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PubMed2026

Reduced FOXP3 expression and its association with genetic ancestry in neuromyelitis Optica spectrum disorder: a Colombian cohort.

BACKGROUND: Autoimmune disorders are characterized by impaired immune tolerance, largely mediated by CD4⁺ regulatory T cells (Tregs), whose function depends on the transcription factor FOXP3. OBJECTIVES: To compare FOXP3 expression levels between patients with neuromyelitis optica spectrum disorder (NMOSD) and healthy controls from Bogotá, Colombia, and to explore their association with genetic ancestry. METHODS: FOXP3 expression was quantified from peripheral blood mononuclear cells using RNA-based analysis. Genomic ancestry proportions were estimated using ancestry-informative markers. RESULTS: FOXP3 mRNA expression was significantly reduced in NMOSD patients compared with controls (∼2.4-fold decrease in median expression; p = 0.027). Lower FOXP3 mRNA expression was associated with optic neuritis (p = 0.0059), but not with historical or current AQP4-IgG seropositivity. In a sensitivity analysis restricted to patients with documented historical AQP4-IgG seropositivity, the direction of reduced FOXP3 mRNA expression was preserved but did not reach statistical significance. In pre-specified exploratory ancestry-related analyses, African (p = 0.035) and Amerindian ancestry (p = 0.012) were associated with FOXP3 mRNA expression levels. CONCLUSIONS: Reduced FOXP3 mRNA expression in Peripheral Blood Mononuclear Cells (PBMCs) suggests an altered immune regulatory profile in NMOSD, potentially involving mechanisms beyond antibody-mediated immunity. The association between genetic ancestry and FOXP3 mRNA expression suggests that population-specific genetic background may influence immune regulatory pathways. These findings should be interpreted as exploratory and require validation in larger, clinically homogeneous cohorts.

Adolescent↗

PubMed2026

Multiparametric flow cytometry immune profiling of pulmonary and extra-pulmonary tuberculosis reveals distinct blood-based biomarker signatures.

This study investigated immune cell distributions, cell-specific immune markers, and selected biomarker targets in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) using multiparametric flow cytometry (MFC). Whole blood was collected from 45 individuals, including healthy controls (HC), EPTB, and PTB patients (n = 15/group). Peripheral blood leukocytes were analysed by MFC to characterize CD4+ and CD8+ T cells, natural killer (NK), invariant NKT (iNKT) and NKT cells, classical (CM), intermediate (IM) and non-classical monocytes (NCM), and activated monocytes (AM). Expression of GBP1, CALCOCO2, IFIT3, SNX10, ARG1, PD-1, and PD-L1 was assessed across these immune subsets. Increased frequencies of NK, NKT, and monocytes were observed in PTB and EPTB compared with HC, while CD4+, CD8+, iNKT, and AM were reduced. Monocyte-to-lymphocyte ratios were incrementally elevated in EPTB and PTB compared with HC. Despite variability of expression within groups, median biomarker fold-change expression changes were found between HC, EPTB and PTB groups; (i) (>2.0FC) for ARG1 in CD4, CD8, CM and AM, for CALCOCO2 in AM, GBP1 in CD8 and NCM, PD-1 in CD4, CD8, NK, IM and AM, PD-L1 in CD4, CD8, iNKT and NKT, NK, IM and AM and SNX10 in CD4, CD8, NCM, IM and AM (ii) (<2.0FC) in TB vs HC for CALCOCO2 in iNKT and NKT, IFIT3 in NCM, PD-1 in NK and NCM, PD-L1 in NCM, IM and AM and SNX10 in AM. Statistical significance was achieved for ARG1 (P = 0.017) in CD4 cells. Our findings highlight distinct immune cell and biomarker signatures in PTB and EPTB.

Humans↗

PubMed2026

Glycaemic burden disrupts innate immunity in TB by modulating CD206 expression and macrophage antimicrobial responses.

