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Objective The use of minimum clinically important difference in the hypothesis formulation for superiority trials is similar in principle to the concept of non-inferiority or equivalence trial. However, most clinical trials are analysed testing zero clinical difference. Since the minimum clinically important difference is pre-defined for power calculation, it is important to incorporate it in both the hypothesis testing and the interpretation of findings from clinical trials. Results We reviewed a set of 50 publications (25 with binary outcome, and 25 with survival time outcome). 20% of the 50 published trials that were statistically significant, were also clinically significant based on the minimum clinically important risk differences (or hazard ratio) used for their power calculations. This snap review seems to suggest that most published trials with statistically significant results were less likely to be clinically significant, which may partly explain the high false positive findings associated with findings from superiority trials. Furthermore, none of the reviewed publications explicitly used minimum clinically important difference in the interpretation of their findings. However, a systematic review is needed to critically appraise the impact of the current practice on false positive rate in published trials with significant findings.

IntroductionAnthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin’s lymphoma (NHL) receiving anthracycline-based chemotherapy.Methods and analysisPROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects.Ethics and disseminationA favourable opinion was given following research ethics committee review by West Midlands—Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication.Trial registration numberNCT03265574.

Background Iron deficiency has deleterious effects in patients with cardiopulmonary disease, independent of anemia. Low ferritin has been associated with increased mortality in patients undergoing cardiac surgery, but modern indices of iron deficiency need to be explored in this population. Methods We conducted a retrospective single-centre observational study of 250 adults in a UK academic tertiary hospital undergoing median sternotomy for non-emergent isolated aortic valve replacement. We characterised preoperative iron status using measurement of both plasma ferritin and soluble transferrin receptor (sTfR), and examined associations with clinical outcomes. Results Measurement of plasma sTfR gave a prevalence of iron deficiency of 22%. Patients with non-anemic iron deficiency had clinically significant prolongation of total hospital stay (mean increase 2.2 days; 95% CI: 0.5–3.9; P  = 0.011) and stay within the cardiac intensive care unit (mean increase 1.3 days; 95% CI: 0.1–2.5; P  = 0.039). There were no deaths. Defining iron deficiency as a plasma ferritin < 100 µg/L identified 60% of patients as iron deficient and did not predict length of stay. No significant associations with transfusion requirements were evident using either definition of iron deficiency. Conclusions These findings indicate that when defined using sTfR rather than ferritin, non-anemic iron deficiency predicts prolonged hospitalisation following surgical aortic valve replacement. Further studies are required to clarify the role of contemporary laboratory indices in the identification of preoperative iron deficiency in patients undergoing cardiac surgery. An interventional study of intravenous iron targeted at preoperative non-anemic iron deficiency is warranted.

ObjectivesTo assess the impact of both the Committee on Safety of Medicines (CSM) warning (December 2003) and the National Institute for Health and Care Excellence (NICE) guidance (September 2005) on antidepressant prescription rates in children and adolescents within the UK primary care service.SettingPopulation based study of primary care antidepressant prescribing using the Clinical Practice Research Datalink (CPRD).ParticipantsUnder-18s presenting to primary care with a depressive disorder or related diagnostic code recorded in the CPRD.Primary outcome measureAntidepressant prescription rates per month per 100 000 depressed 4–17 year olds.ResultsFollowing the CSM warning, the prior trend towards increased prescribing rates for selective serotonin reuptake inhibitors (SSRIs) in children was significantly reversed (β for change in trend −12.34 (95% CI −18.67 to −6.00, p<0.001)). However, after the publication of the NICE guidelines the prior trend towards increased prescribing resumed for those SSRIs mentioned as potential treatments in the guidance (fluoxetine, citalopram and sertraline) (β for change in trend 11.52 (95% CI 5.32 to 17.73, p<0.001)). Prescribing of other SSRIs and tricyclics remained low.ConclusionsDespite a strong emphasis on psychosocial interventions for child and adolescent depression, it may be that the NICE guidelines inadvertently encouraged further antidepressant prescribing, at least for those SSRIs cited. Although the guidelines gave cautions and caveats for the use of antidepressants, practitioners may have interpreted these recommendations as endorsing their use in young people with depression and related conditions. However, more accurate prevalence trend estimates for depression in this age group, and information on the use of psychosocial interventions would be needed to rule out other reasons underlying this increase in prescribing.

