Citations

Abstract Rationale Dyspnea is a prominent symptom of fibrotic hypersensitivity pneumonitis (fHP), limiting patients’ activity and impairing their quality of life. The University of California San Diego Shortness of Breath questionnaire (UCSD-SOBQ) is a 24-item instrument used to assess dyspnea severity in patients with various respiratory conditions. Objectives This study aimed to examine the reliability and responsiveness of the UCSD-SOBQ score, its validity as a measure of dyspnea severity, and its prognostic value in a prospective cohort with fHP. Methods We conducted psychometric analyses on UCSD-SOBQ response data and assessed the association between score changes and survival in patients with fHP who completed the UCSD-SOBQ and other HP severity metrics at baseline, 6 and 12 months. We introduce the reliable change index (RCI) and the likely change index (LCI) to assess the statistical significance of within-individual change in UCSD scores. Results At baseline, internal consistency was high (Cronbach’s alpha = 0.97). Significant moderately strong correlations were observed between UCSD-SOBQ scores and percent predicted forced vital capacity (FVC%), r = -0.46, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%), r = -0.32, and Borg dyspnea scores r = 0.56. UCSD-SOBQ scores were significantly different between the lowest and highest strata of FVC% (64.9 ± 18.9 vs. 36.2 ± 22.9), DLCO% and Borg scores. The threshold for worsening within-individual change in the UCSD-SOBQ score at 95% confidence was 12 points. A 1-point higher baseline UCSD-SOBQ score was associated with a 2% increase in the risk of death or transplant (HR 1.02, 95% CI 1.00, 1.04). Conclusions In fHP, the UCSD-SOBQ score is a reliable and valid measure of dyspnea severity, is responsive to change, discriminates patients with differing severities, and is associated with transplant free survival. Additional qualitative data and psychometric analyses could tailor the UCSD-SOBQ to fHP and may further improve its measurement properties.

Abstract Rationale Quantitative CT using multiple instance learning (MIL)-usual interstitial pneumonia (UIP) classifier and data-driven textural analysis (DTA) provides objective and reproducible measurements of disease pattern and extent, respectively. However, the understanding of their individual or combined relationships with outcomes in fibrotic hypersensitivity pneumonitis (fHP) remains limited. Objectives To determine whether visual CT patterns of fHP or UIP, a MIL-UIP classifier, baseline and changes in DTA over 12-months and DTA at 12 months are associated with progression-free survival (PFS) in fHP. Methods The primary cohort included 134 participants with fHP. Associations between CT variables and subsequent lung function change, and PFS were assessed using linear mixed models and Cox hazards models. Results were validated in a combined dataset from three independent populations (N = 216). Results Visual patterns of fHP or UIP were not associated with PFS. A baseline MIL-UIP classification and DTA were significantly associated with 24-month PFS. However, the MIL-UIP did not predict PFS after adjusting for DTA fibrosis extent. Over 12 months, a 1-point increase in DTA across and within patients resulted in a significant decline in FVC% and DLCO%. A 12-month change in DTA (HR = 1.07, 95%CI 1.01-1.13) and DTA at 12-months (HR = 1.03, 95%CI 1.01-1.05) were associated with subsequent 12-month PFS. Similar estimates were observed in the validation cohort. Conclusions In fHP, the objectively measured extent of lung fibrosis is more prognostic than either a UIP classifier or visual CT patterns of fHP or UIP. Baseline DTA, DTA at 12 months, and its change over 12-months are associated with PFS.

