u000a      for paediatric shunts were: control 5.8%, [text removed for publication]\u000d\u000a      0.9% [c]. [text removed for publication] is currently the subject of\u000d\u000a      application for regulatory approval by the Chinese FDA, in which Bayston\u000d\u000a      plays a pivotal role, having face-to-face meetings with Chinese officials.\u000d\u000a      In addition, the observed patient benefits of [text removed for\u000d\u000a      publication] have influenced the Department of Health's National Institute\u000d\u000a      for Health Research (NIHR), causing them to invest in a large multicentre\u000d\u000a      clinical trial of [text removed for publication] shunts (the BASICS trial;\u000d\u000a      £2.04M http:\/\/www.nets.nihr.ac.uk\/projects\/hta\/1010430).Bayston\u000a      has declined to be involved in this trial in order to avoid bias, but has\u000d\u000a      given advice on diagnostic criteria and microbiological investigations.\u000d\u000a    In 2001, the technology was licensed for catheters for external ventricular\u000d\u000a    drainage (EVD), a temporary means of 3 Use Adult intracranial Use Paed\u000d\u000a    pressure control. Since launch in Risk adult 2002 390,000 Risk Paed patients\u000d\u000a    have benefitted from the new EVD. In 2010, we licensed our technology\u000d\u000a    extending the antibacterial spectrum for EVD to cover multi-drug-resistant\u000d\u000a    Gram negative bacteria such as ESBL E coli and Acinetobacter to\u000d\u000a    [text removed for publication]. A 2010 study has shown a significant\u000d\u000a    reduction in brain infection, from 7.6% to 0.9%, using [text removed for\u000d\u000a    publication] EVD [d]. Use of our EVD catheter applies prophylactic\u000d\u000a    antibiotics only at the site of bacterial exposure, and a 2010 study has\u000d\u000a    shown that [text removed for publication] significantly reduces the need for\u000d\u000a    systemic antibiotics, so reducing their adverse events including Clostridium\u000a      difficile infection (an increasing antibiotic-related problem\u000d\u000a    worldwide resulting in superinfection and often need for colectomy) [J\u000d\u000a    Neurol Neurosurg Psychiatry 2010,81:1064-7]. [text removed for publication]\u000d\u000a    therefore has an important role in cutting antibiotic use and reduction of\u000d\u000a    associated risk.\u000d\u000a\u000d\u000a\u000d\u000a\u0009\u000d\u000a\u0009The current beneficiaries of the [text removed for publication] research\u000d\u000a      are primarily neurosurgical patients with hydrocephalus or head trauma,\u000d\u000a      who require intracranial pressure management, and who have been shown to\u000d\u000a      experience significantly fewer episodes of ventriculitis, abdominal sepsis\u000d\u000a      and other complications. In the US, approximately 33,000 patients are\u000d\u000a      shunted each year costing $100 million [Ped Neurosurg 1995,23: 254-259].\u000d\u000a      Clinical trials of [text removed for publication] shunts since 2008 have\u000d\u000a      shown a reduction in infection rate from 8.75% to 3.6% [c]. Treatment of\u000d\u000a      shunt infections is by shunt removal and systemic antibiotics, and, after\u000d\u000a      2-3 weeks, insertion of a new shunt. In up to 26% of cases this needs to\u000d\u000a      be repeated due to infection recurrence [J Neurosurg (Ped)\u000d\u000a      2006;105,177-181]. Therefore, applying the reduction in infection rate of\u000d\u000a      8.75% to 3.6% [c] to the 198,000 shunts inserted in USA since 2008, just\u000d\u000a      over 10,000 patients would have been spared at least two, and possibly\u000d\u000a      four or more, extra operations had [text removed for publication] been\u000d\u000a      used throughout. Similar results (reduction in infection rate 7.6% to\u000d\u000a      0.9%) are seen when our antimicrobial EVD catheter is used in\u000d\u000a      neurocritical care [d].\u000d\u000a    Dialysis and urinary catheters\u000d\u000a    Our modifications to the technology for other applications requiring\u000d\u000a      broad antimicrobial spectrum and long duration have led to other licensing\u000d\u000a      deals. The rights to our catheter for reducing peritonitis in Continuous\u000d\u000a      Ambulatory Peritoneal Dialysis (CAPD) patients, with activity against\u000d\u000a      staphylococci and Gram negative bacilli, were licensed to USA company\u000d\u000a      [text removed for publication] in 2005, and this catheter is now\u000d\u000a      undergoing CE Marking. Since 2009, the company has invested approximately\u000d\u000a      $1.337M in new construction and production equipment and employed one full\u000d\u000a      time engineer and two part-time regulatory \/ marketing executives\u000d\u000a      specifically for this venture. The company have decided to name the\u000d\u000a      product the `Bayston Catheter' [e,f].\u000d\u000a    Beneficiaries of the CAPD catheter are those with end-stage renal disease\u000d\u000a      (ESRD) who are expected to experience significantly fewer episodes of\u000d\u000a      peritonitis and fewer catheter changes (each a surgical procedure).\u000d\u000a      Approximately 1m people in the USA and probably several times this figure\u000d\u000a      in Korea and China are affected. Worldwide, an average of 11% of ESRD\u000d\u000a      patients are treated with CAPD, but in EU and Korea, CAPD is used more\u000d\u000a      often, and 75% of ESRD patients in Mexico use CAPD [J Am Soc Nephrol\u000d\u000a      2012;23,533-544].\u000d\u000a    Long-term urinary catheters are used in tens of millions of patients\u000d\u000a      worldwide, with infection rates around 40%. We are working with the\u000d\u000a      international devices company [text removed for publication] to evaluate\u000d\u000a      our recently developed urinary catheter for regulatory approval.\u000d\u000a    Training senior surgeons\u000d\u000a    The research surrounding the base technology and its clinical\u000d\u000a      applications has underpinned Bayston's contributions to the DePuy\u000d\u000a      Hydrocephalus and Neurocritical Care Learning Centre (http:\/\/www.depuy.com\/uk\/healthcare-professionals\/education-and-training),\u000a      held three times each year for senior professionals in Hamburg, Istanbul,\u000d\u000a      Neuchatel and Prague. Since 2008, approximately 400 senior surgeons have\u000d\u000a      attended, and Continuing Professional Development (CPD) points are awarded\u000d\u000a      for these sessions at rates depending on national systems. As an example,\u000d\u000a      a 3-day training session in Neuchatel in 2010 was attended by 61\u000d\u000a      professionals from South America, EU, Eastern Europe, Africa, Russia and\u000d\u000a      Korea. Up-to-date best practice is taught and discussed so that delegates\u000d\u000a      return to their home countries in a position to institute regimens to\u000d\u000a      reduce complications and improve patient outcome.\u000d\u000a    Commercial benefits\u000d\u000a    Cost-savings for the NHS\u000d\u000a    One large USA [text removed for publication] shunt study [g] showed a\u000d\u000a      reduction in infection rate from 12% to 3.2%, a reduction of 53 days'\u000d\u000a      hospital stay for every 100 patients shunted, and an associated saving of\u000d\u000a      $442,133 per 100 patients shunted. In one German hospital, use of the\u000d\u000a      antimicrobial shunt catheters led to reduction in infection rate from 5.8%\u000d\u000a      to 1%, yielding annual savings of $1.3m [h]. In England, the technology\u000d\u000a      prevents around 370 brain infections and 38 deaths each year, thereby\u000d\u000a      saving NHS England an estimated £18.4m in treatment costs annually [b].\u000d\u000a      Costs of infections vary between countries and institutions, but an\u000d\u000a      estimated $100m annual cost worldwide of shunt complications (which\u000d\u000a      includes non-infective causes) would be reduced by $35m-$50m by the use of\u000d\u000a      [text removed for publication] shunts (calculated from figures in the\u000d\u000a      literature).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The use of implantable polymeric devices is limited by infection.\u000d\u000a      University of Nottingham research led to patented technology for\u000d\u000a      hydrocephalus shunts that provides biomaterials with long-acting\u000d\u000a      antimicrobial action. Almost 70% of shunts used annually in England now\u000d\u000a      comprise our [text removed for publication] shunt, and UK usage has grown\u000d\u000a      by 22% since 2008. The technology has reduced infection rates from 8.75%\u000d\u000a      (2008) to 3.6% (2013), and prevents around 370 brain infections and 38\u000d\u000a      deaths in England each year. This is saving NHS England an estimated\u000d\u000a      £18.4m in treatment costs each year, and generating company revenue.\u000d\u000a      Furthermore, our [text removed for publication] EVD catheters for\u000d\u000a      temporary relief of intracranial hypertension have reduced the rate of\u000d\u000a      brain infections from 7.6% to 0.9%.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Nottingham\u000d\u000a    ","Institutions":[{"AlternativeName":"Nottingham (University of)","InstitutionName":"University of Nottingham","PeerGroup":"A","Region":"East Midlands","UKPRN":10007154}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"3067696","Name":"Prague"},{"GeoNamesId":"745044","Name":"Istanbul"}],"References":"\u000d\u000a    \u000a1.  Bayston R, Ashraf W, Bhundia C. Mode of\u000d\u000a      action of an antimicrobial biomaterial for use in hydrocephalus shunts.\u000d\u000a      2004 J Antimicrob Chemother; 53: 778-782.\u000d\u000a      http:\/\/dx.doi.org\/10.1093\/jac\/dkh183\u000d\u000a    \u000a\u000a2.  Bayston R. 2007. Medical devices\u000d\u000a      and methods of making medical devices. EP1804845 (W02006032904) Europe.\u000d\u000a    \u000a\u000a3.  Abed WT, Alavijeh MS, Bayston R,\u000d\u000a      Shorvon S, Patsalos PN. An evaluation of the epileptogenic properties of a\u000d\u000a      rifampicin \/ clindamycin — impregnated shunt catheter. Br J Neurosurg\u000d\u000a      1994; 8: 725-730.\u000d\u000a      http:\/\/dx.doi.org\/10.3109\/02688699409101187\u000d\u000a    \u000a\u000a4.  Bayston R, Fisher LE, Weber K. An\u000d\u000a      antimicrobial modified silicone peritoneal catheter with activity against\u000d\u000a      both Gram positive and Gram negative bacteria. Biomater 2009; 30:\u000d\u000a      3167-3173.\u000d\u000a      http:\/\/dx.doi.org\/10.1016\/j.biomaterials.2009.02.028\u000d\u000a    \u000a\u000a5.  Bayston R, Vera L, Ashraf W.\u000d\u000a      Activity of an Antimicrobial Hydrocephalus Shunt Catheter against\u000d\u000a      Propionibacterium acnes. Antimicrob Ag Chemother 2010; 54: 5082-5085.\u000d\u000a      http:\/\/dx.doi.org\/10.1128\/AAC.00540-10\u000d\u000a    \u000aPatents filed on this technology since 1993 — Medical devices and methods\u000d\u000a      of making medical devices (Bayston, R):\u000d\u000a    \u000d\u000a      \u000d\u000a        \u000d\u000a          UK\u000d\u000a          0303033.5 & 0421164.5\u000d\u000a          \u000d\u000a          \u000d\u000a        \u000d\u000a        \u000d\u000a          PCT\u000d\u000a          GB2005\/003667\u000d\u000a          JP\u000d\u000a          2007-532961\u000d\u000a        \u000d\u000a        \u000d\u000a          Euro\u000d\u000a          05781960.9\u000d\u000a          CA\u000d\u000a          2 580 894\u000d\u000a        \u000d\u000a        \u000d\u000a          US\u000d\u000a          11\/690 567\u000d\u000a          MYA\u000d\u000a          PI.20070453\u000d\u000a        \u000d\u000a        \u000d\u000a          Euro Div1\u000d\u000a          10178080.7\u000d\u000a          Euro Div2\u000d\u000a          10178073.2\u000d\u000a        \u000d\u000a      \u000d\u000a    \u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"9","Level2":"3","Subject":"Biomedical Engineering"},{"Level1":"6","Level2":"5","Subject":"Microbiology"}],"Sources":"\u000d\u000a    a. Cambridge shunt registry data. Supplied in confidence by [text removed\u000d\u000a      for publication]. Available on request.\u000d\u000a    b. Economic analysis by Professor R Elliott, Lord Trent Professor of\u000d\u000a      Medicines and Health. The University of Nottingham.\u000d\u000a    c. Parker SL, Anderson WN, Lilienfeld S, Megerian JT, McGirt MJ.\u000d\u000a      Cerebrospinal shunt infection in patients receiving antibiotic-impregnated\u000d\u000a      versus standard shunts. J Neurosurg 2011; 8: 259-265. http:\/\/dx.doi.org\/10.3171\/2011.6.PEDS11257\u000d\u000a    d. Harrop JS, Sharan A, Ratliff J, et al. Impact of standardized protocol\u000d\u000a      and antibiotic-impregnated catheters on ventriculostomy infection rates in\u000d\u000a      cerebrosvascular patients. Neurosurg 2010; 67: 187-191. http:\/\/dx.doi.org\/10.1227\/01.NEU.0000370247.11479.B6\u000d\u000a      (pdf available on request).\u000d\u000a    e. Email correspondence from [text removed for publication]; and Gary\u000d\u000a      Evans, Head of IP Management and Legal Services, BEIS, The University of\u000d\u000a      Nottingham.\u000d\u000a    f. Letter from [text removed for publication], President, [text removed\u000d\u000a      for publication].\u000d\u000a    g. Attenello FJ, Garces-Ambrossi GL, Zaidi HA, Sciubba DM, Jallo GI.\u000d\u000a      Hospital costs associated with shunt infections in patients receiving\u000d\u000a      antibiotic-impregnated shunt catheters versus standard shunt catheters.\u000d\u000a      Neurosurg 2010; 66: 284-289 (pdf available on request). http:\/\/dx.doi.org\/10.1227\/01.NEU.0000363405.12584.4D\u000d\u000a    h. Eymann R, Chehab S, Strowitzki M, Steudel WI, Kiefer M. Clinical and\u000d\u000a      economic consequences of antibiotic impregnated cerebrospinal fluid shunt\u000d\u000a      catheters. J Neurosurg Pediatr 2008; 1: 444-450. http:\/\/dx.doi.org\/10.3171\/PED\/2008\/1\/6\/444\u000d\u000a    ","Title":"\u000d\u000a    Development of long-acting antimicrobial implantable devices that prevent\u000d\u000a      disabling infections, cut healthcare costs and reduce bacterial\u000d\u000a      resistance.\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Biomaterials-associated infection is a common complication of surgical\u000d\u000a      implant devices, regardless of the biomaterial used. These infections are\u000d\u000a      highly resistant to the immune system and to antimicrobials. In\u000d\u000a      hydrocephalus, where treatment is by insertion of a shunt or temporary\u000d\u000a      external ventricular drain (EVD), infections account for one-third of all\u000d\u000a      shunt-related mortality and worsen the overall prognosis. Despite\u000d\u000a      modifications in surgical technique, the incidence of cerebrospinal fluid\u000d\u000a      shunt infection remains unacceptably high at 5-15%, and in EVD this can\u000d\u000a      reach 25-30% of cases. Even when successfully treated, infections are\u000d\u000a      associated with reduced intelligence and cognition, increased risk of\u000d\u000a      seizures and psychomotor retardation.\u000d\u000a    In 1993, Professor Roger Bayston began a research programme in the\u000d\u000a      Biomaterials-Related Infection Group at the University of Nottingham to\u000d\u000a      address this problem. In researching appropriate antimicrobial\u000d\u000a      biomaterials for shunts, we discovered that individual infecting bacteria\u000d\u000a      attached to the biomaterial and developed highly adherent and resistant\u000d\u000a      biofilms. We showed that eradication of biofilm bacteria requires\u000d\u000a      prolonged exposure to local high antimicrobial concentrations and that\u000d\u000a      this needs to be sited at the interface of bacteria and implant polymer\u000d\u000a      [1]. Since antimicrobial coatings do not give sufficient duration of\u000d\u000a      activity, we developed a novel process [text removed for publication] that\u000d\u000a      allowed devices to be impregnated, not just coated, with antimicrobials\u000d\u000a      post- manufacture. In this way, the antimicrobials remain evenly\u000d\u000a      distributed in the polymer matrix as molecules rather than drug particles,\u000d\u000a      giving more controlled release and improved mechanical properties.\u000d\u000a      Crucially, we designed the process to enable the molecules to migrate\u000d\u000a      freely through the crosslinked polymer, thus repeatedly replenishing the\u000d\u000a      surface layer. The manufacturing process permitted antimicrobial devices\u000d\u000a      to withstand sterilisation by autoclaving or ethylene oxide. The patented\u000d\u000a      technology has been commercialised only by the University of Nottingham\u000d\u000a      and is unique [2]. Studies of the mode of action of the antimicrobial\u000d\u000a      biomaterial showed that bacteria attached to the polymer and were then\u000d\u000a      killed. But approximately 48hrs were needed to kill all the bacteria and\u000d\u000a      antimicrobial coatings are rapidly depleted by fluid flow before this\u000d\u000a      time-point, hence explaining the failure of these coatings. The\u000d\u000a      bactericidal activity of the [text removed for publication] shunt was\u000d\u000a      found to last for 50 days using rifampicin and clindamycin, compared with\u000d\u000a      three days for existing technologies. This was sufficient to avoid\u000d\u000a      infection in the crucial first month after shunt implant in hydrocephalus\u000d\u000a      patients. Safety studies were carried out [3] and commercialisation of the\u000d\u000a      shunt by [text removed for publication] has led to clinical evaluation and\u000d\u000a      use (see Section 4).\u000d\u000a    The process was further adapted to cover EVD and peritoneal dialysis\u000d\u000a      catheters with a long period of infection risk and with a need for broader\u000d\u000a      spectrum antimicrobial activity (4,5). In both cases, where biofilm growth\u000d\u000a      occurs both in the lumen and down the outside, 80-100 days effectiveness\u000d\u000a      against a range of pathogens, including Staphylococcus epidermidis,\u000d\u000a      MRSA, anaerobes and multi-drug-resistant Gram negative bacteria such as\u000d\u000a      ESBL E coli and Acinetobacter, was achieved. These modifications\u000d\u000a      were patent protected [2]. Our recently developed long-term urinary\u000d\u000a      catheter (Fisher, Ashraf and Bayston, in preparation) is also active for\u000d\u000a      three months against these pathogens, as well as against Proteus\u000d\u000a        mirabilis, known as the scourge of catheterised spinal injuries\u000d\u000a      patients.\u000d\u000a    "},{"CaseStudyId":"41011","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2328926","Name":"Nigeria"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    A diagnosis of DSD can be devastating for patients and their families;\u000d\u000a      consequently, the clinical\u000d\u000a      symptoms and psychological consequences of DSD must be managed by\u000d\u000a      healthcare professionals\u000d\u000a      with sensitivity and compassion. This aim is best achieved by a\u000d\u000a      multidisciplinary team of healthcare\u000d\u000a      professionals who take a holistic approach to DSD. Clinical management\u000d\u000a      plans should focus on the\u000d\u000a      needs of the patient to ensure that care is individually tailored and\u000d\u000a      targeted to provision of the\u000d\u000a      correct services. In addition, parents and other family members must be\u000d\u000a      fully involved in the\u000d\u000a      decision-making process to help support patients.\u000d\u000a    Ambitious work conducted by the University of Glasgow has successfully\u000d\u000a      bridged gaps in DSD\u000d\u000a      healthcare provision by establishing: i) the first set of UK clinical\u000d\u000a      guidelines for the initial evaluation\u000d\u000a      and diagnosis of children with suspected DSD; ii) the first managed\u000d\u000a      clinical network and\u000d\u000a      telemedicine service for DSD within NHS Scotland; iii) the first national\u000d\u000a      and international patient\u000d\u000a      registries for DSD, giving clinicians worldwide unparalleled online access\u000d\u000a      to medical histories of\u000d\u000a      patients with DSD; iv) access to clinical expertise for DSD support\u000d\u000a      groups; and v) an internationally\u000d\u000a      accessible diagnostic advisory service.\u000d\u000a    UK guidelines\u000d\u000a    Given the rarity of DSD, very few experts in this condition exist\u000d\u000a      worldwide and clinical care can\u000d\u000a      vary enormously between regions. The development of guidelines outlining\u000d\u000a      best practice is,\u000d\u000a      therefore, paramount to ensuring equality of care. The Society for\u000d\u000a      Endocrinology recognised\u000d\u000a      Ahmed's extensive research and clinical experience in DSD and invited him\u000d\u000a      to chair a UK taskforce\u000d\u000a      to define the most appropriate methods for initial evaluation and\u000d\u000a      diagnosis of suspected DSD. This\u000d\u000a      taskforce developed the first UK set of DSD clinical guidelines, which\u000d\u000a      were published in 2011 in\u000d\u000a      association with nine other UK organisations.a Key\u000d\u000a      recommendations included:\u000d\u000a    \u000d\u000a      a structured framework of evaluation and diagnosis by a\u000d\u000a        multidisciplinary clinical team\u000d\u000a        experienced in all aspects of paediatric care, including endocrinology,\u000d\u000a        urology, radiology\u000d\u000a        and clinical psychology\u000d\u000a      access to a regional DSD centre that specialises in this condition\u000d\u000a      essential psychological support for all patients and their families,\u000d\u000a        and access to patient\u000d\u000a        support groups\u000d\u000a      contribution of patient data to national and international patient\u000d\u000a        registries\u000d\u000a    \u000d\u000a    Publication of these guidelines was reported by several health-related\u000d\u000a      media outlets, including\u000d\u000a      Medical News Today and ScienceDaily.b\u000d\u000a    Managed clinical network and patient registries for DSD\u000d\u000a      The SAGA study led by University of Glasgow researchers directly shaped\u000d\u000a      the establishment, in\u000d\u000a      2006, of one of the first managed clinical networks in the UK, the\u000d\u000a      Scottish DSD network (SDSD;\u000d\u000a      previously Scottish Genital Anomaly Network). A managed clinical network\u000d\u000a      is a virtual clinic\u000d\u000a      created to increase standards of care through collaboration and\u000d\u000a      integration of key services. The\u000d\u000a      SDSD network is centralised at the Royal Hospital for Sick Children in\u000d\u000a      Glasgow, with Ahmed as\u000d\u000a      part of the Executive Group that oversees this enterprise. The SDSD\u000d\u000a      network operates a\u000d\u000a      telemedicine clinic service between its major centres in Glasgow,\u000d\u000a      Edinburgh and Aberdeen,\u000d\u000a      accessible by nonspecialist clinicians for advice, case review and as a\u000d\u000a      referral route to specialist\u000d\u000a      centres. The SDSD network also includes a registry that holds data on over\u000d\u000a      600 Scottish DSD\u000d\u000a      patients, including their diagnosis, recommended investigations,\u000d\u000a      treatments and outcomes. The\u000d\u000a      clinical network team use the SDSD registry as an invaluable resource to\u000d\u000a      inform appropriate\u000d\u000a      diagnosis and treatment of new cases and thereby equalise patient care\u000d\u000a      across Scotland. The\u000d\u000a      SDSD registry has been adopted by the National Services Division of NHS\u000d\u000a      Scotland within its\u000d\u000a      national Clinical Audit Systems, which manages the flow of information\u000d\u000a      through clinical care\u000d\u000a      networks operating within Scotland. Furthermore, the SDSD network has\u000d\u000a      produced a range of\u000d\u000a      patient information leaflets and a management pathway for the care of\u000d\u000a      patients with suspected\u000d\u000a      DSD, all of which are freely available to download from the website. The\u000d\u000a      SDSD has also used the\u000d\u000a      registry to connect families affected by similar DSD conditions.\u000d\u000a    Internationally, incorporation of data into the I-DSD registry from 23\u000d\u000a      centres located in 15 countries\u000d\u000a      worldwide (Europe, Middle East and Africa) has created a common dataset\u000d\u000a      with clinical information\u000d\u000a      on the most extreme forms of DSD from 1,161 patients.c The\u000d\u000a      I-DSD registry has improved the\u000d\u000a      available knowledge that can be shared on these rare forms of DSD and\u000d\u000a      provided a platform to\u000d\u000a      enhance clinical understanding of their underlying causes. Since 2012, 174\u000d\u000a      unique visitors have\u000d\u000a      accessed the I-DSD registry website, with 325 visits in total (202 return\u000d\u000a      visitors) and 727 page\u000d\u000a      views; 75 registered users (74 of them return visitors) have logged on to\u000d\u000a      the secure pages of the\u000d\u000a      registry.d The I-DSD project page has received 1,162 page views\u000d\u000a      (906 unique).d In 2013, a survey\u000d\u000a      of the 134 registered I-DSD users was conducted to assess functionality of\u000d\u000a      the resource.e\u000d\u000a      Approximately 30% of respondents were clinicians; around one-quarter of\u000d\u000a      respondents were\u000d\u000a      involved in clinical care, while others were specialists in biochemical or\u000d\u000a      genetic evaluations (27%).\u000d\u000a      More than 30% of respondents logged on to the I-DSD registry every 3\u000d\u000a      months, with 20% logging\u000d\u000a      on monthly. Some users also provided feedback on their experiences of\u000d\u000a      using the registry.e\u000d\u000a      Benefits highlighted included the ability to communicate with other\u000d\u000a      experts and discuss DSD\u000d\u000a      cases; the capacity to transfer patients to another registered user within\u000d\u000a      the I-DSD network should\u000d\u000a      they relocate to a different country; and the comprehensive clinical data\u000d\u000a      provided.\u000d\u000a    Clinical expertise for DSD patient support groups\u000d\u000a      Given the rarity, social stigma and delay in diagnosis of DSD, the role of\u000d\u000a      support groups for\u000d\u000a      patients and parents cannot be overestimated. University of Glasgow\u000d\u000a      researchers have enabled\u000d\u000a      the work of DSD support groups by providing expert advice about these\u000d\u000a      conditions and\u000d\u000a      encouraging participation of the affected community in discussions about\u000d\u000a      education and clinical\u000d\u000a      care.\u000d\u000a    For example, in 2011, Ahmed provided both clinical content and input to\u000d\u000a      the development of\u000d\u000a      dsdfamilies, an international online resource that provides users with\u000d\u000a      connections to DSD\u000d\u000a      healthcare specialists and testimonials of patient and parent experiences\u000d\u000a      from around the world.f\u000d\u000a      The website has around 700-800 individual visitors per month of which 25%\u000d\u000a      are from the UK and\u000d\u000a      39% from the USA; return visitors account for 20% of all visits. Users\u000d\u000a      from Canada, India,\u000d\u000a      Australia, the Netherlands, Japan, Germany and Spain have also visited the\u000d\u000a      website. In June\u000d\u000a      2013, the I-DSD convened a conference in Glasgow that welcomed the\u000d\u000a      involvement of patients\u000d\u000a      and support groups.g The Administrator of dsdfamilies, who is\u000d\u000a      also a member of the I-DSD\u000d\u000a      Steering Committee, was the opening speaker at this conference and both\u000d\u000a      organised and chaired\u000d\u000a      a parallel session for support groups (\"Meet the Experts — A Joint\u000d\u000a        Effort\"). Ahmed and dsdfamilies\u000d\u000a      secured funding that enabled 16 members of the affected community\u000d\u000a      (parents, adult patients and\u000d\u000a      representatives of other support groups) to attend the I-DSD conference.\u000d\u000a      As a consequence of this\u000d\u000a      session, the Glasgow Working Group was initiated to foster relationships\u000d\u000a      between the affected\u000d\u000a      community (23 members) and clinical staff (27 members) and to progress\u000d\u000a      nine key goals across\u000d\u000a      three functional groups.f The Administrator of dsdfamilies\u000d\u000a      stated that Ahmed's influence has two\u000d\u000a      key elements: \"[first] by supporting dsdfamilies he gives legitimacy\u000d\u000a        to the resource which is\u000d\u000a        invaluable when it comes to reaching stakeholders (in both affected and\u000d\u000a        medical communities) and\u000d\u000a        [second] by supporting myself personally and creating the opportunity\u000d\u000a        for me to speak at medical\u000d\u000a        events he gives a voice to the affected community.\"\u000d\u000a    Ahmed has also worked with other DSD support groups. As chair of the\u000d\u000a      Society for Endocrinology\u000d\u000a      taskforce, he invited AIS Support Group and Living with CAH to participate\u000d\u000a      in developing the 2011\u000d\u000a      UK clinical guidelines.a The Society for Endocrinology's\u000d\u000a      dedicated patient support website `You &\u000d\u000a      Your Hormones' successfully promoted these guidelines,h\u000d\u000a      increasing the extent to which reliable\u000d\u000a      information on DSD was publicly accessible and facilitating discussion of\u000d\u000a      concerns, questions and\u000d\u000a      personal experiences of patients and their families online.\u000d\u000a    Internationally accessible advisory service for DSD diagnosis\u000d\u000a      Establishing the underlying cause of DSD is vital for directing the\u000d\u000a      appropriate course of long-term\u000d\u000a      clinical care; however, no single facility in the UK offered the combined\u000d\u000a      services of specialist\u000d\u000a      genetic tests for DSD and their interpretation by both scientific and\u000d\u000a      clinical DSD experts. To\u000d\u000a      address this deficit, in 2012, Ahmed established a team of paediatric\u000d\u000a      endocrinologists, clinical and\u000d\u000a      molecular geneticists and clinical biochemists at the Royal Hospital for\u000d\u000a      Sick Children in Glasgow\u000d\u000a      who provide diagnostic advice to nonspecialist clinicians worldwide on a\u000d\u000a      case-by-case basis. There\u000d\u000a      have been 30 separate cases discussed at the DSD diagnostic meeting, 27 of\u000d\u000a      which were from the\u000d\u000a      UK, two from Nigeria and one from Israel (January-July 2013).i\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Disorders of sex development (DSD) represent a broad group of rare\u000d\u000a      genetic conditions (affecting\u000d\u000a      0.1-2.0% of the UK population) characterised by ambiguous external\u000d\u000a      genitalia or atypical sexual\u000d\u000a      development that manifests at birth or puberty, respectively. University\u000d\u000a      of Glasgow researchers\u000d\u000a      have established the first patient registries for DSD in the world,\u000d\u000a      developed comprehensive UK\u000d\u000a      clinical guidelines for DSD, worked closely with international patient\u000d\u000a      support groups to raise\u000d\u000a      awareness of the condition and improve the support available to those\u000d\u000a      affected, and created a\u000d\u000a      cutting-edge DSD clinical management network and diagnostic service for\u000d\u000a      use worldwide. These\u000d\u000a      innovations have improved clinical awareness of DSD and the ability to\u000d\u000a      provide consistent\u000d\u000a      treatment and professional support to affected individuals.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Hughes IA et al. on behalf of the LWPES\/ESPE Consensus Groups.\u000d\u000a      Consensus statement on\u000d\u000a        management of intersex conditions. Arch. Dis. Child. 91,\u000d\u000a      554-563 (2006)\u000d\u000a      doi:10.1136\/adc.2006.098319.\u000d\u000a    \u000a\u000a2. Ahmed\u000d\u000a        SF et al. Prevalence\u000d\u000a        of hypospadias and other genital anomalies among singleton\u000d\u000a        births, 1988-1997, in Scotland. Arch. Dis. Child. Fetal Neonatal\u000d\u000a        Ed. 89, F149-F151 (2004)\u000d\u000a      doi:10.1136\/adc.2002.024034.\u000d\u000a    \u000a\u000a3. Ahmed SF et al. The\u000d\u000a        European Disorder of Sex Development registry: a virtual research\u000d\u000a        environment. Sex. Dev. 4, 192-198 (2010)\u000d\u000a      doi:10.1159\/000313434.\u000d\u000a    \u000a\u000a4. Duguid A et al., on behalf of the Scottish Genital Anomaly\u000d\u000a      Network. The\u000d\u000a        psychological impact\u000d\u000a        of genital anomalies on the parents of affected children. Acta\u000d\u000a        Paediatr. 96, 348-352 (2007)\u000d\u000a      doi:10.1111\/j.1651-2227.2006.00112.x.\u000d\u000a    \u000a\u000a5. Rodie\u000d\u000a        M et al. Factors\u000d\u000a        that influence the decision to perform a karyotype in suspected\u000d\u000a        disorders of sex development: lessons from the Scottish Genital Anomaly\u000d\u000a        Network register. Sex.\u000d\u000a        Dev. 5, 103-108 (2011) doi:10.1159\/000326815.\u000d\u000a    \u000a\u000a6. Cox K et al. Novel associations in disorders of sex\u000d\u000a      development: findings from the I-DSD\u000d\u000a      Registry. J Clin Endocrinol Metab (in press; PDF available on\u000d\u000a      request).\u000d\u000a    \u000aGrant funding\u000d\u000a    EU Seventh Framework Programme. EuroDSD (e-Health grant 20144). Awarded\u000d\u000a      to RO Sinnott\u000d\u000a      (Principal Investigator) and SF Ahmed (Co-Principal Investigator),\u000d\u000a      2008-2011, €385,000.\u000d\u000a      Medical Research Council. The International DSD network (G1100236).\u000d\u000a      Awarded to SF Ahmed\u000d\u000a      (Principal Investigator), M Rodie and RO Sinnott, 2011-2016, £660,157.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    a. Society for Endocrinology UK\u000d\u000a        clinical guidelines (see Executive Summary, p2) and\u000d\u000a      accompanying press\u000d\u000a        release, 2011\u000d\u000a    b. Media coverage of UK clinical guidelines, 2011: Medical\u000d\u000a          News Today; Science\u000d\u000a          Daily\u000d\u000a    c. I-DSD registry metrics (available on request)\u000d\u000a    d. I-DSD registry and project\u000d\u000a        page web statistics (available on request)\u000d\u000a    e. I-DSD registry user\u000d\u000a        survey and feedback (available on request)\u000d\u000a    f. Statement from the Administrator, dsdfamilies\u000d\u000a      (available on request)\u000d\u000a    g. I-DSD symposium final\u000d\u000a        programme, June 2013 (p4, 5, 10 and 12)\u000d\u000a    h. You & Your Hormones patient\u000d\u000a        factsheet\u000d\u000a    i. Diagnostic advisory service metrics (available on request)\u000d\u000a    ","Title":"\u000d\u000a    Improved healthcare management of children with disorders of sex\u000d\u000a      development\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2657832","Name":"Aberdeen"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Disorders of sex development (DSD) is an umbrella term used to describe a\u000d\u000a      group of very rare\u000d\u000a      genetic conditions affecting the hormone-secreting (endocrine) system in\u000d\u000a      the body. These\u000d\u000a      conditions are characterised by atypical external genitalia of varying\u000d\u000a      severity and include androgen\u000d\u000a      insensitivity syndrome (AIS; 1 in 20,000 UK births) and congenital adrenal\u000d\u000a      hyperplasia (CAH; up to\u000d\u000a      1 in 18,000 UK births). DSD typically present clinically in newborns; in\u000d\u000a      some instances, the\u000d\u000a      condition is so complex that sex determination is near impossible, even by\u000d\u000a      experts. However, DSD\u000d\u000a      can also manifest in otherwise healthy young people at puberty.\u000d\u000a    A substantial body of research on DSD has been conducted at the\u000d\u000a      University of Glasgow under the\u000d\u000a      leadership of Prof. S Faisal Ahmed, a paediatric endocrinologist and\u000d\u000a      world-leading authority on\u000d\u000a      these rare conditions. Ahmed's standing in this discipline is underlined\u000d\u000a      by his lead in developing\u000d\u000a      clinical guidelines for DSD. For example, in 2006, he was a member of the\u000d\u000a      Consensus Group that\u000d\u000a      developed a guideline on behalf of two leading paediatric endocrinology\u000d\u000a      societies.1 This document\u000d\u000a      was the first to address the psychological issues surrounding the\u000d\u000a      nomenclature for patients with\u000d\u000a      DSD, previously known by the controversial (and potentially stigmatising)\u000d\u000a      term `intersex'.\u000d\u000a    Establishment of a Scottish registry for DSD\u000d\u000a      Approximately 100 children with DSD are born every year in Scotland;\u000d\u000a      however, the epidemiology\u000d\u000a      of DSD was poorly understood until relatively recently. University of\u000d\u000a      Glasgow researchers sought\u000d\u000a      to address this question by retrospectively analysing data from over\u000d\u000a      600,000 births that occurred\u000d\u000a      across Scotland during 1988-1997 and uncovered striking regional and\u000d\u000a      temporal variations in the\u000d\u000a      birth prevalence of DSD (2004).2 These findings indicated that\u000d\u000a      establishing a national registry of\u000d\u000a      affected individuals would be useful for further research into DSD.\u000d\u000a      Consequently, NHS Quality\u000d\u000a      Improvement Scotland (now Health Improvement Scotland) funded Ahmed's team\u000d\u000a      to create the\u000d\u000a      Scottish Audit of Genital Anomalies (SAGA) registry (2003). SAGA\u000d\u000a      established a process for\u000d\u000a      collecting clinical data on all new Scottish DSD cases that occurred\u000d\u000a      between 2003 and 2006 and\u000d\u000a      conducted an audit of variations in clinical management practice across\u000d\u000a      NHS Scotland.\u000d\u000a    European and international DSD registries\u000d\u000a      Ahmed went on to develop a bespoke DSD computational virtual research\u000d\u000a      environment (VRE) for\u000d\u000a      paediatric endocrinology in collaboration with Prof. Richard Sinnott\u000d\u000a      (University of Glasgow National\u000d\u000a      e-Science Centre). A VRE is a web-based platform that enables multicentre\u000d\u000a      research\u000d\u000a      collaborations, including data sharing among authorised users. The Glasgow\u000d\u000a      VRE was piloted by a\u000d\u000a      European consortium (EuroDSD) in 2010 as part of a programme to establish\u000d\u000a      a Europe-wide\u000d\u000a      registry of DSD cases (2010).3 Use of this VRE enabled secure\u000d\u000a      management and dissemination of\u000d\u000a      information held in the registry. In 2011, Ahmed took EuroDSD a stage\u000d\u000a      further by establishing the\u000d\u000a      International DSD (I-DSD) registry, a project co-ordinated by the\u000d\u000a      University of Glasgow that\u000d\u000a      gathers scientific and clinical information on DSD cases from across the\u000d\u000a      world into a single\u000d\u000a      database. University of Glasgow researcher Dr Martina Rodie deputises for\u000d\u000a      Ahmed in the I-DSD\u000d\u000a      project management group.\u000d\u000a    The DSD registries expedite clinical research\u000d\u000a      The DSD registries established by the University of Glasgow have enabled\u000d\u000a      long-term review of\u000d\u000a      how individual DSD cases are managed, and supported additional DSD\u000d\u000a      research projects. For\u000d\u000a      example, Ahmed's team used SAGA to assess the psychological effects of a\u000d\u000a      diagnosis of DSD on\u000d\u000a      the parents of affected children (2007).4 Their findings\u000d\u000a      revealed the extent to which anxiety over\u000d\u000a      social stigma and treatment outcomes was intensified by inadequate\u000d\u000a      professional support and\u000d\u000a      information. This study was the first to highlight deficiencies in the\u000d\u000a      assistance made available to\u000d\u000a      parents and led Ahmed to call for multidisciplinary input to both the\u000d\u000a      clinical management of patients\u000d\u000a      and the needs of their families. In addition, SAGA data were used to\u000d\u000a      investigate the clinical benefit\u000d\u000a      of diagnostic blood and DNA tests and to explore the genetic basis of\u000d\u000a      specific hormonal causes of\u000d\u000a      DSD (2011).5 In 2013, Ahmed's group mined the I-DSD database to\u000d\u000a      show that people with rare\u000d\u000a      forms of DSD have a wide range of associated malformations; understanding\u000d\u000a      these conditions may\u000d\u000a      increase the likelihood of reaching a diagnosis and enhance patient care.6\u000d\u000a    Key University of Glasgow researchers: S Faisal Ahmed (Honorary\u000d\u000a      Senior Clinical Lecturer,\u000d\u000a      2000-2012; Samson Gemmell Chair of Child Health, 2012-present); Richard\u000d\u000a      Sinnott (National e-Science\u000d\u000a      Centre Technical Director, 2002-present); Martina Rodie (Clinical\u000d\u000a      Lecturer, 2010-present).\u000d\u000a    "},{"CaseStudyId":"41119","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000a    Time pressures, coupled with increased access to convenience foods, mean\u000a      that busy people continue to buy ready meals. Approximately 270 million of\u000a      these products were sold in the UK in 2012, demonstrating their hold over\u000a      the nation's eating habits.\u000a    Researchers from the University of Glasgow have helped consumers to make\u000a      straightforward choices between healthy and unhealthy convenience foods.\u000a      Using an innovative dual approach, they developed the highly successful\u000a      line of Eat Balanced pizzas,a as well as a 7-day online menu\u000a      plan that is available on the Eatwell Everyday website.b These\u000a      two complementary initiatives offer a fresh approach to tackling poor\u000a      nutritional choices and have received extensive global media attention.\u000a      Lean has also conveyed the concept of healthy fast food directly to\u000a      consumers through his involvement in public engagement activities. For\u000a      example, in June 2013, he was invited to speak at the York Festival of\u000a      Ideas, a two-week cultural programme comprising more than 120 free events\u000a      held across the city.\u000a    The Eat Balanced pizzas come to market\u000a    Pizza is a popular ready meal that is worth around £800 million annually\u000a      in UK sales. The Eat Balanced pizzas are the direct result of\u000a      collaboration between the University of Glasgow and Glasgow-based food\u000a      company Eat Balanced. The CEO of Eat Balanced,c Mr Donnie\u000a      Maclean — whose business objective was to make it easier for people to\u000a      achieve a balanced diet without compromising convenience and taste —\u000a      explains how the partnership with the University of Glasgow came about: \"I\u000a        ran various ideas past a few leading academics, but the one who was most\u000a        engaged and shared my passion was Professor Lean. His wealth of\u000a        experience with the balanced plate and many other publications were very\u000a        relevant to what we wanted to achieve and meant that we quickly shared\u000a        the same vision. When we experienced challenges, Mike always used his\u000a        experience and wisdom to tackle the issue and find solutions.\"\u000a      Bringing the Eat Balanced pizzas to market also involved other UK\u000a      companies, including Cosmo's (a pizza manufacturer) and Seagreens®\u000a      (who sourced the seaweed included in the pizza dough).\u000a    The Eat Balanced pizza range, which currently comprises cheese and\u000a      tomato, spicy chicken, and ham and pineapple varieties,a fills\u000a      a gap in the market by providing a ready meal that is both quick to\u000a      prepare or cook and healthy. More than 25,000 Eat Balanced pizzas have\u000a      been sold in the UK since they went on sale in September 2012.c\u000a      The pizzas are stocked in Scottish stores by Sainsbury's and Asda and are\u000a      available for home delivery by Ocado in England and Wales.a\u000a      Asda and Sainsbury's are the second and third largest supermarket chains\u000a      in the UK by market share, respectively, while online grocery retailer\u000a      Ocado makes more than 18,000 deliveries to British households daily.\u000a    The University of Glasgow concept of nutritionally balanced convenience\u000a      meals has earned considerable media attention; consequently, the Eat\u000a      Balanced pizza has achieved international recognition within an extremely\u000a      short timeframe (around 18 months). The pizzas have featured in BBC\u000a      Scotland News TV coverage (second most shared and third most read page on\u000a      the whole BBC News website that day, and the most popular story in the\u000a      Scotland section of the BBC website), the BBC Radio 4 Today Programme\u000a      (interview with Lean) and the BBC Radio 2 Factoids show with Steve Wright.\u000a      They have also been mentioned in articles published (either online, in\u000a      print, or both) by Daily Mail, Guardian, Metro, Daily Record, The\u000a      Scotsman, The Courier, Yahoo.com, New York Daily News, Times of India, Die\u000a      Welt, Asian Correspondent, Canada TV News, Top News Arab Emirates,\u000a      Huffington Post, and Gizmodo.a,d The Eat Balanced pizzas also\u000a      featured on primetime UK television when Maclean appeared in The\u000a      Entrepreneurs, a two-part documentary following the fortunes of a group of\u000a      Scottish new-start businesses that aired on BBC2 on 24th April and 1st May\u000a      2013 to an audience of about 24 million.\u000a    Eat Balanced has been recognised by several business organisations and\u000a      has received a total of 10 awards.a The pizzas were showcased\u000a      in March 2012 at the Food & Drink Expo in Birmingham, UK. This\u000a      exhibition is the largest food and drink trade show held annually in the\u000a      UK, with around 550 exhibitors and 20,000 attendees, including buyers from\u000a      major retailers and wholesale distributors. The Eat Balanced pizza range\u000a      won the Best New Idea award at this event, an initiative designed to\u000a      support the launch of new products.a,e More than 50 exhibiting\u000a      companies put their products forward in 2012 and visitors to the show\u000a      voted for their favourite product. The manager of the showa\u000a      stated: \"Eat Balanced Pizzas are truly innovative and have the scope to\u000a        make a huge impact on how consumers eat; we hope being named Food &\u000a        Drink Expo's Best New Idea helps them achieve this.\" The pizza range\u000a      also won the Best New Product award at the UK Best Business Awards (2012).a,f\u000a      These awards recognise business excellence and are open to private, public\u000a      and third-sector organisations; four rounds of judging are conducted\u000a      annually by 20 independent experts, with winners holding their title for\u000a      12 months. The winner of the Best New Product award is determined by\u000a      factors such as product innovation, pricing, after-sales service, design\u000a      and performance.\u000a    Credibility of meal-based balanced nutrition endorsed by leading\u000a          experts\u000a    In addition to creating the Eat Balanced range of healthy pizzas, the\u000a      University of Glasgow researchers have delivered practical targeted advice\u000a      to further help the general public engage with nutritionally-balanced\u000a      eating. The Eatwell Everyday website — which features the menu plan\u000a      developed and tested at the University of Glasgow — was launched by the\u000a      FSAS in Dundee on the 30th April 2013.g This event, which\u000a      focused on the science of nutrition, was opened by Michael Matheson MSP,\u000a      the Scottish Government Minister for Public Health. In the first 3 months\u000a      after its launch, the Eatwell Everyday website received 9,058 page views\u000a      from 1,397 unique visitors in nine countries, including the UK, USA,\u000a      India, and Australia.h The user-friendly and common-sense\u000a      nature of the Eatwell Everyday menu plan was highlighted by The Herald and\u000a      Medical Xpress (with a combined potential audience of around 2.5 million).i\u000a    The Eat Balanced pizzas show solely green (low) and amber (medium) levels\u000a      of fat and salt content on their food labels (in accordance with the June\u000a      2013 Department of Health front-of-pack nutrition labelling scheme). In\u000a      February 2013, a representative from the Scottish National Rugby team\u000a      announced that the Eat Balanced pizzas formed part of the preparatory diet\u000a      of the players ahead of their winning Royal Bank of Scotland 6 Nations\u000a      match against Italy.a,j The team's lead nutritionist stated: \"The\u000a        Eat Balanced pizza is not only a great idea, it's a great product too\u000a        and one which can easily be integrated into the player's nutrition\u000a        plans. Typically pizza is seen as a guilty pleasure but the Eat Balanced\u000a        pizza can be used as part of a fuelling or recovery strategy without the\u000a        player being concerned about an excessive salt or fat intake.\"\u000a    ","ImpactSummary":"\u000a    Chronic diseases associated with poor nutrition are on the rise; however,\u000a      people increasingly eat nutritionally-deficient ready meals owing to their\u000a      convenience. Researchers from the University of Glasgow took an innovative\u000a      two-fold approach to tackling this worrying trend. First, they created a\u000a      nutritionally-balanced frozen pizza in collaboration with local start-up\u000a      company Eat Balanced. Second, they developed content for the Eatwell\u000a      Everyday website, a government-funded resource that provides user-friendly\u000a      nutritionally-balanced meal plans. These initiatives have attracted\u000a      extensive media coverage, with an estimated global audience of about 93\u000a      million people. The Eatwell Everyday website has received 9,058 page\u000a      visits since its launch in April 2013. The Eat Balanced pizza has won 10\u000a      business or product awards, has been endorsed by a leading sports\u000a      nutritionist and is currently stocked by retail giants Sainsbury's, Asda\u000a      and Ocado. More than 25,000 Eat Balanced pizzas have been sold in the UK\u000a      since September 2012.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Leslie, W. S. et al. A\u000a        transferable programme of nutritional counselling for rehabilitation\u000a        following myocardial infarction: a randomised controlled study. Eur.\u000a        J. Clin. Nutr. 58: 778-786 (2004)\u000a      doi:10.1038\/sj.ejcn.1601876.\u000a    \u000a\u000a2. Leslie, W. S. et al. Improving\u000a        the dietary intake of under nourished older people in residential care\u000a        homes using an energy-enriching food approach: a cluster randomised\u000a        controlled study. J. Hum. Nutr. Diet 26: 387-394\u000a      (2013) doi:10.1111\/jhn.12020.\u000a    \u000a\u000a3. Celnik, D. et al. Time-scarcity,\u000a        ready-meals, ill-health and the obesity epidemic. Trends Food\u000a        Sci. Tech. 27: 4-11 (2012) doi:10.1016\/j.tifs.2012.06.001.\u000a    \u000a\u000a4. Combet, E. et al. Development\u000a        of a nutritionally balanced pizza as a functional meal designed to meet\u000a        published dietary guidelines. Public Health Nutr. (online\u000a      ahead of print 28 October 2013) doi:10.1017\/S1368980013002814.\u000a    \u000a\u000a5. Leslie, W. S. et al. Designing\u000a        the eatwell week: the application of eatwell plate advice to weekly food\u000a        intake. Public Health Nutr. 16: 795-802 (2013)\u000a      doi:10.1017\/S1368980012004193.\u000a    \u000a\u000a6. Leslie, W. S. et al. What,\u000a        not just salad and veg? Consumer testing of the eatwell week. Public Health\u000a        Nutr. 28: 1-7 (2013) doi:10.1017\/S1368980013001663.\u000a    \u000aGrant funding:\u000a    FSAS. The Eatwell week: application of the Eatwell plate advice to\u000a      weekly food intake (2009-2011; £185,223). Awarded to University of Glasgow\u000a      (C. R. Hankey, M. E. Lean, and W. S. Leslie).\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"11","Subject":"Nutrition and Dietetics"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. Eat Balanced website\u000a    b. Eatwell Everyday website\u000a    c. Statement from the CEO of Eat Balanced (available on request)\u000a    d. Media\u000a        coverage of the Eat Balanced pizzas; The\u000a        Entrepreneurs\u000a    e. Winner of the Best\u000a        New Idea award at the Food\u000a        & Drink Expo at Birmingham, UK, in March 2012 (quote\u000a      from Eat Balanced website)\u000a    f. Winner of the Best\u000a        New Product award at the UK Best Business Awards, 2012\u000a    g. Launch\u000a      of the Eatwell Everyday website in March 2013\u000a    h. Eatwell Everyday website usage (available on request)\u000a    i. Media coverage of the Eatwell Everyday menu plan, 2012: The\u000a        Herald and Medical\u000a        Xpress\u000a    j. Press\u000a        release from the Scottish National Rugby team on 5th February 2013 (quote\u000a      from Eat Balanced website)\u000a    ","Title":"\u000a    Promoting nutritional balance with the Eat Balanced pizza and Eatwell\u000a      Everyday website\u000a    ","UKLocation":[{"GeoNamesId":"2655603","Name":"Birmingham"},{"GeoNamesId":"2648579","Name":"Glasgow"},{"GeoNamesId":"2650752","Name":"Dundee"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Diet-related chronic diseases, such as obesity and diabetes, cost the NHS\u000a      more than £5 billion per year. National campaigns aim to promote a\u000a      nutritionally-balanced diet, yet people continue to value the convenience\u000a      of pre-packaged ready meals over healthy eating. University of Glasgow\u000a      research, led by Professor Mike Lean and Dr Catherine Hankey, set out to\u000a      change consumer behaviour by producing nutritionally-balanced meals and\u000a      meal plans.\u000a    The meal as the key component of dietary change\u000a    Hankey and colleagues evaluated 98 individuals undergoing a 12-week\u000a      rehabilitation programme after suffering a heart attack and found that\u000a      these patients were more likely to respond to dietary alterations on a\u000a      per-meal basis than to general advice about healthy eating (2004).1\u000a      They also demonstrated that a programme of meal enrichment with\u000a      energy-dense foodstuffs (such as cream or butter) resulted in significant\u000a      weight gain and increased body mass index in a group of 41 older adults in\u000a      residential care who were malnourished (2013).2 The findings of\u000a      these two research papers suggested that dietary change is implemented\u000a      most effectively when the unit of modification is the meal and that\u000a      meal-by-meal interventions are far more effective than general advice in\u000a      two distinct populations (heart attack survivors and institutionalised\u000a      older adults).\u000a    Ready meals are not nutritionally balanced\u000a    In 2012, Lean and colleagues analysed the nutritional value of four\u000a      popular supermarket ready meals and found that none met accepted UK\u000a      Department of Health standards, regardless of labelling line (for example,\u000a      \"standard\", \"economy\", \"healthy\" or \"finest\").3 These\u000a      standards, which are endorsed by the World Health Organization, advocate\u000a      daily consumption of 2,000-2,500 calories for adults. This intake energy,\u000a      in terms of macronutrients, ought to provide around 50% energy from\u000a      carbohydrate, and no more than 35% of energy should come from total fat.\u000a      This dietary composition will usually supply the recommended daily intakes\u000a      for vitamins and minerals. The researchers found that many convenience\u000a      products contained 100% of the recommended daily fat and salt intake in a\u000a      single meal, making it impossible for consumers to eat a\u000a      nutritionally-balanced diet.\u000a    Eat Balanced pizza provides proof of concept for\u000a          nutritionally-balanced meals\u000a    Given the poor nutritional value of most ready meals, Lean and colleagues\u000a      aimed to produce a ready meal that provides 30% of a person's daily energy\u000a      intake, while incorporating all 27 essential nutrients in the recommended\u000a      amounts. This approach reflected UK and European nutritional advice that\u000a      total daily intake should be divided equally between three meals. Lean\u000a      joined forces with Eat Balanced (a local start-up company) to produce a\u000a      healthy frozen pizza as proof of concept that ready meals can be\u000a      nutritionally balanced. This project was funded by a £5,000 grant to Lean\u000a      and Eat Balanced by Encompass, a programme designed to stimulate academic\u000a      and industrial engagement in Scotland and funded by the Universities of\u000a      Glasgow, Strathclyde, Aberdeen and Stirling, along with support agencies\u000a      in Scotland. Lean's team created a Margherita pizza with optimised\u000a      proportions of dough base to topping and novel ingredients, such as\u000a      seaweed (which is high in iron, zinc and vitamin B12), to boost\u000a      nutrient levels (2013).4 The final product was taste-tested in\u000a      two urban areas of Scotland (Glasgow West End and Clydebank) from opposite\u000a      ends of the socioeconomic spectrum. Factors evaluated in testing sessions\u000a      included taste, appearance and willingness of adult testers to buy the\u000a      pizza. In all, 77% of adults and 81% of children rated the nutritionally\u000a      balanced Margherita pizza as \"at least as good as their usual choice of\u000a        pizza.\" The University of Glasgow researchers conducted the\u000a      following aspects of the pizza development process: design, using an\u000a      existing template;3 selection of key ingredients;\u000a      computer-based nutrition analysis leading to the prototype pizza; recipe\u000a      refinement; design of protocol for tasting sessions; taste testing in one\u000a      of the two locations; and analysis of all taste test data.\u000a    Combining healthy meals to establish a nutritionally-balanced\u000a          weekly diet\u000a    The Eat Balanced pizza confirmed that nutritional balance could be\u000a      achieved on a per-meal basis using convenience foods. Following the\u000a      success of this project, the Foods Standards Agency Scotland (FSAS)\u000a      commissioned Hankey, Leslie and Lean to create an online menu to promote\u000a      the concept of quick and healthy meals. The FSAS is the government body\u000a      tasked with handling policy issues in Scotland relating to food standards,\u000a      nutrition and diet. The online resource conceived by Hankey and colleagues\u000a      provides recipes for three meals a day that are interchangeable to allow a\u000a      mix-and-match approach while still ensuring nutritional balance over a\u000a      seven-day period (2013).5 Nutritionally-equivalent\u000a      substitutions are encouraged, allowing the menu to be extended\u000a      indefinitely; in this scenario, the Eat Balanced pizza would be equivalent\u000a      to one lunch or dinner. The meals require only basic cooking skills and\u000a      incorporate popular affordable foodstuffs (fresh, frozen and tinned goods)\u000a      that are readily available in UK supermarkets. Focus-group testing at four\u000a      UK locations confirmed that consumers enjoyed the meals, found the menu\u000a      plan \"acceptable\" to use and were able to prepare meals with their\u000a      existing level of skill and available time (2013).6\u000a    Key University of Glasgow researchers: Mike Lean, Chair of Human\u000a      Nutrition (1990-present); Catherine Hankey, Senior Lecturer in Human\u000a      Nutrition (1992-present); Emilie Combet, Lecturer in Nutrition\u000a      (2009-present); Wilma Leslie, Research Assistant (1997-present).\u000a      Key external collaborators: Donnie Maclean (Eat Balanced, Glasgow);\u000a      Heather Peace and Fiona Comrie (FSAS, Aberdeen). Kantar Worldpanel and\u000a      Scotland Ipsos MORI conducted market research for the weekly menu plan.\u000a    "},{"CaseStudyId":"41127","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Coronary heart disease is the narrowing of the coronary arteries as a\u000a      result of deposition of atherosclerotic plaque (hardening of the\u000a      arteries), accounting for nearly 125,000 deaths per year. As a result of\u000a      pre-clinical and initiation of trials in the area of stent technology, the\u000a      work of the Leicester team, together with others' global efforts, has\u000a      resulted in the recurrence after stenting being reduced from 35% to 5%.\u000a      The first drug-eluting stent (releasing agents that inhibit the\u000a      inflammatory over repair response) deployed in the UK was by Gershlick at\u000a      UHL, as was the first drug-eluting absorbable stent.\u000a    Underpinning guidance on management of heart attack patients\u000a      Translational and clinical research based in Leicester has contributed to\u000a      angioplasty and coronary stenting becoming a mainstream standard clinical\u000a      procedure. The Unit's research has allowed stenting to evolve into an\u000a      effective and safe procedure by testing the efficacy, safety and\u000a      cost-efficiencies of stent designs and the drugs on them.\u000a    The REACT trial was the first definitive study to show the absolute\u000a      clinical benefit of angioplasty in the 35% of patients whose occluded\u000a      artery had failed to be re-opened following the use of clot-busting drugs\u000a      (thrombolysis). Across the world, patients are now managed according to a\u000a      protocol that states that, if they receive thrombolysis, the ECG should be\u000a      reviewed after 90 minutes and if the changes due to the heart attack have\u000a      not resolved then they should have rescue angioplasty.