Faculty Bibliography

BACKGROUND:Long-term effect of COVID-19 (Long COVID) may persist for months or years after SARS-CoV-2 infection, but longer-term cardiopulmonary manifestations have not been previously reported. OBJECTIVES/OBJECTIVE:The objective of the study was to characterize cardiopulmonary function after SARS-CoV-2 infection in a digital health substudy of the nationwide Researching COVID-19 to Enhance Recovery Adult Cohort Study. METHODS:Associations between wearable sensor device measures of cardiopulmonary fitness and survey-derived Long COVID symptoms were estimated over a 6-month window at least 6 months after infection using linear regression models adjusted for wear time, age, sex, race/ethnicity, and body mass index. RESULTS:Among 1,475 participants (72% female, 65% non-Hispanic White) a median of 21 months (IQR: 15-31 months) after infection, 498 (34%) had high symptom burden as characterized by the Researching COVID-19 to Enhance Recovery Long COVID Research Index (LCRI). High LCRI (vs low LCRI) was associated with significantly lower heart rate variability (-4.4 ms; 95% CI: -6.5 to -2.4; P < 0.001), higher resting heart rate (+1.5 beats/min [+0.7 to +2.4]; P < 0.001), fewer metabolic equivalent of task minutes (-96.3 [-128.8 to -63.8]; P < 0.001), lower step counts (-1,624 steps/day [-1,952 to -1,296]; P < 0.001), and lower activity levels (-7.9 minutes/day very or fairly active [-10.9 to -5.0]; P < 0.001). Hierarchal clustering analysis identified two subphenotypes with abnormal cardiovascular measures associated with low quality of life scores. CONCLUSIONS:Long COVID is associated with worse cardiovascular fitness. Additional studies are needed to determine if Long COVID is a novel risk factor for incident cardiovascular disease.

BACKGROUND:Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. METHODS:Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE-ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. RESULTS:Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC = 0.91, PPV = 0.80; DIAGNOSE CTE: AUC = 0.84, PPV = 0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. CONCLUSION/CONCLUSIONS:TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

BACKGROUND/UNASSIGNED:The long-term efficacy and safety of vutrisiran in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) were assessed in the HELIOS-A randomized treatment extension (RTE). METHODS/UNASSIGNED:Patients who completed the 18-month, phase 3, open-label HELIOS-A study could enter an open-label RTE with re-randomization 1:1 to vutrisiran 25 mg every 3 months (Q3M) or 50 mg every 6 months (Q6M; transitioned to 25 mg Q3M following an amendment) for up to 42 months (RTE M18 efficacy assessment; RTE M42 safety and transthyretin (TTR) levels). RESULTS/UNASSIGNED: = 73]). Mean serum TTR reduction from study baseline at RTE M42 for the total vutrisiran group was 84.5%. Efficacy was sustained from RTE baseline through RTE M18 in modified Neuropathy Impairment Score +7, Norfolk Quality of Life-Diabetic Neuropathy score, 10-meter walk test, Rasch-built Overall Disability Scale and modified body mass index (mBMI); most patients (67.8%) had stable polyneuropathy disability scores. Most AEs were mild/moderate in severity with no new safety concerns. CONCLUSIONS/UNASSIGNED:Results from the HELIOS-A RTE demonstrate relative stability with only modest changes in disease activity, sustained serum TTR reductions, and an acceptable safety profile with long-term vutrisiran treatment in patients with ATTRv-PN. UNLABELLED:ClinicalTrials.gov: NCT03759379.

Human microbiome research has become pivotal in advancing our understanding of complex diseases such as diabetes, inflammatory bowel disease, and cancer. Much of this work relies on comparing microbial communities across health and disease states, or case-control cohorts, using high-throughput metagenomic sequencing. Yet the very nature of sequencing-derived microbiome data makes robust cohort design and power-based sample-size estimation unusually difficult. Unlike other omics, microbiome profiles are compositional, sparse, and often zero inflated, properties that complicate statistical modeling and inflate sample-size requirements. These challenges are further compounded by the diversity of analytical frameworks-ranging from diversity indices to causal inference-each built on different statistical assumptions and optimized for a distinct research hypothesis. This review synthesizes current approaches around the study design and sample-size estimation in microbiome research, aiming to provide clinicians and researchers with practical guidance for navigating the statistical complexities unique to this field.

INTRODUCTION/BACKGROUND: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/CONCLUSIONS:In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

We sought to generate recommendations for the tennis community regarding the provision of mental healthcare and the promotion of mental wellness among elite tennis athletes, including junior tennis athletes. Recommendations were generated using a multimethod approach that included an in-person summit held during the 2022 US Open Tennis Championships in New York, New York, USA, and an asynchronous Delphi consensus process. Participants (n=83) were purposively selected to ensure diverse representation from all seven governing bodies of tennis and the broader tennis ecosystem, including: current and former elite adult and junior players, coaches, sport administrators, parents, physiotherapists, athletic trainers, physicians (sports medicine, psychiatry, neurology), other licensed mental health providers, epidemiologists and other academic subject matter experts. The summit included expert presentations and cross-organisation group discussion, which were used to generate provisional consensus statements. Statements were rated anonymously and refined iteratively based on synthesis of open-ended feedback until predetermined numeric thresholds were reached. The summit also included discussion of implementation challenges and priorities. As a result of this process, 2 foundational principles and 25 actionable recommendations were adopted, covering 5 domains: (1) standards of care, (2) education, (3) media and social media, (4) safeguarding and (5) research. The foundational principles emphasised that mental health must be prioritised by tennis governing bodies and that these bodies should collaborate across the tennis ecosystem. This output is a starting point for coordinated mental health efforts in tennis. More broadly, this pragmatic process is a replicable model for cross-organisational collaboration in other high-performance sports.