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PubMed2021

Genetic Relationship Between Endometriosis and Melanoma.

Epidemiological studies have observed that risk of endometriosis is associated with history of cutaneous melanoma and vice versa. Evidence for shared biological mechanisms between the two traits is limited. The aim of this study was to investigate the genetic correlation and causal relationship between endometriosis and melanoma. Summary statistics from genome-wide association meta-analyses (GWAS) for endometriosis and melanoma were used to estimate the genetic correlation between the traits and Mendelian randomization was used to test for a causal association. When using summary statistics from separate female and male melanoma cohorts we identified a significant positive genetic correlation between melanoma in females and endometriosis (r g = 0.144, se = 0.065, p = 0.025). However, we find no evidence of a correlation between endometriosis and melanoma in males or a combined melanoma dataset. Endometriosis was not genetically correlated with skin color, red hair, childhood sunburn occasions, ease of skin tanning, or nevus count suggesting that the correlation between endometriosis and melanoma in females is unlikely to be influenced by pigmentary traits. Mendelian Randomization analyses also provided evidence for a relationship between the genetic risk of melanoma in females and endometriosis. Colocalization analysis identified 27 genomic loci jointly associated with the two diseases regions that contain different causal variants influencing each trait independently. This study provides evidence of a small genetic correlation and relationship between the genetic risk of melanoma in females and endometriosis. Genetic risk does not equate to disease occurrence and differences in the pathogenesis and age of onset of both diseases means it is unlikely that occurrence of melanoma causes endometriosis. This study instead provides evidence that having an increased genetic risk for melanoma in females is related to increased risk of endometriosis. Larger GWAS studies with increased power will be required to further investigate these associations.

endometriosis↗

PubMed2026

SARS-CoV-2-related immune dysregulation and biologically plausible pathways to lymphomagenesis: a PRISMA-ScR-based scoping review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related immune dysregulation has generated interest in diagnostic pathology because infection-related inflammation, long coronavirus disease (COVID)-related immune disturbance, and post-vaccination lymphoid reactions may overlap with lymphoid-biological mechanisms and complicate the distinction between reactive lymphoid proliferations and lymphoid neoplasia. AIM: This scoping review aimed to map biologically plausible pathways through which SARS-CoV-2-associated immune perturbation may intersect with lymphomagenesis-related mechanisms, emphasizing diagnostic implications rather than causality. MATERIALS AND METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). PubMed∕MEDLINE, Scopus, and Web of Science were searched from January 2020 to March 2026, with selected pre-2020 sources retained for mechanistic or diagnostic relevance. Sources were charted across mechanistic, immunological, virological, clinicopathological, and diagnostic domains. RESULTS: After screening and eligibility assessment, 63 sources were retained for thematic synthesis. Evidence clustered around lymphoma-relevant but non-specific mechanisms, including inflammatory signaling, impaired immune surveillance, latent oncogenic viral reactivation, prolonged germinal-center activity with activation-induced cytidine deaminase (AID)-related genomic vulnerability, and lymphoid microenvironment remodeling. These mechanisms appear most relevant in predisposed hosts with chronic immune dysregulation, latent viral infection, defective deoxyribonucleic acid (DNA) repair, or occult abnormal lymphoid clones. Infection and vaccination are distinct contexts, because infection may produce broader immune disruption, whereas most post-vaccination nodal events are reactive and self-limited. CONCLUSIONS: Current evidence supports biological plausibility rather than a direct or generalizable causal relationship. The main diagnostic implication is careful clinicopathological correlation and distinction between reactive lymphoid proliferations and lymphoid neoplasia in post-COVID-19 and post-vaccination settings.

Humans↗

PubMed2026

Multi-Ancestry Survival GWAS of Substance Use Initiation in the ABCD Study.

