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Objective To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran’s Q and I2 statistics. Quality of evidence assessed by GRADE criteria.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials’ registry for data not evident in databases. Authors were contacted for unpublished data.Eligibility criteria for selecting studies RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up ≥1 year.Results 54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).Conclusions Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.Systematic review registration PROSPERO CRD42016033217.

Background A reliable biomedical literature is critical to scientific advances and patient care. When concerns about the integrity of a publication are raised, it is very commonly by journal readers. Published evidence reports that responses from publishers to integrity concerns raised by readers are slow, incomplete, inconsistent and opaque. Here, we examine publisher responses and propose a schema for improving them. Analyses Supported by published evidence and examples from our extensive experience in communicating integrity concerns to journal and publishers, we conclude that many aspects of publisher responses to notification of integrity concerns are unsatisfactory. We propose that the quality of publisher responses and the outcomes of their integrity assessments could be improved by the adoption of a proactive and collaborative approach at manuscript submission, a primary focus on publication integrity instead of researcher behaviour, adoption of systematic and unconflicted assessment methodologies, commitment to timely, transparent and comprehensive assessments, timely, respectful communication with journal readers, and timely correction of the published record. Conclusion Publishers, who are ultimately responsible for the integrity of the biomedical literature, could and should substantially improve their response to the receipt of concerns about the integrity of publications in their journals.

To describe statistical tools available for assessing publication integrity of groups of randomized controlled trials (RCTs). Narrative review. Freely available statistical tools have been developed that compare the observed distributions of baseline variables with the expected distributions that would occur if successful randomization occurred. For continuous variables, the tools assess baseline means, baseline P values, and the occurrence of identical means and/or standard deviation. For categorical variables, they assess baseline P values, frequency counts for individual or all variables, numbers of trial participants randomized or withdrawing, and compare reported with independently calculated P values. The tools have been used to identify publication integrity concerns in RCTs from individual groups, and performed at an acceptable level in discriminating intentionally fabricated baseline summary data from genuine RCTs. The tools can be used when concerns have been raised about RCT(s) from an individual/group and when the whole body of their work is being examined, when conducting systematic reviews, and could be adapted to aid screening of RCTs at journal submission. Statistical tools are useful for the assessment of publication integrity of groups of RCTs.

ObjectiveAnalyses of the impact of a body of clinical trial reports subject to research misconduct have been few. Our objective was to examine the impact on clinically relevant research of a group of researchers’ trial reports (‘affected trial reports’) affected by research misconduct, and whether identification of misconduct invoked a reappraisal.DesignIn 2016, we used five databases and search engines to identify ‘citing publications’, that is, guidelines, systematic and other reviews, and clinical trials citing any of 12 affected trial reports, published 1998–2011, eventually retracted for research misconduct. The affected trial reports were assessed more likely to have had impact because they had hip fracture outcomes and were in journals with impact factor >4. Two authors assessed whether findings of the citing publications would change if the affected trial reports were removed. In 2018, we searched for evidence that the citing publications had undertaken a reassessment as a result of the potential influence of the affected trial reports.ResultsBy 2016 the affected trial reports were cited in 1158 publications, including 68 systematic reviews, meta-analyses, narrative reviews, guidelines and clinical trials. We judged that 13 guidelines, systematic or other reviews would likely change their findings if the affected trial reports were removed, and in another eight it was unclear if findings would change. By 2018, only one of the 68 citing publications, a systematic review, appeared to have undertaken a reassessment, which led to a correction.ConclusionsWe found evidence that this group of affected trial reports distorted the evidence base. Correction of these distortions is slow, uncoordinated and inconsistent. Unless there is a rapid, systematic, coordinated approach by bibliographic databases, authors, journals and publishers to mitigate the impact of known cases of research misconduct, patients, other researchers and their funders may continue to be adversely affected.

The amino acid glutamine has numerous important roles including particularly antioxidant defence, immune function, the inflammatory response, acid–base balance and N economy. The present systematic review of randomised controlled trials of nutrition support with glutamine up to August 2008 has found that parenteral glutamine in critical illness is associated with a non-significant reduction in mortality (risk ratio 0·71 (95% CI 0·49, 1·03)) and may reduce infections. However, poor study quality and the possibility of publication bias mean that these results should be interpreted with caution. There is no evidence to suggest that glutamine is harmful in terms of organ failure and parenteral glutamine may reduce the development of organ failure.

Background Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient. Methods In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large ( N  ≥ 1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications. Results Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was < 25, 25–49, 50–74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD < 25, 25–49, 50–74, and ≥ 75 nmol/L respectively; in 2011–15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD > 40 nmol/L. 44% (8/18) of large completed RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews. Conclusions Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.

