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Abstract Exercise training improves cardiovascular health and reduces the risk for future cardiovascular events and mortality. However, emerging evidence suggests that Masters athletes may have a higher prevalence of cardiovascular abnormalities, such as atrial arrhythmias, coronary atherosclerosis, aortic dilatation, and myocardial fibrosis, compared to their less active peers. The clinical management of Masters athletes may be challenging as available guidelines for such conditions are generally based on data derived from symptomatic sedentary patients, limiting their applicability to highly trained individuals. Other unique challenges in the clinical assessment of Masters athletes include differences in symptomatic presentations compared to sedentary individuals, potential resistance to the initiation of pharmacologic treatment, and the increasing availability of consumer wearable health data that may provide relevant information on their cardiovascular health status. The purpose of this joint EAPC/ESC and ACC Clinical Consensus Statement is to provide an in-depth update on the current state of knowledge on abnormal cardiovascular findings in Masters athletes. We present an expert-based approach on the diagnostic assessment, management, and prognosis of (i) atrial fibrillation, (ii) bradyarrhythmias, (iii) ventricular arrhythmias, (iv) coronary atherosclerosis, (v) aortic dilatation, (vi) myocardial fibrosis, and (vii) exercise-induced arrhythmogenic cardiomyopathy. Clinical challenges, areas of ongoing controversy, and uncertainty and the potential underlying mechanisms are discussed. We also present future perspectives and research directives to further refine current best practice strategies. This includes the need for clinical outcome studies, dedicated randomized controlled trials in athletes, and international registries with diverse populations and longitudinal follow-up to evaluate the natural history of cardiac abnormalities and facilitate development of evidence-based approaches in the clinical management of Masters athletes with cardiovascular abnormalities.

619 Background: Well-differentiated G3 GEP-NETs are rare and heterogeneous diseases, limiting phase III trials and definition of clear standards of care. Building upon our preliminary cohort of 76 patients (pts), we present an updated and expanded retrospective analysis across three Mayo Clinic tertiary centers. Methods: We included pts with histologically confirmed well-differentiated G3 GEP-NETs diagnosed since 2017 (new WHO classification) from the three Mayo Clinic sites (Rochester, Phoenix, Jacksonville). Endpoints were ORR, DCR, PFS, and OS across treatment lines. PFS/OS were estimated by Kaplan-Meier. OS was defined from treatment start. Multivariate Cox regression was used to evaluate the association of clinic-pathologic features (age, sex, tumor functionality, Ki-67, primary tumor site, stage at diagnosis, presence of liver metastasis, number of metastatic sites at diagnosis) with OS (p<0.05). Results: 111 pts (median age 62 y, range 22–83). Primary sites were pancreas (58%), small bowel (19%), unknown (9%), and rectum (5%). Most tumors were G3 at diagnosis (88%); the remainder evolved from prior G1/G2. Ki-67 was 20–55% in 83% of cases. Most were nonfunctional (70%); functional subtypes included carcinoid (13%) and gastrinoma (8%). Median plasma 5-HIAA was 38.5 ng/ml (5–1394). Advanced disease was present in 85%. Common metastatic sites included liver (85%), lymph nodes (32%), bone (26%), peritoneum (10%), and lung (9%). Median number of metastatic sites was 1 (range 0–5). Median number of systemic treatment lines was 2 (range 0–8). The most frequent regimens and outcomes are shown in the Table. Insulin-secreting tumors (HR 2.16, 95% CI 1.33–25.73, p=0.019) and ≥2 metastatic sites (HR 2.13, 95% CI 1.05–4.31, p=0.035) were associated with inferior OS. Conclusions: This represents one of the largest real-world datasets of well-differentiated G3 GEP-NETs and provides a deeper evaluation of treatment strategies and prognostic factors. CAPTEM, SSAs, and PRRT with Lu-177 emerged as the most commonly used therapies, with PRRT showing the most favorable outcomes. Insulin secretion and higher metastatic burden were confirmed as adverse prognostic factors. CAPTEM SSAs PRRT Lu-177 Carboplatin plus etoposide FOLFOX Everolimus Sunitinib N of pts (%) 64 (58) 44 (40) 37 (33) 24 (19) 18 (13) 11 (10) 8 (7) Line of therapy (%) First 36 (56.3) 27 (61.4) 5 (13.5) 13 (59.2) 5 (7.2) 1 (9.0) 1 (12.5) Second 15 (23.4) 13 (29.5) 13 (35.2) 3 (13.6) 5 (35.7) 3 (27.3) 2 (37.5) Third or higher 13 (20.3) 4 (9.1) 19 (51.3) 6 (27.2) 8 (57.1) 7 (63.7) 5 (62.5) DCR (%) 60.9 56.8 75.0 52.2 71.4 45.5 37.5 ORR (%) 34.4 13.6 44.4 30.4 35.7 18.2 12.5 mPFS (95% CI) 8.0 (5.3-10.6) 6.2 (2.8-9.5) 11.2 (9.1-13.3) 7.3 (2.8-11.8) 4.4 (2.4-6.4) 3.9 (2.2-5.6) 3.9 (1.54-6.26) mOS (95% CI) 40.1 (23.0-57.2) 50 (22.6-77.4) 76.1 (16.3-135.8) 33.0 (21.0-45.0) 21.1 (15.0-27.2) NE NE

