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Background: Infants born at term by elective caesarean section are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications. It is unclear whether administration at term gestations, prior to caesarean section, improves the respiratory outcomes for these babies without causing any unnecessary morbidity to the mother or the infant., Objectives: The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual care (which could be placebo or no treatment), on fetal, neonatal and maternal morbidity. We also assessed the impact of the treatment on the child in later life., Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (20 January 2021) and reference lists of retrieved studies., Selection Criteria: We included randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation). Quasi-randomised and cluster-randomised controlled trials were also eligible for inclusion., Data Collection and Analysis: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness (based on predefined criteria developed by Cochrane Pregnancy and Childbirth), extracted data and checked them for accuracy and assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were respiratory distress syndrome (RDS), transient tachypnoea of the neonate (TTN), admission to neonatal special care for respiratory morbidity and need for mechanical ventilation. We planned to perform subgroup analyses for the primary outcomes according to gestational age at randomisation and type of corticosteroid (betamethasone or dexamethasone). We also planned to perform sensitivity analysis, including only studies at low risk of bias., Main Results: We included one trial in which participants were randomised to receive either betamethasone or usual care. The trial included 942 women and 942 neonates recruited from 10 UK hospitals between 1995 and 2002. This review includes only trials that met predefined criteria for trustworthiness. We removed three trials from the analysis that were included in the previous version of this review. The risk of bias was low for random sequence generation, allocation concealment and incomplete outcome data. The risk of bias for selective outcome reporting was unclear because there was no published trial protocol, and therefore it is unclear whether all the planned outcomes were reported in full. Due to a lack of blinding we judged there to be high risk of performance bias and detection bias. We downgraded the certainty of the evidence because of concerns about risk of bias and because of imprecision due to low event rates and wide 95% confidence intervals (CIs), which are consistent with possible benefit and possible harm Compared with usual care, it is uncertain if antenatal corticosteroids reduce the risk of RDS (relative risk (RR) 0.34 95% CI 0.07 to 1.65; 1 study; 942 infants) or TTN (RR 0.52, 95% CI 0.25 to 1.11; 1 study; 938 infants) because the certainty of evidence is low and the 95% CIs are consistent with possible benefit and possible harm. Antenatal corticosteroids probably reduce the risk of admission to neonatal special care for respiratory complications, compared with usual care (RR 0.45, 95% CI 0.22 to 0.90; 1 study; 942 infants; moderate-certainty evidence). The proportion of infants admitted to neonatal special care for respiratory morbidity after treatment with antenatal corticosteroids was 2.3% compared with 5.1% in the usual care group. It is uncertain if antenatal steroids have any effect on the risk of needing mechanical ventilation, compared with usual care (RR 4.07, 95% CI 0.46 to 36.27; 1 study; 942 infants; very low-certainty evidence). The effect of antenatal corticosteroids on the maternal development of postpartum infection/pyrexia in the first 72 hours is unclear due to the very low certainty of the evidence; one study (942 women) reported zero cases. The included studies did not report any data for neonatal hypoglycaemia or maternal mortality/severe mortality., Authors' Conclusions: Evidence from one randomised controlled trial suggests that prophylactic corticosteroids before elective caesarean section at term probably reduces admission to the neonatal intensive care unit for respiratory morbidity. It is uncertain if administration of antenatal corticosteroids reduces the rates of respiratory distress syndrome (RDS) or transient tachypnoea of the neonate (TTN). The overall certainty of the evidence for the primary outcomes was found to be low or very low, apart from the outcome of admission to neonatal special care (all levels) for respiratory morbidity, for which the evidence was of moderate certainty. Therefore, there is currently insufficient data to draw any firm conclusions.  More evidence is needed to investigate the effect of prophylactic antenatal corticosteroids on the incidence of recognised respiratory morbidity such as RDS. Any future trials should assess the balance between respiratory benefit and potential immediate adverse effects (e.g. hypoglycaemia) and long-term adverse effects (e.g. academic performance) for the infant. There is very limited information on maternal health outcomes to provide any assurances that corticosteroids do not pose any increased risk of harm to the mother.  