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) ( n  = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes. Trial registration Trial ID: ISRCTN15550611 Date registered: 07/08/2018. Sponsor and Monitor: Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust R&D Manager Lyndsey Dixon, Address: St Nicholas Hospital, Jubliee Road, Gosforth, Newcastle upon Tyne NE3 3XT, lyndsey.dixon@cntw.nhs.uk, Tel: 0191 246 7222

Prehabilitation prior to surgery has been shown to reduce postoperative complications, reduce length of hospital stay and improve quality of life after cancer and limb reconstruction surgery. However, there are minimal data on the impact of prehabilitation in patients undergoing cardiac surgery, despite the fact these patients are generally older and have more comorbidities and frailty. This trial will assess the feasibility and impact of a prehabilitation intervention consisting of exercise and inspiratory muscle training on preoperative functional exercise capacity in adult patients awaiting elective cardiac surgery, and determine any impact on clinical outcomes after surgery. PrEPS is a randomised controlled single-centre trial recruiting 180 participants undergoing elective cardiac surgery. Participants will be randomised in a 1:1 ratio to standard presurgical care or standard care plus a prehabilitation intervention. The primary outcome will be change in functional exercise capacity measured as change in the 6 min walk test distance from baseline. Secondary outcomes will evaluate the impact of prehabilitation on preoperative and postoperative outcomes including; respiratory function, health-related quality of life, anxiety and depression, frailty, and postoperative complications and resource use. This trial will evaluate if a prehabilitation intervention can improve preoperative physical function, inspiratory muscle function, frailty and quality of life prior to surgery in elective patients awaiting cardiac surgery, and impact postoperative outcomes. A favourable opinion was given by the Sheffield Research Ethics Committee in 2019. Trial findings will be disseminated to patients, clinicians, commissioning groups and through peer-reviewed publication. ISRCTN13860094.

ObjectivesUniversity academic achievement may be inversely related to the performance of the secondary (high) school an entrant attended. Indeed, some medical schools already offer ‘grade discounts’ to applicants from less well-performing schools. However, evidence to guide such policies is lacking. In this study, we analyse a national dataset in order to understand the relationship between the two main predictors of medical school admission in the UK (prior educational attainment (PEA) and performance on the United Kingdom Clinical Aptitude Test (UKCAT)) and subsequent undergraduate knowledge and skills-related outcomes analysed separately.MethodsThe study was based on national selection data and linked medical school outcomes for knowledge and skills-based tests during the first five years of medical school. UKCAT scores and PEA grades were available for 2107 students enrolled at 18 medical schools. Models were developed to investigate the potential mediating role played by a student’s previous secondary school’s performance. Multilevel models were created to explore the influence of students’ secondary schools on undergraduate achievement in medical school.ResultsThe ability of the UKCAT scores to predict undergraduate academic performance was significantly mediated by PEA in all five years of medical school. Undergraduate achievement was inversely related to secondary school-level performance. This effect waned over time and was less marked for skills, compared with undergraduate knowledge-based outcomes. Thus, the predictive value of secondary school grades was generally dependent on the secondary school in which they were obtained.ConclusionsThe UKCAT scores added some value, above and beyond secondary school achievement, in predicting undergraduate performance, especially in the later years of study. Importantly, the findings suggest that the academic entry criteria should be relaxed for candidates applying from the least well performing secondary schools. In the UK, this would translate into a decrease of approximately one to two A-level grades.

