Citations

CD4 + effector T helper 1 (T H 1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T H 1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T H 1 cell–associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA–dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T H 1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn’s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4 + T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell–transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains T H 1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

The immune tumor microenvironment (iTME) plays a crucial role in disease biology of plasma cell (PC) dyscrasias, but remains poorly characterized in self-identified Black individuals, a population at increased risk. Mass cytometry and scRNA-seq of 128 bone marrow aspirates revealed significant changes in immune cell composition across the disease spectrum, including shifts from naïve to effector T cells with declines in B cells, MAIT, pDCs, and increases in monocytes with disease progression. Self-identified Black patients had higher relative proportions of terminally differentiated T cells and lower monocytes in newly diagnosed and treated multiple myeloma (MM). ScRNA-seq revealed genes overexpressed in self-identified Black individuals were enriched for E2F targets and G2-M checkpoints, while reduced genes were enriched for TNF-α/NF-kB, interferon and inflammatory responses pathways. These findings were supported by genetic ancestry and validated in an independent dataset of 286 patients with MM from the MMRF Immune Atlas. Self-identified race and African genetic similarity are significantly associated with remodeling the MM iTME, with potential implications for disease biology and treatment response.

Background: While tobacco use is a well-known risk factor for adverse outcomes after carpal tunnel release (CTR), the impact of non-tobacco nicotine products remains unclear. This study evaluated complications in CTR patients with non-tobacco nicotine dependence (NTND) compared with tobacco users and controls. Methods: Patients who underwent CTR with ≥2-year follow-up were identified using a large national database. After 1:1 propensity score matching, patients with NTND (n = 6319) were matched to controls, tobacco users (n = 86 430) were matched to controls, and patients with NTND (n = 6325) were matched to tobacco users. Matching was based on age, gender, Charlson comorbidity index, and comorbidities. Outcomes including 90-day medical complications, infection, emergency department (ED) visits, readmissions, and 2-year revision rates were compared using multivariable logistic regression. Results: Compared with controls, patients with NTND demonstrated higher 90-day medical complication rates (2.4% vs 1.7%; odds ratio [OR], 1.35; 95% CI, 1.04-1.77) and ED visits (10.3% vs 8.1%; OR, 1.16; 95% CI, 1.02-1.32). Compared with tobacco users, patients with NTND had decreased ED visits (10.4% vs 14.2%; OR, 0.74; 95% CI, 0.66-0.83) and revision surgery (1.9% vs 2.5%; OR, 0.78; 95% CI, 0.62-0.99), with no significant differences in medical complications, infection, or readmissions. Conclusions: Non-tobacco nicotine dependence was associated with increased medical complications and ED visits compared with controls, but decreased ED visits and revision surgery compared with tobacco users. There were no significant differences in medical complications, infections, or readmissions between tobacco users and patients with NTND. These findings underscore the importance of screening for non-tobacco nicotine use during preoperative evaluations for CTR.

Traditional home-call managing after-hours pager communications remains a common component of hematology-oncology fellowship and modern practice. Little is known about these patient-related interactions and implications. This project aimed to characterize after-hours pager volumes and evaluate perceived impacts on care, physician wellbeing, and trainee education. We performed a mixed-methods study at a tertiary academic center, analyzing after-hours pager activity from 2020-2024 across Hematology Consult (HCP), Hematology Outpatient (HOP), and Medical Oncology (MOP) pagers. A survey of hematology-oncology fellows evaluated perceptions and attitudes toward the home-call experience using free-text responses and a 5-point Likert scale. After-hours pager burden was substantial and sustained. The MOP received >3,000 pages annually, with medians of 5-6 per weekday and 15-15.5 per weekend day. The HOP volume nearly doubled over the study period (960 to 1,721 annually) with median pager volumes of 1-3 per weekday and 2-7 per weekend day. The HCP volume ranged from 594-768 pages annually. Survey response rate was 58% (19/33). Only 16% of fellows endorsed educational value from patient calls on MOP or HOP, and ≤5% agreed that call tasks required physician-level expertise. Respondents reported that the pager resulted in fatigue, anxiety, and social disruptions. Free text responses revealed themes of low educational value, high non-urgent call volume, and system inefficiencies. Contemporary home-call had substantial pager burdens with limited actionability, adverse effects on wellbeing, and low educational value. Systems engineering, including triage processes and augmented patient education, could help optimize patient care, physician wellbeing, and trainee education.