Further research should consider investigating the effectiveness of antenatal steroids at different gestational ages prior to caesarean section. There are nine potentially eligible studies that are currently ongoing and could be included in future updates of this review., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: A key question concerning coronavirus disease 2019 (COVID-19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the risk of SARS-CoV-2 re-infections in the general population in Austria., Methods: This is a retrospective observational study using national SARS-CoV-2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS-CoV-2 re-infections of COVID-19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)-confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re-infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive., Results: We recorded 40 tentative re-infections in 14 840 COVID-19 survivors of the first wave (0.27%) and 253 581 infections in 8 885 640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13)., Conclusions: We observed a relatively low re-infection rate of SARS-CoV-2 in Austria. Protection against SARS-CoV-2 after natural infection is comparable with the highest available estimates on vaccine efficacies. Further well-designed research on this issue is urgently needed for improving evidence-based decisions on public health measures and vaccination strategies., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Infants born at term by elective caesarean section are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications., Objectives: The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications., Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register (14 June 2017), and reference lists of retrieved studies., Selection Criteria: Randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation)., Data Collection and Analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach., Main Results: We included four trials (3956 women and 3893 neonates) at a moderate risk of bias, comparing prophylactic administration of betamethasone or dexamethasone versus placebo or usual treatment without steroids in term elective caesarean section. Women randomised to treatment group received either two intramuscular doses of betamethasone in the 48 hours before delivery, or intramuscular dexamethasone (two or four doses) prior to delivery (at 37 weeks' gestation or 48 hours before delivery), and were compared to the control group who received a saline placebo or treatment as usual.Prophylactic antenatal corticosteroid administration appeared to decrease the risk of respiratory distress syndrome (RDS) (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.87; 4 studies; 3817 participants; low-quality evidence), transient tachypnoea of the neonate (TTN) (RR 0.43; 95% CI 0.29 to 0.65; 4 studies; 3821 participants; low-quality evidence), admission to the neonatal intensive care unit (NICU) for respiratory morbidity (RR 0.42; 95% CI 0.22 to 0.79; 3 studies; 3441 participants), and admission to neonatal special care (all levels) for respiratory complications (RR 0.45; 95% CI 0.22 to 0.90; 1 study; 942 participants; low-quality evidence). Administration of antenatal corticosteroids also appeared to reduce admission to neonatal special care (RR 0.62; 95% CI 0.43 to 0.89; 2 studies; 2169 participants) and neonatal intensive care (RR 0.14; 95% CI 0.03 to 0.61; 1 study; 452 participants) for any indication, compared to placebo or usual care. Finally, prophylactic antenatal corticosteroids also appeared to reduce the length of stay in NICU by 2.70 days (mean difference (MD) -2.70; 95% CI -2.76 to -2.64; 2 studies; 32 participants).No reduction was found in the need for mechanical ventilation (RR 0.67; 95% CI 0.27 to 1.68; 3 studies; 3441 participants; very-low quality), perinatal death (RR 0.67; 95% CI 0.11 to 4.10; 4 studies; 3893 participants) or neonatal sepsis (RR 1.00; 95% CI 0.06 to 15.95; 2 studies; 2214 participants) .There were no reported events of neonatal respiratory complications (other than RDS and tachypnoea of the newborn (TTN)), chronic lung disease, duration of mechanical ventilation or maternal postpartum infection, therefore results on these outcomes are non-estimable. The studies did not provide data on other pre-defined outcomes.The quality of evidence, as assessed using GRADE was low for the outcomes of RDS, TTN and admission to NICU for respiratory morbidity, indicating that the true effect could potentially be substantially different from our estimate of effect., Authors' Conclusions: The results from the four trials are promising, but more high-quality studies with larger sample sizes that are adequately powered to detect the effect of prophylactic antenatal corticosteroids on outcomes of respiratory morbidity are needed, given the potential of the current studies for bias. Consideration should be given to the balance between statistical significance and clinical significance, particularly in view of the low event rates of significant respiratory morbidity (RDS or admission to NICU for respiratory complications) in this population. In addition, further trials on the long-term outcomes of these infants are needed to identify any potential harms and complications of antenatal corticosteroid administration at term.

