Community Health Workers (CHWs) are increasingly being involved in screening for hypertension in rural sub-Saharan Africa. However the diagnostic accuracy of CHW-led attended (CHW present during procedure) and unattended (CHW absent) automated blood pressure (BP) in home settings has not been compared. We conducted a cross-sectional, population-based diagnostic accuracy study in two health and demographic surveillance systems in Kenya and The Gambia. A random age-stratified sample of individuals aged ≥ 30 years were included. The index tests were attended and unattended automated BP measurements conducted by CHWs at participants’ homes (AHBP). The reference test, 24-hour ambulatory BP monitoring (ABPM), was also conducted by the CHWs. We applied BP cutoffs derived from the European Society of Hypertension to determine sensitivity, specificity, predictive values and area under receiver operating characteristic curve (AUC). We included 1220 participants (659 in Kenya and 561 in The Gambia). The median age was 54 years (interquartile range 43 years, 66 years) and 775 (63.5
The benefit of adjuvant chemotherapy (ACT) for patients with gastric cancer (GC) after first-line neoadjuvant chemotherapy (NACT) is debated. This study developed and validated a machine learning (ML) model to predict disease-free survival (DFS) and identify patients who benefit from ACT. A total of 1150 patients treated with NACT and radical gastrectomy across four centers in China were retrospectively analyzed. Feature selection and model development employed multiple ML learners. The optimal model was determined using the concordance index (C-index), time-dependent receiver operating characteristic curves, time-dependent calibration curves, and decision curve analysis. ACT efficacy was evaluated in different risk groups using inverse probability of treatment weighting. Eleven ML learners identified eleven feature subsets. Subsequently, eleven feature subsets and eleven machine learning learners were combined, resulting in the development of 121 models. The GAMB-AORSF model, which combines a Generalized Additive Models via Gradient Boosting-selected feature subset with an Accelerated Oblique Random Survival Forest learner, exhibited the highest prediction performance. The model demonstrated robust discrimination with C-indices of 0.864 in the training cohort, and 0.813 and 0.789 in two validation cohorts. The GAMB-AORSF model successfully stratified patients to guide decision-making. High-risk patients derived significant survival benefits from ACT, with a 3-year restricted mean survival time extension of 5–7 months and an absolute recurrence risk reduction of 14–20
Carotid vulnerable plaque rupture is a major cause of ischemic stroke. However, accurate identification of high-risk plaques using medical images heavily relies on radiologists’ expertise. This study aimed to develop an artificial intelligence (AI) system for automated segmentation and classification of carotid plaques using high-resolution vessel wall imaging (HR-VWI) to assist in diagnostic workflow. A total of 1610 carotid arteries from 1315 patients who underwent multi-contrast HR-VWI between January 2019 and July 2025 were included from four centers. The dataset was partitioned into training, internal test, pooled external test, and prospective test sets. A carotid fully automated pipeline system (CFAPS) was developed to perform plaque segmentation and vulnerability classification. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), while classification performance was assessed using the area under the curve (AUC), visualized with Grad-CAM heatmaps and histopathology. Diagnostic performance and efficiency were compared between CFAPS and radiologists. In the prospective cohort who underwent 18F-FDG PET/MRI, maximum standardized uptake value (SUVmax) and tissue-to-background ratio (TBR) were compared between CFAPS-classified vulnerable and stable plaque groups. Additionally, Kaplan-Meier analysis for stroke-free survival was performed on patients from two follow-up centers. CFAPS achieved DSCs of 0.863 ± 0.064, 0.855 ± 0.122, and 0.857 ± 0.069 on internal, external, and prospective test sets, respectively. For vulnerability classification, it attained AUCs of 0.942 (95
At present, the impact of microplastic (MP) exposure on children’s emotional and behavioral development remains unclear. Moreover, empirical research on the potential interaction between MP exposure and dietary patterns is particularly scarce, which constitutes a key research gap in this field. A total of 1234 10-year-old children were enrolled in this cross-sectional study. Laser Direct Infrared spectroscopy was utilized to quantify and identify the types and abundances of MPs in urine samples. We used a multiple linear regression model to analyze the effects of MP exposure and dietary adherence on children’s emotional and behavioral development, and further conducted a stratified analysis based on dietary adherence. The study revealed that the detection rate of MPs among 10-year-old school-aged children reached 91.41
