European Journal of Human Genetics

Although the Y chromosome represents roughly 2% of the male genome, it is often ignored in genome-wide association studies (GWAS). Subsequently, the potential health impacts of Y-chromosomal genetic variation remain incompletely understood. To fill this gap, we performed a phenome-wide association study (PheWAS) in FinnGen across 1,426 binary and quantitative traits using Y-chromosomal variation (frequency [&ge;] 1%) in 104,334 genotyped men. As Y chromosome variation is prone to population stratification, we performed carefully adjusted association analyses and further examined these through kin-based validation in 19,275 female and 24,712 male 1st degree relatives. We found 121 suggestive (p < 5.6x10-3) phenotypic associations in the Y chromosome, yet none of these were strong enough to reach phenome-wide significance (p < 3.9x10-6). While only 38 associations were supported in the kin-based validation, intriguingly we found support for a previously suggested link between haplogroup I1 and coronary heart disease (CHD; OR=1.06, 95%CI=1.02-1.11, p=3.7x10-3; male validation OR=1.05; female validation OR=0.97). The I1-CHD association was detected across distinct geographical areas within Finland and was independent from Loss of Y (LOY) and the autosomal risk to CHD, proposing a link between germline Y-chromosomal variation and heart disease risk. Overall, this study presents a comprehensive phenome-wide analysis of Y-chromosomal associations, highlighting the potential relevance of Y-chromosomal variation beyond sex determination. Our findings further emphasize the need for improved capture of Y-chromosomal variants and further analyses in biobank-scale data to allow for deeper exploration of male-specific genetic architecture of complex diseases.

Abstract Purpose: Published clinical outcome data on preconception carrier screening (PCS) in Central Asia are limited. We report the first clinical implementation study from Uzbekistan of a whole-exome sequencing (WES)-based multi-platform PCS program combining exome sequencing with targeted SMA, FMR1, and DMD assays. Methods: We retrospectively analyzed anonymized data from 65 individuals (19 couples, 27 singletons) screened at IMC Genomics, Tashkent, between January 2024 and May 2026. WES covering the protein-coding regions of approximately 20,000 genes was followed by exome-wide bioinformatics filtering and clinical geneticist interpretation. Partly overlapping cohorts underwent SMA carrier screening (n=179), FMR1 CGG-repeat analysis in females (n=155), and DMD deletion/duplication testing in preconception females (n=29). Variants were classified by ACMG/AMP criteria against gnomAD v4.1. Results: Sixty-one of 65 WES-screened individuals (93.8%; 95% CI 85.2 - 97.6%) carried at least one reportable variant (152 instances across 126 genes). Four of 19 couples (21.1%; 95% CI 8.5 - 43.3%) were concordant for pathogenic or likely pathogenic variants in the same autosomal recessive gene; two were referred for preimplantation genetic testing for monogenic disease. SMA screening identified four carriers, including two 2+0 silent carriers; FMR1 analysis identified one intermediate allele; DMD MLPA identified no exonic rearrangements. Conclusion: This first reported WES-based multi-platform PCS program in Uzbekistan was feasible and clinically informative, identifying actionable couple-level reproductive risks and supporting structured implementation of reproductive genetic screening in Central Asia.

Background: Two-thirds of Dutch cardiovascular risk management (CVRM) for patients at risk of cardiovascular disease is delivered in primary care practices. While individual risk scores are increasingly used during consultation, a population-level structure for risk-based patient outreach is not currently available. We therefore developed the PROSPERA programme, a multilevel intervention comprising population-level risk stratification and individual-level support tools. Aim: To assess anticipated and experienced barriers and facilitators among healthcare professionals (HCPs) to inform implementation in primary care. Methods: We conducted four focus groups and six interviews with nine primary care HCPs to explore anticipated and experienced barriers and facilitators. Inductive codes were thematically analysed and assigned to corresponding domains of the Theoretical Domains Framework (TDF) and the related Capability, Opportunity, Motivation model of Behaviour. Results: Barriers and facilitators were identified in 11 TDF domains. Population-level barriers included altered professional roles and limitations in technological infrastructure. Individual-level barriers were limited skills in interpreting risk calculations and difficulty integrating tools into clinical routine. Facilitators were related to beliefs on the importance of providing proactive care (population level), the use of U-Prevent for risk communication (individual level) and positive patient responses to the Lifestylecheck questionnaire (individual level). Conclusion: Addressing barriers and facilitators identified at both the population and individual levels can support implementation of the PROSPERA programme. Opportunities exist in education and training of HCPs in risk communication, as well as support in restructuring the physical and digital environment.

