A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

BACKGROUND: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known. METHODS: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA. RESULTS: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively). CONCLUSIONS: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02933697.

Impact of impaired fractional flow reserve after coronary interventions on outcomes: a systematic review and meta-analysis.

BACKGROUND: FFR is routinely used to guide percutaneous coronary interventions (PCI). Visual assessment of the angiographic result after PCI has limited efficacy. Even when the angiographic result seems satisfactory FFR after a PCI might be useful for identifying patients with a suboptimal interventional result and higher risk for poor clinical outcome who might benefit from additional procedures. The aim of this meta-analysis was to investigate available data of studies that examined clinical outcomes of patients with impaired vs. satisfactory fractional flow reserve (FFR) after percutaneous coronary interventions (PCI). METHODS: This meta-analysis was carried out according to the Cochrane Handbook for Systematic Reviews. The Mantel-Haenszel method using the fixed-effect meta-analysis model was used for combining the results. Studies were identified by searching the literature through mid-January, 2016, using the following search terms: fractional flow reserve, coronary circulation, after, percutaneous coronary intervention, balloon angioplasty, stent implantation, and stenting. Primary endpoint was the rate of major adverse cardiac events (MACE). Secondary endpoints included rates of death, myocardial infarction (MI), repeated revascularisation. RESULTS: Eight relevant studies were found including a total of 1337 patients. Of those, 492 (36.8 %) had an impaired FFR after PCI, and 853 (63.2 %) had a satisfactory FFR after PCI. Odds ratios indicated that a low FFR following PCI was associated with an impaired outcome: major adverse cardiac events (MACE, OR: 4.95, 95 % confidence interval [CI]: 3.39-7.22, p <0.001); death (OR: 3.23, 95 % CI: 1.19-8.76, p = 0.022); myocardial infarction (OR: 13.83, 95 % CI: 4.75-40.24, p <0.0001) and repeated revascularisation (OR: 4.42, 95 % CI: 2.73-7.15, p <0.0001). CONCLUSIONS: Compared to a satisfactory FFR, a persistently low FFR following PCI is associated with a worse clinical outcome. Prospective studies are needed to identify underlying causes, determine an optimal threshold for post-PCI FFR, and clarify whether simple additional procedures can influence the post-PCI FFR and clinical outcome.

Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta-analysis with few studies.

BACKGROUND: Random-effects meta-analysis is commonly performed by first deriving an estimate of the between-study variation, the heterogeneity, and subsequently using this as the basis for combining results, i.e., for estimating the effect, the figure of primary interest. The heterogeneity variance estimate however is commonly associated with substantial uncertainty, especially in contexts where there are only few studies available, such as in small populations and rare diseases. METHODS: Confidence intervals and tests for the effect may be constructed via a simple normal approximation, or via a Student-t distribution, using the Hartung-Knapp-Sidik-Jonkman (HKSJ) approach, which additionally uses a refined estimator of variance of the effect estimator. The modified Knapp-Hartung method (mKH) applies an ad hoc correction and has been proposed to prevent counterintuitive effects and to yield more conservative inference. We performed a simulation study to investigate the behaviour of the standard HKSJ and modified mKH procedures in a range of circumstances, with a focus on the common case of meta-analysis based on only a few studies. RESULTS: The standard HKSJ procedure works well when the treatment effect estimates to be combined are of comparable precision, but nominal error levels are exceeded when standard errors vary considerably between studies (e.g. due to variations in study size). Application of the modification on the other hand yields more conservative results with error rates closer to the nominal level. Differences are most pronounced in the common case of few studies of varying size or precision. CONCLUSIONS: Use of the modified mKH procedure is recommended, especially when only a few studies contribute to the meta-analysis and the involved studies' precisions (standard errors) vary.

Meta-analysis on occupational exposure to pesticides--neurobehavioral impact and dose-response relationships.

