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Summary: Background: Almost a quarter of the world's undernourished people live in India. We tested the effects of three nutrition-sensitive agriculture (NSA) interventions on maternal and child nutrition in India. Methods: We did a parallel, four-arm, observer-blind, cluster-randomised trial in Keonjhar district, Odisha, India. A cluster was one or more villages with a combined minimum population of 800 residents. The clusters were allocated 1:1:1:1 to a control group or an intervention group of fortnightly women's groups meetings and household visits over 32 months using: NSA videos (AGRI group); NSA and nutrition-specific videos (AGRI-NUT group); or NSA videos and a nutrition-specific participatory learning and action (PLA) cycle meetings and videos (AGRI-NUT+PLA group). Primary outcomes were the proportion of children aged 6–23 months consuming at least four of seven food groups the previous day and mean maternal body-mass index (BMI). Secondary outcomes were proportion of mothers consuming at least five of ten food groups and child wasting (proportion of children with weight-for-height Z score SD

Purpose To assess the effect of venovenous extracorporeal membrane oxygenation (ECMO) compared to conventional management in patients with severe acute respiratory distress syndrome (ARDS). Methods We conducted a systematic review and individual patient data meta-analysis of randomised controlled trials (RCTs) performed after Jan 1, 2000 comparing ECMO to conventional management in patients with severe ARDS. The primary outcome was 90-day mortality. Primary analysis was by intent-to-treat. Results We identified two RCTs (CESAR and EOLIA) and combined data from 429 patients. On day 90, 77 of the 214 (36%) ECMO-group and 103 of the 215 (48%) control group patients had died (relative risk (RR), 0.75, 95% confidence interval (CI) 0.6–0.94; P = 0.013; I2 = 0%). In the per-protocol and as-treated analyses the RRs were 0.75 (95% CI 0.6–0.94) and 0.86 (95% CI 0.68–1.09), respectively. Rescue ECMO was used for 36 (17%) of the 215 control patients (35 in EOLIA and 1 in CESAR). The RR of 90-day treatment failure, defined as death for the ECMO-group and death or crossover to ECMO for the control group was 0.65 (95% CI 0.52–0.8; I2 = 0%). Patients randomised to ECMO had more days alive out of the ICU and without respiratory, cardiovascular, renal and neurological failure. The only significant treatment-covariate interaction in subgroups was lower mortality with ECMO in patients with two or less organs failing at randomization. Conclusions In this meta-analysis of individual patient data in severe ARDS, 90-day mortality was significantly lowered by ECMO compared with conventional management. Electronic supplementary material The online version of this article (10.1007/s00134-020-06248-3) contains supplementary material, which is available to authorized users.

Poor recruitment to, and retention in, clinical trials is a source of research waste that could be reduced by more informed choices about participation. Barriers to effective recruitment and retention can be wide-ranging but relevance of the questions being addressed by trials and the outcomes that they are assessing are key for potential participants. Decisions about trial participation should be informed by general and trial-specific information and by considering broader assessments of ‘informedness’ and how they impact on both recruitment and retention. We suggest that more informed decisions about trial participation should encourage personally appropriate decisions, increase recruitment and retention, and reduce research waste and increase its value.

BackgroundInterventions to modify school environments are effective in promoting young people’s health across outcomes, but mechanisms are poorly understood. We assessed mediation in a trial of the Learning Together intervention, building on the recent publication of results of effectiveness for reducing bullying and benefits across secondary outcomes and generally good implementation fidelity.MethodsWithin a cluster-randomised trial involving 40 English schools, we examined student-reported and staff-reported school climate and student-reported involvement with delinquent peers at 24-month and 36-month follow-up, assessing the reliability of measures and whether these mediated health outcomes at a final follow-up.ResultsResponse rates and reliability were good for student-reported but not staff-reported measures. The intervention increased student-reported but not staff-reported-positive school climate but, like effects on student health outcomes, these manifested only at a final follow-up. The intervention reduced student-reported contact with delinquent peers at an interim follow-up. Student-reported potential mediators measured at the interim follow-up were associated with most health outcomes at the final follow-up. Adjustment for student-reported school climate and contact with delinquent peers at the interim follow-up did not reduce the associations between trial arm and our health outcomes.ConclusionDespite being constrained by imperfect measures and by the late manifestation of impacts on student-reported school climate undermining ability to assess mediation, our study for the first time provides tentative evidence that mediation of intervention effects via improved climate and disengagement from delinquent peers is plausible. Our study provides the first evidence from a trial that whole-school interventions may work by modifying school environments and student relationships.Trial registration numberISRCTN10751359.

Evidence shows that the quality of reporting of randomised controlled trials (RCTs) is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings and researchers from extracting information for systematic reviews and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of RCTs. Within person trials are used for conditions that can affect two or more body sites, and are a useful and efficient tool because the comparisons between interventions are within people. Such trials are most commonly conducted in ophthalmology, dentistry, and dermatology. The reporting of within person trials has, however, been variable and incomplete, hindering their use in clinical decision making and by future researchers. This document presents the CONSORT extension to within person trials. It aims to facilitate the reporting of these trials. It extends 16 items of the CONSORT 2010 checklist and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT within person checklist items are provided.

Objective Serum potassium levels frequently are maintained at high levels (≥4.5 mEq/L) to prevent atrial fibrillation after cardiac surgery (AFACS), with limited evidence. Before undertaking a noninferiority randomized controlled trial to investigate the noninferiority of maintaining levels ≥3.6 mEq/L compared with this strategy, the authors wanted to assess the feasibility, acceptability, and safety of recruiting for such a trial. Design Pilot and feasibility study of full trial protocol. Setting Two university tertiary-care hospitals. Participants A total of 160 individuals undergoing first-time elective isolated coronary artery bypass grafting. Interventions Randomization (1:1) to protocols aiming to maintain serum potassium at either ≥3.6 mEq/L or ≥4.5 mEq/L after arrival in the postoperative care facility and for 120 hours or until discharge from the hospital or AFACS occurred, whichever happened first. Measurements and Main Results Primary outcomes: (1) whether it was possible to recruit and randomize 160 patients for six months (estimated 20% of those eligible); (2) maintaining supplementation protocol violation rate ≤10% (defined as potassium supplementation being inappropriately administered or withheld according to treatment allocation after a serum potassium measurement); and (3) retaining 28-day follow-up rates ≥90% after surgery. Between August 2017 and April 2018, 723 patients were screened and 160 (22%) were recruited. Potassium protocol violation rate = 9.8%. Follow-up rate at 28 days = 94.3%. Data on planned outcomes for the full trial also were collected. Conclusions It is feasible to recruit and randomize patients to a study assessing the impact of maintaining serum potassium concentrations at either ≥3.6 mEq/L or ≥4.5 mEq/L on the incidence of AFACS.

Despite large schooling and learning gains in many developing countries, children in highly deprived areas are often unlikely to achieve even basic literacy and numeracy. We study how much of this problem can be resolved using a multi-pronged intervention combining three interventions known to be separately effective. We conducted a cluster-randomized trial in The Gambia evaluating a literacy and numeracy intervention designed for primary-aged children in remote parts of poor countries. The intervention combines para teachers delivering after-school supplementary classes, scripted lesson plans, and frequent monitoring focusing on improving teacher practice (coaching). A similar intervention previously demonstrated large learning gains in rural India. After three academic years, Gambian children allocated to the intervention scored 46 percentage points (3.2 SD) better on a combined literacy and numeracy test than control children. Our results demonstrate that, in this type of area, aggressive interventions can yield far greater learning gains than previously shown.

