Citations

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).

ABSTRACT The novel HLA‐DQA1*01:217 allele differs from DQA1*01:01:01:12 by a single non‐synonymous change in exon 3′.

Introduction Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in immune signaling and has been implicated in tumor-intrinsic resistance to DNA-damaging therapies. Although SYK activity has been associated with poor outcomes in triple-negative breast cancer (TNBC), its role in resistance to combined radiotherapy and immune checkpoint blockade remains unclear. Methods SYK expression and clinical relevance were assessed across multiple breast cancer cohorts, including radiotherapy-treated datasets. Integrated transcriptomic analyses were used to characterize SYK-associated immune states. The functional effects of pharmacologic SYK inhibition were evaluated using in vitro assays and an immunocompetent bilateral 4T1 tumor model in female BALB/c mice treated with radiotherapy and PD-1 blockade. Treatment-associated immune remodeling was assessed by flow cytometry and transcriptomic profiling. Results Across multiple cohorts, elevated SYK expression, particularly in TNBC, was associated with inferior clinical outcomes and immune dysregulation. Pharmacologic SYK inhibition enhanced tumor responses to radiotherapy and PD-1 blockade at both irradiated and distant tumor sites. These effects were accompanied by coordinated remodeling of the tumor immune microenvironment, including suppression of neutrophil-associated signatures and reductions in immunosuppressive myeloid populations, including M2-like macrophages and myeloid-derived suppressor cells. Discussion Pharmacologic SYK inhibition enhances responses to radiotherapy and PD-1 blockade in preclinical TNBC models and is accompanied by remodeling of the immunosuppressive myeloid compartment. These findings support further investigation of SYK-targeted strategies to improve responses to combined radiotherapy and immune checkpoint blockade.

Abstract Circumscribed meningeal melanocytic neoplasms (CMMNs) represent a spectrum of rare central nervous system (CNS) tumors. Knowledge of their clinical behavior and molecular correlates remains limited. In this single‐institution retrospective study, we analyzed 31 patients (14 male, 17 female; median age, 59 years) diagnosed with CMMN between 2004 and 2025. In this patient cohort, based on the current World Health Organization Central Nervous System Tumor Classification (WHO CNS5) criteria, the majority of cases (18, 58.1%) fell into the intermediate‐grade melanocytic tumor (IMT) category based on histology, with either increased mitotic activity, CNS invasion, or both; 7 (22.6%) were melanocytomas, 5 (16.1%) melanomas, and 1 (3.2%) indeterminate case because of limited tissue. By next‐generation sequencing, mutations were identified in GNAQ/GNA11 in 21/24 cases, BAP1 in 5/23 (2 IMT, 3 melanoma), EIF1AX in 9/21 (1 melanocytoma, 8 IMT), and SF3B1 in 3/23 (2 IMT, 1 melanoma). Primary sites were spinal (20), posterior fossa (6), and supratentorial (5). During follow‐up, progression was observed in 5/6 melanocytomas, 9/13 IMTs, and 4/5 melanomas, suggesting a high frequency of progression across all groups. Two‐year progression‐free survival was 83.3% (95% confidence interval [CI], 53.5%–100.0%) for melanocytoma, 55.9% (95% CI, 26.7%–85.2%) for IMT, and 25.0% (95% CI, 0.0%–67.4%) for melanoma. Five‐year overall survival (OS) was 80.0% (95% CI, 44.9%–100.0%) for melanocytoma, 65.3% (95% CI, 37.0%–93.6%) for IMT, and 0.0% for melanoma. OS was significantly worse in melanoma compared with melanocytoma ( p = 0.002). BAP1 mutation correlated with worse OS (hazard ratio 8.73, p = 0.006). Upfront maximal safe resection appeared to be associated with improved outcomes in selected patients, whereas radiotherapy and systemic therapy did not demonstrate clear additional benefit in this cohort. In summary, our study shows that all CMMNs, irrespective of grade, have a high propensity to recur and melanoma histology and BAP1 mutation are associated with significantly worse OS.

Stellate ganglion blockade (SGB) is an uncommon but increasingly relevant therapy used to modulate the autonomic nervous system and reduce the risk of atrial fibrillation (AF). This narrative review focuses specifically on the potential therapeutic role of SGB in new-onset perioperative atrial fibrillation (POAF), a complication associated with adverse long-term outcomes that may diminish the overall benefits of surgery. SGB may reduce AF through several inflammation-mediated mechanisms, including attenuation of direct sympathetic activation and modulation of perioperative inflammatory responses. Because the clinical effects of SGB may persist beyond the expected duration of local anesthetic nerve blockade, we emphasize immunomodulation as a potential mechanism sustaining its beneficial effects and influencing longer-term outcomes. In this review, we examine the immunological effects of SGB in the context of postoperative AF, with particular emphasis on human studies most relevant to clinical practice. Available evidence suggests that, beyond nonspecific inflammation, several less commonly studied cellular components, including mast cells and T cells, may contribute to the initiation and persistence of POAF. These findings support the hypothesis that SGB may reduce POAF by limiting stellate ganglionitis driven by perioperative localized leukocyte activation. Future studies should define the extent, timing, and frequency of this inflammatory process and determine whether specific inflammatory or autonomic phenotypes can identify patients most likely to benefit from SGB.