Social determinants of health (SDOH) are fundamental drivers of behavioral outcomes; however, their impact on adolescents’ brain age gap (BAG)—an integrated neural marker reflecting deviations from normative brain maturation and potential brain plasticity—remain poorly understood. Moreover, the biological mechanisms underlying the effects are unknown. We conducted a prospective cohort analysis using magnetic resonance imaging (MRI) data from the Adolescent Brain Cognitive Development study (T1: n = 7330, 46.9
Endocannabinoid (eCB) signaling has been implicated in the physiological and affective responses to endurance exercise, including phenomena such as the runner’s high. However, although humans have the capacity to run for several hours and even days, evidence regarding eCB signaling is largely limited to exercise bouts shorter than 60 min. Consequently, the temporal dynamics of eCB signaling during prolonged running and the accompanying acute affective responses remain unclear. This study investigated eCB signaling during long-distance running and following a 45-minute break. Two studies were conducted: In Study 1, 19 trained runners completed both a marathon and a duration-matched walking session, with repeated blood sampling every 14 km during the marathon and after a 45-minute recovery. In Study 2, 36 ultramarathon runners completed races of 100 km, 160 km, or 230 km and provided blood samples before and after their respective races. Plasma concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. Euphoria, anxiety, and pain were assessed as core features of the runner’s high using visual analog scales. AEA increased progressively throughout the marathon and remained elevated after 45 min, whereas walking elicited only modest changes. In line, after all ultramarathon distances AEA levels were increased compared with baseline. By contrast, an increase in 2-AG during exercise was observed only in the regular marathon, where concentrations rose significantly during the later stages of running and into early recovery. Elevated post-race 2-AG levels were also observed following all ultramarathon distances, consistent with a delayed, recovery-related response. Marathon running was associated with higher euphoria and lower anxiety than walking, while pain increased after 28 km of running. Ultramarathon running increased pain, reduced anxiety, and did not significantly alter euphoria post-exercise. Together, these findings show robust, time-dependent changes in circulating eCB concentrations during and after prolonged endurance running, as well as gradual increases in AEA during walking. These eCB dynamics occurred alongside acute affective changes during sustained endurance exercise.
Globally, one-in-twenty children experience the death of a significant adult, such as a parent, before adulthood. Deprivation is a key driver for health inequalities with cancer-related deaths greater for families living in deprivation. Deprivation is the state of observable and demonstrable disadvantage relative to the local community or wider society. The objective of this study was to explore health and social care professionals’ (professionals) experience of providing family-centred supportive cancer care to families living in deprivation, when an adult with significant caregiving responsibilities for children (<18) has incurable cancer. A qualitative study involving one-to-one semi-structured interviews with 44 professionals from 23 countries. Over 40
Climate change is occurring at an accelerated pace in high-latitude regions, with implications for the health and well-being of rural northern communities– places that have long navigated significant health disparities with limited resources. Here, we present a community-driven effort to identify community priorities for improving health in the context of a changing climate. We used Q-methodology in four rural Alaska Native communities to systematically identify complex perspectives related to climate change and health priorities. The mixed qualitative-quantitative approach helped to engage the community, prioritize the most locally relevant issues, and identify targets for future interventions. Consistently top-ranked priorities include food security, Indigenous knowledge and practices, and the transmission of culture and traditional ways of living to the younger generations. Community perspectives reflect a holistic view of health that connects climate change to individual health and community well-being. These three components are linked together through the social-ecological landscape, providing resources that are embedded in the local and Indigenous cultural practices. We show that a community-engaged approach can generate consensus data, directing research and interventions towards the highest needs and priorities of Alaska Native communities highly affected by climate change. Overall, participating rural Alaska Native communities prioritized the impacts of climate change on traditional ways of living from the land to subsist and thrive in these remote, culturally important areas. Additionally, the well-being and futures of young people arose as a primary shared concern, directing interventions to address the impacts of climate change on health towards place-based solutions that protect and preserve environmental resources and engage young people in the transmission of traditional knowledge and practices on the land.