Background Rural areas of India exhibit high neonatal mortality, and low literacy and numeracy. We assess the effect of a complex package of health interventions on neonatal survival and the effect of out-of-school-hours teaching on children’s literacy and numeracy in rural Madhya Pradesh. Methods/design This is a cluster-randomised controlled trial with villages (clusters) receiving either a health (CHAMPION2) or education (STRIPES2) intervention. Building on the design of the earlier CHAMPION/STRIPES trial, villages receiving the health intervention are controls for the education intervention and vice versa. The clusters are 196 villages in Satna district, Madhya Pradesh, India: each is at least 5 km from a Community Health Centre, has a population below 2500, and has at least 15 children eligible for the education intervention. The participants in CHAMPION2 are resident married women younger than 50 years of age who had not undergone a family planning operation, provided they are enumerated pre-randomisation or marry a man enumerated pre-randomisation. The participants in STRIPES2 are resident children born 16 June 2010 to 15 June 2013, not in school before the 2018–2019 school year and intending to enrol in first grade in 2018–2019 or 2019–2020. Discussion In CHAMPION2, the NICE Foundation will deliver a 3.5-year programme comprising Accredited Social Health Activists or village health workers and midwives promoting health knowledge and providing antenatal, postnatal, and neonatal healthcare; community mobilisation; referrals to appropriate government health facilities; and a health education campaign. In STRIPES2, the Pratham Education Foundation will deliver a programme of village-based, before/after school support focusing on literacy and numeracy. As controls, the CHAMPION2 control villages will receive the usual health services (plus the STRIPES2 intervention). STRIPES2 control villages will receive the usual education services (plus the CHAMPION2 intervention). The primary outcome in CHAMPION2 is neonatal mortality. Secondary outcomes include antenatal, delivery, immediate neonatal and postnatal care practices, maternal mortality, stillbirths, early neonatal deaths, perinatal deaths, health knowledge, hospital admissions, maternal blood transfusions, and cost effectiveness. The primary outcome in STRIPES2 is a composite literacy and numeracy test score. Secondary outcomes include separate literacy and numeracy scores, reported school enrolment and attendance, parents’ engagement with children’s learning, and cost effectiveness. Independent research and implementation teams will conduct the trial. Trial Steering and Data Monitoring Committees, with independent members, will supervise the trial. Trial registration Clinical Trial Registry of India: CTRI/2019/05/019296. Registered on 23 May 2019. http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=31198&EncHid=&modid=&compid=%27,%2731198det%27

Summary Background 78% of neonatal deaths occur in sub-Saharan Africa and southern Asia, among which, more than 80% are in low birthweight babies. Existing neonatal mortality risk scores have primarily been developed for high-resource settings. The aim of this study was to develop and validate a score that is practicable for low-income and middle-income countries to predict in-hospital mortality among neonates born weighing 2000 g or less using datasets from the UK and The Gambia. Methods This analysis used retrospective data held in the UK National Neonatal Research Database from 187 neonatal units, and data from the Edward Francis Small Teaching Hospital (EFSTH), Banjul, The Gambia. In the UK dataset, neonates were excluded if birthweight was more than 2000 g; if the neonate was admitted aged more than 6 h or following discharge; if the neonate was stillborn; if the neonate died in delivery room; or if they were moribund on admission. The Gambian dataset included all neonates weighing less than 2000 g who were admitted between May 1, 2018, and Sept 30, 2019, who were screened for but not enrolled in the Early Kangaroo Mother Care Trial. 18 studies were reviewed to generate a list of 84 potential parameters. We derived a model to score in-hospital neonatal mortality risk using data from 55 029 admissions to a random sample of neonatal units in England and Wales from Jan 1, 2010, to Dec 31, 2016. All candidate variables were included in a complete multivariable model, which was progressively simplified using reverse stepwise selection. We validated the new score (NMR-2000) on 40 329 admissions to the remaining units between the same dates and 14 818 admissions to all units from Jan 1, to Dec 31, 2017. We also validated the score on 550 neonates admitted to the EFSTH in The Gambia. Findings 18 candidate variables were selected for inclusion in the modelling process. The final model included three parameters: birthweight, admission oxygen saturation, and highest level of respiratory support within 24 h of birth. NMR-2000 had very good discrimination and goodness-of-fit across the UK samples, with a c-index of 0·8859–0·8930 and a Brier score of 0·0232–0·0271. Among Gambian neonates, the model had a c-index of 0·8170 and a Brier score of 0·1688. Predictive ability of the simplified integer score was similar to the model using regression coefficients, with c-indices of 0·8903 in the UK full validation sample and 0·8082 in the Gambian validation sample. Interpretation NMR-2000 is a validated mortality risk score for hospitalised neonates weighing 2000 g or less in settings where pulse oximetry is available. The score is accurate and simplified for bedside use. NMR-2000 requires further validation using a larger dataset from low-income and middle-income countries but has the potential to improve individual and population-level neonatal care resource allocation. Funding Bill & Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health & Human Development; Wellcome Trust; and Joint Global Health Trials scheme of Department of Health and Social Care, Department for International Development, Medical Research Council, and Wellcome Trust.

Background There are 2.5 million neonatal deaths each year; the majority occur within 48 h of birth, before stabilisation. Evidence from 11 trials shows that kangaroo mother care (KMC) significantly reduces mortality in stabilised neonates; however, data on its effect among neonates before stabilisation are lacking. The OMWaNA trial aims to determine the effect of initiating KMC before stabilisation on mortality within seven days relative to standard care. Secondary objectives include exploring pathways for the intervention’s effects and assessing incremental costs and cost-effectiveness between arms. Methods We will conduct a four-centre, open-label, individually randomised, superiority trial in Uganda with two parallel groups: an intervention arm allocated to receive KMC and a control arm receiving standard care. We will enrol 2188 neonates (1094 per arm) for whom the indication for KMC is ‘uncertain’, defined as receiving ≥ 1 therapy (e.g. oxygen). Admitted singleton, twin and triplet neonates (triplet if demise before admission of ≥ 1 baby) weighing ≥ 700–≤ 2000 g and aged ≥ 1– Discussion The OMWaNA trial aims to assess the effectiveness of KMC in reducing mortality among neonates before stabilisation, a vulnerable population for whom its benefits are uncertain. The trial will improve understanding of pathways underlying the intervention’s effects and will be among the first to rigorously compare the incremental cost and cost-effectiveness of KMC relative to standard care. The findings are expected to have broad applicability to hospitals in sub-Saharan Africa and southern Asia, where three-quarters of global newborn deaths occur, as well as important policy and programme implications. Trial registration ClinicalTrials.gov, NCT02811432. Registered on 23 June 2016.

Background There is now clear systematic review evidence that measurement can affect the people being measured; much of this evidence focusses on how asking people to complete a questionnaire can result in changes in behaviour. Changes in measured behaviour and other outcomes due to this reactivity may introduce bias in otherwise well-conducted randomised controlled trials (RCTs), yielding incorrect estimates of intervention effects. Despite this, measurement reactivity is not currently adequately considered in risk of bias frameworks. The present research aims to produce a set of guidance statements on how best to avoid or minimise bias due to measurement reactivity in studies of interventions to improve health, with a particular focus on bias in RCTs. Methods The MERIT study consists of a series of systematic and rapid reviews, a Delphi study and an expert workshop to develop guidance on how to minimise bias in trials due to measurement reactivity. An existing systematic review on question-behaviour effects on health-related behaviours will be updated and three new rapid reviews will be conducted to identify (1) existing guidance on measurement reactivity; (2) systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes in health and non-health contexts and (3) trials that have investigated the effects of objective measurements of behaviour on concurrent or subsequent behaviour itself. A Delphi procedure will be used to combine the views of experts with a view to reaching agreement on the scope of the guidance statements. Finally, a workshop will be held in autumn 2018, with the aim of producing a set of guidance statements that will form the central part of new MRC guidance on how best to avoid bias due to measurement reactivity in studies of interventions to improve health. Discussion Our ambition is to produce MRC guidance on measurement reactions in trials which will be used by future trial researchers, leading to the development of trials that are less likely to be at risk of bias. Electronic supplementary material The online version of this article (10.1186/s13063-018-3017-5) contains supplementary material, which is available to authorized users.