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Abstract Background Plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration provide a non‐invasive method to assess brain pathology associated with dementia and cognitive decline. However, it remains unclear whether these biomarkers are differentially associated with changes in specific cognitive domains or how they relate to subsequent cognitive change in participants with or without cognitive impairment. Methods Plasma biomarkers were assayed in a subset of ARIC participants using Quanterix SiMoA technology on stored specimens collected in midlife (visit 3: 1993‐95, mean age: 59) and late‐life (visit 5: 2011‐13, mean age: 77). Biomarkers included amyloid‐β 42 to amyloid‐β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Factor scores for global cognition and cognitive domains (memory, language, executive function) were calculated from ten neuropsychological tests administered at visits 5 (2011‐13), 6 (2016‐17), 7 (2018‐19), 8 (2020), and 9 (2021‐22). Linear mixed effects models with multiple imputation of pre‐death cognitive change estimated the association between biomarkers in midlife and late‐life, and biomarker change from midlife to late‐life, with 5‐year change in late‐life global and domain‐specific cognition, adjusting for demographics, lifestyle and cardiovascular risk factors, and APOE‐ε4 status. Exploratory analyses examined effect modification of the biomarker‐global cognition associations by visit 5 adjudicated cognitive impairment. Results Among 1515 participants with plasma biomarkers (60.7% female, 25.5% identified as Black), 39% had late‐life cognitive impairment (Table 1). Higher midlife NfL and GFAP were associated with faster 5‐year declines in global cognition and language during late‐life (Table 2). Only midlife NfL was associated with faster late‐life memory decline. No midlife biomarkers were associated with executive function. In late‐life, lower Aβ42:Aβ40 and higher p ‐Tau 181, NfL, and GFAP were associated with faster declines in global cognition, memory, and language. Midlife to late‐life changes in p ‐Tau 181, NfL, and GFAP were associated with declines in global cognition and language. No consistent effect modification by cognitive impairment was observed (Figure 1). Conclusions Plasma biomarkers of AD pathology, neuronal injury, and astrogliosis, measured at different life epochs (midlife vs. late‐life) show distinct association patterns with subsequent changes in cognitive function across domains.

Abstract Background Plasma biomarkers show promise as a noninvasive method for measuring Alzheimer's disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late‐life brain morphology in community‐dwelling populations requires further investigation. Method Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and underwent 3 Tesla magnetic resonance imaging scans. Whole‐brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993‐95, mean age 59.0 years) and late‐life (2011‐13, mean age 76.8 years) from a subsample of 1,515 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of plasma biomarkers from midlife, late‐life, and the change from midlife to late‐life with cortical thickness in late‐life. Interactions and effect modification by age were examined in exploratory analyses. Result The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late‐life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p ‐Tau181 and increases from midlife to late‐life in NfL and GFAP were associated with lower cortical thickness in late‐life (Table 2). Concurrent measures of plasma biomarkers in late‐life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3). Conclusion Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late‐life were associated with late‐life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.

Abstract INTRODUCTION We standardized positron emission tomography (PET) data across multiple cohorts and tracers to characterize the frequency of amyloid and tau PET severity along the clinical continuum. METHODS Clinical stage was defined using cohort‐specific criteria and included cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia. Amyloid severity was staged using Centiloids (CL). Tau severity was staged using a hierarchical Braak‐based schema. The cumulative probabilities of PET‐based stages were estimated using ordinal logistic regressions. RESULTS Among 10,396 individuals (mean [standard deviation] age: 71.9 [7.1] years), amyloid levels ≥ 25 CL increased with age among CU and MCI, while amyloid levels ≥ 100 CL were most common in dementia. In 3295 with tau PET, tau severity increased with amyloid and clinical stage and showed complex associations with age. Within each clinical stage, the full spectrum of amyloid and tau PET severity was observed. DISCUSSION PET‐based staging revealed heterogeneous amyloid and tau burden along the clinical continuum. Highlights PET‐based staging is feasible across multiple cohorts and PET tracers. There is heterogeneity in amyloid and tau severity across the clinical spectrum. The frequency of amyloid and tau PET severity increased with clinical severity. The likelihood of tau PET severity differed by age, amyloid, and clinical severity.

The treatment landscape for multiple myeloma (MM) is evolving rapidly and includes several new options. The management must be tailored to the individual. The NCCN Guidelines for MM provide a framework to base decisions regarding diagnosis, workup, treatment, and follow-up of both newly diagnosed and previously treated relapsed/refractory MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to newly diagnosed MM (NDMM).

Cigarette smoking is associated with numerous adverse pregnancy outcomes, due in part to polycyclic aromatic hydrocarbons and free radicals produced by combustion. Less is known about the impact of smokeless tobacco (ST) use during pregnancy. Alaska Native women report higher rates of cigarette and ST use during pregnancy than non-Native women. We investigated oxidative stress and hypoxia pathways in term placentae from Alaska Native women who did (commercial or iqmik; n = 10) or did not ( n = 18) use ST during pregnancy. Despite substantial maternal exposure to nicotine, placentae of women who used ST had similar mRNA levels of antioxidant enzymes and markers of hypoxia compared to those who did not use tobacco. Although mRNA levels of angiogenesis markers vegf and vegfr2 were similar between groups, vegfr1 mRNA levels are increased in placentae of women using ST compared to women who did not use tobacco. Together these results suggest that, while ST use may not have as significant an effect on oxidative stress pathways in the placenta as cigarette smoking, an effect is present. It is not clear what this limited effect may have on the developing fetus.

This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals’ tolerance levels for progressive blood loss.