Citations

Objective To characterize regional brain atrophy patterns, evaluate their association with regional leucine‐rich glioma‐inactivated‐1 ( LGI1 ) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE). Methods This study compared regional brain volumes in LGI1‐AE patients versus age‐ and sex‐matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized. Results A total of 55 LGI1‐AE patients were included. Median age was 68 years (IQR 62.5–74.2 years) at volumetric analysis, after 19 months (IQR 11–45 months) from symptom onset. Compared with HC ( n = 55) and AD patients ( n = 55), LGI1‐AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen ( p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non‐lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC ( p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis ( β = −0.56; p = 0.002) and longer disease duration ( β = −0.01; p = 0.001) independently predicted total hippocampal volume ( R 2 = 0.31). Interpretation LGI1‐AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026

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.

Background: This qualitative study sought to understand factors related to low rates of screening mammography among transgender and gender-diverse (TGD) individuals and how these rates might be improved. Methods: Individuals who self-reported as TGD were recruited from multiple sites and national patient advocates. Consenting participants completed an individual interview using a semistructured guide informed by the Health Belief Model (HBM). Interview data were analyzed using thematic analysis. Results: A total of 44 individuals completed the interview (median age, 44.9 years; range, 19–77 years); 11% were a racial/ethnic minority; and 52%, 20%, and 25%, respectively, self-identified as a transgender woman, transgender man, or nonbinary. Three themes emerged around constructs in the HBM. First, individuals voiced a hope to be treated equally (“I just want to go to work, pay my taxes, love my family, and go along my day and be a good human”) and described how such equitable treatment during screening guarded against gender dysphoria and favored gender affirmation (“it is affirming…being treated as any other woman”). Second, barriers and facilitators related to mammography were identified, including the need to address cost/low cost (“screenings are a luxury”); prior negative/positive experiences (“they would call my name and look at me but dismiss me”); absence/presence of education (“none of the doctors…ever told me what that process looks like”); and perceived low/high cancer risk (“my mom died pretty young from breast cancer”). Finally, practical recommendations were offered, including individual changing/waiting rooms, hiring gender-diverse staff, and engaging clinicians who provide whole-person, trauma-informed care. Conclusions: Mammographic screening among TGD individuals could be improved by proactively creating safe, affirming spaces; working to lower costs; providing educational materials tailored to the TGD community about cancer risk and the practical aspects of screening; and hiring gender-diverse staff. These recommendations from TGD participants merit implementation as well as further study.

Cardiovascular (CV) dysfunction is common in severe acute pancreatitis (AP) and contributes substantially to mortality. Although sex differences in CV diseases are well recognized, with males generally exhibiting higher risk and poorer outcomes, their influence on AP-associated CV responses remains poorly defined. Here, we examined sex-dependent alterations in vascular integrity and cardiac function using cerulein-induced mouse models of AP. Because obesity is associated with more severe forms of AP, cerulein was used to induce mild AP in lean wild-type C57BL/6J mice and a more severe phenotype in obese C57BL/6J mice. Across both models, pancreatic injury was comparable between sexes. A modest sex difference in vascular permeability was observed in the mild but not severe AP model. In mild AP, both males and females showed similar compensatory increases in cardiac systolic function; however, in severe AP, only female mice maintained this adaptive systolic augmentation. Circulating levels of free fatty acids, reflecting systemic tissue lipolysis, were lower in females. Impaired cardiac adaptation in males was accompanied by higher levels of seven different myocardial inflammatory cytokines, as well as elevated circulating levels of angiopoietin-2 (Angpt2). While Angpt2 levels correlated with the severity of cardiac dysfunction, Angpt2 neutralization did not improve, and indeed worsened cardiac function in males. Together, these findings delineate both sex-dependent and sex-independent CV responses in mild and severe AP and identify Angpt2 as a potential compensatory cardioprotective factor under obesity-associated severe AP.

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.

Introduction Platelets contain a wide range of bioactive mediators, many of which accumulate during storage of platelet concentrates and have immunomodulatory properties. Our objective was to investigate how mediators derived from stored platelet concentrates modulate the acute inflammatory response using an ex vivo model. Methods Platelet-depleted whole blood from healthy donors (n=8) was supplemented with pooled platelet concentrate supernatants generated from six platelet concentrates sampled on storage days 1, 3, 5, and 7, and incubated with or without heat-inactivated Escherichia coli for four hours at 37 °C. Inflammatory responses were assessed by measuring complement activation, platelet-derived mediators, and cytokines. Results In the absence of E. coli , addition of platelet concentrate supernatants increased the levels of 24 of 32 measured inflammatory mediators. In contrast, under E. coli -stimulated conditions, the supernatants increased 10 markers and attenuated 14 markers, including the key pro-inflammatory cytokines IL-1β, IL-6, and TNF. The attenuation of these cytokines ranged from 25-43%, whereas several other mediators were unchanged or increased. The majority of biomarkers showed limited differences across the investigated storage time points. Conclusions Our findings demonstrate that soluble factors released from platelet concentrates can modulate inflammatory responses in platelet-depleted blood in an ex vivo setting, with context-dependent, bidirectional, and selective immunomodulatory effects.

AI skill development is essential in health professions education (HPE), yet this type of faculty development is complex to design and implement. While competency frameworks and AI education programs are emerging, many faculty developers are themselves still building AI literacy and confidence, and practical guidance for how to design a faculty development program on AI that is accessible, skill-oriented, and responsive to rapid technological change remains limited. Although webinars and workshops can only do so much, a well-planned faculty development program can provide a great introduction to AI, alleviate fears, and inspire participants to keep growing and learning. Drawing on our experience designing and hosting the AAMC GEA AI Skill-Building Webinar Series and the current literature in AI, this article offers twelve practical tips for faculty developers who are creating AI-focused learning opportunities for everyone involved in HPE. These tips will help readers create robust AI skill-building sessions that move participants beyond awareness of AI and shift their perspectives toward applied, reflective, and responsible use of AI in HPE.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a promising therapeutic option for women with polycystic ovary syndrome (PCOS). Clinical trials and data demonstrate significant improvements in body weight, insulin resistance, hyperandrogenism, and, in some studies, menstrual regularity and reproductive outcomes. However, the current evidence base remains disproportionately focused on short-term metabolic and anthropometric endpoints, while outcomes most relevant to patients—including treatment satisfaction, gastrointestinal tolerability, psychological well-being, body image, fertility planning, financial burden, and long-term adherence—remain inadequately characterized. Methods: We searched PubMed and Google Scholar for English-language literature published between 2021 and 2026, using structured keyword searches. This narrative review evaluates the literature on GLP-1RA use in PCOS beyond weight-focused outcomes, examining mechanisms of action, comparative tolerability across agents, and patient-centered domains including quality of life, eating behavior, and reproductive planning. Results: The published literature reveals a substantial gap between trial-reported completion rates and treatment success, and actual persistence and patient satisfaction. This discrepancy is particularly consequential in PCOS, where treatment decisions intersect with high baseline rates of depression, anxiety, and body image disturbance, and where ovulatory benefits must be weighed against mandatory discontinuation before conception. Conclusions: We identify a systematic absence of validated patient-reported outcome measures, standardized core outcome sets, and long-term follow-up data after treatment withdrawal. This review proposes a research agenda prioritizing patient-centered endpoints as co-primary outcomes, structured assessment of acceptability and persistence, qualitative and mixed-methods approaches, and a dedicated study of fertility planning and treatment interruption.

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.