Polygenic risk scores (PRSs) are emerging as powerful tools for quantifying inherited risk for common diseases and, in some cases, are approaching clinical implementation. A major concern for PRS implementation is their limited accuracy in non-European populations, particularly in those of African ancestry. However, past evaluations have focused on metrics such as relative risk or AUC, which do not capture background risk arising from contextual factors. We introduce a novel measure of variable importance, the conditional average derivative estimator (CADE), to evaluate PRS utility across diverse contexts and populations within absolute risk models that integrate PRSs with other relevant risk factors. We illustrate this framework by integrating PRSs for breast and prostate cancer within age-specific absolute risk models for incidence and mortality fit using individual-level data from the All of Us Research Program with inputs from the National Cancer Institute SEER cancer registry. Our projections show that although the PRSs are known to have the lowest discriminatory accuracy in African Americans (AA), there are contexts in which they provide greater utility, such as for the stratification of prostate cancer risk and mortality, where the CADE values for AA were 2- and 7-fold higher than for European Americans. These findings suggest that conclusions about the limited clinical utility of PRS in non-European populations may be premature and underscore the need to quantify PRS risk-stratification utility at the absolute-risk level, while accounting for disease onset, survival, and broader health and economic factors.

Consanguinity is a reproductive union between individuals who share a recent common ancestor. These unions are common in many regions of the world and increase the burden of rare recessive disorders by elevating autozygosity in offspring. Current reproductive genetic screening focuses on a limited set of known pathogenic variants, leaving most recessive risk unaddressed. Here we argue that embryo-level autozygosity, quantified as the fraction of the genome in long runs of homozygosity (FROH), is a potentially actionable genomic biomarker that can be integrated into routine preimplantation genetic testing as a homozygosity-informed embryo-prioritization framework (PGT-H) that can be layered onto existing embryo biopsy workflows when couples are already undergoing IVF with PGT-A or PGT-M. Using forward simulations of first-cousin and double-first-cousin couples, we show that siblings conceived by the same couple span a wide range of FROH; selecting the lowest-FROH candidate from a cohort of five embryos reduces FROH by approximately 40% on average. Combining these reductions with empirical effect-size estimates, we estimate that for first-cousin couples this strategy could reduce risk of intellectual disability by roughly 35-45% (corresponding to an absolute risk reduction of about 1.8-2.2%) and potentially reduce excess recessive disease burden, while also modestly reducing risk of common diseases such as type 2 diabetes. We outline how existing PGT-A and PGT-M workflows could potentially be extended to report embryo-level FROH and discuss ethical and counseling considerations. Autozygosity-based embryo prioritization offers a principled way to address a component of recessive risk that current variant-centric approaches miss.

Background Fertility rates in Australia have been declining over recent decades, reaching a record low total fertility rate of 1.48 births per woman in 2024. Concurrently, vasectomy remains widely accessible and increasingly normalised as a permanent contraceptive option. Despite extensive commentary on falling birth rates, no contemporary Australian study has examined vasectomy rates relative to birth rates over time. We aimed to compare population level vasectomy and birth rates across Australian jurisdictions and age groups. Study design Nationwide retrospective time-series study. Retrospective population-based study using Medicare Benefits Schedule item 37623 to identify vasectomy procedures performed between July 2015 and December 2024. Rates were calculated per 100,000 male population using quarterly Australian Bureau of Statistics (ABS) population estimates and summarised as rolling 12-month averages. Birth rates were derived using matched ABS data for women across equivalent age strata (18-24, 25-34, 35-44 years). Results: Vasectomy rates increased nationally from 32 per 100,000 in 2016 to 55 per 100,000 in 2023 before declining modestly in 2024. Birth rates declined from 5,200 to 3,800 per 100,000 over the same period. Trends were consistent across states and age groups, with the greatest vasectomy uptake in men aged 35-44 years. Conclusion: Australia is undergoing a demographic shift characterised by rising vasectomy uptake and declining fertility. While vasectomy rates remain lower than birth rates, their convergence signals changing reproductive intentions and contraceptive behaviours. Ongoing monitoring of permanent and long-acting contraception is essential to understand evolving population dynamics and inform reproductive health policy.