Background\ud Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.\ud \ud Methods\ud In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.\ud \ud Findings\ud Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.\ud \ud Interpretation\ud Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.\ud \ud Funding\ud London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.

Objective To compare the effect of two methods of perineal management used during spontaneous vaginal delivery on the prevalence of perineal pain reported at 10 days after birth. Design Randomised controlled trial. Setting Two English maternity care units. Sample 5471 women who gave birth between December 1994 and December 1996. Methods At the end of the second stage of labour women were allocated to either the ‘hands on’ method, in which the midwife's hands put pressure on the baby's head and support (‘guard’) the perineum; lateral flexion is then used to facilitate delivery of the shoulders, or the ‘hands poised’ method, in which the midwife keeps her hands poised, not touching the head or perineum, allowing spontaneous delivery of the shoulders. Main outcome measure Perineal pain in the previous 24 hours reported by women in self-administered questionnaire 10 days after birth. Results Questionnaires were completed by 97% of women at 10 days after birth. 910 (34.1%) women in the ‘hands poised’ group reported pain in the previous 24 hours compared with 823 (31.1%) in the ‘hands on’ group (RR 1.10, 95% CI 1.01 to 1.18: absolute difference 3%, 0.5% to 5%, P = 0.02). The rate of episiotomy was significantly lower in the ‘hands poised’ group (RR 0.79, 99% C1 0.65 to 0.96, P= 0.008) but the rate of manual removal of placenta was significantly higher (RR 1.69, 99% CI 1.02 to 2.78; P= 0.008). There were no other statistically significant differences detected between the two methods. Conclusion The reduction in pain observed in the ‘hands on’ group was statistically significant and the difference detected potentially affects a substantial number of women. These results provide evidence to enable individual women and health professionals to decide which perineal management is preferable.

Effective contemporary midwifery practice often combines the use of high level analytical skills with appropriate and unbiased communication of evidence to support women's decisions and choices. Although the results of sufficiently large randomized controlled trials provide the most robust evidence about comparative effectiveness of alternatives forms of care, all evidence should be subject to rigorous quality review, irrespective of its origins. This article demonstrates how criticisms that the conclusions of the HOOP trial were flawed and cannot be used to inform midwifery care for individual women, are wrong. In fact, HOOP provides clear and enduring evidence for women and midwives about important health outcomes and should be used to underpin discussion and practice of routine perineal care.

Objectives Factorial designs can allow efficient evaluation of multiple treatments within a single trial. We evaluated the design, analysis, and reporting in a sample of factorial trials. Study Design and Setting Review of 2 × 2 factorial trials evaluating health-related interventions and outcomes in humans. Using Medline, we identified articles published between January 2015 and March 2018. We randomly selected 100 articles for inclusion. Results Most trials (78%) did not provide a rationale for using a factorial design. Only 63 trials (63%) assessed the interaction for the primary outcome, and 39/63 (62%) made a further assessment for at least one secondary outcome. 12/63 trials (19%) identified a significant interaction for the primary outcome and 16/39 trials (41%) for at least one secondary outcome. Inappropriate methods of analysis to protect against potential negative effects from interactions were common, with 18 trials (18%) choosing the analysis method based on a preliminary test for interaction, and 13% (n = 10/75) of those conducting a factorial analysis including an interaction term in the model. Conclusion Reporting of factorial trials was often suboptimal, and assessment of interactions was poor. Investigators often used inappropriate methods of analysis to try to protect against adverse effects of interactions.

BackgroundThe theory of human functioning and school organisation proposes that schools with rigid ‘boundaries’ (weaker relationships), for example, between staff and students, or learning and broader development, engender weaker student school commitment and sense of belonging, particularly among disadvantaged students, leading to greater involvement in risk-behaviours. Existing studies provide some support but rely on a proxy exposure of ‘value-added education’ and have not explored effects by disadvantage.MethodsWe used longitudinal data from English secondary schools from the control arm of a trial, assessing school-level measures of rigid boundaries, and student commitment and belonging at age 11/12, and student risk-behaviours at age 14/15.ResultsOur direct measures were more strongly associated with risk-behaviours than was value-added education. School-level rigid boundaries were associated with increased alcohol use and bullying. Student belonging was more consistently associated with reduced risk-behaviours than was student commitment. Some school effects were greater for students from disadvantaged subgroups defined in terms of poverty, ethnicity and family structure.ConclusionOur results provide direct support for the theory of human functioning and school organisation and suggest a sense of belonging in school might be particularly protective factor among secondary school students. School effects on risk are generally stronger among disadvantaged students as theorised.Trial registration numberISRCTN10751359

The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration (2001) (Part II).

BackgroundWe have previously reported benefits for reduced bullying, smoking, alcohol and other drug use and mental health from a trial of ‘Learning Together’, an intervention that aimed to modify school environments and implement restorative practice and a social and emotional skill curriculum.ObjectivesTo conduct post hoc theory-driven analyses of broader impacts.DesignCluster randomised trial.Settings40 state secondary schools in southern England.ParticipantsStudents aged 11/12 years at baseline.OutcomesStudent self-reported measures at 24 and 36 months of: cyberbullying victimisation and perpetration; observations of other students perpetrating aggressive behaviours at school; own perpetration of aggressive behaviours in and outside school; perceived lack of safety at school; participation in school disciplinary procedures; truancy and e-cigarette use.ResultsWe found evidence of multiple impacts on other health (reduced e-cigarette use, cyberbullying perpetration, perpetration of aggressive behaviours) and educational (reduced participation in school disciplinary procedures and truancy) outcomes.ConclusionThese analyses suggested that the intervention was effective in bringing about a broader range of beneficial outcomes, adding to the evidence that the intervention is a promising approach to promote adolescent health via an intervention that is attractive to schools.Trial registration numberISRCTN10751359.

BackgroundSince the introduction of the Teenage Pregnancy Strategy (TPS), England’s under-18 conception rate has fallen by 55%, but a continued focus on prevention is needed to maintain and accelerate progress. The teenage birth rate remains higher in the UK than comparable Western European countries. Previous trials indicate that school based social marketing interventions are a promising approach to addressing teenage pregnancy and improving sexual health. Such interventions are yet to be trialled in the UK. This study aims to optimise and establish the feasibility and acceptability of one such intervention: Positive Choices.MethodsDesign: Optimisation, feasibility testing and pilot cluster randomised trialInterventions: The Positive Choices intervention consists of: a student needs survey; a student/staff led School Health Promotion Council (SHPC); a classroom curriculum for year nine students covering social and emotional skills and sex education; student led social marketing activities; parent information; and a review of school sexual health services. Systematic optimisation of Positive Choices will be carried out with the National Children’s Bureau Sex Education Forum (NCB SEF), one state secondary school in England and other youth and policy stakeholders. Feasibility testing will involve the same state secondary school and will assess progression criteria to advance to the pilot cluster RCT.Pilot cluster RCT will involve six different state secondary schools (four intervention and two control) and will assess the feasibility and utility of progressing to a full effectiveness trial. The following outcome measures will be trialled as part of the pilot:•self-reported pregnancy and unintended pregnancy (initiation of pregnancy for boys) and sexually transmitted infections, •age of sexual debut; number of sexual partners; use of contraception at first and last sex; non-volitional sex;•educational attainmentThe feasibility of linking administrative data on births and termination to self-report survey data to measure our primary outcome (unintended teenage pregnancy) will also be tested. DiscussionThis will be the first UK based pilot trial of a school-wide social marketing intervention to reduce unintended teenage pregnancy and improve sexual health. If this study indicates feasibility and acceptability of the optimised Positive Choices intervention in English secondary schools, plans will be initiated for a phase III trial and economic evaluation of the intervention. Trial RegistrationISRCTN registry (ISCTN 12524938. Registered 03/07/2017) Keywords: teenage pregnancy; sexual health; SRE; RSE; school intervention; adolescent; cluster-randomised trial.

