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Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Hematoxylin and eosin (H&E) slides are routinely available in cancer care, but molecular profiling often requires additional tissue processing and turnaround time. We introduce HistoMethyl, a DNA methylation-aware pathology foundation model that aligns whole-slide histopathology with matched genome-scale methylation beta-value profiles during pre-training while requiring only an H&E slide at inference. We evaluated HistoMethyl across four task groups: gene mutation prediction, morphology-associated classification, overall survival prediction, and direct DNA methylation beta-value recovery. Evaluation spanned TCGA cross-validation, a disease-held-out lower-grade glioma cohort, and external cohort validation in CPTAC glioblastoma and SurGen rectal adenocarcinoma, totaling 14 cancer cohorts and 81 gene mutation tasks. The best-performing configuration improved mean mutation AUROC by 5.03 percentage points. By converting DNA methylation supervision into an H&E-only representation, His-toMethyl could support an early molecular triage layer that helps prioritize cases for confirmatory sequencing, methylation profiling, immunohistochemistry, and molecular tumor board review. These image-only predictions are intended to accelerate downstream molecular testing and tissue allocation while leaving final diagnosis and treatment selection anchored in validated molecular assays.

The ever-changing landscape of cardiology necessitates continuous education of healthcare providers. Case-based learning (CBL) provides an inquiry-based form of learning where learners apply knowledge to realistic clinical scenarios under instructor guidance. However, current case-based learning curricula are limited to representing 3-dimensional content in 2-dimensions with distinct modalities utilized for various data sources. Virtual reality (VR) shows promise for CBL given it provides an immersive and interactive 3-dimensional medium in which multi-source content can be incorporated into a unified learning experience, potentially translating to improved learning efficiency and lower cognitive load. With VR case-based learning, learners can view medical imaging in 3-dimensions or seamlessly interact with various 2-dimensional images within one unified medium. Further, additional content including simulated patients or procedures can be incorporated with a higher level of fidelity. Herein, we summarize the current literature exploring VR-CBL, demonstrate a proof-of-concept VR application, and review the implications for cardiology education. The proof-of-concept exemplifies many of the key advantages unique to VR-CBL, such as medical imaging rendered in 3-dimensions, integration of multiple imaging sources, and novel interaction methodologies. Given the importance and rapid evolution of ongoing medical education, VR-CBL, with its immersive and engaging nature, appears to be a promising form of instruction that may serve a larger role in continuing medical education initiatives.

ABSTRACT Inpatient, acute care clinical pharmacists have contributed to many notable improvements in patient outcomes. Several studies have shown a reduction in mortality and other clinical markers when pharmacists are integrated within the care team. Economic analyses of inpatient clinical pharmacy services (CPS) generally demonstrate cost savings related to specific medication classes, prevention of adverse drug events, decreased length of stay, and decreased rehospitalization. Studies also show high satisfaction from other health care professionals, noting improvements in medication‐related patient safety. Finally, studies conducted in tertiary care hospital settings report high levels of patient satisfaction with CPS. As such, the ECHO framework, based on economic, clinical, and humanistic outcomes, is used herein to organize the summary of literature associated with CPS. Given the growing body of evidence, numerous health professional and government organizations recognize the role of pharmacists as an integral part of the inpatient team. Yet implementation of CPS has not been fully realized by hospitals and health systems. This paper briefly describes inpatient CPS, highlights many benefits of and endorsements for clinical pharmacist participation on interdisciplinary teams, and provides high‐level recommendations for health system administrators and the profession of pharmacy to further encourage broader integration of CPS into patient care teams. Effectively positioning inpatient clinical pharmacists as indispensable team members will require intentional work and strategic planning with a focus on high‐impact value, visibility, and leadership.

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

Background Despite consistent epidemiological evidence identifying smoking as a risk factor for medication-overuse headache (MOH), the mechanisms underlying this association remain incompletely elucidated. The aim of this work was to explore the relationship between the severity of analgesic dependence, headache-related disability, nicotine dependence, psychological distress, and addiction-related personality traits in patients with MOH. Methods This multicenter cross-sectional study was conducted on 442 patients with primary headache disorders. Participants underwent structured face-to-face interviews and were asked to fill out the following questionnaires: Headache Impact Test–6 (HIT-6), Severity of Dependence Scale (SDS), Depression Anxiety Stress Scales-12 (DASS-12), and Substance Use Risk Profile Scale (SURPS). Smoking status was documented for all participants. Current smokers were asked to complete Fagerström Test for Nicotine Dependence questionnaire (FTND). Results This study included 442 patients with primary headache disorders, of whom 150 had MOH and 292 did not. Patients with MOH (n = 150) reported significantly higher monthly headache days (MHD), acute medication days (AMD), HIT-6, DASS-12, and SURPS scores than those without MOH (n = 292) (all P-values < 0.001). Smoking prevalence and FTND scores were significantly higher among MOH patients than those without MOH (all P-values < 0.001). Smokers demonstrated higher MHD, AMD, prevalence of MOH, DASS-12, and SURPS scores than non-smokers (all P-values < 0.05). Among smokers, FTND correlated positively with MHD, AMD, HIT-6, DASS-12, and SURPS (all P-values < 0.001). In patients with MOH, SDS scores showed positive correlations with AMD, HIT-6, DASS-12, and SURPS (all P-values < 0.05). Conclusion Severity of dependence on analgesics in patients with MOH is strongly associated with headache burden, nicotine dependence, psychological distress, and addiction-related personality traits.

Background: Liver transplantation (LT) remains the definitive treatment for end-stage liver disease; however, post-LT outcomes may differ depending on underlying disease etiology. Our study aimed to compare post-LT outcomes between alcoholic and non-alcoholic steatohepatitis (NASH)-related liver transplant recipients in the United States. Methods: A retrospective cohort study was conducted using the TriNetX Research Network. Adult liver transplant recipients (≥18 years) were categorized into two mutually exclusive cohorts: alcoholic liver disease and NASH-related liver disease. Propensity score matching (1:1) was performed to balance baseline characteristics. Clinical outcomes were assessed. Comparative analyses included risk ratios, risk differences, odds ratios, Kaplan–Meier survival analysis, and hazard ratios with log-rank testing. Results: Compared with NASH recipients, alcoholic LT recipients had a significantly higher risk of rejection (14.5% vs. 12.1%; RR 1.195, 95% CI 1.076–1.327; p = 0.001) and hepatic encephalopathy (14.3% vs. 8.3%; RR 1.720, 95% CI 1.526–1.938; p < 0.001). Acute kidney injury was also more frequent in the alcoholic cohort (47.3% vs. 43.6%; RR 1.084, 95% CI 1.036–1.133; p < 0.001). In contrast, sepsis (15.6% vs. 18.0%; RR 0.869, 95% CI 0.794–0.952; p = 0.003) and CKD (46.1% vs. 51.1%; RR 0.901, 95% CI 0.863–0.939; p < 0.001) occurred less frequently in alcoholic LT patients. No significant differences were observed for liver transplant failure or ascites. Kaplan–Meier analyses demonstrated significantly lower rejection-free survival (HR 1.241, p < 0.001), higher hepatic encephalopathy (HR 1.808, p < 0.001), increased AKI risk (HR 1.150, p < 0.001) and higher all-cause mortality in the alcoholic cohort (HR 1.106, p = 0.031). Conclusions: In this large real-world matched cohort study, alcoholic LT recipients demonstrated higher risks of complications and all-cause mortality compared with NASH LT recipients.