Redline, Susan

Abstract Introduction Sleep-disordered breathing (SDB) is a potentially modifiable risk factor for the prevention of dementia, of which Alzheimer’s disease (AD) is the most common cause. However, there is a lack of longitudinal evidence relating SDB to AD pathology >20 years later. We examined the association between late-midlife SDB and late-life brain β-amyloid (Aβ) deposition—a hallmark of AD—assessed approximately 23 years later. Methods The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing prospective cohort study initiated in 1987. Participants at two ARIC sites (Washington County, Maryland; Minneapolis, Minnesota) with primarily White participants also completed polysomnography (PSG) in the Sleep Heart Health Study (SHHS) in 1995-98. SDB measures included apnea-hypopnea index (AHI; number of apneas + hypopneas with ≥3% oxygen desaturation/hour of sleep), arousal index, and percentage of total sleep time in apnea, in hypopnea, and with oxygen saturation < 90%. A subset of participants completed florbetapir positron emission tomography (PET) scans through several ARIC ancillary studies (2011-2025 including the ARIC Sleep-PET study). We defined Aβ deposition as a global standardized uptake value ratio (SUVR) >1.2 (vs. SUVR ≤1.2). We used Poisson regression with robust standard errors to estimate relative risk (RR) of Aβ deposition by SDB, adjusting for demographics and vascular risk factors, and applied inverse probability attrition weighting to account for selective drop-out. Results Among 186 dementia-free participants (mean age=59 years at PSG and 82 years at PET scan, 58% female, 98% White), every 10% increase in total sleep time in hypopnea was associated with higher risk of Aβ deposition (RR=1.40, 95% confidence interval [CI]: 1.03, 1.91). When compared to no SDB (AHI < 5), moderate to severe SDB (AHI ≥15) was associated with elevated Aβ deposition (RR=2.36, 95% CI: 1.22, 4.57); mild SDB (AHI 5 to < 15) was not (RR=1.05, 95% CI: 0.53, 2.07). Conclusion SDB in late midlife was associated with greater risk of Aβ deposition approximately 23 years later. SDB may play a role in the early stages of AD pathogenesis. Future longitudinal studies are needed to optimize strategies for screening and treating SDB for dementia prevention. Support (if any) Supported in part by RF1AG050745.

Background: Long COVID, the chronic sequela of SARS-CoV-2 infection, has affected millions of people worldwide. However, its pathogenesis and treatment remain unknown. To address this critical gap, the National Institutes of Health (NIH) developed the Researching COVID to Enhance Recovery (RECOVER) Initiative that included the Viral Persistence and Reactivation, and Immune Dysregulation (RECOVER-VITAL) study as one of the first of five NIH-sponsored, integrated platform protocols to support the rigorous and rapid investigation of potential interventions for Long COVID. Methods: Experts across academia, the NIH, and the community of patients and caregivers were brought together to design the RECOVER-VITAL protocol. We present the challenges and rationale underpinning critical components of this protocol and provide evidence for use of the platform for efficient execution of current and future Long COVID clinical trials. Facets of the RECOVER-VITAL protocol, including inclusion criteria, intervention groups, study procedures, investigation of biomarkers, and endpoints, were carefully crafted to advance the current and future science and operations of Long COVID clinical trials, particularly in the absence of existing data. The initial trial within the RECOVER-VITAL platform evaluated two durations of an antiviral drug, nirmatrelvir/ritonavir, to test the proposed etiology of viral persistence on the Long COVID symptom clusters of autonomic dysfunction, cognitive dysfunction, and exercise intolerance. The primary outcome measures were patient-reported, and secondary outcomes included performance-based measures for each of the symptom clusters of interest. Conclusions: The RECOVER-VITAL platform protocol has substantial implications for the design and conduct of future Long COVID clinical trials.

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

ABSTRACT Background Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). Methods Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence‐based review (EBR), or evidence‐based review with recommendations (EBR‐R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. Results The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA‐associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. Conclusion This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence‐based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.