Heterogeneity in elevated glucose and A1C as predictors of the prediabetes to diabetes transition: Framingham Heart Study, Multi-Ethnic Study on Atherosclerosis, Jackson Heart Study, and Atherosclerosis Risk In Communities.

Introduction: There are a number of glycemic definitions for prediabetes; however, the heterogeneity in diabetes transition rates from prediabetes across different glycemic definitions in major US cohorts has been unexplored. We estimate the variability in risk and relative risk of adiposity based on diagnostic criteria like fasting glucose and hemoglobin A1C% (HA1C%). Research Design and Methods: We estimated transition rate from prediabetes, as defined by fasting glucose between 100-125 and/or 110-125 mg/dL, and HA1C% between 5.7-6.5% in participant data from the Framingham Heart Study, Multi-Ethnic Study on Atherosclerosis, Atherosclerosis Risk in Communities, and the Jackson Heart Study. We estimated the heterogeneity and prediction interval across cohorts, stratifying by age, sex, and body mass index. For individuals who were prediabetic, we estimated the relative risk for obesity, blood pressure, education, age, and sex for diabetes. Results: There is substantial heterogeneity in diabetes transition rates across cohorts and prediabetes definitions with large prediction intervals. We observed the highest range of rates in individuals with fasting glucose of 110-125 mg/dL ranging from 2-18 per 100 person-years. Across different cohorts, the association obesity or hypertension in the progression to diabetes was consistent, yet it varied in magnitude. We provide a database of transition rates across subgroups and cohorts for comparison in future studies. Conclusion: The absolute transition rate from prediabetes to diabetes significantly depends on cohort and prediabetes definitions.

Twelve years after the ARRIVE guidelines: Animal research has not yet arrived at high standards.

The reproducibility crisis across animal studies jeopardizes the credibility of the main findings derived from animal research, even though these findings are critical for informing human studies. To clarify and improve transparency among animal studies, the ARRIVE reporting guidelines were first announced in 2010 and upgraded to version 2.0 in 2020. However, compliance with and awareness of those reporting guidelines has remained suboptimal. Journal editors should encourage the authors to adhere to those guidelines. Authors, editors, referees, and reviewers should be aware of the ARRIVE guideline 2.0 when assessing and evaluating the methodology and findings of animal studies. However, we should also question whether reporting guidelines alone can change a research culture and improve the reproducibility of animal investigations. Reported research may not reflect actual research. Large segments of animal research efforts are wasted because of poor design choices and because of non-publication rather than suboptimal reporting. Better training of the scientific workforce, interventions at improving animal research at the design stage, registration practices, and alignment of the reward system with the publication of rigorous animal research may achieve more than reporting guidelines alone.

Mapping and systematic appraisal of umbrella reviews in epidemiological research: a protocol for a meta-epidemiological study.

INTRODUCTION: Umbrella review is one of the terms used to describe an overview of systematic reviews. During the last years, a rapid increase in the number of umbrella reviews on epidemiological studies has been observed, but there is no systematic assessment of their methodological and reporting characteristics. Our study aims to fill this gap by performing a systematic mapping of umbrella reviews in epidemiological research. METHODS: We will perform a meta-epidemiological study including a systematic review in MEDLINE and EMBASE to identify all the umbrella reviews that focused on systematic reviews of epidemiological studies and were published from inception until December 31, 2022. We will consider eligible any research article which was designed as an umbrella review and summarized systematic reviews and meta-analyses of epidemiological studies. From each eligible article, we will extract information about the research topic, the methodological characteristics, and the reporting characteristics. We will examine whether the umbrella reviews assessed the strength of the available evidence and the rigor of the included systematic reviews. We will also examine whether these characteristics change across time. DISCUSSION: Our study will systematically appraise the methodological and reporting characteristics of published umbrella reviews in epidemiological literature. The findings of our study can be used to improve the design and conduct of future umbrella reviews, to derive a standardized set of reporting and methodological guidelines for umbrella reviews, and to allow further meta-epidemiological work. SYSTEMATIC REVIEW REGISTRATION: osf.io/sxzc6.

