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Key Points In an observational cohort of mostly non-Hispanic White women, pregnancy was not associated with later-life accelerated kidney function decline. Pregnancy occurring during the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial was not associated with kidney disease progression relative to women who did not become pregnant. Prior evidence indicates that adverse pregnancy outcomes may be involved in autosomal dominant polycystic kidney disease progression; pregnant women should be closely monitored. Background Data are conflicting regarding whether pregnancy influences disease progression in women with autosomal dominant polycystic kidney disease (ADPKD). This study examined whether pregnancy or number of pregnancies was associated with kidney disease progression in women with ADPKD. Methods Women with early- (study A) and late-stage (study B) ADPKD from the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial were included to examine the association between self-reported number of pregnancies (categorical predictor: no pregnancy versus 1–2 pregnancies and ≥3 pregnancies), annual slope of eGFR, annual percent change in total kidney volume (%ΔTKV), and a composite outcome (kidney failure, 50% decline in eGFR, or death) using multivariable linear regression and Cox proportional hazard models. In addition, women who became pregnant, had full-term pregnancies, and available data during study participation ( n =13) were propensity matched (1:4) to women who were not pregnant during study participation, and a mixed model was applied to determine the association of pregnancy with eGFR slope and %ΔTKV. Results Across all analyses, 455 women with a median age of 45 (interquartile range, 38–50) years and eGFR of 69±25 ml/min per 1.73 m 2 at baseline were included. One hundred ninety-nine women had 1–2 pregnancies, and 165 women had ≥3 pregnancies. There was no association of 1–2 pregnancies or ≥3 pregnancies (versus no pregnancies) with eGFR slope ( β -estimate [95% confidence interval (CI)]; 1–2 pregnancies: 0.22 [−0.44 to 0.89]; ≥3 pregnancies: −0.46 [−1.16 to 0.25]), %ΔTKV ( β -estimate [95% CI]; 1–2 pregnancies: 0.92 [−0.34 to 2.17]; ≥3 pregnancies: 0.69 [−0.67 to 2.04]), or time to composite outcome (hazard ratio [95% CI]; 1–2 pregnancies: 1.04 [0.56 to 1.93]; ≥3 pregnancies: 1.48 [0.78 to 2.77]) in adjusted models. Moreover, there was no difference in annual eGFR slope ( β -estimate: −0.14 [95% CI, −2.72 to 2.44]) and %ΔTKV ( β -estimate: 0.04 [95% CI, −3.74 to 3.82]) in women who became pregnant matched to women who did not became pregnant during their participation in the study. Conclusions Pregnancy was not associated with ADPKD progression among women with early- and late-stage ADPKD enrolled in the HALT-PKD trial.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