While the health impact of high exposures to pesticides is acknowledged, the impact of chronic exposures in the absence of acute poisonings is controversial. A systematic analysis of dose-response relationships is still missing. Its absence may provoke alternative explanations for altered performances. Consequently, opportunities for health prevention in the occupational and environmental field may be missed. Objectives were (1) quantification of the neurotoxic impact of pesticides by an analysis of functional alterations in workers measured by neuropsychological performance tests, (2) estimates of dose-response relationships on the basis of exposure duration, and (3) exploration of susceptible subgroups. The meta-analysis employed a random effects model to obtain overall effects for individual performance tests. Twenty-two studies with a total of 1758 exposed and 1260 reference individuals met the inclusion criteria. At least three independent outcomes were available for twenty-six performance variables. Significant performance effects were shown in adults and referred to both cognitive and motor performances. Effect sizes ranging from dRE=-0.14 to dRE=-0.67 showed consistent outcomes for memory and attention. Relationships between effect sizes and exposure duration were indicated for individual performance variables and the total of measured performances. Studies on adolescents had to be analyzed separately due to numerous outliers. The large variation among outcomes hampered the analysis of the susceptibility in this group, while data on female workers was too scant for the analysis. Relationships exist between the impact of pesticides on performances and exposure duration. A change in test paradigms would help to decipher the impact more specifically. The use of biomarkers appropriate for lower exposures would allow a better prevention of neurotoxic effects due to occupational and environmental exposure. Intervention studies in adolescents seem warranted to specify their risk.

The impact of the coronary collateral circulation on mortality: a meta-analysis.

AIMS: The coronary collateral circulation as an alternative source of blood supply has shown benefits regarding several clinical endpoints in patients with myocardial infarction (MI) such as infarct size and left ventricular remodelling. However, its impact on hard endpoints such as mortality and its impact in patients with stable coronary artery disease (CAD) is more controversial. The purpose of this systematic review and meta-analysis was to explore the impact of collateral circulation on all-cause mortality. METHODS AND RESULTS: We searched MEDLINE, EMBASE, ISI Web of Science (2001 to 25 April 2011), and conference proceedings for studies evaluating the effect of coronary collaterals on mortality. Random-effect models were used to calculate summary risk ratios (RR). A total of 12 studies enrolling 6529 participants were included in this analysis. Patients with high collateralization showed a reduced mortality compared with those with low collateralization [RR 0.64 (95% confidence interval 0.45-0.91); P= 0.012]. The RR for 'high collateralization' in patients with stable CAD was 0.59 [0.39-0.89], P= 0.012, in patients with subacute MI it was 0.53 [0.15-1.92]; P= 0.335, and for patients with acute MI it was 0.63 [0.29-1.39]; P= 0.257. CONCLUSIONS: In patients with CAD, the coronary collateralization has a relevant protective effect. Patients with a high collateralization have a 36% reduced mortality risk compared with patients with low collateralization.

Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis.

BACKGROUND: The benefit of the coronary collateral circulation (natural bypass network) on survival is well established. However, data derived from smaller studies indicates that coronary collaterals may increase the risk for restenosis after percutaneous coronary interventions. The purpose of this systematic review and meta-analysis of observational studies was to explore the impact of the collateral circulation on the risk for restenosis. METHODS: We searched the MEDLINE, EMBASE and ISI Web of Science databases (2001 to 15 July 2011). Random effects models were used to calculate summary risk ratios (RR) for restenosis. The primary endpoint was angiographic restenosis > 50%. RESULTS: A total of 7 studies enrolling 1,425 subjects were integrated in this analysis. On average across studies, the presence of a good collateralization was predictive for restenosis (risk ratio (RR) 1.40 (95% CI 1.09 to 1.80); P = 0.009). This risk ratio was consistent in the subgroup analyses where collateralization was assessed with intracoronary pressure measurements (RR 1.37 (95% CI 1.03 to 1.83); P = 0.038) versus visual assessment (RR 1.41 (95% CI 1.00 to 1.99); P = 0.049). For the subgroup of patients with stable coronary artery disease (CAD), the RR for restenosis with 'good collaterals' was 1.64 (95% CI 1.14 to 2.35) compared to 'poor collaterals' (P = 0.008). For patients with acute myocardial infarction, however, the RR for restenosis with 'good collateralization' was only 1.23 (95% CI 0.89 to 1.69); P = 0.212. CONCLUSIONS: The risk of restenosis after percutaneous coronary intervention (PCI) is increased in patients with good coronary collateralization. Assessment of the coronary collateral circulation before PCI may be useful for risk stratification and for the choice of antiproliferative measures (drug-eluting stent instead bare-metal stent, cilostazol).

