Citations

Abstract Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer’s disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.

ABSTRACT First‐line therapy for mantle cell lymphoma (MCL) represents a critical opportunity for clinical benefit via sustained complete response. We conducted a phase 2 multicenter trial in the academic and community cancer research united (ACCRU) network, testing a multitargeted 1st line regimen. CARiBOU (ACCRU‐LY‐1804) employs alternating VR‐CAP and R‐cytarabine with continuous acalabrutinib, in six 21‐day cycles, for previously untreated MCL. The primary endpoint was complete metabolic response (CMR) rate. Secondary endpoints included safety, feasibility of stem cell collection, proportion proceeding to ASCT, and progression‐free (PFS) and overall survival (OS). Peripheral blood measurable residual disease (MRD) was tested using the ClonoSEQ assay (Adaptive Biotechnologies). Of 41 patients enrolled, 39 (95%) responded to therapy, including 37 patients achieving CMR (90%). Two nonresponders discontinued therapy for toxicity early, prior to study‐defined restaging, and received alternate therapy. Undetectable MRD at a 10 6 threshold was achieved in 26/33 tested patients (79%), and 94% at 10 5 . 18‐month estimated PFS is 79% (95% CI 64%–97%), and OS is 96% (95% CI 88%–100%). Toxicities were primarily hematologic (grade 3 hematologic AE in 32 patients, [78%]). Twelve required platelet transfusions, and one grade 3 bleeding event occurred. Febrile neutropenia occurred in 4 patients, and 6 (14%) experienced SAEs. There were no treatment‐related deaths. CARiBOU is an efficient, highly effective outpatient 1st line MCL regimen, employing intermediate‐dose cytarabine and continuous acalabrutinib for 6 cycles. This multitargeted regimen addresses the biologic heterogeneity of MCL and permits flexible MRD‐guided decisions on consolidation and maintenance. Trial Registration: ClinicalTrials.gov identifier: NCT04626791

Purpose: Adolescents and young adults (AYAs) with cancer have unique physical, emotional, and social challenges. We aimed to identify key concerns among AYAs with cancer, evaluate pathways for connecting patients with resources, and inform the development of an AYA oncology program. Methods: This study was conducted at Mayo Clinic in Arizona and included English-speaking patients aged 18–39 years with recently diagnosed cancer. Participants completed a modified Needs Assessment Service Bridge questionnaire, which assessed patient-perceived needs with 39 items spanning 7 domains. An AYA nurse navigator discussed each participant’s results with them and connected them to the desired resources. Results: Of 52 eligible patients, 32 (62%) completed the questionnaire. Among them, 30 (94%) reported unmet needs in at least 1 domain and 19 (59%) reported unmet needs in 5 or more domains. The domains with the most frequently reported needs were health behaviors and wellness (81%), emotional health (72%), finances and everyday needs (59%), and work- and education-related assistance (56%). Younger participants reported more needs related to school life and scholarships/loans than did older participants. No significant differences were observed between the responses of men and women. Of 133 total needs identified by all participants, 93 (70%) were addressed by connecting patients to relevant resources. Conclusion: Systematic assessment of AYA needs and targeted connection to resources are essential for individualized and developmentally appropriate care. The current study identified key service gaps at our institution and will guide the continued evolution of our comprehensive AYA oncology program.

ABSTRACT Background Alcohol intake is a modifiable risk factor for breast cancer, yet patterns of alcohol intake in women with breast cancer remain underexplored. This study evaluates demographic and clinical predictors of alcohol intake in patients with breast cancer. Methods Patients at Mayo Clinic Rochester diagnosed with breast cancer (Stage 0–3) between July 2014 to March 2022 were surveyed about their average alcohol intake over the 10 years prior to their diagnosis. Alcohol intake was categorized as < 1, 1–4, 5–14, and ≥ 15 drinks per week. Demographic, behavioral, and clinical data were analyzed using univariate Fisher exact tests and multivariate multinomial logistic regression. Results Of 2030 participants (mean age at diagnosis: 59 years; 99.3% female; 95.9% White), 29% consumed < 1 drink/week, 48% reported 1–4 drinks/week, 20% consumed 5–14 drinks/week, and 3% reported ≥ 15 drinks/week. Older age at diagnosis (≥ 60 years), non‐White race, financial difficulty, and never smoking were associated with less alcohol intake. Patients who reported higher levels of mild–moderate intensity exercise reported more alcohol intake. Tumor stage, tumor receptors, and BRCA mutation status were not associated with alcohol intake. PROMIS‐10 physical health scores correlated with alcohol intake in univariate but not multivariate models. Conclusion Alcohol intake is more common prior to a breast cancer diagnosis for patients who are younger, White, financially secure, exercising, and smoking. These findings may inform alcohol intake‐related breast cancer prevention efforts and highlight patient subgroups who could benefit from targeted counseling at the time of diagnosis.