BACKGROUND: Substance use initiation in adolescence is influenced by both genetic and environmental factors; however, large-scale genetic studies often treat initiation as a binary outcome and underuse longitudinal timing information. METHODS: We conducted time-to-event (survival) genome-wide association analyses (GWAS) of initiation for four outcomes-alcohol, nicotine, cannabis, and any substance use-using longitudinal follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study. We performed ancestry-stratified GWAS within European (EUR), African (AFR), and Hispanic (HISP) groups, applying consistent quality control and covariate adjustment. Summary statistics were harmonized across ancestries and meta-analyzed using inverse-variance weighted fixed-effects and DerSimonian-Laird random-effects models. We evaluated genomic inflation and heterogeneity (Cochran's Q and I 2), identified independent lead variants at genome-wide and suggestive significance thresholds, and assessed cross-trait overlap of associated loci. RESULTS: In the multi-ancestry meta-analysis, we observed suggestive association signals across traits (minimum p-values: alcohol ~ 1 × 10-7, any ~ 1 × 10-7, cannabis ~ 5 × 10-8, nicotine ~ 1 × 10-8). Nicotine initiation showed one genome-wide significant variant in both fixed- and random-effects meta-analyses (p < 5 × 10-8). Across traits, suggestive loci demonstrated limited overlap, with the strongest concordance between alcohol and any substance use, consistent with shared liability. Heterogeneity statistics indicated that some loci exhibited cross-ancestry variation in effect estimates. CONCLUSIONS: Survival GWAS leveraging initiation timing can identify genetic signals that may be missed by binary designs and enables principled multi-ancestry synthesis. Our results highlight both shared and trait-specific genetic contributions to early substance initiation and provide a foundation for downstream functional annotation and integrative modeling with environmental risk factors. These findings demonstrate the value of incorporating developmental timing into genetic discovery and provide a framework for integrating longitudinal risk modeling with genomic analyses.

ABCD↗

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed2026

The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration.

Rare coding variants can have large effects on disease risk and provide direct routes from human genetics to disease mechanisms and therapeutic targets, but their discovery is constrained by sample size, particularly for low-prevalence diseases. Here we establish the Biobank Rare Variant Analysis (BRaVa) consortium, a global rare variant association resource that integrates sequencing and linked health-record data from ten biobanks and cohorts comprising over 1.2 million individuals across diverse ancestries. We performed gene-based meta-analyses of rare coding variation across 33 clinical endpoints and 11 quantitative traits. Aggregating evidence across biobanks and ancestries identified 514 gene-trait associations, including 31 not previously reported in prior studies or curated association resources following systematic literature review. Notably, 36.1% of gene-level associations were undetectable in any individual biobank, and 91 emerged only through cross-ancestry meta-analysis, demonstrating that federated integration enables discovery beyond the reach of single cohorts. Similar gains were observed at the variant level, where 25.0% of phenotype-locus associations were detectable only through meta-analysis. Effect size estimates were correlated across ancestries with concordant directions of effect, supporting the generalizability of rare variant associations. The identified signals implicate pathways involved in transcriptional and epigenetic regulation, metabolism, vascular and epithelial biology, and immune function, highlighting rare coding variation as an engine for biological discovery across medical record phenotypes. For example, damaging variation in ANKRD12 implicates inflammatory transcriptional dysregulation in asthma and chronic obstructive pulmonary disease, and ultra-rare predicted loss-of-function variants in NAA15 link protein acetylation processes to type 2 diabetes risk. BRaVa establishes a scalable framework and freely available community resource for rare variant meta-analysis across global biobanks. Public release of gene- and variant-level association summary statistics provides a reference map of rare coding variant associations to support disease gene discovery, biological interpretation, and therapeutic target prioritization as sequencing-linked health-record resources continue to expand.

Journal Article↗

PubMed1992

A consumer's guide to subgroup analyses.

The extent to which a clinician should believe and act on the results of subgroup analyses of data from randomized trials or meta-analyses is controversial. Guidelines are provided in this paper for making these decisions. The strength of inference regarding a proposed difference in treatment effect among subgroups is dependent on the magnitude of the difference, the statistical significance of the difference, whether the hypothesis preceded or followed the analysis, whether the subgroup analysis was one of a small number of hypotheses tested, whether the difference was suggested by comparisons within or between studies, the consistency of the difference, and the existence of indirect evidence that supports the difference. Application of these guidelines will assist clinicians in making decisions regarding whether to base a treatment decision on overall results or on the results of a subgroup analysis.

Causality↗

PubMed2026

Evolving Role of Immunotherapy in Advanced Esophageal Squamous Cell Carcinoma: Are Programmed Death-Ligand 1 (PD-L1) Cutoffs Still Relevant?