Importance: Hereditary breast and ovarian cancer (HBOC) variant carriers benefit from risk-reducing interventions, but only if identified. The extent to which carriers are clinically recognized, and whether recognition is equitable across diverse populations, is poorly characterized in a single large U.S. cohort. Objective: To estimate P/LP HBOC carrier prevalence across genetic ancestry groups, quantify documented clinical genetic testing among carriers, and evaluate ancestry and socioeconomic disparities in testing. Design, Setting, and Participants: Cross-sectional analysis of the All of Us Research Program Controlled Tier (Curated Data Repository v8/C2024Q3R9), comprising participants with short-read whole genome sequencing and linked electronic health record (EHR) and survey data. Carriers were ascertained from research genomic data independent of clinical testing. Exposures: Genetically inferred ancestry (African [AFR], Admixed American [AMR], East Asian [EAS], European [EUR], Middle Eastern [MID], South Asian [SAS]); self-reported household income and educational attainment. Main Outcomes and Measures: (1) Carrier prevalence with Wilson 95% CIs; (2) documented clinical genetic testing (procedure codes) among carriers; (3) adjusted odds of documented testing among women, by ancestry, before and after socioeconomic adjustment, using multivariable logistic regression. Results: Among 414,830 participants, P/LP HBOC carrier prevalence was 1.42% (95% CI, 1.38-1.45) overall and similar across ancestry groups (AFR 1.24%, AMR 1.32%, EAS 1.19%, EUR 1.52%, MID 1.68%, SAS 1.33%; overlapping CIs). Among 250,071 women in the testing analysis, documented clinical genetic testing was rare: only 74 of 5,878 carriers overall (1.3%) and 59 of 3,572 European-ancestry carriers (1.7%) had a documented test, with counts below reportable thresholds in all other ancestry groups. African-ancestry women had lower adjusted odds of documented testing than European-ancestry women (Model 1 adjusted odds ratio [aOR], 0.32; 95% CI, 0.27-0.39), an association that attenuated but persisted after adjustment for income and education (Model 2 aOR, 0.48; 95% CI, 0.40-0.58; P < 0.001); Admixed American women also had reduced adjusted odds (aOR, 0.71; 95% CI, 0.61-0.84). Lower income and lower education were independently and dose-dependently associated with lower testing odds (income <$25,000 aOR, 0.46; high-school education aOR, 0.54). Conclusions and Relevance: High-risk HBOC variant carriers are present across all ancestry groups at similar frequencies, yet documented clinical genetic testing was disparate in the different ancestry groups. African-ancestry women experience a testing gap that is not fully explained by socioeconomic position, implicating structural barriers in access and referral. Population-level strategies that decouple carrier identification from current referral pathways may be required to close this gap.

Background: Polygenic risk scores (PRS) for breast cancer are increasingly used for risk stratification to inform screening and prevention. However, for PRSs to be equitable and clinically useful, they need to perform well across diverse populations. While PRS performance is known to be ancestry-dependent, it is not well understood how environmental context, such as that of socioeconomic status (SES), affects PRS transferability. Here, we assess whether SES, measured via self-reported household income, modifies breast cancer PRS performance and, if so, whether socioeconomic context contributes predictive information beyond genetic risk alone. Methods: We used the US-based All of Us biobank to evaluate how SES impacts breast cancer PRS performance. First, we quantified changes in breast cancer PRS performance by modeling a commonly-cited polygenic score for breast cancer previously described by Mavaddat et al. with SES. We then reestimated the genetic effect sizes of the 3,820 variants from Mavaddat et al. in All of Us with and without income as a covariate. Because social determinants of health affect breast cancer detection and outcomes, we stratified analyses by socially defined populations on the basis of self-identified race and ethnicity. We further stratified individuals whose self-identified race is White (''White'') into three SES groups (high, middle, low) based on self-reported income and re-estimated genetic effect sizes to create SES-specific PRSs. We then applied these PRSs to White participants, the largest group in the study, and to Black or African American (''Black'') and Hispanic or Latino (''Hispanic'') participants, groups underrepresented in breast cancer research. Model discrimination between cases and controls was measured by area under the curve (AUC). Results: We analyzed 163,715 women from the All of Us biobank, which included 8,833 breast cancer cases (6,619 White, 1,178 Black, and 1,036 Hispanic), with relative income available for a subset of these cases (5,525 White, 848 Black, and 566 Hispanic). The ancestry-dependent performance of the breast cancer PRS described in Mavaddat et al. was replicated in All of Us. In Black individuals, this PRS (AUC and 95% CI: 0.576 [0.571, 0.582]) produced a similar increase in AUC as relative income (AUC: 0.573 [0.568, 0.577]) when added to an age-only model. Incorporating income with PRS, age, and genetic PCs 1-3 improved AUC by 0.007 in White Americans and 0.018 in Black Americans (both p < 10-11), while attenuating the contribution of PRS in the full model. PRS performance also varied among SES categories. Notably, PRSs with variant effect sizes that were recalibrated in low-SES White participants performed best in low-SES White participants (AUC: 0.605 [0.583, 0.628]) and Black Americans (AUC: 0.588 [0.586, 0.591]), both better than performance in high-SES White Americans (AUC: 0.579 [0.577, 0.580]) and middle-SES White Americans (AUC: 0.578 [0.569, 0.586]). Conclusion: Socioeconomic context, measured by income, significantly impacts the transferability of a PRS for breast cancer within and among groups defined by self-identified race and ethnicity. Accounting for SES improves PRS performance, most notably in Black Americans and low-SES White individuals.