Dual HER2 blockade combined with chemotherapy is the standard neoadjuvant approach for HER2-positive early breast cancer. Pyrotinib is an irreversible pan-HER tyrosine kinase inhibitor. This study aimed to evaluate the efficacy and safety of a pyrotinib-based neoadjuvant regimen in patients with HER2-positive early breast cancer. This multicenter, phase II prospective study evaluated neoadjuvant pyrotinib combined with epirubicin and cyclophosphamide followed by docetaxel plus trastuzumab (ACPy-THPy). A concurrent prospective cohort receiving standard docetaxel, carboplatin, trastuzumab, and pertuzumab (TCbHP) served as a real-world comparator. Propensity score matching (PSM) was applied to reduce baseline imbalances. The primary endpoint was pathological complete response (pCR). A total of 249 patients were included (ACPy-THPy, n = 120; TCbHP, n = 129). After 1:1 PSM (n = 83 per group), baseline characteristics were well balanced between groups. Before PSM, the pCR rate was numerically higher with ACPy-THPy than with TCbHP (65.0
Physical inactivity, sedentary behaviour and inadequate sleep are established risk factors for non-communicable diseases. Although older adults are traditionally expected to be less active and more sedentary than young adults, contemporary social, occupational and educational environments may have changed this. Here, we characterised 24-hour movement behaviours (physical activity [PA], sedentary behaviour [SB], and sleep) across adulthood using wearable devices and examined their cardiometabolic correlates using a compositional data approach. Data were analysed from 1,967 adults across three Singaporean cohorts: university students (n = 500; mean[SD] age 19.9[1.3] years), working-age adults (n = 437; 41.1[10.0] years), and community-dwelling older adults (n = 1,030; 74.0[2.6] years). Each person contributed 4 weeks of Oura Ring recordings on time spent in PA, SB and sleep. BMI, body roundness index (BRI), pulse wave velocity (PWV), and a composite vascular health score (zComposite) were additionally assessed. Associations between reallocations of time across 24 h-movement behaviours and these cardiometabolic outcomes were estimated using compositional data regression models. University students accumulated the most SB (mean 633.89 min/day) and the lowest PA (320.28 min/day) and sleep (431.75 min/day), whereas older adults accumulated the least SB (500.86 min/day) and greatest PA (420.28 min/day) and sleep (455.62 min/day). Working-age adults showed profiles in-between the students and older adults (SB: 581.28 min/day; PA: 346.55 min/day; sleep: 445.77 min/day). In compositional models, reallocating 30 min per day to PA from other behaviours was associated with lower BMI (-0.13 kg/m²), BRI (-0.04), PWV (-0.05 m/s), and zComposite (-0.01). Reallocating 30 min per day from SB to other behaviours was associated with lower BMI (-0.28 kg/m²) and BRI (-0.07). Reallocating 30 min per day to sleep from other behaviours was related to lower BMI (-0.21 kg/m2) and BRI (-0.05). University students exhibited lower physical activity and higher sedentary time than older adults. Reallocation of time toward greater PA, less SB and longer sleep was associated with lower cardiometabolic risk. These findings challenge conventional expectations about age-related inactivity and highlight young adulthood as a critical, under-recognised target for interventions to promote PA and reduce SB for long-term health.
Acute ischemic stroke (AIS) is a major contributor to long-term disability despite current therapies. Although remote ischemic conditioning (RIC) has potential benefits in patients with AIS, its underlying mechanisms remain poorly understood. We aimed to explore the effects of RIC on the regulation of cerebral blood flow (CBF) among patients with AIS. This was a randomized controlled trial with participant-and-blinded endpoints that included 120 patients with AIS from June 2023 to May 2024. RIC/sham RIC treatment was performed at a pressure of 200 mmHg or 60 mmHg twice a day for seven consecutive days. The primary efficacy outcome was the difference in CBF regulation 7 days after randomization between the two groups. Patients were followed up for 90 days after randomization to assess modified Rankin Scale (mRS) scores. One hundred and twenty (120) patients with AIS were included in the intention-to-treat population (60 in each group). The results showed that the phase difference, which is a key parameter of CBF regulation, in the RIC group was significantly higher than that in the sham RIC group [affected side: RIC group: 36.84° (interquartile range [IQR], 21.49° to 51.36°), sham RIC group: 28.57° (17.17°, 38.52°), adjusted β coefficient = 11.336, 95