The central purpose of this study is to document how a sharper focus upon statistical power may reduce the impact of selective reporting bias in meta-analyses. We introduce the weighted average of the adequately powered (WAAP) as an alternative to the conventional random-effects (RE) estimator. When the results of some of the studies have been selected to be positive and statistically significant (i.e. selective reporting), our simulations show that WAAP will have smaller bias than RE at no loss to its other statistical properties. When there is no selective reporting, the difference between RE's and WAAP's statistical properties is practically negligible. Nonetheless, when selective reporting is especially severe or heterogeneity is very large, notable bias can remain in all weighted averages. The main limitation of this approach is that the majority of meta-analyses of medical research do not contain any studies with adequate power (i.e. >80%). For such areas of medical research, it remains important to document their low power, and, as we demonstrate, an alternative unrestricted weighted least squares weighted average can be used instead of WAAP. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objectives: To evaluate whether biases may influence the findings of whole-brain structural imaging literature., Methods: Forty-seven whole-brain voxel-based meta-analyses including voxel-based morphometry (VBM) studies in neuropsychiatric conditions were included, for a total of 324 individual VBM studies. The total sample size, the overall number of foci, and different moderators were extracted both at the level of the individual studies and at the level of the meta-analyses., Results: Sample size ranged from 12 to 545 (median n = 47) per VBM study. The median number of reported foci per study was six. VBM studies with larger sample sizes reported only slightly more abnormalities than smaller studies (2% increase in the number of foci per 10-patients increase in sample size). A similar pattern was seen in several analyses according to different moderator variables with some possible modulating evidence for the statistical threshold employed, publication year and number of coauthors. Whole-brain meta-analyses (median sample size n = 534) found fewer foci (median = 3) than single studies and overall they showed no significant increase in the number of foci with increasing sample size. Meta-analyses with ≥10 VBM studies reported a median of three foci and showed a significant increase with increasing sample size, while there was no relationship between sample size and number of foci (median = 5) in meta-analyses with <10 VBM studies., Conclusions: The number of foci reported in small VBM studies and even in meta-analyses with few studies may often be inflated. This picture is consistent with reporting biases affecting small studies., (Copyright © 2013 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA., Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant., Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened., Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated., (Copyright © 2014 by the American College of Rheumatology.)