Objective To determine if it is possible to assess individual patient risk of the development of colorectal cancer (CRC) in people in high-risk groups due to their family history. Design/Method Retrospective observational study of prospectively collected data from consecutive patients referred for a colonoscopy. 2,478 consecutive patients were referred to a single colorectal surgical practice in Sydney, Australia between 1977 and 2018 for a colonoscopy because of a family history of CRC. Of these, 1,963 have been followed for more than 10 years and are the subject of this paper. Histopathological findings categorised as normal (N), non-advanced adenoma (NAA) or advanced neoplasia (AN) with AN proven to be the precursor to CRC. Intervention Colonoscopic screening on the basis of contemporary practice to 2006 and subsequently according to Australian National Health and Medical Research Council guidelines. Results Participants with normal or low-risk findings in the first decade remain at lower risk of CRC for 30 years from the commencement of screening. Conclusion It is possible to stratify individual patients in a high relative risk cohort into those with high or low personal risk of CRC based on colonoscopic findings in the first 10 years of surveillance. Those with no AN in the first ten years have a lower 30-year risk of developing AN than the general community. This offers the possibility of structuring surveillance programs around individual risk rather than group risk, lessening the need for multiple surveillance colonoscopies in the majority of such patients and improving the cost effectiveness of CRC screening at the population level.

Background: Neurological, neuropsychiatric, and neurodevelopmental disorders cluster in ALS families, sharing a common genetic architecture with ALS. Pathogenic variants in genes associated with other neurological, neurodevelopmental, or neuropsychiatric disorders may also co-occur in ALS and modify phenotype. We have sought to determine the prevalence and clinical pattern of likely-pathogenic/pathogenic (LP/P) non-ALS neurological, neurodevelopmental, and neuropsychiatric variants, alone and in combination with ALS-gene variants, in two large ALS cohorts. Methods: Whole-genome sequencing (WGS) of 469 Irish and 774 Answer ALS people with ALS (pwALS) was analysed for ClinVar LP/P variants associated with other neurological (n = 15541), neurodevelopmental (n = 9761), and neuropsychiatric (n = 321) phenotypes. Inheritance patterns for associated genes (autosomal recessive/autosomal dominant) along with the associated phenotype were validated using OMIM. Standardised clinical data included family history, site and age of onset, El Escorial category, survival, motor decline, and cognitive and behavioural assessments. Known ALS-gene variants and C9orf72 repeat expansion status were included for each cohort. Results: Non-ALS neurological variants were identified in 47/469 (10.0%) Irish and 69/774 (8.9%) Answer ALS participants, most frequently in hereditary spastic paraplegia-associated genes (3.2% Irish; 2.8% Answer ALS). Irish neurological variant carriers showed higher frequency of respiratory onset (10.6% vs 1.2%, Fisher's exact p = 0.002, {Phi} = 0.20) and fewer premorbid behavioural symptoms (0.92 +/- 0.56 vs 3.08 +/- 0.97, Cohen's d = -0.40). Neurodevelopmental variants occurred in 12/469 (2.6%) Irish and 20/774 (2.6%) Answer ALS participants. In the Irish cohort, neurodevelopmental variant carriers had significantly shorter survival in Cox proportional hazards model (log-rank p = 0.005), corresponding to a more than two-fold increased hazard of death (HR = 2.25, 95% CI 1.26-4.00), and had significantly increased familial burden of neuropsychiatric disorders among first- and second-degree relatives (negative binomial IRR for carriers = 2.41, 95% CI: 1.12-5.18, p = 0.025). Across combined cohorts, 18 individuals (Irish n = 8; Answer ALS n = 10) carried [&ge;]2 LP/P variants spanning ALS and non-ALS genes. Conclusion: Rare LP/P variants in genes associated with other neurological and neurodevelopmental disorders occur in up to 12% of pwALS across two independent cohorts. Carriers show distinct phenotypes, shorter survival, and characteristic family history patterns. These findings suggest that extended pleiotropic and oligogenic architectures may contribute to ALS heterogeneity.

