BackgroundThresholds for statistical significance when assessing meta-analysis results are being insufficiently demonstrated by traditional 95% confidence intervals and P-values. Assessment of intervention effects in systematic reviews with meta-analysis deserves greater rigour.MethodsMethodologies for assessing statistical and clinical significance of intervention effects in systematic reviews were considered. Balancing simplicity and comprehensiveness, an operational procedure was developed, based mainly on The Cochrane Collaboration methodology and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.ResultsWe propose an eight-step procedure for better validation of meta-analytic results in systematic reviews (1) Obtain the 95% confidence intervals and the P-values from both fixed-effect and random-effects meta-analyses and report the most conservative results as the main results. (2) Explore the reasons behind substantial statistical heterogeneity using subgroup and sensitivity analyses (see step 6). (3) To take account of problems with multiplicity adjust the thresholds for significance according to the number of primary outcomes. (4) Calculate required information sizes (≈ the a priori required number of participants for a meta-analysis to be conclusive) for all outcomes and analyse each outcome with trial sequential analysis. Report whether the trial sequential monitoring boundaries for benefit, harm, or futility are crossed. (5) Calculate Bayes factors for all primary outcomes. (6) Use subgroup analyses and sensitivity analyses to assess the potential impact of bias on the review results. (7) Assess the risk of publication bias. (8) Assess the clinical significance of the statistically significant review results.ConclusionsIf followed, the proposed eight-step procedure will increase the validity of assessments of intervention effects in systematic reviews of randomised clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2288-14-120) contains supplementary material, which is available to authorized users.

A cornerstone of epidemiologic research is to understand the causal pathways from an exposure to an outcome. Mediation analysis based on counterfactuals is an important tool when addressing such questions. However, none of the existing techniques for formal mediation analysis can be applied to survival data. This is a severe shortcoming, as many epidemiologic questions can be addressed only with censored survival data. A solution has been to use a number of Cox models (with and without the potential mediator), but this approach does not allow a causal interpretation and is not mathematically consistent. In this paper, we propose a simple measure of mediation in a survival setting. The measure is based on counterfactuals, and measures the natural direct and indirect effects. The method allows a causal interpretation of the mediated effect (in terms of additional cases per unit of time) and is mathematically consistent. The technique is illustrated by analyzing socioeconomic status, work environment, and long-term sickness absence. A detailed implementation guide is included in an online eAppendix (http://links.lww.com/EDE/A476).

BACKGROUNDPatients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao 2 ) would result in lower mortality than using a higher target. METHODSIn this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao 2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higheroxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTSAt 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONSAmong adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

EGDN did not appear to affect physical quality of life at 6 months or other important outcomes as compared to standard nutrition care in acutely admitted, mechanically ventilated, adult ICU patients. Clinicaltrials.gov identifier no. NCT01372176.