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.

Abstract Introduction: Otolaryngology trainees must master complex three-dimensional (3D) head and neck anatomy for safe surgical practice. Existing educational resources, including cadaveric dissection and 3D-printed models, are limited by cost and accessibility. Virtual reality (VR) has demonstrated efficacy for anatomy education, yet no published immersive VR module addresses the facial nerve and parotid gland, which are structures critical to otolaryngology training. We describe the design and development of a multimodal VR anatomy module targeting this gap. Methods CTA DICOM data were segmented in Mimics 23.0 and sculpted in ZBrush to generate high-fidelity 3D models. Models were optimized for the Meta Quest 3 standalone headset using the Unity game engine. A reusable, step-based architecture organized content into sequential, otolaryngologist-scripted narrated scenes featuring progressive anatomical disclosure and dynamic highlighting. Multimodal features include CT/MRI slice viewers, parotidectomy surgical video, and 2D anatomical diagrams. Development involved iterative build cycles, followed by informal usability testing with surgeons, residents, and medical students. Results The final module incorporated 65 anatomical structures, achieving a 96.4% polygon reduction (22.7 million to approximately 806,000 polygons) while preserving clinical fidelity. Most users navigated the environment independently. Feedback identified refinement needs including orientation aids, automated narrator pronunciation corrections, and expanded interaction capabilities. Conclusions This proof-of-concept demonstrates that optimized 3D models derived from clinical imaging can be successfully integrated with standalone educational assets in an immersive VR environment. This module addresses a key gap in otolaryngology education and provides a reusable technical and pedagogical framework adaptable to multiple anatomical regions and learner populations.

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.

ABSTRACT Background Pectus excavatum (PE), the most common congenital chest wall deformity, has known associations with connective tissue disorders and may lead to cardiopulmonary impairment; however, its relationship with atrial fibrillation (AF) remains underexplored. Objectives This study aimed to describe the frequency, clinical characteristics, and management of AF within an institutional cohort of patients with PE, and to determine whether the outcomes observed in clinically distinct subgroups persisted after adjustment for baseline risk. Methods This was a retrospective cohort study design. Patients with both PE and documented AF between January 1, 1990, and November 10, 2024, were included. Clinical, echocardiographic, and therapeutic data were collected. Bleeding and thromboembolic outcomes were evaluated using multivariable logistic regression adjusted for age, sex, CHA 2 DS 2 ‐VASc score, and anticoagulant class, and the surgically treated subgroup was additionally compared using propensity score matching. Results Among 11,578 patients with PE, 1309 (11.3%) had AF. Of those who had AF, mean age was 66.9 years; 54% were female, and 83% had paroxysmal AF. The mean CHA 2 DS 2 ‐VASc and HAS‐BLED scores were 2.8 and 1.9, respectively. Thromboembolic events occurred in 196 (15%) patients, most commonly stroke (11%), followed by pulmonary embolism (4%) and deep venous thrombosis (4%). Bleeding events occurred in 313 patients (24%), most commonly hematuria (12%), gastrointestinal bleed (11%), epistaxis (5%), and intracranial hemorrhage (1%). Seventy‐two patients (6%) underwent the Nuss procedure and were younger (45.3 vs. 68.2 years, p < 0.001), predominantly male (65%), and had lower risk scores compared to the non‐Nuss cohort. Patients who underwent the Nuss procedure had significantly fewer bleeding events (5.6% vs. 25%, p < 0.001) with similar thromboembolic rates. The pectus severity index, available in the 370 patients who underwent dedicated radiologic review, was not associated with bleeding (adjusted OR 0.89, 95% CI 0.75–1.05). The difference in bleeding by surgical status persisted after multivariable adjustment (adjusted OR 0.28, 95% CI 0.10–0.79) and after propensity score matching (5.6% vs. 16.7%, p = 0.030). Conclusions AF was identified in approximately one in nine patients within this single‐institution cohort of adults with PE, with paroxysmal AF representing the predominant subtype. Patients who had undergone surgical repair demonstrated a lower incidence of bleeding events than anticipated based on their baseline risk profile; however, given the limited number of events observed, this finding should be interpreted with caution and requires validation in larger studies. In the absence of a non–PE comparator group, these data are insufficient to determine whether PE independently confers an elevated risk of AF, and prospective, controlled investigations are necessary to elucidate this relationship.

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.