Interval estimation of the overall treatment effect in random-effects meta-analyses: Recommendations from a simulation study comparing frequentist, Bayesian, and bootstrap methods.

There exists a variety of interval estimators for the overall treatment effect in a random-effects meta-analysis. A recent literature review summarizing existing methods suggested that in most situations, the Hartung-Knapp/Sidik-Jonkman (HKSJ) method was preferable. However, a quantitative comparison of those methods in a common simulation study is still lacking. Thus, we conduct such a simulation study for continuous and binary outcomes, focusing on the medical field for application. Based on the literature review and some new theoretical considerations, a practicable number of interval estimators is selected for this comparison: the classical normal-approximation interval using the DerSimonian-Laird heterogeneity estimator, the HKSJ interval using either the Paule-Mandel or the Sidik-Jonkman heterogeneity estimator, the Skovgaard higher-order profile likelihood interval, a parametric bootstrap interval, and a Bayesian interval using different priors. We evaluate the performance measures (coverage and interval length) at specific points in the parameter space, that is, not averaging over a prior distribution. In this sense, our study is conducted from a frequentist point of view. We confirm the main finding of the literature review, the general recommendation of the HKSJ method (here with the Sidik-Jonkman heterogeneity estimator). For meta-analyses including only two studies, the high length of the HKSJ interval limits its practical usage. In this case, the Bayesian interval using a weakly informative prior for the heterogeneity may help. Our recommendations are illustrated using a real-world meta-analysis dealing with the efficacy of an intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting.

Do Intervention Studies to Promote Physical Activity and Reduce Sedentary Behavior in Children and Adolescents Take Sex/Gender Into Account? A Systematic Review.

BACKGROUND: Physical inactivity is often reported in youth and differs among boys and girls. The aim of this study is to assess sex/gender considerations in intervention studies promoting physical activity and reducing sedentary behavior in youth using a sex/gender checklist. METHODS: A systematic search was conducted in August 2018 to identify all relevant controlled trials. Studies screened must have reported a quantified measure of physical activity and/or sedentary behavior, and identified participants by sex/gender at baseline. For evaluation of the sex/gender consideration, the authors used a sex/gender checklist developed by expert consensus. RESULTS: The authors reviewed sex/gender considerations in all aspects of intervention development, implementation, and evaluation in 217 studies. Sex/gender aspects were only rudimentarily taken into account, most frequently during statistical analyses, such as stratification or interaction analysis. CONCLUSIONS: Sex/gender effects are not sufficiently reported. To develop guidelines that are more inclusive of all girls and boys, future interventions need to document sex/gender differences and similarities, and explore whether sex/gender influences different phases of intervention programs. The newly developed sex/gender checklist can hereby be used as a tool and guidance to adequately consider sex/gender in the several steps of intervention planning, implementation, and evaluation.

