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New study finds a link, but vaccination remains overwhelmingly the safest option

BackgroundAdvance care planning is widely advocated to improve outcomes in end-of-life care for patients suffering from heart failure. But until now, there has been no systematic evaluation of the impact of advance care planning (ACP) on clinical outcomes. Our aim was to determine the effect of ACP in heart failure through a meta-analysis of randomized controlled trials (RCTs).MethodsWe searched CINAHL, Cochrane Central Register of Controlled Trials, Database of Systematic Reviews, Embase, ERIC, Ovid MEDLINE, Science Citation Index and PsycINFO (inception to July 2018). We selected RCTs including adult patients with heart failure treated in a hospital, hospice or community setting. Three reviewers independently screened studies, extracted data, assessed the risk of bias (Cochrane risk of bias tool) and evaluated the quality of evidence (GRADE tool) and analysed interventions according to the Template for Intervention Description and Replication (TIDieR). We calculated standardized mean differences (SMD) in random effects models for pooled effects using the generic inverse variance method.ResultsFourteen RCTs including 2924 participants met all of the inclusion criteria. There was a moderate effect in favour of ACP for quality of life (SMD, 0.38; 95% CI [0.09 to 0.68]), patients’ satisfaction with end-of-life care (SMD, 0.39; 95% CI [0.14 to 0.64]) and the quality of end-of-life communication (SMD, 0.29; 95% CI [0.17 to 0.42]) for patients suffering from heart failure. ACP seemed most effective if it was introduced at significant milestones in a patient’s disease trajectory, included family members, involved follow-up appointments and considered ethnic preferences. Several sensitivity analyses confirmed the statistically significant direction of effect. Heterogeneity was mainly due to different study settings, length of follow-up periods and compositions of ACP.ConclusionsACP improved quality of life, patient satisfaction with end-of-life care and the quality of end-of-life communication for patients suffering from heart failure and could be most effective when the right timing, follow-up and involvement of important others was considered.

The BMJ’s statistical editors relish a quiet Christmas, so make their wish come true and pay attention to the list of common statistical faux pas presented here by Riley and colleagues

External validation studies create evidence about a clinical prediction rule's (CPR's) generalizability by evaluating and updating the CPR in populations different from those used in the derivation, and also by contributing to estimating its overall performance when meta-analysed in a systematic review. While most cardiovascular CPRs do not have any external validation, some CPRs have been externally validated repeatedly. Hence, we examined whether external validation studies of the Framingham Wilson coronary heart disease (CHD) risk rule contributed to generating evidence to their full potential. A forward citation search of the Framingham Wilson CHD risk rule's derivation study was conducted to identify studies that evaluated the Framingham Wilson CHD risk rule in different populations. For external validation studies of the Framingham Wilson CHD risk rule, we examined whether authors updated the Framingham Wilson CHD risk rule when it performed poorly. We also assessed the contribution of external validation studies to understanding the Predicted/Observed (P/O) event ratio and c statistic of the Framingham Wilson CHD risk rule. We identified 98 studies that evaluated the Framingham Wilson CHD risk rule; 40 of which were external validation studies. Of these 40 studies, 27 (67.5%) concluded the Framingham Wilson CHD risk rule performed poorly but did not update it. Of 23 external validation studies conducted with data that could be included in meta-analyses, 13 (56.5%) could not fully contribute to the meta-analyses of P/O ratio and/or c statistic because these performance measures were neither reported nor could be calculated from provided data. Most external validation studies failed to generate evidence about the Framingham Wilson CHD risk rule's generalizability to their full potential. Researchers might increase the value of external validation studies by presenting all relevant performance measures and by updating the CPR when it performs poorly.

Randomization, allocation concealment, and blind outcome assessment have been shown to reduce bias in human studies. Authors from the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) collaboration recently found that these features protect against bias in animal stroke studies. We extended the scope the work from CAMARADES to include investigations of treatments for any condition. We conducted an overview of systematic reviews. We searched Medline and Embase for systematic reviews of animal studies testing any intervention (against any control) and we included any disease area and outcome. We included reviews comparing randomized versus not randomized (but otherwise controlled), concealed versus unconcealed treatment allocation, or blinded versus unblinded outcome assessment. Thirty-one systematic reviews met our inclusion criteria: 20 investigated treatments for experimental stroke, 4 reviews investigated treatments for spinal cord diseases, while 1 review each investigated treatments for bone cancer, intracerebral hemorrhage, glioma, multiple sclerosis, Parkinson's disease, and treatments used in emergency medicine. In our sample 29% of studies reported randomization, 15% of studies reported allocation concealment, and 35% of studies reported blinded outcome assessment. We pooled the results in a meta-analysis, and in our primary analysis found that failure to randomize significantly increased effect sizes, whereas allocation concealment and blinding did not. In our secondary analyses we found that randomization, allocation concealment, and blinding reduced effect sizes, especially where outcomes were subjective. Our study demonstrates the need for randomization, allocation concealment, and blind outcome assessment in animal research across a wide range of outcomes and disease areas. Since human studies are often justified based on results from animal studies, our results suggest that unduly biased animal studies should not be allowed to constitute part of the rationale for human trials.

