Type 2 diabetes mellitus (T2DM) has been inversely associated with prostate cancer (PrCa) risk. However, it remains unclear whether a polygenic risk score (PRS) for PrCa can effectively stratify risk among men with T2DM. The primary objective of this study was to assess whether a PrCa PRS predicts PrCa risk independently of T2DM status. The secondary objective was to evaluate potential mediating factors, including insulin-like growth factor-1 (IGF-1) and sex hormones. We analysed data from over 140 000 men in the UK Biobank and Penn Medicine Biobank. A PrCa PRS was constructed using summary statistics from a large-scale genome-wide association study. Cox proportional hazards models were used to evaluate the association between PRS and incident PrCa, adjusting for relevant covariates and testing for interaction by T2DM status. Additionally, sex hormones and IGF-1 levels were analysed to explore potential mediators. T2DM was associated with a reduced incidence of PrCa. The PrCa PRS was significantly associated with PrCa risk regardless of T2DM status (p < 0.001), and men in the highest PRS category exhibited the greatest risk, especially among those without T2DM. IGF-1 levels were positively associated with PrCa risk among both diabetic and non-diabetic men, while sex hormone levels showed no significant association in men with T2DM. Adjusting for testosterone and IGF-1 did not attenuate the association between PRS and PrCa. PrCa PRS effectively stratifies risk among men with and without T2DM, highlighting the independent contribution of genetic susceptibility. Lower IGF-1 levels in T2DM patients may partly mediate the reduced PrCa risk, suggesting a possible biological mechanism underlying these observations.

Association of circulating leptin concentration with the risk of Clostridium difficile colitis and exploration of their associated mediators: A mendelian randomisation study

To assess the impact of cardiorespiratory fitness (CRF) and muscle strength on depression and individual depression symptoms. Mendelian randomisation (MR) analysis was conducted in up to 341,326 participants of European ancestry from UK Biobank (aged 37-73years). Genetic variants from previous genome-wide association studies (GWAS) of CRF and grip strength (to proxy overall muscle strength) were utilised to instrument exposures. A broad depression phenotype based on self-report and hospital records, as well as individual measures of depression symptoms from the Patient Health Questionnaire-9 (PHQ-9) were used as outcomes. Analysis was repeated stratifying by sex and using summary statistics from a major depressive disorder (MDD) GWAS. There was no clear evidence for association between CRF and any depression outcome. There was robust evidence suggesting greater grip was associated with lower odds of broad depression (OR per 0.1kg increase in weight adjusted grip: 0.86, 95% CI:0.80,0.93), as well as the PHQ-9 items appetite changes (OR:0.56, 95% CI:0.49,0.65), and anhedonia (OR:0.79, 95% CI:0.69,0.90), a core symptom of depression. There was also some evidence for associations between greater grip and lower odds of depressed mood (OR:0.85, 95% CI:0.74,0.97), psychomotor changes (OR:0.79, 95% CI:0.64,0.97), fatigue (OR:0.83, 95% CI:0.74,0.93) and concentration problems (OR:0.85, 95% CI:0.74,0.98) in the MR-inverse variance weighted analysis. Effects were mostly driven by stronger associations in females and results replicated in the two-sample MR for MDD. Muscle strength may represent an important modifiable factor for preventing and treating depression and several specific symptoms, including core symptoms such as anhedonia.

The growing availability of high-dimensional, complex datasets demands analysis methods that are both interpretable and flexible. We introduce FlowSets, a novel framework for identifying and analysing flows-fuzzy, interpretable patterns-across multiple, diverse, and heterogeneous data sets. Views are constructed as an interpretation of biological features of the data sets by grouping absolute or relative values, summary statistics (such as fold changes or P-values), or higher-order comparisons into fuzzy, linguistically defined categories based on their underlying distributions. FlowSets builds on these fuzzy categorizations and then tracks how features transition between categories across different conditions or data types, uncovering structural patterns that conventional methods often overlook. The FlowSets framework enables users to define, analyse, and manipulate complex patterns across heterogeneous datasets in a flexible and interpretable manner. With FlowSets, users can visualize feature flows, quantify pattern memberships, and perform enrichment analysis explicitly designed for sets with gradual memberships. This approach offers a robust and customizable alternative to rigid clustering or hard thresholding, allowing for a more transparent and insightful interpretation of multidimensional biological data.