Tuberculosis (TB) and diabetes mellitus (DM) represent a growing dual global health burden, with chronic hyperglycaemia recognized as a major modifier of host immunity against Mycobacterium tuberculosis (Mtb). Macrophages, central to pathogen recognition, phagocytosis, antigen presentation, and intracellular killing, may be particularly vulnerable to diabetic metabolic dysregulation. This study evaluated phenotypic and functional macrophage alterations in individuals with pulmonary TB, type 2 DM, TB-DM comorbidity, and healthy controls. Surface receptor expression was analysed by multicolour flow cytometry, while phagocytosis and intracellular bacterial clearance were assessed using FITC-labelled Mtb assays and colony-forming unit enumeration. Hyperglycaemia was associated with reduced CD11b, MARCO, and TLR2 expression alongside upregulation of the mannose receptor CD206, which correlated positively with HbA1c levels, indicating a shift toward a permissive M2-like phenotype. Phagocytic uptake of Mtb was significantly impaired and inversely correlated with HbA1c. Antigen-presenting capacity was selectively compromised, with reduced CD80 and CD86 expression in DM and TB-DM groups, while HLA-DR remained unchanged. Intracellular Mtb killing was markedly diminished in diabetic macrophages. These findings demonstrate that chronic hyperglycaemia profoundly disrupts macrophage innate immunity, contributing to increased TB susceptibility and poor infection control in diabetic populations.

Humans↗

PubMed2026

Integrative machine learning models to unravel gut microbial dysbiosis and functional disruption in polycystic ovary syndrome.

OBJECTIVE: To study gut microbial diversity and metabolic pathway disruptions in women with PolyCystic Ovary Syndrome (PCOS) compared with healthy controls, and to evaluate the diagnostic potential of microbiome-driven machine learning models. DESIGN: Case-controlled metagenomic data analysis SUBJECTS: Gut metagenomic data from women diagnosed with PCOS and age-matched healthy female controls EXPOSURE: Presence of PCOS MAIN OUTCOME MEASURES: The primary outcome measures will include gut microbial alpha and beta diversity indices, microbial taxon abundance, functional pathway profiles, predicted metabolite levels, microbe-functional pathway-metabolite interaction networks, and the diagnostic accuracy of microbiome-based machine learning models. RESULTS: Alpha and beta diversity analyses revealed marked gut microbial dysbiosis in women with PCOS, despite comparable species richness to healthy controls. Differential abundance analysis identified 41 significantly altered microbial species, including enrichment of proinflammatory taxa, such as Bacteroides vulgatus and Ruminococcus gnavus, and depletion of beneficial commensals, including Roseburia hominis and Prevotella copri. These compositional shifts indicate a proinflammatory microbial community structure in PCOS. Functional profiling demonstrated the upregulation of pathways involved in nucleotide turnover, lipid and carbohydrate metabolism, and neurotransmitter synthesis, potentially contributing to metabolic and neuroendocrine disruption. Network analysis revealed fragmented and unstable microbial-metabolite associations in PCOS compared with cohesive networks in controls. Microbiome-based machine learning models achieved a diagnostic accuracy of 84.25% (area under the curve 0.93), underscoring their predictive potential. CONCLUSION: The gut microbiome in PCOS is characterized by a proinflammatory community structure and disrupted metabolic pathways. These findings demonstrate the diagnostic potential of microbiome-based models and underscore the gut microbiome as a promising target for therapeutic interventions in the management of PCOS.

Polycystic Ovary Syndrome↗

PubMed2026

Variants in the interferon regulatory factor 5 gene confer genetic risk for systemic lupus erythematosus in a Han Chinese population.

