Citations

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive and deadly disease characterized by pulmonary vascular remodeling and eventual right heart failure. A mainstay of treatment for PAH is prostacyclin therapy which can be delivered via continuous subcutaneous (SQ) or intravenous (IV) infusion. Infusion site reactions are a common occurrence with SQ Treprostinil resulting in discontinuation in approximately 10% of patients. Given that switching from SQ to IV prostacyclin therapy contains risks associated with long-term central venous access such as blood stream infections and deep venous thrombosis, the development of better strategies to improve SQ Treprostinil tolerability are needed. Case Report We report two patients with PAH who developed delayed infusion site reactions to SQ Treprostinil. Both patients were female, in their 30s, with severe group 1 PAH (mean pulmonary artery pressures of 44 and 81 mmHg on right heat catheterization at diagnosis), who had been on SQ Treprostinil for approximately 6 years on a dose around 60 ng/kg/min. Within two weeks of starting a new SQ infusion site, each patient developed a raised, hyperemic site reaction in the area of the infusion catheter draining yellow fluid (Figure 1). Skin patch testing was done from an ampule of preservative-free Treprostinil demonstrating a type 1 hypersensitivity reaction. There was no skin reaction to the Tegaderm dressing alone. Dupilumab 300 mg weekly SQ injections were started for these type 1 hypersensitivity reactions with resolution of the site reactions and pain. Because of this, both patients were able to remain on their SQ Treprostinil infusions. Discussion Infusion site reactions to SQ Treprostinil are common and can necessitate discontinuation of the medication. SQ Treprostinil infusion site reactions typically occur within 48 hours of establishing a new SQ infusion site and are thought to be a local vasodilatory reaction to the Treprostinil itself. These reactions can be minimized by analgesic pain medication and by increasing the Treprostinil infusion concentration. Here we describe two infusion site reactions that occurred two weeks after establishing a new site and were consistent with a type 1 hypersensitivity reaction. These reactions were successfully treated with Dupilumab which allowed the patients to remain on SQ Treprostinil. This abstract is funded by: None

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, >99] %; p < 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, >99] %; p < 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Rationale Deficiency of alpha-1 antitrypsin (AAT), the protein encoded by SERPINA1, remains the strongest genetic risk factor for COPD. Individuals heterozygote for the type Z variant, termed the PI*MZ genotype (estimated global prevalence n = 35,000,000), experience varying respiratory morbidity beyond expected from tobacco smoking alone. AAT is a pleiotropic protein which inhibits not only neutrophil elastase but also neutrophil chemotaxis mediated by leukotriene B4 (LTB4) [by antagonizing the LTB4 receptor (LTB4R)] and interleukin-8 (IL-8). Although LTB-4 and IL-8 gene variants and protein levels have independently been implicated in COPD, their potential role in PI*MZ is unknown. Methods COPDGene and SPIROMICS are observational tobacco-smoke and COPD-enriched cohort studies. Participants were phenotyped by spirometry and CT imaging, with whole genome sequencing data available via TOPMed. We analyzed participants with PI*MM (COPDGene n = 9,732; SPIROMICS n = 2,105) and PI*MZ (COPDGene n = 300; SPIROMICS n = 83). LTB-4 (ALOX5AP, LTA4H, LTB4R) and IL-8 (CXCL8, CXCR1, CXCR2) associated gene variants (exonic and intronic) with a minor allele frequency of ≥ 0.05 were extracted. We assessed statistical interactions between MZ status and chest CT outcomes or FEV1% predicted using the SPAGxECCT package with adjustment for relatedness (genetic related matrix) and ancestry (top ten PCs). Baseline protein LTB4R (SPIROMICS only) and IL-8 (both cohorts) protein levels were measured via SomaScan, and statistical interactions between MZ status and AAT concentration were explored. Models were adjusted for age, sex, BMI, smoking status, and pack-years. Given the candidate gene discovery approach, significance was defined as nominal p-value<0.05 Results We identified the following number of variants in genes of the LTB-4 or IL-8 pathways: 87 shared between cohorts; 133 unique to COPDGene; 1 unique to SPIROMICS. LTB-4-related polymorphisms were associated (p < 0.05) with any radiographic outcomes in 22 variants (COPDGene) vs. 23 variants (SPIROMICS), with a single overlap (rs17074984 in ALOX5AP). Two LTB-4-pathway variants were associated with FEV1% predicted in SPIROMICS (both in ALOX5AP), but none in COPDGene. AAT plasma concentrations displayed a statistically significant interaction with FEV1% predicted (p = 0.046) and PRMemphysema (p = 0.013) for LTBR4, but not for IL-8. There was not an interaction by MM/MZ status and protein levels. Conclusions Predominantly LTB-4, and not IL-8, pathway-related genetic variants and protein levels may contribute to disease heterogeneity among PI*MZ individuals. The association of circulating LTB4R protein with reduced lung function, particularly among those with low AAT levels, further suggest interactions between AAT and the leukotriene pathway in PI*MZ individuals. Thus, PI*MZ individuals may uniquely derive benefit from leukotriene-targeting pharmacotherapy. This abstract is funded by: NIH NHLBI K23HL173570

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.