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AbstractBackgroundDisease‐modifying therapies for Alzheimer’s Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort.MethodParticipants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI.ResultOur results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2).ConclusionOur results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker.

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer’s disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alterations observed in AD brains are also detected in blood from living patients is unknown. Further, these GVU molecular perturbations require further investigation in different model systems to identify both human brain‐specific and cross‐species conserved alterations. In this study, we investigated prioritized GVU molecules altered in AD brains for their conservation in blood and cross‐species model systems.MethodsWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in AD and control brains. We analyzed this data to detect cell‐specific GVU molecular perturbations and their interactions. We investigated molecular interactions between vascular and astrocyte clusters, the major cell types of the GVU of the BBB. To determine whether GVU transcriptional alterations detected in the brain are preserved in the blood, existing blood expression, genetic, and neuroimaging data from two longitudinal antemortem cohorts were analyzed. Using model systems, including mouse, drosophila, and zebrafish, we evaluated the cross‐species conservation of the top GVU alterations detected in AD brains.ResultsBrain snRNAseq revealed transcriptional profiles of 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as pericytes, endothelia and perivascular fibroblasts. We identified differentially expressed genes and their enriched pathways within these clusters and observed the highest levels of transcriptional changes within pericytes. Vascular targets that interact with astrocytic ligands have biological functions in cell signaling, angiogenesis, amyloid ß metabolism, and cytoskeletal architecture. We discovered that genetic variants influencing blood expression levels of some of the prioritized GVU genes were associated with neuroimaging burden of cerebrovascular disease in living human cohorts. Our ongoing studies in model systems revealed conservation of some of the top prioritized molecular perturbations across species.ConclusionOur findings prioritized by multiscale, cross‐tissue human data revealed GVU perturbations within interacting pericyte and astrocyte molecules, which are conserved across multiple cross‐species models. These results nominate new molecular targets and mechanistic insights for BBB disruptions in AD.

AbstractBackgroundAlzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms, the identification of which may reveal important biological insights into AD pathophysiology. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm clusters from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, and CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from neuropathologically‐confirmed AD cases available through the Mayo Clinic brain bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Neuropathology was scored by an experienced neuropathologist. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged. Averaged CpGm clusters were tested for their association with each endophenotype through multi‐variable linear regression. The influence of CpGm clusters on expression levels of nearby genes was also investigated through multi‐variable regression.ResultsOur innovative binning method demonstrated expected and biologically relevant CpGm patterns. We identified multiple epigenome‐wide significant CpGm clusters unique to each AD‐related endophenotype and brain region. Comparisons between the TCX and CER further revealed brain region‐specific enrichment of distinct CpGm clusters. Significant CpGm clusters were further characterized by their influence on gene expression.ConclusionsAlthough all neuropathologic and biochemical endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. By discovering brain region‐specific DNAm changes that contribute to each neuropathologic or biochemical outcome, we can identify core components of complex mechanisms that individually and jointly contribute to AD.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03652181.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project ( https://www.clinicaltrials.gov ; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% ( P =0.03) and 100% ( P =0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years ( P =0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

Abstract Background Pediatric residents frequently manage critically ill neonates but have limited systematic training in mechanical ventilation (MV). Competing demands, varying learner levels, and topic complexity contribute to inconsistent education. A blended learning approach may be ideally suited to achieve meaningful learning but has not been described for this topic and learner. Objective To design, implement, and evaluate a flipped classroom for pediatric residents in neonatal MV. Methods We used Kern’s six-step framework for curricular development to create a flipped classroom curriculum in neonatal MV. Individual prework included interaction with six prerecorded animated whiteboard videos, while in-person learning occurred in small groups at the bedside of a ventilated infant. A mixed-methods evaluation included surveys, quantitative knowledge test scores (before, immediately after, and six months after course completion), and qualitative analysis of participant focus groups. Results Twenty-six learners participated in the curriculum. Mean knowledge test scores rose and were sustained after course completion (51% baseline, 82% immediate posttest, 90% retention; P < 0.001). Learners identified various design elements, technology affordances, and instructor factors as meaningful, and they identified unexpected impacts of the curriculum beyond knowledge acquisition, including effects on professional identities, interdisciplinary communication skills, and contribution to the culture of safety. Conclusion This curriculum aligned with resident roles, was meaningful to learners, and led to long-term increases in knowledge scores and access to quality education; flipped classroom design using meaningful learning theory and leveraging animated whiteboard technology may be a useful strategy for other highly complex topics in graduate medical education.