A billion deaths from tobacco are expected by 2100. Many policy interventions such as increased taxation, restrictions on advertisement, smoking bans, as well as behavioral interventions, such as pharmacological and psychological treatments for smoking cessation, decrease tobacco use, but they reach their limits. Endgame scenarios focusing on tobacco supply rather than demand are increasingly discussed, but meet with resistance by the industry and even by many tobacco control experts. A main stumbling block that requires more attention is what to do with the tobacco industry in endgame scenarios. This industry has employed notoriously talented experts in law, business, organization, marketing, advertising, strategy, policy, and statistics and has tremendous lobbying power. Performance-based regulatory approaches can pose a legal obligation on manufacturers to decrease - and eventually - eliminate tobacco products according to specified schedules. Penalties and rewards can make such plans both beneficial for public health and attractive to the companies that do the job well. We discuss caveats and reality checks of engaging the tobacco industry to eliminate its current market and change focus. Brainstorming is warranted to entice the industry to abandon tobacco for other profit goals. To get the dialogue started, we propose the wild possibility of hiring former tobacco companies to reduce the costs of healthcare, thereby addressing concurrently two major challenges to public health., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

We have generated a list of highly influential biomedical researchers based on Scopus citation data from the period 1996-2011. Of the 15,153,100 author identifiers in Scopus, approximately 1% (n=149,655) have an h-index >=20. Of those, we selected 532 authors who belonged to the 400 with highest total citation count (>=25,142 citations) and/or the 400 with highest h-index (>=76). Of those, we selected the top-400 living core biomedical researchers based on a normalized score combining total citations and h-index. Another 62 authors whose focus is outside biomedicine had a normalized score that was at least as high as the score of the 400th core biomedical researcher. We provide information on the profile of these most influential authors, including the most common Medical Subject Heading terms in their articles that are also specific to their work, most common journals where they publish, number of papers with over 100 citations that they have published as first/single, last, or middle authors, and impact score adjusted for authorship positions, given that crude citation indices and authorship positions are almost totally orthogonal. We also show for each researcher the distribution of their papers across 4 main levels (basic-to-applied) of research. We discuss technical issues, limitations and caveats, comparisons against other lists of highly-cited researchers, and potential uses of this resource., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Expenditure on industry products (mostly drugs and devices) has spiraled over the last 15 years and accounts for substantial part of healthcare expenditure. The enormous financial interests involved in the development and marketing of drugs and devices may have given excessive power to these industries to influence medical research, policy, and practice., Material and Methods: Review of the literature and analysis of the multiple pathways through which the industry has directly or indirectly infiltrated the broader healthcare systems. We present the analysis of the industry influences at the following levels: (i) evidence base production, (ii) evidence synthesis, (iii) understanding of safety and harms issues, (iv) cost-effectiveness evaluation, (v) clinical practice guidelines formation, (vi) healthcare professional education, (vii) healthcare practice, (viii) healthcare consumer's decisions., Results: We located abundance of consistent evidence demonstrating that the industry has created means to intervene in all steps of the processes that determine healthcare research, strategy, expenditure, practice and education. As a result of these interferences, the benefits of drugs and other products are often exaggerated and their potential harms are downplayed, and clinical guidelines, medical practice, and healthcare expenditure decisions are biased., Conclusion: To serve its interests, the industry masterfully influences evidence base production, evidence synthesis, understanding of harms issues, cost-effectiveness evaluations, clinical practice guidelines and healthcare professional education and also exerts direct influences on professional decisions and health consumers. There is an urgent need for regulation and other action towards redefining the mission of medicine towards a more objective and patient-, population- and society-benefit direction that is free from conflict of interests., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by Blackwell Publishing Ltd.)

While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Systemic corticosteroids have been proposed for numerous indications and there are many claims that corticosteroids can reduce mortality in diverse conditions., Methods: We performed an umbrella, agenda-wide review of the evidence on systemic corticosteroids and mortality, focusing primarily on large trials (defined as those with > 100 deaths) and meta-analyses. Searches were performed in PubMed and Cochrane Central Register of Controlled Trials (last update February 2011). We also examined whether spurious subset analyses may be responsible for claims of survival benefits in indications where only small trials had been available., Results: Among 257 identified randomized trials with mortality data in their abstract, we found 14 large trials pertaining to 10 different indications. Although 10 of these 14 trials have reported statistically significant survival differences in subset analyses, none shows a nominally statistically significant (P < 0·05) decrease in death risk for any of the tested conditions when all deaths on all randomized patients are analysed. Meta-analyses for these conditions show statistically significant reductions in mortality only with antenatal corticosteroids for preterm labour (relative risk 0·77, 95% CI, 0·67-0·89) and in tuberculous meningitis (relative risk 0·78, 95% CI, 0·67-0·91). For conditions without any large trials, statistically significant reductions in mortality in meta-analyses were noted for Pneumocystis pneumonia (relative risk 0·54, 95% CI, 0·38-0·79) and alcoholic hepatitis (relative risk 0·63, 95% CI, 0·50-0·80). Many small trials that claim significant benefits, even those for classic indications such as typhoid fever and tetanus, have shown these benefits only in subset analyses., Conclusions: Corticosteroids have been documented to decrease mortality in some indications, in particular, antenatal use for preterm labour, tuberculous meningitis, Pneumocystis pneumonia, and alcoholic hepatitis. Many postulated benefits of corticosteroids on mortality may reflect 'vibration of treatment effects' leading to false-positive claims from spurious subset analyses and even for standard indications, such biases may have inflated the treatment effect estimates. More large trials are needed for serious, common conditions where use of corticosteroids is proposed., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Advances in laboratory techniques have led to a rapidly increasing use of biomarkers in epidemiological studies. Biomarkers of internal dose, early biological change, susceptibility and clinical outcomes are used as proxies for investigating interactions between external and/or endogenous agents and body components or processes. The need for improved reporting of scientific research led to influential statements of recommendations such as the STrengthening Reporting of OBservational studies in Epidemiology (STROBE) statement. The STROBE initiative established in 2004 aimed to provide guidance on how to report observational research. Its guidelines provide a user-friendly checklist of 22 items to be reported in epidemiological studies, with items specific to the three main study designs: cohort studies, case-control studies and cross-sectional studies. The present STrengthening the Reporting of OBservational studies in Epidemiology -Molecular Epidemiology (STROBE-ME) initiative builds on the STROBE statement implementing nine existing items of STROBE and providing 17 additional items to the 22 items of STROBE checklist. The additions relate to the use of biomarkers in epidemiological studies, concerning collection, handling and storage of biological samples; laboratory methods, validity and reliability of biomarkers; specificities of study design; and ethical considerations. The STROBE-ME recommendations are intended to complement the STROBE recommendations., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