Chest compressions before defibrillation for out-of-hospital cardiac arrest: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: Current 2005 guidelines for advanced cardiac life support strongly recommend immediate defibrillation for out-of-hospital cardiac arrest. However, findings from experimental and clinical studies have indicated a potential advantage of pretreatment with chest compression-only cardiopulmonary resuscitation (CPR) prior to defibrillation in improving outcomes. The aim of this meta-analysis is to evaluate the beneficial effect of chest compression-first versus defibrillation-first on survival in patients with out-of-hospital cardiac arrest. METHODS: Main outcome measures were survival to hospital discharge (primary endpoint), return of spontaneous circulation (ROSC), neurologic outcome and long-term survival. Randomized, controlled clinical trials that were published between January 1, 1950, and June 19, 2010, were identified by a computerized search using SCOPUS, MEDLINE, BIOS, EMBASE, the Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts database, and Web of Science and supplemented by conference proceedings. Random effects models were used to calculate pooled odds ratios (ORs). A subgroup analysis was conducted to explore the effects of response interval greater than 5 min on outcomes. RESULTS: A total of four trials enrolling 1503 subjects were integrated into this analysis. No difference was found between chest compression-first versus defibrillation-first in the rate of return of spontaneous circulation (OR 1.01 [0.82-1.26]; P = 0.979), survival to hospital discharge (OR 1.10 [0.70-1.70]; P = 0.686) or favorable neurologic outcomes (OR 1.02 [0.31-3.38]; P = 0.979). For 1-year survival, however, the OR point estimates favored chest compression first (OR 1.38 [0.95-2.02]; P = 0.092) but the 95% CI crossed 1.0, suggesting insufficient estimate precision. Similarly, for cases with prolonged response times (> 5 min) point estimates pointed toward superiority of chest compression first (OR 1.45 [0.66-3.20]; P = 0.353), but the 95% CI again crossed 1.0. CONCLUSIONS: Current evidence does not support the notion that chest compression first prior to defibrillation improves the outcome of patients in out-of-hospital cardiac arrest. It appears that both treatments are equivalent. However, subgroup analyses indicate that chest compression first may be beneficial for cardiac arrests with a prolonged response time.

Zero-cell corrections in random-effects meta-analyses.

The standard estimator for the log odds ratio (the unconditional maximum likelihood estimator) and the delta-method estimator for its standard error are not defined if the corresponding 2 × 2 table contains at least one "zero cell". This is also an issue when estimating the overall log odds ratio in a meta-analysis. It is well known that correcting for zero cells by adding a small increment should be avoided. Nevertheless, these zero-cell corrections continue to be used. With this Brief Method Note, we want to warn of a particularly bad zero-cell correction. For this, we conduct a simulation study comparing the following two zero-cell corrections under the ordinary random-effects model: (a) adding 1 2 to all cells of all the individual studies' 2 × 2 tables independently of any zero-cell occurrences and (b) adding 1 2 to all cells of only those 2 × 2 tables containing at least one zero cell. The main finding is that correction (a) performs worse than correction (b). Thus, we strongly discourage the use of correction (a).

Methods to calculate uncertainty in the estimated overall effect size from a random-effects meta-analysis.

Meta-analyses are an important tool within systematic reviews to estimate the overall effect size and its confidence interval for an outcome of interest. If heterogeneity between the results of the relevant studies is anticipated, then a random-effects model is often preferred for analysis. In this model, a prediction interval for the true effect in a new study also provides additional useful information. However, the DerSimonian and Laird method-frequently used as the default method for meta-analyses with random effects-has been long challenged due to its unfavorable statistical properties. Several alternative methods have been proposed that may have better statistical properties in specific scenarios. In this paper, we aim to provide a comprehensive overview of available methods for calculating point estimates, confidence intervals, and prediction intervals for the overall effect size under the random-effects model. We indicate whether some methods are preferable than others by considering the results of comparative simulation and real-life data studies.

Interventions on children's and adolescents' physical activity and sedentary behaviour: protocol for a systematic review from a sex/gender perspective.