Immune checkpoint inhibitors have transformed the management of advanced esophageal squamous cell carcinoma (ESCC) across first-line, second-line, and perioperative settings. Programmed death-ligand 1 (PD-L1) expression has served as the principal biomarker guiding patient selection for these agents, yet it is measured inconsistently across trials and antibody platforms, and its predictive value has come under renewed scrutiny as follow-up data have matured. This review synthesizes the pivotal randomized trials that established anti-programmed cell death protein-1 therapy in ESCC, critically appraises the pooled and patient-level meta-analyses that have re-examined outcomes across biomarker subgroups, and situates recent regulatory reassessment of PD-L1 thresholds within this broader evidence base. Assay heterogeneity between scoring systems, discordance across antibody clones, and the biological distinction between PD-L1 as a prognostic versus a predictive marker are examined as sources of continued uncertainty. The review concludes by considering emerging genomic and microenvironmental biomarkers that may eventually complement or refine PD-L1-based patient selection, and offers a framework for interpreting a single expression threshold as an approximate, assay-dependent stratifier rather than a precise biological boundary.

combined positive score↗

PubMed1992

[Mishaps with anti-arrhythmic agents used to reduce mortality after infarction].

The presence of isolated and/or repetitive ventricular arrhythmias following myocardial infarction identifies a group of patients at increased risk of death. The availability of anti-arrhythmic drugs, noticeably drugs with class I activity, efficient at suppressing arrhythmias has led to the hope that their administration could reduce post-myocardial infarction mortality. However, this hypothesis has not been confirmed. The Cardiac Arrhythmia Suppression Trial, which was designed to have the power to test the hypothesis that suppression of ventricular arrhythmias is associated with a decrease in mortality following myocardial infarction, even showed an increase in mortality with two drugs with class I activity. Several meta-analyses have confirmed that administration of class I antiarrhythmic drugs is of no clinical benefit in patients with non sustained ventricular arrhythmias following myocardial infarction. Ongoings studies are testing the hypothesis that such benefit could exist with amiodarone. The clinical benefit of beta-blockers, in terms of reduction of both total and sudden death post-myocardial infarction, has been clearly documented and mandates their administration in this setting. Futures studies of anti-arrhythmic drugs will have to focus on groups of patients at increased risk of arrhythmic death.

Amiodarone↗

PubMed1992

Review articles and publication bias.

Publication bias occurs if the results from studies which have not been published are different from the published ones. From a Bayesian viewpoint, it also concerns non-publication of studies with similar results as the published ones because the strength of the evidence will be influenced. Publication bias complicates the interpretation of reviews and meta-analyses. If favourable results are published more often there will be an overestimation of the effects of a treatment. There have been several attempts to assess the magnitude of publication bias. Unpublished trials could be identified by means of a survey among researchers, and the results could subsequently be compared with the outcomes of published trials. Also, the results from published trials could be compared with trials from a registry. Furthermore, the results from registered but unpublished trials could be compared with those of registered and subsequently published trials. Studies addressing publication bias have shown that it is a serious problem which complicates the interpretation of reviews. In assessments of publication bias other factors must be taken into account. These include the mode of publication: refereed journals, other journals, books, etc. Differences could also be related to the quality of trials. Finally, the source of funding may influence both the results and subsequent publication. Publication bias can only be avoided by registration of all trials before data collection is started; several of such registries have already been installed. Perhaps, if more of such registries exist, reviewers could only use registered trials for their main conclusions. All other information could then be considered sensitive to publication bias.

Meta-Analysis as Topic↗

PubMed1992

Paroxetine in the treatment of melancholia and severe depression.

Meta-analyses of the worldwide paroxetine database assessed the efficacy of this compound in the treatment of both DSM-III defined melancholia and hospitalised patients with severe depression (HAMD > or = 25). The analysis for melancholia included 178 paroxetine treated patients and 66 patients treated with placebo. Paroxetine was significantly superior to placebo in the treatment of melancholia and a clear dose-response relationship was established. The meta-analysis for severely depressed hospitalised patients included 109 paroxetine treated patients and 107 patients treated with a tricyclic/tetracyclic control. Paroxetine and active controls showed comparable efficacy in the treatment of severely depressed hospitalised patients.

Adult↗

PubMed1992

The exclusion of the elderly and women from clinical trials in acute myocardial infarction.