Peripheral impairment: a novel therapeutic target in Fontan physiology? Exercise intolerance is nearly universal in adults post-Fontan procedure. This exercise catheterization study showed that two-thirds of adults with Fontan circulation exhibited peripheral limitation to exercise, alongside established central hemodynamic constraints. Moreover, peripheral oxygen extraction was an independent determinant of exercise capacity in multivariable analyses. As demonstrated in HFpEF, peripheral oxygen extraction may represent a modifiable therapeutic target in Fontan physiology.

BACKGROUND: Hemorrhoids are common and relief anchors on symptom improvement. Despite several available treatment options, the optimal patient-reported outcome measure for contemporary clinical trials is not established. OBJECTIVE: We aimed to systematically assess patient-reported outcome measures that measure hemorrhoid symptom severity and/or health-related quality of life. DATA SOURCES: A systematic review was performed using PubMed and Embase (1980-2025). STUDY SELECTION: Prospective development/validation studies evaluating patient-reported outcome measures relevant to hemorrhoidal disease. MAIN OUTCOME MEASURES: Patient-reported outcome measures were evaluated on key measurement properties of reliability, internal consistency, construct validity, and responsiveness according to COSMIN v2.0 criteria. RESULTS: Of the 1,266 total studies reviewed, nine patient-reported outcome measures were identified: seven measure symptom severity and six measure health-related quality-of-life. Three demonstrated reliability, internal consistency, construct validity, and responsiveness. The Patient Reported Outcome Measure-Haemorrhoidal Impact And Satisfaction Score comprehensively measures symptom severity, health-related quality-of-life, and treatment satisfaction. The Hemorrhoidal Disease Symptom Score classifies patients with high or low symptom load, and when used in combination with Short Health Scale-Hemorrhoidal Disease, also measures impact on health-related quality of life. LIMITATIONS: Preference toward specific measures may differ between clinical trials and clinical practice. CONCLUSIONS: We identify two viable patient-reported outcome measures for use in future clinical trials that evaluate hemorrhoid interventions.

BET bromodomain inhibitors are efficacious as anti-inflammatory compounds, but clinical translation is hampered by dose-limiting toxicities from non-selective inhibition. We herein report compounds 16 and 26, based on previously reported 4-methyl-1,2,3-triazole-based inhibitor, DW34. 16 has a BRD4 BD1 Ki of 10 nM, and up to 13–38-fold selectivity for BRD4 BD1 over other BD2 domains, and an improved hERG affinity of 4.24 µM over DW34. 26, A biscyclopropyl analog of 16 showed further enhancement of BD1 selectivity over BD2 (26–203-fold), but exhibited more potent hERG inhibition. Compound 16 had improved liver and plasma clearance over DW34, with good biodistribution to the liver, and had an intracellular target-engagement affinity Ki of 92 nM, with reduction of Ccl2, Cxcl1, AST, and ALT in in vitro and in vivo mouse models of liver inflammation. 16 represents a useful lead for treating inflammatory liver diseases, with improved specificity, drug-like properties, and reduced hERG affinity.

BACKGROUND: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial (PA) hypertension. Sotatercept improves clinical outcomes, but its effects on the right ventricle have been inconsistent. We evaluated the effects of sotatercept on load-independent measures of RV contractility, RV–PA coupling, and right heart deformation at rest and exertion in patients with PA hypertension. METHODS: In this prospective trial among participants with PA hypertension recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload (PA elastance [Ea]), RV–PA coupling (ratio of arterial Ea to Ees), and right heart deformation, including RV and right atrial strain, before and after 24 weeks of sotatercept using mixed models. RESULTS: Among 30 participants (n=21; 70% female; mean age, 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, PA pulsatility index, and the maximal rate of RV pressure increase over time (dP/dt max ; P <0.001 for all). The decrease in Ees was associated with a decrease in PA Ea (r=+0.70 [95% CI, +0.44 to +0.85]; P <0.0001) with preserved RV–PA coupling (mean difference, +0.08 [95% CI, −0.11 to +0.26]; P =0.42). Although systolic indices measured at the base of the right ventricle (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept use, there was an increase in RV free wall–dependent systolic indices, including resting and exercise RV free wall strain (mean difference, +6.2% [95% CI, +4.5 to +7.8]; P <0.0001) and fractional area change ( P =0.0001). Beyond the right ventricle, there was also improved right atrial filling and contractile performance across rest and exercise ( P <0.0001 for all). CONCLUSIONS: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV–PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance, such as RV free wall strain and RA strain, improve, alongside redistribution of RV deformation from annular motion to free wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free wall contractile mechanics and exertional right heart reserve. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06409026.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.