• The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. • Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

• The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting vary. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. • A detailed Explanation and Elaboration document is published as an accompanying article [1]., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Multiple studies have evaluated diverse allergens in paediatric populations. Consensus is still lacking on which allergens are most commonly implicated in allergic contact dermatitis., Objectives: To evaluate the proportion of positive reactions for allergens tested in children and to identify allergens with positive reactions in at least 1% of them., Methods: This was a systematic review of studies in PubMed (1966-2010) investigating allergens in at least 100 enrolled children. Proportions of positive reactions for each allergen were combined with random effects models across studies., Results: We included 49 studies with available data on 170 allergens. Each study tested a median of two allergens. Among the 94 allergens evaluated by at least two studies, 58 had estimates of positive reactions of at least 1% by random effects calculations, and for 21 of them the 95% confidence interval ensured that the proportion of positive reactions was at least 1%. The top five allergens tested by at least two studies included nickel sulfate, ammonium persulfate, gold sodium thiosulfate, thimerosal, and toluene-2,5-diamine (p-toluenediamine). For most allergens, the proportion of positive reactions was higher in studies published after 1995 than in earlier studies (p = 0.0065)., Conclusions: This meta-analysis offers guidance on which allergens are most prevalent in the paediatric population and should have priority for inclusion in standardized allergen series., (© 2011 John Wiley & Sons A/S.)

Multiple-treatments meta-analyses are increasingly used to evaluate the relative effectiveness of several competing regimens. In some fields which evolve with the continuous introduction of new agents over time, it is possible that in trials comparing older with newer regimens the effectiveness of the latter is exaggerated. Optimism bias, conflicts of interest and other forces may be responsible for this exaggeration, but its magnitude and impact, if any, needs to be formally assessed in each case. Whereas such novelty bias is not identifiable in a pair-wise meta-analysis, it is possible to explore it in a network of trials involving several treatments. To evaluate the hypothesis of novel agent effects and adjust for them, we developed a multiple-treatments meta-regression model fitted within a Bayesian framework. When there are several multiple-treatments meta-analyses for diverse conditions within the same field/specialty with similar agents involved, one may consider either different novel agent effects in each meta-analysis or may consider the effects to be exchangeable across the different conditions and outcomes. As an application, we evaluate the impact of modelling and adjusting for novel agent effects for chemotherapy and other non-hormonal systemic treatments for three malignancies. We present the results and the impact of different model assumptions to the relative ranking of the various regimens in each network. We established that multiple-treatments meta-regression is a good method for examining whether novel agent effects are present and estimation of their magnitude in the three worked examples suggests an exaggeration of the hazard ratio by 6 per cent (2-11 per cent).

Background: Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products., Methods: Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period., Results: Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors., Conclusions: Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition.