BACKGROUND: Interferon regulatory factor 5 (IRF5), integral to interferon signaling pathways, has been identified as a susceptibility locus for systemic lupus erythematosus (SLE). Nevertheless, the relationship between IRF5 variants and SLE risk within the Han Chinese demographic remains inadequately characterized. MATERIALS AND METHODS: Genotyping of two functional single nucleotide variants (SNVs) in IRF5 was conducted in 167 individuals with SLE and 246 healthy controls utilizing sequence-specific primer polymerase chain reaction (PCR-SSP). Chi-square and Fisher's exact tests were employed to assess associations. RESULTS: The rs10954213 variant demonstrated a significant association with SLE susceptibility under the recessive model (GG vs. AG+AA, OR = 2.20, 95% CI: 1.30-3.75, p = 0.003, adjusted p [pc] = 0.030) and homozygous model (GG vs. AA, OR = 2.43, 95% CI: 1.36-4.42, p = 0.003, pc = 0.032). Similarly, the rs2004640 variant was associated with an increased risk of SLE across allelic (T vs. G, OR = 1.66, 95% CI: 1.22-2.26, p = 0.001, pc = 0.011), dominant (TG+TT vs. GG, OR = 1.77, 95% CI: 1.19-2.63, p = 0.005, pc = 0.047), and homozygous models (TT vs. GG, OR = 3.72, 95% CI: 1.58-8.78, p = 0.002, pc = 0.016). Haplotype analysis identified protective haplotype HT1 (A/G, OR = 0.54, 95% CI: 0.41-0.73, p < 0.001) and risk haplotype HT4 (G/T, OR = 2.51, 95% CI: 1.42-4.42, p = 0.001). CONCLUSIONS: These findings indicate that IRF5 gene variants substantially modulate susceptibility to SLE in the Han Chinese population. They hold potential as biomarkers for evaluating SLE risk and offer valuable perspectives into disease pathogenesis.

Adult↗

PubMed2026

Sex- and age-specific associations of VEGFA polymorphisms with multiple sclerosis susceptibility.

AIM: To evaluate six VEGFA polymorphisms (rs1570360, rs699947, rs3025033, rs2146323, rs1413711 and rs833061) and serum VEGFA concentrations in 270 Lithuanian patients with multiple sclerosis (MS) and 270 matched healthy controls. METHODS: Genotyping was performed using real-time PCR, and serum VEGFA levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were conducted using IBM SPSS version 31.0. RESULTS: Nominal differences in VEGFA genotype and allele distributions were observed in sex- and age-stratified analyses. Among females, the rs1413711 C allele was more frequent (p = 0.005), whereas the rs833061 C allele was less frequent (p = 0.006), in MS patients than controls. In participants aged >38 years, the rs1413711 C allele was also more frequent in MS cases (57.5% vs. 46.0%, p = 0.008). Logistic regression identified nominal associations, particularly for rs1413711, rs699947 and rs833061, but none remained significant after correction for multiple testing. Serum VEGFA levels were higher in MS patients than controls (p = 0.004). Nominal genotype-related differences in serum VEGFA levels and haplotype associations with reduced MS odds were also observed, but did not remain significant after multiple-testing correction. No consistent associations were found between VEGFA variants and clinical parameters. CONCLUSION: VEGFA genetic variation and elevated serum VEGFA may be associated with MS, but the genetic findings require confirmation in larger independent cohorts.

Humans↗

PubMed2026

Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.

BACKGROUND AND AIMS: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. METHODS: All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. RESULTS: Most variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. CONCLUSIONS: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Humans↗

PubMed2026

Immature Neutrophil Programs Associate With Burn Mortality and Extend Across Critical Illnesses.

Severe burns provoke a systemic "genomic storm," yet cell states associated with divergent outcomes remain unclear. We profiled blood cells by single-cell RNA-Sequencing (73 014 cells) from adult patients with burn injuries within postburn day 17 (n = 4) and healthy donors (n = 5), integrated data with bulk signatures of burn size, inhalation injury, and mortality, and evaluated clinical associations in the American Burn Association National Burn Repository. Burn was associated with emergency hematopoiesis marked by expansion of hematopoietic stem/progenitor-like cells, immature neutrophils, and plasmablast/plasma cell states, alongside depletion of naïve CD4+/CD8+ T cells and dendritic cells. Larger burns (>20% TBSA) showed enrichment of humoral transcriptional programs, including plasmablast/plasma cell activation and suppression of cytotoxic CD8+ T-cell states. In multivariable models, inhalation injury was a stronger predictor of death (adjusted odds ratio [OR] 1.9) than burn size (adjusted OR 1.1) and shared greater overlap with the most perturbed single cells in non-survivors; 55% of co-perturbed cells were neutrophils, implicating granulocyte dysregulation as a common lethal axis. We identified a neutrophil-specific 5-gene panel (OLFM4, RETN, LCN2, ARG1, and BTNL3) that discriminated survivors vs non-survivors after burns (area under the curve [AUC] > 0.9) and generalized to trauma (n = 158; AUC 0.81) and intensive care unit COVID-19 (n = 103; AUC 0.75), providing information orthogonal to conventional biomarkers and severity scores. Cytomorphology corroborated transcriptomic immaturity, with ~2-fold higher band neutrophils and larger neutrophil size in a fatal case. Computational drug-reversal analysis highlighted galectin-1 inhibition as a candidate modulator of mortality-associated neutrophil programs. Together, our findings suggest that immature neutrophils represent a shared immune feature across severe burns and other forms of critical illness.