Ensemble perception refers to the ability to extract summary statistics (e.g., mean, variance) from groups of similar objects. In some ensemble perception tasks, participants must select specific items from a set before calculating a summary statistic (e.g., the average size of red circles among blue ones). It is generally assumed that this selection process does not alter the ability being measured. However, research in working memory suggests that introducing selection into tasks can shift the focus of what is measured-from working memory capacity to attention control. In this study, we examined whether selection alters ensemble perception's role in mean discrimination tasks using a latent variable approach. We found that ensemble perception and attention control are correlated at a construct level and that both contribute approximately equally to performance in mean discrimination tasks, irrespective of task format. We found no support for the idea that selective ensemble perception tasks are more strongly predicted by attention control than nonselective ensemble tasks. PUBLIC SIGNIFICANCE STATEMENT: We find that ensemble perception-the ability to gauge collective properties of a group of objects-relies on attention control, even in tasks designed to measure ensemble perception alone. This suggests that when people assess group characteristics, like the average size or color of items, they also use mental resources to focus selectively on specific items. Understanding interactions between perception and attention could improve the design of tasks that measure cognitive abilities, helping researchers better distinguish between different types of mental skills.

Patients with schizophrenia spectrum disorders (SSDs) have a higher risk for post-diagnostic cardiometabolic comorbidities. While antipsychotic use partly explains this, the contribution of genetic susceptibility remains unclear. We investigated the relationships between cardiometabolic-related polygenic risk scores (PRSes) with cardiometabolic outcomes using data from 671 patients with SSDs in the Dutch Genetic Risk and Outcome of Psychosis study. Seven PRSes were calculated for body mass index (BMI), high- and low-density lipoprotein cholesterol (HDL, LDL), triglycerides, glucose, systolic (SBP) and diastolic blood pressure (DBP) using summary statistics from most recent genome-wide association studies. Four linear regression models assessed the cross-sectional associations between PRSes and cardiometabolic outcomes including BMI, HDL, LDL, triglycerides, glycated hemoglobin, SBP, DBP, and a composite metabolic score. Model #1 included baseline factors (age, sex, and population substructure); #2 included model 1 with a single-trait PRS; #3 included model 1 with all PRSes of designated traits; and #4 included model 1 and a composite PRS score. All seven cardiometabolic PRSes were significantly associated with their corresponding outcomes. Significant cross-trait associations were observed including PRSBMI with lower HDL (explained variance (R2)=2.33%), higher DBP (R2=3.35%), and higher SBP (R2=2.29%); PRSHDL with higher HDL(R2=2.05%) and LDL levels(R2=2.31%); PRSDBP with higher SBP(R2=1.75%), and PRSSBP with higher DBP(R2=2.94%). The current study suggests that genetic susceptibility contributes modestly but significantly to poor cardiometabolic outcomes. Shared genetic susceptibility may underpin the frequent co-occurrence of cardiometabolic morbidities in SSDs, supporting the potential utility of PRSes in identifying high-risk patients for early intervention in practice.

Polygenic and spatial insights into the genetic uniqueness of essential tremor using common variants.

Shared genetic architecture between major depressive disorder and inflammatory bowel disease: Insights from large-scale genome-wide cross-trait analysis.

Depressive symptoms and psoriasis: Domain-specific associations in national cohorts.

Trends and outcomes of lung transplant listings for connective tissue disease-associated interstitial lung disease (CTD-ILD): A 20-Year analysis from the organ procurement and transplantation network database.

Adolescent pain reports share genetic overlap with adult chronic pain conditions: A polygenic score analysis using the ABCD study.

Studies examining the relationship between tinnitus and speech-in-noise (SIN) perception have produced conflicting results, possibly due to observational study designs and confounders related to aging, hearing loss, and tinnitus-related distress. To address this concern, the present study investigated the relationship between tinnitus and SIN perception using complementary observational and genetic epidemiological approaches across multiple independent cohorts, enabling the identification of converging evidence to clarify this relationship. A total of 216 young adults, including 87 with continuous chronic tinnitus (bothersome tinnitus for >1 y), aged 18 to 37 y, with hearing thresholds (HTs) ≤20 dB HL for 250 to 8000 Hz, participated in the study. Speech perception was evaluated using the Speech, Spatial, and Quality of Hearing scale (SSQ12), QuickSIN, and 3-digit Dichotic Digit Test. Extended high-frequency HTs (up to 16 kHz) were evaluated. A linear mixed-effects model was used to assess the influence of tinnitus on audiological measures while controlling for confounders, including lifetime noise exposure (LNE), firearm use, and a history of recurring ear infections. To obtain causal inference, we employed latent causal variant (LCV) analysis using the summary statistics of genome-wide association studies, followed by functional enrichment analyses to identify shared tissues and pathways between tinnitus and SIN deficits. Multimarker Analysis of GenoMic Annotation was conducted to obtain gene-based statistics. Gene-based gene statistics were integrated with single-cell transcriptomic data from mice cochlear tissues to identify cell types shared between the two phenotypes. Tinnitus was associated with lower SSQ12 scores and poorer dichotic digit test performance, even after statistically controlling for the differences in HTs. Tinnitus severity was negatively correlated with SSQ12 scores. Lifetime noise exposure and firearm use were associated with elevated HTs and lower SSQ12 scores. Tinnitus and SIN deficits revealed significant genetic correlations, but the latent causal variant analysis found no evidence of a causal impact of tinnitus on SIN deficits. The Multimarker Analysis of GenoMic Annotation-based analysis identified several brain tissues, including the frontal cortex, anterior cingulate cortex, cerebellum, nucleus accumbens, caudate, putamen, hippocampus, amygdala, and hypothalamus, that were shared between tinnitus and SIN deficits. Gene ontology terms for synaptic functioning were jointly enriched. No cochlear cell types revealed significant associations with tinnitus and SIN deficits. Tinnitus and SIN deficits are comorbid conditions with a shared genetic basis. Tinnitus is not causally associated with SIN deficits; rather, a shared genetic architecture independently predisposes individuals to both phenotypes. A converging line of evidence from observational and genome-wide association study-based enrichment analyses suggests that a shared genetic basis likely alters synaptic functioning in key brain regions involved in audition, cognition, and emotional regulation. Future studies are necessary to elucidate the shared biological pathways underlying tinnitus and SIN deficits.