Climate change is intensifying the frequency and severity of extreme heat events. While the impact of temperature on respiratory health is well-documented, the synergistic effects of combined heat and humidity are less clear, especially for children, a population with heightened vulnerability. This study investigates the differential impacts of humid heat (measured by Wet-Bulb Globe Temperature, WBGT) and temperature alone on paediatric asthma emergency department visits (EDVs) in Shanghai, China, and projects the future disease burden under climate change. We conducted a time-series analysis of 42,604 paediatric asthma EDVs recorded across 66 hospitals in Shanghai during the summer seasons of 2016–2018. Distributed lag non-linear models were used to quantify the association between daily EDVs and both WBGT and temperature. We projected future humid-heat-related asthma burden through 2099 under four Shared Socioeconomic Pathway scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0, SSP5-8.5). Daily mean WBGT demonstrated a stronger association with paediatric asthma EDVs than temperature alone. Exposure to high humid-heat (WBGT at the 95th percentile) was associated with a significant cumulative relative risk (RR) of 1.38 (95
The development of effective cancer immunotherapies is hindered by the lack of preclinical models that faithfully preserve tumor-immune interactions. Current approaches provide limited representation of immune components, creating a critical translational gap between laboratory findings and clinical outcomes. Precision Cut Tumor Slices (PCTS) offer a promising solution by maintaining complete tumor architecture including native immune cell populations and spatial organization. We established a PCTS platform using fresh bladder cancer specimens and optimized culture conditions to preserve tissue integrity and cell viability. Comprehensive phenotyping was performed using flow cytometry to characterize tumor and immune cell populations. Immune functionality was validated through CD3/CD28 stimulation experiments measuring activation markers (CD69, CD137, HLA-DR) and cytokine secretion. Nine patient samples were treated with the PD-1 checkpoint inhibitor nivolumab to assess ex vivo effects. Additionally, multiplex immunofluorescence microscopy was employed on fixed PCTS as a readout for spatial distribution and cytotoxic effects of chemotherapy agents. PCTS maintained viability of both cancer cells and diverse immune populations for up to six days. Functional validation demonstrated immune responsiveness upon T cell stimulation, with elevated activation markers and significantly increased secretion of inflammatory mediators including IFNγ and CXCL10, in treated as compared to control samples. The platform successfully addressed intra-tumor heterogeneity while maintaining experimental reproducibility across patient samples. Treatment with nivolumab revealed heterogeneous responses, with two out of nine samples (22
Bone metastasis is a common and lethal complication of breast, prostate, and lung cancers. TGF-β in the bone microenvironment is pivotal for metastatic progression. We previously demonstrated that TGF-β induces acetylation of KLF5 at K369 and that acetylated KLF5 (Ac-KLF5) drives epithelial-mesenchymal transition, invasiveness, and bone metastasis, positioning Ac-KLF5 and its effectors as therapeutic targets. Tetracycline derivatives, including doxycycline, show anti-metastatic activity, yet their molecular targets remain unidentified, limiting their clinical repurposing. Therapeutic development targeting Ac-KLF5 and elucidating targets of tetracycline derivatives are important areas of research in cancer therapy. Surface plasmon resonance (SPR) screening of the FDA-approved drug library (1987 compounds) targeting purified KLF5K369Q (KQ, Ac-KLF5 mimic) protein identified candidates that bound to KQ, and the binding selectivities were verified by SPR and circular dichroism with wild-type KLF5 and acetylation-deficient KLF5K369R (KR) as controls. We assessed the anti-invasive activities of verified candidates in KQ-expressing prostate cancer cells using spheroid invasion and Transwell assays. In vivo therapeutic efficacy against bone metastasis was evaluated in tibial injection xenograft models using bioluminescence imaging, micro-CT, and histology. Mechanistic integration of RNA-seq and ChIP-seq, validated by qPCR, siRNA, and rescue experiments, elucidated downstream effectors and pathways. Doxycycline (D) and methacycline (M), but not their parent compound tetracycline (T), selectively bound to the KQ protein, with no binding to the KR acetylation-deficient KLF5 mutant. D and M, but not T, inhibited KQ-induced cell invasion, osteoclast differentiation, and osteolytic bone metastasis. RNA-seq and ChIP-seq analyses identified 22 genes whose transcription was regulated not only by KQ via direct promoter binding but also by D and M treatments. One of the genes, PGK1, was further confirmed to be responsible for D and M’s suppressive effects in cell invasion, osteolytic differentiation, and bone metastasis. Doxycycline and methacycline are potential therapeutic agents for TGF-β-induced bone metastasis through selectively binding to Ac-KLF5.