Humans↗

PubMed2026

TMEM176B is co-expressed with TMEM176A and upregulated in peripheral blood monocytes of patients with primary Sjögren's syndrome.

OBJECTIVES: This study aims to determine the role of acid‑sensitive nonspecific cation channels transmembrane protein 176A (TMEM176A) and TMEM176B in autoimmune diseases, with a focus on primary Sjögren's Syndrome (pSS). METHODS: We examined the expression patterns of TMEM176A and TMEM176B across tissues and cells utilizing bulk RNA-seq and scRNA-seq datasets. Immunophenotyping analysis was performed by flow cytometry to compare CD62L expression between TMEM176B⁺ and TMEM176B⁻ monocytes. The proportion of TMEM176B+ cells in monocytes was interrogated in both pSS patients and healthy controls. Clinical correlations of TMEM176B with anti‑SSB antibody and complement C4 levels were also evaluated. RESULTS: TMEM176A and TMEM176B showed conserved co‑expression and were significantly upregulated in autoimmune diseases. TMEM176B⁺ monocytes displayed higher CD62L positivity rate than TMEM176B- monocytes. In pSS patients, the proportion of TMEM176B⁺ monocytes was elevated in total monocytes, classical monocytes (cMo) and intermediate monocytes (iMo). The proportion of TMEM176B+ monocytes positively correlated with anti‑SSB levels, while several TMEM176B-associated monocyte subset markers inversely correlated with C4. CONCLUSION: TMEM176A and TMEM176B are highly correlated. TMEM176B expression in monocytes is linked to pSS and may serve as a novel auxiliary diagnostic biomarker.

Humans↗

PubMed2026

ATM Variants and Breast Cancer Risk in North Macedonia: Focus on the Regionally Enriched p.(Leu2492Arg) Variant.

BACKGROUND: Germline pathogenic variants (PVs) in the ataxia-telangiectasia mutated (ATM) gene are established moderate-risk factors for breast cancer (BC), however, population-specific variant spectra and the clinical significance of many missense variants remain incompletely characterized. AIMS: To evaluate the prevalence of ATM variants in a large cohort of patients with BC from North Macedonia and compare it with that in the general population, with a particular focus on the frequency of the p.(Leu2492Arg) variant and its distribution relative to global genomic datasets. STUDY DESIGN: Retrospective case–control study. METHODS: ATM variants were analyzed in 1,211 patients with BC from North Macedonia using a targeted hereditary cancer gene panel. These findings were compared with those from 1,303 population-based controls analyzed by clinical exome or whole-exome sequencing. RESULTS: Pathogenic ATM variants were identified in 1.9% of BC cases and 0.4% of controls, indicating a significantly increased risk of BC [odds ratio (OR) = 5.02, p = 0.0006]. Most PVs were protein-truncating, with six recurrent variants accounting for over 70% of detections, suggesting regional enrichment. Carriers showed a significantly higher prevalence of human epidermal growth factor receptor 2-positive tumors (OR = 2.92, p = 0.0189). Variants of uncertain significance were observed at comparable frequencies in cases and controls. The p.(Leu2492Arg) missense variant was more frequently detected in cases than in controls (1.9% vs. 1.1%; OR = 1.78, p = 0.086) and exhibited a markedly higher allele frequency in this population than in global databases. CONCLUSION: These findings confirm ATM as a clinically relevant BC susceptibility gene in North Macedonia and highlight the population-specific enrichment of both PVs and the p.(Leu2492Arg) missense variant. The results emphasize the importance of using population-matched controls and regional genomic data for accurate risk assessment and variant interpretation.