Over 70% of cancer survivors also have chronic conditions requiring coordinated care throughout survivorship. Few intervention studies have focused on improving care coordination between oncology and primary care during active treatment, specifically among under- and uninsured survivors. This study evaluated the effectiveness of Project CONNECT, a system-level intervention using an EHR-based registry and an oncology nurse coordinator, in improving patient-reported care coordination among breast and colorectal cancer survivors with at least one chronic condition seen in a large, urban, safety-net health system. Using a pre-post quasi-experimental design, 294 patients diagnosed with stage I to III breast or colorectal cancer and ≥1 chronic condition were administered a telephone survey before intervention and 6 and 12 months after intervention to measure patient-reported care coordination. Summary statistics described patient characteristics, and generalized estimating equation assessed adjusted population-average changes in care coordination. The mean age of eligible patients was 56 years (standard deviation = 9.54). The majority of the survivors were women (78.6%). Race/ethnicity distribution of the sample represented the patient population of the safety-net health system with 45% White, 34% Black, and 51% Hispanic. Nearly 80% had ≥1 chronic conditions. After the intervention, patient-reported care coordination scores demonstrated significant improvement (β = -.05, P = .016). Notably, the proportion of survivors reporting never or rarely receiving confusing or differing information about their health or treatments decreased by 11% after the intervention. An EHR-based registry of cancer survivors with chronic conditions supported by an oncology nurse coordinator assisting survivors to establish or maintain primary care during active cancer treatment is a promising strategy to bridge the transition between oncology and primary care for cancer survivors receiving care in a safety-net heath system.

Improving and maintaining high detection rates for major congenital heart disease (CHD) is a priority for successful prenatal anatomy screening programmes. The primary objective of this study was to evaluate the utility of on-site multidimensional targeted training in fetal cardiac screening. A prospective study evaluating a targeted fetal echocardiography (FE) training programme in two obstetric tertiary care units was established. The programme was designed and approved by a dedicated fetal cardiology team. The one-day intervention involved supervised hands-on sonography and a prescribed educational programme for sonographers and doctors. The programme was completed by 23 trainees. Evaluation of the programme involved pre and post-training questionnaires and retrospective evaluation of cardiac images from 10 randomly-selected anatomy screening examinations performed by each trainee before and after training. Images were assessed for both technical quality and 6 priority elements of cardiac screening taught in the programme. The results were described with summary statistics and non-parametric tests. 1850 fetal cardiac images obtained before and after training by 21/23 trainees were assessed. Significant improvement was seen in the priority cardiac views obtained, for example from 24%(5/21) to 86%(18/21) for bifurcating pulmonary artery (P-value 0.001), from 33%(7/21) to 86%(17/21) for differential atrio-ventricular valve insertion (P-value 0.001), In addition, technical image quality improvements were observed following training as well as sonographer confidence. A targeted FE training programme can improve understanding of the priority elements required to exclude major CHD in prenatal screening, improve image quality, and sonographer confidence in cardiac screening.

This study integrates Mendelian randomization (MR) and observational data to investigate the causal roles of PCSK9 and LDL-C in chronic kidney injury (CKI) of various etiologies, with a focus on diabetes-associated CKI. We performed two-sample MR analyses using GWAS summary statistics to assess the effects of circulating PCSK9, LDL-C, and PCSK9-inhibitor-modulated LDL-C on CKI risk, complemented by a 5-year prospective cohort study of 101 type 2 diabetes patients evaluating serum PCSK9 and composite renal endpoints. MR revealed genetically proxied elevated PCSK9 significantly increased diabetic nephropathy risk (OR = 1.985, 95% CI : 1.019-3.867, P = 0.044), whereas LDL-C reduction (including PCSK9-inhibitor-mediated) showed no association. This effect was specific to diabetic CKI, with sensitivity analyses confirming robustness. In the prospective cohort, elevated serum PCSK9 levels (>216.14 ng/mL) independently predicted a higher risk of adverse renal outcomes in T2DM patients (HR = 2.677; 95% CI: 1.094-6.548; P = 0.031), whereas LDL-C showing no prognostic relevance. These findings establish PCSK9 as a causal factor in diabetic nephropathy potentially via lipid-independent mechanisms, highlighting its therapeutic potential beyond LDL-C modulation.