\u000a    The following national and international guidelines, underpinned by the\u000a      Unit's research, directly influence how patients with heart disease are\u000a      treated in the UK, Europe and the US:\u000a    \u000a      In July 2008, NICE updated its guidance on drug-eluding stents. The\u000a        Unit's research is cited in the assessment report for the appraisal\u000a        prepared by University of Liverpool (Drug-eluting stents: a systematic\u000a        review and economic evaluation, November 2005), the literature review\u000a        which underpins the 2008 guidance (Technology Appraisal 152). (1)\u000a        Gershlick represented the British Cardiovascular Society (BCS) as\u000a        Medical Expert presenting data to NICE.\u000a      In 2008 and 2012, European Society of Cardiology published guidelines\u000a        for the management of acute myocardial infarction in patients presenting\u000a        with ST-segment elevation. Gershlick was co-author on the European\u000a        Guideline Writing Committee on STEMI. (2)\u000a      In 2008, the American College of Cardiology and American Heart\u000a        Association issued a \"focused update\" of their 2004 guidelines for the\u000a        management of ST-segment elevation myocardial infarction (STEMI). (3)\u000a    \u000a    The results of the STREAM trial were presented at the late-breaking\u000a      session at The American College of Cardiology meeting in April 2013, with\u000a      simultaneous publication in New England Journal of Medicine, and had an\u000a      immediate impact on clinical practice, particularly in parts of the world\u000a      with geographical challenges to delivery of angioplasty for heart attacks.\u000a      Editorial accompanying the NEJM article stated: \"The findings of this\u000a      trial could have a major effect on clinical practice.'' (4)\u000a    Influencing national service provision\u000a      The UK Government's National Service Framework (NSF) for coronary heart\u000a      disease was a 10-year strategy launched in 2000 to reduce coronary heart\u000a      disease and stroke-related deaths by 40% by March 2010. The original NSF\u000a      proposal was inter-hospital transfer of patients for PCI, with the journey\u000a      time between hospitals should not exceed 30 minutes. (5.5) Work on stents\u000a      and representations to NICE, underpinned by the Unit's research into\u000a      angioplasty and stenting and Gershlick's representation on the British\u000a      Cardiovascular Intervention Society (BCIS), has resulted in the\u000a      development of network systems and also the devolution of stenting to all\u000a      hospitals judged as angioplasty capable (BCIS visits).\u000a    The driving force behind the roll-out of angioplasty as standard care was\u000a      a joint project launched in 2005 between the Department of Health and the\u000a      British Cardiac Society. The National Infarct Angioplasty Project (NIAP)\u000a      was set up to test the feasibility of implementing a countrywide\u000a      angioplasty service for heart attack victims. Gershlick was a founder\u000a      member of the NIAP Academic Group. The final report was used to inform\u000a      commissioners, cardiac networks and service providers in their discussions\u000a      on the configuration of acute services and to feed into the development of\u000a      primary care trust (PCT) annual operating plans. A recent Department of\u000a      Health report indicates that >90% patients in the UK now receive\u000a      primary PCI. Charting the change, the report shows that in the third\u000a      quarter of 2008, just 46% of those STEMI patients in England who received\u000a      reperfusion treatment were being treated by primary angioplasty while the\u000a      remaining 54% were treated with thrombolysis. By the second quarter of\u000a      2011, 94% of patients were treated with primary angioplasty.(6)\u000a    Guiding the development of new pharmaceutical therapies and\u000a        drug-eluting stents\u000a      Since the 1990s, Gershlick has worked with medical device and drug\u000a      manufacturers to guide the design of drug-eluding stents. He has been\u000a      involved in comparative trials of different drug-eluting stents including\u000a      steering and Data and Safety Monitoring Board committees which have\u000a      assessed the efficacy of stents and drug treatments for heart patients.\u000a      Such studies were precedents in the development of drug-eluting stents\u000a      which are used in over two million patients worldwide.\u000a    ","ImpactSummary":"\u000a    Every year in the UK, 150,000 heart attacks are caused by coronary artery\u000a      occlusion (blockage); worldwide, the figure is 17 million, according to\u000a      the World Health Organization (WHO). Since 1993, the Leicester\u000a      Interventional Cardiology group has been at the forefront of research to\u000a      determine how best to manage such patients. Its findings have been\u000a      incorporated into official UK (2008), European (2008, 2012) and US (2008)\u000a      guidelines and have helped to change the way coronary heart disease and\u000a      heart attacks are treated, with the number of patients treated with\u000a      primary angioplasty doubling between 2008 and 2011. By guiding service\u000a      provision, supporting industrial innovation and informing clinical\u000a      practice, the Unit has contributed to improved healthcare and outcomes for\u000a      thousands of heart patients. Overall, one-month mortality according to\u000a      European figures has fallen from 15% to 4% between 2008 and 2013.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Leicester\u000a    ","Institutions":[{"AlternativeName":"Leicester (University of)","InstitutionName":"University of Leicester","PeerGroup":"A","Region":"East Midlands","UKPRN":10007796}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Underwood MJ, More RS, Gershlick AH, de Bono DP. Effect\u000a        of locally applied tissue-type plasminogen activator on venous\u000a        fibrinolytic activity: in vitro and in vivo investigations.\u000a      Cardiovasc Res. 1993 Dec;27(12):2270-3.\u000a    \u000a\u000a2. Aggarwal RK, Ireland DC, Azrin MA, Ezekowitz MD, de Bono DP, Gershlick\u000a        AH Antithrombotic potential of polymer-coated stents eluting\u000a      platelet glycoprotein IIb\/IIIa receptor antibody. Circulation. 1996 Dec\u000a      15;94(12):3311-7.\u000a    \u000a\u000a3. Chitkara K, Hogrefe K, Vasa-Nicotera M, Swanson N, Gershlick\u000a      AH Eptifibatide-eluting\u000a        stent as an antiproliferative and antithrombotic agent: in vitro\u000a        evaluation. J Invasive Cardiol. 2006 Sep;18(9):417-22.\u000a    \u000a\u000a4. Gershlick A, De Scheerder I, Chevalier B, Stephens-Lloyd A,\u000a      Camenzind E, Vrints C, Reifart N, Missault L, Goy JJ, Brinker JA, Raizner\u000a      AE, Urban P, Heldman AW. Inhibition\u000a        of restenosis with a paclitaxel-eluting, polymer-free coronary stent:\u000a        the European evaLUation of pacliTaxel Eluting Stent (ELUTES) trial.\u000a      Circulation. 2004 Feb 3;109(4):487-93. Epub 2004 Jan 26.\u000a    \u000a\u000a5. Gershlick AH, Stephens-Lloyd A and Hughes S, et al.\u000a      Rescue angioplasty after failed thrombolytic therapy for acute myocardial\u000a      infarction. N Engl J Med. 2005 353: 2758-2768.\u000a    \u000a\u000a6. Reperfusion\u000a        therapy for STEMI: is there still a role for thrombolysis in the era of\u000a        primary percutaneous coronary intervention? Gershlick AH,\u000a      Banning AP, Myat A, Verheugt FW, Gersh BJ. Lancet. 2013 Aug\u000a      17;382(9892):624-32.\u000a    \u000a\u000a7. Paul W. Armstrong, M.D., Anthony H. Gershlick, M.D., et\u000a        al. Fibrinolysis or Primary PCI in ST-Segment Elevation Myocardial\u000a      Infarction. N Engl J Med 2013; 368:1379-1387 April 11, 2013 DOI:\u000a      10.1056\/NEJMoa1301092.\u000a    \u000aGrant income over the past decade exceeds £5 million, including:\u000a      BHF Complete v Lesion-only Primary PCI (CVLPRIT) 2010: £250,530;\u000a      McCann Dr G CO-PI Gershlick A NIHR Complete V Lesion-only Primary PCI -\u000a      Cardiac MRI substudy (CVLPRI-t-CMR) 2011-2013: £386,323;\u000a      EC-Cooperation Research PRESTIGE-PREvention Late Stent Thrombosis by an\u000a      Interdisciplinary Global European effort 2010-2014: £446,243.00;\u000a      NIHR MRC Randomized Controlled Trial Intracoronary Administration\u000a      Adenosine or Sodium Nitroprusside v Control for Attenuation of\u000a      Microvascular Obstruction During PPCI 2011-2013: £484,993.00\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      NICE guidelines on Drug Eluding Stents: http:\/\/www.nice.org.uk\/ta152\u000a\u000a      The European Society of Cardiology Guideline documents for: Acute\u000a        Myocardial Infarction in patients presenting with ST-segment elevation http:\/\/www.escardio.org\/guidelines-surveys\/esc-guidelines\/GuidelinesDocuments\/Guidelines_AMI_STEMI.pdf\u000a\u000a      American College of Cardiology and American Heart Association update\u000a        of 2004 guidelines\u000a        http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18519158?log$=activity\u000a\u000a      New England Journal of Medicine editorial: http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMe1302670\u000a\u000a      National Service Framework for Coronary Heart Disease:\u000a        https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/198931\/National_Service_Framework_for_Coronary_Heart_Disease.pdf\u000a\u000a      Department of Health report showing the increase in patients treated\u000a        with primary angioplasty by 2011. http:\/\/www.improvement.nhs.uk\/LinkClick.aspx?fileticket=PWttejHG45M%3d&tabid=63\u000a\u000a    \u000a    ","Title":"\u000a    Heart attacks: improving therapeutic options for patients through the\u000a      development of life-saving medical techniques and devices\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Leicester has a long history of pioneering work in the treatment of\u000a      coronary artery occlusion, initially in the era of thrombolytic\u000a      ('clot-busting') drugs to proactively unblock the coronary arteries\u000a      attenuating heart attack outcomes. Professor David deBono was the first in\u000a      the UK to treat a heart attack patient with a thrombolytic, while\u000a      Professor Tony Gershlick was the first to deploy a drug- eluting stent\u000a      (bare-metal stents or `scaffolds' coated with a drug to reduce\u000a      inflammation or cell proliferation). DeBono and Gershlick were foremost in\u000a      the European Cooperative working group (with Arnold AE, Simoons ML,\u000a      Serruys PW (Rotterdam), Van de Werf F (Belgium) and Lubsen J (Switzerland)\u000a      publishing on optimal delivery of thrombolytics, with seminal studies\u000a      showing benefit from mechanical balloon angioplasty (opening an artery\u000a      mechanically using a balloon and stent), thus improving the outcomes when\u000a      used in conjunction with thrombolysis. Between 1993 and 2000, their basic\u000a      lab science (1, 2) allowed for optimising of thrombolysis at cellular\u000a      levels: these studies were combined with clinical trials including\u000a      first-in-man designed to improve outcomes following angioplasty and\u000a      delivery of anti-thrombotic\/lytic drugs by coronary stents.\u000a    Testing the efficacy and safety of different drug-eluding stents\u000a      During this period and between 2005 and 2007, the group led the field in\u000a      research on drug-eluting stent development, with studies assessing\u000a      benefits in animal models of anti-platelet\/anti-thrombotic eluting stents\u000a      (3, 4). This work highlighted that thrombolytic agents were limited and\u000a      could open only 65% of occluded arteries. The 'open artery hypothesis'\u000a      proposed that the earlier and more complete the artery could be opened,\u000a      the better the outcomes (with a reduction in mortality >60% for those\u000a      with maximal flow). Between 2005 and 2010, Gershlick was UK PI for a\u000a      number of studies which tested the efficacy and safety of different\u000a      drug-eluding stents. These included: REDUCE (Low molecular weight\u000a      heparin, Reviparin, in the prevention of restenosis after PTCA) in 1998, CLASSICS\u000a      (Clopidogrel in subacute stent thrombosis) in 2000, RENO (European\u000a      surveillance with the Novoste Beta Cath System) in 2000, E-SIRIUS\u000a      (European Rapamycin trial) from 2001-2003, e-CYPHER (Real world\u000a      Registry 15 000 patients) from 2002-2005, and ELUTES International\u000a      (Drug Eluting Stent) trial from 2001-2003. This was combined with national\u000a      leadership to develop and evolve angioplasty as a treatment for heart\u000a      attack victims (British Cardiovascular Intervention Society, NICE and\u000a      National Infarct Angioplasty Programme (NIAP)).\u000a    REACT UK trial\u000a      A question arose early on as to whether thrombolysis could be combined\u000a      with angioplasty in heart attack victims and, if so, in which cohort. In\u000a      the late 1990s, Gershlick devised the British Heart Foundation\u000a      (BHF)-funded multi-centre REACT UK trial to determine which of three\u000a      commonly and empirically used strategies (a second dose of the\u000a      thrombolytic agent, or transport to the catheter lab for angioplasty as\u000a      soon as possible, or just managing the patient conservatively) was\u000a      superior in those patients in whom thrombolytic drugs failed to establish\u000a      full flow. This study established that viewing of the ECG 90 minutes after\u000a      the thrombolytic treatment to see if the changes (indicating a myocardial\u000a      infarction) had resolved, was a good way of determining whether the vessel\u000a      had been opened by a thrombolytic agent. This is still used worldwide.\u000a      REACT also showed, with a hazard ratio of around 0.5 (a 50% reduction in\u000a      the primary endpoint of the study - death, stroke and heart attack), that\u000a      those patients whose ECGs had not normalised at 90 minutes\u000a      post-thrombolytic did much better in terms of major adverse cardiac\u000a      events, including death, with angioplasty (5).\u000a    International comparisons\u000a      Although it has become clear that angioplasty for heart attacks appears\u000a      better than thrombolytic (since it is mechanical opening of the artery),\u000a      not all patients in the UK and elsewhere are able to receive it in a\u000a      timely fashion. An international study devised by Gershlick has addressed\u000a      the circumstances in which angioplasty may not be deliverable because of\u000a      time delays in getting patients to hospital, particularly in rural areas\u000a      where transfer of patients for angioplasty is delayed beyond the time\u000a      considered in the Guidelines as beneficial (6).\u000a    The STREAM trial (2009 -2012) (7) of 1,850 patients compared angioplasty\u000a      for myocardial infarction with a strategy of thrombolytic plus REACT-based\u000a      angioplasty, and showed that these were equivalent. This has enabled\u000a      better outcomes for the 20% of patients in areas where there are\u000a      geographical challenges to delivery of angioplasty for heart attacks.\u000a    Key staff: Professor A H Gershlick (1989-present); Dr D Adlam\u000a      (2011-present); Dr Elved Roberts (2009-present); Professor N Samani\u000a      (1985-present); Professor David deBono, Foundation BHF Professor\u000a      (1989-1998).\u000a    "},{"CaseStudyId":"41130","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2510769","Name":"Spain"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Biologic DMARDs have revolutionised treatment of patients with PsA. Even\u000d\u000a      so, partial responses occur in approximately 60% of patients and over 5\u000d\u000a      years up to 60% of patients will withdraw from treatment owing to drug\u000d\u000a      intolerance or loss of effect. Consequently, there remains a considerable\u000d\u000a      unmet need for these patients. Ustekinumab is unique among the biologic\u000d\u000a      DMARDs that have been approved to treat PsA, as it targets a novel\u000d\u000a      pathway. The clinical findings of PSUMMIT1 underpinned Janssen's\u000d\u000a      application to EMA to extend the European marketing licence for\u000d\u000a      ustekinumab to include patients with PsA. This application was approved in\u000d\u000a      July 2013. University of Glasgow research has, therefore, exerted\u000d\u000a      considerable influence by facilitating EU licensing authorisation for a\u000d\u000a      new use of an existing drug. Furthermore, the University of Glasgow has a\u000d\u000a      unique claim to this impact as no other UK institutions were represented\u000d\u000a      on the PSUMMIT1 steering committee.\u000d\u000a    PSUMMIT1 provides the evidence base for ustekinumab as a novel\u000d\u000a          treatment for PsA\u000d\u000a    Janssen is a subsidiary of Johnson & Johnson, the 2012 market leader\u000d\u000a      in pharmaceuticals, with sales of approximately $67 billion and a research\u000d\u000a      and development spend of almost $8 billion. In July 2009, Janssen invited\u000d\u000a      McInnes to be Lead Investigator on the PSUMMIT1 trial of ustekinumab\u000d\u000a      (ClinicalTrials.gov identifier NCT01009086).b\u000d\u000a      As the sole UK researcher, McInnes was joined on the Steering Committee by\u000d\u000a      three North American rheumatologists and two dermatologists (from Spain\u000d\u000a      and the USA). The preliminary results of PSUMMIT1 were presented by\u000d\u000a      McInnes at the European League Against Rheumatism (EULAR) annual congress\u000d\u000a      in June 2012; this meeting was held in Berlin and attracted more than\u000d\u000a      15,000 delegates from over 115 countries. The data caught the attention of\u000d\u000a      online news outlets, including Medscape.c Speaking to Medscape,\u000d\u000a      the chair of the committee of EULAR for abstract selection explained the\u000d\u000a      novelty of PSUMMIT 1: \"This is a first-in-kind [study].... They can get\u000d\u000a        two for the price of one here, because if you can help the skin and the\u000d\u000a        joints, that's a good outcome.\"\u000d\u000a    McInnes remains a key consultant for Janssen in directing their clinical\u000d\u000a      trials of ustekinumab, including evaluating effects on PsA-related\u000d\u000a      structural damage to the joints (PSUMMIT 1 and PSUMMIT2). This aspect is\u000d\u000a      particularly important as damage to the joints predicts loss of function\u000d\u000a      and possible disability.\u000d\u000a    EMA approves ustekinumab as a novel therapy for PsA\u000d\u000a    On 6 December 2012, Janssen filed ustekinumab for EMA regulatory approval\u000d\u000a      as a treatment for adults with PsA, citing the results of PSUMMIT1 in\u000d\u000a      support of this application. The EMA Committee for Medicinal Products for\u000d\u000a      Human Use (CHMP) granted Janssen's bid to extend the use of ustekinumab on\u000d\u000a      25 July 2013.d,e,f Media coverage of the EMA ruling included\u000d\u000a      FirstWord Pharma.g Janssen summed up the impact of the CHMP\u000d\u000a      ruling: \"It was with the exceptional guidance of Prof McInnes that this\u000d\u000a        study medication was brought to phase III and CHMP approval for\u000d\u000a        treatment of PsA ... More importantly for the medical community, it\u000d\u000a        represents the first new mechanism of action to achieve clinical and\u000d\u000a        radiographic efficacy for this condition since the approval of anti-TNF\u000d\u000a        agents approximately one decade ago.\"a Ustekinumab for\u000d\u000a      treatment of PsA was approved by the Federal Drug Administration in\u000d\u000a      September 2013.\u000d\u000a    Conservative estimates suggest that at least 0.5% of the EU population,\u000d\u000a      approximately 2.5 million people, are likely to have PsA. Assuming half of\u000d\u000a      these individuals will require treatment with a biologic DMARD, the\u000d\u000a      potential uptake of ustekinumab for this novel indication could exceed\u000d\u000a      1.25 million patients across the 28 member states. Consequently, EMA\u000d\u000a      approval of ustekinumab represents a breakthrough for individuals who\u000d\u000a      might otherwise be left without treatment options for this devastating\u000d\u000a      disease.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Psoriatic arthritis (PsA) is a chronic inflammatory disease of joints,\u000d\u000a      skin and tendons that affects 0.5-0.8% of the population worldwide. PsA\u000d\u000a      can cause substantial psychological and social problems and also causes\u000d\u000a      increased risk of death from cardiovascular disease. Research conducted by\u000d\u000a      Prof Iain McInnes at the University of Glasgow in partnership with leading\u000d\u000a      pharmaceutical company, Janssen, has provided robust evidence of the\u000d\u000a      clinical benefits and safety of the cytokine blocker ustekinumab, leading\u000d\u000a      to its approval for use for PsA by the European Medicines Agency in July\u000d\u000a      2013. This was the first approval of a PsA drug with a new mode of action\u000d\u000a      in a decade, providing a novel treatment for approximately 1.25 million\u000d\u000a      PsA patients across Europe.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2950159","Name":"Berlin"}],"References":"\u000d\u000a    \u000a1. McInnes IB & Schett G. Cytokines\u000a        in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol\u000d\u000a      2007; 7: 429-442 doi:10.1038\/nri2094.\u000d\u000a    \u000a\u000a2. Sattar N et al. Effects\u000a        of tumor necrosis factor blockade on cardiovascular risk factors in\u000d\u000a        psoriatic arthritis: a double-blind, placebo-controlled study. Arthritis\u000a        Rheum 2007; 56: 831-839 doi:10.1002\/art.22447.\u000d\u000a    \u000a\u000a3. Kavanaugh A et al. Golimumab,\u000a        a new human tumor necrosis factor alpha antibody, administered every\u000d\u000a        four weeks as a subcutaneous injection in psoriatic arthritis:\u000d\u000a        Twenty-four-week efficacy and safety results of a randomized,\u000d\u000a        placebo-controlled study. Arthritis Rheum 2009; 60: 976-986\u000d\u000a      doi:10.1002\/art.24403.\u000d\u000a    \u000a\u000a4. McInnes IB et al. Efficacy\u000a        and safety of secukinumab, a fully human anti-interleukin-17A monoclonal\u000d\u000a        antibody, in patients with moderate-to-severe psoriatic arthritis: a\u000d\u000a        24-week, randomised, double-blind, placebo-controlled, phase II\u000d\u000a        proof-of-concept trial. Ann Rheum Dis 2013 (online ahead of\u000d\u000a      print 29 January) doi:10.1136\/annrheumdis-2012-202646.\u000d\u000a    \u000a\u000a5. Lemos HP et al. Prostaglandin\u000a        mediates IL-23\/IL-17-induced neutrophil migration in inflammation by\u000d\u000a        inhibiting IL-12 and IFN03b3 production. PNAS USA 2009; 106:\u000d\u000a      5954-5959 doi:10.1073\/pnas.0812782106.\u000d\u000a    \u000a\u000a6. McInnes IB et al., on behalf of the PSUMMIT 1 Study Group. Efficacy\u000a        and safety of ustekinumab in patients with active psoriatic arthritis: 1\u000d\u000a        year results of the phase 3, multicentre, double-blind,\u000d\u000a        placebo-controlled PSUMMIT 1 trial. Lancet 2013; 382:\u000d\u000a      780-789 doi:10.1016\/S0140-6736(13)60594-2\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"7","Subject":"Immunology"}],"Sources":"\u000d\u000a    a. Statement from Senior Director, Immunology R&D, Johnson &\u000d\u000a      Johnson (available on request)\u000d\u000a    b. Detailed description of PSUMMIT1 in the ClinicalTrials.gov database, NCT01009086\u000d\u000a    c. Coverage of PSUMMIT 1 at EULAR\u000a        2012 by Medscape (registration required — PDF available on request)\u000d\u000a    d. EMA\u000a        assessment report, 2013 (PDF available on request)\u000d\u000a    e. CHMP\u000a        meeting report, 2013\u000d\u000a    f. EMA\u000a        summary of opinion, 2013\u000d\u000a    g. Coverage of EMA approval by FirstWord\u000a        Pharma \u000d\u000a    ","Title":"\u000d\u000a    Novel treatment for psoriatic arthritis receives regulatory approval\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Treatments for psoriatic arthritis (PsA)\u000d\u000a    It is generally accepted that drug development will most likely succeed\u000d\u000a      when a putative target has been defined in the context of deeper\u000d\u000a      understanding of the causes of disease (`pathogenesis'). The pathogenesis\u000d\u000a      of PsA combines an exaggerated response to environmental triggers like\u000d\u000a      infection or stress, operating on a predisposing inherited underlying\u000d\u000a      genetic background. This leads to uncontrolled inflammation in affected\u000d\u000a      tissues. First-line treatment of PsA involves symptom relief with\u000d\u000a      painkillers and anti-inflammatory agents. Second-line treatment with\u000d\u000a      conventional disease-modifying anti-rheumatic drugs (DMARDs) aims to\u000d\u000a      dampen down the immune system, slowing disease progression and limiting\u000d\u000a      joint damage. Conventional DMARDs are blunt instruments that interact with\u000d\u000a      multiple, ill-defined immune-regulatory pathways. Their use may be\u000d\u000a      associated with severe side effects, and drug resistance. Only 30% of\u000d\u000a      patients are good responders, with the remainder exhibiting either partial\u000d\u000a      or non-response — consequent long-term joint damage and hence disability\u000d\u000a      occurs in up to 60% of individuals. By contrast, biologic DMARDs offer a\u000d\u000a      more targeted approach. These antibody-based drugs are designed to\u000d\u000a      modulate critical `focal points' within the immune system that, when\u000d\u000a      blocked, confer substantial beneficial impact on the signs, symptoms and\u000d\u000a      progression of disease. Cytokines are small proteins that regulate immune\u000d\u000a      function; they represent excellent focal points amenable to blockade by\u000d\u000a      biologic medicines.\u000d\u000a    Pathogenesis-driven research facilitates targeted therapy of PsA\u000d\u000a          with biologic DMARDs\u000d\u000a    The choice of the correct cytokine for targeting has now become a\u000d\u000a        critical decision point in drug development. University of Glasgow\u000d\u000a      rheumatologist Prof Iain McInnes has guided an internationally recognised\u000d\u000a      research programme that aims to understand the cellular and molecular\u000d\u000a      pathways behind the development of inflammatory joint diseases. McInnes'\u000d\u000a      research group has not only helped to develop substantial understanding of\u000d\u000a      the immunological processes that underlie the mechanism of action of\u000d\u000a      biologic DMARDs, but has also been involved in clinical trials of these\u000d\u000a      drugs in patients with PsA who did not respond to treatment with\u000d\u000a      conventional DMARDs, and in the generation of international guidelines to\u000d\u000a      govern their eventual clinical use. In particular, University of Glasgow\u000d\u000a      advances in dissecting the roles of cytokines in the inflammatory process1\u000d\u000a      have provided a platform for major pharmaceutical companies to develop\u000d\u000a      pre-clinical findings into clinical trials of innovative therapies.\u000d\u000a    Tumour necrosis factor (TNF)\u000d\u000a     Drugs that specifically block the cytokine TNF were the first biologic\u000d\u000a      DMARDs to be approved for use in patients with PsA. University of Glasgow\u000d\u000a      research was the first to show that TNF blockers can reduce the risk of\u000d\u000a      developing cardiovascular disease, a potential complication of PsA (2007).2\u000d\u000a      In addition, McInnes was a member of the Steering Committee for GO-REVEAL,\u000d\u000a      the first phase III study of a new TNF blocker, golimumab, that was\u000d\u000a      conducted at 58 sites in North America and Europe. Treatment with this\u000d\u000a      drug improved several symptoms of PsA, including pain; number of swollen\u000d\u000a      joints\/tendons; skin and nail symptoms; physical function; and quality of\u000d\u000a      life (2009).3\u000d\u000a    Interleukin 17 (IL-17)\u000d\u000a    Although TNF blockers have expanded the therapeutic options for PsA,\u000d\u000a      around half of all patients who receive these drugs either fail to respond\u000d\u000a      or discontinue treatment because of severe side effects. Consequently,\u000d\u000a      efforts are underway to identify and target other molecules implicated in\u000d\u000a      this disease. Patients with PsA have increased levels of the cytokine\u000d\u000a      IL-17A. McInnes, therefore, led a 24-week proof-of-concept trial of an\u000d\u000a      IL-17A-blocking drug among 42 PsA patients recruited from 11 centres in\u000d\u000a      Europe (2013).4 Treatment with this drug improved measures of\u000d\u000a      both disability and quality of life.\u000d\u000a    IL-12 and IL-23\u000d\u000a    The cytokines IL-12 and IL-23 act in a common pathway of inflammation and\u000d\u000a      genetic variants associated with this pathway are implicated in\u000d\u000a      susceptibility to PsA. In 2009, McInnes' team was involved in a study\u000d\u000a      using an experimental model of rheumatoid arthritis that demonstrated that\u000d\u000a      these cytokines (along with IL-17A and cells of the immune system) were\u000d\u000a      involved in the development of joint inflammation.5 These\u000d\u000a      findings establish the existence and role of these cytokines in a\u000d\u000a      functional network involved in the pathogenesis of PsA.\u000d\u000a    University of Glasgow research sparks a collaborative partnership\u000d\u000a          with Janssen\u000d\u000a    In March 2009, McInnes' world-leading research programme on the\u000d\u000a      pathogenesis of arthritic disease presented an ideal environment for\u000d\u000a      Janssen (a subsidiary of Johnson & Johnson previously known as\u000d\u000a      Centocor) to directly seek out a collaborative partnership. This decision\u000d\u000a      reflected McInnes' position within \"the rheumatologic scientific\u000d\u000a        community as one of the key research minds working in the field today.\u000d\u000a        His expertise, through his basic research in his laboratory at the\u000d\u000a        University of Glasgow and clinical trials, is renowned.\" (Senior\u000d\u000a      Director, Immunology R&D, Johnson & Johnson).a\u000d\u000a    The partnership focused on dual inhibition of IL-12 and IL-23 as a novel\u000d\u000a      treatment for PsA. Janssen's drug portfolio included an IL-12 and IL-23\u000d\u000a      blocker (known as ustekinumab) that was already approved worldwide for the\u000d\u000a      treatment of adult patients with the inflammatory skin condition\u000d\u000a      psoriasis. The fact that PsA shares pathogenic features with psoriasis\u000d\u000a      supported a novel use for this drug. McInnes subsequently led PSUMMIT 1,\u000d\u000a      the first phase III clinical trial of ustekinumab as a therapeutic option\u000d\u000a      for PsA (2013).6 PSUMMIT 1 was initiated in October 2009 and\u000d\u000a      McInnes was instrumental in the PSUMMIT 1 trial design, guiding the team\u000d\u000a      to choose the most appropriate and clinically relevant end points;\u000d\u000a      including not only established articular and skin scores, but also\u000d\u000a      sub-analyses of treatment effects on dactylitis (swelling of the entire\u000d\u000a      finger), enthesitis (inflammation at sites where tendons and ligaments\u000d\u000a      attach to bone) and bone remodelling. A total of 615 adult patients were\u000d\u000a      recruited at 104 sites in 14 countries in North America, Europe and\u000d\u000a      Australasia. More than 49% of patients receiving ustekinumab experienced a\u000d\u000a      20% reduction in their arthritis symptoms by 24 weeks of treatment, while\u000d\u000a      around 23% of patients receiving placebo achieved the same response.\u000d\u000a      Notably, up to 38% and 28% of patients achieved a sustained 50% or 70%\u000d\u000a      improvement when followed out to 1 year. Remarkable improvements were\u000d\u000a      obtained in dactylitis (reduced by 100%) and enthesitis (reduced by\u000d\u000a      approximately 80%) scores after 1 year. Ustekinumab also improved skin\u000d\u000a      symptoms, measures of disability and quality of life. Favourable responses\u000d\u000a      were maintained at 52 weeks and the safety profile was similar to that\u000d\u000a      reported in psoriasis.\u000d\u000a    Key University of Glasgow researchers: Iain McInnes (Muirhead\u000d\u000a      Chair of Medicine and Director of Institute of Infection, Immunity and\u000d\u000a      Inflammation, 1993-present); Naveed Sattar (Professor of Metabolic\u000d\u000a      Medicine, 1999-present); Foo Liew (Gardiner Chair of Infection, Immunity\u000d\u000a      and Inflammation, 1991-2011).\u000d\u000a    Key research collaborators: Members of the PSUMMIT1 study group;\u000d\u000a      see original article for details.6\u000d\u000a    Key researcher roles in PSUMMIT 1: All authors participated in the\u000d\u000a      study design, analysis and manuscript writing.6 As Lead\u000d\u000a      Investigator, McInnes had full access to the study data and was ultimately\u000d\u000a      responsible for the decision to publish.\u000d\u000a    "},{"CaseStudyId":"41136","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    It has been suggested that thrombophilia screening may help to identify\u000a      women at risk of VTE and provide an opportunity to intervene with\u000a      thromboprophylaxis. Nevertheless, as with any testing strategy, the\u000a      potential benefits must be weighed against the potential harm of\u000a      screening-related anxiety and the adverse effects of thromboprophylaxis\u000a      among women who are either genuinely at risk or who may be misdiagnosed as\u000a      being at risk. Furthermore, substantial investment in healthcare, such as\u000a      large-scale screening, must demonstrate value for money to ensure that\u000a      limited resources are appropriately deployed. The need to provide direct,\u000a      evidence-based guidance to clinicians about risk stratification and\u000a      screening is therefore paramount. University of Glasgow research into VTE\u000a      risk among women has provided substantial insight into this issue - TREATS\u000a      data influenced the development of clinical guidelines and recommendations\u000a      both in the UK and internationally and shaped the VTE prevention strategy\u000a      of NHS Scotland.\u000a    TREATS informs recommendations on patient stratification for VTE\u000a          risk\u000a    Medical societies\u000a    The UK Royal College of Obstetricians and Gynaecologists (RCOG) have\u000a      produced three clinical guidelines on VTE risk citing TREATS research:\u000a    \u000a      Green-top guideline 37a on pregnancy (November 2009) cites Robertson et\u000a          al.4 as level 2++ evidence for the recommendation that\u000a        pregnant women with asymptomatic heritable thrombophilia (i.e. those\u000a        showing no symptoms) should be stratified by degree of risk, taking\u000a        family history and other clinical risk factors, such as age and weight,\u000a        into account.a\u000a\u000a      Green-top guideline 40 on COCs (July 2010) cites Wu et al.\u000a        2005b6 as level 1- evidence against routine screening for\u000a        thrombophilia before starting COCs.b\u000a\u000a      Green-top guideline 19 on HRT (May 2011) cites Wu et al. 2005a5\u000a        as level 2+ evidence against universal screening for heritable\u000a        thrombophilias before starting HRT.c University of Glasgow\u000a        investigator Prof Isobel Walker was a member of this guideline\u000a        committee.\u000a    \u000a    Walker was also a member of the writing group tasked by the British\u000a      Committee for Standards in Haematology (BCSH) with developing a guideline\u000a      on testing for heritable thrombophilia (April 2010).d These\u000a      guidelines cite two TREATS papers:\u000a    \u000a      Wu et al. 2005b6 is cited as evidence for the\u000a        recommendation against screening before prescribing HRT or COCs unless a\u000a        high-risk thrombophilia has been confirmed in a relative showing\u000a        symptoms.\u000a      Robertson et al.4 is cited in the section on\u000a        preventing VTE during pregnancy, with the recommendation for targeted\u000a        screening of asymptomatic women with a family history of VTE triggered\u000a        by pregnancy or use of COCs. \u000a    \u000a    The American College of Chest Physicians (ACCP) guidelines on VTE during\u000a      pregnancy were published in February 2012.e Data from Robertson\u000a      et al.4 is cited as follows:\u000a    \u000a      Tables 3 and S10 list factors the ACCP recommends clinicians use to\u000a        identify women at elevated risk of VTE after caesarean delivery\u000a        (Robertson et al. was one of seven studies cited).\u000a        Recommendation 6.2.2 states that women with at least one major risk\u000a        factor or two minor risk factors qualify for thromboprophylaxis (Grade\u000a        2B).\u000a      Table 7 outlines the risk of VTE among pregnant women with heritable\u000a        thrombophilias (Robertson et al. was one of 11 studies cited).\u000a        Recommendations 9.2.1-9.2.3 state that thromboprophylaxis should be\u000a        considered only for pregnant women with both copies of the gene affected\u000a        for factor V Leiden or prothrombin 20210 regardless of their family\u000a        history and for women with other heritable thrombophilias and a family\u000a        history of VTE (Grade 2B and 2C).\u000a      Table 9 summarises the risk of pregnancy complications among women\u000a        with heritable and acquired thrombophilias (Robertson et al. was\u000a        the only study cited). For women with a history of recurrent early\u000a        miscarriage, screening for antiphospholipid syndrome is advised\u000a        (recommendation 10.2.1, Grade 1B) whereas screening for heritable\u000a        thrombophilias is not advised (recommendation 10.2.2, Grade 2C).\u000a    \u000a    The ACCP recommendations are endorsed by several other US medical\u000a      societies, including the Amerian Society of Hematology and the American\u000a      College of Obstetricians and Gynecologists.\u000a    Government bodies\u000a    The Scottish Intercollegiate Guidelines Network (SIGN) has responsibility\u000a      for developing evidence-based clinical guidelines for NHS Scotland. In\u000a      addition, SIGN takes a proactive approach to dissemination and\u000a      implementation of its guidelines, campaigning for inclusion in national\u000a      strategies and action plans. Named individuals within each regional\u000a      Scottish health board are recruited to promote new and updated SIGN\u000a      guidelines and to draw up plans for their subsequent implementation. SIGN\u000a      guideline 122 on prevention and management of VTE was published in\u000a      December 2010.f Walker was a member of the guideline\u000a      development group, with Lowe participating in the literature review. This\u000a      guideline cites Wu et al. 20063 and Robertson et\u000a        al.4 as evidence for the evaluation of VTE risk\u000a      associated with pregnancy, HRT or COCs. These papers are also cited in\u000a      recommendations advising against routine screening for thrombophilias\u000a      because it is neither cost-effective nor indicated. In the 3 months\u000a      following publication, 77,263 copies of SIGN 122 were downloaded; in\u000a      addition, 1,803 copies of the junior doctor audit activity based on this\u000a      guideline were downloaded between April 2011 and April 2013.g\u000a    TREATS highlights the need for a Scotland-wide policy on VTE\u000a          prevention\u000a    In light of their expertise on VTE risk, the TREATS researchers were\u000a      commissioned by NHS Quality Improvement Scotland (now Healthcare\u000a      Improvement Scotland) to assess the national VTE prevention strategy. This\u000a      inspection (undertaken in 2007) identified unacceptable deficiencies and\u000a      substantial variation in guideline implementation, audit and clinical\u000a      practice. The key findings of this audit were later summarised in the British\u000a        Journal of Haematology (2010); this paper also included an analysis\u000a      of audit activity in England.h\u000a    As a result of the 2007 TREATS audit, the Chief Medical Officer for\u000a      Scotland and NHS Quality Improvement Scotland contacted all 14 Scottish\u000a      health boards to request a report on their efforts to write up-to-date\u000a      standard operating procedures for VTE prevention that were based on SIGN\u000a      recommendations. A summary report of this exercise, published in May 2008\u000a      and citing the TREATS audit, suggested that implementation of these\u000a      national guidelines was still a work in progress for many health boards.i\u000a      However, a follow-up report in December 2008 found that all health boards\u000a      \"provided reasonable reassurance that the actions originally outlined\u000a        in the May 2008 report have continued to be implemented and, in some\u000a        Board areas, completed.\"i In March 2010, the thrombosis\u000a      charity Lifeblood presented a report to the Scottish Parliament on VTE\u000a      prevention in NHS Scotland that included an audit it had conducted as a\u000a      follow-up to the original TREATS inspection.j The Lifeblood\u000a      audit showed that 11 of the Scottish health boards had a written policy in\u000a      place for VTE; 13 had policies for mandatory risk assessment of all\u000a      inpatients, with 6 boards undertaking routine reassessments; and 5\u000a      conducting regular audit of their risk assessment policies. These findings\u000a      confirmed that marked improvements had occurred in Scottish VTE prevention\u000a      policy since deficiencies were first highlighted by TREATS in 2007.\u000a    The TREATS audit also stressed the need for consistent and accessible\u000a      patient information on VTE as part of the Scotland-wide policy for\u000a      preventing this condition.h,i The Scottish Government therefore\u000a      provided Lifeblood with funds to develop a leaflet for dissemination via\u000a      general practitioners to promote awareness of VTE among their patients.k\u000a      The Lifeblood leaflet covered risk factors for VTE, including pregnancy,\u000a      use of oral oestrogens and family history of thrombophilia. In March 2008,\u000a      50 copies of this leaflet were mailed to every GP practice in Scotland\u000a      (approximately 1,000 practices in total), a campaign that featured in the\u000a      Scottish press.l The leaflet was also made freely available to\u000a      download from the Lifeblood website.\u000a    ","ImpactSummary":"\u000a    Approximately 25,000 people in the UK die each year from venous\u000a      thromboembolism (VTE); furthermore, VTE affects 1 in 100,000 women of\u000a      childbearing age and causes one-third of all maternal deaths.\u000a      Thrombophilia, pregnancy and the use of oral oestrogens can all place\u000a      women at increased risk of VTE when compared with other individuals.\u000a      University of Glasgow researchers quantified the probability of VTE among\u000a      at-risk women and analysed the benefits and cost-effectiveness of\u000a      thrombophilia screening. Their research is cited in the recommendations\u000a      and evidence bases of leading national and international clinical\u000a      guidelines. This work also galvanised an overhaul of VTE prevention policy\u000a      within NHS Scotland by emphasising the need for regional health boards to\u000a      implement and audit standardised in-house protocols and provide accessible\u000a      patient information on VTE.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Lowe GD et al. Different\u000a        effects of oral and transdermal hormone replacement therapies on factor\u000a        IX, APC resistance, t-PA, PAI and C-reactive protein—a cross-sectional\u000a        population survey. Thromb Haemost, 2001; 86:\u000a      550-556.\u000a    \u000a\u000a2. McColl MD et al. Risk\u000a        factors for pregnancy associated venous thromboembolism. Thromb\u000a        Haemost, 1997; 78: 1183-1188. PDF available on request.\u000a    \u000a\u000a3. Wu O et al. Screening\u000a        for thrombophilia in high-risk situations: systematic review and\u000a        cost-effectiveness analysis. The Thrombosis: Risk and Economic\u000a        Assessment of Thrombophilia Screening (TREATS) study. Health\u000a        Technol Assess 2006; 10: 1-110. doi:10.3310\/hta10110.\u000a    \u000a\u000a4. Robertson L et al. Thrombophilia\u000a        in pregnancy: a systematic review. Br J Haematol 2005; 132:\u000a      171-196. doi:10.1111\/j.1365-2141.2005.05847.x.\u000a    \u000a\u000a5. Wu O et al. Screening\u000a        for thrombophilia in high-risk situations: a meta-analysis and\u000a        cost-effectiveness analysis. Br J Haematol 2005a; 131:\u000a      80-90. doi:10.1111\/j.1365-2141.2005.05715.x.\u000a    \u000a\u000a6. Wu O et al. Oral\u000a        contraceptives, hormone replacement therapy, thrombophilias and risk of\u000a        venous thromboembolism: a systematic review. The Thrombosis: Risk and\u000a        Economic Assessment of Thrombophilia Screening (TREATS) study. Thromb\u000a        Haemost 2005b; 94: 17-25. doi:10.1160\/TH04-11-0759.\u000a    \u000aGrant funding\u000a    National Institute for Health Research. Screening\u000a          for thrombophilia in high-risk situations: systematic review and\u000a          cost-effectiveness analysis. The Thrombosis: Risk and Economic\u000a          Assessment of Thrombophilia Screening (TREATS) study (July\u000a      2002-April 2006, £119,211); awarded to Ian Greer.\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    a. RCOG\u000a        Green-top guideline 37a, 2009 (see ref 47, subsection 4.2 and Table\u000a      2a, pg 11-13)\u000a    b. RCOG\u000a        Green-top guideline 40, 2010 (see ref 58, section 6, pg 9)\u000a    c. RCOG\u000a        Green-top guideline 19, 2011 (see ref 74, section 6, pg 7)\u000a    d. BCSH\u000a        guideline [doi:10.1111\/j.1365-2141.2009.08022.x], 2010 (see pg\u000a      215-216)\u000a    e. ACCP\u000a        guideline [doi:10.1378\/chest.11-2300], 2012 (see ref 151, e708S and\u000a      e715S-e721S)\u000a    f. SIGN\u000a        guideline 122, 2010 (see refs 64 and 69, section 3.2,\u000a      recommendations 3.3 and 7.2)\u000a    g. SIGN guideline No. 122 download metrics - available on request\u000a    h. TREATS\u000a        audit summary, 2010 [doi: 10.1111\/j.1365-2141.2010.08080.x]\u000a    i. NHS\u000a        Quality Improvement Scotland implementation and follow-up reports\u000a      (May 2008, pg 2; December 2008, pg 3)\u000a    j. Lifeblood\u000a        Scottish VTE audit, 2010 (see pg 2-3 and Tables 5, 8, 10 and 13)\u000a    k. Lifeblood\u000a        patient information leaflet, 2008\u000a    l. Media\u000a        coverage of the Lifeblood patient information leaflet mail drop,\u000a      2008\u000a    ","Title":"\u000a    Changing clinical guidelines and government policy on VTE prevention\u000a      among women\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    University of Glasgow researchers have acknowledged expertise in\u000a      blood-clotting research, women's health, systematic review (evidence\u000a      synthesis), risk assessment and health economics. This knowledge was\u000a      applied to quantify risk of venous thromboembolism (VTE) and determine\u000a      whether identifying thrombophilia in at-risk groups would be clinically\u000a      beneficial and cost-effective.\u000a    Thrombophilia increases the risk of VTE\u000a    Thrombophilia is a broad term used to describe an increased tendency of\u000a      blood to clot; this condition may be heritable or else result from another\u000a      medical issue. Within the UK population, heritable thrombophilias (`factor\u000a      V Leiden' and `prothrombin 20210') affect 1 in 20 and 1 in 50 individuals\u000a      of European background, respectively. The prevalence of antiphospholipid\u000a      syndrome (an acquired form of thrombophilia) is around 2-4%. Individuals\u000a      with thrombophilia are at greater risk of developing a clot within a deep\u000a      vein than people without this condition. If this clot becomes dislodged\u000a      and travels elsewhere in the body, a potentially life-threatening event\u000a      (pulmonary embolism) can occur. The combination of deep-vein thrombosis\u000a      and pulmonary embolism is referred to as VTE. In addition, pregnancy or\u000a      the intake of oral oestrogen preparations, such as combined oral\u000a      contraceptives (COCs) or menopausal hormone replacement therapy (HRT), can\u000a      also place women at a higher risk of VTE. In 2001, University of Glasgow\u000a      researcher Prof Gordon Lowe demonstrated that the levels of three\u000a      thrombotic factors associated with VTE were more likely to be increased\u000a      among menopausal women who received HRT orally rather than through the\u000a      skin.1 Women not taking HRT were included as the comparator\u000a      group.\u000a    Who should be screened for thrombophilia?\u000a    VTE is an avoidable condition. Clinicians have, therefore, come under\u000a      increasing pressure to identify at-risk women and offer them preventative\u000a      treatment (thromboprophylaxis). Two thrombophilia screening strategies\u000a      have been considered. Universal screening involves testing all individuals\u000a      within a particular population to identify unrecognised disorders (that\u000a      is, before the onset of any symptoms). By contrast, targeted screening is\u000a      conducted among only those individuals who are thought to be at increased\u000a      risk based on their medical or family history. In 1997, a study led by\u000a      Prof Ian Greer of the University of Glasgow showed that universal\u000a      screening for thrombophilia during pregnancy was unlikely to be useful for\u000a      preventing VTE.2 His team evaluated 72,000 pregnancies and\u000a      found only 62 confirmed VTE events. Of the 62 affected women, 50 underwent\u000a      screening for factor V Leiden, which was detected in only 4 cases. These\u000a      data suggested that the level of risk was too low to support the screening\u000a      of all pregnant women.\u000a    TREATS study group defines VTE risk and the need for targeted\u000a          screening among women\u000a    The National Institute for Health Research recognised the importance of\u000a      quantifying the value of targeted screening of high-risk women for\u000a      clinical practice and policy decision-making; this organisation therefore\u000a      issued a call for research proposals. The Thrombosis: Risk and Economic\u000a      Assessment of Thrombophilia Screening (TREATS) team - a group of experts\u000a      in thrombosis, haemostasis and health technology assessment led by Greer -\u000a      won the commissioning bid. Between 2002 and 2006, the TREATS team used\u000a      hypothetical modelling methods to evaluate populations of women known to\u000a      be at risk of VTE. Their key findings are summarised below:\u000a    \u000a      Significant risk factors for pregnancy-associated VTE, as well as for\u000a        adverse pregnancy outcomes (including miscarriage and restricted growth\u000a        of the foetus), correlate with different types of heritable or acquired\u000a        thrombophilia.3,4\u000a\u000a      There is a substantial risk of VTE among women taking COCs compared\u000a        with other at-risk populations, although taking into account the\u000a        potential number of women who may be affected, the absolute number of\u000a        women at risk is low.3,5 Thus, screening at-risk women before\u000a        prescribing COCs is unlikely to be cost-effective, as this strategy\u000a        potentially prevents only three VTE events for every 10,000 women\u000a        screened.3,5\u000a\u000a      Women with thrombophilia who also take COCs are 5-15 times more likely\u000a        to develop VTE than those without thrombophilia; a similar effect was\u000a        found among women taking HRT.3,6\u000a\u000a    \u000a    Key University of Glasgow TREATS researchers: Olivia Wu (Research\u000a      Associate, 2001-2008; Reader in Health Economics and Health Technology\u000a      Assessment, 2008-present); Ian Greer (Professor of Obstetrics and\u000a      Gynaecology, 1991-2007); Gordon Lowe (Professor of Vascular Medicine,\u000a      1978-2009; Honorary Senior Research Fellow, 2009-present); Isobel Walker\u000a      (Honorary Professor, 2005-present); Peter Langhorne (Professor of Stroke\u000a      Care, 1994-present); Lindsay Robertson (Research Assistant, 2006-2007). External\u000a        members of the TREATS steering committee: Peter Clark (Ninewells\u000a      Hospital, Dundee, UK; deceased); Mike Greaves (University of Aberdeen,\u000a      UK); Sara Twaddle (Health Improvement Scotland, UK).\u000a    "},{"CaseStudyId":"41138","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"}],"Funders":[],"ImpactDetails":"\u000d\u000a    The ECG is used routinely in medicine to assess the health status of the\u000d\u000a      heart. In addition to\u000d\u000a      routine monitoring of heart function (e.g. in the general practice setting\u000d\u000a      or prior to surgery), the ECG\u000d\u000a      can provide critical insights into various clinical conditions, such as a\u000d\u000a      heart attack, disorders of\u000d\u000a      heart rhythm or an enlargement of the heart (as seen in heart failure).\u000d\u000a      However, the interpretation\u000d\u000a      of the ECG is complex and requires the reader to have knowledge, skill and\u000d\u000a      practice to undertake\u000d\u000a      the task accurately. The University of Glasgow's wealth of research on the\u000d\u000a      normal ECG, showing\u000d\u000a      the differences associated with age, sex and race, particularly on the\u000d\u000a      height of the ST segment,\u000d\u000a      has driven the revision of clinical guidelines defining the ECG criteria\u000d\u000a      for diagnosing heart attacks.\u000d\u000a    Influencing international guidelines on heart attack\u000d\u000a      An ECG is considered to be the single most important clinical test\u000d\u000a      in the rapid, initial evaluation of\u000d\u000a      patients experiencing chest pain due to suspected myocardial infarction\u000d\u000a      (heart attack). In 2009,\u000d\u000a      Macfarlane was one of 10 experts who revised the joint recommendations of\u000d\u000a      the American Heart\u000d\u000a      Association (AHA), the American College of Cardiology and the Heart Rhythm\u000d\u000a      Society. The revised\u000d\u000a      guidelinesa directly adopted Macfarlane's findings published in\u000d\u000a      2001, which defined different ST-height\u000d\u000a      thresholds for men and women and stipulated two sets of age-based\u000d\u000a      thresholds among\u000d\u000a      men.1 In 2012, the AHA joined the World Heart Federation and\u000d\u000a      the European Society of Cardiology\u000d\u000a      (ESC) to publish the `Third universal definition of myocardial\u000d\u000a      infarction'.a In this guideline, the ST\u000d\u000a      segment elevation thresholds for diagnosing heart attacks are again based\u000d\u000a      directly on the\u000d\u000a      University of Glasgow's work (Table 3 in the document and reference 38).\u000d\u000a      This consensus\u000d\u000a      guideline from the leading global cardiovascular authorities is the most\u000d\u000a      powerful guidance currently\u000d\u000a      available to cardiologists and standardises the diagnosis of heart attack\u000d\u000a      around the world.\u000d\u000a    Commercial adoption of the Glasgow Program by the medical devices\u000d\u000a          industry\u000d\u000a      Correct interpretation of the ECG, particularly in the ambulance or the\u000d\u000a      accident and emergency\u000d\u000a      department, is usually the basis for immediate treatment\u000d\u000a      and\/or subsequent diagnostic tests.\u000d\u000a      Whilst cardiologists are expert at interpreting the ECG, these specialists\u000d\u000a      are not readily available in\u000d\u000a      all clinical settings. Automated ECG interpretation provides a solution to\u000d\u000a      this problem.\u000d\u000a    The global market for ECG monitoring systems is estimated to reach more\u000d\u000a      than US$800 million in\u000d\u000a      the next few years. Coupled with the rising incidence of heart disease,\u000d\u000a      there is a highly lucrative\u000d\u000a      market for automated ECG interpretation software. The Glasgow Program is a\u000d\u000a      major competitor in\u000d\u000a      this market and remains at the cutting edge of electrocardiographic\u000d\u000a      research. As such it has been\u000d\u000a      adopted commercially by some of the world's leading electro-medical device\u000d\u000a      manufacturers in\u000d\u000a      various product formats, all of which have gained approval from the FDA.\u000d\u000a    Firstly, the Glasgow Program has been integrated into ECG machines that\u000d\u000a      acquire, read out and\u000d\u000a      interpret ECGs. Cardiac Science, a US-based market-leading company with\u000d\u000a      customers in over 100\u000d\u000a      countries worldwide, offers this type of product through its Burdick\u000d\u000a      brand [models 8300 & 8500].\u000d\u000a      Mindray, a leading Chinese medical device manufacturer, now uses the\u000d\u000a      program in its R3\u000d\u000a        electrocardiograph. Secondly, the Glasgow Program has been embedded\u000d\u000a      into computer software\u000d\u000a      packages that accompany Holter monitor ECG systems: Telemed Solutions'\u000d\u000a      flagship product is the\u000d\u000a      TM-12 recorder. Thirdly, Draeger use the software in its patient\u000d\u000a      monitoring system — the Infinity®\u000d\u000a        Central Station. Finally, the Glasgow Program has been combined with\u000d\u000a      defibrillator\/patient monitor\u000d\u000a      devices such as the Physio-Control Lifepak®15.b\u000d\u000a      Physio-Control states that:\u000d\u000a    \"It is important that our product use an ECG analysis program that is\u000d\u000a        widely used in clinical\u000d\u000a        practice and is recognized as being among best in class. The Glasgow\u000d\u000a        program meets those\u000d\u000a        requirements. The Glasgow program gave us an advantage over our previous\u000d\u000a        generation\u000d\u000a        product in that the Glasgow program adjusts its STEMI criteria based on\u000d\u000a        patient gender and,\u000d\u000a        for men, on patient age.\" — Principal Scientist, Physio-Control Inc.c\u000d\u000a    [text removed for publication]. Inclusion of the Glasgow Program in the\u000d\u000a      above devices allows faster\u000d\u000a      recording and immediate interpretation of ECGs, thereby reducing, and even\u000d\u000a      eliminating, the need\u000d\u000a      for routine manual ECG interpretation and filing. The read-out format of\u000d\u000a      the Program contains\u000d\u000a      headline statements (such as `CONSIDER ACUTE STEMI' and `SIGNIFICANT\u000d\u000a      ARRHYTHMIA'),\u000d\u000a      which can aid initial diagnosis. Such headline statements are especially\u000d\u000a      important for emergency\u000d\u000a      ambulance services, which need to decide quickly whether a patient should\u000d\u000a      be taken to a heart\u000d\u000a      specialist centre, for example. Furthermore, the Glasgow Program is one of\u000d\u000a      the few automated\u000d\u000a      systems that can accurately interpret ECGs from birth, thereby enabling\u000d\u000a      clinicians to use this\u000d\u000a      diagnostic tool in a paediatric setting.\u000d\u000a    Since 2008, over 40,000 devices containing the Glasgow Program have been\u000d\u000a      sold worldwide to a\u000d\u000a      range of end-users.d For example, Physio-Control has sold a\u000d\u000a      significant number of Lifepak®15\u000d\u000a      devices to UK ambulance services, including around 740 to the\u000d\u000a      London Ambulance Service (LAS).c\u000d\u000a      LAS responds to an estimated 1.5 million emergency calls per annum and has\u000d\u000a      reported an\u000d\u000a      increase in survival following a cardiac arrest from 12% to 32% in the\u000d\u000a      last five years. It is\u000d\u000a      conceivable that the rapid and reliable interpretation of ECGs with the\u000d\u000a      Glasgow Program will have\u000d\u000a      contributed to this improvement.e Similarly, Physio-Control\u000d\u000a      Inc. has sold devices to fire services as\u000d\u000a      well as other medical service vehicles, ships and hospitals.c\u000d\u000a      As each of these 40,000 devices will\u000d\u000a      undoubtedly be used on multiple patients, the software is estimated as\u000d\u000a      being used to interpret the\u000d\u000a      ECGs of millions of patients annually.\u000d\u000a    Influence on practice-changing clinical trials and epidemiological\u000d\u000a          studies\u000d\u000a      The Glasgow Program has been used in a number of large multi-centre\u000d\u000a      randomised controlled\u000d\u000a      clinical trials and epidemiological studies. The dedicated University of\u000d\u000a      Glasgow Core Labf acts as a\u000d\u000a      partner to a number of stakeholders in clinical trials by providing a\u000d\u000a      standardised approach to ECG\u000d\u000a      interpretation that is used in all centres. Since 2008, the Glasgow\u000d\u000a      Program and Core Lab have\u000d\u000a      been involved in over 12 trials and studies. These trials have established\u000d\u000a      major clinical outcomes of\u000d\u000a      international significance, for example the benefits of statins in\u000d\u000a      preventing cardiovascular disease,\u000d\u000a      which have themselves led to changes in guidelines and clinical practice.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The electrocardiogram (ECG) is one of the most commonly used medical\u000d\u000a      tests which assist in\u000d\u000a      diagnosing heart disorders worldwide. However, diagnosis relies on\u000d\u000a      accurate interpretation of ECG\u000d\u000a      recordings. Studies by University of Glasgow researchers have led to\u000d\u000a      changes to international\u000d\u000a      guidelines for ECG-based diagnosis of a heart attack (myocardial\u000d\u000a      infarction; MI) and have led to\u000d\u000a      significant refinements to the automated ECG analysis software called the\u000d\u000a      `Glasgow Program'.