Objective To assess effectiveness of school-based smoking prevention curricula keeping children never-smokers. Design Systematic review, meta-analysis. Data: MEDLINE (1966+), EMBASE (1974+), Cinahl, PsycINFO (1967+), ERIC (1982+), Cochrane CENTRAL, Health Star, Dissertation Abstracts, conference proceedings. Data synthesis: pooled analyses, fixed-effects models, adjusted ORs. Risk of bias assessed with Cochrane Risk of Bias tool. Setting 50 randomised controlled trials (RCTs) of school-based smoking curricula. Participants Never-smokers age 5–18 (n=143 495); follow-up ≥6 months; all countries; no date/language limitations. Interventions Information, social influences, social competence, combined social influences/competence and multimodal curricula. Outcome measure Remaining a never-smoker at follow-up. Results Pooling all curricula, trials with follow-up ≤1 year showed no statistically significant differences compared with controls (OR 0.91 (0.82 to 1.01)), though trials of combined social competence/social influences curricula had a significant effect on smoking prevention (7 trials, OR 0.59 (95% CI 0.41 to 0.85)). Pooling all trials with longest follow-up showed an overall significant effect in favour of the interventions (OR 0.88 (0.82 to 0.95)), as did the social competence (OR 0.65 (0.43 to 0.96)) and combined social competence/social influences curricula (OR 0.60 (0.43 to 0.83)). No effect for information, social influences or multimodal curricula. Principal findings were not sensitive to inclusion of booster sessions in curricula or to whether they were peer-led or adult-led. Differentiation into tobacco-only or multifocal curricula had a similar effect on the primary findings. Few trials assessed outcomes by gender: there were significant effects for females at both follow-up periods, but not for males. Conclusions RCTs of baseline never-smokers at longest follow-up found an overall significant effect with average 12% reduction in starting smoking compared with controls, but no effect for all trials pooled at ≤1 year. However, combined social competence/social influences curricula showed a significant effect at both follow-up periods. Systematic review registration Cochrane Tobacco Review Group CD001293.

The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years. Nearly all focus to date has been on intervention reporting in randomised trials. Yet clinicians are encouraged to use systematic reviews, whenever available, rather than single trials to inform their practice. This article explores the problem and implications of incomplete intervention details during the planning, conduct, and reporting of systematic reviews and makes recommendations for review authors, peer reviewers, and journal editors

To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence. Patients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines. A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported. Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5μg/L achieves at best 50.0% sensitivity (95% CI: 40.1-59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2-64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5μg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5-46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others-at the 5μg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals. Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed.

IntroductionHypertension is a leading cause of cardiovascular disease, which is the cause of one-third of global deaths and is a primary and rising contributor to the global disease burden. The objective of this systematic review was to determine the prevalence and awareness of hypertension among the inhabitants of Tibet and its association with altitude, using the data from published observational studies.MethodsWe conducted electronic searches in Medline, Embase, ISI Web of Science and Global Health. No gender or language restrictions were imposed. We assessed the methodological characteristics of included studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. Two reviewers independently determined the eligibility of studies, assessed the methodology of included studies and extracted the data. We used meta-regression to estimate the degree of change in hypertension prevalence with increasing altitude.ResultsWe identified 22 eligible articles of which eight cross-sectional studies with a total of 16 913 participants were included. The prevalence of hypertension ranged between 23% and 56%. A scatter plot of altitude against overall prevalence revealed a statistically significant correlation (r=0.68; p=0.04). Meta-regression analysis revealed a 2% increase in the prevalence of hypertension with every 100 m increase in altitude (p=0.06). The locations and socioeconomic status of subjects affected the awareness and subsequent treatment and control of hypertension.ConclusionsThe results from cross-sectional studies suggest that there is a significant correlation between altitude and the prevalence of hypertension among inhabitants of Tibet. The socioeconomic status of the inhabitants can influence awareness and management of hypertension. Very little research into hypertension has been conducted in other prefectures of Tibet where the altitude is much higher. Further research examining the impact of altitude on blood pressure is warranted.

Placebos are widely used in clinical practice in spite of ethical restrictions. Whether such use is justified depends in part on the relative benefit of placebos compared to 'active' treatments. A direct test for differences between placebo and 'active' treatment effects has not been conducted. We aimed to test for differences between treatment and placebo effects within similar trial populations. A Cochrane Review compared placebos with no treatment in three-armed trials (no treatment, placebo, and treatment). We added an analysis of treatment and placebo differences within the same trials. SYNTHESIS METHODS: For continuous outcomes we compared mean differences between placebo and no treatment with mean differences between treatment and placebo. For binary outcomes we compared the risk ratio for treatment benefit (versus placebo) with the risk ratio for placebo benefit (versus no treatment). We conducted several preplanned subgroup analyses: objective versus subjective outcomes, conditions tested in three or more trials, and trials with varying degrees of bias. In trials with continuous outcomes (n = 115) we found no difference between treatment and placebo effects (MD = -0.29, 95% CI -0.62 to 0.05, P = 0.10). In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). Treatment and placebo effects were not different in 22 out of 28 predefined subgroup analyses. Of the six subgroups with differences treatments were more effective than placebos in five. However when all criteria for reducing bias were ruled out (continuous outcomes) placebos were more effective than treatments (MD = 1.59, 95% CI = 0.40 to 2.77, P = 0.009). Placebos and treatments often have similar effect sizes. Placebos with comparatively powerful effects can benefit patients either alone or as part of a therapeutic regime, and trials involving such placebos must be adequately blinded.