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Objectives To propose a checklist that can be used to assess trustworthiness of randomized controlled trials (RCTs). Design A screening tool was developed using the four-stage approach proposed by Moher et al . This included defining the scope, reviewing the evidence base, suggesting a list of items from piloting, and holding a consensus meeting. The initial checklist was set-up by a core group who had been involved in the assessment of problematic RCTs for several years. We piloted this in a consensus panel of several stakeholders, including health professionals, reviewers, journal editors, policymakers, researchers, and evidence-synthesis specialists. Each member was asked to score three articles with the checklist and the results were then discussed in consensus meetings. Outcome The Trustworthiness in RAndomised Clinical Trials (TRACT) checklist includes 19 items organised into seven domains that are applicable to every RCT: 1) Governance, 2) Author Group, 3) Plausibility of Intervention Usage, 4) Timeframe, 5) Drop-out Rates, 6) Baseline Characteristics, and 7) Outcomes. Each item can be answered as either no concerns, some concerns/no information, or major concerns. If a study is assessed and found to have a majority of items rated at a major concern level, then editors, reviewers or evidence synthesizers should consider a more thorough investigation, including assessment of original individual participant data. Conclusions The TRACT checklist is the first checklist developed specifically to detect trustworthiness issues in RCTs. It might help editors, publishers and researchers to screen for such issues in submitted or published RCTs in a transparent and replicable manner.

We performed a systematic review and meta-analysis of the association between sexual risk factors and bacterial vaginosis (BV). Forty-three studies reported new or multiple sexual partners and condom use relative to prevalent, incident, or recurrent BV. The summary estimate of the relative risk for the association between BV new or multiple male partners was 1.6 (95% confidence interval, 1.5–1.8), between BV and any female partners was 2.0 (95% confidence interval, 1.7–2.3), and between BV and condom use was 0.8 (95% confidence interval, 0.8–0.9). This review is the first to summarize available observational data for BV. It shows that BV is significantly associated with sexual contact with new and multiple male and female partners and that decreasing the number of unprotected sexual encounters may reduce incident and recurrent infection. Investigation of sexual transmission of BV is limited by the absence of a clear microbiological etiology; however, we have shown that the epidemiological profile of BV is similar to that of established sexually transmitted infections.

Background When summary results from studies of counts of events in time contain zeros, the study-specific incidence rate ratio (IRR) and its standard error cannot be calculated because the log of zero is undefined. This poses problems for the widely used inverse-variance method that weights the study-specific IRRs to generate a pooled estimate. Methods We conducted a simulation study to compare the inverse-variance method of conducting a meta-analysis (with and without the continuity correction) with alternative methods based on either Poisson regression with fixed interventions effects or Poisson regression with random intervention effects. We manipulated the percentage of zeros in the intervention group (from no zeros to approximately 80 percent zeros), the levels of baseline variability and heterogeneity in the intervention effect, and the number of studies that comprise each meta-analysis. We applied these methods to an example from our own work in suicide prevention and to a recent meta-analysis of the effectiveness of condoms in preventing HIV transmission. Results As the percentage of zeros in the data increased, the inverse-variance method of pooling data shows increased bias and reduced coverage. Estimates from Poisson regression with fixed interventions effects also display evidence of bias and poor coverage, due to their inability to account for heterogeneity. Pooled IRRs from Poisson regression with random intervention effects were unaffected by the percentage of zeros in the data or the amount of heterogeneity. Conclusion Inverse-variance methods perform poorly when the data contains zeros in either the control or intervention arms. Methods based on Poisson regression with random effect terms for the variance components are very flexible offer substantial improvement.

In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

Background Use of intracytoplasmic sperm injection (ICSI) continues to increase as the most common mode of oocyte insemination during in vitro fertilisation (IVF), sometimes in the absence of clear indications (i.e. male factor infertility). Several studies suggest an increased risk of congenital abnormalities after ICSI. The association between the ICSI technique and long-term childhood development remains unclear. Methods Our population-based study included singleton infants conceived via IVF and born between 2005 and 2013. The cohort included state-wide linked maternal and childhood administrative data from Victoria, Australia. The primary exposure was conception via ICSI (without severe male factor infertility), with those born following standard IVF as controls. Childhood development was examined using the Australian Early Development Census (AEDC), a broad assessment of childhood development across five domains of health and neurodevelopment performed in Australian schools every triennium at school entry (age 4–6 years). Our primary outcome used a validated global measure—developmental vulnerability—defined as scoring less than the 10th percentile in two or more of the five developmental domains (DV2). Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The adjustment variable set was determined a priori via a modified Delphi procedure. Given the use of observational data, there were missing data and inherent differences in the covariate profile between exposure cohorts. Multiple imputation, bootstrapping and doubly robust inverse probability weighted regression adjustment modelling was utilised to allow a causal interpretation of results. Results Our cohort ( N  = 3656) included 1489 IVF and 2167 ICSI-conceived children. We found no causal effect of ICSI on the risk of AEDC-defined developmental vulnerability at school-entry age compared with children conceived via standard IVF; adjusted risk difference − 1.11% (95% CI − 4.23 to 2.01%) and adjusted risk ratio 0.90 (95% CI 0.68 to 1.21). Conclusions Our findings suggest that the use of ICSI in IVF cycles without severe male factor infertility does not increase the risk of early childhood developmental vulnerability among children in their first year of school. These findings provide important reassurance for current and prospective parents and clinicians alike.