\u000d\u000a      Commercialisation of the Program since 2008 has resulted in its\u000d\u000a      incorporation into some of the\u000d\u000a      market-leading medical devices, with approval of the Glasgow Program by\u000d\u000a      the FDA and more than\u000d\u000a      40,000 devices sold worldwide, potentially aiding millions of patients\u000d\u000a      around the world. The\u000d\u000a      Program assists hospital doctors, family practitioners and others such as\u000d\u000a      first responding\u000d\u000a      emergency services, e.g. ambulance and fire services, with the reliable\u000d\u000a      interpretation of ECGs,\u000d\u000a      enabling rapid and accurate diagnosis and treatment of patients with a\u000d\u000a      variety of heart problems.\u000d\u000a    ","ImpactType":"Technological","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Macfarlane PW. Age,\u000d\u000a        sex and the ST amplitude in health and disease. J Electrocardiol\u000d\u000a      2001;\u000d\u000a      34 (suppl):235-41. doi: 10.1054\/jelc.2001.28906\u000d\u000a    \u000a\u000a2. Macfarlane PW,\u000d\u000a\u0009       Browne D,\u000d\u000a         Devine B,\u000d\u000a\u0009\u0009 Clark E,\u000d\u000a\u0009\u0009Miller E,\u000d\u000a\u0009\u0009 Seyal J,\u000d\u000a\u0009\u0009 Hampton D.\u000d\u000a\u0009\u0009 Modification\u000d\u000a        of\u000d\u000a        ACC\/ESC criteria for acute myocardial infarction. J\u000d\u000a        Electrocardiol 2004; 37 (suppl):98-103. doi:\u000d\u000a      10.1016\/j.jelectrocard.2004.08.032\u000d\u000a    \u000a\u000a3. Clark EN,\u000d\u000a\u0009  Sejersten M,\u000d\u000a\u0009  Clemmensen P,\u000d\u000a\u0009  Macfarlane PW.\u000d\u000a\u0009  Automated\u000d\u000a        electrocardiogram\u000d\u000a        interpretation programs versus cardiologists' triage decision making\u000d\u000a        based on teletransmitted\u000d\u000a        data in patients with suspected acute coronary syndrome. Am J\u000d\u000a        Cardiol. 2010; 106(12):1696-702.\u000d\u000a      doi: 10.1016\/j.amjcard.2010.07.047.\u000d\u000a    \u000a\u000a4. Macfarlane PW, McLaughlin SC, Devine B, Yang TF. Effects\u000d\u000a        of age, sex, and race on ECG\u000d\u000a        interval measurements. J Electrocardiol. 1994;27 Suppl:14-19\u000d\u000a    \u000a\u000a5. Shepherd  J,\u000d\u000a\u0009Cobbe SM,\u000d\u000a\u0009Ford I,\u000d\u000a\u0009Isles CG,\u000d\u000a\u0009Lorimer  AR,\u000d\u000a\u0009MacFarlane PW,\u000d\u000a\u0009McKillop  JH,\u000d\u000a\u0009Packard CJ.\u000d\u000a\u0009Prevention\u000d\u000a        of coronary heart disease with pravastatin in men with\u000d\u000a        hypercholesterolemia.\u000d\u000a      West of Scotland Coronary Prevention Study Group. N\u000d\u000a          Engl J Med. 1995; 333(20):1301-7. doi:\u000d\u000a      10.1056\/NEJM199511163332001\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    a. International guidelines\u000d\u000a    \u000d\u000a      Wagner GS, Macfarlane P, et al. AHA\/ACCF\/HRS\u000d\u000a          recommendations for the standardization\u000d\u000a          and interpretation of the electrocardiogram. J Am Coll\u000d\u000a          Cardiol. 2009; 53:1003-11. (Ref 8 is\u000d\u000a        Macfarlane J Electrocardiol 2001, cited in ST-segment\u000d\u000a        recommendations, p1005)\u000d\u000a      \u000aThygesen\u000d\u000a          K et al., Joint\u000d\u000a          ESC\/ACCF\/AHA\/WHF Task Force for the Universal Definition of\u000d\u000a          Myocardial Infarction. Third universal definition of myocardial\u000d\u000a          infarction. Eur\u000d\u000a            Heart J. 2012 Oct;\u000d\u000a        33:2551-67. (Ref 38 is Macfarlane J Electrocardiol 2001, cited\u000d\u000a        in `Electrocardiographic detection\u000d\u000a          of myocardial infarction' — `ECG manifestations' Table 3\u000d\u000a        and evidence base, p8).\u000d\u000a    \u000d\u000a    b. Medical device companies citing inclusion of the Glasgow\u000d\u000a          Program in their product:\u000d\u000a      Cardiac Science — Burdick 8300 ECG and Burdick 8500 ECG\u000d\u000a      (until mid-2013 available directly\u000d\u000a      from Cardiac Science, now sold via distributors e.g. Moore\u000d\u000a        Medical Burdick 8300 ECG and\u000d\u000a      Fisher\u000d\u000a        Medical Burdick 8300 ECG); Mindray — R3\u000d\u000a          electrocardiograph; Telemed Solutions — TM-\u000a         12\u000d\u000a          recorder; Draeger — Infinity®\u000d\u000a          Central Station; Physio-Control — Lifepak®15\u000a         monitor\/defibrillator\u000d\u000a          device (`Interpretive algorithm' section, p17)\u000d\u000a    c. Statement from Principal Scientist, Physio-Control Inc. available on\u000d\u000a      request\u000d\u000a    d. Commercial adoption of the Glasgow Program\u000d\u000a    \u000d\u000a      Full list of medical device companies who have purchased or extended\u000d\u000a        rights to use the\u000d\u000a        Glasgow Program since 2008 is as follows: Schmidt, McKesson,\u000d\u000a          Cardiolex, Cardiac Science,\u000d\u000a          Draeger, Epiphany, Heartlab, Spacelabs Healthcare Inc., Physio-Control\u000d\u000a          Inc., Dan Medical,\u000d\u000a          AMPS, Mindray Inc., Memtec Corporation (who licence to Telemed\u000d\u000a          Solutions), Vitalograph Ltd.,\u000d\u000a          Allengers, Gestio Agfa, Mediana Co., Maestros Mediline Systems Ltd.,\u000d\u000a          Quinton.\u000a\u000d\u000a    \u000d\u000a    e. Physio-Control `Inside\u000d\u000a        Physio' website. The link at the bottom of this page `Click here\u000d\u000a        to read\u000d\u000a        about LAS' redirects to a PDF document `LAS NHS Trust: A model\u000d\u000a      system of care' confirming\u000d\u000a      enhanced survival rates (p1) and 740 devices purchased (p3).\u000d\u000a    f. ECG\u000d\u000a        core lab, a service for large multi-centre clinical trials.\u000d\u000a    ","Title":"\u000d\u000a    Advancing heart disease diagnosis — influencing international guidelines\u000d\u000a      and\u000d\u000a      commercial adoption of automated ECG analysis software\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Each heartbeat is controlled by an electrical signal which\u000d\u000a      travels through the heart, causing the muscle to contract,\u000d\u000a      pump blood around the body and relax in time for the next\u000d\u000a      beat. By placing electrodes on a person's chest and limbs,\u000d\u000a      this electrical activity can be detected and plotted (normally in\u000d\u000a      millivolts [mV] as a function of time) to form an ECG. As\u000d\u000a      shown in the diagram (right), the ECG cycle representing one\u000d\u000a      heartbeat consists of a series of waves (P, QRS and T) with\u000d\u000a      corresponding segments and intervals, which map the\u000d\u000a      electrical signal as it travels through the heart. The standard\u000d\u000a      12-lead (waveform) ECG is typically recorded over a 10-second period so\u000d\u000a      that many cycles (hence\u000d\u000a      heartbeats) are recorded. Alterations in the normal ECG recording (changes\u000d\u000a      in the shape of waves\u000d\u000a      or the length and height of segments or intervals) might indicate\u000d\u000a      abnormalities and can be used to\u000d\u000a      diagnose disorders associated with abnormal heart rate and rhythm,\u000d\u000a      enlarged heart (hypertrophy)\u000d\u000a      or heart attacks. However, accurate detection of ECG abnormalities\u000d\u000a      requires a clear appreciation of\u000d\u000a      the normal limits of the ECG signal in apparently healthy populations.\u000d\u000a    \u000d\u000a    \u000d\u000a    \u000d\u000a    The Glasgow Program: key advances since 1993\u000d\u000a      Professor Peter Macfarlane and his team at the University of Glasgow have\u000d\u000a      an extensive track\u000d\u000a      record in ECG research and pioneered the development of automated analysis\u000d\u000a      and interpretation\u000d\u000a      of the ECG. By the early 1980s, the team had developed a basic computer\u000d\u000a      algorithm called the\u000d\u000a      'Glasgow Program', which could automatically detect ECG components,\u000d\u000a      compare these with\u000d\u000a      reference `normal' values and provide an interpretation to aid the\u000d\u000a      clinical diagnosis of heart\u000d\u000a      problems. From 1993 onwards, the team has systematically studied the\u000d\u000a      effects of age, sex and\u000d\u000a      race on the normal limits of the 12 lead ECG and refined criteria so that\u000d\u000a      ECG signals can be\u000d\u000a      accurately interpreted in different patient subpopulations, e.g. males,\u000d\u000a      females, Caucasians,\u000d\u000a      Chinese, Africans. The current form of the Glasgow Program incorporates\u000d\u000a      these refined criteria.\u000d\u000a    Heart attacks are associated with a characteristic change in the ST\u000d\u000a      segment on an ECG recording\u000d\u000a      and consequently the height of the ST segment is used to diagnose heart\u000d\u000a      attacks. Joint guidelines\u000d\u000a      issued by the American College of Cardiology (ACC) and European Society of\u000d\u000a      Cardiology (ESC) in\u000d\u000a      2000 stated a common diagnostic upper limit for the ST segment height in\u000d\u000a      most of the 12 leads for\u000d\u000a      all adults, regardless of age, sex or race. Between 1993 and 2000, the\u000d\u000a      University of Glasgow team\u000d\u000a      defined age-based and sex-based criteria for evaluating the height of the\u000d\u000a      ST segment in the adult\u000d\u000a      12-lead ECG. In 2001, Macfarlane reported findings obtained through the\u000d\u000a      examination of ECGs\u000d\u000a      from 1,338 healthy men and women (age range between 18 and 78 years).\u000d\u000a      These showed that the\u000d\u000a      upper limit for the normal ST segment's height in three specific chest\u000d\u000a      leads was at least 50% higher\u000d\u000a      in men than in women, and for one of these leads, the upper limit was\u000d\u000a      distinctly different from the\u000d\u000a      other two in both men and women.1 The latter finding\u000d\u000a      demonstrated that this lead should be\u000d\u000a      evaluated independently of the other two leads when defining the\u000d\u000a      diagnostic criteria for heart\u000d\u000a      attacks. Furthermore, the work revealed an age-dependent decrease in the\u000d\u000a      upper limit in two of\u000d\u000a      these leads, which is observed only in men. These findings were\u000d\u000a      incorporated into the existing\u000d\u000a      Glasgow Program to produce an enhanced version for reporting ST elevation\u000d\u000a      MI (STEMI).\u000d\u000a    Validation of the enhanced Glasgow Program's sensitivity and\u000d\u000a          specificity for diagnosing\u000d\u000a          heart attack\u000d\u000a      In a collaborative research study with the medical device manufacturer\u000d\u000a      Medtronic Physio Control,\u000d\u000a      the Glasgow team compared almost 3000 ECG recordings taken from Scottish\u000d\u000a      and American men\u000d\u000a      and women (approximate age range 20-80 years, 60% of whom had presented\u000d\u000a      with chest pain)\u000d\u000a      using either the enhanced Glasgow Program or the 2000 guideline criteria.\u000d\u000a      The results showed that\u000d\u000a      the Glasgow Program significantly improved the sensitivity and specificity\u000d\u000a      of the ECG-based\u000d\u000a      diagnosis of heart attacks.2 In 2010, the enhanced Glasgow\u000d\u000a      Program's ability to accurately\u000d\u000a      diagnose a heart attack was comparable to that of specialist cardiologists\u000d\u000a      and, in fact, it proved to\u000d\u000a      be superior in its ability to reduce the number of false-positive\u000d\u000a      diagnoses.3\u000d\u000a    The University of Glasgow researchers also provided vital data on\u000d\u000a      paediatric ECGs by\u000d\u000a      characterising recordings of over 1,700 healthy neonates, infants and\u000d\u000a      children.4 This study\u000d\u000a      revealed that the components of the ECG (particularly the QRS height)\u000d\u000a      change over the course of\u000d\u000a      the first few days of life. These findings led to the incorporation of\u000d\u000a      age-adjusted normal limits for\u000d\u000a      ECG values in neonates, infants and children into the Glasgow Program.\u000d\u000a    Use of the Glasgow Program in large-scale clinical trials\u000d\u000a      The Glasgow Program has been at the design core of a number of\u000d\u000a      high-profile cardiovascular\u000d\u000a      randomised clinical trials. The value of combining automated\u000d\u000a      interpretation with automated coding,\u000d\u000a      using an internationally agreed scheme, was first demonstrated in the\u000d\u000a      landmark West of Scotland\u000d\u000a      Coronary Prevention Study (WOSCOPS).5 As part of this, the\u000d\u000a      participants' ECGs were recorded\u000d\u000a      annually for a minimum of 5 years in various health centres in the west of\u000d\u000a      Scotland, and the\u000d\u000a      recordings were transmitted electronically over the telephone network to a\u000d\u000a      central computer for\u000d\u000a      automated analysis using the Glasgow Program. In this way, the Glasgow\u000d\u000a      Program detected heart\u000d\u000a      attacks of which the participants had been unaware. In addition, the ECGs\u000d\u000a      were automatically\u000d\u000a      coded using an internationally agreed scheme known as the Minnesota Code.\u000d\u000a      This approach is\u000d\u000a      accepted worldwide by epidemiologists as a standardised method for\u000d\u000a      classifying ECG waveforms.\u000d\u000a      WOSCOPS highlighted the potential of this approach to control for\u000d\u000a      variation in ECG-based\u000d\u000a      diagnosis of heart attacks between clinicians within the same trial centre\u000d\u000a      and those who are\u000d\u000a      physically separated on different sites\/countries thereby improving the\u000d\u000a      trial outcome assessment.\u000d\u000a    Key University of Glasgow researchers: Peter Macfarlane\u000d\u000a      (Professor in Medical Cardiology\u000d\u000a      [1991-1995]; Professor of Electrocardiology, [1996-2010]; Honorary\u000d\u000a      Research Fellow [2010-\u000d\u000a      present]); Brian Devine (Software Development Manager [1988-present]);\u000d\u000a      Elaine Clark (Software\u000d\u000a      Applications Specialist [1998-present); WOSCOPS study group members (see\u000d\u000a      article for full\u000d\u000a      details). Key external collaborators: Medtronic Physio\u000d\u000a      Control\u000d\u000a    "},{"CaseStudyId":"41139","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    In the UK, approximately 152,000 strokes cause around 50,000 deaths\u000d\u000a      annually; furthermore, 1.1 million stroke-related deaths are recorded in\u000d\u000a      Europe each year. The resulting economic burden attributed to stroke in\u000d\u000a      the UK alone is £3.75 billion. University of Glasgow research has driven\u000d\u000a      improvements in management of patients with hypertension, exerting marked\u000d\u000a      influence on stroke prevalence and fatality by underpinning clinical\u000d\u000a      guideline recommendations and implementation.\u000d\u000a    Clinical guidelines for hypertension and stroke\u000d\u000a    The University of Glasgow's international reputation in hypertension and\u000d\u000a      stroke research has invited involvement in clinical guideline development\u000d\u000a      at the highest level. Professor Anna Dominiczak — Regius Professor of\u000d\u000a      Medicine in the University's Institute of Cardiovascular and Medical\u000d\u000a      Sciences — held a key role on the Scientific Council for the 2013 European\u000d\u000a      Society for Hypertension (ESH) guidelines. Lees currently serves as\u000d\u000a      President Elect of the European Stroke Organisation (ESO) and was a\u000d\u000a      co-author of the 2008 ESO guidelines. The University of Glasgow's\u000d\u000a      contribution to landmark studies on hypertension provided a strong\u000d\u000a      evidence-base that has informed both European and UK guideline\u000d\u000a      recommendations published since 2008.\u000d\u000a    2013 ESH\/European Society of Cardiology (ESH\/ESC) joint guidelines for\u000d\u000a        the management of arterial hypertensiona\u000d\u000a    \u000d\u000a      The PROGRESS,1 ASCOT-BPLA,4 and LIFE6\u000d\u000a        studies are included in the key underpinning evidence (Table 16) used to\u000d\u000a        develop the `Summary of recommendations on treatment strategies and\u000d\u000a          choice of drug' (Section 5.2.3), which list a series of\u000d\u000a        hypertension treatment paradigms relating to ACE inhibitors,\u000d\u000a        calcium-channel blockers and ARBs.\u000d\u000a      The influence of PROGRESS1 in defining the clinical utility\u000d\u000a        of BP reduction in preventing recurrent stroke is highlighted by its\u000d\u000a        citation as one of only two to three references underpinning the\u000d\u000a        following recommendations: \"Antihypertensive treatment is recommended\u000d\u000a          in hypertensive patients with a history of stroke or TIA even when\u000d\u000a          initial SBP is in the 140-159 mmHg range\" and \"In hypertensive\u000d\u000a          patients with a history of stroke or TIA, a SBP goal of <140 mmHg\u000d\u000a          should be considered\" (Section 16.10.4).\u000d\u000a    \u000d\u000a    2008 ESO guidelines for management of ischaemic stroke and transient\u000d\u000a        ischaemic attackb\u000d\u000a    \u000d\u000a      The BP-lowering effects of losartan demonstrated in the LIFE6\u000d\u000a        study are cited in the key underpinning evidence base for the following\u000d\u000a        recommendation to reduce vascular risk factors and prevent first-time\u000d\u000a        stroke (primary prevention): \"Blood pressure should be checked\u000d\u000a          regularly. It is recommended that high blood pressure should be\u000d\u000a          managed with lifestyle modification and individualized pharmacological\u000d\u000a          therapy (Class I recommendation, Level A evidence) aiming at normal\u000d\u000a          levels of 120\/80 mmHg.\"\u000d\u000a      The value of the PROGRESS1 findings in demonstrating BP\u000d\u000a        reduction to prevent recurrent stroke (secondary prevention) is cited in\u000d\u000a        the evidence base to support the following: \"It is recommended that\u000d\u000a          BP be checked regularly. BP lowering is recommended after the acute\u000d\u000a          phase, including in patients with normal BP (Class I recommendation,\u000d\u000a          Level A evidence).\"\u000d\u000a    \u000d\u000a    Effective management of hypertension has the greatest impact on reducing\u000d\u000a      stroke incidence. Consequently, national guidance documents that align\u000d\u000a      with international guideline recommendations play an important role in\u000d\u000a      influencing patient care at a local level. Guidelines developed by the UK\u000d\u000a      National Institute for Health and Care Excellence (NICE) and the Scottish\u000d\u000a      Intercollegiate Guidance Network (SIGN) are instrumental in driving best\u000d\u000a      practice within the NHS.\u000d\u000a    2011 NICE guideline Hypertension — the clinical management of primary\u000d\u000a        hypertension in adultsc This guideline replaces NICE CG34\u000d\u000a      (2006), in which the findings ASCOT-BPLA4 and LIFE6\u000d\u000a      were extensively cited in the evidence synthesis for recommendations on\u000d\u000a      hypertension treatment strategies and algorithms (i.e. preferential use of\u000d\u000a      ACE inhibitors or ARBs over β-blockers). The 2011 update (CG127) cites\u000d\u000a      PROSPER,1 ASCOT-BPLA4 and LIFE in the evidence base;6\u000d\u000a      furthermore, many of the original recommendations supported by University\u000d\u000a      of Glasgow research remain in CG127, testament to the enduring impact of\u000d\u000a      this body of work.\u000d\u000a    2008 Scottish Intercollegiate Guidelines Network (SIGN) guideline 108\u000d\u000a        — management of patients with stroke or TIAd\u000d\u000a    SIGN has responsibility for development of evidence-based clinical\u000d\u000a      guidelines for use within NHS Scotland. The SIGN 108 recommendations on\u000d\u000a      the secondary prevention of stroke draw directly on the University of\u000d\u000a      Glasgow research:\u000d\u000a    \u000d\u000a      \"All patients with a previous stroke or TIA should be considered\u000d\u000a          for treatment with an ACE inhibitor (for example, perindopril) and\u000d\u000a          thiazide (for example, indapamide) regardless of blood pressure,\u000d\u000a          unless contraindicated.\" PROGRESS1 is cited in the\u000d\u000a        underpinning evidence for this Class A advisory on the secondary\u000d\u000a        prevention of ischaemic stroke.\u000d\u000a      \u000a\"Lowering blood pressure (non-acutely) following ICH using a\u000d\u000a          combination therapy of ACE inhibitor and thiazide diuretic\u000d\u000a          should be considered to prevent further vascular events.\"\u000d\u000a        PROGRESS1 is cited in the underpinning evidence for this\u000d\u000a        Class A advisory on the secondary prevention of haemorrhagic stroke.\u000d\u000a    \u000d\u000a    Uptake of UK clinical guidance\u000d\u000a    A 2010 NICE implementation uptake report evaluated national trends\u000d\u000a      following publication of NICE CG34 (2006).e Findings confirmed\u000d\u000a      a sharp drop in the prescribing of β-blockers from 14% (July-September\u000d\u000a      2005) to 3% (April-June 2009), while use of ACE inhibitors rose from 27%\u000d\u000a      to 48% in the same period. By June 2009, 75% of all newly diagnosed\u000d\u000a      hypertensive patients aged less than 55 years were prescribed either an\u000d\u000a      ACE inhibitor or an ARB.\u000d\u000a    In Scotland, SIGN takes a proactive approach to dissemination and\u000d\u000a      implementation of its guidelines. Named individuals within each of the 14\u000d\u000a      regional Scottish Health Boards are recruited to promote new and updated\u000d\u000a      SIGN guidelines and to draw up plans for their subsequent implementation.\u000d\u000a      In the 2 months following publication, SIGN 108 was downloaded 66,150\u000d\u000a      times.f In addition, the following national strategies and\u000d\u000a      action plans draw on the recommendations of SIGN 108: i) Better Heart\u000d\u000a        Disease and Stroke Care Action Plan (2009) and ii) Clinical\u000d\u000a        Standards for Stroke Services (2009).f\u000d\u000a    The Quality and Outcomes Framework (QOF) is an incentive scheme for GP\u000d\u000a      practices providing financial rewards for patient care across multiple\u000d\u000a      disease domains. Where available, QOFs are based on NICE and SIGN\u000d\u000a      guidelines. The SIGN 108 and NICE CG34 guidelines are cited in the\u000d\u000a      2011-2012 QOF guidance on stroke and hypertension, respectively. PROGRESS1\u000d\u000a      is cited in the evidence base for QOF stroke indicator 6 (secondary\u000d\u000a      prevention); around 85% of patients in England with a previous stroke\u000d\u000a      received treatment to target BP-lowering during 2011-2012.g\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Stroke is the leading cause of disability and a major cause of death in\u000d\u000a      the developed world. Hypertension (high blood pressure) is the single most\u000d\u000a      important modifiable risk factor for stroke, contributing to around 50% of\u000d\u000a      all events. University of Glasgow researchers have played lead roles in\u000d\u000a      the design, conduct and analysis of pivotal clinical trials on treatment\u000d\u000a      regimens for hypertension. These research findings have informed European\u000d\u000a      and UK hypertension and stroke guidelines, advancing treatment strategies,\u000d\u000a      and contributed to the observed ~25% reduction in the incidence of primary\u000d\u000a      (first) and secondary (recurrent) stroke.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. PROGRESS Collaborative Group. Randomised\u000a        trial of a perindopril-based blood pressure-lowering regimen among 6,105\u000d\u000a        individuals with previous stroke or transient ischaemic attack. Lancet\u000d\u000a      2001; 358: 1033-1041 doi:10.1016\/S0140-6736(01)06178-5.\u000d\u000a    \u000a\u000a2. Walters MR et al. Effect\u000a        of perindopril on cerebral and renal perfusion in stroke patients with\u000d\u000a        carotid disease. Stroke 2001; 32: 473-478\u000d\u000a      doi:10.1161\/01.STR.32.2.473.\u000d\u000a    \u000a\u000a3. Lewsey J et al. Temporal\u000a        trends in hospitalisation for stroke recurrence following incident\u000d\u000a        hospitalisation for stroke in Scotland. BMC Medicine 2010;\u000d\u000a      8: 23 doi:10.1186\/1741-7015-8-23.\u000d\u000a    \u000a\u000a4. Dahlöf B et al. Prevention\u000a        of cardiovascular events with an antihypertensive regimen of amlodipine\u000d\u000a        adding perindopril as required versus atenolol adding\u000d\u000a        bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac\u000d\u000a        Outcomes Trial-Blood Pressure Lowering Arm(ASCOT-BPLA): a multicentre\u000d\u000a        randomised controlled trial. Lancet 2005; 366: 895-906\u000d\u000a      doi:10.1016\/S0140-6736(05)67185-1.\u000d\u000a    \u000a\u000a5. Dolan E et al. Ambulatory\u000a        blood pressure monitoring predicts cardiovascular events in treated\u000d\u000a        hypertensive patients — an Anglo-Scandinavian cardiac outcomes trial\u000d\u000a        substudy. J Hypertens. 2009; 27: 876-885\u000d\u000a      doi:10.1097\/HJH.0b013e328322cd62.\u000d\u000a    \u000a\u000a6. Dahlöf B et al. Cardiovascular\u000a        morbidity and mortality in the Losartan Intervention for Endpoint\u000d\u000a        reduction in hypertension study (LIFE): a randomised trial against\u000d\u000a        atenolol. Lancet 2002; 359: 995-1003\u000d\u000a      doi:10.1016\/S0140-6736(02)08089-3.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    a. ESH\/ESC\u000a        guidelines for the management of arterial hypertension, 2013\u000d\u000a      [doi:10.1097\/01.hjh.0000431740.32696.cc]. Cites PROGRESS (ref 296; p1304,\u000d\u000a      1306, 1313, 1314, 1323, 1324); ASCOT-BPLA (ref 423; p1310, 1313, 1314);\u000d\u000a      LIFE (ref 457; p1313, 1314). See Table 16 (p1314); Section 5.2.3\u000d\u000a      (p1315-1316); Section 6.10.4 (p1324).\u000d\u000a    b. ESO\u000a        guidelines for management of ischaemic stroke and transient ischaemic\u000d\u000a        attack, 2008. Cites PROGRESS (ref 290; p39, 83); LIFE (ref 213;\u000d\u000a      p30). See recommendations (p29, 38)\u000d\u000a    c. NICE\u000a        CG127 guideline on the clinical management of primary hypertension in\u000d\u000a        adults, 2011. Cites PROGRESS (ref 500; Table 3, p201); ASCOT-BPLA\u000d\u000a      (ref 157; p206, 248); LIFE (ref 154; p35).\u000d\u000a    d. SIGN 108 guidelines\u000d\u000a        on management of patients with stroke or TIA, 2008. Cites PROGRESS\u000d\u000a      (ref 228, p37 and 40).\u000d\u000a    e. NICE\u000a        CG34 implementation uptake report, 2010. (Figure 4, Table 2).\u000d\u000a    f. SIGN 108 download data — available on request.\u000d\u000a    g. QOF\u000a        guidance for GMS contract (p52, 53, 56) and QOF\u000a        data (STROKE06), 2011-2012. \u000d\u000a    ","Title":"\u000d\u000a    Redefining hypertension treatment practice to reduce primary and secondary\u000d\u000a    stroke risk\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Working at the forefront of hypertension and stroke research for more\u000d\u000a      than 40 years, investigators at the University of Glasgow are recognised\u000d\u000a      leaders in both laboratory-based and clinical research into the causes of\u000d\u000a      hypertension and its treatment. A theme of particular interest is the link\u000d\u000a      between hypertension and stroke. University of Glasgow researchers have a\u000d\u000a      global reputation in the design and execution of landmark clinical trials\u000d\u000a      in this area.\u000d\u000a    Perindopril Protection Against Recurrent Stroke Study (PROGRESS;\u000d\u000a          1995-2000)1,2\u000d\u000a    A University of Glasgow team — comprising Professors Kennedy Lees, John\u000d\u000a      Reid and Matthew Walters — led ground-breaking clinical studies of the\u000d\u000a      angiotensin-converting enzyme (ACE) inhibitor, perindopril, the first\u000d\u000a      long-acting, once-daily preparation available for use in hypertensive\u000d\u000a      patients. Previously, treatments that lowered blood pressure (BP) had been\u000d\u000a      shown to reduce the risk of primary stroke, but it was unclear whether\u000d\u000a      they also prevented secondary strokes. The University of Glasgow\u000d\u000a      researchers designed and led the pioneering PROGRESS randomised controlled\u000d\u000a      clinical trial, which established the safety and tolerability of\u000d\u000a      perindopril among healthy volunteers and patients with hypertension or\u000d\u000a      stroke (172 participating centres; 6,105 patients recruited). Members of\u000d\u000a      the University of Glasgow research team also played significant roles in\u000d\u000a      comparative studies of perindopril versus other BP-lowering drugs.\u000d\u000a      Eligibility criteria for patient enrolment was broad (including previous\u000d\u000a      stroke of any kind during the previous 5 years with no stroke-related\u000d\u000a      disability), thus providing a heterogeneous population in which to test\u000d\u000a      the efficacy of perindopril. The findings of PROGRESS (published in 2001)\u000d\u000a      were profound, showing that a perindopril-based regimen reduced the\u000d\u000a      overall relative risk of recurrent stroke by 28%. Results were\u000d\u000a      far-reaching for the management of stroke risk, suggesting that all\u000d\u000a      patients with stroke should receive BP-lowering therapy irrespective of\u000d\u000a      their actual BP reading; this strategy represented a major departure from\u000d\u000a      previous practice.\u000d\u000a    University of Glasgow researchers also led a very large epidemiological\u000d\u000a      study of recurrent stroke (5.1 million people in Scotland), evaluating\u000d\u000a      hospitalisations and outcomes over a 15-year period (1986-2001).3\u000d\u000a      By comparing data from 1986 with those from 2001, this study demonstrated\u000d\u000a      improved survival following stroke, with a 28% decreased risk of death and\u000d\u000a      a 27% decreased chance of hospitalisation for recurrent stroke. These\u000d\u000a      findings confirmed the value of secondary prevention strategies to improve\u000d\u000a      stroke outcomes.\u000d\u000a    Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; 1998-2002)4,5\u000d\u000a    ASCOT was the largest study of hypertension ever conducted in Europe.\u000d\u000a      University of Glasgow researcher Professor Gordon McInnes played an\u000d\u000a      integral role in the design, direction and management of the ASCOT trial,\u000d\u000a      and contributed greatly to patient recruitment. The ASCOT BP-lowering arm\u000d\u000a      (ASCOT-BPLA), which was led by McInnes and recruited 19,257 patients with\u000d\u000a      hypertension, was the first study to perform a head-to-head comparison of\u000d\u000a      two different BP-lowering treatment regimens on cardiovascular (CVD)\u000d\u000a      outcomes, including stroke. One treatment regimen combined perindopril\u000d\u000a      with amlodipine (a calcium-channel blocker), while the other combined\u000d\u000a      atenolol (a β-blocker) and thiazide (a diuretic). The\u000d\u000a      perindopril-amlodipine combination provided superior risk reduction over\u000d\u000a      the atenolol-thiazide combination for multiple CVD parameters, including a\u000d\u000a      23% reduction in the composite end point of fatal and non-fatal stroke.\u000d\u000a      The ambulatory BP-monitoring (ABPM) sub-study of ASCOT-BPLA tested whether\u000d\u000a      this difference in CVD outcomes between the two treatment regimens could\u000d\u000a      be attributed to the method used to monitor, and if so, whether ABPM a\u000d\u000a      more useful predictor of CVD risk than a single-visit clinic measurement.\u000d\u000a      Ambulatory BP-monitoring involves regular BP measurements during normal\u000d\u000a      living and working conditions over a 24-hour period. ASCOT-ABPM revealed\u000d\u000a      that people with high night-time ABPM readings were at increased risk of a\u000d\u000a      CVD event, demonstrating incremental utility over clinic BP measures in\u000d\u000a      this group of patients.\u000d\u000a    The two ASCOT studies clearly demonstrated the benefit of reducing CVD\u000d\u000a      risk and mortality through: i) choice of BP-lowering regimen and ii)\u000d\u000a      qualifying ABPM over single-visit BP readings in influencing CVD risk,\u000d\u000a      especially stroke. These findings challenged long-held prescribing\u000d\u000a      recommendations that first-line therapy for hypertension should comprise a\u000d\u000a      diuretic plus β-blocker.\u000d\u000a    Losartan Intervention For Endpoint reduction in hypertension study\u000d\u000a          (LIFE; 1995-2001)6\u000d\u000a    LIFE was another breakthrough hypertension trial that investigated the\u000d\u000a      use of angiotensin II-receptor blockers (ARBs) among individuals with high\u000d\u000a      CVD risk. ARBs first became available in the mid-1990s; they display\u000d\u000a      similar benefits to ACE inhibitors but can potentially be offered as an\u000d\u000a      alternative treatment for patients unable to tolerate ACE inhibitors.\u000d\u000a      McInnes and Reid both played important roles in LIFE, with McInnes as the\u000d\u000a      Principal Investigator of the fastest recruiting site (Glasgow) in this\u000d\u000a      global multi-centre study. LIFE recruited 9,193 hypertensive patients and\u000d\u000a      compared the first ARB (losartan) with the established β-blocker,\u000d\u000a      atenolol. Treatment with losartan reduced both mortality and secondary CVD\u000d\u000a      events, including fatal and non-fatal stroke (25% reduction). LIFE was the\u000d\u000a      first study to directly compare the effects of ARBs and β-blockers on the\u000d\u000a      rates of stroke-related outcome, independent of BP reading.\u000d\u000a    Key Researchers: Kennedy Lees (Professor of Cerebrovascular\u000d\u000a      Medicine, 1985-present); John Reid (Regius Professor of Medicine and\u000d\u000a      Therapeutics, 1978-2010); Matthew Walters (Senior Lecturer in Medicine,\u000d\u000a      2003-2008; Reader, 2008-2010; Professor of Clinical Pharmacology,\u000d\u000a      2010-present); Gordon McInnes (Professor of Clinical Pharmacology,\u000d\u000a      1980-2007). Key positions held in clinical trials: PROGRESS: Lees\u000d\u000a      and Reid, members of Management Committee; regional Principal\u000d\u000a      Investigators. ASCOT: McInnes, Steering Committee; Lead for ASCOT-ABPM\u000d\u000a      sub-study; Regional Trial Coordinator for UK and Ireland. LIFE: McInnes\u000d\u000a      and Reid, Principal Investigators, Glasgow study centre. Key research\u000d\u000a        collaborators: PROGRESS: Stephen MacMahon and John Chalmers\u000d\u000a      (University of Sydney, Australia). ASCOT: Neil Poulter and Peter Sever\u000d\u000a      (Imperial College, London); Björn Dahlöf (Sahlgrenska University Hospital,\u000d\u000a      Sweden). LIFE: Dahlöf (as above).\u000d\u000a    "},{"CaseStudyId":"41141","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2921044","Name":"Germany"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000a    Roughly half the human population is infected with human cytomegalovirus\u000a      (HCMV). In general, HCMV is kept in check by healthy immune systems, but\u000a      is the major viral cause of birth defects and developmental disabilities\u000a      such as hearing loss, visual problems and other neural impairments. HCMV\u000a      is also the most significant complication in solid organ transplantation\u000a      (affecting 15-60% of patients) and a major complication of bone marrow\u000a      transplantation (20-35% of patients), leading to life-threatening disease\u000a      due to immune system impairment. HCMV also presents a significant risk to\u000a      patients with HIV\/AIDS. The care costs associated with these high-risk\u000a      groups in the USA alone have been estimated at over $4 billion per year.\u000a    Improved screening and management of HCMV\u000a      HCMV has poorly defined clinical symptoms, so diagnosis of congenital HCMV\u000a      or HCMV-related neurological, eye or respiratory illness (and monitoring\u000a      of immunosuppressed patients) is accomplished by laboratory testing.\u000a      Antibody-based qualitative tests struggle to distinguish between active\u000a      disease and latent infection. However, quantitative techniques, based on\u000a      polymerase chain reaction (PCR), amplify viral DNA markers in a specific\u000a      manner and in proportion to the amount of HCMV present. The amount of HCMV\u000a      correlates with the appearance of disease, and the quantity of virus in\u000a      blood or urine (the `viral load') provides a reliable way to identify HCMV\u000a      infection. Quantitative PCR-based tests can help clinicians decide when to\u000a      initiate treatment and how to manage HCMV with antivirals, the benefits of\u000a      which must be balanced against their toxicity.\u000a    Prior to research at the University of Glasgow, HCMV quantitative-PCR\u000a      assays developed in individual laboratories used different reference\u000a      standards (controls to check diagnostic assay performance), which often\u000a      included only parts of the viral genome or clinically irrelevant\u000a      laboratory strains. This lack of consistency meant that there was no\u000a      consensus agreement that could establish the viral load in the blood to\u000a      indicate when to start, stop or modify treatment. The International\u000a      Herpesvirus Management Forum recognised this in 2004, advising in a\u000a      statement that:\u000a    `an international quantitation standard distributed by an external\u000a        quality control organisation is required to compare studies using\u000a        different PCR-based systems and to facilitate patient management at\u000a        multiple care centres.'a\u000a    Merlin as a reference standard\u000a      WHO International Standards are the highest order of reference for\u000a      biological substances. They facilitate the calibration of secondary\u000a      references used in routine laboratory assays and provide a uniform measure\u000a      for comparison between laboratories, regardless of instrumentation or\u000a      reaction conditions. The development of the 1st WHO International Standard\u000a      for HCMV was initiated in June 2008, at a meeting of the Standardisation\u000a      of Genomic Amplification Techniques Clinical Diagnostics group at the\u000a      National Institute for Biological Standards and Control (NISBC), UK. The\u000a      participants agreed that an international standard for HCMV would come\u000a      from a well-characterised `laboratory-cultured strain similar to\u000a        circulating clinical isolates, and containing all potential PCR gene\u000a        targets.'b The work of the Glasgow groups, together with\u000a      Cardiff collaborators, to sequence and characterise Merlin, had\u000a      established Merlin as the prototype HCMV virus, so the participants\u000a      decided that `the candidate standard would comprise a whole virus\u000a        preparation of the prototype clinical HCMV strain Merlin.'c\u000a      The whole virus was chosen to standardise the complete assay process\u000a      (extraction of viral DNA and subsequent amplification).\u000a    This recommendation was adopted into the WHO biological standardisation\u000a      programme by the WHO Expert Committee. The Merlin strain was chosen\u000a      because it was `well characterised and more likely to represent a\u000a        clinical virus than other laboratory-adapted strains'.c\u000a      The standard was tested in a collaborative study coordinated by NISBC,\u000a      involving clinical and commercial laboratories in 14 countries that agreed\u000a      that the international standard represented a much needed advance. WHO\u000a      approved Merlin as the 1st WHO International Standard for CMV\u000a      in November 2010. The standard is held in the NIBSC as the nominated WHO\u000a      reference laboratory and distributed under the designation `09\/162'.d\u000a      Between January 2011 and July 2013, NIBSC shipped 409 vials of the\u000a      standard to 274 laboratories in 43 countries.e\u000a    Commercial and clinical impact\u000a      The International Standard is now used for calibration in commercial\u000a      quantitative-PCR assays by leading international biotechnology companies,\u000a      including Altona Diagnostics GmbH (Germany)f, Abbott Molecular\u000a      Inc. (USA)g, Argene\/bioMérieux SA (France)h and\u000a      Roche Diagnostics Ltd. (Switzerland).i In July 2012, the Roche\u000a      diagnostic assay was the first DNA test approved by the US Food & Drug\u000a      Administration for monitoring patients undergoing CMV antiviral therapy,\u000a      and was `based on information that included an assessment of the test's\u000a        accuracy in measuring viral load and its ability to accurately measure\u000a        variations in the amount of [human] CMV virus'.j This was\u000a      an important step forward to standardize treatment of HCMV disease, and\u000a      facilitated by the WHO International Standard. A calibrated assay produced\u000a      by Abbott Molecular Inc. was also approved for evaluation of the first\u000a      HCMV vaccine trial to reach phase III, undertaken by Astellas Pharma Inc.k\u000a    Clinical laboratories can adopt standardised commercial tests or\u000a      recalibrate their own to the WHO International Standard. The West of\u000a      Scotland Specialist Virus Centre, which was also one of the UK centres\u000a      involved in the WHO\/NISBC validation study, uses its own International\u000a      Standard- recalibrated test and performs 5,000 assays per year. The\u000a      majority of these tests are to monitor patients who are at high-risk of\u000a      HCMV infection or undergoing anti-viral treatment, and occasionally for\u000a      diagnostic purposes, to identify underlying cause for neurological, eye or\u000a      respiratory illness.l\u000a    The report of the international multicentre performance analysis of HCMV\u000a      tests stated that implementation of an international standard, together\u000a      with the availability of such standards in commercial tests, will improve\u000a      the reporting of meaningful clinical data on HCMV. This includes\u000a      monitoring of viral load, and establishing the cut-off values that\u000a      represent different disease stages in different patient groups. Thus, by\u000a      providing a means to enable validated and consistent PCR tests for HCMV,\u000a      research at the University of Glasgow has facilitated the crucial first\u000a      step towards improved `management guidelines that should significantly\u000a        clarify decision making for clinicians and improve infection outcomes in\u000a        at-risk patients.'m\u000a    ","ImpactSummary":"\u000a    Human cytomegalovirus (HCMV) infection can lead to life-threatening\u000a      disease in people with weakened immune systems. Research at the University\u000a      of Glasgow has genetically characterised a strain of HCMV, known as\u000a      `Merlin'. This research directly led to the adoption of this strain as the\u000a      first diagnostic standard by the World Health Organisation (WHO). The\u000a      standard has been distributed to 43 countries and is used in major\u000a      commercial diagnostic test kits, including the first standardised test\u000a      approved by the United States Food & Drug Administration. The standard\u000a      provides consistency across healthcare centres in relation to the\u000a      diagnosis of HCMV-associated disease and the clinical management of\u000a      patients treated with HCMV antiviral drugs.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2653822","Name":"Cardiff"}],"References":"\u000a    \u000a1. Tomasec, P. et al. Downregulation\u000a        of natural killer cell-activating ligand CD155 by human cytomegalovirus\u000a        UL141. Nat. Immunol. 2005; 6, 181-188 doi:10.1038\/ni1156.\u000a    \u000a\u000a2. Davison, A.J. et al. The\u000a        human cytomegalovirus genome revisited: comparison with the chimpanzee\u000a        cytomegalovirus genome. J. Gen. Virol. 2003; 84, 17-28\u000a      doi:10.1099\/vir.0.18606-0.\u000a    \u000a\u000a3. Bradley, A. et al. High-throughput\u000a        sequence analysis of variants of human cytomegalovirus strains Towne and\u000a        AD169. J. Gen. Virol. 2009; 90, 2375-2380\u000a      doi:10.1099\/vir.0.013250-0.\u000a    \u000a\u000a4. Dolan, A. et al. Genetic\u000a        content of wild type human cytomegalovirus. J. Gen. Virol.\u000a      2004; 85, 1301-1312 doi:10.1099\/vir.0.79888-0.\u000a    \u000a\u000a5. Human herpesvirus 5 strain Merlin, complete genome. National Center\u000a      for Biotechnology Information Reference Sequence: NC_006273.2 (link)\u000a    \u000a\u000a6. Gatherer, D. et al. High\u000a        resolution human cytomegalovirus transcriptome. Proc. Natl Acad.\u000a        Sci. USA 2011; 108, 19755-19760 doi:10.1073\/pnas.1115861108.\u000a    \u000a\u000a7. Stanton, R.J., et al. Reconstruction\u000a        of the complete human cytomegalovirus genome in a BAC reveals RL13 to be\u000a        a potent inhibitor of replication. J. Clin. Invest. 2010;\u000a      120, 3191- 3208 doi:10.1172\/JCI42955.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"7","Subject":"Immunology"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a    a. Razonable RR, Emery VC; 11th\u000a        Annual Meeting of the IHMF (International Herpes Management Forum).\u000a        Management of CMV infection and disease in transplant patients. 27-\u000a      29 February 2004. Herpes, 11, 77-86 (2004), p78.\u000a    b. Fryer J & Morris C. International\u000a        working group on the standardisation of genome amplification techniques\u000a        (SoGAT) for clinical diagnostics, NIBSC UK, 24-25 June 2008. (PDF,\u000a      p8)\u000a    c. Fryer, J.F., et al. and the Collaborative Study Group. A\u000a      report of the Expert Committee on Biological Standardization, Geneva, 18\u000a      to 22 October 2010. Collaborative\u000a        study to evaluate the proposed 1st WHO international standard for human\u000a        cytomegalovirus (HCMV) for Nucleic Acid Amplification (NAT)-Based Assays.\u000a    d. CMV\u000a        International Standard.\u000a    e. Data from the National Institute for Biological Standards and Control;\u000a      available on request.\u000a    f. Altona\u000a        RealStar® CMV PCR Kit 1.0, 2012 (p10)\u000a    g. Abbott\u000a        RealTime CMV\u000a    h. Argene\u000a        CMV R-gene®\u000a    i. Roche\u000a        COBAS® AmpliPrep\/COBAS® TaqMan® CMV\u000a    j. FDA\u000a        approval for Roche COBAS® AmpliPrep\/COBAS® TaqMan® CMV Test -\u000a      P110037 diagnostic assay based on Merlin standard.\u000a    k. Abbot\u000a        PCR assay based on Merlin standard used to monitor HCMV vaccine\u000a      trial\u000a    l. Consultant Clinical Scientist, Head of Molecular Development and\u000a      Specialist Typing, West of Scotland Specialist Virology Centre (available\u000a      on request)\u000a    m. Hirsch, H.H. et al. An\u000a        International Multicenter Performance Analysis of Cytomegalovirus Load\u000a        Tests. Clinical infectious diseases: an official publication of the\u000a        Infectious Diseases Society of America. Clin. Infect. Dis.\u000a      2012; 56, 367-373 \u000a    ","Title":"\u000a    Developing the first international diagnostic standard for human\u000a      cytomegalovirus\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Human cytomegalovirus (HCMV) is one of nine herpes viruses known to\u000a      infect humans. Work in Glasgow on the genomics of this pathogen was\u000a      initiated in the groups of Dr Andrew Davison and Prof Duncan McGeoch in\u000a      2001. This was taken forward latterly by Davison's group, with Dr Katarina\u000a      Balachova and Dr Derek Gatherer as key players. Davison has researched the\u000a      content, expression, function and evolution of herpesvirus genomes since\u000a      1976. He is a world leader in the genomics of these viruses, and his 121\u000a      research articles provide a frame of reference for much of the research\u000a      being conducted worldwide. The key work underpinning this case study\u000a      involved the characterisation of the genome of wild-type HCMV strain\u000a      Merlin.\u000a    Characterisation of a definitive HCMV strain\u000a      HCMV has the largest genome of the known human viruses. For decades,\u000a      researchers have grown (`passaged') laboratory strains of HCMV in human\u000a      tissue culture cells. However, such high- passage strains have mutated and\u000a      are now unrepresentative of original wild-type viruses. For example, they\u000a      have lost the capacity to evade the host immune response.1\u000a      Indeed, substantial subsets of genes have been deleted from the two most\u000a      widely used laboratory strains, AD169 and Towne.2,3 Davison's\u000a      and McGeoch's groups at Glasgow initiated a collaboration with Professor\u000a      Gavin Wilkinson (Cardiff Institute of Infection & Immunity, Cardiff\u000a      University), to characterise the wild-type HCMV genome using three\u000a      low-passage strains. The complete genome of one of these strains, known as\u000a      Merlin, was sequenced by the Glasgow groups, leading to the first\u000a      description of a clinically relevant HCMV genome.4 The Merlin\u000a      sequence has been designated the official reference for HCMV by the\u000a      National Center for Biotechnology Information, thereby providing a key\u000a      resource for medical, functional and diversity studies.5\u000a    Further characterisation of Merlin in Davison's group determined the HCMV\u000a      transcriptome. In 2011, this study produced the latest map of functional\u000a      protein-coding regions in the HCMV genome, and provided researchers with\u000a      the most complete information resource available.6\u000a    Generation of a stable source of HCMV\u000a      To derive a stable source of wild-type virus, Dr Baluchova (Glasgow) and\u000a      Dr Richard Stanton (Cardiff) jointly reported their generation and\u000a      characterisation of a bacterial artificial chromosome (BAC) containing the\u000a      Merlin strain genome, the structure and sequence of which was determined\u000a      by Davison's group.7 The few mutations present were repaired to\u000a      generate a BAC that recapitulated the wild-type Merlin genome. This\u000a      reagent is an important research and clinical tool: it provides a stable\u000a      source of HCMV genes; a means of generating genetically defined viruses in\u000a      perpetuity by transfection of BACs into human cell lines; and a tool for\u000a      characterising the virus further and contributing to vaccine development.\u000a      Merlin is now the most well characterised low- passage HCMV strain. The\u000a      Merlin BAC is the only current, manipulable source of wild-type HCMV.\u000a    Key University of Glasgow researchers: Dr Andrew Davison\u000a      (MRC Virology Unit, 1988-2013; Honorary Lecturer, 2000-2013), Dr Derek\u000a      Gatherer (MRC Senior Investigator Scientist, 2003- 2013), Dr Katarina\u000a      Baluchova (MRC Career Development Fellow, 2005-2010) and Prof Duncan\u000a      McGeoch (MRC Virology Unit, 1977-2010). Key external collaborators:\u000a      (Cardiff University): Prof Gavin Wilkinson (Professor, Cardiff\u000a      Institute of Infection & Immunity) and Dr Richard Stanton (Lecturer,\u000a      Cardiff Institute of Infection & Immunity)\u000a    The MRC virology Unit in Glasgow was one of the MRC's intramural units,\u000a      and all staff, including these key researchers, were employed by the MRC.\u000a      In 2010, the MRC-University of Glasgow Centre for Virus Research (CVR) was\u000a      established, bringing together the MRC virology Unit with University\u000a      virologists under a single management structure. The formal transfer of\u000a      MRC staff to the University of Glasgow took place on 1 May 2013.\u000a      Permission has been granted by HEFCE to include researchers within the\u000a      former MRC Virology Unit within the REF2014.\u000a    "},{"CaseStudyId":"41142","Continent":[],"Country":[],"Funders":[],"ImpactDetails":"\u000a    University of Glasgow research has exerted marked impact on patient care\u000a      by improving clinical\u000a      management and widening access to thrombolytic therapy.\u000a    International and national guidelines for AIS\u000a    Integral to the EMEA licensing conditions for alteplase, Lees proposed\u000a      the concept of a time-window-extension\u000a      study (ECASS III) to explore the wider use and benefits of alteplase among\u000a      patients with AIS.2 This study was instrumental in ensuring\u000a      that the EMEA extended the approved\u000a      timeframe for use of alteplase from 3 hours up to 4.5 hours (2011). The\u000a      SITS-MOST and ECASS\u000a      III studies are extensively cited as key supporting evidence directly\u000a      driving clinical guideline\u000a      recommendations that endorse the safe use of alteplase (rtPA).\u000a    \u000a      The 2008 ESO guidelinea states: \"intravenous rtPA (0.9\u000a          mg\/kg body weight, maximum 90\u000a          mg), with 10% of the dose given as a bolus followed by a 60-minute\u000a          infusion, is\u000a          recommended within 4.5 hours of onset of ischaemic stroke.\" (Class\u000a        I, Level A,; p53).\u000a      The 2009 joint American Stroke Association\/American Heart Association\u000a        (ASA\/AHA)\u000a        Science Advisoryb recommended that: \"rtPA should be\u000a          administered to eligible patients who\u000a          can be treated in the time period of 3 to 4.5 hours after stroke.\"\u000a        (Class I Recommendation,\u000a        Level of Evidence B; p2947).\u000a      The UK National Institute for Health Care and Excellence (NICE) 2012\u000a        review of\u000a        Technology Appraisal Guidance 122c advised: \"Alteplase is\u000a          recommended within its\u000a          marketing authorisation for treating acute ischaemic stroke in adults\u000a          if treatment is started\u000a          as early as possible within 4.5 hours of onset of stroke symptoms, and\u000a          intracranial\u000a          haemorrhage has been excluded by appropriate imaging techniques.\"\u000a        (1.1; p20).\u000a    \u000a    Other UK guidelines influencing treatment practice also align with\u000a      international recommendations\u000a      on the use of alteplase. For example, the 2008 Scottish Intercollegiate\u000a      Guidelines Network (SIGN)\u000a      Guidance 108 recommendation 2.4.1 (p4)d and the 2012 Royal\u000a      College of Physicians National\u000a      Clinical Guidelines for Stroke recommendations 4.6.1A (xiii) and 4.6.1B\u000a      (xiv).e\u000a    University of Glasgow researchers are internationally recognised in the\u000a      field of acute stroke care.\u000a      Professor Kennedy Lees has held key positions in clinical trials,\u000a      including the landmark ECASS III\u000a      study of alteplase (sections 2 and 3). Furthermore, as founding member of\u000a      the SITS-ISTR Steering\u000a      Committee and Chair of VISTA, Lees has driven the creation of patient\u000a      registries to aid on-going\u000a      assessment of the clinical benefits and safety of treatments for stroke.\u000a      Lees currently serves as\u000a      President elect of the European Stroke Organisation (ESO) and influences\u000a      European guideline\u000a      development strategy through chairmanship of this organisation's main\u000a      committees.\u000a    Audit of alteplase use by the NHS\u000a    Clinical guidelines represent the best available scientific evidence and\u000a      are considered the gold-standard\u000a      in directing clinical practice. The above revisions to the ESOa\u000a      and ASA\/AHAb guidelines\u000a      encouraged clinicians to adopt recommendations on the use of alteplase up\u000a      to 4.5 hours, even\u000a      though this recommendation was beyond the scope of the alteplase product\u000a      licence at the time\u000a      (EMEA only granting an extended use licence in 2011). The National\u000a      Sentinel Stroke Clinical Audit\u000a      reportf confirmed the influence of guidelines to encourage\u000a      wider use of alteplase. This audit of NHS\u000a      England, Wales and Northern Ireland showed an increased use of\u000a      thrombolysis (within 3 hours)\u000a      from 1.8% in 2008 to 5% in 2010. The Sentinel report also highlighted that\u000a      levels of alteplase\u000a      usage could be improved: 14% of eligible patients were sampled, with only\u000a      5% actually receiving\u000a      treatment. Nevertheless, the audit authors predicted that uptake of\u000a      thrombolysis would increase as\u000a      more centres provided acute stroke services and with the further education\u000a      of healthcare\u000a      professionals and the public. They forecasted that use of alteplase would\u000a      rise to 16% by increasing\u000a      the treatment window to 4.5 hours and to 26% if patents older than 80\u000a      years proved eligible.\u000a    Extending the treatment window for thrombolysis is cost effective\u000a    The 2012 NICE Technology Appraisalc considered whether giving\u000a      alteplase within 4.5 hours of\u000a      stroke was a cost-effective use of NHS resources. Within this assessment,\u000a      the manufacturer's\u000a      submission and appraisal committee were in agreement that ECASS III2\u000a      represented the `the only\u000a      directly relevant trial' and primary source (respectively) providing\u000a      evidence on the clinical-effectiveness\u000a      of an extension of the treatment window from 3 to 4.5 hours — the ECASS\u000a      III2 trial is\u000a      discussed in detail throughout sections 3 and 4 of this document. An\u000a      economic model containing\u000a      data from both SITS-MOST1 (background patient population) and\u000a      ECASS III2 (for the 3 to 4.5 hour\u000a      window effect) showed an incremental cost-effectiveness ratio (ICER, used\u000a      to evaluate the cost\u000a      impact of medical interventions) of £6,272 per quality adjusted life-year\u000a      (QALY, an indicator of\u000a      improved health). The NICE appraisal committee agreed that: \"alteplase\u000a        either dominated standard\u000a        care or had an ICER below £10,000 per QALY gained depending on the\u000a        time-to-treatment window\u000a        considered,\" concluding that treating AIS with alteplase within up\u000a      to 4.5 hours after onset of stroke\u000a      symptoms was a cost-effective use of NHS resources (4.10, p20). Therefore,\u000a      through their key\u000a      involvement in the ECASS III study, University of Glasgow researchers have\u000a      directly influenced the\u000a      expansion of NHS-funded treatment for stroke patients.\u000a    Acute stroke care saves lives\u000a    The provision of acute stroke care has benefitted patients by reducing\u000a      the risk of death following an\u000a      event. The National Sentinel Stroke Clinical Audit found that deaths\u000a      within the first 30 days after\u000a      stroke dropped from 24% in 2004 to 17% in 2010, while admissions to a\u000a      stroke unit rose from 46%\u000a      to 88% in the same period.f The 2013 Scottish Stroke Care Audit\u000a      states that deaths from stroke\u000a      among people aged less than 75 years dropped by 60% in the 15 years to\u000a      2010, exceeding the\u000a      original target of 50%.g Furthermore, death rates in Scotland\u000a      have continued to fall, with a 5.7%\u000a      reduction recorded between 2010 and 2011. NHS Scotland has also set\u000a      targets to ensure that\u000a      most stroke patients (90%) are admitted to a stroke unit within 24 hours\u000a      of being hospitalised. Early\u000a      access to dedicated stroke care increases the possibility that eligible\u000a      patients will receive alteplase\u000a      within the 4.5 window timeframe defined by University of Glasgow research.\u000a    Facilitating education and training\u000a    The need for appropriately trained healthcare professionals working\u000a      within specialist acute stroke\u000a      units and raising of public awareness about stroke were highlighted in the\u000a      ESOa (Class II, Level B\u000a      p7 and Class I, Level A; p17) and NICEh guidelines (1.4.1.1 and\u000a      1.4.1.2; p14-15). The University\u000a      of Glasgow has used its internationally-recognised research knowledge and\u000a      pivotal roles with\u000a      global collaborative groups to help foster best practice in stroke\u000a      treatment to ensure wider adoption\u000a      of thrombolysis treatment in accordance with guideline recommendations. In\u000a      collaboration with\u000a      Professor Gary Ford (Newcastle), Lees developed an education programme for\u000a      stroke specialist\u000a      registrars comprising seven thrombolysis training days, as well as master\u000a      classes to ensure more\u000a      widespread training of UK healthcare practitioners and to establish\u000a      thrombolysis treatment as the\u000a      standard of care. Through consultant training, the University of Glasgow\u000a      has helped to ensure that\u000a      every UK hospital offers a specialist stroke service with regional\u000a      thrombolysis.f\u000a    ","ImpactSummary":"\u000a    Approximately 152,000 strokes and 49,000 stroke-related deaths occur in\u000a      the UK every year; of\u000a      these, 85% are caused by blockage of a blood vessel in the brain (acute\u000a      ischaemic stroke). The\u000a      economic burden of stroke in the UK is estimated at £3.75bn with hospital\u000a      inpatient care\u000a      accounting for 82% this cost. Since the 1990s advances in thrombolytic\u000a      treatments (which dissolve\u000a      blood clots) have limited the extent of damage and subsequent impairment;\u000a      however their use has\u000a      been restricted due to ambiguity between stroke onset and stroke symptom\u000a      presentation.