Objective To describe the incidence of injuries and illnesses among paediatric Team USA athletes competing in the Tokyo 2020 Olympic and Paralympic Games, and the 2022 Beijing Olympic and Paralympic Games. Methods An electronic medical record system documented all injuries and illnesses that occurred while competing in the four Games periods. Incidence (IR) with 95% CI per 1000 athlete days were calculated for both injuries and illnesses. Incidence rate ratios (IRR) were calculated to compare injury and illness rates based on age (paediatric vs non-paediatric) sex, Games period and sport type. Results Two hundred paediatric athletes (age range, 15–21 years) competed across the four Games periods, representing 16.1% of all Team USA athletes. The overall injury IR (95% CI) was 13.4 (9.8 to 18.1), and the overall illness IR was 5.5 (3.3 to 8.7). There were no differences in incidence between paediatric and non-paediatric athletes for either injury (IRR (95% CI): 0.9 (0.6 to 1.2)) or illness (IRR (95% CI): 0.9 (0.5 to 1.5)). Female paediatric athletes were more likely to sustain an injury compared with male paediatric athletes (IRR (95% CI): 2.4 (1.1 to 5.3)). The most common mechanism of injury was gradual onset (IR, 4.3 (2.3 to 7.2)), and injuries most commonly occurred during practices (IR, 7.0 (4.5 to 10.5)). Conclusion Paediatric athletes account for a substantial proportion of Team USA athletes. It is essential that paediatric sports medicine experts are included in the medical team given that paediatric Team USA athletes are just as likely as their adult teammates to sustain an injury or illness.

Abstract Introduction Obesity is a global health crisis that has been growing over the past few decades. The economic burden associated with obesity is substantial as it is associated with multiple disabling chronic diseases, such as cardiovascular disease, certain cancers, osteoarthritis, chronic pain, and mental illness. Obesity is known to be a risk factor for sexual dysfunction in men, but this association is less well understood in women. Aims To provide a narrative review of the available literature on the relationship between overweight/obesity and female sexual dysfunction, elaborate on the possible mechanisms explaining this association, and discuss the effects of weight loss on sexual function in those with obesity. Methods A search of the medical literature was carried out in PubMed and Medline, focusing on original research and systematic reviews of original research on obesity and sexual function in women. Results The relationship between obesity and female sexual function is not consistent across studies. While women with obesity are more likely to have worse sexual function and avoid sexual activity, many studies have failed to identify these associations. Lifestyle changes resulting in weight loss lead to better sexual function, and bariatric surgery has been shown to improve sexual function in the first couple of years following the procedure; yet, the long-term effects of weight loss and bariatric surgery are still uncertain. Conclusions The evidence on the relationship between obesity and female sexual function is mixed. Nevertheless, weight loss has been shown to improve sexual function in women with obesity. The impact of weight loss medications and the long-term effect of bariatric surgery on female sexual function require further study.

Background: The incidence and causes of sudden cardiac death (SCD) among young competitive athletes impact prevention strategies yet remain incompletely understood. Methods: National Collegiate Athletic Association (NCAA) athlete deaths from 7/1/2002-6/30/2022 were identified through 4 independent databases/search strategies. Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. Poisson regression was used to calculate incidence rate ratios (IRR) for 5-year intervals over the 20-year study. Results: A total of 143 SCD cases were identified among 1102 athlete deaths and 9,106,516 athlete-years (AYs). The incidence of SCD among NCAA athletes was 1:63,682 AYs [95% CI 1:54,065, 1:75,010]. Incidence was higher in males compared to females (1:43,348 vs. 1:164,504 AYs) and Black compared to White athletes (1:27,217 vs. 1:74,581 AYs). The highest incidence of SCD was among Division 1 male basketball players (1:8,188; White 1:5,848; Black 1:7,696 AYs). The incidence rate for SCD decreased over the study period (5-year IRR 0.71 [95% CI 0.61,0.82]), whereas the rate of non-cardiovascular deaths remained stable (5-year IRR 0.98 [95% CI 0.94,1.04]; Figure 1A ). Autopsy-negative sudden unexplained death (AN-SUD, 19.5%) was the most common post-mortem exam finding, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (CM, 16.9%) and hypertrophic CM (12.7%) in cases with enough information for adjudication (118/143, Figure 1B ). There were 8 cases of myocarditis, with none attributed to COVID-19 infection. SCD events occurred most commonly during exertion among athletes with coronary artery anomalies (100%) and arrhythmogenic CM (83%), whereas AN-SUD and hypertrophic CM had a higher proportion of non-exertional SCD (44% and 40%, respectively). Conclusions: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.