Background Moderate vitamin B-12 deficiency is relatively common in older people. However, there is little robust evidence on the effect of vitamin B-12 supplementation on neurologic and cognitive outcomes in later life. Objective We investigated whether vitamin B-12 supplementation benefits neurologic and cognitive function in moderately vitamin B-12-deficient older people. Design We conducted a double-blind, randomized, placebo-controlled trial in 7 general practices in South East England, United Kingdom. Study participants were aged ≥75 y and had moderate vitamin B-12 deficiency (serum vitamin B-12 concentrations: 107-210 pmol/L) in the absence of anemia and received 1 mg crystalline vitamin B-12 or a matching placebo as a daily oral tablet for 12 mo. Peripheral motor and sensory nerve conduction, central motor conduction, a clinical neurologic examination, and cognitive function were assessed before and after treatment. Results A total of 201 participants were enrolled in the trial, and 191 subjects provided outcome data. Compared with baseline, allocation to vitamin B-12 was associated with a 177% increase in serum concentration of vitamin B-12 (641 compared with 231 pmol/L), a 331% increase in serum holotranscobalamin (240 compared with 56 pmol/L), and 17% lower serum homocysteine (14.2 compared with 17.1 μmol/L). In intention-to-treat analysis of covariance models, with adjustment for baseline neurologic function, there was no evidence of an effect of supplementation on the primary outcome of the posterior tibial compound muscle action potential amplitude at 12 mo (mean difference: -0.2 mV; 95% CI: -0.8, 0.3 mV). There was also no evidence of an effect on any secondary peripheral nerve or central motor function outcome, or on cognitive function or clinical examination. Conclusion Results of the trial do not support the hypothesis that the correction of moderate vitamin B-12 deficiency, in the absence of anemia and of neurologic and cognitive signs or symptoms, has beneficial effects on neurologic or cognitive function in later life. This trial was registered at www.isrctn.com as ISRCTN54195799.

Background Atrial fibrillation (AF) occurs in approximately one in three patients after cardiac surgery, and is associated with increased short-term and long-term mortality, intensive care unit (ICU) and hospital stay, and increased cost of care. In an attempt to reduce AF incidence in these patients, serum potassium (K+) levels are commonly maintained at the high end of normal (4.5–5.5 mEq/L). However, such potassium supplementation is without proven benefit, and is not without negative consequences. It carries clinical risk, negatively impacts patient experience and is both time-consuming and costly. This protocol describes a randomised controlled pilot trial to assess the feasibility of a proposed randomised non-inferiority trial to investigate the impact of maintaining serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on the incidence of new-onset atrial fibrillation in the first 120 hours after isolated elective coronary artery bypass grafting. Methods Design: this is a randomized feasibility trial as a pilot for a randomized non-inferiority trial. Participants: are 160 patients undergoing isolated coronary artery bypass grafting at two centres. Allocation: patients will be randomized (1:1) to protocols aiming to maintain serum potassium at either ≥ 3.6 mEq/L (“relaxed control”) or ≥ 4.5 mEq/L (“tight control”). Primary analytic aim: was to assess the feasibility and acceptability of planning and delivering the intervention and trial methods to inform a full-scale non-inferiority trial. Outcome: the primary indicative efficacy outcome measures being field-tested are feasibility of participant recruitment and randomization, maintaining a protocol violation rate

Background Child maltreatment is a significant public health problem. Group Family Nurse Partnership (gFNP) is a new intervention for young, expectant mothers implemented successfully in pilot studies. This study was designed to determine the effectiveness and cost-effectiveness of gFNP in reducing risk factors for maltreatment with a potentially vulnerable population. Methods A multi-site, randomized controlled, parallel-arm trial and prospective economic evaluation was conducted, with allocation via remote randomization (minimization by site, maternal age group) to gFNP or usual care. Participants were expectant mothers aged below 20 years with at least one live birth, or aged 20–24 years with no live births and with low educational qualifications. Data from maternal interviews at baseline and when infants were 2, 6 and 12 months, and video-recording at 12 months, were collected by researchers blind to allocation. Cost information came from weekly logs completed by gFNP family nurses and other service delivery data reported by participants. Primary outcomes measured at 12 months were parenting attitudes (Adult-Adolescent Parenting Index, AAPI-2) and maternal sensitivity (CARE Index). The economic evaluation was conducted from a UK NHS and personal social services perspective with cost-effectiveness expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The main analyses were intention-to-treat with additional complier average causal effects (CACE) analyses. Results Between August 2013 and September 2014, 492 names of potential participants were received of whom 319 were eligible and 166 agreed to take part, 99 randomly assigned to receive gFNP and 67 to usual care. There were no between-arm differences in AAPI-2 total (7 · 5/10 in both, SE 0.1), difference adjusted for baseline, site and maternal age group 0 · 06 (95% CI − 0 · 15 to 0 · 28, p = 0 · 59) or CARE Index (intervention 4 · 0 (SE 0 · 3); control 4 · 7 (SE 0 · 4); difference adjusted for site and maternal age group − 0 · 68 (95% CI − 1 · 62 to 0 · 16, p = 0 · 25) scores. The probability that gFNP is cost-effective based on the QALY measure did not exceed 3%. Conclusions The trial did not support gFNP as a means of reducing the risk of child maltreatment in this population but slow recruitment adversely affected group size and consequently delivery of the intervention. Trial registration ISRCTN78814904. Registered on 17 May 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2259-y) contains supplementary material, which is available to authorized users.

Women with experience of being ‘looked after’ are more likely than their peers to become young mothers. There has been limited research investigating support for their needs. This study, embedded in a randomised trial of Group Family Nurse Partnership (gFNP), involved interviews with young mothers with care experience, Family Nurses delivering group gFNP, and health and social care professionals. This first qualitative study to explore the views of these varied stakeholders found consensus regarding young mothers’ social isolation and lack of trusting relationships but diversity in views about the potential of gFNP to meet their needs.

Background In the mid-2000s, neonatal mortality accounted for almost 40% of deaths of children under 5 years worldwide, and constituted 65% of infant deaths in India. The neonatal mortality rate in Andhra Pradesh was 44 per 1,000 live births, and was higher in the rural areas and tribal regions, such as the Nagarkurnool division of Mahabubnagar district (which became Nagarkurnool district in Telangana in 2014). The aim of the CHAMPION trial was to investigate whether a package of interventions comprising community health promotion and provision of health services (including outreach and facility-based care) could lead to a reduction of the order of 25% in neonatal mortality. Methods and findings The design was a trial in which villages (clusters) in Nagarkurnool with a population < 2,500 were randomised to the CHAMPION package of health interventions or to the control arm (in which children aged 6–9 years were provided with educational interventions—the STRIPES trial). A woman was eligible for the CHAMPION package if she was married and, In CHAMPION, a cluster-randomized trial carried out in rural India, Diana Elbourne and colleagues investigate the benefit of a package of interventions for neonatal care., Author summary Why was this study done? At the time this study was planned, the rate of death of children in the first 28 days of life was very high in parts of rural India. Earlier research had suggested that community health promotion, along with buttressing existing maternity and neonatal services, might reduce this rate. What did the researchers do and find? We randomised small villages in the Nagarkurnool district in Telangana either to the package of health interventions or to control. We provided married women in the intervention villages with community health promotion (including health education via village health worker–led participatory discussion groups), outreach (including mobile teams providing antenatal check-ups), and facility-based care (including subsidised access to non-public health centres). We enrolled 14,137 women in 232 control villages and 15,532 in 232 intervention villages. In all, 4,885 control women had 5,474 eligible pregnancies and gave birth to 4,998 eligible children. The corresponding numbers in intervention villages were 5,664 women, 6,351 pregnancies, and 5,798 children. We found that, of the live-born babies, 343 (6.9%) in the control arm and 303 (5.2%) in the intervention arm died in their first 28 days of life, suggesting that there were 92 fewer deaths as a result of the intervention. We also found evidence of improved health knowledge and health practices including health service usage in the intervention arm compared to the control arm. What do these findings mean? The research findings mean that interventions such as those in the CHAMPION trial can be strongly justified in much of rural India. Further research is needed to assess whether the interventions are of use in other rural settings with similar socioeconomic and cultural patterns, similar neonatal mortality rates, and the existence of some private health provision.