\u000a      University of Glasgow research has challenged the restrictions associated\u000a      with thrombolysis\u000a      treatment which has significantly influenced the wider use and\u000a      applicability of thrombolytic\u000a      treatment. This research has influenced new guideline recommendations and\u000a      emergency stroke\u000a      care patterns, through the implementation of dedicated acute stroke\u000a      centres, and contributed to the\u000a      on-going improvement in stroke survival rates.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Wahlgren N et al. Thrombolysis\u000a        with alteplase for acute ischaemic stroke in the Safe\u000a        Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST):\u000a        an observational\u000a        study. Lancet 2007; 369: 275-282\u000a      doi:10.1016\/S0140-6736(07)60149-4.\u000a    \u000a\u000a2. Hacke W et al. Thrombolysis\u000a        with altephase 3 to 4.5 hours after acute ischemic stroke. N\u000a        Engl\u000a        J Med. 2008; 359: 1317-1329 doi:10.1056\/NEJMoa0804656.\u000a    \u000a\u000a3. Lees et al. Time\u000a        to treatment with intravenous alteplase and outcome in stroke: an\u000a        updated\u000a        pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet\u000a      2010; 375: 1695-1703\u000a      doi:10.1016\/S0140-6736(10)60491-6\u000a    \u000a\u000a4. Wahlgren N et al. Thrombolysis\u000a        with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR):\u000a        an observational study. Lancet 2008; 372: 1303-1309\u000a      doi:10.1016\/S0140-\u000a      6736(08)61339-2.\u000a    \u000a\u000a5. Weimar C et al. The\u000a        Virtual International Stroke Trials Archive (VISTA): results and impact\u000a        on\u000a        future stroke trials and management of stroke patients. Int J\u000a        Stroke. 2010; 5: 103-109\u000a      doi:10.1111\/j.1747-4949.2010.00414.x.\u000a    \u000a\u000a6. Mishra NK et al. Thrombolysis\u000a        in very elderly people: controlled comparison of SITS\u000a        International Stroke Thrombolysis Registry and Virtual International\u000a        Stroke Trials Archive. BMJ\u000a      2010; 341: c6046 doi:10.1136\/bmj.c6046\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000a    a. ESO\u000a        updated guidelines for management of ischaemic stroke and TIA 2008.\u000a      (Recommendation Class I, Level B p7; education Class I, Level A p17)\u000a    b. ASA\/AHA\u000a        Science Advisory on expansion of time window for treatment of acute\u000a        ischaemic\u000a        stroke 2009. doi: 10.1161\/STROKEAHA.109.192535 (p2947)\u000a    c. \u000a        NICE technology appraisal 264: Alteplase for treating acute ischaemic\u000a        stroke (review of\u000a        technology appraisal guidance 122) 2012. (Recommendation 1.1, p20)\u000a    d. SIGN 108 guidance on\u000a        management of patients with stroke or TIA 2008. (Recommendation\u000a      2.4.1, p4)\u000a    e. RCP\u000a        national clinical guidelines for stroke 2012. (Recommendations 4.1.6\u000a      A and B, pxiii-xiv)\u000a    f. National\u000a        Sentinel Audit for stroke 2010. (Thrombolysis use, p34; specialist\u000a      stroke centres, p16-\u000a      52)\u000a    g. Scottish\u000a        Stroke Care Audit, 2013 (p1 and 6)\u000a    h. NICE\u000a        CG68 guidance on diagnosis and initial management of acute stroke and\u000a        TIA 2008.\u000a      (Recommendations 1.4.1.1 and 1.4.1.2, p14-15)\u000a    \u000a    ","Title":"\u000a    Expanding treatment options and management of acute ischaemic stroke\u000a    ","UKLocation":[{"GeoNamesId":"2641673","Name":"Newcastle-upon-Tyne"},{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2641364","Name":"Northern Ireland"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Before the late 1990s, no drug treatment was available for acute\u000a      ischaemic stroke (AIS) and only\u000a      the resulting complications of this condition were managed. Considerable\u000a      progress has since been\u000a      made through the use of thrombolytic agents; these drugs dissolve blood\u000a      clots and reduce the\u000a      extent of damage and physical impairment. Nevertheless, use of\u000a      thrombolysis is restricted\u000a      depending on i) the time between stroke onset and hospitalisation and ii)\u000a      the patient's\u000a      risk\/susceptibility of brain haemorrhage. University of Glasgow\u000a      researchers have been at the\u000a      forefront of stroke research since the late 1980s, holding central\u000a      positions (outlined at the end of\u000a      section 2) in the design, recruitment and management of landmark clinical\u000a      trials and collaborative\u000a      research registries of thrombolytic therapy.\u000a    Clinical trials confirm the safety, efficacy and treatment window\u000a          of alteplase\u000a    The thrombolytic drug, alteplase, had been shown to be beneficial when\u000a      used within 3 hours of\u000a      stroke. Although this drug was licenced in North America for AIS by the\u000a      late 1990s, concerns\u000a      remained in Europe regarding the routine use of alteplase owing to the\u000a      short time-to-treatment\u000a      window and potential side effects (bleeding within the brain,\u000a      intracerebral haemorrhage). The\u000a      European Medicines Evaluation Agency (EMEA) granted a licence for\u000a      alteplase in 2002; however,\u000a      this licence was conditional upon the manufacturer implementing an\u000a      observational safety study and\u000a      a time-extension trial.1,2\u000a    Safe Implementation of Thrombolysis in Stroke Monitoring Study\u000a        (SITS-MOST; 2002-2006)\u000a      SITS is an internet-based, academic-driven, non-profit international\u000a      collaboration of clinicians that\u000a      aims to accelerate clinical trials and certify excellence in treatment and\u000a      prevention of stroke. SITS-MOST\u000a      was designed to assess the safety profile of alteplase in routine clinical\u000a      practice within a 3-hour\u000a      window and offer reassurance that results from other studies conducted\u000a      internationally could\u000a      be replicated.1 University of Glasgow researcher Professor\u000a      Kennedy Lees took a lead role in the\u000a      direction and conduct of this 285-centre study. The findings of SITS-MOST\u000a      confirmed both the\u000a      safety and efficacy of alteplase. In addition, the results obtained were\u000a      comparable regardless of the\u000a      experience level of individual participating centres, establishing the\u000a      potential for wider use of\u000a      alteplase in clinical practice.\u000a    European Cooperative Acute Stroke Study III (ECASS III; 2003-2007)\u000a      ECASS III evaluated whether the time window for alteplase use could be\u000a      extended beyond the\u000a      approved 3 hours.2 Lees was integral to the design of ECASS\u000a      III, while Professor Matthew Walters\u000a      led the University of Glasgow participating study centre. ECASS III was\u000a      the first study to support\u000a      the safety and efficacy of using alteplase within an extended treatment\u000a      window (up to 4.5 hours\u000a      after stroke). A pooled data analysis of several additional trials led by\u000a      Lees validated the positive\u000a      risk-benefit ratio of alteplase treatment within this timeframe.3\u000a    Collaborative international registries advance best practice for\u000a          stroke care\u000a    SITS-International Stroke Thrombolysis Registry (SITS-ISTR;\u000a        2000-present)\u000a      SITS-ISTR was instituted by the EMEA as part of the conditional licensing\u000a      procedure for alteplase.\u000a      As such, SITS-ISTR was instrumental in verifying the safety and efficacy\u000a      of this drug, leading to the\u000a      EMEA granting an unconditional licence.4 SIT-ISTR audits the\u000a      safety and efficacy of routine\u000a      therapeutic use of thrombolysis; the registry hosts 1,369 participating\u000a      centres and holds data on\u000a      97,119 patients. Currently, SITS-ISTR supports eight on-going studies.\u000a    Virtual International Stroke Trials Archive (VISTA; 2001-present)\u000a      VISTA is an academic-led venture that pools data from completed stroke\u000a      clinical trials\u000a      internationally; the archive provides access to anonymised data for\u000a      testing hypotheses and novel\u000a      exploratory analyses that inform clinical trial design.5 Lees\u000a      played a prominent role in a key study,\u000a      using the VISTA and SITS registries, which examined the efficacy of\u000a      alteplase among older\u000a      patients (≥80 years).6 The study findings confirmed that the\u000a      association between thrombolysis and\u000a      improved treatment outcome was maintained in this age group, potentially\u000a      extending the use of\u000a      alteplase to include the elderly.\u000a    Key University of Glasgow researchers: Kennedy R Lees (Professor\u000a      of Cerebrovascular\u000a      Medicine, 1985-present); Matthew R Walters (Senior Lecturer in Medicine,\u000a      2003-2008; Reader,\u000a      2008-2010; Professor of Clinical Pharmacology, 2010-present); Keith W Muir\u000a      (SINAPSE Chair of\u000a      Clinical Imaging, 2008-present).\u000a    Key positions held (clinical trials and registries): Kennedy R\u000a      Lees: Chair, Data and Safety\u000a      Monitoring Board (ECASS III); Founding and Executive Steering Committee\u000a      member (SITS-ISTR);\u000a      Chair (VISTA). Matthew R Walters: Principal Investigator for Glasgow study\u000a      centre (ECASS III).\u000a      Keith W Muir: Investigator (ECASS III).\u000a    Key research collaborators: SITS-MOST: Nils Wahlgren (Karolinska\u000a      University Hospital,\u000a      Sweden) and Gary Ford (Newcastle General Hospital, UK). ECASS III: Werner\u000a      Hacke (University\u000a      of Heidelberg, Germany).\u000a    "},{"CaseStudyId":"41144","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Statins are one of the most widely prescribed medications in the world.\u000a      In 2011 an estimated 27\u000a      million people in the UK and USA alone took statins to control their blood\u000a      cholesterol levels. Whilst\u000a      their clinical benefit in reducing the risk of vascular disease is\u000a      irrefutable, there is a need for\u000a      improved guidance on which patient populations should be given the drugs\u000a      and for a better\u000a      understanding of the side effects associated with statins.\u000a    Influencing clinical guidelines to stratify patients for statin\u000a          therapy \u000a    University of Glasgow findings on the accurate assessment of baseline\u000a      lipid levels, prescription of\u000a      statins to patients with rheumatoid arthritis and diabetes as a potential\u000a      side effect of statins\u000a      (references 1-4 in section 2) have been cited as the leading evidence to\u000a      support recommendations\u000a      in a number of international clinical guidelines and consensus statements\u000a      on statins published\u000a      since 2008. These include guidelines from some of the most high-profile\u000a      and influential\u000a      organisations in the clinical arena, including the European Society of\u000a      Cardiology (ESC; estimated\u000a      professional membership of over 80,000), the European League Against\u000a      Rheumatism (EULAR;\u000a      encompassing 45 member societies throughout Europe) and the American\u000a      Diabetes Association\u000a      (ADA; the leading US diabetes organisation).\u000a    \u000a      \u000aCardiovascular risk assessment: The 2011 joint ESC and European\u000a        Atherosclerosis Society\u000a        (EAS) guidelines on the management of dyslipidaemiasa cite\u000a        the 2009 ERFC study as the\u000a        single evidence source to support their recommendation for the potential\u000a        use of apolipoproteins\u000a        as alternative markers to total cholesterol (and the high and low\u000a        density forms) for assessing\u000a        cardiovascular risk. However, the paper clearly shows that apoproteins\u000a        give equal but not\u000a        superior information to routine lipids, an important clinical\u000a        interpretation of the result.\u000a      \u000aRheumatoid arthritis patients: The 2010 EULAR guidelines on\u000a        cardiovascular risk management\u000a        in patients with rheumatoid arthritisb cite the 2004 TARA\u000a        paper as part of the evidence base for\u000a        recommendation number 7, which promotes the use of statins to address\u000a        the increased\u000a        cardiovascular risk in rheumatoid arthritis patients. There are an\u000a        estimated 3 million adults\u000a        living with rheumatoid arthritis in Europe and these guidelines form the\u000a        first set of clinical\u000a        recommendations in the world to direct statin allocation in this patient\u000a        group.\u000a      \u000aDiabetes risk: The ADA 2013 position statement on standards of\u000a        medical care in diabetesc, the\u000a        International Atherosclerosis Society 2013 position paper on global\u000a        recommendations for the\u000a        management of dyslipidaemiad and the 2011 joint ESC\/EAS\u000a        guidelines on the management of\u000a        dyslipidaemiasb all cite the Glasgow 2010 Lancet and\u000a        2011 JAMA papers as the primary\u000a        sources to acknowledge that statins carry a small, dose-dependent\u000a        increase in diabetes risk.\u000a        Each of these statements is in harmony with the Glasgow conclusions in\u000a        recommending statin\u000a        use given that the cardiovascular benefit far outweighs the diabetes\u000a        risk. The impact of these\u000a        statements highlights the diabetes risk to both physicians (who should\u000a        now check glycaemia\u000a        parameters before and after prescribing statins) and patients (who\u000a        should be told that lifestyle\u000a        changes will also help mitigate against any increased diabetes risk).\u000a    \u000a    Directly motivating revised statin labelling and product\u000a          information to inform patients of\u000a          diabetes risk\u000a    In direct response to the 2010 Lancet paper, which demonstrated\u000a      the small, dose-dependent\u000a      increase in risk of diabetes in patients treated with statins, the US Food\u000a      and Drug Administration\u000a      (FDA) and the European Medicines Agency (EMA) both revised the mandatory\u000a      labelling on all\u000a      statin drugs.\u000a    \u000a      \u000aFDA: In February 2012, the FDA released a drug\u000a          safety communicatione, noting reports of\u000a        increased blood sugars and haemoglobin A1 in patients treated with\u000a        statins with the Glasgow\u000a        2010 Lancet paper cited in the evidence base. Consequently, the\u000a        adverse event labelling for\u000a        statins was revised to include the potential for the drugs to increase\u000a        the risk of diabetes; this\u000a        information is distributed within every packet of statins prescribed in\u000a        the US.\u000a      \u000aEMA: The Glasgow 2010 Lancet paper was the catalyst for\u000a        a joint EMA, Heads of Medicines\u000a        Agencies and Pharmacovigilance Working\u000a          Party reviewf of 130 publications which concluded\u000a        that:\u000a      `[Statins] may increase the risk of [new onset diabetes] in patients\u000a          already at risk of developing\u000a          this disease, but [that] overall the risk-benefit balance remains\u000a          clearly positive ... A warning\u000a          should therefore be included in the product information of all\u000a          [statins] authorised in the EU ...\u000a          The warning should state that patients at risk (i.e. those with\u000a          fasting glucose 5.6 - 6.9 mmol\/L,\u000a          body mass index > 30 kg\/m2, raised\u000a          triglycerides or hypertension) should be monitored both\u000a          clinically and biochemically according to national guidelines.'\u000a      In March 2012, the EMA formally endorsed these conclusions and\u000a        implemented changes to\u000a        add diabetes risk to the adverse reaction section of both the Summary\u000a          of Product\u000a          Characteristics (new class warning sections 4.4 and 4.8) and package\u000a          leaflets (sections 2 and\u000a          4) for all statinsg; the wording is also published on\u000a        their website. This change in safety labelling\u000a        is communicated to every recipient of statins in all 27 member states of\u000a        the EMA.\u000a    \u000a    Both the FDA and EMA qualified these amendments to safety labelling by\u000a      advising that statins\u000a      remain the recommended therapy for cholesterol lowering due to their\u000a      overwhelming benefits on\u000a      vascular risk reduction.\u000a    Informing patients and health professionals regarding\u000a          statin-related diabetes risk\u000a    The changes to statin safety labelling have been communicated to both\u000a      patients and health\u000a      professionals via press release statements and media articles that\u000a      coincided with the revised\u000a      safety announcements in February 2012. The FDA published consumer safety\u000a      announcements on\u000a      their websites to raise patient awareness of the issueh and\u000a      there was significant press coverage,\u000a      including that by Reuters\u000a      and Medscape.k,l\u000a      In the UK, the revisions to safety labelling were\u000a      highlighted by the Medicines and Healthcare products Regulatory Agency\u000a      (MHRA)i and added as a\u000a      side effect in the current British National Formulary (BNF) lipid\u000a        lowering section (2.12) on statinsj to\u000a      ensure that clinicians are informing patients appropriately.\u000a    Consequently, the slight increase in diabetes risk with statin therapy\u000a      has highlighted the need for\u000a      clinicians to monitor blood glucose and haemoglobin A1C levels in patients\u000a      who are at high pre-\u000a      existing risk of developing diabetes before and after commencement of\u000a      statin therapy.\u000a      Furthermore, it has emphasised the responsibility of patients to maintain\u000a      lifestyle changes (diet,\u000a      weight reduction and increased exercise) to mitigate this small risk while\u000a      taking statins. These\u000a      messages are now being widely disseminated to the clinical community.m\u000a    ","ImpactSummary":"\u000a    Over the past ten years, the prescription of cholesterol-lowering statins\u000a      has soared and they are\u000a      now the most prescribed drugs in the UK and the US. However, this has\u000a      raised concerns about\u000a      inappropriate prescribing. University of Glasgow research has been pivotal\u000a      in addressing this issue\u000a      and has triggered revision of major international guidelines to stratify\u000a      patients in the general\u000a      population for statin therapy and guide statin use in the rheumatoid\u000a      arthritis patient population. The\u000a      identification of a statin-associated risk for diabetes prompted the\u000a      European Medicines Agency and\u000a      the US Food & Drug Administration to revise safety labelling for all\u000a      classes of statins. This risk is\u000a      now communicated to the 27 million patients in the UK and US who are\u000a      prescribed statins.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Emerging Risk Factors Collaboration et al. Major\u000a        lipids, apolipoproteins, and risk of vascular\u000a        disease. JAMA 2009; 11;302(18):1993-2000. doi:\u000a      10.1001\/jama.2009.1619\u000a    \u000a\u000a2. McCarey\u000a        DW, et al. Trial\u000a        of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind,\u000a        randomised placebo-controlled trial. Lancet 2004;\u000a      19;363(9426):2015-21. doi:10.1016\/S0140-6736(04)16449-0\u000a    \u000a\u000a3. Sattar N, et al. Statins\u000a        and risk of incident diabetes: a collaborative meta-analysis of\u000a        randomised\u000a        statin trials. Lancet 2010; 27;375(9716):735-42.\u000a      doi:10.1016\/S0140-6736(09)61965-6\u000a    \u000a\u000a4. Preiss D, et al. Risk\u000a        of incident diabetes with intensive-dose compared with moderate-dose\u000a        statin therapy: a meta-analysis. JAMA 2011;\u000a      22;305(24):2556-64. doi: 10.1001\/jama.2011.860.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"}],"Sources":"\u000a    Clinical guidelines and consensus statements\u000a    a. ESC\/EAS\u000a        guidelines for the management of dyslipidaemias (2011):\u000a      Recommendation for\u000a      apolipoprotein measurements as alternative markers (reference 1 in section\u000a      2 is cited as\u000a      reference 42, p1780&1782, Table 5) and recognition of increased\u000a      diabetes incidence with\u000a      statins but advocating their use (reference 3 in section 2 is cited as\u000a      reference 101 in this\u000a      paper).\u000a    b. EULAR\u000a        evidence-based recommendations for cardiovascular risk management in\u000a        patients with\u000a        rheumatoid arthritis and other forms of inflammatory arthritis (2010\u000a        [Online 2009]). (reference 2\u000a      in section 2 is cited as reference 78 on page 4, recommendation number 7).\u000a    c. ADA\u000a        Position Statement: Standards of medical care in diabetes - 2013 Diabetes\u000a          Care January\u000a        2013 36:S11-S66; Recognition of increased diabetes incidence with\u000a      statins, while still\u000a      advocating their use (reference 3 in section 2 is cited as reference 290).\u000a    d. International\u000a        Atherosclerosis Society 2013 Position Paper: global recommendations for\u000a        the\u000a        management of dyslipidemia. Recognition of increased diabetes\u000a      incidence with statins but\u000a      advocating their use (references 3 and 4 in section 2 are cited on page\u000a      9).\u000a    Revised safety labelling for statins\u000a    e. FDA drug\u000a        safety communication: important safety label changes to\u000a        cholesterol-lowering statin\u000a        drugs. 28 Feb 2012.\u000a    f. Pharmacovigilance Working Party. December 2011 plenary meeting. Monthly\u000a        report issue no.\u000a        1112.\u000a    g. HMG-CoA\u000a        reductase inhibitors (atorvastatin, fluvastatin, lovastatin,\u000a        pravastatin, simvastatin,\u000a        pitavastatin, rosuvastatin) and safety the risk of new onset\u000a        diabetes\/impaired glucose\u000a        metabolism. Agreed by PhVWP March 2012.\u000a    h. FDA Consumer health information. FDA\u000a        expands advice on statin risks. Feb 2012\u000a    i. MHRA\u000a        safety update. Statins risk of hyperglycaemia and diabetes. Drug Safety\u000a        Update 5, issue\u000a        6 January 2012.\u000a    j. BNF lipid\u000a        lowering information (login required, PDF available on request)\u000a    Media coverage of revised labelling for statins\u000a    k. Reuters. FDA\u000a        adds diabetes, memory loss warnings to statins. Feb 28 2012\u000a    l. Medscape. FDA\u000a        adds warnings to statin label Feb 28 2012\u000a    m. Goldfine AB. Statins:\u000a        is it really time to reassess benefits and risks? N Engl J Med.\u000a      2012;\u000a      366(19):1752-5. doi: 10.1056\/NEJMp1203020.\u000a    \u000a    ","Title":"\u000a    Statin Therapy: Patient Selection, Clinical Guidelines and revision of\u000a      safety\u000a      labelling\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Raised levels of cholesterol are linked to an increased risk of vascular\u000a      disease, such as heart\u000a      attack and stroke. The clinical benefit of cholesterol-lowering statins in\u000a      reducing the risk of vascular\u000a      disease has been demonstrated through a vast number of randomised clinical\u000a      trials over the past\u000a      20 years. However these trials have been carried out with different\u000a      patient populations, used\u000a      different types of statin and yielded variable data relating to side\u000a      effects. The University of Glasgow\u000a      metabolic medicine group has expertise in conducting detailed\u000a      meta-analyses of existing trial and\u000a      cohort data to answer well-defined and clinically relevant questions.\u000a    Lipid levels can be measured non-fasting as a marker of vascular\u000a          risk\u000a    Lipid levels have traditionally been measured in blood taken from\u000a      patients who have fasted for 12\u000a      hours. However, there was widespread uncertainty as to which groups of\u000a      lipids to assess and\u000a      whether measuring fasting or non-fasting lipids made a difference to the\u000a      accuracy of predicting\u000a      vascular risk. University of Glasgow researchers, Prof Naveed Sattar and\u000a      Prof Chris Packard were\u000a      senior investigators in the Emerging Risk Factor Collaboration (ERFC)\u000a      project, which examined\u000a      individual records of 302,430 people without initial vascular disease from\u000a      68 long-term prospective\u000a      studies (including two Glasgow trials) linking the results to over 10,000\u000a      cardiovascular events.\u000a      Sattar and Packard provided essential clinical interpretation and\u000a      analytical input to the results and\u000a      strongly influenced the final conclusions of the paper. The results,\u000a      published in JAMA in 20091,\u000a      suggested that lipid assessment can be simplified by measuring the levels\u000a      of either: (i) total\u000a      cholesterol and a form of cholesterol called high-density lipoprotein\u000a      cholesterol, or (ii)\u000a      apolipoproteins (the protein part of the major forms of cholesterol) and\u000a      that neither required\u000a      measurement of another blood lipid, triglyceride. The key conclusion of\u000a      the study was that patients\u000a      do not need to fast to enable accurate prediction of their cardiovascular\u000a      risk.\u000a    Statins safely lower cholesterol in rheumatoid arthritis patients\u000a    With the growing recognition in the mid to late 1990s that certain\u000a      sub-populations had an increased\u000a      risk of cardiovascular disease, University of Glasgow researchers Prof\u000a      Iain McInnes, Prof Naveed\u000a      Sattar and Prof Ian Ford conceived and undertook the first randomised\u000a      trial of the use of a statin in\u000a      patients with rheumatoid arthritis. This patient sub-population is at\u000a      increased vascular risk because\u000a      of chronic activation of their immune systems. The trial of atorvastatin\u000a      in rheumatoid arthritis\u000a      (TARA) was a double-blind, randomised, placebo-controlled trial that ran\u000a      from 2000 to 2004 and\u000a      was published in 2004 in The Lancet.2 The statin not\u000a      only lowered cholesterol in patients with\u000a      rheumatoid arthritis, but it did so safely, with no adverse liver effects.\u000a      In addition, the patients on\u000a      atorvastatin seemed to experience an improvement in their\u000a      rheumatoid-associated symptoms.\u000a    Statins are associated with a small but dose-dependent risk of\u000a          diabetes \u000a    As trials examining whether statin use was associated with an increased\u000a      risk of diabetes had\u000a      provided mixed results, University of Glasgow staff Prof Sattar, Dr David\u000a      Preiss and Prof Ford\u000a      designed and led an exhaustive meta-analysis that was published in The\u000a        Lancet in 20103. The\u000a      collaborative multi-centre study collated all the available trial data\u000a      (from 13 trials and more than\u000a      91,000 patients) and wrote an original analysis plan for seven of the\u000a      trials for which new-onset\u000a      diabetes data had been collected but not examined. The data were analysed\u000a      to determine diabetes\u000a      risk and showed that risk did increase with use of statins, albeit\u000a      modestly (9% increased relative\u000a      risk)3. Preiss and Sattar also led a meta-analysis of diabetes\u000a      risk in five trials that compared the\u000a      use of high doses of statins with the use of moderate doses. Published in\u000a      JAMA in 2011, the\u000a      investigators showed that higher dose statins increased diabetes risk more\u000a      than statins prescribed\u000a      at moderate doses, thereby indicating that the increased risk is\u000a      dose-dependent4. Importantly, both\u000a      studies concluded that the risk of statin-induced diabetes was low\u000a      compared with the\u000a      cardiovascular benefits of statins and that this should not affect the\u000a      clinical practice of prescribing\u000a      statins to individuals at increased risk of cardiovascular disease or\u000a      those with existing disease.\u000a    Key University of Glasgow researchers: Naveed Sattar\u000a      (Professor of Metabolic Medicine, 1999-\u000a      present); Chris Packard (Honorary Professor [clinical biochemistry],\u000a      1993-present); Iain McInnes\u000a      (Professor of Experimental Medicine, 1993-2010; Muirhead Chair of\u000a      Medicine, 2010-present);\u000a      David Preiss (Clinical Research Fellow, 2008-2012; Clinical Senior\u000a      Lecturer 2012-present); Ian\u000a      Ford (Professor of Biostatistics, 1998-present).\u000a    Key collaborators and roles: ERFC members: John\u000a      Danesh (study supervisor), Emanuele Di\u000a      Angelantonio and Nadeem Sarwar; all University of Cambridge (Sattar and\u000a      Packard held writing\u000a      committee positions). Diabetes risk: Kausik Ray, University of\u000a      Cambridge (contributed equally to\u000a      the study alongside Sattar, Ford and Preiss).\u000a    "},{"CaseStudyId":"41146","Continent":[{"GeoNamesId":"6255148","Name":"Europe"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2963597","Name":"Ireland"}],"Funders":[],"ImpactDetails":"\u000a    Growth charts are used universally in hospitals and baby clinics to\u000a      monitor child health and are also important to parents seeking reassurance\u000a      that their child is healthy and thriving. However, growth charts are\u000a      complex clinical tools that can mislead as well as inform. Successful,\u000a      accurate use of charts relies on robust design and unambiguous\u000a      instructions for their use. Professor Wright's research has supported the\u000a      adoption of the WHO Child Growth Standard (2006) in the UK. Moreover, it\u000a      has initiated the development of improved Child Growth Charts for the UK,\u000a      which are more comprehensible to health staff and parents. In addition,\u000a      this work has provided improved professional guidance and training to\u000a      health professionals involved in weighing and measuring babies and\u000a      children as well as identifying overweight and obesity.\u000a    Introduction of new child growth charts\u000a    The new early years child growth charts were launched in May 2009\u000a      (England)a and January 2010 (Scotland).b A set of A5\u000a      charts is currently distributed to those caring for every newborn in the\u000a      UK through their Personal Child Health Record. The A4 clinical charts are\u000a      also widely used in hospitals and primary care, with 500,000 copies\u000a      distributed between April 2012 and April 2013.c In May 2012,\u000a      charts for school-age children were launched.d By April 2013\u000a      around 300,000 copies had been distributed to NHS Trusts and Boards.c\u000a      In June 2013 a specialist Childhood and Puberty Close Monitoring growth\u000a      chart and a Body Mass Index (BMI) chart were published to complete the\u000a      set.e\u000a    The UK child growth charts that have been developed by Wright have been\u000a      endorsed by, the Department of Health in England,a the Scottish\u000a      Government,b the Royal College of Nursing (where they have been\u000a      incorporated into new guidance on measuring children)f, the\u000a      British Dietetic Association,g the National Child Birth Trusth\u000a      and the Breast Feeding Network.i They are also being used\u000a      internationally, to assess around 60,000 children born each year in New\u000a      Zealand since 2010 and around 72,000 children born each year in Ireland\u000a      since 2011.j,k The charts and associated educational material\u000a      are free to download and there were over 162,000 visits to the RCPCH\u000a      growth chart webpage in the year up to July 2013 alone. The charts can be\u000a      printed locally and have also been used in developing countries, such as\u000a      Pakistan.l\u000a    Improved information for parents\u000a    For the first time, the accompanying instructions for parent-held child\u000a      growth charts were explicitly aimed at parents, and parent groups were\u000a      actively involved in drafting them. These instructions inform a section on\u000a      growth in `Birth to Five' (2009), a publication by the UK Department of\u000a      Health that was distributed to all new parents in England in the years\u000a      2009-2011, which is now available to download on the Department of Health\u000a      website. The book is still provided freely in print and online from the\u000a      public health departments of Wales and Northern Ireland.m\u000a    The new UK child growth charts differ substantially from previous charts\u000a      in terms of their layout and graphic presentation. Discussion with focus\u000a      groups of parents revealed that parents tend to expect all `normal'\u000a      children to grow close to the 50th centile line, so the new charts place\u000a      less emphasis on the 50th centile and encourage parents to understand the\u000a      wide range of normal stature. Moreover, parents often want to know how\u000a      tall their child will be as an adult, and while doctors use parent's\u000a      height to assess whether growth is within expected limits, the\u000a      calculations required for this are complex and not always accurate. For\u000a      this reason, the new charts incorporated a new scale for predicting adult\u000a      height, designed by Wright and Cole, which is quicker to use and\u000a      statistically more valid than previous methods.\u000a    Training of health professionals and improved clinical practice\u000a    The new guidance on completing RCPCH growth charts addressed the many\u000a      aspects of the old charts that were poorly understood and inconsistently\u000a      used by health visitors and paediatricians. In particular, Wright and\u000a      colleagues had observed discrepancies in the plotting of varying gestation\u000a      at birth and the assessment of puberty. As a result they were able to\u000a      develop carefully worded, instructions, which were tested in parallel with\u000a      the design, and which for the first time provided authoritative,\u000a      evidence-based guidance on the use of charts and growth monitoring. Wright\u000a      then led the development and evaluation of more detailed supporting\u000a      educational materials, working with Eileen Birks (University of\u000a      Northumbria) and Gary Butler (University College London Hospital).n\u000a    These have since been incorporated into e-learning packages for NHS staff\u000a      that are currently in use throughout the UK.o Wright also\u000a      organised and participated in a number of `train the trainers' events in\u000a      2009-2010 mainly attended by Nurse trainers: three in London, four English\u000a      regional events and four in Scotland. In 2010, the Royal College of\u000a      Nursing issued guidance on standards for measuring children to nurses\u000a      working with infants and young people in the acute care setting children\u000a      which reference the use of the new charts.f\u000a    Making chart use easier\u000a    The charts incorporate novel tools that are simple and accurate to use.\u000a      Health staff have tended not to use BMI to assess whether a child is\u000a      overweight as a matter of routine, as calculating BMI requires the use of\u000a      a calculator and separate BMI charts. The new charts therefore have a BMI\u000a      centile `look-up' (designed by Cole) that allows the BMI centile to be\u000a      identified without the need for extra calculation. The 2-18 charts also\u000a      have a mid-parental height (average of father's and mother's height)\u000a      calculator, designed previously by Wright, which avoid the need for\u000a      complex calculation, as well as their new adult height predictor described\u000a      above.\u000a    ","ImpactSummary":"\u000a    Every child born in the UK receives a set of growth charts with their\u000a      Personal Child Health Record. These charts have been developed and\u000a      designed by Professor Charlotte Wright, University of Glasgow. Growth\u000a      monitoring is fundamental for the assessment of health and the\u000a      identification of growth abnormalities in children, and growth charts are\u000a      used to interpret these measurements. The design of child growth charts\u000a      and the instructions for their use influences perceptions of normality and\u000a      drives screening activity for conditions such as failure to thrive or\u000a      obesity. The newly developed UK child growth charts more accurately\u000a      reflect healthy growth patterns than previous versions, and feature a\u000a      range of design improvements and evidence-based, straightforward\u000a      instructions for use. They have been endorsed by the key professional\u000a      societies for child health and nutrition in the UK, and are being used by\u000a      health professionals and parents throughout the UK, Ireland and New\u000a      Zealand.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Wright CM et al. (2006) How\u000a        does maternal and child feeding behavior relate to weight gain and\u000a        failure to thrive? Data from a prospective birth cohort. Pediatrics\u000a      117, 1262-1269. doi:10.1542\/peds.2005-1215\u000a    \u000a\u000a2. Wright CM et al. (2008) Implications\u000a        of adopting the WHO 2006 Child Growth Standard in the UK:\u000a        two prospective cohort studies. Arch Dis Child. 93, 566-569.\u000a      doi:10.1136\/adc.2007.126854\u000a    \u000a\u000a3. Cole TJ et al. (2012) Designing\u000a        the new UK-WHO growth charts to enhance assessment of growth\u000a        around birth. Arch Dis Child Fetal Neonatal Ed. 97,\u000a      F219-F222 doi:10.1136\/adc.2010.205864\u000a    \u000a\u000a4. Wright CM et al. (2012) Designing\u000a        new UK-WHO growth charts: implications for health staff use\u000a        and understanding of charts and growth monitoring. Matern Child\u000a        Nutr. 8, 371-379. doi:10.1111\/j.1740-8709.2010.00296.x\u000a    \u000a\u000a5. Cole TJ & Wright CM. (2011) A\u000a        chart to predict adult height from a child's current height. Ann\u000a        Hum Biol. 38, 662-668. doi:10.3109\/03014460.2011.598189\u000a    \u000a\u000a6. Wright CM et al. (2010) Using\u000a        the new UK-WHO growth charts. BMJ 340, c1140.\u000a      doi:10.1136\/bmj.c1140\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"},{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000a    a. New\u000a        UK-WHO Growth Charts — birth to 4 years.\u000a    b. Letter from\u000a        the Deputy Director, Child and Maternal Health Division (Scotland)\u000a      to all NHS Board Chief Executives introducing the Early Years Charts.\u000a    c. Print and distribution figures of all UK Growth Charts from April 2012\u000a      — April 2013, Harlow Printing Ltd., South Shields, Tyne & Wear, NE33\u000a      4PU.\u000a    d. Letter from\u000a        the Director General Health & Social Care and Chief Executive NHS\u000a        Scotland on the launch of the School Age Charts.\u000a    e. UK-WHO growth charts,\u000a      Royal College of Paediatrics and Child Health [Prof Wright acknowledged\u000a      under `Additional information']\u000a    f. Royal College of Nursing guidance, `Standards\u000a        for the weighing of infants, children and young\u000a        people in the acute health care setting' [Completion of RCPCH charts\u000a      recommended, p10].\u000a    g. British\u000a        Dietetic Association press release welcoming new charts.\u000a    h. National\u000a        Childbirth Trust NCT endorsement in press release [See comment]\u000a    i. The\u000a        Breastfeeding Network announcement welcomes the release of the new\u000a      growth charts.\u000a    j. Chief Advisor, Child & Youth, Ministry of Health, New Zealand\u000a\u0009[book\u000a        download — Growth charts, p.73]\u000a    k. Department of Health and Children, Ireland [`Note for the Record'\u000a      confirming that the UK Charts will be used for full-term babies, infants\u000a      and children from birth to 4 years in Ireland from 2011]; available on\u000a      request.\u000a    l. Statement by a Resident in Paediatrics, Military Hospital, Rawalpindi,\u000a      Pakistan [Request to use Growth Charts in their staff handbook]; available\u000a      on request.\u000a    m. `How\u000a        will your child grow' Chapter 4, p.66. In, Birth to five\u000a      (2009), Department of Health [Prof Wright acknowledged]\u000a    n. `Education\u000a        and training materials', Royal College of Paediatrics and Child\u000a      Health website\u000a    o. e-Learning for packages for NHS staff (Module\u000a        8 — Growth & Nutrition): 08-07, Weighing and Measuring Infants\u000a      and Children; 08_08, Growth Charts and their Interpretation\u000a    ","Title":"\u000a    Development and use of new, improved UK child growth charts\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"},{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"},{"GeoNamesId":"2638360","Name":"Scotland"},{"GeoNamesId":"2634895","Name":"Wales"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Child growth charts allow growth data to be interpreted in the context of\u000a      a child's age and gender. They are vital for health evaluation and medical\u000a      diagnosis, but until recently, presented two problems. First, all the\u000a      growth references in use before 2006 were based on small, unrepresentative\u000a      samples of largely bottle-fed infants and thus could not be used as a\u000a      standard of healthy growth. Second, few child growth charts anywhere in\u000a      the world had undergone any formal evaluation of how they performed as\u000a      clinical tools.\u000a    Professor Charlotte Wright, Professor of Community Child Health at the\u000a      University of Glasgow (2001-present), has an established research record\u000a      in the use, interpretation and validation of growth charts in child\u000a      health, which she further developed on moving to Glasgow in October 2001.\u000a      Here, Wright led research on the factors that affect weight gain or\u000a      underlie failure to thrive in infancy,1 and on the norms and\u000a      limits for postnatal weight loss in newborns. The findings of this\u000a      research have implications for the design and use of growth charts.\u000a      Between 2006 and 2008, Wright participated in a joint Scientific Advisory\u000a      Committee on Nutrition (SACN) and Royal College of Paediatrics and Child\u000a      Health (RCPCH) group to evaluate the possible implementation of the World\u000a      Health Organization (WHO) 2006 Child Growth Standard in the UK.\u000a    The WHO Standard was based on healthy breast-fed children from six\u000a      countries (Brazil, Ghana, India, Norway, Oman and USA) and defined for the\u000a      first time how all children aged 0-5 years should grow. Wright sought to\u000a      determine how well the WHO Child Growth Standard matched data on UK child\u000a      growth. Analyses undertaken by herself and by Drs Lakshman and Ong at\u000a      Cambridge University revealed that UK children matched the WHO Standard\u000a      well for length and height at all ages, but tended to become heavier than\u000a      the standard by the end of the first year.2 As this pattern\u000a      seemed compatible with rising rates of obesity, the committee recommended\u000a      adoption of the WHO standards from 2 weeks to 4 years as a means of\u000a      applying a healthier standard of weight gain. Their findings also\u000a      highlighted the need for better understanding and education about the\u000a      correct use of child growth charts among health visitors, doctors and\u000a      dieticians working with children.\u000a    In 2008, the Department of Health commissioned the RCPCH to design new\u000a      early years child growth charts for the UK, based on the WHO Standard,\u000a      with Wright as the academic lead of an expert panel, which included Tim\u000a      Cole, Professor of Medical Statistics, University College London; Tony\u000a      Williams, Reader in Child Nutrition, University of London; and Robert J\u000a      Moy, Senior Lecturer in Community Child Health, University of Birmingham.\u000a      Wright was involved in every element of the project, from commissioning\u000a      the layout of the charts to writing and evaluating the charts and the\u000a      extensive supporting educational material.\u000a    All previous UK child growth charts had artificially joined birth and\u000a      postnatal weight data from preterm and term children, which Wright had\u000a      already shown to misrepresent growth around birth. Wright now explored how\u000a      children born at different term gestations (37-42 weeks) grew in the\u000a      neonatal period. This revealed that if birth weight for a child born at 37\u000a      weeks' gestation is plotted at 37, rather than 40, weeks, their growth\u000a      rate appears to falter dramatically between birth and 12 days of age.3\u000a      This research informed the guidance that birth weight for all term infants\u000a      should be plotted at `age zero' (40 weeks' gestation). Professor Cole and\u000a      Wright also developed a new tool to predict adult height from a child's\u000a      current height centile, which was added to the height charts.5\u000a    Wright and her team involved parents and health professionals in the\u000a      process of designing and testing the charts and their accompanying\u000a      information. Most child growth charts had not been assessed through any\u000a      formal evaluation procedure for ease of use, accuracy and clarity. Wright\u000a      was responsible for designing such an evaluation procedure for the new UK\u000a      child growth charts. In this context, the new elements of the chart design\u000a      were tested by groups of health staff using a range of different child\u000a      growth scenarios and pre-plotted data. Dr Magda Sachs (NHS Salford)\u000a      recorded the group discussion of the charts, while Wright analysed the\u000a      quantitative data. These results prompted further refinements and changes\u000a      to the chart design and instructions.4 In parallel with the\u000a      chart design and evaluation process, the group interacted with parents and\u000a      health professionals to develop detailed instructions for use of the\u000a      growth chart. This helped to identify and eliminate inconsistencies and\u000a      ambiguities about chart use.6\u000a    After the pre-school charts had been published in 2009, the group went on\u000a      to design charts for school-age children. These were based on pre-existing\u000a      research, using both WHO and UK 1990 data. They also included new work\u000a      undertaken by Wright, Cole and Prof Gary Butler (Consultant in paediatric\u000a      and adolescent medicine and endocrinology, University College Hospital,\u000a      London), which explored new ways of describing pubertal progression and\u000a      assessing growth during puberty. Wright designed a new format BMI chart\u000a      for use in children with special health needs which allows assessment of\u000a      exceptionally overweight and underweight children. These charts were also\u000a      evaluated and refined by Wright and her team using the approach described\u000a      above.\u000a    "},{"CaseStudyId":"41147","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Ovarian cancer is the fifth most common cancer in women, affecting 6,500\u000a      individuals per year in the UK and 22,000 in the USA. Surgery and\u000a      chemotherapy are both used to treat ovarian cancer, and most patients are\u000a      considered for both treatments. At least 55% of women are diagnosed with\u000a      stage III or IV cancer. The survival rate five years after diagnosis is\u000a      20% for stage III and only 6% for stage IV ovarian cancer (Cancer Research\u000a      UK), although if ovarian cancer is diagnosed early (in stage I) the\u000a      survival rate after five years is 90%. University of Glasgow research has\u000a      helped to develop chemotherapy treatment for ovarian cancer, and is cited\u000a      in current guidelines around the world, which include:\u000a    \u000a      The establishment of paclitaxel as a key chemotherapy component in\u000a        ovarian cancer, which led to an 11% gain in survival rates over previous\u000a        drugs;\u000a      The establishment of docetaxel as an alternative to paclitaxel with a\u000a        different toxicity profile\u000a    \u000a    Adoption of paclitaxel in clinical guidelines\u000a    The OV-10 study4, which was co-led by researchers at the\u000a      University of Glasgow, established paclitaxel as the most effective\u000a      chemotherapy treatment for ovarian cancer, and since publication of the\u000a      results, the use of paclitaxel as the preferred chemotherapy for women\u000a      with ovarian cancer has been adopted by international clinical guidelines\u000a      that influence the treatment of patients throughout the UK and Europe.\u000a      These include guidelines written by the European Society for Medical\u000a      Oncology (ESMO), The Scottish Intercollegiate Network (SIGN) and the\u000a      National Institute for Clinical Excellence (NICE).\u000a    The membership of the European Society for Medical Oncology (ESMO)\u000a      includes 7,000 oncologists in 100 countries internationally; its biennial\u000a      congresses are attended by over 15,000 medical professionals worldwide.\u000a      ESMO has published guidelines entitled `Newly diagnosed and relapsed\u000a      epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for\u000a      diagnosis, treatment and follow-up' each year since 2005. Since 2008,\u000a      these recommended paclitaxel with carboplatin for advanced ovarian cancer,\u000a      as described University of Glasgow's collaborative OV-10 study, and cite\u000a      the long term follow-up (2003) survey.a This follow-up study\u000a      confirmed that paclitaxel- carboplatin conferred a survival advantage when\u000a      compared to cyclophosphamide-cisplatin. EMSO guidelines are followed\u000a      extensively throughout Europe and by oncologists around the world.\u000a    The SIGN guidelines inform chemotherapy throughout Scotland. From\u000a      2003-2013, Guideline No. 75, `Epithelial ovarian cancer', has recommended\u000a      the use of paclitaxel-cisplatin over cyclophosphamide-cisplatin, citing\u000a      Glasgow research5 as Level 1++ evidence, representing the\u000a      highest quality data (ref 103, Sections 5.5.3 and 5.5.4).b The\u000a      guidelines describe use of taxane combination therapy as being widespread\u000a      throughout Scotland.\u000a    NICE technology appraisals are the mechanism by which drugs gain approval\u000a      for funding and use within the UK National Health Service. In 2003, NICE\u000a      published their recommendation `TA55 - Guidance on the use of paclitaxel\u000a      in the treatment of ovarian cancer', which examines the use of paclitaxel\u000a      and refers to OV-10 as one of the randomised controlled trials that\u000a      demonstrate clinical effectiveness of paclitaxel in the first-line\u000a      treatment of ovarian cancer (TA55 Section 4.3.1).c In 2009,\u000a      TA55 was added to the static list; guidance is added to the static list\u000a      when no new research is available with any material effect on the current\u000a      guidance, thereby preserving the NHS funding.c The NHS funds\u000a      prescription of drugs that are recommended by NICE and requires that all\u000a      NICE- recommended treatments be made available within 90 days in their\u000a      formularies (databases of medicines approved for use on the NHS).d\u000a    A UK-wide resource for prescription data is not yet launched. For this\u000a      case study, data were requested from the West of Scotland Cancer Care\u000a      Network. Taking into account the comparative low incidence of epithelial\u000a      ovarian cancer, since January 2011, 66% of 490 women treated for newly\u000a      diagnosed epithelial ovarian cancer within the West of Scotland Cancer\u000a      Care Network have received a combination paclitaxel-platinum\u000a      (paclitaxel-carboplatin or paclitaxel-cisplatin) therapy.e\u000a    Docetaxel as alternative chemotherapy\u000a    Studies carried out by the Glasgow CTU demonstrated that docetaxel could\u000a      be used as an alternative to paclitaxel, was equally effective and had\u000a      different side effects, making it a valuable alternative treatment for\u000a      patients who react badly to paclitaxel. The side effects of chemotherapy\u000a      have serious implications on the quality of life and potential recovery of\u000a      the patient, and the existence of an alternative therapy enables more\u000a      tailored treatment for patients who may react badly to the recommended\u000a      drug. This 2004 study5 has enabled oncologists to safely\u000a      prescribe an alternative, yet equally effective, option for patients for\u000a      whom the side effects of paclitaxel, particularly neuropathy and alopecia,\u000a      present major problems.\u000a    The National Comprehensive Cancer Network (NCCN) is a not-for-profit\u000a      alliance of 23 leading cancer centres in the USA, dedicated to improving\u000a      the quality and effectiveness of care. Since 2010, the NCCN `Clinical\u000a      Practice Guidelines in Oncology' have recommended docetaxel- carboplatin\u000a      as an alternative to paclitaxel-carboplatin, citing Glasgow research5\u000a      as Category 1 evidence (the highest evidence level indicating uniform\u000a      consensus of experts) under Epithelial Ovarian Cancer — Primary Treatment\u000a      (ref 148, Section MS-8 in v.2.2013).f Analysis of the potential\u000a      side effects of each therapy also cites the Glasgow CTU trial. The 2013\u000a      NCCN patient guidelines on ovarian cancer specify prescription of\u000a      docetaxel-carboplatin as an alternative to paclitaxel with carboplatin or\u000a      cisplatin in chemotherapy, describing how docetaxel is more likely to\u000a      increase the risk of infection, whereas paclitaxel is more likely to cause\u000a      nerve damage.g\u000a    The NCCN.org website, aimed specifically at clinicians, received more\u000a      than 1.6 million unique visitors in 2012; the full clinical guidelines\u000a      (including those for ovarian cancer) are freely available to patients,\u000a      relatives and health professionals, and in 2012 were distributed to 97,000\u000a      people in paper or flash drive format, while 4.3 million copies were\u000a      downloaded as PDF documents.h\u000a    ","ImpactSummary":"\u000a    University of Glasgow research has led to the adoption of first-line\u000a      chemotherapy for ovarian cancer, which has improved patient survival by\u000a      11% and has been used to treat 66% of women with ovarian cancer since\u000a      January 2011 in the West of Scotland Cancer Care Network alone. These\u000a      therapies are recommended by guidelines for ovarian cancer treatment in\u000a      the USA, Europe and the UK. The USA guidelines are disseminated to 4.3\u000a      million people worldwide and the European guidelines reach 15,000 health\u000a      professionals. The UK guidelines are used to identify those drugs that are\u000a      funded by the NHS and used in NHS hospitals.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Bissett, D. et al. Phase\u000a        I and pharmacokinetic study of Taxotere (RP 56976) administered as a 24\u000a        h infusion. Cancer Res. 1993; 53, 523-527 (no doi available)\u000a    \u000a\u000a2. Vasey, P.A. et al. Docetaxel\u000a        and cisplatin in combination as first-line chemotherapy foradvanced\u000a        epithelial ovarian cancer. Scottish Gynaecological Cancer Trials\u000a      Group. J. Clin. Oncol. 1999; 17, 2069-2080 (no doi available)\u000a    \u000a\u000a3. Vasey, P. A. et al. and on behalf of the Scottish\u000a      Gynaecological Cancer Trials Group.\u000a      Docetaxel-carboplatin\u000a        as first line chemotherapy for epithelial ovarian cancer. Brit.\u000a        J. Cancer 2001; 84, 170-178 doi: 10.1054\/bjoc.2000.1572\u000a    \u000a\u000a4. Piccart, M. J. et al. Randomized\u000a        intergroup trial of cisplatin-paclitaxel versus\u000a        cisplatin-cyclophosphamide in women with advanced epithelial ovarian\u000a        cancer: Three-year results. J. Natl. Cancer Inst. 2000; 92,\u000a      699-708 doi:10.1093\/jnci\/92.9.699\u000a    \u000a\u000a5. Vasey, P. A. et al. Phase\u000a        III randomized trial of docetaxel-carboplatin versus\u000a        paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma.\u000a      J. Natl. Cancer Inst. 2004; 96,1682-1691 doi:10.1093\/jnci\/djh323.\u000a    \u000a\u000a6. Piccart, M. J. et al. Long-term\u000a        follow-up confirms a survival advantage of the paclitaxel- cisplatin\u000a        regimen over the cyclophosphamide-cisplatin combination in advanced\u000a        ovarian cancer. Int. J. Gynecol. Cancer 2003; 13, 144-148\u000a      doi:10.1111\/j.1525-1438.2003.13357.x\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. Colombo, N. et al. Newly\u000a        diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical\u000a        Practice Guidelines for diagnosis, treatment and follow-up. Ann.\u000a        Oncol. 2010; 21, v23-v30 doi: 10.1093\/annonc\/mdq244.\u000a    b. SIGN, Guideline No. 75: Epithelial\u000a        ovarian cancer (Sections 5.5.3 and 5.5.4); the peer- reviewed draft\u000a      of the 2013 update is available on request.\u000a    c. NICE TA55: Guidance\u000a        on the use of paclitaxel in the treatment of ovarian cancer (Section\u000a      4.1 and 4.3.1); Review\u000a        decision in 2009.\u000a    d. NICE, GPG1 (2012) Good\u000a        practice guidance: developing and updating formularies.\u000a    e. Audit of WOSCC Network data from Chemocare system provided by NHS\u000a      Greater Glasgow & Clyde; available on request.\u000a    f. NCCN Clinical Practice Guidelines in Cancer: Ovarian\u000a        cancer v.2.2013 (Section MS-8) [Note: free registration required];\u000a      document can also be provided on request.\u000a    g. NCCN Guidelines\u000a        for patients, for discussion with clinical teams.\u000a    h. National Comprehensive Cancer Network (NCCN) Annual\u000a        Report 2012.\u000a    ","Title":"\u000a    Systemic therapies for ovarian cancer\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Since 1993, University of Glasgow investigators have conducted a series\u000a      of large-scale randomised clinical trials, in association with the\u000a      Scottish Gynaecological Clinical Trials Group and the Gynecologic Cancer\u000a      InterGroup, proving the clinical value of taxane-based drugs (such as\u000a      docetaxel and paclitaxel) in combination with other anti-cancer agents\u000a      (such as cisplatin and carboplatin) for the treatment of primary ovarian\u000a      cancer.\u000a    Docetaxel\u000a    In the early 1990s, taxanes were a new class of anti-cancer agents with a\u000a      novel mechanism of action (microtubule stabilisation). Advanced ovarian\u000a      cancer is a fatal disease in most cases, so any agent that offered a\u000a      potential treatment for this disease was significant. In 1993, one of the\u000a      first phase I trials in the development of the taxane-based drug,\u000a      docetaxel, identified the type and reversibility of drug toxicities at\u000a      different doses.1 This was led by a University of Glasgow team\u000a      including Professor Stan Kaye who subsequently, as Chair of EORTC\u000a      (European Organisation for Research and Treatment of Cancer) Early\u000a      Clinical Trials Group, led Glasgow's contribution to phase II clinical\u000a      trials of the drug, in several diseases including ovarian cancer.\u000a    In 1995 Dr Paul Vasey led a study to establish the optimum dose of\u000a      docetaxel in combination therapy, initially with cisplatin, a\u000a      platinum-containing anti-cancer agent.2 This work established\u000a      that cisplatin and docetaxel can each be administered at a dose of 75 mg\/m2,\u000a      every three weeks. As it became apparent that carboplatin has a very\u000a      similar efficacy to cisplatin, but with less toxicity, a subsequent dose\u000a      escalation study was conducted with carboplatin by researchers at Glasgow.3\u000a      This study demonstrated that docetaxel and carboplatin could be combined\u000a      safely and effectively. Moreover, the study aimed to study the pattern of\u000a      toxicity of docetaxel in terms of neurotoxicity (nerve damage) and\u000a      neutropenia (reduction of a key type of immune cell). Among the 139\u000a      patients in the trials, the incidence of significant peripheral nerve\u000a      damage for patients treated with docetaxel-carboplatin was very low (less\u000a      than 6% of patients), but with the caveat of neutropenia being relatively\u000a      high (86% of patients), yet tolerable.\u000a    This study led to an international large scale phase III trial with 1077\u000a      patients, led by Vasey in 1998, demonstrating that docetaxel-carboplatin\u000a      was as effective as paclitaxel-carboplatin, with a different toxicity\u000a      profile. Fewer patients experienced nerve damage with docetaxel compared\u000a      with paclitaxel (11% versus 30%), although slightly more patients\u000a      experienced neutropenia (94% versus 84%).5 These studies were\u000a      led, designed, co-ordinated and analysed by the Glasgow Clinical Trials\u000a      Unit (CTU).\u000a    Paclitaxel\u000a    In 1995, a key study in the USA (GOG-111) had shown that\u000a      paclitaxel-cisplatin treatment was significantly more effective for\u000a      ovarian cancer than the previous standard treatment\u000a      (cyclophosphamide-cisplatin). However, the results were not conclusive\u000a      enough to establish paclitaxel-cisplatin as a new standard; more data were\u000a      needed, particularly to establish the optimum dosage and to determine how\u000a      the quality-of-life and economic impacts of the paclitacel- cisplatin\u000a      regimen compared with those of the cyclophosphamide-cisplatin regimen.