Background: Infants born at term by elective caesarean delivery are more likely to develop respiratory morbidity than infants born vaginally. Prophylactic corticosteroids in singleton preterm pregnancies accelerate lung maturation and reduce the incidence of respiratory complications., Objectives: The objective of this review was to assess the effect of prophylactic corticosteroid administration before elective caesarean section at term, as compared to usual management without corticosteroids, in reducing neonatal respiratory morbidity and admission to special care with respiratory complications., Search Strategy: We searched the Cochrane Pregnancy and Chilbirth Group's Trials Register (30 June 2009)., Selection Criteria: Randomised and quasi-randomised controlled trials comparing prophylactic antenatal corticosteroid administration (betamethasone or dexamethasone) with placebo or with no treatment, given before elective caesarean section at term (at or after 37 weeks of gestation)., Data Collection and Analysis: The co-authors assessed the results of the only available trial independently to retrieve data on perinatal outcomes. Results were expressed as risk ratio (RR) or mean differences (MD), together with their 95% confidence intervals (CI)., Main Results: One study comparing prophylactic administration of betamethasone (N = 467) versus usual treatment without steroids (N = 475) in term elective caesarean section was included in the review. Women randomised to treatment group received two intramuscular doses of betamethasone in the 48 hours before delivery, whereas the control group received treatment as usual.Prophylactic betamethasone appeared to significantly decrease the risk of admission to the neonatal intensive care unit for respiratory morbidity (RR 0.15; 95% CI 0.03 to 0.64). However, no statistically significant reduction was found in the incidence of neonatal respiratory distress syndrome (RR 0.32; 95% CI 0.07 to 1.58), transient tachypnoea of the newborn (RR 0.52; 95% CI 0.25 to 1.11), need for mechanical ventilation (RR 4.07; 95% CI 0.46 to 36.27) and length of stay in neonatal intensive care unit (MD) -2.14 days; 95% CI -5.58 to 1.30).There were no reported events of neonatal sepsis, perinatal deaths or maternal trauma infection, therefore results on these outcomes are non-estimable. The study did not provide data on other pre-defined outcomes., Authors' Conclusions: The results from the single trial are promising, but more studies with larger samples are needed to investigate the effect of prophylactic steroids in the incidence of neonatal complications per se. Also more data and longer follow up would be needed for potential harms and complications.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.

Evidence-based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence-based and molecular medicine are complementary and they should be converging. I define molecular evidence-based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and 'significant' biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace.

Violation of Hardy-Weinberg equilibrium (HWE) can raise doubts about the validity of the conclusions from genetic association studies. However, for most currently performed gene-disease association studies, the available tests have low power to detect deviations from HWE. We consider this issue from a meta-analysis perspective, and suggest an approach to estimate the deviation and investigate its relationship with the observed genetic effects. Different degrees of deviation from HWE have previously been proposed as a potential source of heterogeneity across studies. We present a hierarchical meta-regression model that can be applied to test this assumption, using the concept of the fixation coefficient. We re-analyse seven meta-analyses to illustrate these methods. The uncertainty in the genetic effect estimate tended to increase once the fixation coefficient was taken into account. Dependence of the genetic effect size on the deviation from HWE was found in one meta-analysis, while in the other six examples, deviations from HWE did not clearly explain between-study heterogeneity in the genetic effects. The proposed hierarchical models allow the synthesis of data across gene-disease association studies with appropriate consideration of HWE issues., (2006 John Wiley & Sons, Ltd.)