Objectives: This study aims to (1) elucidate whether the Hawthorne effect exists, (2) explore under what conditions, and (3) estimate the size of any such effect. Study Design and Setting: This systematic review summarizes and evaluates the strength of available evidence on the Hawthorne effect. An inclusive definition of any form of research artifact on behavior using this label, and without cointerventions, was adopted. Results: Nineteen purposively designed studies were included, providing quantitative data on the size of the effect in eight randomized controlled trials, five quasiexperimental studies, and six observational evaluations of reporting on one’s behavior by answering questions or being directly observed and being aware of being studied. Although all but one study was undertaken within health sciences, study methods, contexts, and findings were highly heterogeneous. Most studies reported some evidence of an effect, although significant biases are judged likely because of the complexity of the evaluation object. Conclusion: Consequences of research participation for behaviors being investigated do exist, although little can be securely known about the conditions under which they operate, their mechanisms of effects, or their magnitudes. New concepts are needed to guide empirical studies. 2014 The Authors. Published by Elsevier Inc.

BACKGROUND: Data Monitoring Committees (DMCs) are increasingly involved in the conduct of randomized controlled trials, but there is little documented evidence of what they do. Three interlinked surveys were carried out as part of the DAMOCLES project to explore recent and current DMC practice and policy. METHODS: 1) A questionnaire about DMC practice was sent to sample of 45 authors of trials published in selected journals in 2000. The sample was stratified by centre (single/multiple), disease area, and presence of DMC. 2) A sample of investigators in trials ongoing in the United Kingdom in 2001-02 was also sent a questionnaire about DMC practice. The sample was drawn from trials funded by the Medical Research Council, the United Kingdom Department of Health's Health Technology Assessment Programme, and a local and a multicentre research ethics committee. The sample was additionally stratified by funder (public/industry), centre (single/ multiple), and disease area. 3) A sample of major organisations involved in randomised controlled trials was sent a questionnaire about DMC policies. RESULTS: Information about DMC practice from the first survey was obtained from 31 trials (69%), of which four had a DMC. Information about DMC practice from the second survey was obtained about 36 trials (90%), of which 20 had a DMC. Information about DMC policy from the third survey was obtained from 25 out of 25 organisations. There was general agreement about the sorts of trials particularly needing independent DMCs, but there were few uniform approaches to their modes of functioning, and few of the organisations surveyed had developed formal policies. CONCLUSIONS: The roles of existing DMCs and policies governing DMC functioning vary widely across trials and organisations that sponsor or oversee trials, both within the UK and internationally. These findings reinforce previous calls for development of such policies across a wider range of organisations, better means to monitor their implementation within trials, and wider use of structured "charters", which set out DMC modus operandi in advance. Clinical Trials 2005; 2: 22-33. www.SCTjournal.com

INTRODUCTION: Type 1 diabetes (T1D) in children and adolescents is increasing worldwide with a particular increase in children

Summary Background Evidence suggests that community-based interventions that promote improved home-based practices and care-seeking behaviour can have a large impact on maternal and child mortality in regions where rates are high. We aimed to assess whether an intervention package based on the WHO Integrated Management of Childhood Illness handbook and community mobilisation could reduce under-5 mortality in rural Guinea-Bissau, where the health service infrastructure is weak. Methods We did a non-masked cluster-randomised controlled trial (EPICS) in the districts of Tombali and Quinara in Guinea-Bissau. Clusters of rural villages were stratified by ethnicity and distance from a regional health centre, and randomly assigned (1:1) to intervention or control using a computerised random number generator. Women were eligible if they lived in one of the clusters at baseline survey prior to randomisation and if they were aged 15–49 years or were primary caregivers of children younger than 5 years. Their children were eligible if they were younger than 5 years or were liveborn after intervention services could be implemented on July 1, 2008. In villages receiving the intervention, community health clubs were established, community health workers were trained in case management, and traditional birth attendants were trained to care for pregnant women and newborn babies, and promote facility-based delivery. Registered nurses supervised community health workers and offered mobile clinic services. Health centres were not improved. The control group received usual services. The primary outcome was the proportion of children dying under age 5 years, and was analysed in all eligible children up to final visits to villages between Jan 1 and March 31, 2011. This trial is registered with ISRCTN, number ISRCTN52433336. Findings On Aug 30, 2007, we randomly assigned 146 clusters to intervention (73 clusters, 5669 women, and 4573 children) or control (73 clusters, 5840 women, and 4675 children). From randomisation until the end of the trial (last visit by June 30, 2011), the intervention clusters had 3093 livebirths and the control clusters had 3194. 6729 children in the intervention group and 6894 in the control group aged 0–5 years on July 1, 2008, or liveborn subsequently were analysed for mortality outcomes. 311 (4·6%) of 6729 children younger than 5 years died in the intervention group compared with 273 (4·0%) of 6894 in the control group (relative risk 1·16 [95% CI 0·99–1·37]). Interpretation Our package of community-based interventions did not reduce under-5 mortality in rural Guinea-Bissau. The short timeframe and other trial limitations might have affected our results. Community-based health promotion and basic first-line services in fragile contexts with weak secondary health service infrastructure might be insufficient to reduce child deaths. Funding Effective Intervention.

BACKGROUND: Research findings are not rapidly or fully implemented into policies and practice in care. OBJECTIVES: To assess whether an 'active' strategy was more likely to lead to changes in policy and practice in preterm baby care than traditional information dissemination. DESIGN: Cluster randomised trial. PARTICIPANTS: 180 neonatal units (87 active, 93 control) in England; clinicians from active arm units; babies born

Background Neonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high. Objectives To determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support. Search strategy The Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007. Selection criteria All randomised trials comparing neonatal ECMO to conventional ventilatory support. Data collection and analysis The authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data. Main results The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. Authors' conclusions A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life. Plain Language Summary Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants A complex life support procedure, called extracorporeal membrane oxygenation (ECMO), can be used in infants who are near term age to overcome severe, potentially reversible breathing problems. ECMO is similar to the technology used in cardiac bypass surgery. Blood is removed from the body of the patient, oxygen is added to the blood, and the blood is returned to the patient. Although the number of babies requiring ECMO is small, and ECMO is a very invasive and potentially expensive procedure, the benefits of this procedure are high. In this review, four randomized trials that compared the use of ECMO to the conventional approach to supporting these infants with severe breathing problems were identified. Overall, these trials showed a strong benefit for ECMO regarding survival at the time of hospital discharge. This is particularly true for infants without a specific problem of lung formation (congenital diaphragmatic hernia). The result implies that for every three babies with breathing problems and lung failure who were treated with ECMO rather than conventional ventilation, one more infant will survive. Although little information is available regarding long-term follow-up, one trial in the United Kingdom shows both benefits of ECMO and cost-effectiveness of the use of ECMO.