\u000a    Researchers from the University of Glasgow were instrumental in the\u000a      subsequent OV-10 study,4 which began in 1995. OV-10 had wider\u000a      patient recruitment eligibility than GOG-111, as it included women with\u000a      both early and advanced cancers and longer intervals between their first\u000a      surgery and chemotherapy, and also used surgical guidelines more closely\u000a      aligned to common clinical practice. These inclusion criteria enabled 680\u000a      patients to be enrolled in 15 months, and gave the study an 80%\u000a      probability of detecting an increase in average progression-free survival\u000a      — the period of time during and after treatment in which the cancer does\u000a      not get worse — and represented a turning point in the history of\u000a      conducting ovarian cancer trials. The UK contribution to this phase III\u000a      initiative was led from the Glasgow CTU initially by Kaye and latterly by\u000a      Professor Jim Cassidy.\u000a    Paclitaxel was administered as a 3-hour infusion at 175 mg\/m2,\u000a      instead of a 24-hour infusion at 135 mg\/m2 as used in the\u000a      GOG-111 trial, and the trial end-point was progression-free survival time.4\u000a      This study provided strong confirmatory evidence (in terms of both\u000a      progression-free survival and overall survival) that paclitaxel-cisplatin\u000a      therapy was superior to cyclophosphamide-cisplatin therapy. A long-term\u000a      follow-up study in 2003 involving the same University of Glasgow team\u000a      showed that patients who had been treated with paclitaxel-cisplatin had an\u000a      11% improvement in survival, i.e. 11% more of them were still alive after\u000a      6.5 years compared with those treated with cyclophosphamide-cisplatin,\u000a      thereby establishing paclitaxel-cisplatin as a new standard regimen for\u000a      treatment of patients with advanced ovarian cancer.6\u000a    Key researchers: (Glasgow): Professor Stan Kaye (Professor\u000a      of Medical Oncology, 1985-2000), Dr Paul Vasey (Clinical Research Fellow,\u000a      1992-1996; Senior Lecturer in Medical Oncology, 1996- 2003; Reader in\u000a      Medical Oncology, 2003-2004; Director of Glasgow CTU, 2001-2004),\u000a      Professor Jim Cassidy (Reader in Clinical Oncology, 1993-1994; Professor\u000a      of Oncology and Head of the Division of Cancer Sciences and Molecular\u000a      Pathology, 2001-2011), Mr Jim Paul (Senior Statistician, 1988-present). Key\u000a          external collaborators: (refs 4 & 6): European\u000a      Organisation for Research and Treatment of Cancer -Profs Martine Piccart\u000a      (Free University of Brussels ULB) and Sergio Pecorelli (University of\u000a      Brescia). National Cancer Institute of Canada Clinical Trials Group- Profs\u000a      Gavin Stuart and Keith James (Queen's University, Kingston, Canada).\u000a    "},{"CaseStudyId":"41152","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    In 2012, approximately 2,700 kidney transplants were performed in the UK\u000a      and 16,812 in the USA. However, up to 50% of transplant recipients will\u000a      have at least one infection within 1 year of transplantation. CMV is one\u000a      of the most common infections in KTRs, and can lead to clinical disease\u000a      involving fever, inflammation of the lungs, liver or gut, and also\u000a      disruption of the local immune response, leading to secondary infections\u000a      and long-term injury to or rejection of the transplanted kidney.\u000a    University of Glasgow research has helped to establish revised standards\u000a      of care for the clinical management of the prevention (IMPACT trial) and\u000a      treatment (VICTOR trial) of CMV disease in KTRs. These trials are cited in\u000a      current guidelines around the world, supporting recommendations that\u000a      include:\u000a    \u000a      Doubling the length of preventative (prophylactic) treatment with\u000a        valganciclovir in KTRs from 100 days to 200 days, which has been shown\u000a        to halve the relative incidence of CMV disease over 12 months.\u000a      The use of oral valganciclovir as an alternative to intravenous\u000a        ganciclovir in the treatment of human CMV disease, which has been shown\u000a        to be equally effective at eradicating disease in 85% of solid-organ\u000a        recipients with non-life-threatening illness (74% of whom were KTRs).\u000a    \u000a    Adoption of oral valganciclovir and extended prophylaxis in\u000a          clinical guidelines\u000a    Since the publication of the IMPACT and VICTOR trials, the findings have\u000a      been adopted to support recommendations for the management of KTRs in\u000a      national and international guidelines. With the exception of Kidney\u000a      Disease: Improving Global Outcomes (KDIGO; discussed later), all of the\u000a      guidelines below cite the VICTOR trial to support oral valganciclovir as\u000a      an alternative to intravenous ganciclovir to treat CMV disease, and cite\u000a      the IMPACT trial to support the use of oral valganciclovir for 200-day\u000a      (6-month) prophylaxis to prevent CMV disease in high-risk adult KTRs.\u000a    National guidelines\u000a    \u000a      The American Society of Transplantation is an organisation of more\u000a        than 2,700 transplant clinicians, whose annual congress attracts in\u000a        excess of 5,000 delegates from around the world. Its 2009 guideline\u000a        `Cytomegalovirus in solid organ transplant recipients' cites University\u000a        of Glasgow research in the \"CMV Prevention\" (level 1 recommendation,\u000a        ref. 26 and 32, p.S80) and \"CMV Treatment\" (ref. 12 and 39, p.S83)\u000a        sections.a\u000a      The British Transplantation Society (BTS) is the professional voice of\u000a        transplantation in the UK, representing all healthcare professionals\u000a        working with transplant patients. Their 2011 guidelines on `Prevention\u000a        and Management of CMV Disease after Solid Organ Transplantation' cite\u000a        University of Glasgow research in the Prophylaxis (ref. 99, p.34-35) and\u000a        Treatment (ref. 131, p.45) sections. The BTS guidelines provide further\u000a        context, describing IMPACT as a `landmark study', and stating\u000a        that, `in practice, many units have begun to use oral valganciclovir\u000a          prophylaxis to avoid the costs and inconvenience of hospital admission\u000a          and\/or home intravenous anti-viral therapy.\" Likewise, they state\u000a        that \"substantial clinical experience in recent years has reinforced\u000a          that [use of oral valganciclovir to treat CMV disease] is an\u000a          appropriate treatment strategy, which has the advantage of being able\u000a          to offer management as an outpatient for a proportion of patients.'b\u000a\u000a      The Renal Association is the professional association for renal\u000a        physicians and scientists in the UK, and has an active role in the\u000a        development of renal services in the UK. In 2011, Prof. Jardine\u000a        co-authored their guidelines on `Post-operative Care of the Kidney\u000a        Transplant Recipient'. The guidelines are intended for those healthcare\u000a        professionals who care for KTRs, but who are not experts in transplant\u000a        infectious disease. They cite University of Glasgow research as\u000a        Prophylaxis recommendation 8.2.1 (level 1 recommendation, ref. 110,\u000a        p.45-46) and Treatment suggestion 8.2.2 (ref. 112 and 113, p.45-46).c\u000a\u000a    \u000a    International guidelines\u000a    \u000a      KDIGO is an independent group with a core mission of developing and\u000a        implementing clinical guidance in kidney disease with an international\u000a        focus. The 2009 KDIGO guideline on `The care of kidney transplant\u000a        recipients' cites University of Glasgow research under\u000a        recommendation 13.2.3.2 (level 1 recommendation, ref. 312, p.S48); the\u000a        guidelines pre-date publication of IMPACT. Whilst they give a strong\u000a        recommendation, they describe the evidence of the VICTOR trial as `D'\u000a        (low) due to the absence of patients with life-threatening CMV disease.\u000a        However, they clarify in their rationale that, `At this point, most\u000a          experts would be willing to use oral therapy to treat adult KTRs with\u000a          mild CMV disease.'d\u000a\u000a      The Transplantation Society is the leading international society of\u000a        physicians, surgeons and scientists involved in the transplantation of\u000a        organs and tissues. Its 2010 guideline `International Consensus\u000a        Guidelines on the Management of Cytomegalovirus in Solid Organ\u000a        Transplantation' was developed using a consensus group of 45 experts\u000a        from 15 countries worldwide, which also included Jardine. These\u000a        guidelines cite University of Glasgow research to support Prophylaxis\u000a        (level 1 evidence, ref. 88, p.785) and Treatment (level 1\u000a        recommendation, ref. 33 and 87, p.787) recommendations.e\u000a\u000a      The implementation of the Transplantation Society's International\u000a        Consensus guidelines was surveyed in 2011, a year after publication,\u000a        receiving responses from 155 transplant clinicians, representing 126\u000a        clinical centres in 41 countries. Feedback from 73% of respondents\u000a        represented kidney transplant practice. Of all respondents, only 99\u000a        specified which antiviral they use in high-risk patients, but of these,\u000a        86% used oral valganciclovir, and just over half of them used it for a\u000a        period of 200 days.f\u000a      \u000a      Amendment of licenses by medicines regulators\u000a      For medicines to be used in a modified way, the national medicines\u000a        regulatory bodies must amend the relevant licenses. The IMPACT trial\u000a        resulted in amendment of licenses for use of valganciclovir for\u000a        preventing CMV disease in KTRs by UK medicines agenciesg-i\u000a        and the United States Food & Drug Administration,\u000a        providing the option of extended 200 day treatment with oral\u000a        valganciclovir. Whilst the UK Medicines and Healthcare products\u000a        Regulatory Agencyi refers to the outcomes of the study in its\u000a        amendment, the statutory advisors to the Scottish and Welsh governments\u000a        (Scottish Medicines Consortiumgand the All Wales Medicines\u000a        Strategy Grouph) published their detailed evaluation of the\u000a        IMPACT evidence.\u000a      The Scottish Medicines Consortium's role is to license (or amend\u000a        licenses for new indications) those drugs that are both clinically\u000a        effective and represent good value for money. This ensures that drugs\u000a        meeting these requirements are accepted for routine use and have access\u000a        to NHS funding. The Scottish Medicines Consortium evaluated the\u000a        comparative efficacy and safety of 100 day versus 200 day treatments,\u000a        citing the IMPACT study,3 including an analysis of the cost-\u000a        effectiveness of using the drug, based on a cost-utility model provided\u000a        by the manufacturers of valganciclovir (Roche). These data supported the\u000a        amendment to the license, on the basis that an additional 100 days of\u000a        preventative treatment was considered to offer both clinical and\u000a        economic value. A 200 day treatment is currently being used in the two\u000a        renal transplant units in Scotland (Glasgow Western and Edinburgh Royal\u000a        and infirmaries).g\u000a      ","ImpactSummary":"\u000a    In 2012, around 19,500 kidney transplant operations were performed in the\u000a      UK and USA. The greatest infection risk to transplant recipients is from\u000a      cytomegalovirus (CMV), the standard 2-4 week treatment for which involves\u000a      an average of 5 days as an inpatient, which can cost up to £13,000.\u000a      University of Glasgow research has led to revised standards of care for\u000a      the prevention and treatment of CMV disease in kidney transplant\u000a      recipients (KTRs). First, that antiviral treatment with oral\u000a      valganciclovir for 200 days can be used to prevent CMV disease in\u000a      postoperative KTRs and is twice as effective as treatment for 100 days.\u000a      Secondly, the team found that the use of oral valganciclovir was a\u000a      practical and cost-effective alternative to intravenous ganciclovir for\u000a      treatment of mild CMV disease in solid-organ transplant recipients. Since\u000a      2009, the use of these therapies has been recommended in key national and\u000a      international guidelines for the care of KTRs. The research also provided\u000a      the evidence base that was used for evaluating, and subsequently amending,\u000a      the marketing authorisation of oral valganciclovir for use in preventative\u000a      treatment of CMV disease in KTRs in the UK and USA.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Asberg A et al. VICTOR Study Group. Oral\u000a        valganciclovir is non-inferior to intravenous ganciclovir for the\u000a        treatment of cytomegalovirus disease in solid organ transplant\u000a        recipients. Am. J. Transplant. 7, 2106-2113 (2007).\u000a      doi:10.1111\/j.1600-6143.2007.01910.x\u000a    \u000a\u000a2. Asberg A et al. Long-term\u000a        outcomes of CMV disease treatment with valganciclovir versus\u000a        IVganciclovir in solid organ transplant recipients. Am. J.\u000a        Transplant. 9, 1205-1213 (2009).\u000a      doi:10.1111\/j.1600-6143.2009.02617.x\u000a    \u000a\u000a3. Humar A et al. The\u000a        efficacy and safety of 200 days valganciclovir cytomegalovirus\u000a        prophylaxis in high-risk kidney transplant recipients. Am. J.\u000a        Transplant. 10, 1228-1237 (2010).\u000a      doi:10.1111\/j.1600-6143.2010.03074.x\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"}],"Sources":"\u000a      a. Humar A & Snydman D. & the AST Infectious Diseases Community\u000a        of Practice. Cytomegalovirus\u000a          in solid organ transplant recipients. Am. J. Transplant.\u000a        9, (Suppl 4): S78- S86 (2009). doi:10.1111\/j.1600-6143.2009.02897.x.\u000a      b. British Transplantation Society Guidelines for the Prevention and\u000a          Management of CMV Disease after Solid Organ Transplantation, 3rd\u000a        edition, August 2011.\u000a      c. Baker R, Jardine A & Andrews P. Post-operative\u000a          Care of the Kidney Transplant Recipient (2011) The Renal\u000a        Association guidelines (Section 8.2).\u000a      d. KDIGO\u000a          clinical practice guideline for the care of kidney transplant\u000a          recipients. Kidney Disease: Improving Global Outcomes (KDIGO)\u000a        Transplant Work Group. Am. J. Transplant. 9: S1- S155 (2009).\u000a        doi:10.1038\/ki.2009.377.\u000a      e. Kotton CN et al. & Transplantation Society International CMV\u000a        Consensus Group. International\u000a          consensus guidelines on the management of cytomegalovirus in solid\u000a          organtransplantation. Transplantation 89, 779-795 (2010).\u000a        doi:10.1097\/TP.0b013e3181cee42f.\u000a      f. Le Page AK. International\u000a          Survey of Cytomegalovirus Management in Solid Organ Transplantation\u000a          After the Publication of Consensus Guidelines. Transplantation\u000a        95, 1455-1460 (2013). doi:10.1097\/TP.0b013e31828ee12e.\u000a      g. Valganciclovir (SMC\u000a          No. 662\/10), Scottish Medicine Consortium, January 2011.\u000a      h. All Wales Medicines Strategy Group (AWMSG) review\u000a        and amendment granted\u000a        (June 2011).\u000a      i. Valganciclovir (SPC-DOC_PL\u000a          00031-0829 \/ 00031-0599, tablet), amendment to Medicines and\u000a        Healthcare Products Regulatory Agency, June 2011.\u000a      j. FDA\u000a        (August 2010) | News article.\u000a      \u000a      ","Title":"\u000a    Improved clinical guidelines to manage postoperative infection risk in\u000a      kidney transplant recipients\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    One of the paradoxes of the successful development of dialysis and\u000a      transplantation for the treatment of end-stage renal failure is that\u000a      affected patients are more likely to die of accelerated cardiovascular\u000a      disease, malignancy and infection, than of renal failure. Roughly half the\u000a      human population carries CMV, often asymptomatically due to the action of\u000a      a healthy immune system. However, CMV is the leading infection risk to\u000a      KTRs due to the use of immunosuppressant agents to prevent rejection. The\u000a      resulting CMV disease is associated with significant risk of illness and\u000a      death, along with an increased risk of kidney graft rejection and other\u000a      opportunistic infections.\u000a    Research by Professor Alan Jardine (Professor of Renal Medicine,\u000a      1994-present) at the University of Glasgow contributed to two phase III,\u000a      international, randomised controlled trials to: (i) evaluate the use of\u000a      the oral antiviral drug valganciclovir as an alternative to intravenous\u000a      ganciclovir for the treatment of CMV disease in solid-organ transplant\u000a      recipients, and (ii) revise use of oral valganciclovir for the prevention\u000a      of CMV disease in postoperative KTRs.\u000a    VICTOR trial\u000a    Between 2004 and 2006, Jardine was the UK lead for the `Valganciclovir\u000a      Compared to Ganciclovir iv in Patients With Cytomegalovirus Disease Who\u000a      Are Solid Organ Transplant Recipients' (VICTOR) trial.1 This\u000a      study, and its subsequent sub-studies, was conducted by an international\u000a      five-member executive steering committee, which included Jardine, in\u000a      collaboration with Roche Pharmaceuticals. While the study comprised\u000a      participants with different solid organ transplants (e.g. liver, heart or\u000a      lung) around 74% of participants were KTRs.\u000a    Prior to the VICTOR study, treatment of CMV infection required frequent\u000a      hospital admission for treatment with intravenous ganciclovir, which is\u000a      both inconvenient for patients and expensive for health authorities. The\u000a      VICTOR study was the first randomised controlled trial to compare the\u000a      efficacy and safety of oral valganciclovir with intravenous ganciclovir in\u000a      solid-organ transplant patients, and was conducted in a total of 321\u000a      patients across 42 centres worldwide. The study showed that oral\u000a      valganciclovir is equivalent to intravenous ganciclovir therapy, with\u000a      successful clearance of CMV disease at day 21 (45.1% valganciclovir versus\u000a      48.1% ganciclovir, P=0.05), rising to 85% of patients (85.4%\u000a      valganciclovir versus 84.1% ganciclovir, P=NS) at day 49 of\u000a      treatment.1 The outcomes following treatment were evaluated\u000a      after 1 year. This found that, independent of which treatment was used,\u000a      detectable CMV virus had recurred (with or without associated disease) in\u000a      30% of participants, with CMV disease recurring in 15% of participants.2\u000a    IMPACT trial\u000a    Key to the management of CMV disease is prevention of infection with CMV,\u000a      especially in high-risk patient groups (patients with no prior exposure to\u000a      the virus who receive an organ from a CMV- infected donor). Before 2009,\u000a      two strategies were used to prevent CMV infection in high-risk KTRs: rapid\u000a      diagnosis and early therapy with an anti-viral agent (so-called\u000a      \"pre-emptive therapy\") or universal prophylaxis with valganciclovir for\u000a      100 days. However, these approaches were associated with delayed-onset\u000a      disease (\"late-onset CMV\") in one-third of patients after discontinuation\u000a      of treatment.\u000a    Between 2006 and 2009, Jardine was on the steering committee of the\u000a      `Improved Protection Against Cytomegalovirus in Transplant' (IMPACT)\u000a      trial.3 This was a phase III trial designed by the group who\u000a      performed the VICTOR study to assess the efficacy and safety of 100 day\u000a      treatment versus 200 day treatment with oral valganciclovir in high-risk\u000a      KTRs, with the aim of determining whether extended prophylaxis would\u000a      prevent late-onset CMV disease. The trial included 326 high- risk KTRs\u000a      across 65 study centres in 13 countries worldwide. The trial showed that\u000a      200 day prophylaxis prevented disease in 84% of high-risk KTRs for up to 1\u000a      year after surgery, with similar tolerability and safety compared with 100\u000a      day treatment. The incidence of CMV disease in the 200 day treatment group\u000a      was 16% compared with 37% observed in the 100 day group; thus, doubling\u000a      the length of prophylaxis reduces the incidence of CMV disease by 56%,\u000a      relative to 100 day prophylaxis, an absolute risk reduction of 21%.3\u000a    These two trials have established that oral valganciclovir provides an\u000a      equally effective treatment to intravenous ganciclovir for CMV disease,\u000a      with no significant difference in safety profile, and that six months (200\u000a      days) of prophylaxis with oral valganciclovir improves the long-term\u000a      outcome for KTRs, by reducing the incidence of late-onset CMV disease.\u000a      They thus provide simplified treatment options, improving the clinical\u000a      management of post-operative KTRs.\u000a    "},{"CaseStudyId":"41153","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"1269750","Name":"India"},{"GeoNamesId":"2077456","Name":"Australia"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"3017382","Name":"France"}],"Funders":[],"ImpactDetails":"\u000a    Heart failure is a complex syndrome in which the heart is unable to pump\u000a      sufficient blood to meet\u000a      the demands of the body. The incidence of heart failure increases with\u000a      age, and the condition\u000a      progressively leads to a significant debilitation of physical capacity and\u000a      quality of life. Heart failure\u000a      is associated with high mortality and more than 50% of patients die within\u000a      5 years of diagnosis.\u000a      The condition represents a substantial economic burden to health services,\u000a      with nearly 17 million\u000a      people living with a heart failure diagnosis in the UK, USA and Europe. In\u000a      2010\/2011 the cost of\u000a      heart failure management in the NHS was in excess of £2 billion;\u000a      approximately 70% of this\u000a      expenditure was due to hospitalisation costs. Drugs can limit progression\u000a      of the disease and\u000a      patients are typically treated with multiple drugs that are prescribed for\u000a      the rest of their lives.\u000a    Impact on international and national heart failure clinical\u000a          guidelines\u000a      Key University of Glasgow studies (detailed in sections 2 and 3) have\u000a      provided the evidence-base\u000a      for current clinical recommendations made by the European Society of\u000a      Cardiology (ESC) and by\u000a      the American College of Cardiology Foundation and American Heart\u000a      Association (ACCF\/AHA) for\u000a      the management of heart failure. The ESC, ACCF and AHA are the most\u000a      prominent and influential\u000a      cardiovascular societies in the world, with estimated professional\u000a      memberships of 30,000, 43,000\u000a      and 73,000 respectively. Owing to his internationally renowned reputation\u000a      and expertise in the\u000a      field, McMurray held the highly prestigious position of Chair of the 2012\u000a      ESC guideline committee\u000a      and the only European member of the writing committee for the 2013\u000a      ACCF\/AHA guidelines. The\u000a      2012 ESCaand 2013 ACCF\/AHAb guidelines, through\u000a      rigorous peer-review, make the highest level\u000a      of recommendations, citing University of Glasgow studies in the key\u000a      evidence base for the\u000a      following drug therapies in patients with heart failure:\u000a    \u000a      ACE inhibitors and beta-blockers to be used in all patients with heart\u000a        failure (based on\u000a        evidence including the ATLAS2, CIBIS-21 and\u000a        CAPRICORN studies).\u000a      ARBs in patients intolerant of ACE inhibitors or those who remain\u000a        symptomatic on\u000a        beta-blockers and ACE inhibitors (based on evidence including VALIANT4\u000a        and the CHARM3\u000a        trials).\u000a      MRAs as the third disease-modifying drug in patients who remain\u000a        symptomatic despite ACE\u000a        inhibitor (or ARB) and beta-blocker (based on evidence from EMPHASIS-HF5).\u000a    \u000a    The landmark demonstration of the lifesaving benefits of the MRA\u000a      eplerenone in patients with heart\u000a      failure is the biggest breakthrough in the drug management of heart\u000a      failure since that of beta-blockers\u000a      and is the most recent change in these new international guidelines.\u000a    The ESC and ACCF\/AHA guidelines dominate the evidence-based best practice\u000a      for treatment of\u000a      heart failure and their recommendations are mirrored in the majority of\u000a      current national guidelines.\u000a      Examples published since 2008 include the National Institute for Health\u000a      and Care Excellence\u000a      (NICE), in the UK (2010c), the Canadian Cardiovascular Society\u000a      (CCS, 2012d) and the National\u000a      Heart Foundation of Australia and Cardiac Society of Australia and New\u000a      Zealand (2011e). Approval\u000a      of these therapies by NICE not only reflects their clinical efficacy but\u000a      their cost-effectiveness,\u000a      confirming they represent `good value for money' for the NHS. The\u000a      influence of neutral or negative\u000a      trials which recommend the discontinuation of harmful drug therapies must\u000a      not be underestimated.\u000a      Evidence from the CORONA study led to removal of the statin therapy\u000a      recommendation in patients\u000a      with heart failure in the current NICE guidelines.c In summary,\u000a      the recommendations based on\u000a      University of Glasgow research outlined above affect the clinical\u000a      management of heart failure\u000a      worldwide. These have contributed to the reduction in mortality and\u000a      hospitalisation rates (by\u000a      approximately 25% and 40% respectively) recorded in the past 2 decades,\u000a      with mortality rates\u000a      post-2008 continuing to follow this trend.\u000a    Dissemination and implementation of heart failure guideline\u000a          recommendations\u000a      A robust process of dissemination has ensured that the above guideline\u000a      recommendations form\u000a      the basis of current clinical heart failure treatment. Since their\u000a      publication in May 2012, the ESC\u000a      guidelines on heart failure management have become the most downloaded\u000a      guideline in the 2012\u000a      ESC series (158,000 copies).f A further 28,500 pocket version\u000a      guidelines of the ESC heart failure\u000a      guideline have been accessed and French, Spanish, Chinese and\u000a      Polish-language editions\u000a      published. Beyond Europe, users are located in South America, India and\u000a      China, thereby\u000a      demonstrating the global reach of these recommendations.f A\u000a      similar process of dissemination is\u000a      operated by the AHA through their `Get with the guidelines — heart failure\u000a      overview' programme.\u000a    Patients with heart failure are receiving the guideline recommended\u000a          first-line therapies\u000a      In the UK, implementation of these recommendations is assessed annually by\u000a      the National Heart\u000a      Failure audit. The 2011\/2012 audit reported that, of the patients\u000a      discharged from hospital in\u000a      England and Wales with heart failure, 84% were prescribed an ACE inhibitor\u000a      and\/or an ARB, 78%\u000a      were prescribed a beta-blocker and 45% were prescribed an MRA thereby\u000a      indicating adherence to\u000a      the guideline recommendations based on University of Glasgow research.g\u000a      In a primary care\u000a      setting, financial incentives standardise delivery of front-line heart\u000a      failure drug therapies to patients\u000a      via the Quality Outcomes Framework (QOF) for all practices on the General\u000a      Medical Services\u000a      contract.h Two QOF indicators have been in existence since 2008\u000a      for the on-going management of\u000a      heart failure patients. QOF data (April 2011-March 2012)\u000a      indicate that 83% of patients in England\u000a      with a current diagnosis of heart failure are being treated with an ACE\u000a      inhibitor or an ARB, 60% of\u000a      whom are additionally treated with a beta-blocker.i In the US,\u000a      the government Health and Human\u000a      Services department operates a standardised clinical quality measurement\u000a      for hospitals, on which\u000a      performance is rated and made publically available. The current measure\u000a      (2012) stipulates that\u000a      patients with heart failure are discharged with a valid prescription for\u000a      ACE inhibitors and ARBs, and\u000a      directly cites the Glasgow evidence base (citing CHARM-Alternative and\u000a      VALIANT4).j\u000a      Approximately 77% of all US hospitals are accredited to this scheme,\u000a      administered by the\u000a      governmental agency The Joint Commission. In 2012 The Joint Commission\u000a      annual report noted\u000a      that accredited hospitals reached an average 97% compliance with the heart\u000a      failure measure.k\u000a    An estimated 7 million people in the UK and US currently live with a\u000a      diagnosis of heart failure.\u000a      Taken together, the above figures indicate the widespread delivery of the\u000a      recommended first-line\u000a      therapies within this patient population.\u000a    Advances in diagnosis and community based management of patients\u000a          with heart failure\u000a      University of Glasgow clinical heart failure researchers were among the\u000a      first to show the potential\u000a      role of BNP as a diagnostic test for heart failure6, which is\u000a      now used universally to improve\u000a      accurate and earlier diagnosis of heart failurea, b. A major\u000a      advancement in the day-to-day care of\u000a      heart failure patients has been achieved through Specialist Heart Failure\u000a      Nurses (SHFNs), the\u000a      concept and benefit behind which was pioneered in the UK in a 2001\u000a      Glasgow-led trial7 (alongside\u000a      two complementary trials conducted in US and Australia). As a result of\u000a      the trial of specialist heart\u000a      failure nurses (SHFNs), there are now more than 400 SHFNs in the UK,\u000a      supported by the NHS and\u000a      the British Heart Foundation. SHFNs help to reduce hospital admissions by\u000a      35% and save the\u000a      NHS approximately £8 million per year.l\u000a    ","ImpactSummary":"\u000a    Approximately 26 million people live with heart failure worldwide.\u000a      University of Glasgow\u000a      researchers have been instrumental in proving the value, in landmark\u000a      clinical trials, of bisoprolol,\u000a      candesartan and eplerenone — three of the four classes of drug that reduce\u000a      mortality, reduce\u000a      hospitalisation rates and improve quality of life for patients with heart\u000a      failure. These trials led\u000a      directly to revision of clinical guidelines on heart failure management\u000a      globally (including in Europe,\u000a      USA, UK, Australia and Canada, all published since 2008). The Glasgow\u000a      researchers have\u000a      established heart failure as a healthcare priority and encouraged the\u000a      introduction of specialist heart\u000a      failure nurses, saving the NHS an estimated £8 million per year.\u000a      Collectively, these advances have\u000a      transformed the treatment and survival rates of heart failure patients\u000a      worldwide.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. CIBIS-2 Investigators and Committees. The\u000a        Cardiac Insufficiency Bisoprolol Study II (CIBIS-II):\u000a        a randomised trial. Lancet 1999; 353: 9-13. doi:\u000a      10.1016\/S0140-6736(98)11181-9.\u000a    \u000a\u000a2. ATLAS Study Group. Comparative\u000a        effects of low and high doses of the angiotensin-converting\u000a        enzyme inhibitor, lisinopril, on morbidity and mortality in chronic\u000a        heart failure. Circulation 1999;\u000a      100: 2312-2318. doi: 10.1161\/01.CIR.100.23.2312\u000a    \u000a\u000a3. CHARM Investigators and Committees. Effects\u000a        of candesartan in patients with chronic heart\u000a        failure and reduced left-ventricular systolic function taking\u000a        angiotensin-converting-enzyme\u000a        inhibitors: the CHARM-Added trial. Lancet 2003; 362:767-771.\u000a      doi: 10.1016\/S0140-\u000a      6736(03)14283.\u000a    \u000a\u000a4. Valsartan in Acute Myocardial Infarction Trial (VALIANT)\u000a      Investigators. Valsartan,\u000a        captopril, or\u000a        both in myocardial infarction complicated by heart failure, left\u000a        ventricular dysfunction, or both. N\u000a        Engl J Med 2003; 349:1893-1906. doi: 10.1056\/NEJMoa032292.\u000a    \u000a\u000a5. EMPHASIS-HF Study Group. Eplerenone\u000a        in patients with systolic heart failure and mild\u000a        symptoms. N Engl J Med 2011; 364:11-21. doi:\u000a      10.1056\/NEJMoa1009492.\u000a    \u000a\u000a6. McDonagh TA, et al. Biochemical\u000a        detection of left-ventricular systolic dysfunction. Lancet\u000a      1998;\u000a      351: 9-13. doi:\u000a        10.1016\/S0140-6736(97)03034-1\u000a    \u000a\u000a7. Blue L, et al. Randomised\u000a        controlled trial of specialist nurse intervention in heart failure.\u000a      BMJ\u000a      2001; 323715-718. doi:10.1136\/bmj.323.7315.715\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. ESC\u000a        Guidelines for the diagnosis and treatment of acute and chronic heart\u000a        failure (2012).\u000a      Table of recommended treatments and key evidence sections; citing: CIBIS-2\u000a      (ref 92), ATLAS\u000a      (ref 90), VALIANT (ref 120), CHARM series (refs 108, 111), EMPHASIS-HF\u000a      (ref 100),\u000a      CAPRICORN (ref 223) p1806-1809 & 1829.\u000a    b. ACCF\/AHA\u000a        Guideline for the management of heart failure (2013). Recommended\u000a      treatments\u000a      and key evidence sections, p47&p49-55; citing: CIBIS-2 (ref 117),\u000a      ATLAS (ref 445), VALIANT\u000a      series (refs 345&120), CHARM series (refs 450&589), EMPHASIS-HF\u000a      (ref 426), CAPRICORN\u000a      (ref 346); data supplements 18-20 p79-85, CORONA (ref 207).\u000a    c. NICE\u000a        Chronic Heart Failure (2010). ATLAS (ref 75), CIBIS-2 (ref 86),\u000a      CHARM (105); p38-46.\u000a    d. CCS\u000a        update, Heart Failure management guidelines update: Focus on Acute and\u000a        Chronic Heart\u000a        Failure (2012). CIBIS-2 (ref 70), VALIANT (ref 63), CHARM (64),\u000a      EMPHASIS-HF (67);\u000a      recommended therapies p174.\u000a    e. National\u000a        Heart Foundation of Australia and Cardiac Society of Australia and New\u000a        Zealand\u000a        update, Guidelines for the prevention, detection and management of\u000a        chronic heart failure in\u000a        Australia (2011). Recommended therapies p406; citing EMPHASIS-HF\u000a      (ref 16).\u000a    f. Download data for ESC 2012 heart failure guidelines (reference a.\u000a      above) were obtained\u000a      directly through correspondence with the ESC and are available on request.\u000a    g. National\u000a        Heart Failure Audit Report, April 2011-March 2012.\u000a    h. 2013\/14\u000a        general medical services (GMS) contract quality and outcomes framework\u000a      (QOF).\u000a    i. QOF 2011-2012 Cardiovascular\u000a          disease primary prevention, England, (HF3 and HF4).\u000a    j. US\u000a        Department of Health and Human Services (HHS).\u000a    k. The\u000a        Joint Commission Annual Report on quality and safety 2012.\u000a    l. BHF\u000a        Specialist Nurses Report 2008 - Changing the face of cardiac care\u000a    \u000a    ","Title":"\u000a    Landmark advances in outcomes for patients with heart failure\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2634895","Name":"Wales"},{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    The University of Glasgow has been a world-renowned centre of heart\u000a      failure research for 30\u000a      years, making seminal contributions to the modern understanding of the\u000a      causes, epidemiology,\u000a      diagnosis and treatment of heart failure, as well as training many of the\u000a      UK's leading experts in this\u000a      area. Glasgow investigators conducted some of the first studies of\u000a      angiotensin-converting enzyme\u000a      (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients,\u000a      studies showing non-ACE\u000a      generation of angiotensin II (rationale for combining ACE inhibitors and\u000a      ARBs) and a proof of\u000a      concept study for using a mineralocorticoid receptor antagonist (MRA) in\u000a      mild heart failure. This\u000a      resulted in their leadership roles on large-scale randomised clinical\u000a      trials demonstrating the value\u000a      of each of the effective drug treatments for heart failure: beta-blockers,\u000a      ACE inhibitors, ARBs and\u000a      MRAs. These drugs act to limit aspects of either the renin-angiotensin\u000a      aldosterone system or the\u000a      sympathetic nervous system, both of which are abnormally regulated in\u000a      patients with heart failure.\u000a    Beta-blockers: In the mid-1990s, University of Glasgow\u000a      researcher Prof Henry Dargie chaired and\u000a      led the first definitive and ground-breaking trial establishing the\u000a      benefit of beta-blockers in heart\u000a      failure (CIBIS-2).1 This randomised study revealed that\u000a      patients with heart failure treated with the\u000a      beta-blocker bisoprolol had a 32% reduction in annual all-cause mortality\u000a      compared with a group\u000a      treated with a placebo. The striking mortality benefit with bisoprolol,\u000a      which was independent of\u000a      heart failure cause, led to early cessation of the CIBIS-2 trial. A\u000a      further study from the group\u000a      confirmed the positive value of another beta-blocker, carvedilol, in\u000a      patients with reduced heart\u000a      function (left ventricular systolic dysfunction; LVSD) following a heart\u000a      attack (CAPRICORN, 2001).\u000a    ACE inhibitors and ARBs: In a parallel trial (1999),\u000a      University of Glasgow researcher Prof John\u000a      Cleland was on the steering committee of the largest multi-centre trial\u000a      with an ACE inhibitor in\u000a      patients with symptomatic heart failure (ATLAS),2 demonstrating\u000a      the importance of adequate\u000a      dosing (showing a 24% reduction in hospitalisation rates with higher doses\u000a      of ACE inhibitors [~35\u000a      mg per day]) than were routinely being prescribed. The University of\u000a      Glasgow's Prof John\u000a      McMurray was a lead investigator in the innovative series of CHARM trials\u000a      (2003-2004). The trials\u000a      examined the effect of the ARB candesartan in three distinct groups of\u000a      patients with heart failure:\u000a      those with reduced left ventricular function intolerant of ACE inhibitors\u000a      (CHARM-Alternative),\u000a      similar patients also taking an ACE inhibitor (CHARM-Added)3\u000a      and, uniquely at the time, heart\u000a      failure patients with preserved function (CHARM-Preserved). In\u000a      CHARM-Alternative and CHARM-Added,\u000a      candesartan significantly reduced death from cardiovascular causes or\u000a      hospitalisation for\u000a      worsening heart failure (by 23% and 15% in CHARM-Alternative and — Added,\u000a      respectively) and\u000a      improved symptoms and quality of life. Patients with heart failure in\u000a      CHARM-Preserved had no\u000a      clear improvement when taking candesartan compared with placebo. A further\u000a      trial co-led by\u000a      McMurray also demonstrated the benefit of the ARB valsartan in patients\u000a      with LVSD, heart failure\u000a      or both following a heart attack (VALIANT).4\u000a    MRAs: In 2010, McMurray was one of the leaders of the\u000a      EMPHASIS-HF randomised controlled\u000a      trial, which assessed the value of adding the MRA eplerenone to standard\u000a      heart failure therapy\u000a      (ACE inhibitor or ARB plus beta-blocker) in patients with mild heart\u000a      failure.5 The design of this trial\u000a      was based upon CHARM-Added. Treatment with eplerenone led to a striking\u000a      37% overall reduction\u000a      in the composite outcome of cardiovascular mortality or heart failure\u000a      hospitalisation (and a 24%\u000a      reduction in the risk of death from any cause and a 22% reduction in\u000a      hospitalisation for any\u000a      reason). The magnitude of reduction on all-cause hospitalisation in\u000a      EMPHASIS-HF was (and still\u000a      is) the greatest of any major trial of a heart failure drug to date; the\u000a      overwhelming benefit of\u000a      eplerenone in this patient group led to early cessation of the trial.\u000a    The University of Glasgow investigators have also shown that all of these\u000a      treatments are cost-effective\u000a      and have also been leaders in key trials establishing (i) the value of the\u000a      biomarker B-type\u000a      natriuretic peptide (BNP) as a diagnostic test for heart failure6,\u000a      (ii) the positive benefit of specialist\u000a      heart failure nurses in reducing hospitalisation rates and improving\u000a      patient outcomes7 and (iii) the\u000a      neutral effect of rosuvastatin in patients with chronic heart failure\u000a      (CORONA, 2007), irbesartan in\u000a      patients with preserved function (I-Preserve, the design of which was\u000a      informed by CHARM-Preserved,\u000a      2008), nesiritide in acute HF (ASCEND-HF, 2011) and darbepoetin in chronic\u000a      heart\u000a      failure (RED-HF, 2013) all of which have led to changes in guidelines,\u000a      clinical practice or both and\u000a      further demonstrate the breadth of University of Glasgow research into\u000a      treatments for heart failure.\u000a    Key University of Glasgow researchers: John Cleland (Senior\u000a      Lecturer, 1994-1999; then\u000a      University of Hull and Imperial College, London); John McMurray (Professor\u000a      of Cardiology, 1999-present);\u000a      Henry Dargie (Professor of Cardiology 1994-1999; Honorary Senior Research\u000a      Fellow\u000a      1999-present); Ian Ford (Professor of Statistics\/Biostatistics,\u000a      1992-present); Theresa McDonagh\u000a      (Senior Lecturer, 1999-2004; then Imperial and King's College, London). Positions\u000a          in large multicentre\u000a          trials: CIBIS-2: Dargie, Chairman of scientific committee and\u000a      writing committee member (1\u000a      of 2). ATLAS: Cleland, steering committee member. CHARM trial series:\u000a      McMurray, executive\u000a      committee member and Principal Investigator, CHARM-Added. VALIANT:\u000a      McMurray, Co-chair of\u000a      executive committee. EMPHASIS-HF: McMurray, executive steering committee\u000a      member. External\u000a          collaborators: Members of trial committees; see\u000a      original articles for details.\u000a    "},{"CaseStudyId":"41154","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    IVFpredict informs National Institute for Health and Care\u000d\u000a          Excellence (NICE) guidelines on fertility\u000d\u000a    Improved prediction of IVF success allows women to be better informed\u000d\u000a      about the procedure, as well as to cope with emotional pressures and the\u000d\u000a      demanding treatment regimens. The IVFpredict model was used to develop\u000d\u000a      best practice on prediction of IVF success and provision of patient\u000d\u000a      information in the NICE \"Fertility: assessment and treatment for people\u000d\u000a        with fertility problems\" guidelines published in February 2013.a\u000d\u000a      Nelson acted as external advisor during the development of these\u000d\u000a      guidelines. In Chapter 13, \"Prediction of IVF success\", Nelson's\u000d\u000a      2011 PLoS Medicine paper1 was cited as one of four\u000d\u000a      studies used to define the factors that predict live birth success from\u000d\u000a      IVF therapy, which underpin recommendations 120-122 of the guidelines:\u000d\u000a    \u000d\u000a      Recommendation 120: \"Inform women that the chance of a live birth\u000d\u000a          following IVF treatment falls with rising female age.\"\u000a\u000d\u000a      Recommendation 121: \"Inform people that the overall chance of a\u000d\u000a          live birth following IVF treatment falls as the number of unsuccessful\u000d\u000a          cycles increases.\"\u000a\u000d\u000a      Recommendation 122: \"People should be informed that IVF treatment\u000d\u000a          is more effective in women who have previously been pregnant and\/or\u000d\u000a          had a live birth.\"\u000a\u000d\u000a    \u000d\u000a    A great deal of controversy exists surrounding which groups of women\u000d\u000a      should be eligible to receive NHS-funded IVF treatment. Chapter 14 of the\u000d\u000a      NICE guidelines, \"Access criteria for IVF\", used the IVFpredict\u000d\u000a      model as one of two calculators to develop the NICE economic costing\u000d\u000a      model, which produced recommendations for access to NHS-funded IVF for\u000d\u000a      women aged 23-39 years. The model defined estimates of IVF costs by age\u000d\u000a      and treatment strategy. Furthermore, a total of 198 patient scenarios,\u000d\u000a      modelled for cost-effectiveness, are provided in the guideline appendix,\u000d\u000a      thereby providing a detailed reference for clinical decisions on access to\u000d\u000a      free treatment.b\u000d\u000a    Stimulating HFEA policy debate on embryo transfer number\u000d\u000a    The most significant risk of IVF therapy is the high probability of\u000d\u000a      multiple births, which is associated with increased rates of miscarriage,\u000d\u000a      premature birth, low birth weight and perinatal mortality (infant death\u000d\u000a      immediately before or after birth). Approximately 20-30% of all IVF\u000d\u000a      pregnancies are multiple births, resulting from the transfer of multiple\u000d\u000a      embryos during treatment (intended to increase the chance of a successful\u000d\u000a      pregnancy). HFEA imposes strict multiple birth targets on all licenced IVF\u000d\u000a      centres in the UK (set at 10% in October 2012), permitting the transfer of\u000d\u000a      three embryos only to women above 40 years (since 2009). Shortly after the\u000d\u000a      publication of Nelson and Lawlor's 2012 Lancet paper,2\u000d\u000a      HFEA released a public statement acknowledging the value of their\u000d\u000a      findings,c which were subsequently reviewed by the HFEA\u000d\u000a      Multiple Birth Stakeholder Group and brought to the attention of the HFEA\u000d\u000a      Authority — the overarching committee determining HFEA Code of Practice\u000d\u000a      for IVF unit regulation — at their June 2013 meeting. Key findings and\u000d\u000a      data from Nelson and Lawlor's 2012 Lancet paper2 were\u000d\u000a      presented at this meeting and consequently members agreed the following\u000d\u000a      decision to:\u000d\u000a    \"Develop guidance for the Code of Practice which discouraged centres\u000d\u000a        from carrying out three-embryo transfers\" (recorded in the meeting\u000d\u000a      minutes, 9.11, page 11)d\u000d\u000a    The revised HEFA Code of Conduct came into force on 1 October 2013.\u000d\u000a    According to 2011 data, around 48,000 women undergo IVF in the UK each\u000d\u000a      year. Through influencing the development of evidence-based clinical\u000d\u000a      guidelines and stimulating revision to regulatory codes of practice,\u000d\u000a      University of Glasgow research has contributed to recommendations on\u000d\u000a      information and clinical treatment delivered to patients, and defined the\u000d\u000a      criteria for access to NHS-funded IVF therapy for all patients in the UK.\u000d\u000a    IVFpredict helps patients to understand their options and manage\u000d\u000a          expectations\u000d\u000a    The freely-available online IVFpredict calculator is a simple\u000d\u000a      questionnaire (nine questions) providing women with rapid (approximately 1\u000d\u000a      minute), accurate, evidence-based estimates of their percentage chance of\u000d\u000a      having a successful pregnancy and live birth following IVF treatment.\u000d\u000a      Armed with this information, women can make informed treatment choices and\u000d\u000a      have realistic expectations of the outcome. The questionnaire is also\u000d\u000a      available via a smartphone application (at a small cost).f\u000d\u000a      Shortly after its release online in January 2011, IVFpredict received\u000d\u000a      extensive media coverage and promotion both nationally and worldwide,\u000d\u000a      including a 5-minute feature on ABC News in the USA (May 2011).g\u000d\u000a      Since then, more than 5 million individuals have accessed the IVFpredict\u000d\u000a      website (predominantly from Europe [39%], North America [24%] and Asia\u000d\u000a      [19%]), according to site traffic data), and over 700 people have\u000d\u000a      purchased the IVFPredict app providing them with a simple and accessible\u000d\u000a      way to obtain information about their treatment choices and outcomes.h\u000d\u000a    Recognition of the University of Glasgow work on personalised IVF\u000d\u000a    The impacts described above formed the basis of a University of Glasgow\u000d\u000a      submission to the Times Higher Education `Research Project of the Year'\u000d\u000a      awards (a category showcasing `significant economic, social, cultural\u000d\u000a        or other public benefit') and was one of only six entries\u000d\u000a      shortlisted. The awards recognise `the excellence and amazing\u000d\u000a        achievements of UK higher education institutions' (winner to be\u000d\u000a      announced on 28 November 2013).i\u000d\u000a    Influencing patient access and prioritisation of IVF therapy\u000d\u000a    University of Glasgow researchers were the first in the world to\u000d\u000a      demonstrate that AMH levels could predict ovarian response before\u000d\u000a      commencement of IVF therapy. This strategy has rapidly become recognised\u000d\u000a      as a leading mechanism by which to classify patients for treatment. The\u000d\u000a      AMH Gen II assay was subsequently developed by Beckman Coulter, a\u000d\u000a      multinational company supporting innovations in biomedical testing. The\u000d\u000a      EMEAI Scientific Manager Immunoassay, Beckman Coulter UK Ltd.,j\u000d\u000a      states: \"The measurement of anti-Müllerian hormone (AMH) is just\u000d\u000a        starting to become accepted into routine clinical practice in fertility\u000d\u000a        centres throughout the world. Professor Nelson's work has clearly\u000d\u000a        established the benefit of the measurement of AMH in this setting by\u000d\u000a        demonstrating that use of AMH levels to individualise therapy results in\u000d\u000a        increased pregnancy rates and reduced complications.\" Before any new\u000d\u000a      diagnostic test can become established in the healthcare pathway, clear\u000d\u000a      evidence is required that it both improves patient outcomes and reduces\u000d\u000a      the cost of care. University of Glasgow research enabled Beckman Coulter\u000d\u000a      to establish this evidence base for the AMH Gen II assay and Nelson's\u000d\u000a      published papers are used as key proof and guidance for healthcare workers\u000d\u000a      who are unfamiliar with the use of the assay. As such, \"it is integral\u000d\u000a        to and underpins our whole marketing strategy which has resulted in the\u000d\u000a        transition of the measurement of AMH from a research tool into routine\u000d\u000a        clinical practice. AMH is a premium product for Beckman Coulter and one\u000d\u000a        of our flagship immunoassays — European sales have trebled from 2008 to\u000d\u000a        2009.\"\u000d\u000a    The University of Glasgow research also formed the evidence basis for\u000d\u000a      inclusion of an AMH criterion in the NHS Scotland Pre-Implantation Genetic\u000d\u000a      Diagnosis and Screening Service framework (2011)j and has\u000d\u000a      therefore been instrumental in the access decisions and prioritisation of\u000d\u000a      women for IVF therapy across Scotland. As a consequence, all women in\u000d\u000a      Scotland are required to meet a threshold level of circulating AMH levels\u000d\u000a      (of greater than 6 pmol\/L) in order to be referred for IVF treatment.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    The ultimate goal of in-vitro fertilisation (IVF) therapy is the live\u000d\u000a      birth of a single, healthy child. However, issues of treatment failure,\u000d\u000a      complications and multiple births (twins or triplets) continue to persist\u000d\u000a      and have a major impact on patient quality of life. Pioneering research at\u000d\u000a      the University of Glasgow has driven the concept of personalised IVF\u000d\u000a      therapy and outcome prediction, reforming clinical guidelines and defining\u000d\u000a      criteria for access to funded IVF therapy. This research has stimulated\u000d\u000a      revision of UK regulatory policy on the number of embryos transferred\u000d\u000a      during IVF. These strategies underpin the recommended practice for the\u000d\u000a      48,000 women undergoing IVF in the UK each year. In addition, the Glasgow\u000d\u000a      team's online, personalised `IVFpredict' calculator, which women can use\u000d\u000a      to predict their success of a live birth, has been completed by more than\u000d\u000a      5 million users worldwide.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Nelson S. M. & Lawlor D. A. Predicting\u000a        live birth, preterm delivery, and low birth weight in infants born from\u000d\u000a        in vitro fertilisation: a prospective study of 144,018 treatment cycles.\u000d\u000a      PLoS Med 2011; 8: e1000386 doi:10.1371\/journal.pmed.1000386.\u000d\u000a    \u000a\u000a2. Lawlor D. A. & Nelson S. M. Effect\u000a        of age on decisions about the numbers of embryos to transfer in assisted\u000d\u000a        conception: a prospective study. Lancet 2012; 379: 521-527\u000d\u000a      doi:10.1016\/S0140-6736(11)61267-1.\u000d\u000a    \u000a\u000a3. Nelson S. M. et al. Serum\u000a        anti-Müllerian hormone and FSH: prediction of live birth and extremes of\u000d\u000a        response in stimulated cycles — implications for individualization of\u000d\u000a        therapy. Hum. Reprod. 2007; 22: 2414-2421\u000d\u000a      doi:10.1093\/humrep\/dem204.\u000d\u000a    \u000a\u000a4. Nelson S. M. et al. Anti-Müllerian\u000a        hormone-based approach to controlled ovarian stimulation for assisted\u000d\u000a        conception. Hum. Reprod. 2009; 24: 867-875\u000d\u000a      doi:10.1093\/humrep\/den480.\u000d\u000a    \u000a\u000a5. Wallace\u000a        A. M. et al. A\u000d\u000a        multicentre evaluation of the new Beckman Coulter anti-Müllerian hormone\u000d\u000a        immunoassay (AMH Gen II). Ann. Clin. Biochem. 2011; 48:\u000d\u000a      370-373 doi:10.1258\/acb.2011.010172\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"14","Subject":"Paediatrics and Reproductive Medicine"}],"Sources":"\u000d\u000a    a. NICE CG156 \"Fertility:\u000a          assessment and treatment for people with fertility problems\"\u000d\u000a      guidelines, February 2013. Chapter 13 (p224); Chapter 14 (Access\u000d\u000a        criteria to IVF, p237); recommendations 120, 121 and 122 (p230-231)\u000d\u000a    b. NICE CG156 Appendix M — Cost-effective\u000a        treatment of IVF analyses\u000d\u000a    c. HFEA `Statement on embryo\u000d\u000a        transfer study', 12 January 2012\u000d\u000a    d. HFEA Authority\u000a        meeting 13 June 2013, Multiple Births update\u000d\u000a    e. HFEA Minutes of Authority\u000d\u000a        meeting, 13 June 2013. Sections 9.7 and 9.11 (p11)\u000d\u000a    f. IVFpredict website including\u000d\u000a      link to IVFpredict app\u000d\u000a    g. Examples of media coverage of IVFpredict:\u000d\u000a    \u000d\u000a      UK: The Daily Mail, 5 January, 2011(article)\u000d\u000a      USA: ABC News, 1 May, 2011 (video\u000a          clip)\u000d\u000a      Australia: ABC radio interview with Professor Scott Nelson, 15 August,\u000d\u000a        2011(recording)\u000d\u000a    \u000d\u000a    h. IVFpredict website download data — available on request\u000d\u000a    i. The Times\u000d\u000a        Higher Research Project of the Year Shortlist, 2013\u000d\u000a    j. Statement from EMEAI Scientific Manager Immunoassay, Beckman Coulter\u000d\u000a      UK Ltd. — available on request\u000d\u000a    k. NHS Scotland National Services Division guidelines, \"A\u000d\u000a          Framework for Decision Making for the Scottish Pre-Implantation\u000d\u000a          Genetic Diagnosis and Screening Service\", April 2011 (p12) \u000d\u000a    ","Title":"\u000d\u000a    Personalisation of in-vitro fertilisation therapy\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The process of in-vitro fertilisation (IVF) has revolutionised human\u000d\u000a      reproductive biology since it was first successfully performed in the\u000d\u000a      1970s, allowing many thousands of women with reduced fertility to\u000d\u000a      conceive. Women undergoing IVF first receive drugs to stimulate ovulation,\u000d\u000a      the process by which eggs are released from specialised structures\u000d\u000a      (follicles) in the ovary. One or more eggs are then harvested in the\u000d\u000a      clinic, fertilised by sperm outside the body and grown under laboratory\u000d\u000a      conditions to establish viable embryos. These embryos are transferred to\u000d\u000a      the patient's uterus with the aim of establishing a normal pregnancy.\u000d\u000a    Development of IVFpredict, a personalised predictor of IVF outcome\u000d\u000a          success\u000d\u000a    Collaborative work between University of Glasgow clinical researcher\u000d\u000a      Professor Scott Nelson and Professor Debbie Lawlor (University of Bristol)\u000d\u000a      led to the development of a model that predicts live birth outcome\u000d\u000a      following IVF treatment. Published in 2011, this carefully designed\u000d\u000a      research involved a prospective analysis of data collected by the UK\u000d\u000a      independent IVF regulatory body, the Human Fertilisation and Embryology\u000d\u000a      Authority (HFEA), on all IVF treatment cycles (163,425) and outcomes in\u000d\u000a      the UK from 2003 to 2007.1 The resultant model offered\u000d\u000a      substantial advances upon other predictor models with improved\u000d\u000a      calibration, inclusion of updated clinical techniques and data on the use\u000d\u000a      of donor eggs, IVF cycle number and previous successful live birth\u000d\u000a      history. Consequently, the ability to predict live births using\u000d\u000a      couple-specific and treatment-specific factors was significantly improved.\u000d\u000a      Nelson and Lawlor subsequently named the model `IVFpredict' and Nelson\u000d\u000a      developed an IVFpredict website with Dr Tom Kelsey (University of St\u000d\u000a      Andrews) in 2011.\u000d\u000a    Transfer of three embryos does not improve outcomes in any maternal\u000d\u000a          age group\u000d\u000a    The number of embryos transferred into the uterus during IVF therapy can\u000d\u000a      affect the success of the pregnancy. An extension of the above-mentioned\u000d\u000a      2011 study used the same dataset to analyse more than 124,000 IVF cycles,\u000d\u000a      yielding vital information on outcomes with the additional prognostic\u000d\u000a      indicator of maternal age. Results showed that overall, live births are\u000d\u000a      more likely to occur among women aged under 40 years than those aged 40\u000d\u000a      years or above, regardless of the number of embryos transferred.\u000d\u000a      Nevertheless, the analysis revealed that the transfer of three embryos\u000d\u000a      does not result in a higher live birth rate in either age group compared\u000d\u000a      with the transfer of two embryos; in fact, transfer of three embryos was\u000d\u000a      associated with a significantly increased risk of adverse outcomes\u000d\u000a      (multiple births, preterm birth and low birth weight). As a result, Nelson\u000d\u000a      and Lawlor's findings advised against the transfer of three embryos for\u000d\u000a      women of all ages undergoing IVF therapy.2 Nelson and Lawlor\u000d\u000a      provided equal contributions to this study which was published in The\u000d\u000a        Lancet in 2012.\u000d\u000a    Anti-Müllerian hormone as a biomarker to stratify patients for IVF\u000d\u000a          therapy\u000d\u000a    A pioneering research project conducted by Nelson and fellow University\u000d\u000a      of Glasgow researcher Professor Richard Fleming revealed that the outcome\u000d\u000a      of IVF could be predicted before treatment was started by measuring the\u000d\u000a      concentration of anti-Müllerian hormone (AMH) in the blood. AMH is\u000d\u000a      produced by growing follicles and levels of this hormone are indicative of\u000d\u000a      the magnitude of a woman's remaining supply of eggs. Nelson and Fleming\u000d\u000a      (2007) analysed blood AMH levels among 340 women and found a strong\u000d\u000a      positive correlation between this measure and the woman's subsequent\u000d\u000a      response to ovarian stimulation and her live birth rate.3\u000d\u000a      Notably, AMH was shown to be a sufficiently sensitive predictor that it\u000d\u000a      could identify the risk of either an excessive ovarian response (ovarian\u000d\u000a      hyperstimulation syndrome; OHSS) or a poor response to treatment. The\u000d\u000a      effectiveness of personalised treatment regimens designed according to AMH\u000d\u000a      levels was validated in 2009.4 This study showed that women in\u000d\u000a      the `excessive response' category (AMH level greater than 15 pmol\/L) who\u000d\u000a      received conventional IVF treatment had a pregnancy rate of 40% (with a\u000d\u000a      20% rate of hospitalisation for OHSS). By contrast, women using\u000d\u000a      personalised IVF protocols experienced a shorter duration of treatment,\u000d\u000a      but with significantly greater pregnancy rates (more than 60%) and no\u000d\u000a      OHSS-related hospital admissions. These results were followed by the\u000d\u000a      development of a commercially-available AMH assay (AMH Gen II) in 2011.5\u000d\u000a    Key University of Glasgow researchers: Scott Nelson\u000d\u000a      (Clinical Lecturer [2005-2008], Muirhead Chair of Reproductive and\u000d\u000a      Maternal Medicine [2008-present]); Richard Fleming (Honorary Professor of\u000d\u000a      Reproductive Medicine, 2006-present).