Humans↗

PubMed2026

Association of ERBB4 and SHBG gene polymorphisms with polycystic ovarian syndrome in South Indian women: a case-control genetic analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a multifactorial endocrinological disorder with a substantial genetic component. However, the role of genes involved in follicular development and androgen regulation remains incompletely understood, particularly in South Indian populations. This study aimed to evaluate how variations in the ERBB4 and SHBG genes affect PCOS risk. METHODOLOGY: A hospital-based case-control study was conducted among 400 South Indian women, comprising 200 women with PCOS and 200 age-matched healthy controls. Genomic DNA was extracted to study SNPs at ERBB4 (rs2178575 and rs1351592) and SHBG (rs1799941 and rs727428) using ARMS-PCR genotyping. The study compared genotype and allele frequencies between cases and controls while assessing their associations with allelic, homozygous, heterozygous, dominant, recessive, and over-dominant genetic models. Genotyping accuracy was confirmed by re-genotyping and Sanger sequencing of a subset of samples. RESULTS: The ERBB4 rs2178575 polymorphism demonstrated a significant association with PCOS, as the AA genotype and A allele combination increased risk across all three genetic models, including homozygous, recessive, and allelic models. The ERBB4 rs1351592 variant was associated with 3-fold higher risk of PCOS in heterozygous and GC carriers. The SHBG rs1799941 polymorphism showed a significant link to PCOS through its effects on heterozygous and allelic states, whereas rs727428 displayed no significant connection due to its monomorphic distribution. CONCLUSION: These findings suggest that polymorphisms in ERBB4 and SHBG may contribute to PCOS susceptibility in South Indian women in a locus- and model-specific manner, revealing the intricate genetic structure that defines this medical condition.

Humans↗

PubMed2026

The Childhood Cancer and Leukemia International Consortium (CLIC): Expanding global collaboration in pediatric cancer etiology research.

Childhood cancers are rare, but incidence has risen modestly in countries with robust registration, partly reflecting improved diagnosis. In high-income countries, cancer is the leading cause of disease-related death in children. Marked inequities in incidence, survival, and research capacity underscore the need for large-scale collaboration to identify environmental, genetic, and contextual determinants of risk. The Childhood Cancer and Leukemia International Consortium (CLIC) was established in 2007 to study the etiology of childhood leukemia and later expanded in 2019 to include other childhood cancers, principally solid tumors. CLIC pools harmonized, individual-level data from case-control and cohort studies, obtained through interviews, record linkage (insurance claims, registries), or geographic information systems, and integrates germline genomic data where available. Membership has grown from 13 studies in 9 countries to 57 studies in 21 countries; recruitment spans the early 1960s to the present and encompasses approximately 150,000 cases across all tumor types and 300,000 controls with clinical, demographic, and exposure data, centralized via harmonized data dictionaries at the Data Coordination Center, established in 2014 at the International Agency for Research on Cancer, and supported by a secure analysis platform. Pooled analyses across diverse populations have implicated parental age, prenatal vitamin or folic acid use, mode of delivery, fetal growth, selected congenital anomalies, occupational or household exposures (e.g., pesticides), paternal smoking, and markers of early-life immune modulation (e.g., breastfeeding, daycare attendance) in leukemia risk, informing carcinogen evaluation and prevention. The integration of genetic ancestry and germline susceptibility data is clarifying ancestry-related differences in leukemia biology and outcomes, while confirming risk loci with population-specific effects. CLIC is now adding polygenic risk scores and exposomic data to refine etiologic subtyping and identify modifiable pathways, while broadening representation from underserved regions through partnership-building and capacity-strengthening.

