Citations

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

ABSTRACT INTRODUCTION Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS In 585 cognitively healthy midlife adults (ages 40–59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS Neighborhood deprivation was associated with poorer cognition ( r = 0.36, p < 0.001), greater prevalence of modifiable risk factors ( r = 0.36, p < 0.001), and greater SVD burden ( β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. Highlights Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)‐related SVD

Background The Woven EndoBridge (WEB) device represents an innovative solution for cerebral aneurysm occlusion, particularly for challenging wide-neck bifurcation aneurysms. However, factors affecting sustained occlusion remain poorly understood. We utilized machine learning to attempt to identify predictors of favorable long-term outcomes following WEB treatment. Methods In this multicenter retrospective study, we collected patient demographics, aneurysm characteristics, procedural details, and clinical outcomes. The primary endpoint was improvement in occlusion status, defined as maintained Raymond-Roy Occlusion Classification (RROC) grade 1, or improvement from grade 2 to 1, or from grade 3 to either 2 or 1 on final angiographic follow up. The dataset was split into training (75%) and validation (25%) sets. The CatBoost algorithm was selected based on performance metrics, with Shapley Additive exPlanations (SHAP) values calculated to determine feature importance. Furthermore, a multivariable binomial logistic regression model was performed to validate machine learning findings. Results Among 720 aneurysms from 36 hospitals, 84% showed improvement in occlusion at follow up. Both machine learning and multivariable logistic regression identified aneurysm height as the most consistent correlate of nonimprovement (odds ratio (OR) 0.90 per mm, p = 0.022). In the CatBoost model, the highest-ranking features by SHAP included aneurysm height, patient age, treatment acuity, ACom location, WEB-SLS device, bifurcation anatomy, aneurysm multiplicity, baseline modified Rankin Scale, access route, and partial thrombosis. Conclusions Machine-learning and regression analyses identified consistent predictors of occlusion improvement after WEB treatment, with aneurysm height most strongly linked to nonimprovement. These insights may guide patient selection and follow up. Findings require cautious interpretation and external validation in larger cohorts.

Background: Sepsis survivors experience substantial long-term cardiovascular (CV) morbidity and mortality. The pooled-cohort atherosclerotic cardiovascular disease (ASCVD) score estimates 10-year risk in the general population, but its accuracy soon after sepsis is unknown. Objectives: (1) Describe the absolute five-year incidence of major adverse cardiovascular events (MACE) after sepsis hospitalization. (2) Evaluate the discrimination and calibration of the 10-year ASCVD score for predicting five-year MACE in this setting. Research Questions: The ASCVD score would underpredict five-year MACE in sepsis survivors, reflecting their heightened risk. Methods: We performed a retrospective closed-cohort study using electronic health records from Mayo Clinic hospitals (USA). Adults aged 40–75 years hospitalized for sepsis between 2018 and 2020 were eligible if follow-up was ≥5 years; the age criterion matched the derivation range of the ASCVD score. The primary outcome was five-year MACE—myocardial infarction (MI), ischemic or hemorrhagic stroke, or CV death. Secondly we evaluated the predictive performance of ASCVD score for five-year MACE. Discrimination was assessed with the area under the receiver-operating curve (AUROC); calibration with Calibration-in-the-Large (CITL, ideal = 0) and slope (ideal = 1). Performance metrics were calculated in patients with complete ASCVD variables. Results: A total of 6306 sepsis admissions were screened. 2424 patients were excluded for age outside 40–75 years and 879 for <5 year follow-up, leaving 2718 patients for incidence analyses. Median age was 65 years (IQR 56–70); 55 % were male, 38 % required ICU care, and 91 % were White. Median body-mass index was 28.2 kg/m2 (IQR 23.7-34.7). During follow-up, 125 patients (4.6 %) had MI, 219 (8.1 %) experienced stroke, and 303 (11.1 %) died of CV causes; overall, 1573 patients (57.9 %) met the composite MACE outcome. Complete ASCVD data were available for 409 patients. In this subset, discrimination was moderate (AUROC 0.65; 95 % CI 0.59–0.71). Calibration showed CITL +0.34 (95 % CI 0.09–0.59) and slope 0.50 (95 % CI 0.28–0.72), indicating systematic infra-prediction and over-fitting, respectively. Conclusion: Five-year MACE incidence after sepsis is high. The 10-year ASCVD score moderately discriminates but underestimates five-year CV risk in this population, highlighting the need for sepsis-specific predictive models or recalibration to guide targeted post-sepsis cardiovascular prevention.

Introduction: Corticosteroid therapy has been demonstrated to improve prognosis and reduce mortality in patients with severe Coronavirus Disease 2019 (COVID-19) infection by attenuating the exaggerated inflammatory response that emerges in the late phase of infection. However, its impact on patients with pre-existing cardiovascular disease, who are at higher risk of complications, has not been specifically studied. The aim of this study is to evaluate the effect of corticosteroid therapy on mortality and long-term COVID-19 symptoms in this high-risk population. Methods: We analyzed the prospective registry HOPE-2. Patients with previous cardiovascular disease were selected, and 18-month all-cause death was defined as the primary endpoint. Long-term COVID-19 symptoms were considered as secondary endpoints. A total of 1188 patients with previous heart disease were included, of which 453 received corticosteroid treatment. Propensity score matching analysis in a 1:1 fashion was performed based on baseline variables that exhibited a p-value < 0.05 in the univariant analysis and outcome variables that defined corticosteroid use, with a final matched population of 796 patients. Results: In patients with pre-existing heart disease, corticosteroid treatment was not associated with differences in 18-month all-cause mortality (p = 0.52). However, a shorter duration of hospitalization (median: 8 days [IQR: 4–14] and 11 days [IQR: 7–18]; p < 0.001) was observed in patients who received corticosteroids. No significant differences in long-term COVID-19 symptoms were observed between the two groups. Conclusions: In patients with pre-existing heart disease, the absence of a clear harmful effect suggests that the positive effects of corticosteroids may be offset by their potential adverse effects which could contribute to the persistence of long COVID symptoms. This finding may reflect a differential response to corticosteroids in this high-risk subgroup, highlighting the need for further studies to clarify the role of this therapy in such patients.

ABSTRACT The American Society for Apheresis (ASFA) Attending Physician Subcommittee of the Physicians' Committee performed an annual review of articles published in 2024 related to apheresis medicine. The 10 seminal apheresis articles selected by the subcommittee members are summarized in this review. PubMed was used to identify manuscripts published in 2024 in four areas of interest: donor apheresis, therapeutic apheresis, apheresis education, and apheresis for cellular therapy. Only full length, peer‐reviewed manuscripts in English with data from human subjects were included. Case reports, review articles, and meta‐analyses were excluded. Articles were considered seminal if they met at least one of the following previously established criteria: novel finding(s), practice‐altering outcomes, international in scope, randomized‐controlled trial, relevant to current clinical practice, and/or provide evidence for category III or IV indications based on the ASFA 9th special issue of the Guidelines on the Use of Therapeutic Apheresis in Clinical Practice‐Evidence‐Based Approach.

Respiratory muscle fatigue could occur following involuntary breathing movements during maximal breath-holds. We measured respiratory muscle strength pre and post three preparatory and maximal breath-holds. We found significant reductions in diaphragm strength and total inspiratory and expiratory strength in some, but not all, divers. Divers that had respiratory muscle fatigue had a lower pseudo O 2 delivery (HR × [Formula: see text]) during the struggle phase. This suggests that reduced oxygen delivery may contribute to respiratory muscle fatigue during a breath-hold.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.