\u000d\u000a    Key external collaborators: Professor Debbie Lawlor\u000d\u000a      (Professor of Epidemiology, University of Bristol);1,2 Tom\u000d\u000a      Kelsey (Senior Lecturer, University of St Andrews);1,2 Dr\u000d\u000a      Sherry Faye (Beckman Coulter UK Ltd., High Wycombe).5\u000d\u000a    "},{"CaseStudyId":"41155","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Statins are the preferred lipid-lowering drugs to prevent CVD\u000d\u000a    Current estimates suggest that more than 7,000 European and US adults die\u000d\u000a      of CVD each day. Internationally recognised clinical trials conducted by\u000d\u000a      the University of Glasgow have provided the cornerstone of the evidence\u000d\u000a      base supporting lipid lowering as a strategy to reduce CVD risk. This\u000d\u000a      landmark research drove the global adoption of statins as the first-line\u000d\u000a      medical option for prevention of CVD and continues to shape modern day\u000d\u000a      lipid-lowering guidance and practice worldwide, with associated benefits\u000d\u000a      for patients and healthcare systems. Statins offer major benefits for\u000d\u000a      patient outcomes, including reduction in mortality and major CVD events.\u000d\u000a    Clinical guidelines support prevention strategies with statins\u000d\u000a    The University of Glasgow led\/steering committee involvement in RCTs on\u000d\u000a      lipid lowering1,2,3,5,6 dominate the evidence base in current,\u000d\u000a      high profile clinical guidelines on lipid lowering including the joint\u000d\u000a      European Society of Cardiology (ESC) and European Atherosclerosis Society\u000d\u000a      (EAS ) and the American Association of Clinical\u000d\u000a      Endocrinologists (AACE). These guidelines recommend statins as the\u000d\u000a      cholesterol-lowering drug of choice.\u000d\u000a    2011 ESC\/EAS guideline on the management of dyslipidaemiasa\u000d\u000a    These state that `not only should those at high risk be identified and\u000d\u000a        managed; those at moderate risk should also receive professional advice\u000d\u000a        regarding lifestyle changes, and in some cases drug therapy will be\u000d\u000a        needed to control their plasma lipids.' The guidelines also\u000d\u000a      underscore the need to promote primary prevention efforts.\u000d\u000a    \u000d\u000a      Recommendations for the use of statins among patients who have been\u000d\u000a        stratified according to CVD risk (via assessment with the ESC\u000d\u000a        Systematic Coronary Risk Evaluation [SCORE] algorithm) and LDL-C level —\u000d\u000a        WOSCOPS1, PROSPER3, ASCOT-LLA5, JUPITER6\u000d\u000a        and TNT are cited in the evidence base; Table 3 (p1780). In summary the\u000d\u000a        ESC\/EAS recommends immediate lipid-lowering intervention for all\u000d\u000a        individuals at high risk (SCORE >5 but <10) with LDL-C levels ≥2.5\u000d\u000a        mmol\/L or at very high risk (SCORE ≥10; LDL-C ≥1.8 mmol\/L).\u000d\u000a        Lipid-lowering may be considered in both groups at lower LDL-C levels\u000d\u000a        and among low-risk and moderate-risk individuals with LDL-C levels\u000d\u000a        uncontrolled by lifestyle intervention.\u000d\u000a      ASCOT-LLA5 and JUPITER6 are two of three papers\u000d\u000a        cited to support the following recommendation on primary prevention \"statin\u000d\u000a          therapy should be considered for reducing the risk of ischaemic stroke\u000d\u000a          and other CV events in accordance with the recommendations given in\u000d\u000a          Table 3.\"\u000d\u000a    \u000d\u000a    2012 AACE guideline on the management of dyslipidaemia and prevention\u000d\u000a        of atherosclerosisb\u000d\u000a    \u000d\u000a      `Lipid goals recommended for patients at risk of coronary artery\u000d\u000a        disease' — PROSPER and ASCOT-LLA underpin five of these seven key\u000d\u000a        recommendations including lowering LDL-C to less than 100 mg\/dL (2.6\u000d\u000a        mmol\/L) for all adults and below 70 mg\/dL (1.8 mmol\/L) for patients at\u000d\u000a        very high risk (Grade A recommendation); p13-14 and Table 12.\u000d\u000a    \u000d\u000a    Taken together, the ESC\/EAS and AACE lipid management guidelines advise\u000d\u000a      that adults with a 20% chance of developing CVD within a 10-year timespan\u000d\u000a      should be offered a statin for primary prevention. Furthermore, statins\u000d\u000a      are unequivocally recommended for individuals considered to be at very\u000d\u000a      high risk; namely, patients with diabetes (if aged over 40 years), chronic\u000d\u000a      kidney disease or peripheral arterial disease, as well as those who have\u000d\u000a      previously experienced a CVD event. These recommendations on lipid\u000d\u000a      lowering are also aligned in the major European and American guidelines on\u000d\u000a      CVD prevention reinforcing the value of lipid lowering in disease\u000d\u000a      prevention.\u000d\u000a    Cochrane Systematic Review\u000d\u000a      Despite the fact that there have been many subsequent clinical trials\u000d\u000a      investigating statin use, the validity and profile of the seminal\u000d\u000a      University of Glasgow studies in driving best practice for patient care\u000d\u000a      remain undiminished. These trials are regularly included in meta-analyses,\u000d\u000a      such as the Cochrane Systematic Reviews, which evaluate primary clinical\u000d\u000a      research and are recognised as the gold standard for providing an evidence\u000d\u000a      base for changing clinical practice. For example, a meta-analysis\u000d\u000a      conducted by the Cholesterol Treatment Trialists (CTT) Collaboration,\u000d\u000a      which was published in 2010 and utilised the University of Glasgow\u000d\u000a      studies, was instrumental in changing the recommendations of the Cochrane\u000d\u000a      Systematic Review on the use of statins for primary prevention of CVD\u000d\u000a      (2013).c The 2013 evidence review stated: \"our previous\u000d\u000a        conclusion urging caution in the use of statins in people at low risk of\u000d\u000a        CV events is no longer tenable in light of the CTT Collaboration\u000d\u000a        findings ... these new findings counter earlier opinion that the\u000d\u000a        evidence is insufficient to support use of statins in primary prevention\u000d\u000a        for women or in older men.\" The 2013 Cochrane Systematic Review also\u000d\u000a      cited WOSCOPS1 and JUPITER6 in the evidence base\u000d\u000a      supporting this conclusion, with JUPITER6 identified as one of\u000d\u000a      four new studies included in the analysis.c\u000d\u000a    Primary prevention with statins provides benefits for patients\u000d\u000a    Reduced mortality\u000d\u000a      The WOSCOPS follow-up study2 showed that primary prevention\u000d\u000a      with statins exerted durable, long-term reduction in death rates. US\u000d\u000a      estimates revealed that deaths as a result of CVD declined by\u000d\u000a      approximately 33% from 1999 to 2009.d The 2013 American Heart\u000d\u000a      Association heart disease and stroke statistics reportd cites\u000d\u000a      evidence that lipid lowering prevents or postpones around 24% of all\u000d\u000a      deaths from CHD, equivalent to an 8.2% drop in deaths during the period\u000d\u000a      1999-2009 in the US.\u000d\u000a    Indicators of quality care\u000d\u000a      The Quality and Outcomes Framework (QOF) is an incentive scheme for GP\u000d\u000a      practices in England providing financial rewards for patient care across\u000d\u000a      multiple disease domains. Several of these QOFs focus on primary and\u000d\u000a      secondary prevention with statins. For example, 74% of diabetes patients,\u000d\u000a      73% of patients with CHD and 68% of stroke patients received a statin to\u000d\u000a      achieve total cholesterol levels at or below 5 mmol\/L (April 2011-March\u000d\u000a      2012).e The fact that cholesterol levels are one of the best\u000d\u000a      adhered to targets is testament to the community acceptance of the\u000d\u000a      benefits of this approach.\u000d\u000a    Health checks\u000d\u000a      University of Glasgow research demonstrated that lipid lowering prevention\u000d\u000a      strategies are valid tools for public health and initiatives are now in\u000d\u000a      place worldwide to promote heart health. For example, the US Million\u000d\u000a      Hearts programme (launched September 2011) has a stated goal to ensure\u000d\u000a      effective implementation of lipid-lowering treatment on a population\u000d\u000a      basis, from a baseline of 33% in 2011 to 65% by 2017.f Since\u000d\u000a      March 2009, vascular risk assessment has been implemented in England\u000d\u000a      through NHS Health Check. All adults aged 40-74 years without diagnosed\u000d\u000a      CVD are invited for a health check once every 5 years for assessment of\u000d\u000a      risk factors including cholesterol level. Personalised primary prevention\u000d\u000a      advice based on the risk assessment is provided. In the period 2012-2013,\u000d\u000a      around 1.3 million eligible adults attended assessments.f\u000d\u000a    Emergence of generic statins drives down cost of primary prevention\u000d\u000a    The detailed extension of the WOSCOPS follow-up4 demonstrated\u000d\u000a      that CVD prevention with statins had saved money for healthcare providers\u000d\u000a      even at levels below the 20% risk of CVD listed in current clinical\u000d\u000a      guidelines. The economic viability of statin use shown by this analysis\u000d\u000a      attracted extensive media coverage, raising public awareness of this\u000d\u000a      strategy.g More than 60 million statin prescriptions were\u000d\u000a      dispensed in England alone in 2012, and the global statin market was\u000d\u000a      valued at $20.5 billion in 2011. However, the increasing availability of\u000d\u000a      generic formulations of statins is predicted to eat into this market.h\u000d\u000a      Consequently, use of statins will become even more prevalent and cost\u000d\u000a      effective for healthcare organisations.4\u000d\u000a    ","ImpactSummary":"\u000d\u000a    More than half of UK adults aged over 45 years have high cholesterol\u000d\u000a      levels, the major modifiable risk factor for cardiovascular disease (CVD).\u000d\u000a      Over the past 20 years, University of Glasgow researchers have led\u000d\u000a      numerous landmark clinical trials establishing the benefits of statins for\u000d\u000a      CVD prevention. High-profile international clinical guidelines on lipid\u000d\u000a      lowering cite these studies in the key evidence base for recommendations\u000d\u000a      to guide statin use, demonstrating the considerable influence this work\u000d\u000a      exerts on current clinical practice and public health. This has driven the\u000d\u000a      global uptake of statins and provided the evidence-base for CVD risk\u000d\u000a      assessment and prevention strategies that are now implemented worldwide.\u000d\u000a      The use of statins has transformed patient care, provided a cost-effective\u000d\u000a      prevention strategy for healthcare providers and made major contributions\u000d\u000a      to the falling CVD mortality rates across Europe and the US.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    University of Glasgow\u000d\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"References":"\u000d\u000a    \u000a1. WOSCOPS study group Prevention\u000a        of coronary heart disease with pravastatin in men with\u000d\u000a        hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307\u000d\u000a      doi: 10.1056\/NEJM199511163332001.\u000d\u000a    \u000a\u000a2. \u000d\u000a        Ford I et al., for the WOSCOPS\u000a        Group. Long-term\u000a        follow-up of the West of Scotland Coronary Prevention Study. N\u000d\u000a        Engl J Med. 2007; 357: 1477-1486 doi: 10.1056\/NEJMoa065994.\u000d\u000a    \u000a\u000a3. PROSPER Study Group. PROspective\u000a        Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly\u000d\u000a        individuals at risk of vascular disease (PROSPER): a randomised\u000d\u000a        controlled trial. Lancet 2002; 360: 1623-1630 doi: 10.1016\/S0140-6736(02)11600-X.\u000d\u000a    \u000a\u000a4. \u000d\u000a        McConnachie A et al. Long-term\u000a        impact on healthcare resource utilization of statin treatment, and its\u000d\u000a        cost effectiveness in the primary prevention of cardiovascular disease:\u000d\u000a        a record linkage study. Eur\u000a          Heart J. 2013 (published online Jul 9)\u000d\u000a      doi:10.1093\/eurheartj\/eht232.\u000d\u000a    \u000a\u000a5. Sever PS et al. Prevention\u000a        of coronary and stroke events with atorvastatin in hypertensive patients\u000d\u000a        who have average or lower-than-average cholesterol concentrations, in\u000d\u000a        the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm\u000d\u000a        (ASCOT-LLA): a multicentre randomised controlled trial. Lancet.\u000d\u000a      2003; 361:1149-1158 doi:10.1016\/S0140-6736(03)12948-0.\u000d\u000a    \u000a\u000a6. Ridker PM et al., for the JUPITER Study Group. Rosuvastatin\u000a        to prevent vascular events in men and women with elevated C-reactive\u000d\u000a        protein. N Engl J Med. 2008; 359: 2195-2207 doi:\u000d\u000a      10.1056\/NEJMoa0807646.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    a. \u000d\u000a        ESC\/EAS guideline, 2011 WOSCOPS (ref 19), PROSPER (ref 26),\u000d\u000a      ASCOT-LLA (ref 28), TNT (ref 33) and JUPITER (ref 37) cited in Table 3\u000d\u000a      (Section 3.2, p1779-1780) as 5 of 27 Level A evidence studies. Also cited\u000d\u000a      on p1790 (section 7.1); p1802 (Section 10.4); p1805 (Section 10.7); and\u000d\u000a      p1809 (Section 10.12)\u000d\u000a    b.  AACE\u000d\u000a        guideline, 2012. WOSCOPS1 (ref 463), WOSCOPS follow-up2\u000d\u000a      (ref 505), PROSPER3 (ref 38), ASCOT-LLA5 (ref 39)\u000d\u000a      and JUPITER6 (ref 338) cited. See Executive Summary (p13-14);\u000d\u000a      Tables 12, 18, 20 and 21; and the evidence base (p22\/23, 28\/29, 32\/34\/39,\u000d\u000a      44\/45\/47\/48 and 52)\u000d\u000a    c. Update to Cochrane\u000a        Systematic Review, 2013. Cites CTT\u000a        2010 and CTT\u000a        2012a (p3-4, 13-14 and 87-94 [feedback summary]); WOSCOPS (p8,\u000d\u000a      12-13, 44 and 52-80); and JUPITER (p8, 11-13, 39 and 52-80)\u000d\u000a    d. American Heart Association heart\u000a        disease and stroke statistics, 2013 (p110 and 187; reference,\u000d\u000a      Table 2)\u000d\u000a    e.  Quality and Outcomes\u000d\u000a        Framework, 2011-2012. See diabetes (DM17) and coronary heart disease\u000d\u000a      (CHD8) and stroke (STROKE8)\u000d\u000a    f. Health checks: Million\u000a        Hearts (USA) and NHS\u000a        Health Check (England)\u000d\u000a    g. Media coverage of primary prevention economic benefit: Herald,\u000d\u000a      Reuters,\u000d\u000a      Express,\u000d\u000a      Scotsman\u000d\u000a    h. Media coverage of generic statins, 2011-2013: Cardiovascular\u000a        Business, Forbes,\u000d\u000a      Crain's\u000a        New York Business, Philly.com\u000d\u000a    ","Title":"\u000d\u000a    Global adoption of statins for cardiovascular disease prevention\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    WOSCOPS establishes the effectiveness of statins for primary\u000d\u000a          prevention of CVD\u000d\u000a    A University of Glasgow research team (see below) conceptualised and led\u000d\u000a      the ground-breaking West of Scotland Coronary Prevention Study (WOSCOPS).\u000d\u000a      Published in 1995, the innovative WOSCOPS study was a clinically driven primary\u000d\u000a        prevention randomised controlled trial (RCT): the researchers\u000d\u000a      purposely targeted individuals with no history of heart attack who were\u000d\u000a      apparently healthy yet were hypothesised to be at a high risk of having a\u000d\u000a      heart attack in the near future based on their cholesterol levels.\u000d\u000a    Drawing on a wealth of experience in cholesterol metabolism research, the\u000d\u000a      University of Glasgow team randomised 6,595 men (aged 45-64 years) with\u000d\u000a      raised low-density lipoprotein cholesterol (LDL-C) levels (two consecutive\u000d\u000a      measurements ≥4 mmol\/L, one ≥4.5 mmol\/L and one ≤6 mmol\/L) to treatment\u000d\u000a      with pravastatin or placebo and participants were followed for an average\u000d\u000a      of 5 years. WOSCOPS showed that pravastatin reduced the risk of a\u000d\u000a      first-time heart attack (myocardial infarction, MI) or death from coronary\u000d\u000a      heart disease (CHD) by 31% and, importantly, the risk of death from any\u000d\u000a      cause by 22%.1 In contrast to previous cholesterol-lowering\u000d\u000a      drugs, pravastatin was well tolerated. WOSCOPS therefore set the stage for\u000d\u000a      statins as a safe primary prevention therapy for reducing CHD risk and\u000d\u000a      provided conclusive evidence in support of the hypothesis that a raised\u000d\u000a      blood cholesterol level is a modifiable risk factor for CVD. In testament\u000d\u000a      to the importance of this study, the publication has received over 6,100\u000d\u000a      citations (Scopus, November 2013).\u000d\u000a    Statins provide long-term protective effects\u000d\u000a    A subsequent seminal study published by the University of Glasgow team in\u000d\u000a      2007 reported on the long-term benefits (`legacy effects') of pravastatin.2\u000d\u000a      Follow-up of the WOSCOPS survivors 10 years after the completion trial\u000d\u000a      revealed that the risk of heart attack or death from CHD remained lower in\u000d\u000a      the pravastatin treated population. The results suggested that 5 years of\u000d\u000a      statin therapy during the trial had slowed disease progression and\u000d\u000a      resulted in on-going CVD risk reduction over the entire 15-year follow-up\u000d\u000a      period.\u000d\u000a    Statins confer primary and secondary prevention among elderly\u000d\u000a          populations\u000d\u000a    Whereas primary prevention seeks to reduce risk before disease develops,\u000d\u000a      the goal of secondary prevention is to limit further episodes\u000d\u000a      after an initial event has occurred. The pravastatin in elderly\u000d\u000a      individuals at risk of vascular disease study (PROSPER, 2002) was a\u000d\u000a      collaborative RCT led by the University of Glasgow.3 The trial\u000d\u000a      enrolled 2,804 men and 3,000 women aged 70-82 years who either had a\u000d\u000a      history of CVD or were at increased risk of CVD due to raised cholesterol\u000d\u000a      levels. Participants received pravastatin or placebo for 3 years.\u000d\u000a      Pravastatin reduced the risk of the primary end point (coronary death,\u000d\u000a      non-fatal stroke, non-fatal MI) by 15% thereby prompting the extension of\u000d\u000a      prevention strategies with statins to include elderly individuals.\u000d\u000a    Statins are cost effective for primary prevention\u000d\u000a    The University of Glasgow extension of the WOSCOPS follow-up categorised\u000d\u000a      the cause-specific reason for hospital admission and number of events in\u000d\u000a      the 10 years post-trial to show the cost effectiveness of statin therapy\u000d\u000a      (saving the NHS £710,000 over 15 years per 1,000 patients treated with\u000d\u000a      pravastatin for 5 years).4 By retrospectively assigning trial\u000d\u000a      participants into three categories based on their pre-trial CHD risk, the\u000d\u000a      analysis revealed that statin therapy was beneficial and cost effective\u000d\u000a      even among patients with the lowest pre-existing risk. The study further\u000d\u000a      confirmed the protective legacy effect and long-term safety of statins in\u000d\u000a      primary prevention.\u000d\u000a    Benefits of statins extend to other clinical scenarios\u000d\u000a    University of Glasgow investigators have gone on to further define the\u000d\u000a      clinical utility of statins through major contributions to landmark\u000d\u000a      multi-centre statin RCTs in patients without raised cholesterol. The\u000d\u000a      ASCOT-LLA trial (2003; Professor Gordon McInnes, steering committee)\u000d\u000a      examined the effect of atorvastatin in patients with high blood pressure,\u000d\u000a      demonstrating a 36% reduction in coronary death and non-fatal MI in the\u000d\u000a      atorvastatin group.5 Furthermore, the JUPITER trial (2008;\u000d\u000a      Professor James Shepherd, steering committee) demonstrated the value of\u000d\u000a      statins in patients with elevated C-reactive protein (CRP) and no history\u000d\u000a      of CHD. Patients treated with rosuvastatin showed a 54% reduction in MI\u000d\u000a      and a 20% reduction in death from any cause6, thereby\u000d\u000a      confirming the benefit of statins in primary prevention as shown by\u000d\u000a      WOSCOPS. Finally, the 2005 TNT trial (Shepherd, steering committee)\u000d\u000a      randomised 10,001 men and women with a history of CHD to either 10 or 80\u000d\u000a      mgs\/day of atorvastatin. The trial not only demonstrated that higher doses\u000d\u000a      of atorvastatin were safe but that more intensive lipid lowering (80\u000d\u000a      mg\/day) reduced CVD events by 22% versus conventional lipid lowering\u000d\u000a      strategies (10 mg\/day).\u000d\u000a    Key University of Glasgow researchers: WOSCOPS1,2\u000d\u000a      — James Shepherd (Honorary Professor of Clinical Biochemistry\u000d\u000a      [1977-present]); Stuart Cobbe (Walton Chair of Medical Cardiology\u000d\u000a      [1985-2008], Honorary Senior Research Fellow [2008-present]); Ian Ford\u000d\u000a      (Professor of Statistics\/Biostatistics [1992-present]); Peter Macfarlane\u000d\u000a      (Professor in Medical Cardiology [1991-1995]; Professor of\u000d\u000a      Electrocardiology, [1996-2010]; Honorary Research Fellow [2010-present]);\u000d\u000a      James McKillop (Muirhead Chair of Medicine [1974-2011]); Christopher\u000d\u000a      Packard (Honorary Professor of Clinical Biochemistry [1993-2011]). PROSPER3\u000d\u000a      — Shepherd and Packard (as above). Cost-effectiveness study4 —\u000d\u000a      Ford, Packard and Cobbe (as above); Alex McConnachie (Assistant Director\u000d\u000a      of Biostatistics [2010-present]). ASCOT-LLA5 — Gordon McInnes\u000d\u000a      (Professor of Clinical Pharmacology [1980-2011]). JUPITER6 and\u000d\u000a      TNT — Shepherd (as above). Key collaborators: Members of\u000d\u000a      the PROSPER, ASCOT-LLA, JUPITER and TNT Steering Committees; see original\u000d\u000a      articles for details.\u000d\u000a    "},{"CaseStudyId":"41156","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255151","Name":"Oceania"}],"Country":[{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2186224","Name":"New Zealand"},{"GeoNamesId":"2077456","Name":"Australia"}],"Funders":[],"ImpactDetails":"\u000a    AF is an enormous and growing medical problem. AF accounts for 1 in 5 of\u000a      all strokes, and doubles an individual's risk of both heart failure and\u000a      premature death. The cost of AF to the NHS in 2000 was conservatively\u000a      estimated to be £459 million (approximately 1% of NHS expenditure) with an\u000a      additional £111 million in nursing home costs. Consequently, the treatment\u000a      of AF is an NHS health priority. AF treatment strategies focus on rhythm\u000a      control (with antiarrhythmic drugs or interventions that are safe) and\u000a      thromboembolism prophylaxis with anticoagulant drugs to prevent stroke\u000a      (ideally maximising effectiveness and minimising risk of bleeding).\u000a      University of Glasgow research has had an overwhelming influence in the\u000a      prevention and treatment of AF.\u000a    Impact on international and national clinical guidelines:\u000a      Key University of Glasgow studies1-6 have contributed to the\u000a      evidence-base for recommendations made by the European Society of\u000a      Cardiology (ESC), American College of Cardiology Foundation (ACCF) and\u000a      American Heart Association (AHA), the world's most influential\u000a      cardiovascular societies with estimated professional memberships of\u000a      30,000, 43,000 and 73,000, respectively. The ESC, ACCF\/AHA and Heart\u000a      Rhythm Society (HRS) guidelines, as well as Australian and Canadian\u000a      Cardiovascular Society (CCS) guidelines on the management of AF and heart\u000a      failure (published since 2008) make the following high level\u000a      recommendations based on key trials led or co-led by University of Glasgow\u000a      investigators as follows:\u000a    \u000a      The use of beta-blockers, ARBs and MRAs for prevention of new onset AF\u000a        (primary prevention) in patients with heart failure (ESC AF 2010a,\u000a        ACCF\/AHA\/HRS 2011b, ESC AHT 2013c) based on\u000a        findings from CAPRICORN1, CHARM2 and EMPHASIS-HF.\u000a      The use of beta-blockers as first-line therapy to control ventricular\u000a        rate in patients with AF, heart failure and low LV ejection fraction\u000a        (LVEF). The addition of a digoxin where monotherapy is inadequate to\u000a        control the rapid heart rate in patients with AF and heart failure (ESC\u000a        AF 2010a, ACCF\/AHA\/HRS 2011b) based on findings\u000a        from Khand et al.3\u000a\u000a      The contraindication of dronedarone for the treatment of AF in\u000a        patients with advanced heart failure (NYHA class III-IV) or with\u000a        recently unstable (decompensated within the last month) HF (ESC AF 2010a,\u000a        ESC AF 2012d, ESC HF 2012e, ACCF\/AHA\/HRS 2011f\/2013g,\u000a        Australia and New Zealand 2011h, CCS 2012i) based\u000a        on findings from ANDROMEDA5\u000a\u000a      The use of apixaban (as one of three NOACs) in all AF patients at high\u000a        risk of stroke; and furthermore, due to the superior safety profile of\u000a        apixaban (versus warfarin), the use of apixaban (as one of three NOACs)\u000a        is recommended in AF patients at lower, intermediate risk of stroke(ESC\u000a        AF 2012d, CCS 2012f) — recommendations based on\u000a        findings from ARISTOTLE6\u000a\u000a    \u000a    The University of Glasgow led-study by MacDonald et al.4\u000a      has also been prominently cited in the leading European guidelines in the\u000a      on-going controversy surrounding the use of radio-frequency ablation to\u000a      treat AF. The University of Glasgow findings have exerted considerable\u000a      caution within the clinical community that this complex, invasive and\u000a      expensive new procedure has limited effectiveness and safety in patients\u000a      with AF and HF (EHRA\/HRS 2012j, ESC HF 2012e).\u000a    Dissemination and implementation of guideline recommendations:\u000a      The major international guideline societies have a robust strategy for\u000a      disseminating guidelines. In 2012, the ESC guideline on AF (2010a)\u000a      was downloaded 75,151 times and its 2012 focused updated\u000a      40,810. Up to 31 July 2013, these numbers were 25,554 and 39,385,\u000a      respectively.k Pocket versions and foreign (non-English)\u000a      language versions have been produced and widely disseminated.\u000a    Regulatory approval and guidance\u000a      Conducting well-designed randomised controlled trials to determine whether\u000a      medications are safe and effective is the cornerstone of gaining\u000a      regulatory and healthcare provider approval for their use in patients, as\u000a      well as ensuring that treatments are targeted to the most appropriate\u000a      populations.\u000a    ARISTOTLE underpins regulatory approval of apixaban\u000a      ARISTOTLE6 was a landmark trial because it demonstrated\u000a      conclusively that apixaban was both safer and more effective than the gold\u000a      standard (warfarin), causing less bleeding, preventing more strokes and\u000a      reducing the risk of death. As warfarin reduces stroke risk by 60-70%,\u000a      these remarkable research findings constitute the only major breakthrough\u000a      in anticoagulant therapy in over 40 years of investigation. Consequently,\u000a      ARISTOTLE was pivotal in gaining marketing authorisation for apixaban from\u000a      the European Medicines Agency (EMA) and the US Food and Drug\u000a      Administration (FDA).\u000a    Apixaban (brand name, Eliquis) was originally approved by the EMA in May\u000a      2011 for the prevention of venous thromboembolism following orthopaedic\u000a      surgery. The findings of ARISTOTLE prompted the manufacturers of this drug\u000a      (Bristol-Myers Squibb and Pfizer) to apply for an extension to the\u000a      original indication. In September 2012, the EMA Committee for Medicinal\u000a      Products for Human Use (CHMP) approved apixaban (2.5 mg and 5 mg) for \"prevention\u000a        of stroke and systemic embolism in adult patients with non-valvular\u000a        atrial fibrillation (NVAF), with one or more risk factors.\"l\u000a      In the accompanying assessment report, ARISTOTLE (study `CV185030') was\u000a      extensively cited as one of two key studies in the supporting evidence for\u000a      clinical efficacy and safety.l FDA approval of apixaban for use\u000a      in AF followed in December 2012, with ARISTOTLE also underpinning this\u000a      licence application.m European and US regulatory approval of\u000a      apixaban was widely reported by major international media outlets,\u000a      including the New York Times, Forbes and PharmaTimes,\u000a      highlighting the pivotal role of ARISTOTLE in gaining these marketing\u000a      licences.n\u000a    ARISTOTLE prompts NHS funded prescribing of apixaban\u000a      Treatment of AF to prevent stroke is a NHS National Priority Project in\u000a      primary care. The UK National Institute for Health and Care Excellence\u000a      (NICE) technology appraisals provide guidance on whether new therapeutic\u000a      options should be funded within the NHS, focusing on value for money by\u000a      weighing up costs and benefits. The findings of ARISTOTLE6\u000a      prompted NICE to approve apixaban as a cost-effective therapy for\u000a      preventing stroke among patients with AF (NICE technology appraisal TA275;\u000a      February 2013).o ARISTOLE was the sole randomised controlled\u000a      trial of apixaban to meet the inclusion criteria for TA275. An economic\u000a      model showed an incremental cost-effectiveness ratio (ICER, used to\u000a      evaluate the cost impact of medical interventions) of £12,757 per quality\u000a      adjusted life-year (QALY, an indicator of improved health) for apixaban\u000a      versus warfarin. The approval by NICE was reported by various media\u000a      outlets.p Therefore, through their key involvement in\u000a      ARISTOTLE, University of Glasgow researchers have directly influenced the\u000a      expansion of NHS-funded treatment for AF patients.\u000a    ANDROMEDA highlights need to restrict use of dronedarone\u000a      The ANDROMEDA5 trial highlighted a potential danger of the\u000a      antiarrhythmic drug dronedarone among patients with heart failure. This\u000a      finding led NICE to restrict use of dronedarone within the NHS in December\u000a      2012.q NICE recommended that \"dronedarone should not be used\u000a        in people with unstable NYHA class III or IV heart failure and to refer\u000a        to the recommendation in the SPC about the use of dronedarone in people\u000a        with LVEF less than 35%.\" The NICE contraindication followed similar\u000a      warnings from the EMA and FDA.\u000a    Changes in prescribing trends for AF — patients receive NOACs\u000a      Regulatory approval and incorporation into clinical guidelines have led to\u000a      rapid uptake of NOACs including apixaban. The superior safety profile of\u000a      NOACs has also supported their use in AF patients at lower risk of stroke,\u000a      a group previously considered unsuitable for anticoagulation with\u000a      warfarin. As a result, these new drugs are already being prescribed to\u000a      6-12% of eligible patients in Europe and the USA.r,s\u000a      Conversely, prescription of dronedarone is decreasing, particularly among\u000a      patients with heart failure (4% prescription rate in Europe).s\u000a      Underuse of anticoagulation therapy is a recognised problem in the NHS.\u000a      However, the availability of NOACs should now increase the proportion of\u000a      patients receiving treatment that is both more effective and safe than\u000a      warfarin and, in turn, drive a large public-health benefit in terms of\u000a      stroke reduction.\u000a    ","ImpactSummary":"\u000a    Atrial fibrillation (AF) is the most common chronic heart rhythm\u000a      disorder, afflicting 1-2% of the total population and up to 10% of\u000a      individuals aged over 70 years. There is an urgent need for safer and more\u000a      effective therapies to prevent and treat AF. University of Glasgow\u000a      researchers have played leading roles in studies that have identified\u000a      strategies which prevent AF, improved the safety of AF therapies, and\u000a      proved the clinical efficacy of a novel anticoagulant to reduce the risk\u000a      of stroke (the major consequence of AF). The findings have rapidly\u000a      informed recommendations in international guidelines, prompted regulatory\u000a      amendments of AF therapies and changed prescribing practices. These\u000a      advances will affect the estimated 12 million Europeans and Americans\u000a      suffering from AF.\u000a    ","ImpactType":"Health","Institution":"\u000a    University of Glasgow\u000a    ","Institutions":[{"AlternativeName":"Glasgow (University of)","InstitutionName":"University of Glasgow","PeerGroup":"A","Region":"Scotland","UKPRN":10007794}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. McMurray J et al. Antiarrhythmic\u000a        effect of carvedilol after acute myocardial infarction: results of the\u000a        Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction\u000a        (CAPRICORN) trial. J Am Coll Cardiol 2005; 45: 525-530\u000a      doi:10.1016\/j.jacc.2004.09.076.\u000a    \u000a\u000a2. Ducharme A et al. Prevention\u000a        of atrial fibrillation in patients with symptomatic chronic heart\u000a        failure by candesartan in the Candesartan in Heart failure: assessment\u000a        of Reduction in Mortality and morbidity (CHARM) program. Am\u000a        Heart J 2006; 151: 985-991 doi:10.1016\/j.ahj.2005.06.036.\u000a    \u000a\u000a3. Khand AU et al. Carvedilol\u000a        alone or in combination with digoxin for the management of atrial\u000a        fibrillation in patients with heart failure? J Am Coll Cardiol\u000a      2003; 42: 1944-1951 doi:10.1016\/j.jacc.2003.07.020.\u000a    \u000a\u000a4. MacDonald MR et al. Radiofrequency\u000a        ablation for persistent atrial fibrillation in patients with advanced\u000a        heart failure and severe left ventricular systolic dysfunction: a\u000a        randomised controlled trial. Heart 2011; 97: 740-747\u000a      doi:10.1136\/hrt.2010.207340.\u000a    \u000a\u000a5. Køber L et al. Increased\u000a        mortality after dronedarone therapy for severe heart failure. N\u000a        Engl J Med 2008; 358: 2678-2687 doi:10.1056\/NEJMoa0800456.\u000a    \u000a\u000a6. Granger CB et al. Apixaban\u000a        versus warfarin in patients with atrial fibrillation. N Engl J\u000a        Med 2011; 365: 981-992 doi:10.1056\/NEJMoa1107039.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"2","Subject":"Cardiorespiratory Medicine and Haematology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    a. ESC\u000a        guidelines for the management of AF, 2010 (Khand et al. Ref\u000a      171 p2415, ANDROMEDA Ref 117 p2405, CHARM Ref 149 p2414)\u000a    b. ACCF\/AHA\/HRS\u000a        focused updates incorporated, 2011 (Khand et al. Ref 754,\u000a      p162, CAPRICORN Ref 858 p168, CHARM Ref 898 p171)\u000a    c. ESC\u000a        guideline for the management of arterial hypertension, 2013\u000a      (EMPHASIS-HF Ref 578 p44)\u000a    d. ESC\u000a        guidelines focused update management of AF, 2012 (ARISTOTLE Ref 4,\u000a      p2726\/2729)\u000a    e. ESC\u000a        Guidelines for the diagnosis and treatment of heart failure, 2012\u000a      (ANDROMEDA Ref 176 p33, MacDonald et al. Ref 175 p32)\u000a    f. ACCF\/AHA\/HRS\u000a        Focussed update on the management of patients with AF, 2011\u000a      (ANDROMEDA Ref 30, p110)\u000a    g. ACCF\/AHA\u000a        task Force on Practice Guidelines — management of patients with AF,\u000a      2013 (ANDROMEDA p1920)\u000a    h. National\u000a        Heart Foundation of Australia and Cardiac Society of Australia and New\u000a        Zealand guideline update, 2011. (ANDROMEDA Ref 21 p406)\u000a    i. Canadian\u000a        Cardiovascular Society atrial fibrillation guidelines focused update,\u000a      2012 (ARISTOTLE Ref 20, p128-130, ANDROMEDA Ref 54 p133)\u000a    j. EHRA\/HRS\u000a        consensus statement on CRT, 2012 (MacDonald et al. Ref 323\u000a      p1267)\u000a    k. Download data for 2010 and 2012 ESC AF guidelines are available on\u000a      request.\u000a    l. EMA approval of apixaban for AF, 2012: CHMP\u000a        statement and EMA\u000a        assessment report. ARISTOTLE [study CV185030] cited throughout,\u000a      specific page numbers available on request.\u000a    m. FDA approval of apixaban for AF, 2012: press\u000a        release\u000a    n. Media coverage of apixaban approval for AF, 2012: Forbes,\u000a      New\u000a        York Times, PharmaTimes\u000a    o. NICE recommendation on apixaban for AF (TA275),\u000a      2013 (p14\/1725-26)\u000a    p. Media coverage of NICE TA275 on apixaban, 2013: PharmaTimes,\u000a      Telegraph,\u000a      Reuters\u000a    q. NICE recommendation on restricted use of dronedarone for AF (TA197),\u000a      2012 (p4\/9\/22\/26-27)\u000a    r. Management\u000a        of atrial fibrillation in seven European countries after the publication\u000a        of the 2010 ESC guidelines on atrial fibrillation: primary results of\u000a        PREFER in AF) (data for 2012-2013)\u000a    s. PINNACLE-AF\u000a        registry shows early patterns for new atrial fibrillation treatments\u000a      (data for 2011) \u000a    ","Title":"\u000a    Transforming the treatment of atrial fibrillation\u000a    ","UKLocation":[{"GeoNamesId":"2648579","Name":"Glasgow"}],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    University of Glasgow researchers were among the first to demonstrate the\u000a      wider health consequences of AF, including risk of heart failure and\u000a      death, over the long-term using the unrivalled, locally recruited Glasgow\u000a      Renfrew\/Paisley epidemiological study (15,399 middle-aged individuals with\u000a      20 year follow-up, MIDSPAN; Stewart et al. 2002, Am J Med).\u000a      They went on to describe the economic cost of AF and assess treatments\u000a      that may prevent the onset of new AF, evaluating the best-treatment of\u000a      patients with the clinically complex combination of AF and heart failure.\u000a      They have proved the superiority of a new anticoagulant to prevent stroke\u000a      in patients with AF and evaluated the best way to diagnose AF in patients\u000a      presenting with a stroke (where AF may be transient and accurate diagnosis\u000a      is critical in ensuring prompt anticoagulation therapy).\u000a    Treatments that may prevent the onset of new AF: AF is\u000a      particularly dangerous in heart failure and after a heart attack\u000a      (myocardial infarction, MI), causing symptomatic worsening, increased risk\u000a      of hospitalisation, greatly increased risk of stroke and higher mortality.\u000a      Professors Henry Dargie, Ian Ford and John McMurray showed that the\u000a      beta-blocker carvedilol reduced the risk of developing arrhythmias,\u000a      including AF, by 59% in patients with reduced heart (left ventricular, LV)\u000a      function after MI (CAPRICORN 2005).1 McMurray was one of the\u000a      leaders of two studies in heart failure which showed that the\u000a      angiotensin-receptor blocker (ARB) candesartan and\u000a      mineralocorticoid-receptor antagonist (MRA) eplerenone reduce the risk of\u000a      new onset AF by 19% and 42%, respectively (CHARM 20062;\u000a      EMPHASIS-HF 2012).\u000a    Management of AF in patients with heart failure: In a\u000a      Glasgow-led study published in 2003, Professors John Cleland and Andrew\u000a      Rankin showed that the combination of a beta-blocker and digoxin provided\u000a      enhanced control of heart rate and an associated improvement in LV\u000a      function (heart pumping function) and symptoms compared with the\u000a      traditional treatment of digoxin alone.3 A 2011 Glasgow-led\u000a      study (McMurray and Dr Mark Petrie) showed that radio-frequency ablation\u000a      was neither effective nor safe in restoring normal rhythm in patients with\u000a      AF and heart failure — the rate of serious complications was 15% and the\u000a      procedure was successful in just 50% of patients.4 McMurray was\u000a      a lead investigator of a trial (ANDROMEDA) of a new antiarrhythmic drug,\u000a      dronedarone, which it was hoped would be a safe and effective treatment in\u000a      patients with AF and heart failure. The study recruited 627 patients with\u000a      advanced heart failure (New York Heart Association [NYHA] functional class\u000a      III or IV) plus AF (or at very high risk of developing AF) who were\u000a      randomised to receive dronedarone or placebo. The trial was stopped early\u000a      after just 2 months of follow-up due to a doubling of mortality in the\u000a      patients receiving dronedarone.5\u000a    New oral anticoagulants to effectively and safely prevent stroke in\u000a          AF: Vitamin K antagonists (VKAs) such as warfarin have been\u000a      the mainstay of anticoagulant treatment for 40 years to reduce the risk of\u000a      stroke in AF patients. However, VKAs have many limitations, particularly\u000a      an unreliable therapeutic effect resulting from food and drug\u000a      interactions, placing the patient at risk of bleeding when\u000a      over-anticoagulated and without stroke protection when\u000a      under-anticoagulated. McMurray was one of the leaders of the multi-centre\u000a      ARISTOTLE trial which randomised 18,201 men and women with AF plus one\u000a      additional risk factor for stroke to the new oral anticoagulant (NOAC)\u000a      apixaban or warfarin. The trial results, published in 2011 showed that\u000a      apixaban was significantly more effective (risk of stroke and death from\u000a      any cause were reduced by 21% and 11%, respectively) and safer (31%\u000a      reduction in serious bleeding) than warfarin.6\u000a    Key University of Glasgow researchers: John Cleland (Senior\u000a      Lecturer, 1994-1999; then University of Hull and Imperial College,\u000a      London); John McMurray (Professor of Cardiology, 1999- present); Henry\u000a      Dargie (Professor of Cardiology 1994-1999; Honorary Senior Research Fellow\u000a      1999-present); Ian Ford (Professor of Statistics\/Biostatistics,\u000a      1992-present); Mark Petrie (Honorary Reader, 2009-present). Positions\u000a          in large multi-centre trials: CAPRICORN: Dargie, Chairman of\u000a      steering committee, Ford, steering committee member, McMurray, endpoint\u000a      committee Chair. ARISTOTLE: McMurray, executive committee member. CHARM\u000a      trial series: McMurray, executive committee member. EMPHASIS-HF: McMurray,\u000a      executive steering committee member. ANDROMEDA: McMurray, steering\u000a      committee member External collaborators: Members of\u000a      trial committees; see original articles for details.\u000a    "},{"CaseStudyId":"41157","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"2782113","Name":"Austria"},{"GeoNamesId":"2661886","Name":"Sweden"},{"GeoNamesId":"660013","Name":"Finland"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2623032","Name":"Denmark"}],"Funders":["Wellcome Trust","Medical Research Council"],"ImpactDetails":"\u000d\u000a    Improved care for patients with genetic muscle disease: The\u000d\u000a      finding that mutations in the Protein\u000d\u000a      Kinase domain of the titin protein were directly responsible for the\u000d\u000a      muscle disease, HMERF, has led to\u000d\u000a      a transformation in the perception of the role of titin in acquired and\u000d\u000a      hereditary muscle diseases, which\u000d\u000a      has had a significant impact on clinical practice. Since the prevalence of\u000d\u000a      titin mutations is high in\u000d\u000a      dilated cardiomyopathy (a condition where the heart muscles become weak\u000d\u000a      and cannot pump enough\u000d\u000a      blood around the body), occurring in 25% of inherited cases and 18% of\u000d\u000a      spontaneously arising cases.\u000d\u000a      KCL-informed screening for titin mutations is now routinely performed in\u000d\u000a      national prenatal genetic\u000d\u000a      diagnosis clinics across Europe, including France [8], Finland [9], Italy\u000d\u000a      [10] and Sweden [11].\u000d\u000a    Improved genetic counselling: Since titin kinase mutations can be\u000d\u000a      inherited in multiple different\u000d\u000a      patterns that lead to a broad spectrum of disease symptoms, the improved\u000d\u000a      understanding of\u000d\u000a      underlying mechanism by the Gautel lab has been key for estimating exactly\u000d\u000a      how their combination\u000d\u000a      will affect muscle function (see [1-5, 7] above), identifying early stages\u000d\u000a      of disease, and providing\u000d\u000a      optimal genetic counselling and treatment recommendations for patients and\u000d\u000a      families. This research is\u000d\u000a      also facilitating reproductive counselling, where genetic screening is\u000d\u000a      performed for in vitro fertilised\u000d\u000a      preimplantation human embryos originating from carrier or affected\u000d\u000a      individuals to prevent children\u000d\u000a      inheriting the same muscle diseases.\u000d\u000a    Based on our prominence in the field of titin mutations and muscle\u000d\u000a      disease, the Gautel group at KCL\u000d\u000a      also serves as a research-based reference laboratory for screening and\u000d\u000a      characterising unique titin\u000d\u000a      mutations [12].\u000d\u000a    KCL research improves clinical diagnostic techniques: KCL's\u000d\u000a      original biomechanical research into\u000d\u000a      muscle function led to the identification of new markers for damaged heart\u000d\u000a      muscles. Methods to detect\u000d\u000a      these markers were incorporated into a novel clinical test capable of\u000d\u000a      rapidly diagnosing patients who\u000d\u000a      had suffered a heart attack. Patents on this technique were granted in\u000d\u000a      2012\/3 (USA, Japan, Europe),\u000d\u000a      assigned to KCL and invented by Professor Mayr (KCL, 2006-present), Dr\u000d\u000a      Jacquet (KCL, 2005-2010),\u000d\u000a      Professor Marber (KCL, 1996-present) and Professor Gautel [13].\u000d\u000a    KCL research shapes international clinical guidelines: KCL\u000d\u000a      research (see [5] above) has informed\u000d\u000a      European clinical guidelines for the diagnosis of muscle disease. This\u000d\u000a      includes the 165th ENMC\u000d\u000a      International workshop guidelines written by the European Neuro Muscular\u000d\u000a      Centre [14], an\u000d\u000a      international research support organisation that informs networks such as\u000d\u000a      the Association Française\u000d\u000a      contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke\u000d\u000a      (Germany), Telethon\u000d\u000a      Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelsvindfonden\u000d\u000a      (Denmark), Prinses\u000d\u000a      Beatrix Fonds & Vereniging Spierziekten Nederland (The Netherlands),\u000d\u000a      Schweizerische Siftung für die\u000d\u000a      Erforschung der Muskelkrankheiten (Switzerland) and Österreichische\u000d\u000a      Muskelforschung (Austria).\u000d\u000a      These clinical guidelines therefore have a very wide reach across Europe\u000d\u000a      and beyond.\u000d\u000a    KCL research (see [1] above) has also been incorporated into clinical\u000d\u000a      genetic guidelines for the\u000d\u000a      diagnosis of the titin-induced myopathy, Udd Distal Myopathy, published\u000d\u000a      online in GeneReviews by\u000d\u000a      the University of Washington, Seattle [15]. GeneReviews are\u000d\u000a      expert-authored disease descriptions\u000d\u000a      focused on clinically relevant and medically actionable information on the\u000d\u000a      diagnosis, management,\u000d\u000a      and genetic counseling of patients and families with specific inherited\u000d\u000a      conditions, and are widely used\u000d\u000a      as a clinical guideline reference.\u000d\u000a    Developing partnerships to establish new treatments for genetic muscle\u000d\u000a        disease: KCL's original\u000d\u000a      research into titin mutations and their impact on muscle function led\u000d\u000a      Rigel Pharmaceuticals, a San\u000d\u000a      Francisco-based \"clinical-stage\" drug development company, to partner with\u000d\u000a      the Gautel lab to initiate a\u000d\u000a      drug discovery programme focussed on titin. This collaboration has\u000d\u000a      facilitated the discovery of several\u000d\u000a      small molecules that target titin kinase, which will be assessed for their\u000d\u000a      effect on titin-related muscle\u000d\u000a      and metabolic diseases [16].\u000d\u000a    KCL research continues to uncover new therapeutic targets: Ongoing\u000d\u000a      KCL research continues to\u000d\u000a      identify important new aspects of muscle biology, in particular new\u000d\u000a      protein interactions, which can be\u000d\u000a      used to inform patient therapies. In collaboration with University College\u000d\u000a      London, the Gautel laboratory\u000d\u000a      has now identified over 500 new titin mutations. In the future, it is\u000d\u000a      anticipated that complementary\u000d\u000a      biophysical and structural studies carried out in collaboration with other\u000d\u000a      international researchers will\u000d\u000a      continue to uncover new therapeutic interventions (see [6] above).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    King's College London (KCL) researchers have had a tremendous impact on\u000d\u000a      furthering the\u000d\u000a      understanding of how titin mutations lead to severe hereditary and\u000d\u000a      spontaneous muscle diseases,\u000d\u000a      which has ultimately improved clinical guidelines, genetic diagnosis and\u000d\u000a      counselling of patients and\u000d\u000a      their families. New genetic tests, driven by KCL research pinpointing how\u000d\u000a      specific mutations adversely\u000d\u000a      impact the normal interaction of titin with other proteins and lead to a\u000d\u000a      loss of muscle function, have\u000d\u000a      been adopted by public health agencies across Europe. Based on these\u000d\u000a      original research insights,\u000d\u000a      novel potential treatment targets continue to be discovered, and drugs\u000d\u000a      aimed at these targets are\u000d\u000a      currently being developed.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    King's College London\u000d\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[{"GeoNamesId":"5809844","Name":"Seattle"}],"References":"\u000d\u000a    \u000a1) Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E,\u000d\u000a      Kristensen J, Brandmeier B,\u000d\u000a      Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T,\u000d\u000a      Richard I, Edstrom\u000d\u000a      L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls\u000d\u000a      muscle gene expression and\u000d\u000a      protein turnover. Science. 2005;308:1599-603.\u000d\u000a    \u000a\u000a2) Grater F, Shen J, Jiang H, Gautel M, Grubmuller H.\u000d\u000a      Mechanically induced titin kinase activation\u000d\u000a      studied by force-probe molecular dynamics simulations. Biophys J.\u000d\u000a      2005;88:790-804.\u000d\u000a    \u000a\u000a3) Puchner E, Alexandrovich A, Kho AL, Hensen U, Schäfer LV, Brandmeier\u000d\u000a      B, Gräter F, Grubmuller\u000d\u000a      H, Gaub HE, Gautel M. Mechanoenzymatics of titin kinase. Proc\u000d\u000a        Natl Acad Sci. 2008:105:13385-90.\u000d\u000a    \u000a\u000a4) Carmignac V, Salih MAM, Quijano-Roy S, Marchand S, Al Rayess MM,\u000d\u000a      Mukhtar MM, Urtizberea\u000d\u000a      JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M,\u000d\u000a      Campbell KP, Richard I, Estournet B,\u000d\u000a      Ferreiro A. C-terminal titin deletions cause a novel early-onset myopathy\u000d\u000a      with fatal cardiomyopathy.\u000d\u000a        Ann. Neurol. 2007;61:340-51.\u000d\u000a    \u000a\u000a5) Fukuzawa A, Lange S, Holt MR, Vihola A, Carmignac V, Ferreiro A, Udd\u000d\u000a      AB, Gautel M. Interactions\u000d\u000a      with titin and myomesin target obscurin and its small homologue,\u000d\u000a      obscurin-like 1, to the sarcomeric\u000d\u000a      M-band: implications for hereditary myopathies J Cell Sci.\u000d\u000a      2008;121:1841-51.\u000d\u000a    \u000a\u000a6) Ochala J, Gustafson AM, Lano Diez M, Renaud G, Li M, Aare S, Qaisar R,\u000d\u000a      Banduseela VC,\u000d\u000a      Hedstrom Y, Tang X, Dworkin B, Ford GC, Nair S, Perera S, Gautel M,\u000d\u000a      Larsson L. Preferential\u000d\u000a      skeletal muscle myosin loss in response to mechanical silencing in a novel\u000d\u000a      rat intensive care unit\u000d\u000a      model: underlying mechanisms. J Physiol. 2011;589:2007-26.\u000d\u000a    \u000a\u000a7) Cullup T, Kho AL, Dionisi-Vivi C, Brandmeier B, Smith F, Urry Z,\u000d\u000a      Simpson MA, Yau S, Bertini E,\u000d\u000a      McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wikburg FA,\u000d\u000a      ten Hoedt AE,\u000d\u000a      Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM,\u000d\u000a      Windpassinger C,\u000d\u000a      Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel\u000d\u000a      HH, Sewry CA, Abbs S,\u000d\u000a      Mohammed S, Josifova D, Gautel M, Jungbluth H. Recessive mutations\u000d\u000a      in EPG5 cause Vici\u000d\u000a      syndrome, a multisystem disorder with defective autophagy. Nature\u000d\u000a        Genetics. 2013;45:83-7.\u000d\u000a    \u000aSince 2007, charitable and industrial funding of more than £4.5 million\u000d\u000a      has been awarded through\u000d\u000a      competitive tender to directly support the research of Professor Gautel in\u000d\u000a      the Cardiovascular Division\u000d\u000a      of KCL. This includes:\u000d\u000a    \u000d\u000a      Medical Research Council 5-year programme grant (2007-2012; 2012-2017)\u000d\u000a        £4.2M\u000a\u000d\u000a      British Heart Foundation Chair Award (2008-2013; 2013-2018) £2.7M\u000a\u000d\u000a      Wellcome Trust Project Grant (2011-2013) £360,909\u000a\u000d\u000a      Leducq Transatlantic Network (2012-2017) £547,867\u000a\u000d\u000a    \u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"},{"Level1":"6","Level2":"4","Subject":"Genetics"}],"Sources":"\u000d\u000a    Genetic testing centres that incorporate clinical assays based on\u000d\u000a          KCL research\u000d\u000a    8) National Early Onset Myopathy Clinic at the INSERM Institut de\u000d\u000a        Myologie, Hôpital La Salpetrière &\u000d\u000a      Université Pierre et Marie Curie, Paris, France. Contact name available\u000d\u000a      separately.\u000d\u000a    9) Folkhälsan Institute of Genetics, University of Helsinki, Finland.\u000d\u000a      Contact name available\u000d\u000a      separately.\u000d\u000a    10) Institute of Neurology, Catholic University School of Medicine, Rome,\u000d\u000a      Italy. Contact name\u000d\u000a      available separately.\u000d\u000a    11) Department of Clinical Neuroscience, Karolinska Institute, Stockholm,\u000d\u000a      Sweden. Contact name\u000d\u000a      available separately.\u000d\u000a    Use of novel data in reference laboratory screening for titin\u000d\u000a          mutations\u000d\u000a    12) Recessive TTN truncating mutations define novel forms of core\u000d\u000a      myopathy with heart disease.\u000d\u000a      Chauveau C, Bonnemann CG, ..........Gautel M, Ferreiro A. Human\u000d\u000a        Mol Genetics. 2013;\u000d\u000a      published October 8, 2013\u000d\u000a      http:\/\/hmg.oxfordjournals.org\/content\/early\/2013\/10\/07\/hmg.ddt494.full.pdf+html\u000d\u000a    Diagnostic tests developed by KCL research group\u000d\u000a    13) CMYBP-C and MLC2 as diagnostic markers of cardiac injury. Mayr M,\u000d\u000a      Jacquet S, Marber M and\u000d\u000a      Gautel M. Patent Application No. 20120156702 http:\/\/www.google.com\/patents\/US20120156702\u000d\u000a    European disease guidelines based on KCL research\u000d\u000a    14) Udd B, 165th ENMC International Workshop: distal myopathies 6-8th\u000d\u000a      February 2009 Naarden,\u000d\u000a      The Netherlands. 2009. Neuromuscul. Disord., 19: 429-38.\u000d\u000a      PMID: 19477645. Cites ref [5], p.432.\u000d\u000a    15) Suominen T, Udd B & Hackman P: Gene Reviews™ Udd Distal Myopathy;\u000d\u000a      Editors: Pagon RA,\u000d\u000a      Adam MP, Bird TD. University of Washington, Seattle, 1993-2013. PMID:\u000d\u000a      20301498. Cites ref [1].\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1323\/\u000d\u000a    Pharmaceutical collaboration with KCL research group\u000d\u000a    16) Rigel Pharmaceuticals, Inc., San Francisco, USA. Contact name\u000d\u000a      available separately.\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Uncovering new titin mutations to develop better clinical tests for\u000d\u000a      patients with\u000d\u000a      genetic muscle disease\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    KCL research on titin mutations and genetic muscle disease is led by\u000d\u000a      Professor Mathias Gautel (KCL,\u000d\u000a      2001-present).\u000d\u000a    Mutated proteins and muscle disease: Several muscle diseases, or\u000d\u000a      `myopathies', are caused by\u000d\u000a      inherited or spontaneously arising genetic mutations that affect proteins\u000d\u000a      involved in muscle\u000d\u000a      contraction. Muscle fibres are organised into structures known as\u000d\u000a      sarcomeres, which are made up of\u000d\u000a      proteins that act to generate force and movement. Titin is the largest\u000d\u000a      protein in the sarcomere — and\u000d\u000a      indeed in the human body — where it links other proteins together and\u000d\u000a      organises the sarcomere.\u000d\u000a      KCL research uncovers a single gene defect responsible for severe adult\u000d\u000a        muscle disease: In a\u000d\u000a      seminal publication in the journal Science in 2005, Professor\u000d\u000a      Gautel, in collaboration with the clinical\u000d\u000a      genetic teams of Professor Udd in Finland and Professor Sejersen in\u000d\u000a      Sweden, discovered that\u000d\u000a      mutations in the titin gene disrupt its normal role in muscle\u000d\u000a      organisation and turnover. Such mutations\u000d\u000a      were found to be directly responsible for hereditary myopathy with early\u000d\u000a      respiratory failure (HMREF), a\u000d\u000a      severe form of adult muscular disease, in families of diverse origins [1].\u000d\u000a    In 2005, KCL research identified that a particular region of the titin\u000d\u000a      gene mutated in HMERF, known as\u000d\u000a      the Protein Kinase domain, was extremely important for the normal function\u000d\u000a      of titin [2]. In 2008, the\u000d\u000a      team led by Professor Gautel determined that this Protein Kinase domain\u000d\u000a      acted as a mechanical force\u000d\u000a      sensor, allowing titin to sense and respond to the physical forces exerted\u000d\u000a      on muscles [3].\u000d\u000a    Identification of a common genetic defect responsible for multiple\u000d\u000a        muscle diseases: In 2007, in\u000d\u000a      collaboration with Professor Ferreiro in France, KCL researchers\u000d\u000a      identified a new titin mutation outside\u000d\u000a      the Protein Kinase domain that resulted in a myopathy that affected\u000d\u000a      patients from birth, rather than\u000d\u000a      manifesting in adulthood [4]. This was the first evidence that distinct\u000d\u000a      titin mutations could cause\u000d\u000a      multiple types of muscle disease that could appear at different ages,\u000d\u000a      either affecting patients from birth\u000d\u000a      or developing over time with a progressive loss in muscle function. Titin\u000d\u000a      mutations were also found to\u000d\u000a      affect not only skeletal muscle, but also heart muscle, and thus may be\u000d\u000a      implicated in heart failure [1,4].\u000d\u000a    Titin mutations prevent normal interactions with other muscle\u000d\u000a        proteins: In 2008, Professor\u000d\u000a      Gautel's team identified why mutations at certain positions in the titin\u000d\u000a      gene led to muscle dysfunction.\u000d\u000a      Many of these mutations adversely affected titin's ability to interact\u000d\u000a      with other proteins [5]. One of\u000d\u000a      these partners, obscurin, binds to titin to organise muscle structure and\u000d\u000a      function. KCL research\u000d\u000a      uncovered mutations that prevented obscurin interacting with titin,\u000d\u000a      thereby causing inherited muscular\u000d\u000a      diseases including Salih Myopathy and limb girdle muscular dystrophy 2J\u000d\u000a      (LGMD2J) [5].\u000d\u000a    Identifying new titin binding partner interactions to reveal novel\u000d\u000a        insights into other muscle\u000d\u000a        diseases: Uncovering new titin binding partners enabled KCL\u000d\u000a      researchers to identify novel candidate\u000d\u000a      genes that could be implicated in other non-titin-related myopathies.