The purpose of the present study was to determine independent predictors for long-term mortality after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to score in-hospital mortality and recent studies have shown its ability to predict long-term mortality as well. We compared forecasts based on EuroSCORE with other models based on independent predictors. Medical records of patients with cardiac surgery who were discharged alive (n = 4852) were retrospectively reviewed. Their operative surgical risks were calculated according to EuroSCORE. Patients were randomly divided into two groups: training dataset (n = 3233) and validation dataset (n = 1619). Long-term survival data (mean follow-up 5.1 years) were obtained from the National Death Index. We compared four models: standard EuroSCORE (M1); logistic EuroSCORE (M2); M2 and other preoperative, intra-operative and post-operative selected variables (M3); and selected variables only (M4). M3 and M4 were determined with multivariable Cox regression analysis using the training dataset. The estimated five-year survival rates of the quartiles in compared models in the validation dataset were: 94.5%, 87.8%, 77.1%, 64.9% for M1; 95.1%, 88.0%, 80.5%, 64.4% for M2; 93.4%, 89.4%, 80.8%, 64.1% for M3; and 95.8%, 90.9%, 81.0%, 59.9% for M4. In the four models, the odds of death in the highest-risk quartile was 8.4-, 8.5-, 9.4- and 15.6-fold higher, respectively, than the odds of death in the lowest-risk quartile (P < 0.0001 for all). EuroSCORE is a good predictor of long-term mortality after cardiac surgery. We developed and validated a model using selected preoperative, intra-operative and post-operative variables that has better discriminatory ability.

Background: Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of benzodiazepines' use in the treatment of alcohol withdrawal symptoms., Objectives: To evaluate the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions. We also screened references of retrieved articles., Selection Criteria: All randomized controlled trials examining the effectiveness and safety of a benzodiazepine in comparison with a placebo or other pharmacological intervention or other benzodiazepine were considered., Data Collection and Analysis: Two reviewers independently assessed trial quality and extracted data., Main Results: Fifty-seven trials, with a total of 4,051 people were included. Despite the considerable number of randomized controlled trials, there was a very large variety of outcomes and of different rating scales and relatively limited quantitative synthesis of data was feasible. Benzodiazepines offered a large benefit against alcohol withdrawal seizures compared to placebo (relative risk [RR] 0.16; 95% confidence interval [CI] 0.04 to 0.69; p = 0.01). Benzodiazepines had similar success rates as other drugs (RR 1.02; 95% CI 0.92 to 1.12) or anticonvulsants in particular (RR 1.00; 95% CI 0.87 to 1.16) and offered a significant benefit for seizure control against non-anticonvulsants (RR 0.23; 95% CI 0.07 to 0.75; p = 0.02), but not against anticonvulsants (RR 1.99; 95% CI 0.46 to 8.65). Changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment were similar with benzodiazepines versus other drugs, although some small studies showed isolated significant differences for other, less commonly, used scales. Data on other comparisons were very limited, thus making quantitative synthesis for various outcomes not very informative., Authors' Conclusions: Benzodiazepines are effective against alcohol withdrawal symptoms, in particular seizures, when compared to placebo. It is not possible to draw definite conclusions about the relative effectiveness and safety of benzodiazepines against other drugs in alcohol withdrawal, because of the large heterogeneity of the trials both in interventions and assessment of outcomes but the available data do not show prominent differences between benzodiazepines and other drugs in success rates.

Background: Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of anticonvulsants' use in the treatment of alcohol withdrawal symptoms., Objectives: To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to October 2004); EMBASE (1988 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions and references of articles., Selection Criteria: All randomized controlled trials examining the effectiveness, safety and overall risk-benefit of an anticonvulsant in comparison with a placebo or other pharmacological treatment or another anticonvulsant were considered., Data Collection and Analysis: The authors independently assessed trial quality extracted data., Main Results: Forty-eight studies, involving 3610 people were included. Despite the considerable number of randomized controlled trials, there was a variety of outcomes and of different rating scales that led to a limited quantitative synthesis of data. For the anticonvulsant versus placebo comparison, therapeutic success tended to be more common among the anticonvulsant-treated patients (relative risk (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19), but no effect reached formal statistical significance. For the anticonvulsant versus other drug comparison, CIWA-Ar score showed non-significant differences for the anticonvulsants compared to the other drugs at the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31). For the subgroup analysis of carbamazepine versus benzodiazepine, a statistically significant protective effect was found for the anticonvulsant (WMD -1.04; 95% CI -1.89 to -0.20), p = 0.02), but this was based on only 260 randomized participants. There was a non-significant decreased incidence of seizures (RR 0.50; 95% CI 0.18 to 1.34) favouring the patients that were treated with anticonvulsants than other drugs, and side-effects tended to be less common in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02)., Authors' Conclusions: It is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal, because of the heterogeneity of the trials both in interventions and the assessment of outcomes. The extremely small mortality rate in all these studies is reassuring, but data on other safety outcomes are sparse and fragmented.