Objective: To characterize pregnancy outcomes and menstrual irregularities in Mexican women with systemic lupus erythematosus (SLE) and identify clinical factors associated with adverse pregnancy outcomes and early-onset menopause. Methods: We conducted a cross-sectional study of women with SLE enrolled in the Mexican Lupus Registry (LupusRGMX) between May 2021 and September 2024. Clinical and reproductive data were collected using standardized questionnaires. Menopause was defined as the absence of menstruation for [&ge;]12 consecutive months, and early menopause as onset before age 40. Univariable and multivariable logistic regression analyses were used to identify factors associated with pregnancy complications and early menopause. Results: A total of 210 women were included. Median age was 38 years (IQR 29-46) and median disease duration was 4 years (IQR 1-10). Among women with a history of pregnancy (47%), full-term delivery predominated (61%), while pregnancy loss occurred in 26% and preterm delivery in 13%. Pregnancy complications were reported in 9.6%, most commonly preeclampsia (6.7%). Younger maternal age was independently associated with pregnancy complications (OR 0.89, 95% CI 0.83-0.95) and adverse outcomes (OR 0.95, 95% CI 0.92-0.98). Higher disease activity was associated with complications in univariable analysis. Most pregnancies (68.3%) occurred before diagnosis. Early menopause was observed in 6.2% and independently associated with longer disease duration and older age. Conclusion: Younger maternal age was independently associated with adverse pregnancy outcomes, whereas disease activity showed an association in univariable analysis. Most pregnancies occurred prior to SLE diagnosis. Early menopause was associated with longer disease duration, suggesting impact of cumulative disease burden on ovarian function.

Purpose: Pathogenic or likely pathogenic (P/LP) variants are increasingly identified in genes more commonly associated with adult-onset cancer predisposition, but their prevalence and relevance to children who present with cancer remain unclear. Methods: We retrospectively analyzed 1,280 consecutive pediatric patients with cancer who underwent clinical germline sequencing, using a virtual panel, from 2021 to 2024. Genes with P/LP variants were categorized as aoCPG or pediatric-onset cancer predisposition genes (poCPG) according to cancer risk before age 18 years and pediatric surveillance recommendations. Variant relevance was adjudicated using tumor diagnosis/histopathology, immunohistochemistry, and tumor molecular features and classified as primary, secondary, or indeterminate. Results: Among 1,280 patients, 197 (15.4%) harbored 211 P/LP variants across 54 genes. Sixty-six variants (31.3%) occurred in aoCPG, 87 (41.2%) in poCPG, and 58 (27.5%) were heterozygous variants in autosomal recessive genes. Among adult-onset variants, 7 (10.6%) were primary, 54 (81.8%) secondary, and 5 (7.6%) indeterminate. Among pediatric-onset variants, 77 (88.5%) were primary and 10 (11.5%) secondary. Six patients (3 adult-onset variants; 3 pediatric-onset variants) received targeted therapy informed by germline/somatic sequencing results. Conclusion: In pediatric oncology, most variants in aoCPG are secondary rather than tumor-related findings. Tumor-informed interpretation, beyond variant classification, may improve reporting, counseling, and therapeutic decision-making

