Ben Vandermeer

Meta-Analysis: Secondary Prevention Programs for Patients with Coronary Artery Disease

Cardiovascular disease remains the most common cause of office visits, hospitalizations, and death in the United States: More than 13 million Americans have documented coronary artery disease (CAD), and costs for CAD are expected to exceed

Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction : meta-analysis

393 billion in 2005 (1). Control of the CAD epidemic requires a multifaceted strategy targeting the currently recognized modifiable risk factors for CAD that account for more than 90% of risk, regardless of sex, age, or region (2). This strategy should include primary prevention maneuvers (for the general population and high-risk individuals) and secondary prevention programs (for patients with established CAD). Despite the abundant evidence base for CAD prevention (3), health outcomes studies consistently demonstrate gaps in applying this evidence to clinical practice; these gaps contribute to suboptimal patient outcomes (4). Secondary prevention programs are often proposed as a way to improve management and outcomes. Although several reviews have shown that cardiac rehabilitation reduces mortality in survivors of myocardial infarction (MI) (5-8), these conclusions are informed largely by trials that tested supervised exercise programs versus no exercise postinfarction. Since exercise training confers substantial physiologic and clinical benefits and activity levels are inversely proportional to cardiovascular mortality (9), it is not surprising that trials of exercise programs found positive effects on survival. However, few trials included in these reviews evaluated secondary prevention programs that were not primarily exercise-based. In an earlier review (10), we identified 12 randomized trials (9803 patients) of nonexercise-based secondary prevention programs in patients with established CAD. We demonstrated improvements in risk factor profiles and processes of care (particularly the prescription of proven efficacious therapies) but indeterminate effect on rates of death or recurrent MIs (10). Because current guidelines recommend that secondary prevention programs should not be restricted to supervised exercise programs but should address the full range of modifiable risk factors (11), we conducted a systematic review to update earlier work and to determine the effects of different types of secondary prevention programs (particularly those with a structured exercise component versus those without). Methods Data Sources We searched MEDLINE (19662004); the Cochrane Central Register of Controlled Trials, Issue 4, 2004; EMBASE (19802004); CINAHL (19822004); SIGLE (19802004); and PubMed (January 2004December 2004). We also conducted a cited reference search for our previous review (10) in Web of Science (19992004). We based the searches on the following terms: case management, comprehensive health care, disease management, health services research, home care services, clinical protocols, patient care planning, quality of health care, rehabilitation, nurse led clinics, special clinics, and myocardial ischemia. We hand-searched reference lists of all identified studies, review articles, and references provided by the Centers for Medicare & Medicaid Services and content experts (search strategy available upon request). We limited our search to English-language publications (no abstracts), and the search extends from 1966 to 2004 (we completed the search on 16 December 2004). Study Selection Two investigators independently reviewed the titles and abstracts of all citations to identify studies reporting the effect of secondary prevention programs on mortality, MI, or hospitalization rates in patients with CAD. Both investigators obtained the full text of potentially relevant articles and reviewed them by using prestandardized data abstraction forms and eligibility criteria defined a priori. Any discrepancies were resolved by consensus. We excluded studies if they were not randomized, if they did not include a usual care group, if the outcomes for CAD patients were not reported or were not obtainable from the study investigators, if they evaluated single-modality interventions except exercise (such as telephone follow-up), if they tested interventions delivered to inpatients, or if the interventions were not provided by health professionals (for example, mailed reminders, self-help groups, or self-directed interventions). Data Extraction and Quality Assessment Two investigators extracted all outcome data independently, and a third investigator checked the data. We assigned outcomes according to the intention-to-treat principle and by using the definitions from the primary studies. When necessary, we contacted original investigators to clarify the data for any trial published in the past decade. Authors for 10 of these 21 studies provided further data. Two investigators independently assigned each intervention to 1 of 3 groups: 1) programs that incorporated education and counseling about coronary risk factors with a supervised exercise program (either in a group setting, per traditional comprehensive cardiac rehabilitation programs, or individually delivered), 2) programs that included education and counseling about coronary risk factors but had no exercise component (either delivered in a group setting or individually), and 3) supervised exercise programs only. Data Synthesis and Analysis We performed analyses by using RevMan 4.2 (Update Software, Oxford, United Kingdom). Our outcomes of interest were all-cause mortality and recurrent MIs. Because the outcomes were relatively common, we calculated risk ratios and used the I2 statistic to assess for heterogeneity in each outcome of interest. We combined studies by using the DerSimonian and Laird random-effects model. For the primary analysis, we used data from the longest follow-up period reported in each trial. In a priori sensitivity analyses, we pooled data for 3 follow-up periods (12, 24, and 60 months). To evaluate whether different types of secondary prevention programs had different effects, we calculated the summary risk ratio for each program type and used adjusted indirect comparisons to compare different types of interventions, according to the method of Song and colleagues (12). Role of the Funding Source An earlier version of this evidence report was produced under contract to the Agency for Healthcare Research and Quality, Rockville, Maryland (contract no. 290-02-0023). The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Study Selection and Evaluation We identified 6345 citations from electronic databases (n= 6207), reference lists (n= 45), and the Centers for Medicare & Medicaid Services (n= 93). After the initial screening, we reviewed 254 full manuscripts and excluded 179 of these studies after detailed evaluation (Figure 1). Figure 1. Flow of trials through the selection process. Sixteen disagreements among the reviewers about eligibility of the studies occurred for a value of 0.81. All disagreements were resolved by consensus. Of the randomized trials that were eligible for inclusion (13-87), 9 were reported in more than 1 publication. The second publication reported different end points in 2 cases (13-16), results from different follow-up periods in 5 cases (13, 17-26), and results from the subgroup of patients with cardiac disease in 1 case (27, 28). The ninth trial (the World Health Organization [WHO] trial) (29) included 24 collaborating centers; however, the original investigators excluded 7 sites because of poor participant follow-up and 4 sites because of statistically significant differences between the intervention and control groups at baseline. We included the outcome data from the remaining 13 sites as 1 trial for our analysis, an approach validated by the nonsignificant test results for statistical heterogeneity for all-cause mortality and MI. While the 2 Finnish centers in the WHO trial published their results separately (and for several follow-up periods), we included only their 3-year outcome data with the other 11 WHO sites for consistency of data presentation (30-32). Studies Included in the Systematic Review Table 1 presents summary data from the 63 unique randomized trials that were eligible for our systematic review (13-87). Our search retrieved 51 trials that were not included in our previous systematic review (which was limited to literature published before 1999 and excluded any studies with exercise components) (10) and 26 trials that were not included in a more recent systematic review of cardiac rehabilitation (which was limited to literature published before 2003 and included few individual counseling programs) (8). Table 1. Description of Included Studies Qualitative Data Synthesis In all trials, patients who were randomly assigned to the control groups received usual care (this was generally undefined). Table 1 describes the types of secondary prevention programs; few trials described the intensity of the interventions. Almost all trials enrolled highly selected study samples: Forty-five trials recruited patients after acute MI or a coronary revascularization procedure. Thirty-five trials excluded elderly patients, and 19 trials excluded women (Table 1). Indeed, women constituted fewer than 50% of study participants in all but 2 trials. No trial was double-blind (which is not surprising, considering the nature of the intervention), and very few trials described randomization procedures or accounted for discrepancies between sample sizes at recruitment and follow-up. As a result, Jadad quality scores clustered around 2 (Table 2). Furthermore, only 15 (24%) trial reports described adequate allocation concealment. Table 2. Methodologic Quality of Included Studies No trial reported side effects with the secondary prevention programs beyond the adverse clinical outcomes described later. Quantitative Data Synthesis All-Cause Mortality Only 1 of the 40 trials reporting this outcome f

