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PURPOSE Remote symptom monitoring using patient-reported outcomes (PROs) has been shown to improve symptom control and physical function among patients with advanced cancer. However, it is unclear whether these benefits are similar across demographic groups. This exploratory analysis of the PRO-TECT trial examined whether the effects of electronic symptom monitoring varied by race, age, sex, and educational attainment. METHODS PRO-TECT was a cluster randomized trial conducted across 52 US community oncology practices comparing weekly electronic symptom monitoring with usual care (UC). Adult patients with metastatic solid tumors receiving systemic therapy were enrolled (N = 1,191). Participants in the PRO arm completed weekly symptom surveys including the PRO-CTCAE, triggering alerts to the care team for severe or worsening symptoms. Patients chose whether to complete weekly PROs online or via telephone-based interactive voice response not requiring Internet access. Outcomes were measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 symptom control and physical function scales. Subgroup analyses were performed by race (Black v White), age (<65 v ≥65 years), sex (male v female), and educational attainment (≤high school v >high school). RESULTS From baseline to 3 months, PRO participants showed greater improvements in symptom control (+2.37 v −0.20, P = .002) and physical function (+1.54 v −0.93, P = .02) versus UC. Benefits were most pronounced among younger, female, Black, and less educated participants. Black participants in the PRO arm were more likely to report that symptom reporting made them feel more in control of their care compared with White participants. CONCLUSION Electronic symptom monitoring improved quality-of-life outcomes overall, including among groups who have historically experienced higher symptom burden or barriers to communication. Remote PRO systems may represent an equitable strategy to enhance cancer care delivery.

Background: Diabetic gastroparesis (DG) is associated with a loss in anti-inflammatory muscularis macrophages (MMs), contributing to delayed gastric emptying (DGE). Lyve1 macrophages, known for their anti-inflammatory phenotype, are involved in lipid metabolism across organs. While diabetes is typically associated with increased lipid levels, the dependence of lipid handling on altered function of Lyve1+ MMs in the stomach remains unknown. Aim: To investigate lipid accumulation in MMs and test the effect of palmitate and CD36 on Lyve1+ macrophages. Methods: FACS sorted CD45+ cells were isolated from the gastric muscularis of non-diabetic mice and analyzed using 10X Genomics Cellranger and Seurat package. Gene Set Enrichment Analysis was performed to identify enriched pathways. Separately, the cells underwent flow cytometry to identify Lyve1+/- MMs then determining lipid accumulation by LipidTox intensity. RAW 264.7 macrophage cells were cultured with macrophage colony stimulating factor (M-CSF), IL-4, and dexamethasone for 7 days to induce Lyve1 expression. RNA was collected from cells treated with palmitate and a CD36 inhibitor, Sulfosuccinimidyl oleate (SSO), for RT-qPCR. Lyve1+ and Lyve1- macrophages treated with 300µM palmitate overnight were collected for lipidomic analysis. Untargeted lipidomic analysis was done with Thermo Orbitrap Exploris 120, and data were analyzed using principal component analysis for group clustering and unpaired t-tests for differential analysis. Results: Unbiased clustering analysis revealed 6 transcriptionally distinct gastric MM populations, one of which was notably enriched in Lyve1 expression. Pathway analysis identified that Lyve1 enriched cluster was associated with lysosomal pathways and receptors involved in lipid uptake, such as CD36, as well as anti-inflammatory markers such as HO1 and CD206. Flow cytometry quantification showed that Lyve1+ MMs had higher accumulation of lipids compared to Lyve1- MMs (10.1±0.7 vs 2.9±0.2 mean fluorescence intensity/cell count, p=0.0002). RT-qPCR validated that Lyve1+ RAW 264.7 macrophages exhibited significantly higher expression of Lyve1 (6.95 times fold change, p=0.023) and CD36 (3.27 times fold change, p=0.011) compared to Lyve1- macrophages. Post palmitate treatment, Lyve1+ macrophages had increased expression of the pro-apoptotic gene caspase-3 (12.15-times fold change, p=0.033), as well as the fatty acid oxidation marker ACADM (4.98 times fold change, p=0.045). Notably, these differences were not found in the presence of SSO. Lipidomic analysis identified 171 differentially expressed lipids, particularly increased levels of ceramides and diacylglycerols in Lyve1+ macrophages compared to Lyve1- macrophages when both are treated with palmitate. Conclusions: Lyve1+ macrophages preferentially uptake lipids compared to Lyve1- macrophages consistent with increased expression of CD36. Lipid treatment of Lyve1+ macrophages increases expression of apoptosis and oxidation markers in a CD36-dependent manner that may lead to cell loss. These mechanisms may contribute to Lyve1+ MMs loss in DG. Funding: DK127992; DK129297; DK115255; ANMS Young Investigator grant; AGA grant#36; P30DK084567; Robert and Arlene Kogod Center on Aging Fundamental Mechanisms of Aging Award. 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.