Humans↗

PubMed2026

Sodium Glucose Co-Transporter 2 Inhibitors and Ventricular Arrhythmias in Patients with Type 2 Diabetes: A Systematic Review of Observational Studies.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) may exert antiarrhythmic effects, but their association with ventricular arrhythmias remains unclear. OBJECTIVE: We conducted a systematic review to evaluate the association between SGLT2i use and the risk of ventricular arrhythmias, cardiac arrest, and sudden cardiac death compared with other antidiabetic medications or no SGLT2i use among patients with type 2 diabetes mellitus. METHODS: MEDLINE, EMBASE, and CENTRAL were searched for observational studies published between March 2013 and March 2026. Quality was assessed using the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool, alongside evaluation of pharmacoepidemiology-specific biases. RESULTS: A total of 17 studies (16 cohort and one nested case-control) were included. Based on ROBINS-I, seven studies had moderate, eight serious, and two critical risks of bias. Eleven studies had at least one pharmacoepidemiology-specific bias. For ventricular arrhythmias, estimates ranged from a protective effect (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.04-0.97) to a potential increased risk (odds ratio 1.87, 95% CI 0.89-3.95) with SGLT2i use. For cardiac arrest, estimates consistently reported a lower risk with estimates that ranged from HR 0.63 (95% CI 0.59-0.68) to HR 0.85 (95% CI 0.82-0.88). The only study on sudden cardiac death reported a potential risk reduction (HR 0.62, 95% CI 0.38-1.01). CONCLUSIONS: While the association between SGLT2i and ventricular arrhythmias remains inconsistent, the use of SGLT2i likely reduces cardiac arrest and may reduce sudden cardiac death, suggesting a possible protective effect on ventricular arrhythmias among patients with type 2 diabetes.

Journal Article↗

PubMed2026

GWAS meta-analysis provides new insights into uveal melanoma risk.

OBJECTIVE: The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5839 individuals with UM (3853 novel) and 349,863 healthy controls. METHODS: Five novel UM genome-wide association studies (GWAS) were performed and included for meta-analysis with four previously published UM GWAS. A fixed-effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case-control cohorts. A follow-up transcriptome-wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma-related phenotypes were measured to elucidate UM's genetic architecture. RESULTS: We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10-8. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non-significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). CONCLUSIONS: This meta-analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Humans↗

PubMed2026

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND: Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS: Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p = 0.002; FDR q = 0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p = 0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS: PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Humans↗

PubMed2026

Approaches to observational study designs and analytical options to evaluate the safety of multi-dose vaccines: a systematic review.

INTRODUCTION: Observational studies require careful considerations when evaluating the safety of multidose vaccines. We reviewed design and analytical approaches in observational studies evaluating the safety of multidose vaccines in the post-licensure phase. METHODS: EMBASE, MEDLINE, Web of Science, and Scopus (2018-2022) were searched for hypothesis-testing studies evaluating the safety of multidose vaccines. Key features from frequently used designs were extracted. RESULTS: Among 123 eligible studies, cohort (46%) and self-controlled case series (SCCS)/self-controlled risk interval (SCRI) (40%) followed by case-control (12%) were the most common designs, and 15% of studies used multiple designs. Among cohort studies evaluating multiple doses, vaccination date (36%) and cohort entry with time-updated exposure status (32%) were frequent approaches used to define time zero. Twenty-eight percent of cohort studies did not report time zero; all but one evaluated COVID-19 vaccine effect on post-delivery and fertility-related outcomes. For SCCS/SCRI, 64% of studies accounted for event-dependent exposures, mainly by including pre-exposure periods (53%) and modified SCCS model (48%), while 20% employed multiple correction strategies. Among studies using multiple designs, 68% reached consistent conclusions. CONCLUSIONS: SCCS/SCRI and cohort designs dominate multidose vaccine safety studies. Clear reporting on time zero in pregnancy and fertility-related cohort studies, and on addressing event-dependent exposures in SCCS/SCRI studies is needed, along with guidance on interpreting results from multiple designs.

Humans↗

PubMed2026

Mining Stored-Specimen Studies for Information about Cancer Natural History.

The advent of new multicancer early detection tests and publication of early diagnostic results have generated expectations of clinical benefit from multicancer screening. The clinical benefit of a cancer screening test depends critically on disease natural history, which is typically learned from prospective screening studies. Retrospective studies of stored blood specimens are important in learning about a test's preclinical diagnostic performance but have rarely been used to infer natural history. The extent to which these studies might be harnessed to also learn natural history is discussed in the context of an article in this issue that infers the combined natural history of a range of cancers targeted by a multicancer early detection test using a case-control subsample of specimens from a large cohort study. The critical question concerns the identifiability of key transition rates in multistate models of natural history alongside state-specific sensitivities. The article suggests that these parameters are estimable within a Bayesian framework that leverages prior information about test sensitivity from diagnostic studies. We offer a heuristic discussion of identifiability in this setting and encourage formal study to determine the extent to which models with varying degrees of complexity may be learned from stored-specimen studies. See related article by Dai et al., p. 1535.