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.

Abstract Objective To conduct a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. Data sources 13 electronic databases and reference lists of relevant reviews and included studies; Associated Professional Sleep Society abstracts (1999 to 2003). Study selection The efficacy review included randomised controlled trials; the safety review included randomised and non-randomised controlled trials. Quality assessment Randomised controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al, and non-randomised controlled trials by the Downs and Black checklist. Data extraction and synthesis One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weight studies and the random effects model was used to analyse data. Main results Six randomised controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference −13.2 (95% confidence interval −27.3 to 0.9) min). Nine randomised controlled trials with 427 participants showed no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (−1.0 (−2.3 to 0.3) min). 17 randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use (three months or less). Conclusions There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.

The efficacy and safety of exogenous melatonin for primary sleep disorders a meta-analysis

BACKGROUND Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. METHODS We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. FINDINGS Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). INTERPRETATION Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. FUNDING None.

Behavioural and developmental interventions for autism spectrum disorder: a clinical systematic review

BACKGROUND: Exogenous melatonin has been increasingly used in the management of sleep disorders.PURPOSE: To conduct a systematic review of the efficacy and safety of exogenous melatonin in the management of primary sleep disorders.DATA SOURCES: A number of electronic databases were searched. We reviewed the bibliographies of included studies and relevant reviews and conducted hand-searching.STUDY SELECTION: Randomized controlled trials (RCTs) were eligible for the efficacy review, and controlled trials were eligible for the safety review.DATA EXTRACTION: One reviewer extracted data, while the other verified data extracted. The Random Effects Model was used to analyze data.DATA SYNTHESIS: Melatonin decreased sleep onset latency (weighted mean difference [WMD]: −11.7 minutes; 95% confidence interval [CI]: −18.2, −5.2)); it was decreased to a greater extent in people with delayed sleep phase syndrome (WMD: −38.8 minutes; 95% CI: −50.3, −27.3; n=2) compared with people with insomnia (WMD: −7.2 minutes; 95% CI: −12.0, −2.4; n=12). The former result appears to be clinically important. There was no evidence of adverse effects of melatonin.CONCLUSIONS: There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less); however, additional large-scale RCTs are needed before firm conclusions can be drawn. There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use. There is evidence to suggest that melatonin is safe with short-term use (3 months or less).

Systematic Review: Implantable Cardioverter Defibrillators for Adults with Left Ventricular Systolic Dysfunction

Background Much controversy exists regarding the clinical efficacy of behavioural and developmental interventions for improving the core symptoms of autism spectrum disorders (ASD). We conducted a systematic review to summarize the evidence on the effectiveness of behavioural and developmental interventions for ASD. Methods and Findings Comprehensive searches were conducted in 22 electronic databases through May 2007. Further information was obtained through hand searching journals, searching reference lists, databases of theses and dissertations, and contacting experts in the field. Experimental and observational analytic studies were included if they were written in English and reported the efficacy of any behavioural or developmental intervention for individuals with ASD. Two independent reviewers made the final study selection, extracted data, and reached consensus on study quality. Results were summarized descriptively and, where possible, meta-analyses of the study results were conducted. One-hundred-and-one studies at predominantly high risk of bias that reported inconsistent results across various interventions were included in the review. Meta-analyses of three controlled clinical trials showed that Lovaas treatment was superior to special education on measures of adaptive behaviour, communication and interaction, comprehensive language, daily living skills, expressive language, overall intellectual functioning and socialization. High-intensity Lovaas was superior to low-intensity Lovaas on measures of intellectual functioning in two retrospective cohort studies. Pooling the results of two randomized controlled trials favoured developmental approaches based on initiative interaction compared to contingency interaction in the amount of time spent in stereotyped behaviours and distal social behaviour, but the effect sizes were not clinically significant. No statistically significant differences were found for: Lovaas versus special education for non-verbal intellectual functioning; Lovaas versus Developmental Individual-difference relationship-based intervention for communication skills; computer assisted instruction versus no treatment for facial expression recognition; and TEACCH versus standard care for imitation skills and eye-hand integration. Conclusions While this review suggests that Lovaas may improve some core symptoms of ASD compared to special education, these findings are based on pooling of a few, methodologically weak studies with few participants and relatively short-term follow-up. As no definitive behavioural or developmental intervention improves all symptoms for all individuals with ASD, it is recommended that clinical management be guided by individual needs and availability of resources.

Benefits and Harms of Treating Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research