The contribution by asthma to the development of fixed airflow obstruction (AO) and the nature of its effect combined with active smoking and atopy remain unclear. To investigate the prevalence and relative influence of lifetime asthma, active smoking, and atopy on fixed AO in middle age. The population-based Tasmanian Longitudinal Health Study cohort born in 1961 (n = 8,583) and studied with prebronchodilator spirometry in 1968 was retraced (n = 7,312) and resurveyed (n = 5,729 responses) from 2002 to 2005. A sample enriched for asthma and chronic bronchitis underwent a further questionnaire, pre- and post-bronchodilator spirometry (n = 1,389), skin prick testing, lung volumes, and diffusing capacity measurements. Prevalence estimates were reweighted for sampling fractions. Multiple linear and logistic regression were used to assess the relevant associations. Main effects and interactions between lifetime asthma, active smoking, and atopy as they relate to fixed AO were measured. The prevalence of fixed AO was 6.0% (95% confidence interval [CI], 4.5-7.5%). Its association with early-onset current clinical asthma was equivalent to a 33 pack-year history of smoking (odds ratio, 3.7; 95% CI, 1.5-9.3; P = 0.005), compared with a 24 pack-year history for late-onset current clinical asthma (odds ratio, 2.6; 95% CI, 1.03-6.5; P = 0.042). An interaction (multiplicative effect) was present between asthma and active smoking as it relates to the ratio of post-bronchodilator FEV(1)/FVC, but only among those with atopic sensitization. Active smoking and current clinical asthma both contribute substantially to fixed AO in middle age, especially among those with atopy. The interaction between these factors provides another compelling reason for atopic individuals with current asthma who smoke to quit.

Quantifying the benefits and harms of breast cancer screening accurately is important for planning and evaluating screening programs and for enabling women to make informed decisions about participation. However, few cohort studies have attempted to estimate benefit and harm simultaneously. We aimed to quantify the impact of mammographic screening on breast cancer mortality and overdiagnosis using a cohort of women invited to attend Australia's national screening program, BreastScreen. In a cohort of 41,330 women without prior breast cancer diagnosis, screening, or diagnostic procedures invited to attend BreastScreen Western Australia in 1994-1995, we estimated the cumulative risk of breast cancer mortality and breast cancer incidence (invasive and ductal carcinoma in situ) from age 50 to 85 years for attenders and non-attenders. Data were obtained by linking population-based state and national health registries. Breast cancer mortality risks were estimated from a survival analysis that accounted for competing risk of death from other causes. Breast cancer risk for unscreened women was estimated by survival analysis, while accounting for competing causes of death. For screened women, breast cancer risk was the sum of risk of being diagnosed at first screen, estimated using logistic regression, and risk of diagnosis following a negative first screen estimated from a survival analysis. For every 1,000 women 50 years old at first invitation to attend BreastScreen, there were 20 (95% CI 12-30) fewer breast cancer deaths and 25 (95% CI 15-35) more breast cancers diagnosed for women who attended than for non-attendees by age 85. Of the breast cancers diagnosed in screened women, 21% (95% CI 13%-27%) could be attributed to screening. The estimated ratio of benefit to harm was consistent with, but slightly less favourable to screening than most other estimates from cohort studies. Women who participate in organised screening for breast cancer in Australia have substantially lower breast cancer mortality, while some screen-detected cancers may be overdiagnosed.

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ.

Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine. Unfortunately, not all RCTs are based on real data. This serious breach of research integrity compromises the reliability of systematic reviews and meta-analyses, leading to misinformed clinical guidelines and posing a risk to both individual and public health. While methods to detect problematic RCTs have been proposed, they are time-consuming and labor-intensive. The use of artificial intelligence large language models (LLMs) has the potential to accelerate the data collection needed to assess the trustworthiness of published RCTs. We present a case study using ChatGPT powered by OpenAI's GPT-4o to assess an RCT paper. The case study focuses on applying the trustworthiness in randomised controlled trials (TRACT checklist) and automating data table extraction to accelerate statistical analysis targeting the trustworthiness of the data. We provide a detailed step-by-step outline of the process, along with considerations for potential improvements. ChatGPT completed all tasks by processing the PDF of the selected publication and responding to specific prompts. ChatGPT addressed items in the TRACT checklist effectively, demonstrating an ability to provide precise “yes” or “no” answers while quickly synthesizing information from both the paper and relevant online resources. A comparison of results generated by ChatGPT and the human assessor showed an 84% level of agreement of (16/19) TRACT items. This substantially accelerated the qualitative assessment process. Additionally, ChatGPT was able to extract efficiently the data tables as Microsoft Excel worksheets and reorganize the data, with three out of four extracted tables achieving an accuracy score of 100%, facilitating subsequent analysis and data verification. ChatGPT demonstrates potential in semiautomating the trustworthiness assessment of RCTs, though in our experience this required repeated prompting from the user. Further testing and refinement will involve applying ChatGPT to collections of RCT papers to improve the accuracy of data capture and lessen the role of the user. The ultimate aim is a completely automated process for large volumes of papers that seems plausible given our initial experience. •Problematic RCT data are common, but detection is time-consuming and labor-intensive.•Case study of ChatGPT's potential to semi-automate trustworthiness assessments.•ChatGPT shows strong capability in extracting and synthesizing information from RCTs.•ChatGPT automates table extraction from PDFs for analysis and verification.•Refining AI models could save time in future RCT assessments.

Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.