Background: Statins are key to preventing atherosclerotic cardiovascular disease and lowering low-density lipoprotein cholesterol and cardiovascular events. However, skepticism regarding their safety and value persists and is increasingly influenced by social media. TikTok has emerged as a major source of health information, but its content varies in quality and accuracy. This study evaluated the quality, attitudes, misinformation, and engagement of statin-related content on TikTok. Methods: Public TikTok videos were collected using predefined search terms and coded by creator type, thematic content, and overall attitude. Video quality was assessed using the DISCERN instrument, the Patient Education Materials Assessment Tool for Audiovisual Materials, and the Global Quality Score. False or misleading claims were independently reviewed by two cardiology fellows. Associations between engagement and quality were also examined. Results: Of 1,349 screened videos, 258 met inclusion criteria. Most were educational (91.0%), with non-physician healthcare providers (34.5%) as the largest creator group. Risks or negative effects were discussed more often than benefits (63.2% vs 42.2%), and 39.5% contained at least one false or misleading claim, most often from complementary and alternative medicine providers and wellness promoters. Quality differed by creator type across all instruments, with physician-created content scoring highest. Video popularity showed minimal association with informational quality. Conclusion: Statin-related TikTok content frequently emphasizes harms, often contains misinformation, and varies substantially in quality by creator type. Greater involvement of healthcare professionals on social media may help improve digital health literacy and counter misleading information about statin therapy.

Whole-exome and whole-genome sequencing technology has enabled the discovery of rare genetic variants associated with human health and diseases. However, existing statistical methods used for rare variant association testing are not well-suited for building genetic risk prediction models that jointly incorporate rare and common variants. We propose STELLAR, a flexible ensemble learning-based approach to compute rare variant polygenic risk scores (PRS) using association summary statistics to enhance conventional common variant PRS. Our method combines burden-based and penalty-based rare variant analysis and leverages functional annotation information to prioritize potentially causal variants within the prediction models. In simulation studies, PRS using STELLAR consistently showed the highest prediction accuracy compared to models using common variants alone or rare variant burdens. Applied to UK Biobank whole-exome sequencing data (n=310,831) across eight continuous and five binary traits, STELLAR significantly improved prediction accuracy, refined stratification of individuals at the highest genetic risk beyond common variants, and prioritized biologically relevant genes. STELLAR provides a scalable strategy to incorporate rare variants into PRS in addition to common variants, advancing precision risk prediction and enabling more comprehensive assessment of genetic contributions to complex diseases.

Background: Primary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear. Methods: We conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin (?1 ng/mL/h), restricted cubic splines evaluated the adjusted association between renin and PA probability. Results: Among 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy. Conclusions: Using the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.

Large language models (LLMs) such as ChatGPT are rapidly reshaping healthcare education and simulation-based training in non-technical skills (NTS), yet no bibliometric analysis has mapped this landscape. We searched seven open-access databases (OpenAlex, PubMed, Europe PMC, Crossref, Semantic Scholar, CORE, DOAJ) for English-language publications from January 2020 to March 2026. From 100,277 initial records, a sequential keyword funnel yielded 830 candidate papers, which were screened by 83 independent Claude Sonnet 4.6 AI agents applying pre-specified inclusion criteria (PRISMA-trAIce compliant; Cohen's kappa = 0.86 pre-reconciliation, 1.0 post-reconciliation). The final AI-verified corpus comprised 551 papers with a compound annual growth rate of 109%, contributions from 2,398 authors across 279 journals in 58 countries, and an h-index of 41. ChatGPT dominated the model landscape (46% of papers), with open-source models virtually absent. Virtual patient chatbots were the leading simulation modality (106 papers). Among NTS domains, communication (145 papers) and decision-making (135 papers) were most studied, whereas teamwork, leadership, situational awareness, and crisis resource management were markedly underrepresented. Only 6 urology-relevant papers were identified, none examining LLM integration within boot camp training formats. The field is growing at extraordinary pace but remains concentrated in a narrow range of NTS domains and a single proprietary model. Critical gaps persist in team-based skills training, open-source model evaluation, and specialty-specific simulation. AI-assisted bibliometric screening using multiple independent agents is feasible, reliable, and scalable, offering a replicable methodology for mapping fast-evolving research fields.