Differential COVID-19 infection rates in children, adults, and elderly: Systematic review and meta-analysis of 38 pre-vaccination national seroprevalence studies.

Background: Debate exists about whether extra protection of elderly and other vulnerable individuals is feasible in COVID-19. We aimed to assess the relative infection rates in the elderly vs the non-elderly and, secondarily, in children vs adults. Methods: We performed a systematic review and meta-analysis of seroprevalence studies conducted in the pre-vaccination era. We identified representative national studies without high risk of bias through SeroTracker and PubMed searches (last updated May 17, 2022). We noted seroprevalence estimates for children, non-elderly adults, and elderly adults, using cut-offs of 20 and 60 years (or as close to these ages, if they were unavailable) and compared them between different age groups. Results: We included 38 national seroprevalence studies from 36 different countries comprising 826 963 participants. Twenty-six of these studies also included pediatric populations and twenty-five were from high-income countries. The median ratio of seroprevalence in elderly vs non-elderly adults (or non-elderly in general, if pediatric and adult population data were not offered separately) was 0.90-0.95 in different analyses, with large variability across studies. In five studies (all in high-income countries), we observed significant protection of the elderly with a ratio of <0.40, with a median of 0.83 in high-income countries and 1.02 elsewhere. The median ratio of seroprevalence in children vs adults was 0.89 and only one study showed a significant ratio of <0.40. The main limitation of our study is the inaccuracies and biases in seroprevalence studies. Conclusions: Precision shielding of elderly community-dwelling populations before the availability of vaccines was indicated in some high-income countries, but most countries failed to achieve any substantial focused protection. Registration: Open Science Framework (available at: https://osf.io/xvupr).

Expert Perspectives on Pilot and Feasibility Studies: A Delphi Study and Consolidation of Considerations for Behavioral Interventions.

Background: In the behavioral sciences, conducting pilot and/or feasibility studies (PFS) is a key step that provides essential information used to inform the design, conduct, and implementation of a larger-scale trial. There are more than 160 published guidelines, reporting checklists, frameworks, and recommendations related to PFS. All of these publications offer some form of guidance on PFS, but many focus on one or a few topics. This makes it difficult for researchers wanting to gain a broader understanding of all the relevant and important aspects of PFS and requires them to seek out multiple sources of information, which increases the risk of missing key considerations to incorporate into their PFS. The purpose of this study was to develop a consolidated set of considerations for the design, conduct, implementation, and reporting of PFS for interventions conducted in the behavioral sciences. Methods: To develop this consolidation, we undertook a review of the published guidance on PFS in combination with expert consensus (via a Delphi study) from the authors who wrote such guidance to inform the identified considerations. A total of 161 PFS-related guidelines, checklists, frameworks, and recommendations were identified via a review of recently published behavioral intervention PFS and backward/forward citation tracking of well-know PFS literature (e.g., CONSORT Ext. for PFS). Authors of all 161 PFS publications were invited to complete a three-round Delphi survey, which was used to guide the creation of a consolidated list of considerations to guide the design, conduct, and reporting of PFS conducted by researchers in the behavioral sciences. Results: A total of 496 authors were invited to take part in the Delphi survey, 50 (10.1%) of which completed all three rounds, representing 60 (37.3%) of the 161 identified PFS-related guidelines, checklists, frameworks, and recommendations. A set of twenty considerations, broadly categorized into six themes (Intervention Design, Study Design, Conduct of Trial, Implementation of Intervention, Statistical Analysis and Reporting) were generated from a review of the 161 PFS-related publications as well as a synthesis of feedback from the three-round Delphi process. These 20 considerations are presented alongside a supporting narrative for each consideration as well as a crosswalk of all 161 publications aligned with each consideration for further reading. Conclusion: We leveraged expert opinion from researchers who have published PFS-related guidelines, checklists, frameworks, and recommendations on a wide range of topics and distilled this knowledge into a valuable and universal resource for researchers conducting PFS. Researchers may use these considerations alongside the previously published literature to guide decisions about all aspects of PFS, with the hope of creating and disseminating interventions with broad public health impact.