Left ventricular (LV) systolic dysfunction carries a high risk for sudden cardiac death (1). Implantable cardioverter defibrillators (ICDs) can potentially mitigate this risk by delivering rapid life-saving therapy and have been substantially refined since their initial development in the late 1970s (2). Randomized, controlled trials (RCTs) have tested the efficacy of ICDs in high-risk individuals. We previously reported a systematic review of 8 RCTs (3 RCTs of secondary prevention in survivors of sudden cardiac death; 5 RCTs of primary prevention in patients without a history of ventricular arrhythmias) demonstrating a 26% reduction in all-cause mortality and a 57% reduction in sudden cardiac death with ICDs (3). Since then, additional RCTs of primary prevention have been published, and questions have arisen about the generalizability of the RCT results for ICDs to clinical practice. In particular, it is uncertain whether the benefits of ICDs seen in the trials extend to nontrial populations and whether the risks associated with ICDs may be higher in clinical practice than reported in trials. Given the public policy implications, we extended our previous systematic review of the efficacy (that is, the risks and benefits of a therapy when tested under ideal circumstances) (4) of ICDs in patients with LV systolic dysfunction by updating it with recently published RCTs that examined efficacy. In addition, we expanded the review to include data from observational studies to determine the effectiveness (that is, the risks and benefits of a therapy when tested under usual clinical practice conditions) and safety of ICDs when used in clinical practice. Methods A study protocol meeting Cochrane criteria, including all of the elements described briefly in the following sections, was developed and followed by the study authors in conjunction with the Agency for Healthcare Research and Quality (AHRQ). Search Strategy We sought studies published between 1980 and 27 April 2007 by searching MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, EMBASE, Science Citation Index Expanded (via Web of Science), International Pharmaceutical Abstracts, PubMed, National Library of Medicine Gateway, OCLC ProceedingsFirst and PapersFirst, Computer Retrieval of Information on Scientific Projects, various trial registries (including the National Research Register [United Kingdom], Australian Clinical Trials Registry, ClinicalTrials.gov, and Current Controlled Trials), and U.S. Food and Drug Administration reports. In addition, we hand-searched abstracts from the annual Heart Rhythm Society meetings and the reference lists of review articles and included studies; we also contacted authors of included studies for additional citations and information. Unpublished studies and individual-patient data were sought from device manufacturers, including Medtronic (Minneapolis, Minnesota), Guidant Corp. (Indianapolis, Indiana), and St. Jude Medical (St. Paul, Minnesota). The search was not limited by language or publication status. The search terms included Medtronic InSync, ELA medical, Guidant, St. Jude, implantable defibrillators, implantable cardioverter defibrillators, AICD, ICD, single chamber ICD, dual chamber ICD, congestive heart failure, CHF, chronic heart failure, and heart diseases. A full list of search strategies (adapted for each database) and search results are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). Study Selection We selected original research studies that had at least 25 participants and reported mortality or peri- or postimplantation complications with ICDs in adult patients with LV systolic dysfunction (left ventricular ejection fraction [LVEF]0.35, regardless of whether the patients had heart failure symptoms). To address efficacy questions, we restricted the analyses to RCTs. To address effectiveness questions, we expanded our inclusion criteria to include observational studies with contemporaneous comparison groups (such as cohort studies) and RCTs that did not report efficacy outcomes. To address safety questions, we included evidence from both RCTs and observational studies (including those without contemporaneous control groups, such as case series and registry data). Data Extraction and Analysis Study selection, quality assessment, and data extraction were completed by several investigators in duplicate and independently, using the methods recommended by the Quality of Reporting of Meta-analyses (QUOROM) group (6). We assessed quality by using the methods of Schulz and colleagues (7), the 5-item Jadad scale (8), and the 27-point Downs and Black scale (9). Publication bias was assessed visually by using funnel plots and quantitatively by using the rank correlation test (10), the graphical test (11), and the trim-and-fill method (12). Random-effects models were used to