BACKGROUND: Low levels of physical activity (PA) and high levels of sedentary behaviour (SB) have been observed in young people. Both behaviours are detrimental for health with patterns tending to continue into adulthood. There is sustained value in establishing health habits in early years. Even though levels of SB and participation in PA differ among boys and girls, and the effectiveness of interventions to promote PA and/or prevent sedentary behaviours varies by sex/gender to date, sex/gender in systematic reviews is not yet widely considered. Additionally, while tools have been proposed, there is no consensus on the criteria to assess sex/gender in systematic reviews in the context of health promotion. The main objectives of this systematic review are to evaluate the effects of interventions on girls' and boys' PA and SB and to appraise the extent to which the studies have taken sex/gender into account. METHODS: Eleven electronic databases will be searched to identify all relevant (randomized) controlled trials. Two independent reviewers will screen studies, extract data and appraise the quality of studies. The main outcome of the studies will be a quantified measure of PA and/or SB. Risk of bias of individual studies will be assessed using the Cochrane Risk of Bias Tool for RCTs. Meta-analyses will be conducted when possible among studies with sufficient homogeneity. To evaluate sex/gender considerations in primary studies, we will use a sex/gender checklist that builds on existing tools and was developed during a 2-day, iterative process among a multidisciplinary panel of 16 experts. The GRADE framework will be used to evaluate evidence across studies for each main efficacy outcome. DISCUSSION: To our knowledge, our systematic review will be the first to analyse how sex/gender is considered in interventions promoting PA and/or reducing SB in children and adolescents in detail. The review will provide information on how sex/gender aspects have been considered in recent research and the extent to which sex/gender might impact study outcomes. Our findings will be of interest to stakeholders, health promoters, researchers and policy makers who wish to support more equal outcomes from interventions promoting PA and/or reducing SB. TRIAL REGISTRATION: PROSPERO CRD42018109528 .

The impact of solvent mixtures on neurobehavioral performance: conclusions from epidemiological data.

The review of epidemiological studies investigating the neurobehavioral effects of occupational exposure to solvent mixtures sought to contribute to the following issues: (1) Identification of affected cognitive and motor functions. (2) Identification of sensitive neuropsychological tests. (3) Analysis of exposure-effect relationships. The approach was based on the meta-analytical method of effect size estimates. Fifty-three groups from occupational studies were included in the meta-analysis. Forty-eight neuropsychological performance variables could be analyzed as they were included in at least three studies. Seventeen articles provided detailed information on the constituents of mixtures, thereby enabling the computation of an exposure index that allowed the comparison of different mixtures. Significant negative effect sizes were obtained for 12 test variables measuring attention, memory, motor performance and constructional abilities. The greatest proportion of lower performance scores in the exposed groups was shown by different tests of attention: significant effect sizes between d=-0.16 and -0.46 were calculated. Tests of cognitive processing speed, response alternation and inhibition seemed to be sensitive tools for the detection of poorer performance. Exposure-effect relationships were mainly characterized by inconsistent patterns. Crude and inappropriately calculated exposure measures were blamed for this outcome. A healthy worker effect was suggested more consistently: studies examining groups with longer exposure duration obtained smaller effect sizes. Indications of confounding were observed; however, they did not seem sufficient to question consistent effect size patterns. Paying greater attention to the measurement of exposure and including measures of confounding is advisable for future studies and would enhance the explanatory power of cross-sectional studies and meta-analyses.

Effects of Exercise on the Resting Heart Rate: A Systematic Review and Meta-Analysis of Interventional Studies.