Objective To ascertain mortality from 1 to 18 years, and predictors of mortality. Design Long-term follow-up of population cohort born 1989–1992. Setting Births in South East Thames Region. Patients 346 children with bilateral cerebral palsy (CP). Interventions Not applicable. Main outcome measures Mortality; predictors of mortality. Results 98% of the cohort were traced. 61/340 (17.9%) had died by age 16–18 years at a steady mortality. The main predictive factor was severity of impairment of functional ability (hazard ratio 5.7, 95% CI 2.1 to 15.0 for poor hand manipulation; 6.8 (1.9 to 23.9).for severe communication problems). Conclusions Although there were deaths throughout the childhood and teenage years, the majority of children with bilateral CP are likely to survive to adulthood, especially if they do not have major functional impairment at 2 years. This confirms findings of other studies of children with CP.

BACKGROUND: Increased consumption of n-3 (omega-3) long-chain polyunsaturated fatty acids (LC PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may maintain cognitive function in later life. OBJECTIVE: We tested the hypothesis that n-3 LC PUFA supplementation would benefit cognitive function in cognitively healthy older people. DESIGN: At total of 867 cognitively healthy adults, aged 70-79 y, from 20 general practices in England and Wales were randomly assigned into a double-blind controlled trial of daily capsules providing 200 mg EPA plus 500 mg DHA or olive oil for 24 mo. Treatment-allocation codes were obtained from a central computerized randomization service. Trained research nurses administered a battery of cognitive tests, including the primary outcome, the California Verbal Learning Test (CVLT), at baseline and 24 mo. Intention-to-treat analysis of covariance, with adjustment for baseline cognitive scores, age, sex, and age at leaving full-time education, included 748 (86%) individuals who completed the study. RESULTS: The mean age of participants was 75 y; 55% of the participants were men. Withdrawals and deaths were similar in active (n = 49 and n = 9, respectively) and placebo (n = 53 and n = 8, respectively) arms. Mean (+/-SD) serum EPA and DHA concentrations were significantly higher in the active arm than in the placebo arm at 24 mo (49.9 +/- 2.7 mg EPA/L in the active arm compared with 39.1 +/- 3.1 mg EPA/L in the placebo arm; 95.6 +/- 3.1 mg DHA/L in the active arm compared with 70.7 +/- 2.9 mg DHA/L in the placebo arm). There was no change in cognitive function scores over 24 mo, and intention-to-treat analysis showed no significant differences between trial arms at 24 mo in the CVLT or any secondary cognitive outcome. CONCLUSIONS: Cognitive function did not decline in either study arm over 24 mo. The lack of decline in the control arm and the relatively short intervention period may have limited our ability to detect any potential beneficial effect of fish oil on cognitive function in this study. The Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) Study was registered at www.controlled-trials.com as ISRCTN 72331636.

Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support.In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score3.0 or pH7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827.766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%.We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK.UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

Observational epidemiological data suggest that habitual consumption in later life of oily fish, rich in n-3 long-chain polyunsaturated fatty acids (n-3 LCPs), is associated with better cognitive function, slower rates of cognitive decline and a lower risk of dementia. In this paper we present data on baseline fish consumption and cognitive function in cognitively healthy older people randomised onto the Older People And n- 3 Long-chain polyunsaturated fatty acid (OPAL) study.In total, 867 older people were recruited to join the OPAL study from 20 general practices in England and Wales. Participants were aged 70-79 years at baseline were free of dementia and diabetes, had a Mini-Mental State Examination score of 24 or greater and did not report daily fish oil supplement consumption. Self-reported habitual fish consumption was assessed at baseline via questions on frequency and type of fish consumption. Cognitive function at baseline was assessed via validated cognitive tests assessing memory, executive function, psychomotor speed and attention, including the Californian Verbal Learning Test (CVLT), the primary outcome of the OPAL study. Reported age at leaving full time education was recorded as a measure of educational achievement and psychological health was measured using the GHQ-30 questionnaire.Unadjusted analysis revealed significant positive associations between reported fish consumption and the CVLT scores with a mean increase of approximately 0.24 words remembered for each increase in level of reported fish consumption. These associations were noticeably attenuated on adjustment for age, gender and reported age at leaving full-time education and did not remain significant on further adjustment for GHQ-30 score. Similar associations were also observed between fish consumption and the global cognitive z-score, memory score, executive function score and delay scores in unadjusted analysis with the associations again attenuated on adjustment.Baseline data from participants randomised into the OPAL study provide support for the hypothesis that higher fish consumption is associated with better cognitive function in later life. However, although in the main associations remain after adjusting for education and psychological health, the data do not allow us to rule out the possibility of residual confounding e.g. from socioeconomic status or other health behaviours. Evidence is needed from randomised clinical trials to clarify the role of n-3 LCPs in cognitive health in later life in the normal older person population.

RATIONALE: Despite encouraging reports suggesting that inhaled nitric oxide (iNO) appear to improve outcome in hypoxemic term and near term infants by improving oxygenation and reducing need for ECMO, the long-term benefits of iNO remain unclear. This study aimed to compare lung function at approximately 1 year in infants who were and were not randomly allocated to iNO as part of their neonatal management for severe respiratory failure at birth. Furthermore, results were compared to lung function of healthy infants. METHODS: Maximal expiratory flow at functional residual capacity (V'maxFRC) was measured at approximately 1 year of age (corrected for any prematurity) in survivors of the INNOVO trial. Results were expressed as Z-scores, adjusted for sex and body size, based on data from healthy controls using identical techniques. RESULTS: Technically satisfactory results were obtained in 30 infants (53% < 34 weeks gestation), 19 of whom were randomized to receive iNO V'maxFRC. Z-score was significantly reduced in infants with prior respiratory failure, whether or not they had been allocated to iNO (mean (SD) Z-score: -2.0 (1.2) and -2.6 (1.1), respectively, 95% CI difference; iNO vs. no iNO: -0.3; 1.6, P = 0.2). There was significant respiratory morbidity in both groups during the first year of life. CONCLUSIONS: These results suggest that airway function remains reduced at 1 year of age following severe respiratory failure at birth, whether or not iNO is administered.

The 1-year results of the tacrolimus versus microemulsified cyclosporin (TMC) study found a benefit with tacrolimus immunosuppression after primary liver transplants in adults with respect to freedom from graft loss and immunological failure. The integrity of the randomization process was preserved for a further 2 years for poststudy surveillance. The data after 3 years confirms the significant difference between tacrolimus and cyclosporin with tacrolimus less likely to meet the composite primary endpoint (log rank p = 0.01; relative risk 0.75; 95% CI 0.60-0.95; p = 0.016). However, freedom from death or retransplantation no longer achieves statistical significance (relative risk 0.79; 95% CI 0.62-1.02; p = 0.065). A total of 62.1% of patients randomized to tacrolimus were alive at 3 years with their original graft and still on their allocated study medication, as compared with only 41.6% in the cyclosporin limb (p < 0.001). No difference was detected between tacrolimus and cyclosporin in hepatitis-C-positive patients with the available data. The TMC study confirms after 3 years of follow-up the benefits of tacrolimus-based immunosuppression over cyclosporin using C(0) monitoring.

BACKGROUND: Low education levels are endemic in much of the developing world, particularly in rural areas where traditional government-provided public services often have difficulty reaching beneficiaries. Providing trained para-teachers to teach regular after-school remedial education classes has been shown to improve literacy and numeracy in children of primary school age residing in such areas in India. This trial investigates whether such an intervention can also be effective in a West African setting with similarly low learning levels and difficult geographic access. METHODS/DESIGN: DESIGN: cluster-randomized controlled trial. Clusters: villages or groups of villages with 15-300 households and at least 15 eligible children in the Lower River and North Bank Regions of The Gambia. PARTICIPANTS: children born between 1 September 2007 and 31 August 2009 planning to enter the first grade, for the first time, in the 2015-2016 school year in eligible villages. We anticipate enrolling approximately 150 clusters of villages with approximately 6000 children as participants. INTERVENTION: a program providing remedial after-school lessons, focusing on literacy and numeracy, 5 to 6 days a week for 3 years to eligible children, based on the intervention evaluated in the Support To Rural India's Public Education System (STRIPES) trial (PLoS ONE 8(7):e65775). CONTROL: both the intervention and control groups will receive small bundles of useful materials during annual data collection as recompense for their time. If the education intervention is shown to be cost-effective at raising learning levels, it is expected that the control group villages will receive the intervention for several years after the trial results are available. OUTCOMES: the primary outcome of the trial is a composite mathematics and language test score. Secondary outcomes include school attendance, enrollment, performance on nationally administered exams, parents' spending on education, spillover learning to siblings and family members, and school-related time use of parents and children. Subgroup analyses of the primary outcome will also be carried out based on ethnic group, gender, distance from the main highway, parents' education level, and school type. The trial will run by independent research and implementation teams and supervised by a Trial Steering Committee. DISCUSSION: Along with the overall impact of the intervention, we will conduct a cost-effectiveness analysis. There are no major ethical issues for this study. TRIAL REGISTRATION: Current controlled trials ISRCTN12500245 . 1 May 2015.