Background: Spasticity after upper motor neuron injury (stroke, spinal cord injury, etc.) alters muscle activity and induces long-term structural remodeling of skeletal muscle [1]. Elbow flexors, including the biceps brachii, are frequently affected, leading to abnormal tone, involuntary co-contraction, and impaired elbow function. Hyper-selective neurectomy (HSN) is a well-established surgical technique that has gained renewed clinical adoption with advances in anatomic understanding and intraoperative nerve mapping [2], yet its effects on muscle properties are poorly defined. Objective: The purpose of this study was to define pre- vs. post-HSN differences in muscle gene expression, sarcomere length, and clinical outcomes of the spastic human biceps. Methods: Individuals with elbow flexor spasticity undergoing a planned two-stage HSN were prospectively enrolled (n=10). Stage 1 released the elbow flexors and provided a pre-biopsy; Stage 2, performed ~3 months later to treat the forearm flexors, provided a second exposure to the biceps and a second biopsy. In both stages, biceps biopsies were obtained with customized clamps [3] at predefined elbow angles (50°, 90°, 135°), fixed, and analyzed for sarcomere length [4]. Total RNA was extracted from pre- and post-HSN biceps samples to characterize transcriptional changes. Clinical spasticity was assessed before Stage 1 and again before Stage 2 using the Modified Ashworth Scale (MAS). Data were compared using repeated-measures models, and single-cell transcriptional changes were analyzed using established analytical pipelines. Results: Sarcomere length (SL) increased significantly after HSN at all joint angles. At 50°, SL increased from 2.45 ± 0.18 µm pre-HSN to 3.05 ± 0.28 µm post-HSN; at 90°, from 2.70 ± 0.29 µm to 2.91 ± 0.16 µm; and at 135°, from 2.72 ± 0.36 µm to 3.24 ± 0.32 µm (all p < 0.05). Clinical spasticity assessment improved significantly as well (p < 0.05), with MAS scores decreasing from 1.89± 0.93 to 0.35 ± 0.53. RNA sequencing revealed changes in key pathways and overall gene expression patterns such as enhanced inflammatory response through increased cytokine production and fibroblast proliferation, leading to elevated collagen synthesis and subsequent fibrosis. We also observed upregulated immune modulation and chemotaxis, while pathways involved in mitochondrial respiration, muscle development, and cellular homeostasis were downregulated. At the transcript level, HSN led to decreased inflammation and adipogenesis, while promoting increased extracellular matrix assembly, and vascular formation. Conclusion: HSN produced coordinated improvements across structural, clinical, and transcriptional levels in the spastic human biceps muscle. Sarcomere lengths increased toward longer resting lengths at all joint angles, clinical spasticity decreased significantly, and RNA sequencing revealed distinct post-operative transcriptional remodeling. The longer sarcomere length and decreased spasticity should contribute to improved patient function after HSN. References: 1. Lieber RL et al. Muscle Nerve. 2002;26:98–105. 2. Leclercq C et al. Hand Clin. 2018;34:537–545. 3. Lieber RL et al. J Neurophysiol. 1994;71:874–881. 4. Ward SR et al. J Biomech. 2009;42:193–196. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Aims SCN5A-E1784K (c.5350G&gt;A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Background: Objective performance assessment is essential in surgical skill training, yet current methods are labor-intensive and focus on observing the trainee rather than the end-product of the procedure. Machine learning (ML) methods offer reproducible feedback but have mainly relied on kinematic or video data, often reducing assessment to binary or ternary classification. Our objective was to compare ML regression models predicting expert-assigned scores of vascular anastomoses from computational fluid dynamics (CFD) features of the final product. Additionally, we aimed to assess biomechanical plausibility of predictions. Methods: A total of 146 participants performed 419 end-to-side anastomoses on case-specific three-dimensional (3D) printed simulators. Anastomoses were digitized via 3D scanning, ranked by experts, and characterized using CFD-derived hemodynamic features. These served as input for linear models (Ridge, Partial Least Squares), support vector machines, and tree-based ensembles (Random Forest, Extremely Randomized Trees, and Extreme Gradient Boosting [XGBoost]), evaluated using 10-fold nested cross-validation with genetic hyperparameter optimization. Results: Inter-rater reliability of expert indicated strong agreement (intraclass correlation coefficient ICC3k = 0.846). XGBoost achieved the lowest mean root mean squared error of 0.758 (95% bootstrap CI: 0.722–0.799) and a coefficient of determination (R2) of 0.673 (0.617–0.725), with the most stable performance across folds. Shapley additive explanations (SHAP) identified the wall shear stress gradient, transverse wall shear stress, and maximum pressure as the most influential features—variables associated with intimal hyperplasia and atherosclerotic remodeling. Conclusions: Tree-based ensemble methods, particularly XGBoost, effectively modeled biomechanical properties against expert scores. Combining CFD and ML can provide reproducible, mechanistically relevant feedback in vascular surgical skill training.

Background The middle meningeal artery (MMA) has emerged as an endovascular route for treating chronic subdural hematoma (CSDH), meningioma, and refractory headaches. The third ARISE roundtable convened experts from neurology, neurosurgery, neuroradiology, industry, and regulatory agencies to develop consensus guidance on current evidence for MMA-based therapies Methods Over 50 experts participated in a multi-stakeholder discussion. Evidence from randomized and observational studies, early-phase interventional series, and preclinical work was reviewed. Breakout groups focused on four domains: (1) MMA embolization (MMAE) for CSDH, (2) preoperative embolization of meningiomas, (3) MMA-targeted therapies for headache, and (4) transvascular access for endovascular drainage of subdural hematomas. Consensus recommendations were developed by a writing committee Results Randomized trials support MMAE as an adjunct to surgery or medical management for selected patients with non-acute, symptomatic CSDH to reduce recurrence, progression, and reoperation. Evidence remains insufficient to support MMAE for acute or asymptomatic subdural hematomas. For meningioma, observational data suggest that preoperative embolization in experienced centers can reduce blood loss and operative time and may delay recurrence in large, hypervascular tumors with predominant dural or external carotid supply; primary embolization and intra-arterial oncologic therapies remain investigational. Early series of MMA-directed lidocaine infusion for refractory migraine, status migrainosus, and post-subarachnoid hemorrhage headache show short-term benefit, highlighting the need for controlled trials. Preclinical and first-in-human studies of combined MMAE and transvascular drainage for CSDH demonstrate high technical success, rapid radiographic and clinical improvement, and no early recurrences Conclusion The MMA represents a vascular pathway for an expanding spectrum of neurointerventional therapies.

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.