Purpose: Supervised walking exercise is a critical component of rehabilitation for patients with peripheral artery disease (PAD); however, various barriers could limit participation in such programs, highlighting the need for accessible exercise strategies that may facilitate a gradual transition to more intensive physical activity while improving vascular function and walking performance in this population. We examined the hypothesis that static muscular stretching would improve microvascular function and walking ability in patients with PAD. Methods: Thirty-six PAD patients, classified as Fontaine Stage II or III, were randomized into stretching or non-stretching groups. The stretching group performed daily calf stretching using an ankle dorsiflexion splint for 30 minutes, 5 days a week, for 4 weeks. The six-minute walk test (6MWT) and a vascular occlusion test were used to assess changes in walking ability and calf microvascular function before and after the intervention. Results: Microvascular hyperemic reperfusion significantly increased in the treatment group (4958±1111 to 5749±1459 %*s, p=0.034), with no change observed in the control group (5502±1231 to 5022±1160 %*s, p=0.155). 6MWT total walking distance increased in all participants (260±88 to 285±85 m, p=0.004). A moderate but non-significant correlation was observed between the changes in 6MWT and total walking distance and reperfusion index in the treatment group (r=0.45, p=0.26). Conclusions: Static muscular stretching improves microvascular perfusion in the calf muscles, which may contribute to improvement in walking ability in patients with PAD. This low-cost and time-saving intervention may serve as a gradual transition to traditional supervised walking exercise rehabilitation, especially in patients with severely impaired walking ability.

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P &amp;lt; .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P &amp;lt; .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P &amp;lt; .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P &amp;lt; .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

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.

The objective of this study was to compare drug response of uveal melanoma patient-derived cell lines (PDLs) and patient-derived organoids (PDOs) with response of commercially available cell lines and contextualize laboratory outputs in terms of clinical trial results. Uveal melanoma commercial cell lines, PDLs, and PDOs were treated with drugs that were ultimately utilized in clinical trials. Four treatments were chosen for promising laboratory results that failed to yield clinical response, while darovasertib was a surrogate positive control given initial favorable clinical trial data in the neoadjuvant setting. Drug concentrations were matched to laboratory work that supported progression to clinical trials. Viability was measured using PrestoBlueHS Cell Viability Reagent. Commercial cell lines showed promising viability reduction similar to prior laboratory results with treatments, including 5-μM darovasertib, 700-nM selumetinib, 700-nM selumetinib + 1000-nM MK-2206, 500-nM sotrastaurin + 1000-nM alpelisib, and 100-nM trametinib, with overall viability reduced to 32.5% for all drugs. However, PDLs (viability 52.8%) and PDOs (viability 80.4%) showed more treatment resistance ( P < 0.05), better simulating ultimate lack of efficacy found in clinical trials. While uveal melanoma with BAP1 loss demonstrated greater treatment resistance under some conditions, other factors such as cell morphology or culture in a three-dimensional environment appeared to be more consistent drivers of therapeutic sensitivity. PDLs and PDOs may more accurately represent uveal melanoma clinical response. Demonstrating efficacy of novel therapeutics in these models could improve the likelihood of successful translation for future clinical trials, but future studies are needed to define clinically meaningful in-vitro response thresholds.

Summary Renal response (RenR) in light‐chain (AL) amyloidosis is associated with a lower risk of end‐stage kidney disease and improved survival. However, substantial variation exists in the time to and depth of RenR. We investigated variables associated with RenR in a retrospective study of newly diagnosed AL amyloidosis patients ( n = 350) assessable for RenR between 2010 and 2022. RenRs were recorded at 6, 12 and 24 months and best response. Deep RenR was defined as a ≥renal very good partial response (RenVGPR, >60% reduction in 24‐h proteinuria or ≤200 mg). Logistic regression and competing risk methods were used to examine variables associated with RenR. The median age was 64 years, and median follow‐up was 5.5 years. On multivariable logistic regression, obtaining ≥HemVGPR within 6 months, kappa isotype, high baseline difference between involved and uninvolved free light chains (dFLC ≥40 mg/dL), renal stage and autologous haematopoietic stem cell transplant (AHSCT) were significantly associated with deep RenR. Cumulative incidence rates for deep RenR, treating death or renal progression as a competing event, demonstrated that early HemR, first‐line AHSCT, lower renal stage and dFLC ≥40 mg/dL significantly increased the likelihood of deep RenR. Specific clonal plasma cell features, namely light‐chain isotype and baseline dFLC levels, independently influence the timing and depth of RenRs in AL amyloidosis following treatment, in addition to renal stage and HemR.