Background: In atrial fibrillation (AF), cerebral microbleed (CMB) burden guides anticoagulation decisions, yet AF is itself inconsistently associated with CMBs, a paradox unexplained by frameworks that treat CMBs as a unitary marker of small vessel disease. We hypothesized that the white matter hyperintensity (WMH) context in which CMBs arise modifies their vascular meaning, and that this context-dependence underlies the inconsistent AF-CMB association. Methods: From a multicenter Korean stroke registry, we analyzed 5,735 first-ever ischemic stroke patients imaged at nine centers using susceptibility-weighted MRI. WMH volume and CMB count were extracted by validated deep learning pipelines. Patients were cross-classified by age-adjusted WMH residual (median split) and CMB count (2) into four groups. The AF-CMB association was estimated by multivariable logistic regression within each WMH stratum with formal interaction testing. Spatial CMB distribution was analyzed against the Automated Anatomical Labeling atlas. Results: In the full cohort (mean age 69.5 years; 57.7% male), AF was not associated with CMBs (OR 1.04; 95% CI 0.87-1.25). Stratification yielded divergent estimates: the adjusted AF OR was 1.46 (1.11-1.93; P = 0.007) in the WMH-low stratum and 0.95 (0.73-1.22; P = 0.665) in the WMH-high stratum, with significant interaction (OR 0.56; P < 0.001). The discordant phenotype (low WMH, high CMB; 8.9%) was enriched for AF (28.0%) and showed fronto-temporal cortical predominance with deep structure sparing. AF independently reduced the proportion of deep CMBs (IRR 0.80; P = 0.040). The interaction was preserved across prespecified sensitivity analyses. Conclusions: The AF-CMB association is confined to patients with low WMH burden relative to age and is accompanied by a topographically distinct CMB distribution. Clinical assessment of small vessel disease based on WMH alone may overlook a CMB phenotype linked to AF.

Suicidal risk may be encoded in everyday communication patterns but diluted in routine digital interactions. We introduce a method for surfacing this latent signal: training per-person language model agents on individuals' authored text (the on-screen text each participant typed, captured whenever a keyboard was visible in screenshots) and placing those agents in simulated social interactionsa communicative stress test. Using data from 79 adults with recent suicidal ideation, we ne-tuned individual LoRA adapters on Qwen3-8B using each participant's authored text, then placed agents in standardized conversations with probe personas. Agent-generated risk language was associated with EMA-measured suicidal ideation (r= .576, p < .001), with a single neutral small-talk probe performing nearly as well (r= 551). A shue control conrmed the signal is person-specic (r= .071 when adapters were mismatched), and automated descriptions of participants' general smartphone activity produced no signal, conrming specicity to interpersonal communication. A prompt ablation demonstrated partial robustness to removal of disclosure-encouraging language (r = .430). This proof-of-concept demonstrates that simulated social interaction can amplify latent vulnerability signals, bridging digital phenotyping, generative AI, andsuicide theory.

Aims This multicenter study aims to compare outcomes of total aortic arch replacement (TAR) using the frozen elephant trunk (FET) technique in patients with and without heritable thoracic aortic disease (HTAD) and to assess whether HTAD influences postprocedural adverse aortic events (AAEs). Methods From 06/2007 to 05/2024, aortic databases from 13 European centers were screened for HTAD patients undergoing TAR with FET. All consecutive dissection and aneurysm non-HTAD patients from the four core centers served as comparator. The primary outcome was AAE, a composite of diameter progression, distal stent graft induced new entry (dSINE), malperfusion, rupture and pseudoaneurysm at 5 years after FET implantation. Results Of 2739 FET patients, 196 (7.2%) were diagnosed with HTAD. The control group consisted of 867 non-HTAD FET patients. Marfan syndrome was the most common condition (72%), followed by Loeys-Dietz syndrome (11%), vascular Ehlers-Danlos syndrome (5.6%) and Turner syndrome (2.0%). Seventeen (8.8%) patients were diagnosed with ns-HTAD. At 5 years 46 (24%) AAEs occurred in the HTAD group, 169 (20%) in the non-HTAD group (p=0.2). Diameter progression was the most common event (10% vs. 12%; p=0.6), followed by dSINE (5.8% vs. 4.5%; p=0.5), malperfusion (4.2% vs. 3.3%; p=0.5), rupture (2.1% vs. 0.7%; p=0.09) and pseudoaneurysm (0.5% vs. 0.2%; p=0.5). Conclusions The FET technique appears safe and effective for acute and chronic aortic disease in HTAD patients, with outcomes comparable to non-HTAD cases and no increase in graft-related complications, challenging traditional concerns about stent graft use in genetically mediated aortic disease.

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.