Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V_T), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (C_RS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (ΔP=V_T/C_RS), in which V_T is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than V_T or PEEP in patients who are not actively breathing. Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined ΔP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. Among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving “protective” plateau pressures and V_T (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in V_T or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, P=0.004 and P=0.001, respectively). We found that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundação de Amparo e Pesquisa do Estado de São Paulo and others.)

Protecting lungs from ventilation-induced injury is an important principle in the management of patients with acute lung injury or acute respiratory distress syndrome (ARDS). Although the critical care community has generally endorsed lower tidal volumes and inspiratory pressures, the optimal level of positive end-expiratory pressure (PEEP) remains unestablished.^1,2 Experimental data suggest that PEEP levels exceeding traditional values of 5 to 12 cm H₂O can minimize cyclical alveolar collapse and corresponding shearing injury to the lungs in patients with considerable edema and alveolar collapse.^3-5 For patients with relatively mild acute lung injury, however, potential adverse consequences of higher PEEP levels, including circulatory depression⁶ or lung overdistension,⁷ may outweigh the benefits. Several multicenter, randomized trials testing the incremental effect of higher levels of PEEP were confounded by baseline imbalances in prognostic factors and underpowered to rule in or rule out an important survival effect.^8-10

Objective To quantify the overall effects of bariatric surgery compared with non-surgical treatment for obesity. Design Systematic review and meta-analysis based on a random effects model. Data sources Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status. Eligibility criteria Eligible studies were randomised controlled trials with ≥6 months of follow-up that included individuals with a body mass index ≥30, compared current bariatric surgery techniques with non-surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events. Results The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference −26 kg (95% confidence interval −31 to −21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference −0.7 mmol/L (−1.0 to −0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%). Conclusions Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. Systematic review registration PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO).

In the past 4 decades, the prevalence of obesity among adults aged 20 to 74 years in the United States increased from 13% to 31%.¹ In the United States, obesity results in an estimated 325 000 deaths annually² and accounts for about 5.5% of total direct health care costs.^3,4 At any given time, approximately 45% of women and 30% of men in the United States are attempting to lose weight.⁵ Numerous diets have been proposed to promote weight loss.⁶ Weight loss from certain diets may lead to prevention of type 2 diabetes and improved control of hypertension⁷ and may reduce cardiovascular morbidity and mortality. In a recent meta-analysis of randomized controlled trials, little evidence was found to support the use of diets other than low-fat diets for weight reduction.⁷ However, there is a lack of data from well-controlled trials about the most effective dietary approaches to achieve meaningful and long-term weight loss in overweight individuals. Although fat- and energy-restricted diets are generally recommended for these individuals,^8,9 low-carbohydrate, high-protein diets are one of the most popular alternative weight loss approaches.¹⁰ Low-carbohydrate diets derive a large proportion of energy intake from protein and fat, and there is concern for the potentially detrimental impact of these diets on blood lipid levels and on cardiovascular risk.¹¹ Results from individual clinical trials and uncontrolled studies suggest that there is insufficient evidence to make recommendations for or against the use of low-carbohydrate diets.¹²

BACKGROUND: Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN). METHODS: To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification. RESULTS: The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument. INTERPRETATION: The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.

How can we tell the difference between spurious and real subgroup effects? This article identifies new criteria and proposes a checklist for judging the credibility of subgroup analyses