\u000d\u000a      Previous analysis of key titin\u000d\u000a      binding partners by the Gautel team revealed that the condition HMERF was\u000d\u000a      due to a disruption in\u000d\u000a      muscle protein mechanics that led to imbalanced muscle activity [1].\u000d\u000a      Building on this finding, the same\u000d\u000a      titin-associated binding partners are now being studied at KCL in cases of\u000d\u000a      acquired, non-hereditary\u000d\u000a      muscle disease. In collaboration with Professor Larsson in Sweden, titin\u000d\u000a      defects have already been\u000d\u000a      linked to muscle diseases that occur as a common complication of critical\u000d\u000a      care unit admission [6].\u000d\u000a    KCL research continues to elaborate new pathways involved in genetic\u000d\u000a        muscle disease:\u000d\u000a      Ongoing research carried out by Professor Jungbluth (Guy's Hospital, KCL,\u000d\u000a      2008-present), in\u000d\u000a      collaboration with Professor Gautel, is continuing to uncover new genetic\u000d\u000a      defects involved in inherited\u000d\u000a      muscle disease [7]. Such insights are being used to guide genetic\u000d\u000a      diagnosis and to develop new\u000d\u000a      therapeutic interventions.\u000d\u000a    "},{"CaseStudyId":"41158","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"298795","Name":"Turkey"},{"GeoNamesId":"2921044","Name":"Germany"},{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"3017382","Name":"France"},{"GeoNamesId":"2750405","Name":"Netherlands"}],"Funders":[],"ImpactDetails":"\u000a    Translation of laboratory research to the clinic: Professor Tutt and\u000a      colleagues\u000a      demonstrated in preclinical and clinical trials that the BRCA1 or\u000a      BRCA2 DNA repair defect that\u000a      occurs in tumours can be exploited by targeting the DNA repair functions\u000a      of PARP-1. This has\u000a      been recognised as a first demonstration of the clinical usefulness of the\u000a      long-described\u000a      principle of synthetic lethality. This landmark in the development\u000a      of \"personalised treatment\"\u000a      for cancer has been recognised by many high profile articles and\u000a      commentaries in leading\u000a      journals such as the New England Journal of Medicine, Cell, and\u000a      the Lancet (7), which cited\u000a      both the preclinical and clinical studies described in Sections 2 and 3\u000a      above.\u000a    KCL research promotes substantial financial investment in large phase\u000a        III clinical trials\u000a        of PARP inhibitors: Following the proof-of-concept and Phase II\u000a      clinical trials led by Professor\u000a      Tutt's team at KCL\/GSTFT, PARP inhibition has been recognised as a major\u000a      avenue of\u000a      research into new treatments for malignancies associated with BRCA1\/2.\u000a      Stimulated by the\u000a      KCL-led trials, five pharmaceutical companies to date are initiating\u000a      randomised Phase III\u000a      clinical trials of different PARP inhibitors for the treatment of BRCA-related\u000a      tumours (8-14).\u000a      This amounts to a financial investment of well over $1 billion. Olaparib,\u000a      the PARP inhibitor\u000a      studied by Tutt and colleagues, is now being tested by Astra Zeneca in\u000a      breast and ovarian\u000a      cancer (8, 9). Other PARP inhibitors in planned clinical trials for BRCA-related\u000a      cancers include\u000a      rucaparib (Clovis Oncology [10]), niraparib (TESARO Inc. [11, 12]), BMN\u000a      673 (Biomarin [13])\u000a      and veliparib (Abbvie [14]). In addition, genetic testing for BRCA\u000a      mutations is being\u000a      incorporated as a companion diagnostic in many of these cancer trials\u000a      [15].\u000a    KCL research alters national and international genetic testing\u000a        guidelines: The KCL\u000a      research by Professor Tutt and colleagues on BRCA-1 and BRCA-2\u000a      cancers has been\u000a      incorporated into national and international clinical guidelines for the\u000a      management of breast\u000a      and ovarian cancer which mandate genetic testing for these mutations.\u000a      These include national\u000a      guidelines in the UK, France, Netherlands and Germany (16, 17); the\u000a      European Society for\u000a      Medical Oncology (ESMO) Clinical Practice Guidelines (18); and the US\u000a      National\u000a      Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in\u000a      Oncology (19). The\u000a      US NCCN guidelines are translated into multiple languages and adapted for\u000a      use across the\u000a      world, including China, Japan, the rest of Asia, Latin America, the Middle\u000a      East, North Africa\u000a      and Turkey. There has therefore been a far-reaching impact of this work.\u000a    Potential impact on treatment of BRCA1\/2 breast\u000a        and ovarian cancers: Although only a\u000a      small proportion of breast and ovarian cancers are associated with BRCA1\u000a      and BRCA2\u000a      mutation, the fact that breast and ovarian cancers are common means that a\u000a      large number of\u000a      patients may benefit from this new therapeutic approach - more patients\u000a      than are diagnosed\u000a      with Hodgkin's lymphoma or testicular cancer.\u000a    Potential impact in triple negative breast cancer (TNBC): TNBCs\u000a      account for 12—15% of\u000a      new breast cancers. They do not carry the oestrogen, progesterone or HER2\u000a      receptors that\u000a      are the basis of targeted treatments for the majority of breast cancers.\u000a      Chemotherapy is\u000a      currently the only option for attempting to eradicate TNBC cells from the\u000a      body. There is thus an\u000a      unmet need for an effective targeted therapy against TNBC. Many TNBCs have\u000a      key similarities\u000a      to BRCA1 mutation-related cancers, and appear to share an impaired\u000a      response to DNA\u000a      damage. PARP is also up-regulated in TNBC, suggesting that PARP inhibition\u000a      could be used\u000a      as part of the treatment of TNBC (20).\u000a    In 2008, the Breakthrough Breast Cancer Research Unit was opened at KCL\u000a      with a £5 million\u000a      award, dedicated to understanding TNBC subtypes and developing novel\u000a      therapeutics for this\u000a      disease. The KCL team are collaborating with the Breast International\u000a      Group (BIG) and with\u000a      pharmaceutical partners to develop clinical trials for TNBC.\u000a    ","ImpactSummary":"\u000a    Work by Professor Andrew Tutt at King's College London (KCL), has had the\u000a      following major\u000a      impacts: (i) it has provided proof through first-in-man clinical trials\u000a      (in collaboration with the\u000a      Royal Marsden\/ICR Phase I Clinical Trials Unit) and Phase II clinical\u000a      trials designed and led by\u000a      Professor Tutt that poly(ADP ribose) polymerase (PARP) inhibitors have an\u000a      anti-cancer action\u000a      in breast and ovarian cancers with BRCA mutations; (ii) it has\u000a      demonstrated that the concept\u000a      of `synthetic lethality' can be applied to the selective targeting of\u000a      cancer cells in humans; (iii) it\u000a      has paved the way for a major programme of investment by the\u000a      pharmaceutical industry (over\u000a      $1 billion to date) in PARP inhibitors for the treatment of BRCA-related\u000a      cancers (which are\u000a      currently being tested in a range of cancers in Phase III trials); and\u000a      (iv) it has been\u000a      incorporated into UK, European, US and other international guidelines on\u000a      genetic testing for\u000a      breast and ovarian cancers that run in families.\u000a    ","ImpactType":"Health","Institution":"\u000a    King's College London\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000a    PARP inhibition and DNA damage repair\u000a    \u000a1. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson\u000a      TB, Santarosa M, Dillon\u000a      KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A.\u000a      Targeting the DNA\u000a      repair defect in BRCA mutant cells as a therapeutic strategy. Nature.\u000a      2005;434:917-21.\u000a    \u000a\u000a2. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara\u000a      S, O'Connor M,\u000a      Tutt AN, Zdzienicka M, Smith G, Ashworth A. Deficiency in the\u000a      repair of DNA damage by\u000a      homologous recombination and sensitivity to poly(ADP-ribose)\u000a      polymeraseinhibition. Cancer\u000a        Res. 2006; 66:8109-15.\u000a    \u000a\u000a3. Tutt AN, Lord CJ, McCabe N, Farmer H, Turner N, Jackson SP,\u000a      Smith GC, Ashworth A.\u000a      Exploiting the DNA repair defect in BRCA mutant cells in the\u000a      design of new therapeutic\u000a      strategies for cancer. Cold Spring Harbour Symposia Quantitative\u000a        Biology. 2005;70:139—48.\u000a    \u000aPhase I first-in-man trials\u000a    \u000a4. Fong PC, Boss DS, Yap TA, Tutt AN, Wu P,\u000a      Mergui-Roelvink M, et al. Inhibition of\u000a      poly(ADP-Ribose) polymerase in tumors from BRCA mutation carriers.\u000a      N Engl J Med.\u000a      2009;361:123-34.\u000a    \u000aPhase II proof-of-concept trials\u000a    \u000a5. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN,\u000a      Friedlander M, Arun\u000a      B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M and\u000a      Carmichael J. Oral\u000a      poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1\u000a      or BRCA2 mutations\u000a      and advanced breast cancer: a proof-of-concept trial. Lancet.\u000a      2010;376:235-44.\u000a    \u000a\u000a6. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B,\u000a      Bell-McGuinn KM, Scott C,\u000a      Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens\u000a      M, Tutt A. Oral\u000a      poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or\u000a      BRCA2 mutations\u000a      and recurrent ovarian cancer: a proof-of-concept trial.. Lancet.\u000a      2010: 376:245-51.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000a    Recognition of landmark in the development of personalized cancer\u000a        treatment.\u000a    \u000a      Iglehart JD, Silver DP. Synthetic lethality — a new direction in\u000a        cancer-drug development. N\u000a          Engl J Med. 2009;361:189-91\u000a        Carey LA, Sharpless NE. PARP and cancer — if it's broke, don't fix it. N\u000a          Engl J Med.\u000a        2011;364:277-9;\u000a        Ashworth A, Lord CJ, Reis-Filho JS. Genetic interactions in cancer\u000a        progression and treatment.\u000a        Cell. 2011;145:30-8\u000a        Chan SL, Mok T. PARP inhibition in BRCA-mutated breast and ovarian\u000a        cancers. Lancet.\u000a        2010;376:211-3.\u000a    \u000a    Financial investment in PARP inhibitors\u000a    \u000a      Olaparib in BRCA mutated Ovarian Cancer - Olaparib Monotherapy in\u000a        Patients With BRCA\u000a        Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy.\u000a        http:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT01844986\u000a\u000a      Olaparib in Patients With BRCA Mutated Platinum-Sensitive Relapsed\u000a        Serous Ovarian\u000a        Cancer: New Data Presented at ASCO http:\/\/online.wsj.com\/article\/PR-CO-20130601-902744.html\u000a\u000a      Pivotal Phase III study or Rucaparib in platinum-sensitive ovarian\u000a        cancer patients starting\u000a        in late 2013, as well as a biomarker study in platinum-sensitive ovarian\u000a        cancer patients\u000a        http:\/\/www.businesswire.com\/news\/home\/20130603005476\/en\/Clovis-Oncology%E2%80%99s-Rucaparib-Demonstrates-Encouraging-Results-Ongoing\u000a\u000a      A Phase III Trial of Niraparib Versus Physician's Choice in Her2\u000a        Negative, Germline BRCA\u000a        Mutation-positive Breast Cancer Patients (BRAVO)\u000a        http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01905592\u000a\u000a      Phase III Trial of Niraparib in ovarian cancer\u000a        http:\/\/www.allfordrugs.com\/2013\/07\/29\/tesaro-begins-phase-iii-trial-of-niraparib-for-treatment-of-ovarian-cancer\/\u000a\u000a      BioMarin Provides BMN 673 Program Update\u000a        http:\/\/www.reuters.com\/article\/2013\/06\/03\/us-cancer-breast-biomarin-idUSBRE9520MA20130603\u000a        http:\/\/investors.bmrn.com\/releasedetail.cfm?ReleaseID=780454\u000a        http:\/\/clinicaltrials.gov\/ct2\/show\/NCT01945775\u000a\u000a      Abbvie plans Randomised Phase III trial of Veliparib in gBRCA Breast\u000a        cancer in\u000a        combination with temozolamide http:\/\/clinicaltrials.gov\/show\/NCT01506609\u000a\u000a      Myriad readying to take BRCA analysis into pivotal trial for\u000a        AstraZeneca's Olaparib as\u000a        companion diagnostic http:\/\/www.genomeweb.com\/clinical-genomics\/myriad-readying-take-bracanalysis-pivotal-trial-astrazenecas-olaparib-companion\u000a\u000a    \u000a    Guidelines for the assessment of breast and ovarian cancer\u000a    \u000a      National Institute for Health and Care Excellence. CG164 Familial\u000a        Breast Cancer, 2013.\u000a        http:\/\/guidance.nice.org.uk\/CG164\/\u000a\u000a      Gadzicki et al. Genetic testing for familial\/hereditary breast\u000a        cancer—comparison of\u000a        guidelines and recommendations from the UK, France, the Netherlands and\u000a        Germany. J\u000a          Community Genet. 2011;2:53-69. http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3186026\/\u000a\u000a      BRCA in breast cancer: European Society for Medical Oncology (ESMO)\u000a        Clinical Practice\u000a        Guidelines. Ann Oncol. 2011;22 (suppl 6): vi31-34.\u000a        http:\/\/annonc.oxfordjournals.org\/content\/22\/suppl_6\/vi31.full\u000a\u000a      US National Comprehensive Cancer Network Clinical Practice Guidelines\u000a        in Oncology.\u000a        Genetic\/familial high-risk assessment: breast and ovarian. (V3.2013)\u000a        http:\/\/www.nccn.org\/professionals\/physician_gls\/f_guidelines.asp#detection\u000a        http:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/genetics_screening.pdf\u000a\u000a      Gelmon, KA et al. (2010) Can we define tumors that will respond to\u000a        PARP inhibitors? A\u000a        phase II correlative study of olaparib in advanced serous ovarian cancer\u000a        and triple-negative\u000a        breast cancer. Journal of Clinical Oncology, 2010 ASCO Annual Meeting\u000a        Proceedings Vol 28,\u000a        No 15 (May 20 Supplement), 2010:3002.\u000a    \u000a    ","Title":"\u000a    The development of \"personalised treatments\" for BRCA1 and BRCA2\u000a      associated breast and ovarian cancers using PARP inhibitors to prolong\u000a      life\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    Background: About 10% of women with cancer of the ovaries and up\u000a      to 5% of women with\u000a      breast cancer carry a mutation in the genes BRCA1 or BRCA2.\u000a      These genes are key\u000a      components of a pathway that repairs double-strand breaks in the DNA\u000a      molecule. Cells\u000a      carrying this mutation cannot repair double-strand DNA breaks. However,\u000a      they still possess a\u000a      single-strand repair mechanism, which uses the enzyme poly(ADP-ribose)\u000a      polymerase\u000a      (PARP).\u000a    KCL researchers contribute to the laboratory discovery that PARP\u000a        inhibition is lethal to\u000a        mutated cells: Working with Professor Alan Ashworth at the Institute\u000a      of Cancer Research\u000a      (ICR), Andrew Tutt (KCL \/ Guy's and St Thomas' NHS Foundation Trust\u000a      [GSTFT]; 2001 - date)\u000a      and co-workers showed in underpinning laboratory studies in cancer models\u000a      with BRCA1 or\u000a      BRCA2 mutation, that inhibiting PARP disables the single-strand\u000a      repair mechanism and kills\u000a      the mutated cancer cells (1, 2). Cell-killing results from the combination\u000a      of the two non-lethal\u000a      repair defects, a concept known as `synthetic lethality'. Normal cells are\u000a      better able to survive\u000a      PARP inhibition. These findings indicated that PARP inhibitors that target\u000a      and kill BRCA-deficient\u000a      cells might be useful as a cancer treatment in patients with these\u000a      mutations, while\u000a      leaving normal tissues unaffected (3). This laboratory work was carried\u000a      out at ICR while Andy\u000a      Tutt was employed by GSTFT\/KCL.\u000a    KCL researchers lead the development of PARP inhibitors for use in\u000a        patients with\u000a        BRCA-related cancer: Up until then, knowledge that a patient had a BRCA\u000a      mutation had not\u000a      affected their treatment, because no treatments specifically targeted to\u000a      the mutation were\u000a      available. PARP inhibition is an example of \"personalised medicine\", in\u000a      which treatment is\u000a      tailored to individual patients based on the genetic or other\u000a      characteristics of their disease.\u000a    After proving the concept in the laboratory, Andrew Tutt moved back to\u000a      GSTFT\/KCL in 2003\u000a      and led the subsequent clinical trial development process of testing PARP\u000a      inhibitors in\u000a      patients. Andrew Tutt and colleagues developed the rationale, designed the\u000a      trial protocols and\u000a      conducted a series of clinical trials testing PARP inhibitors in patients\u000a      with breast and ovarian\u000a      cancers associated with BRCA1 and BRCA2. This work ran\u000a      from the first tests using human\u000a      subjects (known as \"first-in-man trials\") to proof-of-concept Phase II\u000a      trials. The first-in-man\u000a      trials were designed by Professor Tutt at KCL and the Royal Marsden\/ICR\u000a      Phase I Clinical\u000a      Trials Unit, and were conducted at the Royal Marsden\/ICR from 2005 to\u000a      2007. The drug used\u000a      was Kudos Pharmaceuticals' PARP inhibitor, which was then named olaparib\u000a      and licensed to\u000a      Astra Zeneca as a result of this first clinical data published in the New\u000a      England Journal of\u000a      Medicine (4).\u000a    KCL researchers demonstrate anti-cancer activity of PARP inhibitors in\u000a        patients with\u000a        BRCA-related tumours: Andrew Tutt then led, as global chief\u000a      investigator, an international\u000a      team that conducted two proof-of-concept Phase II trials from 2007 to 2009\u000a      to assess how\u000a      effective and how safe olaparib is for treating advanced BRCA1\/BRCA2\u000a      ovarian or breast\u000a      cancer (5, 6). These studies, funded by Astra Zeneca and Kudos\u000a      Pharmaceuticals, were both\u000a      published in the Lancet, and demonstrated a significant anti-cancer\u000a      activity for olaparib in\u000a      patients carrying BRCA1 and BRCA2 mutations with either\u000a      breast cancer (5) or ovarian cancer\u000a      (6). They were amongst the top ten most highly cited Lancet publications\u000a      of 2010.\u000a    This KCL research has led to substantial investment by the pharmaceutical\u000a      industry in PARP\u000a      inhibitors for the treatment of a range of cancers in phase II and III\u000a      trials. In addition, the need\u000a      for genetic testing for breast and ovarian cancers that run in families\u000a      has now been\u000a      incorporated into UK, European, US and other international guidelines\u000a      since the identification\u000a      of BRCA mutations now affects clinical trial eligibility and the\u000a      patient's treatment.\u000a    "},{"CaseStudyId":"41159","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"1861060","Name":"Japan"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"1814991","Name":"China"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":["Wellcome Trust"],"ImpactDetails":"\u000a    Impact 1: Recommendations adopted for chlorhexidine-based\u000a        decolonisation in preventing MRSA transmission [References 2, 3, 4,\u000a      7, 8 and 9].\u000a    KCL work on the importance of decolonisation in preventing MRSA\u000a        transmission, particularly in critical care areas, had a very considerable impact in\u000a      the preparation of the Department of Health's Saving Lives — High Impact\u000a      Interventions care bundles `Screening for MRSA colonisation' that\u000a      recommend pre-emptive decolonisation as an integral part of MRSA control\u000a      for high-risk patients in all NHS Trusts [10]. Professor Gary French was a\u000a      member of the Department of Health committee preparing these guidelines,\u000a      and the findings from KCL were instrumental in their development. Guy's\u000a      and St Thomas' Trust is therefore cited in these guidelines, which links\u000a      our research to this advice and impact (see p.6). Subsequent guidance from\u000a      the Department of Health [11, p.3] reiterates the previous guidance [10]\u000a      on the importance of decolonisation for patients who test positive for\u000a      MRSA after screening.\u000a    From April 2009, all NHS Trusts were expected to screen all elective\u000a      admissions for MSRA in line with Department of Health guidance [11]. In\u000a      response, many Trusts published and implemented their own guidelines and\u000a      procedures for MRSA screening and decolonisation [12]. A clear pathway can\u000a      therefore be seen from the KCL work to the following major impact: a\u000a      dramatic fall of 75% in MRSA bacteraemia cases reported by NHS Trusts\u000a      between 2008\/09 and 20012\/13, according to Public Health England (Trust\u000a      apportioned cases) [13] (p.1). Recent data from the Shelford group of 10\u000a      leading UK academic healthcare organisations shows a continuing decrease\u000a      in incidence of MRSA rates [14].\u000a    KCL work showing that some MRSA strains carrying qacA can be\u000a      clinically resistant to chlorhexidine has raised concerns and has\u000a      led to considerable impact across the infection control community [15-17].\u000a      Locally, a 4-fold increase in the presence of qacA in MRSA\u000a      bacteraemia cases has been seen at Guys and St Thomas' Hospital, which has\u000a      prompted a change from the use of chlorhexidine to an alternative\u000a      antiseptic, octenisan. Octenisan is now being increasingly introduced for\u000a      decolonisation in acute NHS Trusts [18].\u000a    Impact 2: Identifying that sasX is associated with MRSA\u000a      strains that are more transmissible and virulent [References 3, 4,\u000a      5, 7 and 8].\u000a    KCL researchers filed an EU-wide patent identifying sasX as a\u000a        potential diagnostic and vaccine target in 2009 (PCT\/GB2010002056;\u000a      [19]). On the basis of the clinical and scientific data described in\u000a      Section 2, this patent\/finding has had considerable impact and the patent\u000a      has now been extended to Europe, Japan, the USA and China. Novartis\u000a      Vaccines took an option to exploit sasX as a component of a\u000a      multivalent S. aureus vaccine under a three-year licensing\u000a      agreement (Nov 2009-Nov 2012) which has now been extended for a further\u000a      year. Studies have been taking place at Novartis Vaccines, Siena, Italy.\u000a    The KCL discovery of sasX has had a significant impact on the\u000a        management of MRSA in China. In a follow-up paper published in\u000a      Nature Medicine in May 2012 [20], a US group took up the KCL findings and\u000a      investigated the epidemiology of sasX in MRSA strains in Chinese\u000a      hospitals. They found that sasX-containing ST239 clones had spread\u000a      rapidly over the past five years to become the dominant\u000a      healthcare-associated MRSA clones in Chinese hospitals and that sasX\u000a      had spread to other MRSA clones. They also found that sasX was\u000a      highly virulent in animal models. They called for \"vaccine efforts aimed\u000a      at sasX to prevent MRSA colonisation and disease\". The\u000a      identification of these highly transmissible strains as the major MRSA\u000a      clones stems directly from the KCL discovery of sasX, impacts on the most\u000a      populous country in the world, and further substantiates the strategy of\u000a      using sasX for vaccination.\u000a    ","ImpactSummary":"\u000a    Two significant impacts have resulted from King's College London (KCL)\u000a      research on preventing infections of the so-called antibiotic-resistant\u000a      MRSA `superbug' associated with hospital treatment. KCL's research\u000a      exemplifies NIHR's stated \"end-to-end\" strategy for translating\u000a      discoveries made in individual infections to population benefit through\u000a      treatment and prevention.\u000a    First, KCL research contributed to Department of Health guidelines.\u000a      Following the publication of those guidelines, NHS Trusts set out stronger\u000a      procedures for screening patients for MRSA and for routine\u000a      `decolonisation' — involving the use of antibacterial shampoo, bodywash\u000a      and nasal cream by patients. This made a major contribution to the\u000a      dramatic 75% fall in MRSA cases reported by Public Health England between\u000a      2008\/09 and 20012\/13.\u000a    Second, KCL research showed that some MRSA strains are more easily\u000a      transmitted and more virulent than others. Specifically, we identified a\u000a      molecule produced by one such strain of bacteria that enabled it to adhere\u000a      to and colonise a host. We patented this molecule as a rational vaccine\u000a      component to prevent MRSA infection, and the Novartis pharmaceutical\u000a      company took up this patent in 2009.\u000a    ","ImpactType":"Health","Institution":"\u000a    King's College London (KCL)\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Clinical application of real-time PCR to screening critically-ill and\u000a      emergency-care surgical patients for methicillin-resistant Staphylococcus\u000a        aureus: a quantitative analytical study. Herdman MT, Wyncoll D,\u000a        Halligan E, Cliff PR, French G, Edgeworth JD. J Clin Microbiol.\u000a      2009;47:4102-8.\u000a    \u000a\u000a2. Screening, isolation and decolonisation strategies in the control of\u000a      methicillin-resistant Staphylococcus aureus in intensive care\u000a      units: cost-effectiveness evaluation. Robotham JV, Graves N, Cookson BD,\u000a      Barnett AG, Wilson JA, Edgeworth JD, Batra R, Cuthbertson\u000a      BH, Cooper BS. BMJ. 2011;343:d5694. doi: 10.1136\/bmj.d5694.\u000a    \u000a\u000a3. Quantifying type-specific reproduction numbers for nosocomial\u000a      pathogens: evidence for heightened transmission of an Asian sequence type\u000a      239 MRSA clone. Cooper BS, Kypraios T, Batra R, Wyncoll D,\u000a      Tosas O, Edgeworth JD. PLOS Computational Biol.\u000a      2012; 8(4):e1002454. doi: 10.1371\/journal.pcbi.1002454.\u000a    \u000a\u000a4. Efficacy and limitation of a chlorhexidine-based decolonization\u000a      strategy in preventing transmission of methicillin-resistant Staphylococcus\u000a        aureus in an intensive care unit. Batra R, Cooper BS, Whiteley\u000a        C, Patel AK, Wyncoll D, Edgeworth JD. Clin\u000a        Infect Dis. 2010;50:210-7.\u000a    \u000a\u000a5. An outbreak in an intensive care unit of a strain of\u000a      methicillin-resistant Staphylococcus aureus sequence type 239\u000a      associated with an increased rate of vascular access device-related\u000a      bacteremia. Edgeworth JD, Yadegarfar G, Pathak S, Batra\u000a        R, Cockfield JD, Wyncoll D, Beale R, Lindsay JA. Clin\u000a        Infect Dis. 2007;44:493-501.\u000a    \u000a\u000a6. An association between bacterial genotype combined with a high\u000a      vancomycin minimum inhibitory concentration and risk of endocarditis in\u000a      methicillin-resistant Staphylococcus aureus blood stream\u000a      infection. Miller CE, Batra R, Cooper BS, Patel A,\u000a        klein J, Otter JA, Kypraios T, French GL, Tosas O, Edgeworth JD.\u000a      Clin Infect Dis. 2012;54:591-600.\u000a    \u000a\u000a7. Genome sequence of a recently emerged, highly transmissible,\u000a      multi-antibiotic- and antiseptic-resistant variant of\u000a      methicillin-resistant Staphylococcus aureus, sequence type 239\u000a      (TW). Holden MT, Lindsay JA, Corton C, Quail MA, Cockfield JD, Pathak\u000a        S, Batra R, Parkhill J, Bentley SD, Edgeworth JD. J\u000a        Bacteriol. 2010;192:888-92.\u000a    \u000a\u000a8. Evolution of\u000a        MRSA during hospital transmission and intercontinental spread.\u000a      Harris SR, Feil EJ, Holden MT, Quail MA, Nickerson EK, Chantratita N,\u000a      Gardete S, Tavares A, Day N, Lindsay JA, Edgeworth JD, de\u000a      Lencastre H, Parkhill J, Peacock SJ, Bentley SD. Science.\u000a      2010;327:469-74.\u000a    \u000a\u000a9. Selection for qacA carriage in CC22 but not CC30 MRSA\u000a      bloodstream infection isolates during a successful institutional infection\u000a      control programme. Otter JA, Patel A, Cliff P, Halligan E,\u000a        Tosas O, Edgeworth JD. J Antimicrob Chemother. 2013,\u000a      68:992-9.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"8","Subject":"Medical Microbiology"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000a    \u000a      Saving Lives — High Impact Interventions. Screening for\u000a        Methicillin-resistant Staphylococcus aureus (MRSA) Colonisation.\u000a        A Strategy for NHS Trusts: A Summary of Best Practice. Department of\u000a        Health, 2007.\u000a        http:\/\/webarchive.nationalarchives.gov.uk\/20130107105354\/http:\/\/www.dh.gov.uk\/prod_consum_dh\/groups\/dh_digitalassets\/@dh\/@en\/documents\/digitalasset\/dh_078128.pdf\u000a        (see page 6)\u000a      MRSA Screening — Operational Guidance 2. Department of Health, 2008.\u000a        http:\/\/www.hpa.org.uk\/webc\/HPAwebFile\/HPAweb_C\/1232094401893\u000a\u000a      Examples of local Trust guidelines include:\u000a        http:\/\/www.cuh.org.uk\/resources\/pdf\/cuh\/profile\/publications\/selected_policies\/mrsa_guidelines.pdf\u000a        http:\/\/www.royalberkshire.nhs.uk\/pdf\/MRSA_screening_policy_v3_october_2010%20_CG179.pdf\u000a        http:\/\/www.uhcw.nhs.uk\/clientfiles\/File\/MRSA_Policy__Dec_2007.pdf\u000a\u000a      Public Health England, July 2013. Summary Points on Methicillin\u000a        Resistant Staphylococcus aureus (MRSA) Bacteraemia\u000a        http:\/\/www.hpa.org.uk\/web\/HPAweb&HPAwebStandard\/HPAweb_C\/1233906819629).\u000a      \u000ahttp:\/\/www.shelfordgroup.org\/\u000a        Data derived from\u000a        http:\/\/www.hpa.org.uk\/web\/HPAweb&HPAwebStandard\/HPAweb_C\/1233906819629\u000a      Jarvis WR. What increases the risk for persistent MRSA after\u000a        decolonization? Medscape Infectious Diseases Mar06 2012, Video\u000a        and transcript discussing our findings of an increase in chlorhexidine\u000a        resistance [4] (http:\/\/www.medscape.com\/viewarticle\/759246)\u000a      Horner C, Mawer D, Wilcox M. Reduced susceptibility to chlorhexidine\u000a        in staphylococci: is it increasing and does it matter? J Antimicrob\u000a          Chemother. 2012;67:2547-59. (Cites ref [4], p. 2555)\u000a      Meyer B and Cookson B. Does microbial resistance or adaptation to\u000a        biocides create a hazard in infection prevention and control? J Hosp\u000a          Infect. 2010;76:200-5. (Cites ref [4], p.203)\u000a      Evidence for use of octenisan in hospitals: Papworth Hospital NHS\u000a        Foundation Trust DN339 MRSA Procedure.\u000a        http:\/\/www.papworthhospital.nhs.uk\/docs\/policy\/DN339_MRSA_Procedure.pdf\u000a\u000a      Patents: Bacteremia-associated antigen from Staphylococcus aureus;\u000a        https:\/\/www.google.com\/patents\/WO2011058302A1?dq=edgeworth+J+2009&ei=OrcMUoSNOfDv0gXzqoHgCg&cl=en\u000a\u000a      Li M, Du X, Villaruz AE, et al. MRSA epidemic linked to a quickly\u000a        spreading colonization and virulence determinant. Nat Med.\u000a        2012;18:816-19. (Cites refs [7,8] p.816).\u000a    \u000a    ","Title":"\u000a    Successful and cost-effective methods of controlling the spread of MRSA\u000a      (methicillin-resistant Staphylococcus aureus) in hospitals\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000a    KCL's multidisciplinary approach to research\u000a    In 2002, Dr Jonathan Edgeworth (Consultant Microbiologist & Reader in\u000a      Clinical Infectious Diseases, KCL 2002-present) and Professor Gary French\u000a      (KCL 1994-2012) brought together a multi-disciplinary group of scientists,\u000a      clinicians, geneticists, mathematicians and epidemiologists, and\u000a      established an embedded centre of clinical-academic excellence within St\u000a      Thomas' Hospital called the Centre for Clinical Infection and Diagnostics\u000a      Research (CIDR) that has gone on to forge vital relationships with leading\u000a      organisations such as the Wellcome Trust Sanger Institute and Novartis.\u000a      The creation of this centre was co-ordinated by the KCL Department of\u000a      Infectious Diseases. The goals of CIDR were (i) to identify factors\u000a      explaining the spread of healthcare- associated MRSA, including its\u000a      virulence mechanisms, and (ii) to apply this research promptly to improve\u000a      the prevention of MRSA infections. These objectives continue to resonate\u000a      closely with the Department of Health's 5-year Antimicrobial Resistance\u000a      Strategy, announced in September 2013.\u000a    KCL research on screening and decolonisation strategies: clinical\u000a        impact and cost-effectiveness\u000a    The KCL team first created large clinical databases and stores of MRSA\u000a      samples. These were taken from 4500 patients admitted to the intensive\u000a      care unit (ICU) at St Thomas' Hospital between 2002 and 2006, of which\u000a      over 20% were colonised with MRSA, and from 850 patients with blood- borne\u000a      MRSA (bacteraemia) between 1999 and 2009.\u000a    KCL research has focused on assessing the effectiveness of different MRSA\u000a      screening methods, including use of polymerase chain reaction (PCR), a\u000a      fast but relatively expensive technique [1]. The group also collaborated\u000a      with Public Health England to determine the cost effectiveness of various\u000a      combinations of control measures (screening method, isolation and\u000a      decolonisation) in order to provide economic evidence to policy makers\u000a      [2]. This involved mathematical models (Bayesian, longitudinal and\u000a      multi-state modelling) of data on ICU patients. Decolonisation was shown\u000a      to improve patients' health outcomes and reduce costs in all scenarios\u000a      [2].\u000a    Studies on the behaviour of MRSA strains: novel results that have had\u000a        significant impact\u000a    The KCL team provided the first evidence that:\u000a    \u000a      a single strain of MRSA can differ in its transmissibility — which has\u000a        improved our understanding of how pathogens adapt to hospital\u000a        environments [3];\u000a      MRSA strains can differ in their response to infection control\u000a        methods, especially with regard to becoming resistant to chlorhexidine\u000a        (one of the antimicrobials most often used for MRSA decolonisation) —\u000a        which has implications for the tailoring of treatments [4]; and\u000a      MRSA strains can differ in their ability to cause bacterial infections\u000a        of the blood [5] and heart lining [6] — which has improved our\u000a        understanding of the causes of disease.\u000a    \u000a    Unique characteristics found for MRSA strain ST239-TW\u000a    Strain ST239-TW (which was most likely imported into the St Thomas' ICU\u000a      from South-East Asia) caused a protracted 2-year MRSA outbreak [7,8]. It\u000a      was unique in being highly transmissible, causing four times more\u000a      catheter-related bloodstream infections than local strains, and being\u000a      resistant to decolonisation using chlorhexidine. Through whole-genome DNA\u000a      sequencing of ST239-TW, the KCL team identified sasX: a\u000a      novel molecule, or adhesin, on the bacterium's surface. These findings\u000a      indicate that sasX was responsible for ST239-TW's increased\u000a      binding to catheters inserted into blood vessels and the bloodstream\u000a      infections associated with this.\u000a    The new MRSA strain ST239-TW was found to carry an antiseptic\u000a        resistance gene, qacA\u000a    qacA had not previously been suspected of any clinically\u000a      significant activity when using chlorhexidine for decolonisation. However,\u000a      epidemic analysis showed that the transmission of ST239-TW actually\u000a      increased after chlorhexidine-based decolonisation [3]. We also found that\u000a      the presence of qacA in ST239-TW was associated with a significant\u000a      reduction in chlorhexidine susceptibility that was also seen in some but\u000a      not all MRSA lineages carrying qacA [9]. These findings indicated\u000a      that the decolonisation strategy may need to be different for different\u000a      MRSA strains.\u000a    "},{"CaseStudyId":"41160","Continent":[{"GeoNamesId":"6255146","Name":"Africa"},{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"3175395","Name":"Italy"},{"GeoNamesId":"6251999","Name":"Canada"},{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"2658434","Name":"Switzerland"},{"GeoNamesId":"953987","Name":"South Africa"},{"GeoNamesId":"2750405","Name":"Netherlands"},{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"1269750","Name":"India"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Improved patient outcomes and quality of life through BTX-A\u000d\u000a        administration using the\u000d\u000a        Dasgupta technique: KCL research has changed the way that OAB\u000d\u000a      syndrome is managed by\u000d\u000a      using a less invasive BTX-A bladder-injection technique that rapidly\u000d\u000a      reduces overactive bladder\u000d\u000a      symptoms and removes the need for major reconstructive surgery to increase\u000d\u000a      bladder capacity.\u000d\u000a      Using validated clinical questionnaires, patients undergoing BTX-A\u000d\u000a      treatment show significant\u000d\u000a      improvements in their quality of life, as they are able to overcome\u000d\u000a      negative emotions and social\u000d\u000a      limitations associated with the syndrome, and experience fewer physical\u000d\u000a      symptoms (10).\u000d\u000a    Enhanced cost effectiveness using BTX-A injections as a treatment for\u000d\u000a        OAB syndrome: A\u000d\u000a      comparison of the more invasive surgical therapy for OAB syndrome,\u000d\u000a      augmentation cystoplasty,\u000d\u000a      with BTX-A micro-injections has shown that the BTX-A approach is cheaper\u000d\u000a      over a 5-year\u000d\u000a      period (11). Given the minimally invasive nature of BTX-A therapy, these\u000d\u000a      lower costs are often\u000d\u000a      directly related to the decreased incidence of surgical complications. The\u000d\u000a      high success rate of\u000d\u000a      BTX-A treatment also reduces the need for additional costly complementary\u000d\u000a      treatments, such as\u000d\u000a      incontinence aids or antibiotics for urinary-tract infections.\u000d\u000a    International uptake of the Dasgupta surgical technique through\u000d\u000a        KCL-based teaching &\u000d\u000a        mentorship programmes: The KCL-pioneered minimally invasive BTX-A\u000d\u000a      injection technique\u000d\u000a      has been taught by the KCL team to more than 60 colleagues from around the\u000d\u000a      world, including\u000d\u000a      the UK, Italy, India, South Africa, the USA, Switzerland, the Netherlands\u000d\u000a      and Belgium (12).\u000d\u000a    Incorporation of KCL-developed BTX-A therapies into national and\u000d\u000a        international clinical\u000d\u000a        guidelines: KCL research has had a significant impact on informing\u000d\u000a      the clinical management of\u000d\u000a      OAB patients around the world. KCL research (see [1] - [8] above) has\u000d\u000a      informed the treatment of\u000d\u000a      lower urinary-tract disorders in NICE guidelines (13) and EU consensus\u000d\u000a      panels (14). This\u000d\u000a      research has been further incorporated into international guidelines\u000d\u000a      established by the Canadian\u000d\u000a      Urological Association (15) and the American Urological Association (16).\u000d\u000a    KCL-developed BTX-A therapies are approved by the FDA and the EU:\u000d\u000a      In 2012, the EU\u000d\u000a      recommended the approval of BTX-A for OAB treatment (17). In January 2013,\u000d\u000a      the FDA\u000d\u000a      approved the use of BTX-A for OAB (18). These approvals substantially\u000d\u000a      extend the reach of this\u000d\u000a      new therapy.\u000d\u000a    KCL researchers invited to advise on development of further\u000d\u000a        innovations: As a result of\u000d\u000a      Professor Dasgupta's discoveries and experience with BTX-A treatment, he\u000d\u000a      has been invited to\u000d\u000a      join the advisory boards of several companies actively developing new\u000d\u000a      surgical innovations and\u000d\u000a      drugs. Examples include Allergan Inc., Intuitive Surgical, Pfizer and\u000d\u000a      Astellas (2008-2013).\u000d\u000a    Coverage of KCL research by international media: The exciting\u000d\u000a      impact of KCL's research\u000d\u000a      (see [5] above) into OAB syndrome has been featured by many media news\u000d\u000a      outlets. This has\u000d\u000a      included national coverage by BBC Radio 4 and the Daily Mail, and\u000d\u000a      international coverage from\u000d\u000a      the Alpha Galileo Foundation, Nursing Times and the Times of India (24).\u000d\u000a    ","ImpactSummary":"\u000d\u000a    King's College London (KCL) researchers contributed to the discovery that\u000d\u000a      increased C fibre\u000d\u000a      nerve activity in the bladder is a major cause of overactive bladder (OAB)\u000d\u000a      syndrome. Based on\u000d\u000a      this insight, KCL researcher Professor Dasgupta, a surgical urologist at\u000d\u000a      Guy's Hospital, and his\u000d\u000a      team pioneered a new surgical technique for micro-injecting Botulinum\u000d\u000a      Toxin-A (BTX-A) directly\u000d\u000a      into the bladder to suppress C fibres and improve bladder control. The KCL\u000d\u000a      team then\u000d\u000a      conducted the world's first successful clinical trials into the minimally\u000d\u000a      invasive injection of BTX-A\u000d\u000a      n OAB patients. These trials received significant international media\u000d\u000a      coverage. This cost-effective\u000d\u000a      OAB therapy is now licensed by the EU and FDA, is recommended in national\u000d\u000a      and\u000d\u000a      international guidelines, and has significantly improved the treatment of\u000d\u000a      a common health\u000d\u000a      problem.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    King's College London\u000d\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1) Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, Dasgupta\u000d\u000a        P, Fowler CJ,\u000d\u000a      Anand P. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve\u000d\u000a      fibers\u000d\u000a      following intradetrusor injections of botulinum toxin for human detrusor\u000d\u000a      overactivity. J Urology.\u000d\u000a      2005;174:977-83.\u000d\u000a    \u000a\u000a2) Apostolidis A, Dasgupta P, Fowler CJ. Proposed mechanism for\u000d\u000a      the efficacy of injected\u000d\u000a      botulinum toxin in the treatment of human detrusor overactivity. Eur\u000d\u000a        Urol. 2006;49:644-50.\u000d\u000a    \u000a\u000a3) Apostolidis A Dasgupta R, Fowler CJ, Dasgupta P. A minimally\u000d\u000a      invasive technique for\u000d\u000a      outpatient local anaesthetic administration of intradetrusor botulinum\u000d\u000a      toxin in intractable\u000d\u000a      detrusor overactivity. BJU Int. 2005;96:917-8.\u000d\u000a    \u000a\u000a4) Popat R, Apostolidis A, Kalsi V, Gonzales G, Fowler CJ, Dasgupta P.\u000d\u000a      A comparison between\u000d\u000a      the response of patients with idiopathic detrusor overactivity and\u000d\u000a      neurogenic detrusor\u000d\u000a      overactivity to the first intradetrusor injection of botulinum-A toxin. J\u000d\u000a        Urol. 2005;174:984-9.\u000d\u000a    \u000a\u000a5) Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A\u000d\u000a      for treating idiopathic detrusor\u000d\u000a      overactivity: results from a single center, randomized, double-blind,\u000d\u000a      placebo controlled trial. J\u000d\u000a        Urol. 2007;177:2231-6.\u000d\u000a    \u000a\u000a6) Kalsi V, Apostolidis A, Gonzales G, Elneil S, Dasgupta P,\u000d\u000a      Fowler CJ. Early effect on the\u000d\u000a      overactive bladder symptoms following botulinum neurotoxin type A\u000d\u000a      injections for detrusor\u000d\u000a      overactivity. Eur Urol. 2008;54:181-7.\u000d\u000a    \u000a\u000a7) Rovner E, Kennelly M, Schulte-Baukloh H, Zhou J, Haag-Molkenteller C,\u000d\u000a      Dasgupta P.\u000d\u000a      Urodynamic results and clinical outcomes with intradetrusor injections of\u000d\u000a      onabotulinumtoxinA\u000d\u000a      in a randomized, placebo-controlled dose-finding study in idiopathic\u000d\u000a      overactive bladder.\u000d\u000a      Neurourol Urodyn. 2011;30:556-62.\u000d\u000a    \u000a\u000a8) Kalsi V, Gonzales G, Popat R, Apostolidis A, Elneil S, Dasgupta P,\u000d\u000a      Fowler CJ. Botulinum\u000d\u000a      injections for the treatment of bladder symptoms of multiple sclerosis. Ann\u000d\u000a        Neurol.\u000d\u000a      2007;62:452-7.\u000d\u000a    \u000a\u000a9) Goldstraw MA, Kirby RS, Dasgupta P. The role of botulinum\u000d\u000a      toxin in benign prostatic\u000d\u000a      hyperplasia. BJU Int. 2006;98:1147-48.\u000d\u000a    \u000aSince 2002, the KCL research programme into improving outcomes in OAB\u000d\u000a      patients has been\u000d\u000a      awarded substantial charitable and industrial funding. This includes major\u000d\u000a      grants from:\u000d\u000a    • Multiple Sclerosis Society. 4-year grant (2003-2007) £198,000\u000d\u000a    • British Urological Foundation. 1-year grant (2005-2006) £35,000\u000d\u000a    • Allergan, Inc. investigator and educational grants (2003-2014) £239,000\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"},{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"}],"Sources":"\u000d\u000a    10) Sahai A, Dowson C, Khan MS, Dasgupta P. Improvement in\u000d\u000a      quality of life after botulinum\u000d\u000a      toxin-A injections for idiopathic detrusor overactivity: results from a\u000d\u000a      randomized double-blind\u000d\u000a      placebo-controlled trial. BJU Int. 2009;103:1509-15.\u000d\u000a    11) Padmanabhan P, Scarpero HM, Milam DF, Dmochowski RR, Penson DF.\u000d\u000a      Five-year cost\u000d\u000a      analysis of intra-detrusor injection of botulinum toxin type A and\u000d\u000a      augmentation cystoplasty for\u000d\u000a      refractory neurogenic detrusor activity. World J Urol.\u000d\u000a      2011:29:51-7.\u000d\u000a    12) Visiting surgeons who have learned and been mentored in the Dasgupta\u000d\u000a    technique: p.88-92 http:\/\/www.theprostatecentre.com\/m\/4e687c502abaa\/file\u000d\u000a    Governmental and professional bodies using KCL research to\u000d\u000a          formulate treatment\u000d\u000a          guidelines:\u000d\u000a    13) NICE guidelines for Urinary incontinence in women: the management of\u000d\u000a      urinary\u000d\u000a      incontinence in women, 2nd edition 2013 Cites ref 5 above.\u000d\u000a      http:\/\/www.nice.org.uk\/nicemedia\/live\/13019\/62658\/62658.pdf\u000d\u000a    14) Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni\u000d\u000a      A, Karsenty G,\u000d\u000a      Schulte-Baukloh H, Schurch B, Wyndaele JJ, European Consensus Panel.\u000d\u000a      Recommendations\u000d\u000a      on the use of botulinum toxin in the treatment of lower urinary tract\u000d\u000a      disorders and pelvic floor\u000d\u000a      dysfunctions: a European consensus report. Eur Urol.\u000d\u000a      2009;55:100-19. Cites refs 1-6 and 8\u000d\u000a        above.\u000d\u000a    15) Bettez M, Tu Le M, Carlson K, Corcos J, Gajewski J, Jolivet M, Bailly\u000d\u000a      G. 2012 Update:\u000d\u000a      Guidelines for adult urinary incontinence collaborative consensus document\u000d\u000a      for the Canadian\u000d\u000a      Urological Association. Can Urol Assoc J. 2012:6:354-63. Cites\u000d\u000a        ref 7 above.\u000d\u000a      http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3478335\/pdf\/cuaj-5-354.pdf\u000d\u000a    16) Gormley EA, Lightner DJ, Burgio KL, Chai TC, Clemens Q, Culkin DJ,\u000d\u000a      Das AK, Foster HEF\u000d\u000a      Jr, Scarpero HM, Tessier CD, Vasavada SP. Diagnosis and treatment of\u000d\u000a      overactive bladder\u000d\u000a      (non-neurogenic) in adults: AUA\/SUFU guidelines. J Urol. 2012;188\u000d\u000a      (6 suppl):2455-63. Cites\u000d\u000a        ref 5 above.\u000d\u000a    17) EU approval, UK Medicines Information website\u000d\u000a      http:\/\/www.ukmi.nhs.uk\/applications\/ndo\/record_view_open.asp?newDrugID=5585\u000d\u000a    18) FDA press release, Jan 18, 2013 http:\/\/www.fda.gov\/newsevents\/newsroom\/pressannouncements\/ucm336101.htm\u000d\u000a    Media coverage of KCL research:\u000d\u000a    24) Media coverage:\u000d\u000a    \u000d\u000a      BBC Radio 4 http:\/\/www.bbc.co.uk\/radio4\/science\/casenotes_tr_20080826.shtml\u000a\u000d\u000a      The Daily Mail http:\/\/www.dailymail.co.uk\/health\/article-1192234\/How-Botox-jabs-help-iron-weak-bladder-problems.html\u000a\u000d\u000a      The Alpha Galileo Foundation\u000d\u000a        http:\/\/www.alphagalileo.org\/ViewItem.aspx?ItemId=58452&CultureCode=en\u000a\u000d\u000a      The Nursing Times http:\/\/www.nursingtimes.net\/nursing-practice\/clinical-\u000d\u000azones\/continence\/botox-could-help-women-with-weak-bladders\/5042638.article#\u000a\u000d\u000a      The Times of India http:\/\/articles.timesofindia.indiatimes.com\/2009-10-04\/beauty\/28100627_1_injections-bladder-placebo\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved treatment and quality of life for patients with overactive\u000d\u000a      bladder\u000d\u000a      syndrome through developing new ways of administering Botulinum Toxin-A\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    The issues of overactive bladder syndrome: Overactive bladder\u000d\u000a      (OAB) syndrome is a major\u000d\u000a      health problem affecting approximately 1 in 6 people. In the UK alone,\u000d\u000a      this translates to 5 million\u000d\u000a      affected individuals. OAB syndrome significantly reduces people's quality\u000d\u000a      of life and is a burden\u000d\u000a      in daily living. Unfortunately, a large proportion of patients suffer in\u000d\u000a      silence as current treatment\u000d\u000a      options are often inadequate.\u000d\u000a    KCL researchers contribute to identification of the molecular\u000d\u000a        mechanisms responsible\u000d\u000a        for overactive bladder syndrome: In 2005, KCL researcher Professor\u000d\u000a      Dasgupta (Guy's\u000d\u000a      Hospital, 2002-present) along with colleagues at University College London\u000d\u000a      and Imperial\u000d\u000a      College London identified that certain receptors within C nerve fibres in\u000d\u000a      the bladder were\u000d\u000a      present at abnormal levels in OAB syndrome (1). These proteins could be\u000d\u000a      targeted and\u000d\u000a      suppressed using Botulinum Toxin-A (BTX-A). A model describing how BTX-A\u000d\u000a      affected the\u000d\u000a      bladder to control overactivity was therefore proposed and published by\u000d\u000a      the combined team in\u000d\u000a      the journal European Urology, where it remains one of the top five cited\u000d\u000a      papers in this field (2).\u000d\u000a    KCL clinicians pioneer a new surgical technique to improve BTX-A\u000d\u000a        injections: In 2005,\u000d\u000a      researchers at King's College London led by Professor Dasgupta (in\u000d\u000a      collaboration with\u000d\u000a      University College surgeon Professor Fowler) pioneered the use of a\u000d\u000a      minimalistic surgical\u000d\u000a      technique to introduce BTX-A into the bladder under local anaesthetic,\u000d\u000a      removing the need for an\u000d\u000a      overnight hospital stay (3). This became known as the \"Dasgupta\u000d\u000a      technique\". KCL researchers\u000d\u000a      further demonstrated that this surgical approach could effectively treat\u000d\u000a      all types of OAB\u000d\u000a      syndrome (4).\u000d\u000a    Original KCL research leads to clinical trials in OAB patients: In\u000d\u000a      2007, the functional\u000d\u000a      urology team at KCL (led by Professor Dasgupta in collaboration with\u000d\u000a      pharmaceutical partners\u000d\u000a      Allergan, Inc.) conducted the first randomised double-blind clinical trial\u000d\u000a      — treating 34 OAB\u000d\u000a      patients with BTX-A injections. These studies demonstrated a substantial\u000d\u000a      benefit of treatment —\u000d\u000a      reducing both incontinence and how often and how urgently patients had to\u000d\u000a      urinate (5). Their\u000d\u000a      subsequent research in 2008 demonstrated that such BTX-A therapies acted\u000d\u000a      quickly, improving\u000d\u000a      symptoms within four days in OAB patients who had previously failed to\u000d\u000a      respond to conventional\u000d\u000a      treatments (6).\u000d\u000a    In 2011, the KCL team led an extended clinical trial recruiting over 300\u000d\u000a      patients across multiple\u000d\u000a      countries — including the USA, Canada, Germany and the UK. Similar\u000d\u000a      significant improvements\u000d\u000a      in bladder control were observed following BTX-A therapy in the OAB\u000d\u000a      patients (7).\u000d\u000a    KCL collaborative research continues to uncover new targets for the\u000d\u000a        treatment of OAB\u000d\u000a        syndrome: Current KCL research by Professor Dasgupta and Dr Smith\u000d\u000a      (Guy's Hospital, 2007-present),\u000d\u000a      in collaboration with the European INCOMB group and pharmaceutical partner\u000d\u000a      Adprotech Ltd., continues to further our understanding of how BTX-A\u000d\u000a      improves bladder\u000d\u000a      performance, leading to the development of better ways to deliver such\u000d\u000a      drugs.\u000d\u000a    KCL-developed therapies are clinically useful for other diseases\u000d\u000a        involving bladder\u000d\u000a        dysfunction: In 2007, KCL researchers analysed the ability of the\u000d\u000a      BTX-A micro-injection\u000d\u000a      technique to improve bladder dysfunction associated with other diseases.\u000d\u000a      More than 40 multiple\u000d\u000a      sclerosis (MS) patients suffering severe bladder incontinence were\u000d\u000a      recruited and treated with\u000d\u000a      BTX-A using the Dasgupta technique. Results showed an extremely\u000d\u000a      significant positive impact\u000d\u000a      on patients' quality of life, and substantial improvements in bladder\u000d\u000a      function (8).\u000d\u000a    KCL researchers also highlighted evidence that BTX-A treatment could be\u000d\u000a      useful for the\u000d\u000a      treatment of benign prostatic hyperplasia (BPH), where an enlarged\u000d\u000a      prostate gland is often\u000d\u000a      associated with bladder incontinence (9).\u000d\u000a    "},{"CaseStudyId":"41161","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"},{"GeoNamesId":"6255147","Name":"Asia"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2802361","Name":"Belgium"},{"GeoNamesId":"102358","Name":"Saudi Arabia"},{"GeoNamesId":"294640","Name":"Israel"},{"GeoNamesId":"3077311","Name":"Czech Republic"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Improved accessibility of genetic testing to couples with a history of\u000d\u000a        hereditary genetic disease: The major innovation arising from KCL\u000d\u000a      research is the development of generic tests to identify any genetic\u000d\u000a      defect in disease risk genes and chromosomes in human embryos. KCL\u000d\u000a      techniques can be performed using standard laboratory equipment, and are\u000d\u000a      sufficiently cost-effective for the NHS to use as a universal, affordable\u000d\u000a      PGD service. In the future, it is expected that the number of genetic\u000d\u000a      conditions for which PGH is available will continue to increase to meet\u000d\u000a      patient demand.\u000d\u000a    KCL's PGD techniques licensed by the UK's human fertilisation\u000d\u000a        regulating body: Since 2008, Guy's and St Thomas' Centre for PGD has\u000d\u000a      been licensed by the Human Fertilisation and Embryo Authority (HFEA) to\u000d\u000a      analyse over 50 genetic conditions affecting single genes. PGH is\u000d\u000a      recognised as a solid, reliable technique to identify embryos affected by\u000d\u000a      such genetic diseases.\u000d\u000a      The centre has also performed PGD for more than 200 different chromosomal\u000d\u000a      mutations [7] and carries out more than half of all PGD cycles done in the\u000d\u000a      UK [8].\u000d\u000a    KCL's PGD techniques improve pregnancy success rates: Successful\u000d\u000a      pregnancy rates for couples undergoing preimplantation genetic analysis of\u000d\u000a      embryos using KCL techniques are higher than rates reported for other\u000d\u000a      methods of genetic analysis [9]. 34% of embryos selected using KCL methods\u000d\u000a      of PGD go on to result in successful pregnancies, compared to a national\u000d\u000a      average of 25% [8]. In November 2011, the Guy's and St Thomas' NHS\u000d\u000a      Foundation Trust celebrated the birth of over 300 babies following PGD\u000d\u000a      analysis, an achievement that was widely covered in the press [10].\u000d\u000a    Adoption of KCL's preimplantation genetic haplotyping technique by\u000d\u000a      in vitro fertilisation clinics worldwide: The\u000d\u000a      generic applicability of the KCL-pioneered PGH approach to detect single\u000d\u000a      gene defects in fertilised human embryos has led to the adoption of the\u000d\u000a      technique by human fertilisation clinics worldwide. Clinics in the USA\u000d\u000a      [11], Saudi Arabia [12], Israel [13] and the Czech Republic [14] have all\u000d\u000a      reported success using PGH. Large-scale clinical trials are also under way\u000d\u000a      in Belgium to validate the performance of PGH with a view to ultimately\u000d\u000a      replacing existing labour-intensive and costly PGD techniques [15].\u000d\u000a    KCL researchers recognised as world-class authorities for in\u000a          vitro genetic testing: The original research performed\u000d\u000a      by KCL scientists has been widely recognised by the wider medical\u000d\u000a      community, and included in publications referred to by clinicians,\u000d\u000a      embryologists and nurses. Both Professor Ogilvie and Dr Scriven were\u000d\u000a      invited to contribute chapters to the second edition of Preimplantation\u000d\u000a        Genetic Diagnosis, published by Cambridge University Press [16]. PGH\u000d\u000a      is also referred to in the sixth edition of Essential Medical Genetics,\u000d\u000a      published by Wiley-Blackwell, as a landmark advance in the field of\u000d\u000a      medical genetics [17]. KCL researchers also contributed to the Galton\u000d\u000a      Institute's Guide to Pre-implantation Genetic Diagnosis [18].\u000d\u000a    KCL research shapes international genetic-testing guidelines: KCL\u000d\u000a      research has significantly contributed to shaping international clinical\u000d\u000a      guidelines. Consolidated PGD best practice guidelines published in 2011 by\u000d\u000a      the European Society for Human Reproduction and Embryology (ESHRE) not\u000d\u000a      only reference original KCL PGD research (see [1], [2] & [4] above),\u000d\u000a      but KCL researchers Professor Braude and Mrs Lashwood (KCL \/ Guy's and St\u000d\u000a      Thomas' NHS Foundation Trust, 1991-present) also co-authored the\u000d\u000a      guidelines dedicated to organising a centre for PGD\/preimplantation\u000d\u000a      genetic screening [19, 20, 21].\u000d\u000a    A number of specialist genetics charitable groups have also used KCL\u000d\u000a      research to inform policies and guide patient choices. These include\u000d\u000a      UNIQUE [22], Genetic Alliance UK [23], the Cystic Fibrosis Trust [24] and\u000d\u000a      the Jennifer Trust [25].\u000d\u000a    ","ImpactSummary":"\u000d\u000a    King's College London (KCL) has developed a generic test format which is\u000d\u000a      being used to cheaply and easily detect a large number of single-gene\u000d\u000a      disorders and chromosomal abnormalities in in vitro fertilised\u000d\u000a      embryos — a highly significant impact. The test resulted from KCL's\u000d\u000a      research to develop new strategies for preimplantation genetic diagnosis\u000d\u000a      (PGD), which involved developing a small number of DNA probes targeted\u000d\u000a      around a known area of genetic risk to identify mutations as well as\u000d\u000a      methods to detect chromosomal translocations. Because the approach is\u000d\u000a      cheap and easy to apply, it is being used by IVF clinics worldwide as well\u000d\u000a      as by the NHS. The KCL\/Guy's and St Thomas' Centre for PGD was licensed in\u000d\u000a      2008 by the UK Human Fertilisation and Embryo Authority to analyse over 50\u000d\u000a      genetic conditions affecting single genes and carries out more than half\u000d\u000a      of all the UK's PGD testing. Embryos can now be tested using these\u000d\u000a      techniques for virtually any inherited genetic disease prior to\u000d\u000a      implantation with a 98% success rate, thus reducing the need for later\u000d\u000a      prenatal diagnosis and termination of an affected foetus.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    King's College London\u000d\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1) Kuo HC, Ogilvie CM, Handyside AH. Chromosomal\u000d\u000a      mosaicism in cleavage-stage human embryos and the accuracy of single-cell\u000d\u000a      genetic analysis. J Assist Reprod Genet. 1998;15:276-80.\u000d\u000a    \u000a\u000a2) Lewis CM, Pinel T, Whittaker JC, Handyside\u000d\u000a        AH. Controlling misdiagnosis errors in preimplantation genetic\u000d\u000a      diagnosis: a comprehensive model encompassing extrinsic and intrinsic\u000d\u000a      sources of error. Hum Reproduction. 2001;16:43-50.\u000d\u000a    \u000a\u000a3) Renwick PJ, Trussler J, Ostad-Saffari E, Fassihi H, Black C, Braude\u000a        P, Ogilvie CM, Abbs S. Proof of principle and first\u000d\u000a      cases using preimplantation genetic haplotyping — a paradigm shift for\u000d\u000a      embryo diagnosis. Reprod Biomed Online. 2006;13:758-67.\u000d\u000a    \u000a\u000a4) Scriven PN, Handyside AH, Ogilvie CM.