Introduction: Inflammatory bowel disease is characterized by remitting and relapsing bouts of intestinal inflammation accompanied by sensory and motor dysfunction that persists beyond the active periods of inflammation. Evidence suggests that neural pathways of the Gut-Brain Axis, particularly the sensory and sympathetic nervous system, are involved in pathophysiology, but until recently technical restrictions have limited our understanding of the underlying neural circuit mechanisms. In this study, we examined how sensory-sympathetic circuits are modified by colitis and how these alterations contribute to dysfunction during both active inflammation and post-inflammatory recovery. Methods: E2a-GCaMP mice were treated with vehicle or 3% dextran sodium sulfate (DSS) for 5 days to induce experimental colitis and switched to normal drinking water. Mice were assessed at two time points: Day 7 (two days after ending DSS treatment), representing active inflammation, and Day 21 to represent recovery. Inflammation and mucosal damage were evaluated using disease activity index scores and hematoxylin and eosin (H&E) staining. Colon motility was assessed in vivo via colonic bead expulsion and ex vivo using whole-colon preparations. We performed Ca 2+ imaging of sympathetic motor neurons in prevertebral ganglia (PVG) and sensory neurons in dorsal root ganglia (DRG) neurons in ex vivo preparations that preserve extrinsic neural circuitry with the colon (intestinofugal-sympathetic and spinal cord-sympathetic pathways). Results: Histological analysis confirmed hallmark features of colitis, including colon shortening, immune infiltration, and mucosal damage at 7 days post-DSS (p< 0.05, n=3–4), which resolved after recovery. During active inflammation, in vivo colon transit time was significantly faster, and this persisted after recovery (p< 0.05, n=7-9). Ex vivo motility assays in isolated colons also revealed DSS-induced dysmotility during active inflammation, but the irregular colon motor complexes became normal after recovery (p< 0.05, n=7-9), suggesting that extrinsic neural pathways contribute to prolonged dysmotility. In preparations without the spinal cord, PVG neurons exhibited increased activity and increased responses to distension during active inflammation but returned to baseline after recovery (p< 0.05, n=3-4), suggesting alternative sensory-PVG pathways contribute to persistent dysmotility. In preparations with spinal circuits intact, thoracolumbar (TL), but not lumbosacral (LS), DRG sensory neurons were hypersensitive to colonic distension during inflammation (p< 0.05, n=8-9). Furthermore, TL spinal stimulation evoked more responses in PVG neurons during active inflammation, but this was associated with decreased inhibition of ENS motor circuits (p< 0.05, n=6-7) and increased Ca 2+ signaling in the epithelium (p< 0.05, n=5), suggesting shifts in TL spinal-sympathetic motor output. Preliminary studies show an increase in spontaneous activity of TL DRG neurons in recovery that does not occur at LS levels (p< 0.05, n=3-6), which suggests that thoracolumbar spinal pathways remain hyperexcitable after recovery.Conclusions: Our findings indicate that TL spinal pathways associated with sympathetic motor outflow contribute to pain and dysmotility during active inflammation and may contribute to the post-inflammatory recovery processes that seem to go awry in IBD patients with relapsing inflammation. 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 Background Interpretation of urodynamic studies (UDS) is central to diagnosing lower urinary tract dysfunction, but it is often complex, time‐consuming, and subject to interobserver variability. Recent advances in artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), have enabled automated analysis of multichannel pressure–flow data and may improve objectivity and efficiency in UDS interpretation. Objective To critically review current applications of ML and DL for interpretation of multichannel UDS data and to evaluate their performance, clinical targets, and limitations. Methods A literature search of PubMed, Scopus, and Web of Science was performed through September 2, 2025, without language or date restrictions. A narrative review was conducted of peer‐reviewed studies applying ML or DL techniques to invasive UDS signals, including vesical, abdominal, and detrusor pressures as well as urinary flow. Studies limited to uroflowmetry or non‐UDS inputs were excluded. Model design, input features, validation strategies, and clinical outcomes were systematically assessed. Results A total of 12 studies met inclusion criteria. AI models were applied to a range of UDS tasks, including detection of detrusor overactivity, classification of bladder outlet obstruction and detrusor underactivity, multi‐feature UDS pattern recognition, severity grading, and real‐time event detection. Reported diagnostic performance was generally high, with many models achieving accuracies or AUCs between 80% and 95% for primary outcomes. However, study designs were heterogeneous, most datasets were retrospective and single‐center, and external validation was limited. Conclusions ML and DL approaches can extract clinically meaningful information from multichannel UDS recordings and demonstrate strong technical performance across several diagnostic tasks. However, variability in methodology, limited generalizability, and lack of prospective validation currently limit clinical adoption. AI‐based UDS interpretation remains an emerging research area requiring standardized data, robust validation, and integration with clinical workflows.