Abstract Anthracycline-induced cardiotoxicity (AIC) remains a dose-limiting complication of cancer treatment, often leading to irreversible heart failure, yet effective cardioprotective therapies remain limited. Graph-driven drug repurposing offers a rapid pathway to identify cardioprotective therapies, but different computational models often generate divergent candidate lists that exceed experimental validation capacity. We applied a novel "Union-then-Filter" framework to prioritize therapeutics for AIC using AI-based approaches and evaluated candidates in zebrafish models. Three state-of-the-art graph learning models (TxGNN, CompGCN, and RLR) were trained on the PrimeKG to generate an initial candidate pool. A Large Language Model (LLM) agent automated evidence synthesis across 4,286 PubMed abstracts for the top 50 drugs from each model. Candidates were stratified using dual decision criteria and filtered against existing clinical trials. The pipeline narrowed 150 initial candidates to four novel candidates: Cysteine, Dasatinib, Tranilast, and Tretinoin. Prospective in vivo validation was subsequently conducted using an adult AIC (aAIC) zebrafish model. Phenotypic screening via echocardiography revealed that Cysteine, Tranilast, and Tretinoin significantly restored ejection fraction (EF) (overall one-way ANOVA: \(\:F\left(\text{4,95}\right)=47.66,\:\:p<0.0001\); Tukey's post hoc: \(\:\:\:p<0.01\) for all three treatments vs. DOX+ control) and normalized cardiac remodeling markers in doxorubicin-treated subjects (Kruskal-Wallis: \(\:{\chi\:}^{2}\left(4\right)=17.21,\:\:p=0.0018\); Dunn’s post hoc: \(\:\:\:p<0.01\) for all three comparisons vs. DOX control). This study demonstrates the translational utility of an LLM-integrated AI pipeline for drug repurposing and highlights zebrafish AIC as an efficient bridge between in silico prediction and in vivo phenotypic validation in cardio-oncology.

Introduction: Crohn’s disease (CD) remains associated with long-term morbidity despite biologic therapies. Surgery, historically considered a last-resort option, is increasingly integrated into disease management earlier. This review examines the evolving role of surgery in the biologic era. Methods: A focused narrative review of randomized controlled trials, meta-analyses, observational studies, and international guidelines addressing contemporary surgical strategies in CD was performed. Results: The LIR!C trial demonstrated that early ileocecal resection provides durable remission and improves long-term outcomes compared with biologic therapy in selected patients. The PISA II trial supported an early combined surgical and medical approach for perianal fistulizing disease. Preoperative optimization, including nutritional support and adjustment of immunosuppressive therapy, has become a cornerstone of perioperative management. Laparoscopic surgery remains the preferred approach whenever feasible, while robotic surgery is emerging as a promising platform that is expected to play an increasingly important role in the surgical management of CD. Postoperative recurrence remains a major challenge, prompting the development of innovative surgical strategies. Although the Kono-S anastomosis initially showed promising reductions in recurrence, recent prospective studies failed to confirm superiority over conventional techniques. Similarly, extended mesenteric excision did not demonstrate improved outcomes despite increasing evidence implicating the mesentery in CD pathogenesis. Strictureplasty remains an effective option for selected fibrotic small-bowel strictures. Conclusions: Surgery remains central to multidisciplinary CD management and offers the potential to modify disease when performed early in selected patients. The impact of innovative surgical strategies on postoperative recurrence remains uncertain, and ongoing trials are expected to further help with surgical decision-making.

ABSTRACT Consumer‐grade wearables, including smartwatches, fitness trackers, and smart rings, are accessible tools for studying pharmacologic responses in real‐time, monitoring participant health in decentralized clinical trials, optimizing outcome measures, and delivering digital interventions that promote behavior change. However, incorporating consumer wearables into clinical studies is not as straightforward as simply purchasing devices and providing them to participants. It requires engaging with a complex engineering ecosystem with multiple investigator decisions on device selection, associated data management practices, and patient/participant engagement and technical support. This tutorial, based on experience running large clinical trials using consumer wearables, outlines the wearables market landscape across varying form factors and manufacturers as well as the data management software products supporting wearable use. It delineates the major decision processes involved in designing studies that incorporate wearables and presents a structured framework to guide the selection of devices and supporting data tools according to study objectives.