Palliative care can be provided alongside curative or life-sustaining treatments and is not limited to the terminal phase, highlighting the need for integration across healthcare settings, including intensive care units (ICUs). Despite its benefits, ICU integration remains limited, leaving patient and family needs unmet. Telehealth, or telepalliative care, is increasingly investigated to improve ICU palliative care access, yet ethical implications remain unexplored. Early citizen consultation can reveal public concerns and facilitate implementation aligned with societal values. In contrast, failing to consider citizens’ perspectives may lead to resistance toward telepalliative care if perceived as conflicting with societal values. Therefore, this study investigates citizens’ perceptions of the ethical aspects of ICU telepalliative care. Constructivist grounded theory guided a qualitative study exploring citizens’ perspectives on ICU telepalliative care. Twelve focus groups (64 participants), including laypeople and healthcare professionals, were conducted in Flanders, Belgium. Data were analyzed iteratively using the Qualitative Analysis Guide of Leuven (QUAGOL). Reporting adhered to the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines. Participants questioned how telehealth could fit ICU palliative care, given conceptual tensions between telehealth, palliative care, and the ICU, and expressed concern that economic or technological motives might undermine ethical implementation. They recognized opportunities if guided by an ethical purpose with the human being at the center of care. Participants noted that telehealth both challenges and supports human contact: absence of physical presence, including touch, can limit relational aspects such as comfort, but virtual visits can help maintain contact when in-person interaction in the ICU is impossible. They also raised practical ethical concerns, including obtaining informed consent from unconscious patients and camera-related privacy risks, such as surveillance or disrupted intimacy, and proposed mitigations. Participants highlighted telehealth’s potential to improve equitable access to palliative care expertise in the ICU, while noting barriers such as limited digital literacy, language proficiency, and functional limitations. Citizens’ perspectives suggest ICU telepalliative care can be valuable under well-defined, human-centered conditions. Its ethical acceptability should be evaluated both for individual patients and for specific applications and continually revisited. Ethical implementation requires specifying use cases rather than treating “telehealth” abstractly.
Abstract Background Established screening programs for colorectal cancer (CRC) based on fecal immunochemical tests (FITs) employ fixed screening intervals of either one year or two years for all participants. We aimed to assess the potential design of risk-adapted FIT screening intervals based on quantitative values of the fecal hemoglobin concentration among FIT negative participants. Methods Using COSIMO, a previously validated simulation tool, we compared CRC risks in subgroups with initially negative FIT. Subgroups were stratified by stool hemoglobin levels at screening (< 8 (low), 8-<10 (medium), 10-<17 µg (high) Hb/g stool), a routinely available measure in FIT-based screening programs. Colorectal neoplasia prevalences at model start were informed by 6,661 screening colonoscopy participants in Germany at average CRC risk with negative FIT and available colonoscopy results (BLITZ study). Simulations were run for hypothetical cohorts of 100,000 individuals. Results Of 6,661 FIT-negative participants, 6,016 (90%), 273 (4%), and 372 (6%) were in the low, medium, and high-negative subgroups, respectively. In those low-negative, expected cancer detection rates were 0.17%, 0.30%, 0.42%, 0.53%, and 0.62%, after screening intervals of 1, 2, 3, 4, and 5 years, respectively. Cancer detection rates among the small groups of medium- and high-negative patients were up to six times higher and exceeded the expected 2-year detection rates of the low-negative group already after 1 year of follow-up. Conclusions Fecal hemoglobin concentrations among FIT negative participants may be a readily available, highly informative tool for defining risk-adapted annual or biennial FIT screening intervals.
Abstract Background Secondary prevention of coronary heart disease (CHD) remains suboptimal due to fragmented care and therapeutic inertia. While digital health interventions offer a promising strategy, few existing tools provide comprehensive, closed-loop management of multidimensional risk factors without increasing clinician workload. This study aimed to evaluate the efficacy of an artificial intelligence (AI)–enhanced management system (AIM-CHD) in improving multidimensional risk factor control among patients with CHD. Methods This single-center, open-label, parallel-group, randomized clinical trial was conducted from November 2024 to June 2025 in China. A total of 1100 adults with confirmed CHD were randomized 1:1 to receive either the AIM-CHD intervention ( n = 549) or usual care ( n = 551) for 3 months. The AIM-CHD system featured automated multi-source data capture, guideline-directed risk stratification, and closed-loop feedback via smartphone. The primary outcome was the low-density lipoprotein cholesterol (LDL-C) level at 3 months. Secondary outcomes included goal attainment rates for LDL-C (< 70 mg/dL) and blood pressure (BP, < 130/80 mm Hg), glycated hemoglobin, smoking cessation, body mass index (BMI), medication adherence, and a composite cardiovascular endpoint at 3 months. Analysis was performed on an intention-to-treat (ITT) basis. Results Of 1100 randomized participants (mean age 61 years; 75.3% male), 943 (85.7%) completed the 3-month follow-up. The intervention group achieved a significantly lower mean LDL-C level compared with the control group (60.4 ± 23.4 vs. 63.7 ± 26.0 mg/dL), with an adjusted mean difference of − 3.2 mg/dL (95% CI, − 6.2 to − 0.3; p = 0.03). Furthermore, participants in the intervention group were more likely to achieve the LDL-C target (71% vs. 64%; RR, 1.10; 95% CI, 1.01–1.20; p = 0.03) and the BP target (45% vs. 35%; RR, 1.27; 95% CI, 1.09–1.48; p = 0.002). No significant differences were observed for HbA1c, BMI, or medication adherence. Conclusions The AIM-CHD system significantly improved short-term lipid and BP control compared with usual care. These findings support interoperable, low-burden digital management systems as a scalable strategy in routine secondary prevention. Trial registration ClinicalTrials.gov Identifier: NCT06686056. Registered on 11 November 2024.