Abstract Introduction Once-nightly sodium oxybate (ON-SXB) is approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients ≥7 years of age with narcolepsy. ON-SXB demonstrated significant improvements in both objective (Maintenance of Wakefulness Test) and subjective (Epworth Sleepiness Scale [ESS] score) measurements of sleepiness in the REST-ON trial and via the ESS in the real-world REFRESH study. Assessing ON-SXB ESS data from a specialty pharmacy and outside of clinical studies further informs the generalizability of effectiveness. Methods Demographic and clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). Participation in ESS assessment was voluntary. ESS scores were assessed for patients who switched from twice-nightly oxybate (TN-OXB) treatment (first ON-SXB prescription filled ≤30 days of last TN-OXB prescription [switch]) and those new to oxybate or with &gt;30 days between TN-OXB and ON-SXB prescription fills (not-on-oxybate) who had ESS data at initial ON-SXB prescription and at each follow-up assessment. Results Of 452 identified patients, 215 had ≥1 follow-up ESS score (switch, n=82 [mean age, 38.4 years; female, 71%]; not-on-oxybate, n=133 [mean age, 40.0 years; female, 71%]). Of patients who had any prior oxybate use (switch, 100%; not-on-oxybate, 46%), the most common prior oxybate was mixed-salt oxybates (switch, 59%; not-on-oxybate, 70%). Stimulants/wake-promoting agents were taken by 51% of switch and 65% of not-on-oxybate patients. Baseline mean (SD) ESS scores were 11.3 (5.5) for switch and 12.5 (5.6) for not-on-oxybate patients; 23% of switch and 38% of not-on-oxybate patients experienced severe EDS. By the first follow-up (median [IQR], 49 [28-94] days), mean (SD) ESS scores were within the normal EDS range with ON-SXB for both subgroups (ie, ESS &lt; 10; switch, 9.7 [5.5]; not-on-oxybate, 9.5 [5.2]); the majority reported normal levels of daytime sleepiness (switch, 56%; not-on-oxybate, 57%). Mean (SD) change in ESS score from baseline to follow-up was -1.6 [4.5] for switch and -3.1 [5.0] for not-on-oxybate groups. Conclusion Patients who initiated ON-SXB experienced improvements in daytime sleepiness regardless of prior TN-OXB use, and many achieved normal levels of daytime sleepiness in ≤2 months of starting ON-SXB. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Findings from 2 studies have demonstrated improvements in objective and subjective EDS with ON-SXB in patients with narcolepsy type 1 (NT1) or 2 (NT2) (NCT02720744, NCT06792708). To evaluate the effect of ON-SXB on EDS in a larger, more diverse narcolepsy patient population, changes in Epworth Sleepiness Scale (ESS) score were analyzed using specialty pharmacy data. Methods Demographic/clinical data were collected from Optum Frontier Therapies pharmacy for adults with NT1 or NT2 with ≥1 filled ON-SXB prescription, ≥1 ON-SXB clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). ESS total scores were assessed at baseline and at each follow-up assessment after ON-SXB initiation. ESS assessment participation was voluntary. Data were analyzed descriptively and stratified by narcolepsy subtype. Results Of 452 patients identified, 195 had ≥1 follow-up ESS score and reported narcolepsy type (NT1, n=123 [63%; mean age, 38.6 years; female, 69%]; NT2, n=72 [37%; mean age, 40.7 years; female, 74%]). More patients with NT1 vs NT2 (72% vs 58%) had any prior oxybate use. Baseline concomitant stimulant/wake-promoting agent use was 58% and 64% for NT1 and NT2, respectively. Mean (SD) ESS total scores at baseline were 12.1 (5.7) and 12.2 (5.3) for patients with NT1 and NT2, respectively; 31% of NT1 and 33% of NT2 had severe EDS. For both subtypes, mean (SD) ESS scores were within the normal EDS range (≤10) by the first follow-up (median time, 52 days; NT1, 10.0 [5.5]; NT2, 9.6 [4.8]). At first follow-up, more than half of patients in the NT1 (55%) and NT2 (54%) subgroups achieved normal levels (ESS total score ≤10) of sleepiness, while 20% of NT1 patients and 10% of NT2 patients had severe EDS. Mean (SD) change from baseline in ESS score was -2.1 (4.3) and -2.6 (5.3) in the NT1 and NT2 subgroups, respectively. Conclusion In this real-world dataset, both NT1 and NT2 patients quickly experienced clinically meaningful improvements in ESS score after initiating ON-SXB. These results support ON-SXB as an effective EDS treatment, regardless of narcolepsy subtype. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Once-nightly sodium oxybate (ON-SXB [LUMRYZ™]) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Real-world demographic/clinical characteristics and treatment adherence in patients with narcolepsy who received ON-SXB from a specialty pharmacy were assessed. Methods Baseline demographic/clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and baseline Epworth Sleepiness Scale (ESS) score from 6/1/2023-9/30/2024. Adherence (≥80% of days covered) was assessed for patients with ≥3 months of ON-SXB use. Data were stratified by narcolepsy subtype (narcolepsy type 1 [NT1] and 2 [NT2] when available) and prior oxybate use (transitioned from prior oxybate therapy to ON-SXB ≤30 days of index [switch]/were oxybate-naive or discontinued oxybate &gt;30 days before index [not-on-oxybate]). Data were analyzed descriptively. Results 452 patients were identified (NT1, 55%; NT2, 37%; NT unknown, 9%; switch, 40%; not-on-oxybate, 60% [oxybate-naive, n=147/271]). Mean (range) age was 38.9 (16.0-88.0) years. Most patients were female (68%) and had commercial insurance (78%). Overall, 67% of patients had prior oxybate use (NT1, 72% [n=179/247]; NT2, 59% [n=98/166]; switch, 100%; not-on-oxybate, 46% [n=124/271]); for these patients, the most common oxybate (65%) was mixed-salt oxybates (NT1, 61%; NT2, 70%; switch, 61%; not-on-oxybate, 70%). Overall, 64% of patients used stimulants/wake-promoting agents (WPAs) (NT1, 64%; NT2, 65%; switch, 60%; not-on-oxybate, 67%). Overall, the mean (SD) baseline ESS score was 12.0 ([5.5]; NT1, 11.7 [5.5]; NT2, 12.5 [5.3]; switch, 11.0 [5.7]; not-on-oxybate, 12.7 [5.3]). At baseline, 29% of patients experienced severe EDS (ESS score ≥16: NT1, 26%; NT2, 30%; switch, 20%; not-on-oxybate, 34%). Of 269 patients with ON-SXB use ≥3 months, 84% (NT1, 84%; NT2, 89%; switch, 94%; not-on-oxybate, 76%) demonstrated adherence. Conclusion Patients not on an oxybate had the highest baseline ESS scores and proportion with severe EDS, despite greater stimulant/WPA utilization. Patients with NT1 used oxybates more frequently than those with NT2 despite those with NT2 having higher baseline ESS scores and a greater proportion having severe EDS, suggesting oxybates merit earlier consideration in patients with NT2. Most patients demonstrated ON-SXB adherence, indicating they would likely receive full therapeutic benefit. Support (if any) Avadel Pharmaceuticals

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

Abstract Background and aims Rural communities have a high incidence of stroke driven by high prevalence of risk factors. We hypothesize that patient centric stroke prevention education can be delivered in rural communities. Methods High risk patients defined as Atherosclerotic Cardiovascular Disease (ASCVD) 10-year risk of ≥ 20% cardio-cerebrovascular events were identified through electronic medical records receiving primary care in Greenville and Lakeview (intervention sites) and Muskegon (control site) were included. Education material included lifestyle modification and stroke signs-symptoms information. Patients completed a pre-intervention survey, recieved standardized stroke education, and were assessed for knowledge retention through quarterly telephone follow-ups and completed a 12-month post-intervention survey. Total study cost is 130,000$ over 18 months. Results High ASCVD score was identified in 758 (Intervention) and 1128 (Control) patients. 70 intervention and 73 control patients were enrolled. Time spent consenting patients and delivering education is 5 minutes with additional 10-15 minutes at each 3-month follow-up call. 65 intervention patients completed 12 month follow up. Intervention vs. Control; Median: IQR: Age [74 (68-76) vs. 73(68-75) years; p=0.20]; Initial ASCVD [24.5 (22-30) vs. 28.6 (26-37); p&lt;0.001], 12-month ASCVD [25(21-30) vs. 30(24-39); p=0.002). Post-intervention survey showed significant improvement in recognition of stroke risk factors (p&lt;0.001) and stroke signs-symptoms (p&lt;0.001). 49 (75%) patients adopted healthy lifestyle at 12-month follow up. Conclusions A primary stroke prevention cost-effective education program can be successfully implemented in a high-risk rural population, demonstrating improved stroke literacy and healthy lifestyle adoption. Conflict of interest