To characterise the non-linear joint dose-response relationship of accelerometer-measured moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF, estimated as maximal oxygen uptake (VO₂max)) with incident cardiovascular disease (CVD), and to assess causal consistency using Mendelian randomisation (MR). We conducted a cohort study in the UK Biobank using accelerometer data linked to hospital and death registries. A Cox generalised additive model characterised the joint MVPA-CRF association with incident CVD (atrial fibrillation, myocardial infarction, heart failure (HF) and stroke), adjusting for confounders. We derived a fitness-stratified matrix quantifying the weekly MVPA minutes associated with prespecified relative hazard reductions. Complementary two-sample MR analyses leveraged genome-wide association study summary statistics for device-measured physical activity (PA) traits and CRF to assess potential causal effects on cardiovascular outcomes. Among 17 088 participants, 1233 incident CVD events occurred over a median follow-up of 7.85 years (IQR, 7.39-8.27). A significant non-linear interaction between MVPA and CRF was observed (p<0.001). Meeting the 150 min/week guideline yielded a modest ~8%-9% risk reduction across fitness levels, whereas achieving a >30% risk reduction required threefold to fourfold higher volumes (~560-610 min/week). Residual analysis indicated that fitness beyond what MVPA and covariates predicted retained a modest protective association with CVD risk (HR, 0.98 per 1 mL/kg/min; 95% CI 0.97 to 0.99; p<0.001). In MR analyses, genetically proxied higher CRF was associated with lower HF risk (OR, 0.79; 95% CI 0.63 to 0.99), whereas genetic evidence for PA traits was weaker and less consistent. Current MVPA guidelines provide a universal but modest safety margin, whereas optimal cardiovascular protection may require substantially higher activity volumes. The fitness-stratified prescription matrix offers quantitative behavioural targets, and genetic findings reinforce the independent importance of CRF in cardiovascular risk reduction.

Infectious disease trials have long used ordinal outcomes, or ranked categorical scales, to capture the full spectrum of response to an intervention. We review 2 summary statistics for ordinal outcomes: the proportional odds ratio (pOR) and the win probability. The pOR asks: How much more likely is a treated participant to be in an improved category compared with control? The win probability asks: In a random treatment-control pair, what is the chance the treated participant fares better? We also introduce visual companions, the stacked-bar chart and bubble plot, to make ordinal trial results more accessible and interpretable.

The bone-brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear. We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics to assess the causal effects of six fat depots-abdominalsubcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat-on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations. Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09-1.51, p = 0.003). Total hip BMAT was inversely related to femoral neck BMD (β = -0.43, 95% CI: -0.61 to -0.24, p < 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89-1.15, p = 0.849), excluding bone loss as a mediator. This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone-brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.

Genetic associations between asthma and type 2 inflammatory Diseases: Insights from pleiotropic loci and genes: Shared Genetics of Type 2 Inflammatory Diseases.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype with no effective targeted therapies. To identify novel therapeutic targets, we conducted transcriptome-wide association studies (TWAS) integrating genome-wide association studies (GWAS) summary statistics from the Breast Cancer Association Consortium (BCAC) and UK Biobank with expression quantitative trait loci (eQTL) summary statistics from breast mammary tissues via the Genotype-Tissue Expression (GTEx) study. Our approach identified novel candidate genes positively or negatively associated with TNBC based on their TWAS effect size. We validated these candidates by confirming their differential expression between TNBC and normal tissues using The Cancer Genome Atlas (TCGA) breast cancer cohort. Among these, Epidermal Growth Factor Receptor Pathway Substrate 15 Like 1 (EPS15L1) emerged as a top candidate significantly associated with TNBC. EPS15L1 was found to be overexpressed in basal-like and claudin-low TNBC tumors and cell lines, with its high expression correlating with poor prognosis. Functional studies demonstrated that EPS15L1 enhances TNBC cell growth, as evidenced by increased metabolic activity in high-density conditions, enhanced clonogenic ability in low-density settings, and improved 3D spheroid formation. Additionally, knockdown of EPS15L1 suppressed the formation and stellate morphology of single-cell-initiated spheroids within the 3D microenvironment. Collectively, these findings establish EPS15L1 as a driver of TNBC initiation, implying its potential as a biomarker for early detection and a target for prevention.