Resting heart rate (RHR) is positively related with mortality. Regular exercise causes a reduction in RHR. The aim of the systematic review was to assess whether regular exercise or sports have an impact on the RHR in healthy subjects by taking different types of sports into account. A systematic literature research was conducted in six databases for the identification of controlled trials dealing with the effects of exercise or sports on the RHR in healthy subjects was performed. The studies were summarized by meta-analyses. The literature search analyzed 191 studies presenting 215 samples fitting the eligibility criteria. 121 trials examined the effects of endurance training, 43 strength training, 15 combined endurance and strength training, 5 additional school sport programs. 21 yoga, 5 tai chi, 3 qigong, and 2 unspecified types of sports. All types of sports decreased the RHR. However, only endurance training and yoga significantly decreased the RHR in both sexes. The exercise-induced decreases of RHR were positively related with the pre-interventional RHR and negatively with the average age of the participants. From this, we can conclude that exercise-especially endurance training and yoga-decreases RHR. This effect may contribute to a reduction in all-cause mortality due to regular exercise or sports.

Physical Activity and Outdoor Play of Children in Public Playgrounds-Do Gender and Social Environment Matter?

BACKGROUND: Few studies have delved into the relationship of the social environment with children’s physical activity and outdoor play in public playgrounds by considering gender differences. The aim of the present study was to examine gender differences and the relationship of the social environment with children’s physical activity and outdoor play in public playgrounds. METHODS: A quantitative, observational study was conducted at ten playgrounds in one district of a middle-sized town in Germany. The social environment, physical activity levels, and outdoor play were measured using a modified version of the System for Observing Play and Leisure Activity in Youth. RESULTS: In total, 266 observations of children (117 girls/149 boys) between four and 12 years old were used in this analysis. Significant gender differences were found in relation to activity types, but not in moderate-to-vigorous physical activity (MVPA). The presence of active children was the main explanatory variable for MVPA. In the models stratified by gender, the presence of opposite-sex children was a significant negative predictor of MVPA in girls but not in boys. CONCLUSIONS: The presence of active children contributes to children’s physical activity levels in public playgrounds. Girls’ physical activity seems to be suppressed in the presence of boys.

Occupational aluminum exposure: evidence in support of its neurobehavioral impact.

Aluminum is a metal with known neurotoxic properties which are linked to encephalopathy and neurodegenerative diseases. The objectives of the current meta-analysis study were: (1) to summarize neurobehavioral data obtained by epidemiological studies in occupational settings and (2) to analyze confounding within these data. The meta-analysis was based on estimates of effect sizes. Overall effect sizes were obtained by application of a random effects model. The final sample consisted of nine studies examining 449 exposed and 315 control subjects. The mean urinary aluminum concentrations in the exposed groups ranged from 13 to 133 microg/l. Six neuropsychological tests, which yielded 10 performance variables, were analyzed. Nine overall effect sizes indicated an inferior performance for the exposed group. A significant overall effect size (d(RE)=-0.43) was obtained for the digit symbol test measuring speed-related components of cognitive and motor performance. Moreover, the individual effect sizes obtained for this test suggested an exposure-response relationship. Results obtained from either raw or adjusted mean scores revealed that confounding in the data could not be excluded. The results were compared to studies not included here due to a shortage of required data. Similarities were discussed in terms of sensitivity of the tests for detecting aluminum-related changes in brain function. There was concurring evidence from different studies that urinary Al concentrations below 135 microg/l have an impact on cognitive performance. The significant effect for the digit symbol might be related to its multifaceted character which requires functioning in different components of cognitive and motor performance. This feature could possibly turn the test into a screening instrument for neurobehavioral effects. However, additional studies are necessary to verify and to differentiate the effect of aluminum on cognitive performance. From a neuropsychological perspective, implicit and explicit memory, visuo-spatial and central odor processing should be examined. A measure of verbal intelligence should be included in order to address the influence of confounding. Internationally standardized exposure measures would enhance the comparability of studies.

Playground usage and physical activity levels of children based on playground spatial features.