Antenatal corticosteroids prior to planned caesarean at term for improving neonatal outcomes.

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.

Large Pediatric Randomized Clinical Trials in ClinicalTrials.gov.

BACKGROUND: Large, randomized controlled trials (RCTs) are essential in answering pivotal questions in child health. METHODS: We created a bird's eye view of all large, noncluster, nonvaccine pediatric RCTs with ≥1000 participants registered in ClinicalTrials.gov (last search January 9, 2020). We analyzed the funding sources, countries, outcomes, publication status, and correlation with the pediatric global burden of disease (GBD) for eligible trials. RESULTS: We identified 247 large, nonvaccine, noncluster pediatric RCTs. Only 17 mega-trials with ≥5000 participants existed. Industry funding was involved in only 52 (21%) and exclusively funded 47 (19%) trials. Participants were from high-income countries (HICs) in 100 (40%) trials, from lower-middle-income countries (LMICs) in 122 (49%) trials, and from both HICs and LMICs in 19 (8%) trials; 6 trials did not report participants' country location. Of trials conducted in LMIC, 43% of investigators were from HICs. Of non-LMIC participants trials (HIC or HIC and LMIC), 39% were multicountry trials versus 11% of exclusively LMIC participants trials. Few trials (18%; 44 of 247) targeted mortality as an outcome. 35% (58 of 164) of the trials completed ≥12 months were unpublished at the time of our assessment. The number of trials per disease category correlated well with pediatric GBD overall (ρ = 0.76) and in LMICs (ρ = 0.69), but not in HICs (ρ = 0.29). CONCLUSIONS: Incentivization of investigator collaborations across diverse country settings, timely publication of results of large pediatric RCTs, and alignment with the pediatric GBD are of pivotal importance to ultimately improve child health globally.

Reporting only relative effect measures was potentially misleading: some good practices for improving the soundness of epidemiological results.

OBJECTIVE: In the medical and epidemiological literature there is a growing tendency to report an excessive number of decimal digits (often three, sometimes four), especially when measures of relative occurrence are small; this can be misleading. STUDY DESIGN AND SETTING: We combined mathematical and statistical reasoning about the precision of relative risks with the meaning of the decimal part of the same measures from biological and public health perspectives. RESULTS: We identified a general rule for minimizing the mathematical error due to rounding of relative risks, depending on the background absolute rate, which justifies the use of one or more decimal digits for estimates close to 1. CONCLUSIONS: We suggest that both relative and absolute risk measures (expressed as a rates) should be reported, and two decimal digits should be used for relative risk close to 1 only if the background rate is at least 1/1,000 py. The use of more than two decimal digits is justified only when the background rate is high (ie, 1/10 py).

SARS-CoV-2 re-infection risk in Austria.

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.

Evaluating and Strengthening the Evidence for Nutritional Bone Research: Ready to Break New Ground?

A healthy diet is essential to attain genetically determined peak bone mass and maintain optimal skeletal health across the adult lifespan. Despite the importance of nutrition for bone health, many of the nutritional requirements of the skeleton across the lifespan remain underexplored, poorly understood, or controversial. With increasingly aging populations, combined with rapidly changing diets and lifestyles globally, one anticipates large increases in the prevalence of osteoporosis and incidence of osteoporotic fractures. Robust, transparent, and reproducible nutrition research is a cornerstone for developing reliable public health recommendations to prevent osteoporosis and osteoporotic fractures. However, nutrition research is often criticized or ignored by healthcare professionals due to the overemphasis of weak science, conflicting, confusing or implausible findings, industry interests, common misconceptions, and strong opinions. Conversely, spurious research findings are often overemphasized or misconstrued by the media or prominent figures especially via social media, potentially leading to confusion and a lack of trust by the general public. Recently, reforms of the broader discipline of nutrition science have been suggested and promoted, leading to new tools and recommendations to attempt to address these issues. In this perspective, we provide a brief overview of what has been achieved in the field on nutrition and bone health, focusing on osteoporosis and osteoporotic fractures. We discuss what we view as some of the challenges, including inherent difficulties in assessing diet and its change, disentangling complex interactions between dietary components and between diet and other factors, selection of bone-related outcomes for nutrition studies, obtaining evidence with more unbiased designs, and perhaps most importantly, ensuring the trust of the public and healthcare professionals. This perspective also provides specific recommendations and highlights new developments and future opportunities for scientists studying nutrition and bone health. © 2021 American Society for Bone and Mineral Research (ASBMR).