PARP inhibitors (PARPi) are standard front-line maintenance therapy for advanced ovarian cancer, but the efficacy of PARPi retreatment after progression remains unclear. This phase Ib/II study evaluated pamiparib, a PARPi, combined with surufatinib, a small-molecule tyrosine kinase inhibitor, in patients with platinum-resistant ovarian cancer who progressed during or after PARPi treatment. Patients with platinum-resistant ovarian cancer progressing during or after PARPi treatment were enrolled. In phase Ib, a 3 + 3 dose de-escalation design was used to determine the recommended phase 2 dose (RP2D) of surufatinib combined with pamiparib (40 mg twice daily). Phase II evaluated antitumor activity at the RP2D. The primary endpoints were the RP2D of surufatinib in phase Ib and the 6-month progression-free survival (PFS) rate in phase II. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Tumor sequencing, homologous recombination deficiency (HRD) assessment, and serial circulating tumor DNA (ctDNA) analyses were performed as exploratory biomarkers. Twenty-nine patients were enrolled. The RP2D of surufatinib was 250 mg once daily, with no dose-limiting toxicities. At data cut-off (June 30, 2024), the median follow-up was 10.0 (range, 6.8–11.0) months. The 6-month PFS rate was 46.7
Despite many reported imaging markers for bipolar disorder (BD), systematic assessment across diverse brain imaging-derived phenotypes (IDPs) is lacking. We used epidemiological and genetic analyses to progress from association to causality and identify candidate biomarkers and potential pathways of BD. We conducted an Exposome-Wide Association Study (ExWAS) in 35,680 UK Biobank participants to assess associations of 686 brain IDPs with BD. Genetic correlations were estimated via linkage disequilibrium score regression (LDSC). Bidirectional two-sample Mendelian randomization (MR) and meta-analysis were performed using large-scale GWAS data to infer causality. Additional analyses, including Functional Mapping and Annotation (FUMA), protein-protein interaction (PPI) network analysis, and spatiotemporal gene expression profiling during human brain development, were performed to investigate potential biological mechanisms of BD and IDPs. In our ExWAS analyses, we identified 10 significant exposome-level IDPs, and LDSC further revealed 67 IDPs with significant genetic correlations with BD. The MR analyses provided robust causal evidence for 12 IDPs, 6 of which were further validated by meta-analysis. Integrative analyses identified two associations supported by both epidemiological and genetic evidence (IDP.1510: fractional anisotropy in the forceps major, and IDP.0387: volume of the right lateral orbital frontal cortex). Additionally, we identified pleiotropic genes between IDPs and BD. Gene enrichment analyses implicated shared biological pathways, such as nucleosome assembly and neutrophil extracellular trap formation . PPI network analysis suggested that histone family members occupied central hubs in the interaction network. Spatiotemporal expression profiling identified region-specific developmental trajectories of pleiotropic genes in brain regions, including the cerebellum and thalamus, with the late fetal to early postnatal period potentially representing a sensitive developmental period for neurodevelopmental effects of BD susceptibility genes. This study establishes an atlas of brain IDPs associated with BD, by integrating epidemiological and genetic evidence. The findings highlight candidate IDPs, including right lateral orbital frontal cortex volume and fractional anisotropy in the forceps major, that were consistently associated with BD across complementary analyses. Our results provide genetically supported targets for early intervention and precision psychiatry.