A role for Epstein Barr virus (EBV) in multiple sclerosis (MS) has been postulated. Previous systematic reviews found higher prevalences of anti-EBV antibodies in MS patients compared to controls, but many studies have since been published, and there is a need to apply more rigorous systematic review methods. We examined the link between EBV and MS by conducting a systematic review and meta-analysis of case-control and cohort studies that examined the prevalence of anti-EBV antibodies in the serum of cases and controls. We searched Medline and Embase databases from 1960 to 2012, with no language restriction. The Mantel-Haenszel odds ratios (OR) for anti-EBV antibodies sero-positivity were calculated, and meta-analysis conducted. Quality assessment was performed using a modified version of the Newcastle Ottawa scale. Thirty-nine studies were included. Quality assessment found most studies reported acceptable selection and comparability of cases and controls. However the majority had poor reporting of ascertainment of exposure. Most studies found a higher sero-prevalence of anti-EBNA IgG and anti-VCA IgG in cases compared to controls. The results for anti-EA IgG were mixed with only half the studies finding a higher sero-prevalence in cases. The meta-analysis showed a significant OR for sero-positivity to anti-EBNA IgG and anti-VCA IgG in MS cases (4.5 [95% confidence interval (CI) 3.3 to 6.6, p<0.00001] and 4.5 [95% CI 2.8 to 7.2, p<0.00001] respectively). However, funnel plot examination suggested publication bias for the reporting of the anti-EBNA IgG. No significant difference in the OR for sero-positivity to anti-EA IgG was found (1.4 [95% CI 0.9 to 2.1, p = 0.09]). These findings support previous systematic reviews, however publication bias cannot be excluded. The methodological conduct of studies could be improved, particularly with regard to reporting and conduct of laboratory analyses.

Comparing observed and expected distributions of baseline continuous variables in randomized controlled trials (RCTs) can be used to assess publication integrity. We explored whether baseline categorical variables could also be used. The observed and expected (binomial) distribution of all baseline categorical variables were compared in four sets of RCTs: two controls, and two with publication integrity concerns. We also compared baseline calculated and reported P-values. The observed and expected distributions of baseline categorical variables were similar in the control datasets, both for frequency counts (and percentages) and for between-group differences in frequency counts. However, in both sets of RCTs with publication integrity concerns, about twice as many variables as expected had between-group differences in frequency counts of one or 2, and far fewer variables than expected had between-group differences of >4 (P < 0.001 for both datasets). Furthermore, about one in six reported P-values for baseline categorial variables differed by > 0.1 from the calculated P-value in trials with publication integrity concerns. Comparing the observed and expected distributions and reported and calculated P-values of baseline categorical variables may help in the assessment of publication integrity of a body of RCTs.

Levayer and colleagues assessed integrity issues in randomized controlled trials (RCTs) in four spine journals using baseline p -values from categorical variables, concluding that there was no evidence of ‘systemic fraudulent behaviour’. We used their published dataset to assess the accuracy of reported p -values and whether observed and expected distributions of frequency counts and p -values were consistent. In 51 out of 929 (5.5%) baseline variables, the sum of frequencies did not agree with the reported number of participants. For one-third of reported p -values (172 out of 522), we could not calculate a matching p -value using a range of statistical tests. Sparse data were common: for 22% (74 out of 332) of variables in which the reported p -value matched the p -value calculated from a chi-square test, the expected cells were smaller than recommended for the use of chi-square tests. There were 20–25% more two-arm trials with differences in frequency counts of 1 or 2 between-groups than expected. There were small differences between observed and expected distributions of baseline p -values, but these depended on analysis methods. In summary, incorrectly reported p -values and incorrect statistical test usage were common, and there were differences between observed and expected distributions of baseline p -values and frequency counts, raising questions about the integrity of some RCTs in these journals.

Glutamine, the most abundant amino acid in the body, is thought to become conditionally essential in critical illness. Some of the important roles for glutamine are as a carrier for inter-organ N, a preferred fuel for enterocytes and cells of the immune system, a substrate for renal NH3 formation and a precursor for glutathione. Mechanisms by which glutamine could improve recovery include attenuating oxidant damage and inflammatory cytokine production, reducing gut bacterial translocation and improving N balance. The present systematic review has found trends to suggest that parenteral and enteral glutamine supplementation reduce mortality, the development of infection and organ failure in critical illness. Trials of parenteral nutrition containing glutamine with patients after elective surgery also suggest reduction of infection, but it is unlikely that glutamine-containing parenteral nutrition would be used for such patients. The evidence base is limited by the quality of the reported trials and the suggestion that there is publication bias, with trials suggesting reduced infection being more likely to be published.