OBJECTIVE: To determine the extent to which the elderly have been excluded from trials of drug therapies used in the treatment of acute myocardial infarction, to identify factors associated with such exclusions, and to explore the relationship between the exclusion of elderly and the representation of women. DATA SOURCES: We conducted a systematic search of the English-language literature from January 1960 through September 1991 to identify all relevant studies of specific pharmacotherapies employed in the treatment of acute myocardial infarction. To accomplish this, we searched MEDLINE, major cardiology textbooks, meta-analyses, reviews, editorials, and the bibliographies of all identified articles. STUDY SELECTION: Only trials in which patients were randomly allocated to receive a specific therapeutic regimen or a placebo or nonplacebo control regimen were included for review. DATA EXTRACTION: Studies were abstracted for year of publication, source of support, performance location, drug therapies to which patients were randomized, use of invasive diagnostic tests or therapeutic procedures, exclusion criteria, size and demographic characteristics of the randomized study population, and principal outcome measures. DATA SYNTHESIS: A total of 214 trials met inclusion criteria, involving 150,920 study subjects. Over 60% of trials excluded persons over the age of 75 years. Studies published after 1980 were more likely to have age-based exclusions compared with studies published before 1980 (adjusted odds ratio, 4.92; 95% confidence interval, 2.33 to 10.54). Trials of thrombolytic therapy involving an invasive procedure were more likely to exclude elderly patients compared with other studies (adjusted odds ratio, 2.45; 95% confidence interval, 1.10 to 5.47). Studies with age-based exclusions had a smaller percentage of women compared with those without such exclusions (18% vs 23%; P = .0002), with the mean age of the study population significantly associated with the proportion of women participants (P = .0001, R2 = .29). CONCLUSIONS: Age-based exclusions are frequently used in clinical trials of medications used in the treatment of acute myocardial infarction. Such exclusions limit the ability to generalize study findings to the patient population that experiences the most morbidity and mortality from acute myocardial infarction.

Age Factors↗

PubMed1992

The impact of stopping rules on heterogeneity of results in overviews of clinical trials.

This paper explores the extent to which application of statistical stopping rules in clinical trials can create an artificial heterogeneity of treatment effects in overviews (meta-analyses) of related trials. For illustration, we concentrate on overviews of identically designed group sequential trials, using either fixed nominal or O'Brien and Fleming two-sided boundaries. Some analytic results are obtained for two-group designs and simulation studies are otherwise used, with the following overall findings. The use of stopping rules leads to biased estimates of treatment effect so that the assessment of heterogeneity of results in an overview of trials, some of which have used stopping rules, is confounded by this bias. If the true treatment effect being studied is small, as is often the case, then artificial heterogeneity is introduced, thus increasing the Type I error rate in the test of homogeneity. This could lead to erroneous use of a random effects model, producing exaggerated estimates and confidence intervals. However, if the true mean effect is large, then between-trial heterogeneity may be underestimated. When undertaking or interpreting overviews, one should ascertain whether stopping rules have been used (either formally or informally) and should consider whether their use might account for any heterogeneity found.

Analysis of Variance↗

PubMed1992

Directory of registries of clinical trials.

Registries of clinical trials are a potentially useful resource for the planning of new studies, the promotion of communication and collaboration between researchers, the conduct of meta-analyses, and the facilitation of patient access and recruitment to trials. However, many physicians and researchers are unaware of their existence, and as a result they remain underused. A directory of registries of clinical trials has been developed as a result of an international survey of 63 organizations and 51 individuals in 13 different countries to identify the existence of such registries. This is intended as a resource to keep physicians, researchers, trial organizers, funding bodies and government agencies abreast of the growing number of registries available, and to assist in the planning of future registries. Twenty-four current and six planned registries of clinical trials have been identified. Most focus on AIDS or oncology, but such diverse areas as neurosurgery, cardiovascular disease, dentistry and perinatology are also represented. This paper presents a descriptive profile on each registry and discusses the relative merits of their different organizational features. Recommendations are given for the establishment of future registries.

Clinical Protocols↗

PubMed1991

[Class I anti-arrhythmia agents and prevention of sudden death following myocardial infarction].

The results of therapeutic trials of Class I antiarrhythmic agents after myocardial infarction are not identical or always compatible with those of the CAST. It is important to determine the reason for this disparity in order to try and identify the patients who should not be given these drugs and those in whom they could be beneficial, providing these benefits are clearly demonstrated. Meta-analyses of controlled therapeutic trials of Class I antiarrhythmics after myocardial infarction have been performed. Depending on the study protocol used, the results of the CAST are compatible or incompatible with those of other trials. A possible reason for this apparent discordance from meta-analysis could be the particularly low cardiac risk in the CAST patients.