AIM: Being outdoors is one of the strongest correlates of physical activity in children. Playgrounds are spaces especially designed to enable and foster physical activity in children. This study aimed to analyze the relationship between the spatial features of public playgrounds and the usage and physical activity levels of children playing in them. SUBJECTS AND METHODS: A quantitative, observational study was conducted of ten playgrounds in one district of a middle-sized town in Germany. Playground spatial features were captured using an audit instrument and the playground manual of the town. Playground usage and physical activity levels of children were assessed using a modified version of the System for Observing Play and Leisure Activity in Youth. Negative binomial models were used to analyze the count data. RESULTS: The number of children using the playgrounds and the number of children actively playing in them were higher in those with more varied facilities and without naturalness. Girls played more actively in playgrounds without multi-purpose areas. Cleanliness, esthetics, play facility quality, division of functional areas and playground size were not related to any outcome variable. CONCLUSION: Playground spatial features are related to playground usage and activity levels of the children in the playgrounds. Playgrounds should offer a wide variety of play facilities and provide spaces for diverse play activities to respond to the needs of large numbers of different children and to provide activity-friendly areas enabling their healthy development.

Methods to estimate the between-study variance and its uncertainty in meta-analysis.

Meta-analyses are typically used to estimate the overall/mean of an outcome of interest. However, inference about between-study variability, which is typically modelled using a between-study variance parameter, is usually an additional aim. The DerSimonian and Laird method, currently widely used by default to estimate the between-study variance, has been long challenged. Our aim is to identify known methods for estimation of the between-study variance and its corresponding uncertainty, and to summarise the simulation and empirical evidence that compares them. We identified 16 estimators for the between-study variance, seven methods to calculate confidence intervals, and several comparative studies. Simulation studies suggest that for both dichotomous and continuous data the estimator proposed by Paule and Mandel and for continuous data the restricted maximum likelihood estimator are better alternatives to estimate the between-study variance. Based on the scenarios and results presented in the published studies, we recommend the Q-profile method and the alternative approach based on a 'generalised Cochran between-study variance statistic' to compute corresponding confidence intervals around the resulting estimates. Our recommendations are based on a qualitative evaluation of the existing literature and expert consensus. Evidence-based recommendations require an extensive simulation study where all methods would be compared under the same scenarios.

Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis.

CONTEXT: The role of percutaneous closure of patent foramen oval (PFO) in patients with cryptogenic stroke has been very controversial for years due to a lack of clear evidence. OBJECTIVE: Systematic review and meta-analysis of the effect of percutaneous PFO closure for secondary prevention of cryptogenic strokes as compared to best medical therapy (BMT). DATA SOURCES: Trials were identified through a literature search until 28 May 2013. STUDY SELECTION: Controlled clinical trials (randomised and non-randomised) comparing percutaneous PFO closure with BMT. DATA EXTRACTION AND SYNTHESIS: Main end point of interest was stroke. A random effects model was used to calculate the pooled relative risks (RR) with 95% CIs. RESULTS: A total of 14 studies (three randomised controlled trials (RCT) and 11 non-randomised observational studies (non-RCT)), and a total of 4335 patients were included for this analysis. There was no significant treatment effect of PFO closure regarding stroke among the RCT (RR 0.66, 95% CI 0.37 to 1.19, p=0.171). However, among non-RCT stroke was reduced (RR 0.37, 95% CI 0.20 to 0.67, p<0.001) after PFO closure. A time-to-event (stroke) analysis, combining all three RCT and the two non-RCT which applied strict multivariate adjustments, showed a borderline significant risk reduction after PFO closure (HR 0.58, 95% CI 0.33 to 0.99, p=0.047). Neither risk of bleeding nor mortality differed significantly between the groups. However, there was a higher incidence of new onset atrial fibrillation in the closure group (RR 3.50, 95% CI 1.47 to 8.35, p=0.005). CONCLUSIONS: Percutaneous closure of PFO in patients with cryptogenic stroke does not appear superior to medical therapy according to currently available randomised data. Furthermore, it is associated with an increased incidence of atrial fibrillation. However, there are signals pointing towards a potential benefit and more research should be strongly encouraged.