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are immune-mediated disorders of the gastrointestinal (GI) tract that, despite involving different tissues, are increasingly recognized to coexist. Epidemiologic studies demonstrate a bidirectional association, with patients affected by one condition showing a higher-than-expected prevalence of the other, suggesting shared susceptibility rather than incidental overlap. Genetic and epigenetic data support partial convergence in immune regulatory pathways, while epithelial barrier dysfunction and antigen-driven immune activation emerge as common upstream features. Overlapping cytokine networks, including IL-4, IL-13, and IL-23 signaling, contribute to chronic inflammation in both diseases, although differences in tissue environment and immune dominance give rise to distinct inflammatory phenotypes and clinical behavior. Clinical outcomes in patients with dual diagnoses appear heterogeneous, with available data suggesting neither uniformly worsened nor clearly protective disease courses, underscoring the complexity of shared immune mechanisms operating within different anatomic contexts. Beyond inflammatory activity, coexistence of EoE and IBD poses important nutritional and quality-of-life challenges, as overlapping dietary restrictions and chronic symptoms increase the risk of malnutrition, micronutrient deficiencies, and psychosocial burden. Current therapies remain disease-specific, with strong evidence supporting proton pump inhibitors, swallowed topical steroids, dietary therapy, and dupilumab in EoE, and biologics and small molecules targeting TNF-α, IL-12/23, IL-23, integrins, and JAK–STAT signaling in IBD, while evidence guiding treatment in patients with dual diagnosis remains limited. Together, current evidence supports a framework of shared immune machinery with tissue-specific expression that explains coexistence while preserving the distinct identities of EoE and IBD. By integrating emerging genetic, immunologic, and clinical evidence, this review aims to provide a framework for understanding and managing patients with coexisting EoE and IBD.

Abstract INTRODUCTION Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau‐PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS Cortical regions with lower typical GM MWF showed higher tau‐PET uptake ( β = −0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau‐PET covariance ( β = −0.238, p < 0.001). Higher typical FC was associated with higher tau‐PET covariance ( β = 0.447, p < 0.001). DISCUSSION In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

Objective: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. Study design: Retrospective analysis. Setting: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. Patients: Patients with NF2-related schwannomatosis. Intervention: Next-generation sequencing. Main outcome measure: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. Results: From 2021 to 2024, there were 32 patients ≥30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed ≥30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for ≥30 vs. <30 years of age; P =0.90. Those ≥30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). Conclusions: Patients diagnosed with NF2-related schwannomatosis at age ≥30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients’ biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

ABSTRACT Background Experiencing weight stigmatization is linked to maladaptive eating, poorer mental health, and increased risk of weight gain, potentially impacting metabolic bariatric surgery (MBS) outcomes. This meta‐analysis aimed to synthesize patient experiences of weight stigmatization before and after MBS and to examine the association of presurgical weight stigma on postsurgical weight loss. Methods This preregistered study followed PRISMA guidelines. Six databases were searched through March 2025; eligible studies included published articles and dissertations/theses available in English that quantitatively measured presurgical weight stigma among MBS samples and included relevant outcomes. Meta‐analyses utilized random effects models with change scores converted to Hedge's g and associations between presurgical experienced weight stigma and post‐MBS weight change converted to coefficient r . Results Forty‐one studies were included, with 36 reporting on experienced weight stigma change pre‐ to post‐MBS and 10 studies reporting on the relationship between pre‐MBS experienced weight stigma and post‐MBS weight loss. Conclusions Results revealed weight stigmatization decreased substantially after MBS (6–12 months, g = 1.28; 13–24 months, g = 1.16; 25–36 months, g = 1.26). Presurgical weight stigma was not associated with weight loss post‐surgery ( r = 0.05). Findings are limited by minimal studies reporting on longer term relationships between baseline stigma, post‐MBS weight loss, and additional health outcomes.

ABSTRACT In a population-based study conducted in rural Ecuador, 635 stroke-free persons aged Z40 years were interviewed with the Epworth sleepiness scale and screened to assess their cardiovascular health (CVH) status. Excessive daytime somnolence was present in 22% persons and a poor CVH status in 69%. In a generalized linear model after adjusting for age and sex, excessive daytime somnolence was not associated with a poor CVH status or with any of the individual metrics in the poor range. Excessive daytime somnolence may not be linked to cardiovascular risk factors at the rural level.

Background: Despite recent advances in cleft care, Vietnam continues to have extensive involvement from international nongovernmental organizations (NGOs), creating a fragmented system with limited coordination. This project seeks to establish a baseline understanding of Vietnam’s cleft care landscape, including major international NGOs and their collaborations with local partners, costs and insurance coverage, and patterns applicable to other low- and middle-income countries with NGO-supported cleft care. Methods: We conducted a mixed-methods study using literature review and semi-structured interviews with surgeons, hospital administrators, and NGO representatives (n = 7). Sources included PubMed, targeted Google searches, and government regulations on NGO involvement, cleft care costs, and insurance policies. Results: Vietnam partners with 17 international NGOs that operate through 3 distinct but complementary models: vertical, horizontal, and diagonal models. These collaborations offer financial support, infrastructure, technology investment, and research development, leading to higher surgical volume, more timely access to care, and implementation of standardized multidisciplinary cleft services in Vietnam. National insurance provides broad coverage but requires a complex referral process with limited benefits for secondary cleft services. Limited awareness of insurance benefits and mistrust of local care further discourage the use of national health insurance. Conclusions: Improving access to comprehensive cleft services in Vietnam requires streamlining insurance referral pathways and decentralizing advanced cleft services to regional centers to ensure continuity of care. Aligning NGO activities with national policies is essential to building a coordinated and sustainable cleft care system in Vietnam and in other low- and middle-income countries with strong insurance frameworks and significant NGO involvement.