Anti-Arrhythmia Agents↗

PubMed1991

Treatment of hypertension: a clinical epidemiologist's view.

The majority of deaths attributable to hypertension are coronary artery disease (CAD) deaths and, consequently, the prevention of CAD should be the primary aim of hypertension management. Recent meta-analyses confirm the results of the individual hypertension intervention trials, which demonstrated a disappointing shortfall in the observed prevention of CAD events and mortality from lowering blood pressure compared with the expected benefits. These trial results, rather than challenging the validity of the causal nature of the association between hypertension and CAD may be interpreted to suggest that the management of hypertension in the trials was suboptimal. The drugs used in the trials were almost exclusively thiazide diuretics and to a lesser extent beta-blockers. Both of these drug groups have been shown to have adverse effects on lipid profiles--a pivotal risk factor for CAD. In addition to the effects on lipids, diuretics also adversely affect potassium, uric acid, glucose metabolism, and insulin resistance, all of which directly or indirectly affect the incidence of CAD. In the face of a major shortfall in the overall benefit from managing hypertension with diuretics and to a lesser extent beta-blockers, it therefore seems more logical to recommend for the management of hypertension the use of agents with a more metabolic-friendly profile.

Coronary Disease↗

PubMed1991

Treatment with verapamil during and after an acute myocardial infarction: a review based on the Danish Verapamil Infarction Trials I and II. The Danish Study Group on Verapamil in Myocardial Infarction.

The effect of verapamil on death and reinfarction after an acute myocardial infarction was studied in two double-blind, randomized, placebo-controlled multicenter trials, the Danish Verapamil Infarction Trials I and II (DAVIT I and II). The studies demonstrated that verapamil 360 mg/day from the 2nd week after an acute myocardial infarction, prevented death and reinfarction. Meta-analyses of the results of DAVITs I and II resulted in a reduction of pooled ratios of 22% (95% confidence limits 1-37, p = 0.04) for death, 21% (5-35, p = 0.02) for first major events (first reinfarction or death), and 27% (6-43, p = 0.02) for first reinfarctions. The effect of verapamil was to prevent myocardial ischemia and reduce sudden death and reinfarction. It is concluded that long-term treatment with verapamil after an acute myocardial infarction may be recommended with the object of reducing overall mortality, major events and reinfarction.

Arrhythmias, Cardiac↗

PubMed1991

Prophylaxis of deep venous thrombosis and pulmonary embolism.

Clinically silent deep venous thrombosis (DVT) develops in up to 25% of patients who undergo general surgical procedures. Approximately 10% of these thromboses are complicated by potentially fatal pulmonary embolism. Two recent meta-analyses of more than 70 published trials of DVT prophylaxis in general surgery have demonstrated conclusively that prophylaxis significantly reduces rates of DVT and fatal pulmonary embolism and results in improved overall survival. Physical methods of prophylaxis, including compression stockings and intermittent pneumatic compression, are as effective as pharmacologic prophylaxis (the most common regimen being heparin, 5000 units subcutaneously ever 8 to 12 hours). Bleeding complications are increased with the use of heparin, although they are clinically minor. Deep venous thrombosis prophylaxis should be routinely instituted for all general surgical patients who undergo major operative procedures.

Heparin↗

PubMed1991

[Rehabilitation following myocardial infarct].

Today rehabilitation after myocardial-infarction is a routine measure in most countries, yet its effectiveness is still under discussion. Rehabilitation aims at ameliorating the quality of life and at preventing a cardiovascular reevent, in other words at prolonging life. The latter "hard" endpoints is best amenable to quantification. Only recent meta-analyses of pooled data were able to show that rehabilitation in fact does prolong life. The relative importance of physical exercise in mostly complex rehabilitation programs is even less clear. This analyses implies a benefit, yet the exact proof is still missing. If rehabilitation could be shown to improve quality of life, its application would, of course, be justified even if it did fail to prolong life. Important open questions relate to the optimizing of rehabilitation: duration, frequency, intensity as well as age and sex of responders. Answering these will be a challenge for tomorrow's rehabilitation medicine.

Combined Modality Therapy↗