Background The UK Clinical Aptitude Test (UKCAT) has been shown to have a modest but statistically significant ability to predict aspects of academic performance throughout medical school. Previously, this ability has been shown to be incremental to conventional measures of educational performance for the first year of medical school. This study evaluates whether this predictive ability extends throughout the whole of undergraduate medical study and explores the potential impact of using the test as a selection screening tool. Methods This was an observational prospective study, linking UKCAT scores, prior educational attainment and sociodemographic variables with subsequent academic outcomes during the 5 years of UK medical undergraduate training. The participants were 6812 entrants to UK medical schools in 2007–8 using the UKCAT. The main outcome was academic performance at each year of medical school. A receiver operating characteristic (ROC) curve analysis was also conducted, treating the UKCAT as a screening test for a negative academic outcome (failing at least 1 year at first attempt). Results All four of the UKCAT scale scores significantly predicted performance in theory- and skills-based exams. After adjustment for prior educational achievement, the UKCAT scale scores remained significantly predictive for most years. Findings from the ROC analysis suggested that, if used as a sole screening test, with the mean applicant UKCAT score as the cut-off, the test could be used to reject candidates at high risk of failing at least 1 year at first attempt. However, the ‘number needed to reject’ value would be high (at 1.18), with roughly one candidate who would have been likely to pass all years at first sitting being rejected for every higher risk candidate potentially declined entry on this basis. Conclusions The UKCAT scores demonstrate a statistically significant but modest degree of incremental predictive validity throughout undergraduate training. Whilst the UKCAT could be considered a fairly crude screening tool for future academic performance, it may offer added value when used in conjunction with other selection measures. Future work should focus on the optimum role of such tests within the selection process and the prediction of post-graduate performance.

IntroductionNumbers of patients undergoing mitral valve repair (MVr) surgery for severe mitral regurgitation have grown and will continue to rise. MVr is routinely performed via median sternotomy; however, there is a move towards less invasive surgical approaches.There is debate within the clinical and National Health Service (NHS) commissioning community about widespread adoption of minimally invasive MVr surgery in the absence of robust research evidence; implementation requires investment in staff and infrastructure.The UK Mini Mitral trial will provide definitive evidence comparing patient, NHS and clinical outcomes in adult patients undergoing MVr surgery. It will establish the best surgical approach for MVr, setting a standard against which emerging percutaneous techniques can be measured. Findings will inform optimisation of cost-effective practice.Methods and analysisUK Mini Mitral is a multicentre, expertise based randomised controlled trial of minimally invasive thoracoscopically guided right minithoracotomy versus conventional sternotomy for MVr. The trial is taking place in NHS cardiothoracic centres in the UK with established minimally invasive mitral valve surgery programmes. In each centre, consenting and eligible patients are randomised to receive surgery performed by consultant surgeons who meet protocol-defined surgical expertise criteria. Patients are followed for 1 year, and consent to longer term follow-up.Primary outcome is physical functioning 12 weeks following surgery, measured by change in Short Form Health Survey (SF-36v2) physical functioning scale. Early and 1 year echo data will be reported by a core laboratory. Estimates of key clinical and health economic outcomes will be reported up to 5 years.The primary economic outcome is cost effectiveness, measured as incremental cost per quality-adjusted life year gained over 52 weeks following index surgery.Ethics and disseminationA favourable opinion was given by Wales REC 6 (16/WA/0156). Trial findings will be disseminated to patients, clinicians, commissioning groups and through peer reviewed publication.Trial registration numberISRCTN13930454.

ObjectiveTo assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children.DesignA clustered randomised controlled trial; classes, 1 per school, were assigned to 1 of 3 intervention arms or a control group based on a 2×2 factorial design. The interventions were peer-mentoring and participative learning. Year 7 children (aged 11–12) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings. Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System (GPS) data. Year 7 children in the combined intervention received both interventions, with the year 9 children only participating in the mentoring sessions.Participants1494 year 7 students from 60 schools in the North of England took part in the trial. Of these, 43 students opted out of taking part in the evaluation measurements, 2 moved teaching group and 58 changed school. Valid accelerometry outcome data were collected for 892 students from 53 schools; and well-being outcome data were available for 927 students from 52 schools.Main outcome measuresThe primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day, and well-being as evaluated by the KIDSCREEN-27 questionnaire. These data were collected 6 weeks after the intervention; a 12-month follow-up is planned.ResultsNo significant effects (main or interaction) were observed for the outcomes. However, small positive differences were found for both outcomes for the participative learning intervention.ConclusionsThese findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored. Change in physical activity may require more comprehensive individual behavioural intervention, and/or more system-based efforts to address wider environmental influences such as family, peers, physical environment, transport and educational policy.Trial registration numberISRCTN82956355.