calculate pooled relative risks (RRs) in Review Manager 4.2.5 (Cochrane Collaboration, Copenhagen, Denmark). The length of study follow-up versus all-cause mortality was plotted for each study, and inverse varianceweighted least-squares regression was used to create a best-fit line. Postimplantation complications were expressed per 100 patient-years (calculated by multiplying the frequency of events in each study by the duration of follow-up, and standardizing to a denominator of 100) and are unadjusted rates. All results were reported with 95% CIs and, where appropriate, SDs or SEs. Statistical heterogeneity was quantified by using the I 2 statistic (13). In addition to examining for differences in point estimates across study designs and study quality, we explored device efficacy in different patient subgroups by using meta-regression. Covariates tested included presence of cardiac resynchronization therapy, length of follow-up, ischemic etiology, New York Heart Association (NYHA) class, age, QRS interval, LVEF, and primary versus secondary prevention. Role of the Funding Source The funding source (AHRQ, U.S. Department of Health and Human Services) had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Literature Search From 4439 citations (Figure 1), we identified 12 RCTs (8516 patients) for the ICD efficacy review (1426), 53 studies (26840 patients from 5 nonefficacy RCTs and 48 observational studies [25 retrospective and 23 prospective]) for the ICD effectiveness review (2778), and 64 studies (86809 patients from 11 efficacy RCTs, 10 RCTs without efficacy outcomes, and 43 observational studies [24 retrospective and 19 prospective]) for the ICD safety review (1417, 1927, 29, 30, 34, 3740, 4245, 47, 48, 52, 54, 60, 61, 6366, 69, 70, 7275, 78101). A full list of search strategies, search results, detailed quality assessments for each included study, and tests for publication bias are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). No publication bias was seen on the funnel plots. Figure 1. Flow diagram of study identification and selection. RCTs with Efficacy Data The 12 efficacy RCTs varied in quality (ranging from 1 to 3 on the Jadad scale) and duration (ranging from 15 to 66 months). All but 2 trials (16, 19) evaluated single-chamber ICDs (although no trials reported protocol adherence to single-chamber vs. dual-chamber ICDs). All patients in the RCTs had LV systolic dysfunction: Mean LVEF ranged from 0.21 to 0.28 in the primary prevention trials and from 0.32 to 0.46 in the secondary prevention trials. Most patients also had symptoms of heart failure: 50% had NYHA class II symptoms at baseline; 36%, class III symptoms; and 3%, class IV symptoms. Eleven percent of trial participants were in NYHA class I at baseline (Appendix Table 1). The mean age of RCT participants was 61 years (SD, 4), 74% were male, and 59% had ischemic heart disease. Appendix Table 1. Description of Randomized Trials Included in the Review Use of ICDs reduced all-cause mortality in patients with LV systolic dysfunction by 20% (95% CI, 10% to 29%; I 2= 44.4%) (Figure 2), largely because of a 54% relative reduction (CI, 37% to 63%; I 2= 0%) in sudden cardiac deaths. In patients with LV systolic dysfunction, ICDs were equally beneficial in reducing all-cause mortality in both primary prevention trials (RR, 0.81 [CI, 0.69 to 0.95]; I 2= 53.1% across 9 RCTs) and secondary prevention trials (RR, 0.77 [CI, 0.65 to 0.91]; I 2= 13.2% across 3 RCTs) (P for this indirect comparison= 0.56). Figure 2. Effect of implantable cardioverter defibrillator ( ICDs ) on all-cause mortality in randomized trials. A single trial included cardiac resynchronization therapy in both study groups for its comparison of ICDs versus control (19). All-cause mortality (RR, 0.83 [CI, 0.66 to 1.05]) was similar to that reported from the remainder of the studies, which did not contain cardiac resynchronization therapy in either study group (RR, 0.79 [CI, 0.69 to 0.91]) (P for indirect comparison= 0.92). Only 1 trial reported a statistically significant difference in the effect of ICDs across NYHA classes: The mortality benefits were greater in patients with NYHA class II symptoms than in those with NYHA class III symptoms in the Sudden Cardiac Death in Heart Failure Trial (P< 0.001 for interaction term of NYHA class and mortality) (22). In a series of univariate meta-regression sensitivity analyses, none of the covariates we examined (duration of follow-up, primary vs. secondary prevention, ischemic cause, presence of cardiac resynchronization therapy, NYHA class, mean age, mean LVEF, or mean QRS duration) contributed to the moderate statistical heterogeneity observed in our meta-analysis of all-cause mortality. In addition, our estimate of treatment effect was not associated with study quality. Implantable cardioverter defibrillators

Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers

BACKGROUND Outcomes of treating gestational diabetes mellitus (GDM) are not well-established. PURPOSE To summarize evidence about the maternal and neonatal benefits and harms of treating GDM. DATA SOURCES 15 electronic databases from 1995 to May 2012, gray literature, Web sites of relevant organizations, trial registries, and reference lists. STUDY SELECTION English-language randomized, controlled trials (n = 5) and cohort studies (n = 6) of women without known preexisting diabetes. DATA EXTRACTION One reviewer extracted data, and a second reviewer verified them. Two reviewers independently assessed methodological quality and evaluated strength of evidence for primary outcomes by using a Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS All studies compared diet modification, glucose monitoring, and insulin as needed with no treatment. Women who were treated had more prenatal visits than those in control groups. Moderate evidence showed fewer cases of preeclampsia, shoulder dystocia, and macrosomia in the treated group. Evidence was insufficient for maternal weight gain and birth injury. Low evidence showed no difference between groups for neonatal hypoglycemia. Evidence was insufficient for long-term metabolic outcomes among offspring. No difference was found for cesarean delivery (low evidence), induction of labor (insufficient evidence), small-for-gestational-age neonates (moderate evidence), or admission to a neonatal intensive care unit (low evidence). LIMITATIONS Evidence is low or insufficient for many outcomes of greatest clinical importance. The strongest evidence supports reductions in intermediate outcomes; however, other factors (for example, maternal weight and gestational weight gain) may impart greater risk than GDM, particularly when glucose levels are modestly elevated. CONCLUSION Treating GDM results in less preeclampsia, shoulder dystocia, and macrosomia; however, current evidence does not show an effect on neonatal hypoglycemia or future poor metabolic outcomes. There is little evidence of short-term harm of treating GDM other than an increased demand for services.

Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis.

OBJECTIVES To assess inter-rater reliability and validity of the Newcastle Ottawa Scale (NOS) used for methodological quality assessment of cohort studies included in systematic reviews. STUDY DESIGN AND SETTING Two reviewers independently applied the NOS to 131 cohort studies included in eight meta-analyses. Inter-rater reliability was calculated using kappa (κ) statistics. To assess validity, within each meta-analysis, we generated a ratio of pooled estimates for each quality domain. Using a random-effects model, the ratios of odds ratios for each meta-analysis were combined to give an overall estimate of differences in effect estimates. RESULTS Inter-rater reliability varied from substantial for length of follow-up (κ = 0.68, 95% confidence interval [CI] = 0.47, 0.89) to poor for selection of the nonexposed cohort and demonstration that the outcome was not present at the outset of the study (κ = -0.03, 95% CI = -0.06, 0.00; κ = -0.06, 95% CI = -0.20, 0.07). Reliability for overall score was fair (κ = 0.29, 95% CI = 0.10, 0.47). In general, reviewers found the tool difficult to use and the decision rules vague even with additional information provided as part of this study. We found no association between individual items or overall score and effect estimates. CONCLUSION Variable agreement and lack of evidence that the NOS can identify studies with biased results underscore the need for revisions and more detailed guidance for systematic reviewers using the NOS.

Systematic review of biomarkers of brain injury in term neonatal encephalopathy.

Objective To evaluate and compare the efficacy and safety of bronchodilators and steroids, alone or combined, for the acute management of bronchiolitis in children aged less than 2 years. Design Systematic review and meta-analysis. Data sources Medline, Embase, Central, Scopus, PubMed, LILACS, IranMedEx, conference proceedings, and trial registers. Inclusion criteria Randomised controlled trials of children aged 24 months or less with a first episode of bronchiolitis with wheezing comparing any bronchodilator or steroid, alone or combined, with placebo or another intervention (other bronchodilator, other steroid, standard care). Review methods Two reviewers assessed studies for inclusion and risk of bias and extracted data. Primary outcomes were selected by clinicians a priori based on clinical relevance: rate of admission for outpatients (day 1 and up to day 7) and length of stay for inpatients. Direct meta-analyses were carried out using random effects models. A mixed treatment comparison using a Bayesian network model was used to compare all interventions simultaneously. Results 48 trials (4897 patients, 13 comparisons) were included. Risk of bias was low in 17% (n=8), unclear in 52% (n=25), and high in 31% (n=15). Only adrenaline (epinephrine) reduced admissions on day 1 (compared with placebo: pooled risk ratio 0.67, 95% confidence interval 0.50 to 0.89; number needed to treat 15, 95% confidence interval 10 to 45 for a baseline risk of 20%; 920 patients). Unadjusted results from a single large trial with low risk of bias showed that combined dexamethasone and adrenaline reduced admissions on day 7 (risk ratio 0.65, 0.44 to 0.95; number needed to treat 11, 7 to 76 for a baseline risk of 26%; 400 patients). A mixed treatment comparison supported adrenaline alone or combined with steroids as the preferred treatments for outpatients (probability of being the best treatment based on admissions at day 1 were 45% and 39%, respectively). The incidence of reported harms did not differ. None of the interventions examined showed clear efficacy for length of stay among inpatients. Conclusions Evidence shows the effectiveness and superiority of adrenaline for outcomes of most clinical relevance among outpatients with acute bronchiolitis, and evidence from a single precise trial for combined adrenaline and dexamethasone.