Background Data Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, their deliberations are seldom exposed to research scrutiny. Although there have been some case studies from trials from mixed specialties which offer insights into some of the common issues faced by DMCs, we have, however, little empirical information about the challenges faced within specific clinical settings. Methods In-depth interviews with participants in the BRACELET Study on death and bereavement in neonatal intensive care trials produced qualitative accounts of experiences and views of a subgroup of 18 DMC members. These interviews explored views of DMC members in relation to the clinical context of neonatal intensive care and the conduct of neonatal intensive care trials. Results Interviewees felt that an understanding of both the neonatal intensive care setting and population was crucial in a DMC. They considered the neonatal intensive care research population especially vulnerable, and that outcomes that included both death and severe disability raised particular challenges rarely faced in other settings. In exploring these key outcomes they were mindful of the need to meet high scientific standards and the needs of babies in the trials and their families. DMC members discussed particular difficulties around the composite outcome of death and severe disability, especially when mortality data were available long before data on longer term disability. While statistical stopping guidance is helpful, DMC members described decisions about stopping, revising or continuing a trial being informed by a wider set of considerations and discussions than a pre-set p value. These included potentially competing needs of current trial participants and future patients, and reflections on the nature of benefit and harm. Given their cognisance of the potential impact and consequences of the decisions made by DMCs in this setting of life, death, and disability, interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve. Conclusions DMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that for neonatal intensive care trials there are some very specific challenges seldom faced elsewhere. The vulnerability of the population, and the different timescales for essential data becoming available to inform decisions, presented particular challenges. We suggest that it is important to consider the challenges raised in other settings to better understand the complex work of these committees and to prepare future generations of DMC members.

Background Independent oversight of clinical trials, recommended by Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC make recommendations. The detailed role and functionality of this executive committee, known as the Trial Steering Committee (TSC) have not been studied since proposed by the MRC.

BackgroundYouth bullying and other aggressive behaviours are a major public health concern owing to their impact on adolescent physical and mental health and well-being. Whole-school restorative approaches have been identified as a promising method of addressing aggressive behaviour but there have been no randomised trials undertaken to examine their effects.AimTo examine the feasibility and acceptability of implementing and trialling the INCLUSIVE (initiating change locally in bullying and aggression through the school environment) intervention in English secondary schools.DesignCluster randomised controlled pilot trial in eight schools (1 : 1 computer-generated random allocation post baseline by a statistician blind to the identity of clusters) and process evaluation.SettingSecondary schools in England (purposively sampled to ensure diversity).ParticipantsYear 8 students (aged 12–13 years), teachers, other school staff and intervention providers.InterventionWhole-school restorative approach to address bullying and aggression, involving the following standard processes: school action group formation and external facilitation to review needs assessment data, identify priorities, and plan and monitor school-level actions; staff training in restorative practices; and a new social and emotional skills curriculum.Comparison groupStandard practice.Main outcome measures(1) The primary outcome of interest was the feasibility and acceptability of delivering and trialling the intervention according to prespecified criteria; (2) process data were analysed to explore participants’ experiences of implementing and trialling the intervention and how these varied according to school context; and (3) indicative primary outcomes (aggressive behaviour measures), secondary outcomes, intermediate outcomes and economic evaluation methods were piloted.Data sourcesStudents (n = 1144 baseline;n = 1114 follow-up) and teachers (n = 387 baseline;n = 336 follow-up) were surveyed at the start and end of the 2011–12 academic year (baseline September 2011; follow-up June–July 2012). A total of 1017 students surveyed at baseline remained in the study at follow-up (89%). Other quantitative data were collected via intervention provider checklists (n = 4) and action group surveys (n = 44); qualitative data were collected via interviews (n = 34), focus groups (n = 20) and observations of action group meetings (n = 16).Results(1) All prespecified feasibility and acceptability criteria were met. (2) Qualitative data indicated that all intervention components and the trial design were feasible and acceptable to students and staff, including in more disadvantaged school contexts. Qualitative data also suggested that student participation may be a core component in improving relationships and engagement across the school. The later-than-planned project start (July) and the timing of the baseline surveys (September), which needed to be completed pre allocation, caused delays in launching the intervention, staff training and other intervention outputs. (3) Three pilot primary outcomes were examined (completion rate at follow-up range: 91.7–94.2%) and the Gatehouse Bullying Scale and the Edinburgh Study of Youth Transitions and Crime school misbehaviour subscale were acceptable, discriminating and reliable measures of bullying and aggression in this context. Our pilot economic analyses support the use of the Child Health Utility 9D scale with this population and the feasibility of cost–utility analysis, although this should be supplemented with a cost–consequence analysis. There was no evidence of harm.ConclusionsIt is feasible and acceptable to implement and trial the INCLUSIVE intervention in English secondary schools, although a longer lead-in time is required to enable timely intervention outputs to occur. A Phase III cluster randomised controlled trial is required to examine the effectiveness and cost-effectiveness over a 3-year period of implementation for reducing aggressive behaviours, promoting mental health and well-being, and reducing health inequalities.Trial registrationCurrent Controlled Trials ISRCTN88527078.FundingThe National Institute for Health Research Health Technology Assessment programme (research), the Paul Hamlyn Foundation, the Big Lottery Fund and the Coutts Charitable Trust (intervention). The report will be published in full inHealth Technology Assessment; Vol. 19, No. 53. See the NIHR Journals Library website for further project information.

Background: Violence against children from school staff is widespread in various settings, but few interventions address this. We tested whether the Good School Toolkit—a complex behavioural intervention designed by Ugandan not-for-profit organisation Raising Voices—could reduce physical violence from school staff to Ugandan primary school children. Methods: We randomly selected 42 primary schools (clusters) from 151 schools in Luwero District, Uganda, with more than 40 primary 5 students and no existing governance interventions. All schools agreed to be enrolled. All students in primary 5, 6, and 7 (approximate ages 11–14 years) and all staff members who spoke either English or Luganda and could provide informed consent were eligible for participation in cross-sectional baseline and endline surveys in June–July 2012 and 2014, respectively. We randomly assigned 21 schools to receive the Good School Toolkit and 21 to a waitlisted control group in September, 2012. The intervention was implemented from September, 2012, to April, 2014. Owing to the nature of the intervention, it was not possible to mask assignment. The primary outcome, assessed in 2014, was past week physical violence from school staff, measured by students' self-reports using the International Society for the Prevention of Child Abuse and Neglect Child Abuse Screening Tool—Child Institutional. Analyses were by intention to treat, and are adjusted for clustering within schools and for baseline school-level means of continuous outcomes. The trial is registered at clinicaltrials.gov, NCT01678846. Findings: No schools left the study. At 18-month follow-up, 3820 (92·4%) of 4138 randomly sampled students participated in a cross-sectional survey. Prevalence of past week physical violence was lower in the intervention schools (595/1921, 31·0%) than in the control schools (924/1899, 48·7%; odds ratio 0·40, 95% CI 0·26–0·64, p