Background: There is controversy regarding whether P-glycoprotein (Pgp) may be a prognostic factor for the response to chemotherapy and clinical disease progression in patients with osteosarcoma., Methods: The authors conducted a meta-analysis of 14 studies (n = 631 patients) that evaluated the correlation between Pgp and histologic response to chemotherapy and clinical disease progression (death, metastasis, or recurrence). Data were synthesized in receiver operating characteristic curves and with fixed-effects and random-effects likelihood ratios and risk ratios., Results: Pgp had no discriminating ability for identifying poor responders versus good responders to chemotherapy: The positive likelihood ratio was 1.15 (95% confidence interval [95% CI], 0.93-1.43), and the negative likelihood ratio was 0.88 (95% CI, 0.65-1.18; random-effects calculations). There was some between-study heterogeneity, but no study showed strong discriminating ability. Conversely, Pgp positivity increased the risk of disease progression 1.92-fold (95% CI, 1.18-3.13; random-effects calculations) with some between-study heterogeneity that disappeared when only studies that employed immunohistochemistry were considered (risk ratio, 2.23; 95% CI, 1.37-3.64). The results were robust in various sensitivity analyses, although smaller studies tended to show stronger associations with the risk of disease progression compared with larger studies (P = 0.03)., Conclusions: The available evidence showed conclusively that Pgp was not associated with the histologic response of patients with osteosarcoma to combination chemotherapy regimens. Conversely, Pgp positivity, as determined by immunohistochemistry, was a strong correlate of more rapid disease progression, although there was heterogeneity across the performed studies that, to some extent, may have reflected bias, differential measurements of Pgp, or confounding with other risk factors., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11546)

Background: We assessed whether antibodies against platelet activating factor (PAF) are related to the presence of antiphospholipid syndrome (APS) clinical manifestations, in particular thrombosis, in patients with connective tissue diseases., Materials and Methods: Anti-PAF, anticardiolipin (aCL), antibeta2 glycoprotein I (antibeta2GPI) and antiphosphatidylcholine (anti-PC) antibodies were determined in 52 patients with APS, 29 patients with systemic lupus erythematosus (SLE) aCL but without APS, 30 patients with SLE without aCL, and 30 patients with scleroderma. A new enzyme-linked immunosorbent assay (ELISA) was developed for determining anti-PAF antibodies in a bovine serum-free fashion., Results: The ELISA showed high specificity. Homologous inhibition experiments showed 60-70% inhibition. Anti-PAF antibodies were found in 18/52 APS patients, 10/29 SLE/aCL+ patients, 9/30 SLE/aCL- patients and 3/30 scleroderma patients. Anti-PAF antibodies were significantly associated with anti-PC antibodies (odds ratio [OR] 12. 7, P < 0.01), and there was a modest association with immunoglobulin G (IgG) aCL (OR 3.1, P > 0.10), but not with IgM aCL or antibeta2GPI. Three SLE/aCL+ patients and five SLE/aCL- patients had clinical manifestations characteristic of APS. All these patients had anti-PAF antibodies, while none had high titres of aCL or antibeta2GPI antibodies and only one had anti-PC antibodies. Among the combined APS and SLE groups, the presence of anti-PAF antibodies was significantly associated with clinical manifestations which are characteristic of APS (OR 2.6, P = 0.02). The effect was independent of IgG aCL and antibeta2GPI antibodies., Conclusions: Anti-PAF antibodies are common in APS and SLE and comprise an independent factor for the development of thrombosis. Several patients experiencing thromboses have anti-PAF antibodies without other antiphospholipid specificities.

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.