\u000d\u000a      Chromosome translocations: segregation modes and strategies for\u000d\u000a      preimplantation genetic diagnosis. Prenat Diagnosis.\u000d\u000a      1998;18:1437-49.\u000d\u000a    \u000a\u000a5) Renwick PJ, Lewis CM, Abbs S, Ogilvie CM.\u000d\u000a      Determination of the genetic status of cleavage-stage human embryos by\u000d\u000a      microsatellite marker analysis following multiple displacement\u000d\u000a      amplification. Prenat Diagnosis. 2007;27:206-15.\u000d\u000a    \u000a\u000a6) Renwick P, Trussler J, Lashwood A, Braude P, Ogilvie\u000a        CM. Preimplantation genetic haplotyping: 127 diagnostic cycles\u000d\u000a      demonstrating a robust, efficient alternative to direct mutation testing\u000d\u000a      on single cells. Reprod Biomed Online. 2010;20:470-6.\u000d\u000a    \u000aThis innovative KCL research has been supported by substantial grant\u000d\u000a      funding obtained by the KCL Genetics Division (approx. £1 million),\u000d\u000a      Innovation Grants from the Guy's and St Thomas' Charity (approx. £150K)\u000d\u000a      and funding from the Guy's & St Thomas' NHS Trust.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"6","Level2":"4","Subject":"Genetics"},{"Level1":"11","Level2":"9","Subject":"Neurosciences"}],"Sources":"\u000d\u000a    7) Guy's and St Thomas' NHS Foundation Trust, Centre for Preimplantation\u000d\u000a      Genetic Diagnosis. Conditions for which we offer PGD. http:\/\/www.pgd.org.uk\/conditionstested\/conditions-tested.aspx\u000d\u000a    8) Guy's and St Thomas' NHS Foundation Trust, Centre for Preimplantation\u000d\u000a      Genetic Diagnosis. Preimplantation Genetic Diagnosis in the United\u000d\u000a      Kingdom.\u000d\u000a      http:\/\/www.pgd.org.uk\/resources\/preimplantation-genetic-diagnosis-uk.pdf\u000d\u000a    9) Goosens B, Harton G, Moutou C, Scriven PN, Traeger-Synodinos J, Sermon\u000d\u000a      K, Harper JC, ESHRE PGD Consortium. ESHRE PGD Consortium data collection\u000d\u000a      VIII: cycles from January to December 2005 with pregnancy follow-up to\u000d\u000a      October 2006. Hum Reprod. 2008;23,2629-45. 10) Party time for\u000d\u000a      children born free of gene disorders, 22 November 2011, The Evening\u000d\u000a      Standard, http:\/\/www.standard.co.uk\/news\/party-time-for-children-born-free-of-gene-disorders-6370713.html;\u000d\u000a      Celebration of hospitals' baby genetics technique, 24 November 2011,\u000d\u000a      Southwark News, http:\/\/www.pgd.org.uk\/resources\/2011-11-24,SouthwarkNews,Celebrationofhospitalsbabygeneticstechnique.pdf;\u000d\u000a      Medical marvels. Little miracles say thanks to hospital, 25 November 2011,\u000d\u000a      South London Press\u000d\u000a      http:\/\/www.pgd.or.uk\/resources\/2011-11-25,SouthLondonPress,Medicalmarvels.pdf\u000d\u000a    11) Lau EC, Janson MM, Roesler MR, Avner ED, Strawn EY, Bick DP. Birth of\u000d\u000a      a healthy infant following preimplantation PKHD1 haplotyping for autosomal\u000d\u000a      recessive polycystic kidney disease using multiple displacement\u000d\u000a      amplification. J Assist Reprod Genet. 2010;27,397-407.\u000d\u000a    12) Qubbaj W, Al-Ageel A, Al-Hassnan Z, Al-Durahim A, Awartani K,\u000d\u000a      Al-Rejjal R, Coskun S. Preimplantation genetic diagnosis of Morquio\u000d\u000a      disease. Prenat Diag. 2008;28:900-3.\u000d\u000a    13) Shamash J, Rienstein S, Wolf-Reznik H, Pras E, Dekel M, Litmanovitch\u000d\u000a      T, Brengauz M, Goldman B, Yonath H, Dor J, Levron J, Aviram-Goldring A.\u000d\u000a      Preimplantation genetic haplotyping a new application for diagnosis of\u000d\u000a      translocation carrier's embryos — preliminary observations of two\u000d\u000a      robertsonian translocation carrier families. J Assist Reprod Genet.\u000d\u000a      2011;28,77-83.\u000d\u000a    14) Putzova M, Eliasova I, Pecnova L, Krutilkova V, Brandejska M,\u000d\u000a      Smetanova D, Hynek M, Stejskal D. Preimplantation diagnosis of monogenic\u000d\u000a      diseases in GENNET. Ultra Obst Gyn. 2010;36(S1):208.\u000d\u000a    15) Genome-wide Single Cell Haplotyping as a Generic Method for\u000d\u000a      Preimplantation Genetic Diagnosis. ClinicalTrials.gov Identifier:\u000d\u000a      NCT01336400. Sponsor: Universitaire Ziekenhuizen Leuven. http:\/\/clinicaltrials.gov\/show\/NCT01336400\u000d\u000a    16) Harper JC. Preimplantation Genetic Diagnosis. 2nd Edition,\u000d\u000a      2009. Cambridge University Press. http:\/\/www.cambridge.org\/gb\/knowledge\/isbn\/item2327550\/?site_locale=en_GB\u000d\u000a    17) Tobias ES, Connor M, Ferguson-Smith M. Essential Medical Genetics,\u000d\u000a      6th Edition, 2011. Wiley-Blackwell. http:\/\/eu.wiley.com\/WileyCDA\/WileyTitle\/productCd-EHEP002300.html\u000d\u000a    18) Taylor A. A Guide to Pre-implantation Genetic Diagnosis. Galton\u000d\u000a      Institute Occasional Papers, Third Series No. 1. May 2008.\u000d\u000a      http:\/\/www.galtoninstitute.org.uk\/Publications\/PGD%20booklet.pdf\u000d\u000a    19) Harton GL, De Rycke M, Fiorentino F, Moutou C, SenGupta S,\u000d\u000a      Traeger-Synodinos J, Harper JC; European Society for Human Reproduction\u000d\u000a      and Embryology (ESHRE) PGD Consortium. ESHRE PGD Consortium best practice\u000d\u000a      guidelines for amplification-based PGD. Hum Reprod.\u000d\u000a      2011a;26:33-40.\u000d\u000a    20) Harton GL, Harper JC, Coonen E, Pehlivan T, Vesela K, Wilton L;\u000d\u000a      European Society for Human Reproduction and Embryology (ESHRE) PGD\u000d\u000a      Consortium. ESHRE PGD Consortium best practice guidelines for fluorescence\u000d\u000a      in situ hybridization-based PGD. Hum Reprod. 2011b;26:25-32.\u000d\u000a    21) Harton G, Braude P, Lashwood A, Schmutzler A, Traeger-Synodinos J,\u000d\u000a      Wilton L, Harper JC; European Society for Human Reproduction and\u000d\u000a      Embryology (ESHRE) PGD Consortium. ESHRE PGD Consortium best practice\u000d\u000a      guidelines for organization of a PGD centre for PGD\/preimplantation\u000d\u000a      genetic screening. Hum Reprod. 2011c;26:14-24.\u000d\u000a    22) UNIQUE: a rare chromosome disorder support group, contact name\u000d\u000a      available.\u000d\u000a      (www.rarechromo.org)\u000d\u000a    23) Genetic Alliance UK: a national charity of over 150 patient\u000d\u000a      organisations supporting all those affected by genetic disorders; contact\u000d\u000a      name available. (www.geneticalliance.org.uk)\u000d\u000a    24) The Cystic Fibrosis Trust: the national charity dealing with all\u000d\u000a      aspects of cystic fibrosis; contact name available. (www.cysticfibrosis.org.uk)\u000d\u000a    25) The Jennifer Trust: the national charity for all forms of spinal\u000d\u000a      muscular atrophy; contact name available. (www.jtsma.org.uk)\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved methods for preimplantation genetic diagnosis help couples avoid\u000d\u000a      the risk of bearing children with inherited diseases\u000d\u000a    ","UKLocation":[],"UKRegion":[],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Analysis of inherited genetic disease in embryos before implantation:\u000d\u000a      Since genetic disorders based on a single gene are relatively rare, and in\u000d\u000a      some cases specific to a family, the costs associated with developing a\u000d\u000a      specific test for individual defects are prohibitive. Prior to the\u000d\u000a      development of KCL's innovative new techniques, PGD was only available for\u000d\u000a      a small number of more common genetic conditions.\u000d\u000a    Adoption of new techniques to enable the accurate analysis of genetic\u000d\u000a        defects in human embryos: Early work in 1998 led by Professor\u000d\u000a      Ogilvie (KCL \/ Guy's and St Thomas' NHS Foundation Trust, 1990-present)\u000d\u000a      showed that, at that time, genetic analyses performed on single cells\u000d\u000a      isolated from an early stage human embryo were not sufficiently accurate,\u000d\u000a      reproducible or conclusive [1]. Similarly, KCL researchers used\u000d\u000a      mathematical models to assess the accuracy of PGD methods used at the time\u000d\u000a      and found that DNA isolated from a single cell sampled from a human embryo\u000d\u000a      was not a reliable basis for accurate diagnosis of genetic abnormalities\u000d\u000a      [2].\u000d\u000a    In order to improve preimplantation genetic testing, KCL researchers\u000d\u000a      first had to find a reliable technique for ensuring that sufficient good\u000d\u000a      quality DNA could be extracted from the small amount originally sampled\u000d\u000a      from an early human embryo. Research led by Dr Renwick and colleagues\u000d\u000a      (KCL\/Guy's and St Thomas' NHS Foundation Trust, 1998-present) showed that\u000d\u000a      multiple displacement amplification (MDA) could amplify the original\u000d\u000a      amount of DNA around a million-fold, generating a substantial quantity for\u000d\u000a      subsequent genetic mutation analyses [3].\u000d\u000a    KCL researchers pioneer new, simple and cost-effective methods of\u000d\u000a        single gene and chromosomal genetic analysis: KCL researchers also\u000d\u000a      determined that a small number of DNA probes targeted at specific genetic\u000d\u000a      regions could cheaply and easily detect single gene defects in\u000d\u000a      preimplantation embryos [3]. This novel technique, known as\u000d\u000a      preimplantation genetic haplotyping (PGH), was based on the concept that a\u000d\u000a      small number of DNA probes targeted within or around a known disease risk\u000d\u000a      gene could accurately determine whether or not an embryo harboured an\u000d\u000a      inherited genetic mutation [3]. Meanwhile, Dr Scriven (KCL \/ Guy's\u000d\u000a      Hospital, 1989-2011) outlined a strategy to diagnose different types of\u000d\u000a      chromosomal translocations — that is, a rearrangement of part of a\u000d\u000a      chromosome onto a different chromosome — in affected embryos as part of\u000d\u000a      PGD [4]. Individuals with balanced chromosomal translocations are\u000d\u000a      themselves usually unaffected but have a high risk of affected pregnancies\u000d\u000a      and therefore require careful PGD. Both these approaches would be quick,\u000d\u000a      cheap and could be performed using basic laboratory equipment.\u000d\u000a    Detecting genetic disorders to prevent severe inherited disease:\u000d\u000a      In 2006, KCL researchers demonstrated that a generic test based on PGH\u000d\u000a      could detect single gene mutations and would be suitable for use in the\u000d\u000a      NHS environment. Collaborating researchers from the Guy's Hospital\u000d\u000a      Genetics Clinic, KCL Genetics laboratories and KCL Women's Health, Dr Abbs\u000d\u000a      (KCL, 1994-2012), Professor Ogilvie, Dr Renwick and Professor Braude (KCL,\u000d\u000a      1997-2011), first published proof of this principle using embryos known to\u000d\u000a      be at risk of cystic fibrosis, a common genetic condition caused by a\u000d\u000a      mutation in a single gene, CFTR [3]. The most common mutation in\u000d\u000a      the CFTR gene, 2206F508, accounts for two-thirds of cases;\u000d\u000a      however, more than 1,500 other known mutations exist. Applying KCL's\u000d\u000a      generic PGH technique identified multiple uncharacterised mutations in the\u000d\u000a      CFTR gene of human embryos, and facilitated the implantation of\u000d\u000a      healthy embryos [3]. Thus, the generic PGH technique could accurately\u000d\u000a      distinguish normal (low-risk) and mutated (high-risk) genes in embryos\u000d\u000a      [3,5].\u000d\u000a    Ongoing KCL research expands the number of inherited genetic diseases\u000d\u000a        available for embryo screening: KCL-pioneered PGD techniques have\u000d\u000a      enabled consistently successful detection of inherited genetic mutations\u000d\u000a      without the need for mapping a family's specific genetic mutation. Using\u000d\u000a      the PGH approach, the number of single-gene conditions detectable by\u000d\u000a      on-demand clinical services has increased to well over 50. At Guy's and St\u000d\u000a      Thomas' Centre for PGD alone, PGH has been used to identify the presence\u000d\u000a      of high-risk genes for multiple inherited diseases in embryos from at-risk\u000d\u000a      couples, including cystic fibrosis [3], Duchenne and Becker muscular\u000d\u000a      dystophy [3,6], trisomy [5], Alport syndrome, Haemophilia A, Huntington's\u000d\u000a      disease, sickle-cell disease and others [6]. Ultimately, KCL research has\u000d\u000a      helped couples avoid the risk of bearing children with inherited diseases\u000d\u000a      or the distress of terminating pregnancies.\u000d\u000a    "},{"CaseStudyId":"41162","Continent":[{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000d\u000a    Outstanding impact on US Food and Drug Administration (FDA) review of\u000d\u000a        prostate cancer drugs: The most notable impact of the research is in\u000d\u000a      a review of the safety of commonly used prostate cancer drugs by the FDA\u000d\u000a      in May 2010 (4). The review was based on the KCL research, as the largest\u000d\u000a      population-based study of its kind, and six other studies. The FDA review\u000d\u000a      concluded that the risk of certain cardiovascular diseases was higher in\u000d\u000a      men treated with one of the main hormone therapies: gonadotropin-releasing\u000d\u000a      hormone agonists.\u000d\u000a    Substantial impact on requirements for drug safety information: In\u000d\u000a      October 2010, the FDA notified the manufacturers of gonadotropin-releasing\u000d\u000a      hormone agonists that they should add new safety information to the\u000d\u000a      Warnings and Precautions section on drug labels (5). The warning alerts\u000d\u000a      users to the risk of cardiovascular disease associated with certain\u000d\u000a      hormone therapies for the treatment of prostate cancer. The World Health\u000d\u000a      Organization issued similar advice.\u000d\u000a    Substantial impact on FDA treatment guidelines: The KCL research\u000d\u000a      findings provided evidence underpinning FDA guidelines for healthcare\u000d\u000a      professionals (5) on treatment for patients with prostate cancer:\u000d\u000a    1) Healthcare professionals should be aware of the potential risks and\u000d\u000a      carefully weigh up the benefits and risks of gonadotropin-releasing\u000d\u000a      hormone agonists when determining treatment for patients with prostate\u000d\u000a      cancer\u000d\u000a    2) Patients receiving gonadotropin-releasing hormone agonists should be\u000d\u000a      closely monitored for signs of diabetes and cardiovascular disease\u000d\u000a    3) Cardiovascular risk factors such as smoking, hypertension,\u000d\u000a      hypercholesterolemia, hyperglycaemia and obesity should be managed\u000d\u000a      according to current clinical practice\u000d\u000a    4) Patients should not stop treatment with a gonadotropin-releasing\u000d\u000a      hormone agonist unless instructed to do so by a healthcare professional.\u000d\u000a    Research corroborated by major US bodies: The research finding\u000d\u000a      \"Based on the small absolute risk difference, the high absolute risk of\u000d\u000a      dying from prostate cancer when undergoing hormone treatment, and the fact\u000d\u000a      that hormone treatment is currently the only effective treatment for\u000d\u000a      metastatic disease, these findings indicate that cardiovascular disease\u000d\u000a      risk should be considered when prescribing hormone treatment, but should\u000d\u000a      not contraindicate when the expected gain is tangible\" was corroborated by\u000d\u000a      the American Heart Association, the American Cancer Society and the\u000d\u000a      American Urological Association (6).\u000d\u000a    Substantial impact on treatment recommendations: Other\u000d\u000a      organisations making similar recommendations to those of the FDA and based\u000d\u000a      partly on the research include the Prostate Cancer Foundation, American\u000d\u000a      Cancer Society, US Too International, Prostate Cancer International,\u000d\u000a      Prostate Health Education Network, Prostate Cancer Research Institute,\u000d\u000a      Men's Health Network, Prostate Cancer Roundtable, Patient Advocates for\u000d\u000a      Advanced Cancer Treatment, and Zero — The Project to End Prostate Cancer.\u000d\u000a    Wide implications for management of prostate cancer patients: The\u000d\u000a      research showed that the risk of non-fatal and fatal cardiovascular\u000d\u000a      disease increases in prostate cancer patients receiving hormone treatment.\u000d\u000a      The risk of cardiovascular disease is also greater in patients who are\u000d\u000a      receiving curative treatment or who are under surveillance. This finding\u000d\u000a      supports growing evidence that diseases associated with prostate cancer\u000d\u000a      are a significant risk and has an impact on management of prostate cancer\u000d\u000a      patients beyond the original intent of the research. It also showed that\u000d\u000a      anti-androgen therapy carries lower risk than other forms of hormone\u000d\u000a      therapy, and so may affect choice of therapy.\u000d\u000a    Very considerable public-facing impact: The research has had very\u000d\u000a      considerable impact in terms of reach. At the joint European CanCer\u000d\u000a      Organisation (ECCO) and European Society for Medical Oncology (ESMO)\u000d\u000a      meeting in September 2009 (7) the researchers were interviewed. Newspapers\u000d\u000a      and other media then published more than 600 articles worldwide (e.g.\u000d\u000a      8-11). All refer to the research finding that men with prostate cancer\u000d\u000a      treated with certain hormone therapies have a higher risk of heart disease\u000d\u000a      and strokes.\u000d\u000a    The research findings are actively disseminated in news stories on the\u000d\u000a      KCL website which also provides a link to the initial press conference.\u000d\u000a    Relevant to treatment of prostate cancer globally: Prostate cancer\u000d\u000a      is the most common male cancer in Europe, accounting for a quarter of all\u000d\u000a      newly diagnosed cases, or about 380,000 men every year. Moreover, prostate\u000d\u000a      cancer is the third most common cause of death from cancer in European\u000d\u000a      men, with 94,000 deaths a year. There are more than 8 million men living\u000d\u000a      with prostate cancer globally, of whom 2 million live in the United\u000d\u000a      States. Wide awareness of this research (such as through the considerable\u000d\u000a      media coverage generated) thus has a very considerable impact on the\u000d\u000a      health of a very large number of prostate cancer patients and their\u000d\u000a      families.\u000d\u000a    Improvements in the health of prostate cancer patients and fewer\u000d\u000a        deaths: The impact on the ultimate beneficiaries, patients with\u000d\u000a      prostate cancer, is significant. Doctors consider the research findings\u000d\u000a      when prescribing therapies. The overall health of prostate cancer patients\u000d\u000a      has improved and there have been fewer deaths as a result of this and\u000d\u000a      other research.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    Research carried out at King's College London (KCL) has raised awareness\u000d\u000a      of the potential risks associated with certain hormone therapies used to\u000d\u000a      treat prostate cancer. The group found that such hormone therapy can raise\u000d\u000a      the risk of heart attack by 24% and the risk of dying from heart disease\u000d\u000a      by 21%. However, for men receiving anti-androgen hormone therapy, the risk\u000d\u000a      of dying from heart disease was lower compared to other hormone therapies\u000d\u000a      such as gonadotropin-releasing hormone agonists. With anti-androgen\u000d\u000a      hormone therapy there was a chance of heart failure but the risk was 5%\u000d\u000a      compared to 34% for other hormone therapies which reduce testosterone\u000d\u000a      production.\u000d\u000a    The research has had very considerable impact in terms of reach, as over\u000d\u000a      600 articles have been published in newspapers and other media which refer\u000d\u000a      to the KCL finding that men with prostate cancer treated with certain\u000d\u000a      hormone therapies have a higher risk of heart disease and strokes.\u000d\u000a    The findings had a very significant impact on US Food and Drug\u000d\u000a      Administration (FDA) advice to healthcare professionals on the benefits\u000d\u000a      and risks of hormone therapy. The FDA also required manufacturers of\u000d\u000a      certain hormone therapy drugs to add safety information to labels.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    King's College London\u000d\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Van Hemelrijck M, Garmo H, Holmberg L, et al.\u000d\u000a      Absolute and relative risk of cardiovascular disease in men with prostate\u000d\u000a      cancer: Results from the population-based PCBaSe Sweden. J Clin Oncol.\u000d\u000a      2010;28:3448-56.\u000d\u000a    \u000a\u000a2. Van Hemelrijck M, Garmo H, Holmberg L, et al.\u000d\u000a      Increased morbidity and mortality following endocrine treatment for\u000d\u000a      prostate cancer: An analysis in 30,642 men in PCBaSe Sweden. Abstract\u000d\u000a      presented at the joint 15th Congress of the European CanCer Organisation\u000d\u000a      (ECCO) and 34th Congress of the European Society for Medical Oncology\u000d\u000a      (ESMO). Eur J Cancer 2009;7(3): Abstract 1BA.\u000d\u000a    \u000a\u000a3. Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of\u000d\u000a      thromboembolic diseases in men with prostate cancer: Results from the\u000d\u000a      population-based PCBaSe Sweden. Lancet Oncol. 2010; 11:450-8.\u000d\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"12","Subject":"Oncology and Carcinogenesis"},{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"}],"Sources":"\u000d\u000a    Impact on safe use of hormone therapy for prostate cancer\u000d\u000a    \u000d\u000a      Jefferson E. FDA Conducting Safety Review of Commonly Used Prostate\u000d\u000a        Cancer Drugs. Preliminary review suggests an increase in the risk of\u000d\u000a        diabetes and certain cardiovascular diseases in men treated with GnRH\u000d\u000a        agonists. FDA News Release on 3 May 2010.\u000d\u000a        http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm210549.htm\u000a\u000d\u000a      FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH\u000d\u000a        Agonists and Notification to Manufacturers of GnRH Agonists to Add New\u000d\u000a        Safety Information to Labeling Regarding Increased Risk of Diabetes and\u000d\u000a        Certain Cardiovascular Diseases.\u000d\u000a        http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm229986.htm\u000d\u000a        (Cites ref [1] on this web page)\u000d\u000a    \u000d\u000a    Impact on advice for treatment of prostate cancer\u000d\u000a    \u000d\u000a      Levine GN, D'Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et\u000d\u000a        al. Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular\u000d\u000a        Risk: A Science Advisory From the American Heart Association, American\u000d\u000a        Cancer Society, and American Urological Association: Endorsed by the\u000d\u000a        American Society for Radiation Oncology. Circulation\u000d\u000a        2010;121:833-40.\u000d\u000a    \u000d\u000a    Public-facing communication\u000d\u000a    \u000d\u000a      \"Prostate cancer patients on hormone therapy at increased risk for\u000d\u000a        various heart diseases.\" Mieke Van Hemelrijck of King's College,\u000d\u000a        London, speaking at an official press conference at ECCO 15 ESMO 34,\u000d\u000a        Berlin, 2009. http:\/\/www.ecancermedicalscience.com\/tv\/?play=248&cid=0&scid=0&q\u000d\u000a        (11,490 views as of 16 October 2013)\u000d\u000a      \"Hormone therapy for prostate cancer 'increases risk of heart\u000d\u000a        problems'\" Hormone therapy used to treat prostate cancer can increase\u000d\u000a        the risk of suffering heart problems by more than a quarter, scientists\u000d\u000a        have found. Telegraph 23 September 2009 (Quotes Van Hemelrijck,\u000d\u000a        cancer epidemiologist at KCL) http:\/\/www.telegraph.co.uk\/health\/healthnews\/6218754\/Hormone-therapy-for-prostate-cancer-increases-risk-of-heart-problems.html\u000a\u000d\u000a      \"Prostate Cancer May Spark Heart Problems\" ThirdAge.com 2 October 2009\u000d\u000a        (Quotes Van Hemelrijck, cancer epidemiologist at KCL) http:\/\/www.thirdage.com\/prostate-conditions\/prostate-cancer-treatment-may-spark-heart-problems\u000a\u000d\u000a      \"Fragwürdige Antihormontherapie bei Prostatakarzinom — Anti-Androgene\u000d\u000a        erhöhen Risiko für Herzinfarkte und Arrhyhthmien — Engmaschige\u000d\u000a        Kontrollen erforderlich\" derStandard 22 September 2009 (Quotes Van\u000d\u000a          Hemelrijck)\u000d\u000a        http:\/\/derstandard.at\/1253596294721\/KrebskongressFragwuerdige-Antihormontherapie-bei-Prostatakarzinom\u000a\u000d\u000a      \"Absolute And Relative Risk Of Cardiovascular Disease In Men With\u000d\u000a        Prostate Cancer: Results From The Population-Based PCBaSe Sweden\"\u000d\u000a        MEDINEWS 11 August 2010\u000d\u000a        http:\/\/www.medicalnewstoday.com\/articles\/197370.php\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Improved understanding of the risk of cardiovascular disease with hormone\u000d\u000a      therapy for prostate cancer\u000d\u000a    ","UKLocation":[{"GeoNamesId":"2643743","Name":"London"}],"UKRegion":[{"GeoNamesId":"6269131","Name":"England"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    Hormone treatment for prostate cancer: Hormone treatment has been\u000d\u000a      the cornerstone of treatment for prostate cancer for decades. It is\u000d\u000a      currently the only effective treatment for advanced prostate cancer, and\u000d\u000a      can keep the disease in check for months or even years. Each year, around\u000d\u000a      36,000 men in the UK are diagnosed with prostate cancer. In the USA,\u000d\u000a      600,000 of the 2 million men diagnosed with prostate cancer receive\u000d\u000a      hormone treatment. Some of the hormone treatments interrupt the supply of\u000d\u000a      testosterone — thought to protect the heart — to the prostate.\u000d\u000a      Cardiovascular disease is recognised as a potential adverse side effect of\u000d\u000a      hormone treatment for prostate cancer. The rise of screening for prostate\u000d\u000a      cancer means earlier detection and that more men receive hormone treatment\u000d\u000a      for a longer time. Longer treatments are more likely to result in patients\u000d\u000a      suffering adverse side effects from hormone treatments.\u000d\u000a    Research on risks of heart disease in hormone treatment for prostate\u000d\u000a        cancer: The research was conducted at KCL by Lars Holmberg\u000d\u000a      (Professor of Cancer Epidemiology, 2007-present), Mieke Van Hemelrijck\u000d\u000a      (Lecturer in Cancer Epidemiology, 2008-present) and Hans Garmo (Senior\u000d\u000a      Statistician 2008-present) of the Cancer Epidemiology Group. At the time\u000d\u000a      of the research, there was no published quantitative data on the risks of\u000d\u000a      cardiovascular disease in men with prostate cancer.\u000d\u000a    Largest, most comprehensive study of prostate cancer in a population:\u000d\u000a      The study was the largest, most comprehensive study of prostate cancer in\u000d\u000a      a population and is very significant in its focus on different types of\u000d\u000a      cardiovascular disease associated with hormone therapy (1-3).\u000d\u000a    KCL collaborates with PCBaSe Sweden, which has data on more than 76,600\u000d\u000a      prostate cancer patients in the Swedish National Prostate Cancer Register\u000d\u000a      (96% of Swedish cases). The KCL group analysed patient information in\u000d\u000a      PCBaSe on age, serum prostate-specific antigen (PSA) level, treatment at\u000d\u000a      the time of diagnosis, the condition and stage of tumours, socioeconomic\u000d\u000a      status, history of cardiovascular disease, and the cause and date of\u000d\u000a      deaths. The condition of tumours was assessed using tumour size, serum PSA\u000d\u000a      and the Gleason score.\u000d\u000a    The KCL research group identified more than 30,000 men who had been\u000d\u000a      treated with a hormone (endocrine) therapy between 1997 and 2006 (1-3).\u000d\u000a      Hormone treatments included anti-androgens, oestrogens, orchiectomy,\u000d\u000a      gonadotropin-releasing hormone (GnRH) agonists, GnRH agonist combined with\u000d\u000a      long term anti-androgens, and other treatments.\u000d\u000a    The group compared the frequency of heart problems in the group of\u000d\u000a      prostate cancer patients to the frequency in the Swedish population (the\u000d\u000a      control group) by calculating standardised incidence ratios and\u000d\u000a      standardised mortality ratios of ischemic heart disease, acute myocardial\u000d\u000a      infarction (heart attack), arrhythmia, heart failure and stroke.\u000d\u000a    Higher risk of cardiovascular disease with hormone treatment\u000d\u000a        established: The research established that prostate cancer patients\u000d\u000a      have a 21% higher chance of dying from heart disease and are 28% more\u000d\u000a      likely to have a fatal heart attack than men without prostate cancer.\u000d\u000a      Prostate cancer patients receiving hormone treatments run the most\u000d\u000a      pronounced risk. There are about eight extra deaths a year from\u000d\u000a      cardiovascular disease for every 1,000 prostate cancer patients treated\u000d\u000a      with hormone drugs. However, men receiving anti-androgen hormone therapy\u000d\u000a      had a lower risk of heart disease than those receiving other hormone\u000d\u000a      therapies.\u000d\u000a    Risks do not outweigh the gains but require consideration: The\u000d\u000a      very significant finding of the research was that in absolute terms the\u000d\u000a      risks of cardiovascular disease with hormone treatment for prostate cancer\u000d\u000a      are low. Hormone treatment is currently the only effective treatment for\u000d\u000a      prostate cancer. The investigation indicates that the risk of\u000d\u000a      cardiovascular disease should be taken into account when prescribing\u000d\u000a      hormone treatment, but should not discourage hormone treatment when the\u000d\u000a      balance between benefit and risks is considered to be positive.\u000d\u000a      Anti-androgen therapy may have a lower risk than other types of hormone\u000d\u000a      therapy.\u000d\u000a    "},{"CaseStudyId":"41163","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"6252001","Name":"United States"},{"GeoNamesId":"2635167","Name":"United Kingdom"}],"Funders":["Medical Research Council"],"ImpactDetails":"\u000d\u000a    A new approach to rheumatoid arthritis care: The 2009 National\u000d\u000a      Institute for Health and Clinical\u000d\u000a      Excellence (NICE) guidelines for rheumatoid arthritis [7], draw heavily on\u000d\u000a      research by KCL's\u000d\u000a      Professor Scott and colleagues, referencing 10 of their publications and\u000d\u000a      changing the way that\u000d\u000a      care is delivered for people with rheumatoid arthritis in England.\u000d\u000a    The guidelines were published by NICE in collaboration with the Royal\u000d\u000a      College of Physicians and\u000d\u000a      the National Collaborating Centre for Chronic Conditions. They include\u000d\u000a      several key priorities for\u000d\u000a      implementation, the most important of which was that \"people with newly\u000d\u000a        diagnosed active\u000d\u000a        rheumatoid arthritis should be offered a combination of\u000d\u000a        disease-modifying anti-rheumatic drugs\u000d\u000a        including methotrexate and at least one other disease modifying drug\u000d\u000a        plus short-term steroids as\u000d\u000a        soon as possible and ideally within 3 months of the onset of persistent\u000d\u000a        symptoms\".\u000d\u000a    This recommendation depended on the following research evidence:\u000d\u000a    a. Early treatment with disease-modifying drugs is effective at limiting\u000d\u000a      disability\u000d\u000a    b. Intensive combination therapy is more effective than treatment with\u000d\u000a      one drug only\u000d\u000a    c. Conventional drugs, including leflunomide, are the mainstay of\u000d\u000a      treatment.\u000d\u000a    The evidence favouring intensive treatment was based on a large body of\u000d\u000a      international research,\u000d\u000a      and one specific guidance point was a direct consequence of the KCL\u000d\u000a      group's work — the\u000d\u000a      recommendation to use combinations of disease-modifying drugs. The most\u000d\u000a      crucial KCL research\u000d\u000a      contributions were those showing that using two or more conventional\u000d\u000a      disease-modifying\u000d\u000a      treatments are effective and that these appear highly cost-effective in\u000d\u000a      early rheumatoid arthritis.\u000d\u000a      This approach is also endorsed by the NICE Quality Standard for rheumatoid\u000d\u000a      arthritis, published in\u000d\u000a      June 2013 [8].\u000d\u000a    Impact on treatment in the UK, Europe and beyond: A number of\u000d\u000a      further measures have been\u000d\u000a      taken to promote the use of intensive treatment in early rheumatoid\u000d\u000a      arthritis in the UK as a result of\u000d\u000a      KCL's work, including the Report from the National Audit Office on\u000d\u000a      Rheumatoid Arthritis (2009) [9]\u000d\u000a      and the National Audit for Early Arthritis led by the Healthcare Quality\u000d\u000a      Improvement Partnership\u000d\u000a      [10]. The NHS Best Practice Tariff for early inflammatory arthritis in\u000d\u000a      2013\/4 Payment by Results\u000d\u000a      also emphasises the importance of early awareness, regular follow-up and\u000d\u000a      appropriate titration\u000d\u000a      (progressive intensification) of therapy [11]. The British Society for\u000d\u000a      Rheumatology guideline also\u000d\u000a      supports this approach [12].\u000d\u000a    Other national and international guidance, including the Scottish\u000d\u000a      Intercollegiate Network Guidance\u000d\u000a      for the management of early rheumatoid arthritis [13], the European\u000d\u000a      (EULAR) guidance for the\u000d\u000a      management of rheumatoid arthritis [14, 15] and North American guidance\u000d\u000a      [16] have also drawn\u000d\u000a      upon the research of Professor Scott and his colleagues.\u000d\u000a    Impact on patients: Professor Scott and his colleagues have also\u000d\u000a      published evidence that the\u000d\u000a      management of rheumatoid arthritis is improving as a result of their work.\u000d\u000a      Fewer patients have\u000d\u000a      uncontrolled active disease, joint replacement needs are declining, and\u000d\u000a      inpatient care is falling.\u000d\u000a      However, they have also shown that uptake of intensive treatment\u000d\u000a      approaches remains suboptimal\u000d\u000a      and that greater efforts to translate evidence into practice are still\u000d\u000a      needed [17, 18]. Patients'\u000d\u000a      organisations' advice makes reference to the benefits of early combination\u000d\u000a      treatment [19, 20].\u000d\u000a    The impact of the research undertaken at KCL has been achieved through\u000d\u000a      the extensive efforts\u000d\u000a      made by the group to disseminate evidence that intensive therapy is\u000d\u000a      effective. These include:\u000d\u000a    a. Serving on national bodies overseeing clinical practice and standards:\u000d\u000a      Professors Panayi and\u000d\u000a      Scott were both Presidents of The British Society for Rheumatology; Dr\u000d\u000a      Kingsley chaired its\u000d\u000a      External Relations Committee\u000d\u000a    b. Working with patient groups: Professor Panayi was Chief Medical\u000d\u000a      Adviser to the National\u000d\u000a      Rheumatoid Arthritis Society (NRAS). Professor Scott Chaired the\u000d\u000a      Scientific Section of the\u000d\u000a      Arthritis and Musculoskeletal Alliance (ARMA) and co-ordinated its working\u000d\u000a      group for\u000d\u000a      Standards of Care in Inflammatory Arthritis\u000d\u000a    c. Contributing to UK and European Guidelines: Professor Scott served on\u000d\u000a      two guidelines groups\u000d\u000a      for rheumatoid arthritis: the National Institute for Health and Clinical\u000d\u000a      Evidence (NICE) group\u000d\u000a      and the European League Against Rheumatism (EULAR) group.\u000d\u000a    ","ImpactSummary":"\u000d\u000a    An estimated 1% of UK adults suffer from rheumatoid arthritis and the\u000d\u000a      long-term pain and disability\u000d\u000a      associated with it, Historically, however, treatments focused on relieving\u000d\u000a      symptoms and did not\u000d\u000a      control the arthritis itself or prevent disability. An extensive series of\u000d\u000a      clinical trials and associated\u000d\u000a      research programmes at King's College London (KCL) over 20 years has now\u000d\u000a      significantly\u000d\u000a      improved treatment recommendations and thus quality of life for thousands\u000d\u000a      of rheumatoid arthritis\u000d\u000a      patients in the UK, Europe and other countries. Multicentre trials of\u000d\u000a      intensive treatments using\u000d\u000a      conventional drugs have extended the range of drugs available, established\u000d\u000a      the effectiveness of\u000d\u000a      early intensive treatment, and shown that early combination therapies are\u000d\u000a      safe.\u000d\u000a    ","ImpactType":"Health","Institution":"\u000d\u000a    King's College London\u000d\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000d\u000a    \u000a1. Scott DL, Smolen JS, Kalden JR, Van De Putte LBA, Larsen A,\u000d\u000a      Kvien TK, Schattenkirchner M,\u000d\u000a      Nash P, Oed C, Loew-Friedrich I: European Leflunomide Study Group..\u000d\u000a      Treatment of active\u000d\u000a      rheumatoid arthritis with leflunomide: Two-year follow-up of a\u000d\u000a      double-blind, placebo-controlled\u000d\u000a      trial versus sulfasalazine. Ann Rheum Dis. 2001;60:913-23.\u000d\u000a    \u000a\u000a2. Choy EH, Scott DL, Kingsley GH, Williams P, Wojtulewski J,\u000d\u000a      Papasavvas G, Henderson E,\u000d\u000a      Macfarlane D, Erhardt C, Young A, Plant MJ, Panayi GS. Treating\u000d\u000a      rheumatoid arthritis early\u000d\u000a      with disease modifying drugs reduces joint damage: a randomised double\u000d\u000a      blind trial of\u000d\u000a      sulphasalazine vs diclofenac sodium. Clin Exp Rheumatol.\u000d\u000a      2002;20:351-8.\u000d\u000a    \u000a\u000a3. Choy EH, Smith CM, Farewell V, Walker D, Hassell A, Chau L, Scott\u000d\u000a        DL: CARDERA\u000d\u000a      (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arthritis) Trial\u000d\u000a      Group. Factorial\u000d\u000a      randomised controlled trial of glucocorticoids and combination disease\u000d\u000a      modifying drugs in early\u000d\u000a      rheumatoid arthritis. Ann Rheum Dis. 2008;67:656-63.\u000d\u000a    \u000a\u000a4. Choy EH, Kingsley GH, Khoshaba B, Pipitone N, Scott DL:Intramuscular\u000d\u000a      Methylprednisolone\u000d\u000a      Study Group. A two year randomised controlled trial of intramuscular depot\u000d\u000a      steroids in patients\u000d\u000a      with established rheumatoid arthritis who have shown an incomplete\u000d\u000a      response to disease\u000d\u000a      modifying antirheumatic drugs. Ann Rheum Dis. 2005; 64:1288-93.\u000d\u000a    \u000a\u000a5. Symmons D, Tricker K, Harrison M, Roberts C, Davis M, Dawes P, Hassell\u000d\u000a      A, Knight S,\u000d\u000a      Mulherin D, Scott DL: British Rheumatoid Outcome Study Group.\u000d\u000a      Patients with stable long-standing\u000d\u000a      rheumatoid arthritis continue to deteriorate despite intensified treatment\u000d\u000a      with\u000d\u000a      traditional disease modifying anti-rheumatic drugs — results of the\u000d\u000a      British Rheumatoid Outcome\u000d\u000a      Study Group randomized controlled clinical trial. Rheumatology.\u000d\u000a      2006;45:558-65.\u000d\u000a    \u000a\u000a6. Choy EH, Smith C, Doré CJ, Scott DL. A meta-analysis\u000d\u000a      of the efficacy and toxicity of\u000d\u000a      combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis\u000d\u000a      based on patient\u000d\u000a      withdrawal. Rheumatology. 2005;44:1414-21.\u000d\u000a    \u000aGrants\u000d\u000a    Over £8 million has been raised in peer-reviewed grants to support the\u000d\u000a      ongoing research\u000d\u000a      programme. This includes ~£2M from MRC, over £1.5M from Arthritis Research\u000d\u000a      UK, more than\u000d\u000a      £4M from NIHR (and NHS R&D), as well as funding from Pharmacia,\u000d\u000a      Hoechst and Aventis.\u000d\u000a    ","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"11","Level2":"17","Subject":"Public Health and Health Services"}],"Sources":"\u000d\u000a    Key UK guidance\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      National Institute for Health and Clinical Excellence. Rheumatoid\u000d\u000a        arthritis: NICE guideline.\u000d\u000a        2009. http:\/\/www.nice.org.uk\/nicemedia\/live\/12131\/43327\/43327.pdf\u000a\u000d\u000a      National Institute for Health and Clinical Excellence. Quality\u000d\u000a        standard 33: Rheumatoid arthritis.\u000d\u000a        2013. http:\/\/publications.nice.org.uk\/quality-standard-for-rheumatoid-arthritis-qs33\u000a\u000d\u000a    \u000d\u000a    Other UK guidance and reports\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      National Audit Office. Services for people with rheumatoid arthritis.\u000d\u000a        Stationery Office, 2009.\u000d\u000a        http:\/\/www.nao.org.uk\/wp-content\/uploads\/2009\/07\/0809823.pdf\u000a\u000d\u000a      National Clinical Audit of Rheumatoid and Early Arthritis. 2013. http:\/\/www.hqip.org.uk\/new-national-clinical-audits-for-kidney-disease-and-arthritis\/\u000a\u000d\u000a      Department of Health. Payment by Results Guidance for 2013-14.\u000d\u000a        https:\/\/www.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/214902\/PbR-Guidance-2013-14.pdf\u000a\u000d\u000a      Chakravarty K et al. BSR\/BHPR guideline for disease-modifying\u000d\u000a        anti-rheumatic drug (DMARD)\u000d\u000a        therapy in consultation with the British Association of Dermatologists.\u000d\u000a        2008.\u000d\u000a        http:\/\/www.rheumatology.org.uk\/includes\/documents\/cm_docs\/2009\/d\/diseasemodifying_antirheumatic_drug_dmard_therapy.pdf\u000a\u000d\u000a      Scottish Intercollegiate Guidelines Network (SIGN). Management of\u000d\u000a        early rheumatoid arthritis.\u000d\u000a        Edinburgh: SIGN; 2011. (SIGN publication no. 123).Available from URL:\u0009\u000d\u000a        http:\/\/www.sign.ac.uk\/pdf\/sign123.pdf\u000a\u000d\u000a    \u000d\u000a    European guidance\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala\u000d\u000a        C, Gorter S,\u000d\u000a        Knevel R, Nam J, Schoels M, Aletaha D, Buch M, Gossec L, Huizinga T,\u000d\u000a        Bijlsma JW,\u000d\u000a        Burmester G, Combe B, Cutolo M, Gabay C, Gomez-Reino J, Kouloumas M,\u000d\u000a        Kvien TK, Martin-Mola\u000d\u000a        E, McInnes I, Pavelka K, van Riel P, Scholte M, Scott DL, Sokka T,\u000d\u000a        Valesini G, van\u000d\u000a        Vollenhoven R, Winthrop KL, Wong J, Zink A, van der Heijde D. EULAR\u000d\u000a        recommendations for\u000d\u000a        the management of rheumatoid arthritis with synthetic and biological\u000d\u000a        disease-modifying\u000d\u000a        antirheumatic drugs. Ann Rheum Dis. 2010;69:964-75.\u0009\u000d\u000a        Also EULAR. EULAR 2013 Rheumatoid Arthritis Management Recommendations,\u000d\u000a        EULAR\u000d\u000a        Data on File, 2013. See\u000d\u000a        http:\/\/www.eular.org\/myUploadData\/files\/EULAR%20RA%20recommendations%20FINAL.pdf\u000a\u000d\u000a      Schoels M, Wong J, Scott DL, Zink A, Richards P, Landewé R, Smolen JS,\u000d\u000a        Aletaha D.\u000d\u000a        Economic aspects of treatment options in rheumatoid arthritis: a\u000d\u000a        systematic literature review\u000d\u000a        informing the EULAR recommendations for the management of rheumatoid\u000d\u000a        arthritis. Ann\u000d\u000a          Rheum Dis. 2010;69:995-1003.\u000d\u000a    \u000d\u000a    International guidance\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM,\u000d\u000a        Moreland LW, O'Dell J,\u000d\u000a        Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE,\u000d\u000a        Suarez-Almazor M,\u000d\u000a        Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL,\u000d\u000a        Schousboe JT,\u000d\u000a        Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS,\u000d\u000a        Patkar NM,\u000d\u000a        Saag KG. 2012 update of the 2008 American College of Rheumatology\u000d\u000a        recommendations for\u000d\u000a        the use of disease-modifying antirheumatic drugs and biologic agents in\u000d\u000a        the treatment of\u000d\u000a        rheumatoid arthritis. Arthritis Care Res. 2012;64:625-39.\u000d\u000a    \u000d\u000a    Editorials and reviews\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      Deighton C, Scott DL. Treating inflammatory arthritis early. BMJ.\u000d\u000a        2010;341:c7384.\u000d\u000a      \u000aScott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet.\u000d\u000a        2010;376:1094-108.\u000d\u000a    \u000d\u000a    Patients' organisation sources\u000d\u000a    \u000d\u000a    \u000d\u000a      \u000d\u000a      National Rheumatoid Arthritis Society: Deighton C. Combination therapy\u000d\u000a        for rheumatoid\u000d\u000a        arthritis 2009\/2011.\u000d\u000a        http:\/\/www.nras.org.uk\/about_rheumatoid_arthritis\/newly_diagnosed\/which_drugs_are_used\/combination_therapy_for_rheumatoid_arthritis.aspx\u000a\u000d\u000a      Arthritis and Musculoskeletal Alliance. Standards Of Care For\u000d\u000a        Inflammatory Arthritis.\u000d\u000a        http:\/\/arma.uk.net\/wp-content\/uploads\/pdfs\/ia06.pdf\u000a\u000d\u000a    \u000d\u000a    ","Title":"\u000d\u000a    Using intensive conventional drug treatment to optimise clinical outcomes\u000d\u000a      in\u000d\u000a      rheumatoid arthritis\u000d\u000a    ","UKLocation":[],"UKRegion":[{"GeoNamesId":"2638360","Name":"Scotland"}],"UOA":"Clinical Medicine","UnderpinningResearch":"\u000d\u000a    A major chronic condition with high care costs: Rheumatoid\u000d\u000a      arthritis is a long-term condition\u000d\u000a      affecting 1% of UK adults. Historically patients were treated\u000d\u000a      conservatively and many became\u000d\u000a      disabled. In 2000 alone in the UK, this resulted in medical costs of over\u000d\u000a      £1 billion and social care\u000d\u000a      costs of £3.5 billion.\u000d\u000a    A 20-year initiative against rheumatoid arthritis: Since 1993,\u000d\u000a      Professor Scott and his\u000d\u000a      colleagues at KCL have made important contributions to improving the\u000d\u000a      management of rheumatoid\u000d\u000a      arthritis. During this time they have led 21 randomised controlled trials\u000d\u000a      (17 completed and\u000d\u000a      published, 2 in analysis and 2 in progress; 14 funded by external grants)\u000d\u000a      and published 9\u000d\u000a      systematic reviews on the treatment of rheumatoid arthritis (all funded by\u000d\u000a      external grants). These\u000d\u000a      trials and systematic reviews have been supported by 38 observational and\u000d\u000a      qualitative studies, and\u000d\u000a      48 editorials and reviews on rheumatoid arthritis management.\u000d\u000a    The KCL team's underpinning research has involved extensive collaboration\u000d\u000a      between academic\u000d\u000a      and clinical units in the UK and other European countries. This research\u000d\u000a      has focused on patients\u000d\u000a      with very active forms of the disease in its early stages, on how disease\u000d\u000a      activity can be controlled\u000d\u000a      and on what approaches would ensure that optimal treatment strategies were\u000d\u000a      adopted throughout\u000d\u000a      the UK and beyond.\u000d\u000a    Early, intensive therapy is optimal: KCL's sustained clinical\u000d\u000a      research programme concluded that\u000d\u000a      the best clinical outcomes are achieved when patients are treated early\u000d\u000a      with combinations of\u000d\u000a      different drugs. Another key finding was that the intensity of therapy is\u000d\u000a      a more important factor than\u000d\u000a      the specific drugs. Treating patients late, with single agents, is less\u000d\u000a      beneficial.\u000d\u000a    Six publications indicate the wide range of evidence generated. Five of\u000d\u000a      these report on multicentre\u000d\u000a      trials of 90-466 patients lasting 12-36 months; the sixth is a systematic\u000d\u000a      meta-analysis of individual\u000d\u000a      studies that provides confirmatory evidence. These papers provide:\u000d\u000a    a. Evidence to extend the range of conventional drugs to include\u000d\u000a      leflunomide [1]\u000d\u000a    b. Confirmatory evidence that early treatment is beneficial and prevents\u000d\u000a      joint damage [2]\u000d\u000a    c. Evidence that drug combinations early in the disease minimise\u000d\u000a      disability and prevent joint\u000d\u000a      damage [3]\u000d\u000a    d. An indication of the benefits and risks of adding steroids in\u000d\u000a      established disease [4]\u000d\u000a    e. An indication of the limitations of delaying intensive treatment until\u000d\u000a      late rheumatoid\u000d\u000a      disease [5]\u000d\u000a    f. A meta-analysis to confirm the substantial benefits of intensive\u000d\u000a      combination therapy [6].\u000d\u000a    The research at KCL involved Professor Scott (1993-present), Professor G\u000d\u000a      Panayi (1993-2006,\u000d\u000a      Arthritis Research Campaign Professor), Dr E Choy (1993-2010, Reader) and\u000d\u000a      Dr G Kingsley\u000d\u000a      (1993-present, Reader and later Professor).\u000d\u000a    "},{"CaseStudyId":"41164","Continent":[{"GeoNamesId":"6255148","Name":"Europe"},{"GeoNamesId":"6255149","Name":"North America"}],"Country":[{"GeoNamesId":"2635167","Name":"United Kingdom"},{"GeoNamesId":"6252001","Name":"United States"}],"Funders":[],"ImpactDetails":"\u000a    Marked improvement in the management of anaemia in chronic kidney\u000a        disease: The research described above has significantly improved the\u000a      management of anaemia in patients with chronic kidney disease worldwide,\u000a      through its contribution to national and international guidelines.\u000a    Contribution to UK NICE guidelines: The 2011 clinical guidelines\u000a      \"CG114: Anaemia management in people with chronic kidney disease\" (13)\u000a      published by the UK National Institute for Health and Care Excellence\u000a      (NICE) extensively incorporates the findings of KCL researchers. Seven\u000a      pieces of original KCL research contribute to the guidelines, including\u000a      the work on management of iron therapy and the use of a 2-minute push of\u000a      intravenous iron sucrose (1,2), target haemoglobin levels in patients on\u000a      erythropoietin therapy (4) and treatment of pure red cell aplasia (9).\u000a    Global impact: International clinical practice guidelines have\u000a      also assimilated the scientific evidence base for the management of renal\u000a      anaemia. The latest of these is the global KDIGO Clinical Practice\u000a      Guideline for Anemia in Chronic Kidney Disease (August 2012) (14). These\u000a      guidelines extensively incorporate the findings of KCL researchers, which\u000a      contributed 6 pieces of original research to the references cited in the\u000a      guideline. These include the work on management of iron therapy (1,2), the\u000a      work addressing normalisation of haemoglobin levels with erythropoietic\u000a      therapy (4), work on the relevance of haemoglobin variability (5),\u000a      research comparing pegylated epoetin with darbepoetin alfa (6), and\u000a      studies on the management of antibody-mediated pure red cell aplasia (9).\u000a    Iron supplementation: Iron supplementation is important in the\u000a      management of anaemia, but giving iron by oral tablet is ineffective in\u000a      dialysis patients. Professor Macdougall's randomised controlled trial\u000a      published in 1996 (1) was one of the first to show that oral\u000a      iron was ineffective in these patients. These patients benefit from\u000a      intravenous iron which corrects the iron deficiency and vastly improves\u000a      patients' quality of life. The practice of administering intravenous iron\u000a      sucrose (2) has been adopted in numerous kidney units worldwide. The\u000a      recommendations within the KDIGO Anemia guideline (14 - Chapter 2)\u000a      reinforce the benefit of this practice as evidenced by the KCL research\u000a      and the international standing of the guideline ensures its impact\u000a      worldwide. This relatively simple yet highly effective intervention has\u000a      had a major impact on patients' quality of life.\u000a    Target haemoglobin level: Although early studies suggested that\u000a      variability in haemoglobin level might be harmful, other studies,\u000a      including KCL research (4,5) suggested that this had little impact. The\u000a      CREATE study (4) provided especially strong data for the evidence base\u000a      supporting the inadvisability of aiming for haemoglobin concentrations\u000a      above 13 g\/dl in kidney patients. The KDIGO Anemia guideline states \"In\u000a      all adult patients, we recommend that ESAs not be used to intentionally\u000a      increase the Hb concentration above 13 g\/dl (130 g\/l). Evidence level 1A\u000a      (ref 14 - Chapter 3). These quote extensively from the CREATE study.\u000a    Comparing alternative epoietins: Since recombinant human\u000a      erythropoietin has become available, two longer-acting erythropoietin\u000a      analogues - darbepoetin alfa and pegylated epoetin beta - have been\u000a      investigated. International research to which KCL made a major\u000a      contribution has shown that when used once-monthly, pegylated epoetin beta\u000a      is superior to darbepoetin alfa (6). The practical benefit to\u000a      patients is in the reduced frequency of injections that is now possible\u000a      and this is also incorporated in the KDIGO Anemia guideline (ref 14 -\u000a      Chapter 3).\u000a    Pure red cell aplasia: The finding that the severe condition of\u000a      antibody-mediated pure red cell aplasia was transformed by peginesatide\u000a      (10) opened a unique treatment option for patients who had developed\u000a      antibodies against the conventional treatment, erythropoietin. It could\u000a      therefore be used to rescue patients who had developed this condition.\u000a      Before the peginesatide rescue study, there was uncertainty over the\u000a      treatment of these patients. The KCL-led research on peginesatide forms\u000a      the basis for the KDIGO global anemia guideline recommendation to consider\u000a      peginesatide as the potential treatment of choice for pure red cell\u000a      aplasia in patients with chronic kidney disease (ref 14 - Chapter 3).\u000a    The results of the studies that assessed the general use of peginesatide\u000a      in chronic kidney disease patients with anaemia (i.e. those without red\u000a      cell aplasia) (11,12) led to initial marketing authorisation for general\u000a      use of this drug by the FDA in the USA (15). However, it has subsequently\u000a      been withdrawn for this indication by the manufacturers because of cases\u000a      of severe allergic reaction (16).\u000a    ","ImpactSummary":"\u000a    King's College London (KCL) research has made a major contribution to\u000a      improving the quality of life for patients who have anaemia linked with\u000a      chronic kidney disease. Studies undertaken by KCL researchers established\u000a      that intravenous iron supplementation was required in anaemic patients\u000a      with advanced kidney disease, in whom oral iron therapy was ineffective,\u000a      and defined the best regimes for administration of intravenous iron.\u000a      Subsequent KCL work on drugs that stimulate production of red blood cells\u000a      (erythropoiesis) defined the target levels of haemoglobin to aim for in\u000a      chronic kidney disease patients. Most recently, KCL researchers made the\u000a      key discovery that the novel drug peginesatide for the first time enables\u000a      the rescue of patients who develop a rare and potentially fatal reaction\u000a      against erythropoietin (which is the commonest treatment for anaemia in\u000a      chronic kidney disease). These KCL research studies have had a significant\u000a      impact by making a major contribution to national and international\u000a      clinical guidelines, including UK NICE guidelines and the 2012 National\u000a      Kidney Foundation KDIGO Clinical Practice Guideline for Anemia in Chronic\u000a      Kidney Disease.\u000a    ","ImpactType":"Health","Institution":"\u000a    King's College London\u000a    ","Institutions":[{"AlternativeName":"King's College London","InstitutionName":"King's College London","PeerGroup":"A","Region":"London","UKPRN":10003645}],"Panel":"A         ","PlaceName":[],"References":"\u000a    \u000a1. Macdougall IC, Tucker B, Thompson J et al. A randomized\u000a      controlled study of iron supplementation in patients treated with\u000a      erythropoietin. Kidney Int. 1996;50:1694-99.\u000a    \u000a\u000a2. Macdougall IC, Roche A. Administration of intravenous iron\u000a      sucrose as a 2-minute push to CKD patients: a prospective evaluation of\u000a      2,297 injections. Am J Kidney Dis. 2005;46:283-89.\u000a    \u000a\u000a3. Vifor Pharma. FIND-CKD study demonstrates that Ferinject® reduces need\u000a      for alternative anaemia treatment. Press release 10 July 2013, reporting\u000a      results of Professor Macdougall's study.\u000a      http:\/\/www.viforpharma.com\/en\/Media\/mediareleases\/2013\/20130710_find-ckd_130710.php\u000a    \u000a\u000a4. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC,\u000a      Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of\u000a      hemoglobin level in patients with chronic kidney disease and anemia. N\u000a        Engl J Med. 2006;355:2071-84.\u000a    \u000a\u000a5. Eckardt KU, Kim J, Kronenberg F, Aljama P, Anker SD, Canaud B,\u000a      Molemans B, Stenvinkel P, Schernthaner G, Ireland E, Fouqueray B, Macdougall\u000a        IC. Hemoglobin variability does not predict mortality in European\u000a      hemodialysis patients. J Am Soc Nephrol. 2010;21:1765-75.\u000a    \u000a\u000a6. Carrera F, Lok CE, de Francisco A, Locatelli F, Mann JF, Canaud B,\u000a      Kerr PG, Macdougall IC, Besarab A, Villa G, Kazes I, Van Vlem B,\u000a      Jolly S, Beyer U, Dougherty FC; PATRONUS Investigators. Maintenance\u000a      treatment of renal anaemia in haemodialysis patients with methoxy\u000a      polyethylene glycol-epoetin beta versus darbepoetin alfa administered\u000a      monthly: a randomized comparative trial. Nephrol Dial Transplant.\u000a      2010;25:4009-17.\u000a    \u000a\u000a7. Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC.\u000a      Pentoxifylline improves hemoglobin levels in patients with\u000a      erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol.\u000a      2004;15:1877-82.\u000a    \u000a\u000a8. Johnson DW, Hawley CM, Rosser B et al. Oxpentifylline versus placebo\u000a      in the treatment of erythropoietin-resistant anaemia: a randomized\u000a      controlled trial. BMC Nephrol. 2008;9:8\u000a    \u000a\u000a9. Verhelst D, Rossert J, Casadevall N, Krüger A, Eckardt KU, Macdougall\u000a        IC. Treatment of erythropoietin-induced pure red cell aplasia: a\u000a      retrospective study. Lancet. 2004;363:1768-71.\u000a    \u000a\u000a10. Macdougall IC, Rossert J, Casadevall N, Stead RB, Duliege AM,\u000a      Froissart M, Eckardt KU. A peptide-based erythropoietin-receptor agonist\u000a      for pure red-cell aplasia. N Engl J Med. 2009;361:1848-55.\u000a    \u000a\u000a11. Macdougall IC, Provenzano R, Sharma A, Spinowitz BS, Schmidt\u000a      RJ, Pergola PE, Zabaneh RI, Tong-Starksen S, Mayo MR, Tang H, Polu KR,\u000a      Duliege AM, Fishbane S; PEARL Study Groups. Peginesatide for anemia in\u000a      patients with chronic kidney disease not receiving dialysis. N Engl J\u000a        Med. 2013;368:320-32.\u000a    \u000a\u000a12. Fishbane S, Schiller B, Locatelli F, Covic AC, Provenzano R, Wiecek\u000a      A, Levin NW, Kaplan M, Macdougall IC, Francisco C, Mayo MR, Polu\u000a      KR, Duliege AM, Besarab A; EMERALD Study Groups. Peginesatide in patients\u000a      with anemia undergoing hemodialysis. N Engl J Med.\u000a      2013;368:307-19.\u000a    \u000a","ResearchSubjectAreas":[{"Level1":"11","Level2":"3","Subject":"Clinical Sciences"},{"Level1":"6","Level2":"1","Subject":"Biochemistry and Cell Biology"}],"Sources":"\u000a      \u000a    NICE Guideline 2011. CG114: Anaemia management in people with chronic\u000a      kidney disease.http:\/\/guidance.nice.org.uk\/CG114\/Guidance\/pdf\/English\u000a\u000a    Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group.\u000a      KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney\u000a        Int. Suppl. 2012;2:279-335.\u000a      http:\/\/www.kdigo.org\/clinical_practice_guidelines\/anemia.php.\u000a    Chapter 2: Use of iron to treat anemia in CKD references.\u000a      Recommendations on \"Treatment with Iron agents\" cite references 1 and 2.\u000a      Recommendations on \"Cautions regarding Iron therapy\" cite reference 2.\u000a    Chapter 3: Use of ESAs and other agents* to treat anemia in CKD.\u000a      Recommendations on \"In initiating and maintaining ESA therapy...\" and on\u000a      \"ESA Maintenance Therapy\" extensively cite ref 4. Recommendations on \"ESA\u000a      Dosing\" cite ref 5. Recommendations on \"Type of ESA\" cite ref 6.\u000a      Recommendation on \"Pure red cell aplasia\" cite references 9 and 10.\u000a    FDA press release March 27, 2012.\u000a      http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm297464.htm\u000a\u000a    FDA press release February 23, 2013.\u000a      http:\/\/www.fda.gov\/Safety\/MedWatch\/SafetyInformation\/SafetyAlertsforHumanMedicalProducts\/ucm340895.htm\u000a\u000a\u000a\u0009  ","Title":"\u000a    Better treatment of anaemia and improved quality of life in patients with\u000a      chronic kidney disease\u00