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.\ud \ud This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants’ views on the processes in the life of a randomised trial that should be covered by Trial Forge.\ud \ud General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a ‘go to’ website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.\ud \ud Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.\ud \ud

Objective: To explore barriers to the involvement of community midwives in identifying women in early pregnancy as potential participants in the XX, a randomised controlled trial of a new intervention to provide health and parenting support to potentially vulnerable women.\ud \ud - Design: Descriptive qualitative investigation using semi-structured audio-recoded interviews.\ud - Setting: Community midwifery offices.\ud - Participants: Volunteer sample of 13 community midwives.\ud - Measurement: Themes derived from content analysis.\ud - Findings: Understanding of their role in the research process was unclear to many midwives. Confusion arose about the difference between potential participant identification and trial recruitment. There were concerns about the eligibility criteria and it was suggested that there was insufficient time during booking appointments, and sometimes insufficient information, to determine potential eligibility. Midwives had concerns about some aspects of the intervention, which incorporated routine midwifery care, and had expectations that women may not like a group programme. This may have led some not to mention the trial. They were, however positive about the programme's potential for beneficial impacts on mothers and infants.\ud - Key conclusions: Dedicated research midwives may be the best option if research studies need to identify potential participants early in pregnancy, so that they can communicate with all their colleagues.\ud - Implications for practice: If community midwives are asked to be involved in time-critical research they are likely to need additional local resources and support.

Well-designed and properly executed randomized controlled trials (RCTs) provide the best evidence about the relative effectiveness of different interventions.1 The results of these trials can have a profound and immediate impact on patient care. Trials conducted with inadequate methodological approaches are associated with exaggerated treatment effects.2–4 Inadequate methodology may be due to several reasons: subversion of randomization resulting in biased allocation to comparison groups; unequal provision of care apart from the intervention under evaluation; biased assessment of outcomes and inadequate handling of dropouts and losses to follow-up.5 Results of such biased studies can mislead decision making in health care at all levels, from treatment decisions for an individual patient to formulation of national public health policies. There is strong evidence to indicate that the quality of reporting of RCTs in the medical literature is less than optimal.6,7 To overcome such problems, the Consolidated Standards for reporting of Trials (CONSORT) Group developed the CONSORT statement8 in 1996, which was followed by a revised version in 2001.7 At least 25 scales have been described for the evaluation of trial quality,9 among which the Jadad score is commonly used and has been validated using established methodologic procedures.10 Although several studies have evaluated the quality of RCTs published in medical journals,10–12 to date there have been none directed at general surgical literature published in general surgery journals. The aim of this study was to assess the quality of reporting of published general surgical RCTs using a checklist based on the CONSORT statement (providing a modified CONSORT score), the Jadad score, and the criteria of allocation concealment alone. We aimed to evaluate differences in reporting quality between studies published in surgical and general medical journals. We also determined whether specific study characteristics such as the number of authors, single or multicenter, statistician/epidemiologist involvement, and funding source were associated with reporting quality.

To identify the proportion of critically ill patients able to consent to participation in a randomised controlled trial (RCT) and to assess to what extent patient consent and relative assent processes could be conducted according to ethics committee permission.Descriptive study nested in an RCT.Fifty-six UK intensive care units participating in the PAC-Man trial.First 500 patients consecutively enrolled into PAC-Man.The outcome measures were patient consent and/or relative assent. Of the 498 patients included, 13 (2.6%) provided consent before randomisation. Of the remaining 485 patients, relative assent was obtained for 394 patients (81.2%), and refused post-randomisation for 3 patients (0.6%). No relatives were available for 15 patients (3.1%), and it was unclear from documentation whether relative assent had been obtained for 73 patients (15.1%). Of the 482 patients who did not provide consent prior to randomisation, 188 (39%) survived. Of these, 175 (93.1%) gave retrospective informed consent, six (3.2%) refused, and seven (3.7%) did not regain mental competency.A very small proportion of patients were able to give consent before randomisation. Due to the high in-hospital mortality (60.6%), only around one third of the remaining patients could provide consent retrospectively. This study demonstrates difficulties experienced in obtaining consent from critically ill patients to participate in medical research and raises important issues about the ethical basis of the consent process in critical care.

Background and Objective To develop and evaluate an Informed Consent Questionnaire (ICQ) for measuring self-reported perceived understanding of informed consent in a randomized clinical trial. Methods The study was embedded in a Department of Veterans Affairs randomized clinical trial of Gulf War veterans' illnesses (CSP#470). The trial was initiated in May 1999 at 20 hospitals and concluded in September 2001; 1,092 participants were enrolled and followed for 12 months. The reliability and validity sample included 1,086 participants evaluated at baseline, 906 at 3 months, 929 at 6 months, and 910 at 12 months. The psychometric evaluations included tests of acceptability (based on missing data, endorsement frequencies, and floor/ceiling effects), item reduction, internal consistency, and construct validity (based on Cronbach's alpha coefficients, item-total correlations, and principal components analysis). Results The ICQ had >5% missing information on some questions at baseline, indicating poor acceptability prior to the initiation of the trial; however, the scale had good acceptability at each of the follow-up visits. Psychometric evaluation following standard item reduction techniques confirmed the reliability and validity of a four-item subscale of the ICQ (ICQ-4). Conclusions The ICQ-4 is a simple and psychometrically sound self-report measure of perceived understanding of informed consent.

With the publication of the CONSORT statement there is now increased awareness of the need to adequately report the findings of randomised controlled trials. The CONSORT statement includes a checklist of items that should be addressed in the trial report. The original CONSORT statement was developed to ensure the appropriate reporting of parallel group randomised controlled trials in which individual participants are allocated to different intervention groups. In cluster randomised trials, however, groups of participants, rather than individuals, are randomly allocated to study groups. The process of allocating groups of participants raises additional reporting considerations and led to the publication of an extension to the CONSORT statement specifically for cluster randomised trials. In this paper we review the CONSORT extension to cluster randomised trials, outlining the special features of the cluster randomised trial which must be considered.

Summary Background Over the past 30 years the pulmonary artery catheter (PAC) has become a widely used haemodynamic monitoring device in the management of critically ill patients, though doubts exist about its safety. Our aim was, therefore, to ascertain whether hospital mortality is reduced in critically ill patients when they are managed with a PAC. Methods We did a randomised controlled trial to which we enrolled 1041 patients from 65 UK intensive care units. We assigned individuals to management with (n=519) or without (n=522) a PAC. The timing of insertion and subsequent clinical management were at the discretion of the treating clinician. Intensive care units decided a priori to have the option of using an alternative cardiac output-monitoring device in control patients. Findings 1014 patients were eligible for analysis. We noted no difference in hospital mortality between patients managed with or without a PAC (68% [346 of 506] vs 66% [333 of 507], p=0·39; adjusted hazard ratio 1·09, 95% CI 0·94–1·27). We noted complications associated with insertion of a PAC in 46 of 486 individuals in whom the device was placed, none of which was fatal. Interpretation Our findings indicate no clear evidence of benefit or harm by managing critically ill patients with a PAC. Efficacy studies are needed to ascertain whether management protocols involving PAC use can result in improved outcomes in specific groups if these devices are not to become a redundant technology.

Individual patient randomized trials are the gold standard for assessing the effects of health care evaluations. However, individual randomization may not be possible for practical, logistical, ethical, or political reasons, for example, when evaluating health care professional and organizational behavior change interventions. Under such circumstances, cluster randomized trials are commonly used. This article discusses the practical and ethical issues in the design, conduct, and analysis of cluster randomized trials of professional behavior and organizational change strategies using examples from two primary studies evaluating health care provider behavior change strategies. Cluster randomized trials are commonly used in health care. They raise distinct ethical and methodological issues that have rarely been adequately addressed in studies to date.