Global assessment of C-reactive protein and health-related outcomes: an umbrella review of evidence from observational studies and Mendelian randomization studies.

C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited.

Examining the robustness of observational associations to model, measurement and sampling uncertainty with the vibration of effects framework.

BACKGROUND: The results of studies on observational associations may vary depending on the study design and analysis choices as well as due to measurement error. It is important to understand the relative contribution of different factors towards generating variable results, including low sample sizes, researchers' flexibility in model choices, and measurement error in variables of interest and adjustment variables. METHODS: We define sampling, model and measurement uncertainty, and extend the concept of vibration of effects in order to study these three types of uncertainty in a common framework. In a practical application, we examine these types of uncertainty in a Cox model using data from the National Health and Nutrition Examination Survey. In addition, we analyse the behaviour of sampling, model and measurement uncertainty for varying sample sizes in a simulation study. RESULTS: All types of uncertainty are associated with a potentially large variability in effect estimates. Measurement error in the variable of interest attenuates the true effect in most cases, but can occasionally lead to overestimation. When we consider measurement error in both the variable of interest and adjustment variables, the vibration of effects are even less predictable as both systematic under- and over-estimation of the true effect can be observed. The results on simulated data show that measurement and model vibration remain non-negligible even for large sample sizes. CONCLUSION: Sampling, model and measurement uncertainty can have important consequences for the stability of observational associations. We recommend systematically studying and reporting these types of uncertainty, and comparing them in a common framework.

Sample size evolution in neuroimaging research: An evaluation of highly-cited studies (1990-2012) and of latest practices (2017-2018) in high-impact journals.

We evaluated 1038 of the most cited structural and functional (fMRI) magnetic resonance brain imaging papers (1161 studies) published during 1990-2012 and 270 papers (300 studies) published in top neuroimaging journals in 2017 and 2018. 96% of highly cited experimental fMRI studies had a single group of participants and these studies had median sample size of 12, highly cited clinical fMRI studies (with patient participants) had median sample size of 14.5, and clinical structural MRI studies had median sample size of 50. The sample size of highly cited experimental fMRI studies increased at a rate of 0.74 participant/year and this rate of increase was commensurate with the median sample sizes of neuroimaging studies published in top neuroimaging journals in 2017 (23 participants) and 2018 (24 participants). Only 4 of 131 papers in 2017 and 5 of 142 papers in 2018 had pre-study power calculations, most for single t-tests and correlations. Only 14% of highly cited papers reported the number of excluded participants whereas 49% of papers with their own data in 2017 and 2018 reported excluded participants. Publishers and funders should require pre-study power calculations necessitating the specification of effect sizes. The field should agree on universally required reporting standards. Reporting formats should be standardized so that crucial study parameters could be identified unequivocally.

PROTOCOL: When and how to replicate systematic reviews.

This is a protocol for a co-registered Cochrane and Campbell Review (Methodology). The objectives are as follows: To identify, describe and assess methods for: when to replicate a systematic review; how to replicate a systematic review.

Hypothesis, analysis and synthesis, it's all Greek to me.

The linguistic foundations of science and technology include many terms that have been borrowed from ancient languages. In the case of terms with origins in the Greek language, the modern meaning can often differ significantly from the original one. Here we use the PubMed database to demonstrate the prevalence of words of Greek origin in the language of modern science, and call for scientists to exercise care when coining new terms.