Humans↗

PubMed2026

Prevalence of unruptured intracranial aneurysms according to comorbidities, risk factors, country, and time period: a systematic review and meta-analysis.

BACKGROUND: The incidence of aneurysmal subarachnoid haemorrhage declined between 1980 and 2010, which coincided with a decline in smoking and prevalence of hypertension. We aimed to investigate whether the decrease in subarachnoid haemorrhage incidence is paralleled by declines in unruptured intracranial aneurysm (UIA) prevalence. METHODS: For this systematic review and meta-analysis, we searched Embase, PubMed, and Web of Science for articles published in any language from Jan 1, 2011 to Dec 31, 2025, and reassessed 68 articles published before March 1, 2011 from a 2011 systematic review and meta-analysis. Articles were eligible for inclusion if they used a cross-sectional or case-control design and provided the crude number of participants and those with UIA. We only included studies reporting numbers of UIA separately from ruptured aneurysms and with ten or more patients. Summary data were independently extracted by JD with AZ or CB and conflicts were resolved by GJER. The primary outcome was proportion of participants with UIA. Relative to a hypothetical reference population (mean age 50 years, 50% women, and no comorbidities), age and/or sex-adjusted prevalence ratios (PRs) for regions, comorbidities, and risk ratios (RRs) for female sex, smoking, and hypertension were estimated using generalised linear mixed models. A time trend analysis was done by binomial meta regression using the mid-year of data acquisition. We assessed the certainty of evidence using GRADE. The study was registered with PROSPERO, number CRD420261296728. FINDINGS: Our search screened 4708 studies. 67 reassessed and 95 newly identified articles, reporting on 316 131 participants and 11 822 people with UIAs, were included in our meta-analysis. In the reference population, the estimated prevalence of UIAs was 3·9% (95% CI 3·0-5·1). The prevalence of UIAs in individuals with atherosclerosis was 5·5% (4·7-6·4; 2229 of 40970 participants) and the adjusted PR was 1·3 (95% CI 0·8-2·0) compared with the reference population. For positive family history of aneurysmal subarachnoid haemorrhage (aSAH) or UIA, the UIA prevalence was 7·9% (5·6-11·1; 412 of 4252 participants) and the adjusted PR was 2·4 (0·5-11·2). For connective-tissue disorder, the UIA prevalence was 10·3% (6·5-16·0; 94 of 879 participants) and the adjusted PR was 3·9 (2·0-7·6). For autosomal dominant polycystic kidney disease (ADPKD), the UIA prevalence was 12·8% (9·2-17·6; 293 of 1990 participants) and the adjusted PR was 4·4 (1·5-12·6). RRs were for current smoking 1·4 (1·2-1·6; 798 of 27911 participants), for having hypertension 1·6 (1·5-1·7, 4043 of 83053 participants), and for female sex 1·9 (1·8-2·0; 3415 of 65020 women and 2122 of 76130 men). In studies on healthy individuals with MR angiography or CT angiography as imaging modality, the prevalence in 2016-2022 was 6·6% (6·3-6·8; 2904 of 41191 participants). The adjusted PR was 1·8 (1·1-2·8) for 2016-2022 versus 2002-2015. Prevalence of UIAs of 5 mm or larger was 0·7% (0·6-0·8) in 2002-2015 and 1·4% (1·0-1·9) in 2016-2022. The UIA prevalence did not differ between countries. τ2 showed significant heterogeneity between studies. The certainty of the evidence ranged from very low to moderate. INTERPRETATION: Prevalence of UIA is increasing, particularly over the past two decades. This increase is only in part explained by improved detection of small UIAs and an ageing population, and other factors-such as environmental-are likely involved. Alongside patients with ADPKD and a positive family history of aSAH, patients with connective-tissue disorders had a higher prevalence of UIA than the reference population. Our findings warrant further investigation into the potential benefit of personalised screening and management strategies in groups at high risk for having UIAs. FUNDING: None.

Humans↗