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BackgroundClonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography.MethodsWe recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes.ResultsWe found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2), has a larger effect size on left main stenosis compared with other CHIP mutations.ConclusionsThis is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

Abstract: Background: Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents. Method: The LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v.10 and used NIA‐AA guidelines for Alzheimer’s diagnoses. As of January 2023, 304 participants (40%) were enrolled in autopsy (20% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 36% White). Result: Of the 304 participants, 59 had died and neuropathological evaluations were completed. The median age of death was 93 years (range 90‐105), 33 (56%) were female, 8 Asian, 5 Black, 10 Latino, 31 White, and 5 Multiracial/Other. At final clinical exam, 17 participants had dementia (29%), 25 questionable/mild cognitive impairment (42%), and 16 were cognitively normal (27%). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure). Twenty two percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in two participants. For vascular pathologies, 98% had some level of arteriolosclerosis, 97% had atherosclerosis, 70% had amyloid angiopathy, and 26% had at least one old microinfarct. Other pathologies were less common: 27% had Lewy bodies, 18% had TDP‐43 deposits, and only one had Hippocampal sclerosis. Although data is sparse to test for associations, the proportion of individuals with dementia tended to increase with increasing pathology severity especially for AD pathologies. Conclusion: This diverse cohort of oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. Future analyses will investigate their role with cognitive impairment.

IntroductionHigher occupational complexity has been linked to favorable cognitive outcomes, but rarely examined in racially and ethnically diverse populations.MethodsIn a diverse cohort (n = 1536), linear mixed-effects models estimated associations between main lifetime occupational complexity and domain-specific cognitive decline (z-standardized). Occupational complexity with data, people, and things were classified using the Dictionary of Occupational Titles.ResultsFor occupational complexity with data, highest tertile (vs. lowest) was associated with higher baseline executive function (β = 0.11; 95% confidence interval [CI] 0.00-0.22) and slower annual rate of decline (β = 0.03; 95% CI 0.01-0.06), and higher baseline semantic memory (β = 0.14; 95% CI 0.04-0.25). Highest tertile of occupational complexity with people was associated with higher baseline executive function (β = 0.29; 95% CI 0.18-0.40), verbal episodic memory (β = 0.12; 95% CI 0.00-0.24), and semantic memory (β = 0.23; 95% CI 0.12-0.34).DiscussionIn a diverse cohort, higher occupational complexity is associated with better cognition. Findings should be verified in larger cohorts.HighlightFew studies have examined associations of occupational complexity with cognition in diverse populations. Racial and ethnic minorities are disproportionately exposed to lower occupational complexity. Occupational complexity with data and people are associated with better cognition.

IntroductionThe challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory.MethodsIn three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data.ResultsAPM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used.DiscussionConstraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change.HighlightsThe magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Abstract: Background: SuperAgers are individuals who maintain superior cognitive performance despite advanced age. Most studies define SuperAgers as superior performers only in episodic memory. Our aim was to assess in a diverse oldest‐old cohort if superior performance in one domain indicates superior performance in other domains and explore demographic characteristics. Methods: The LifeAfter90 study is a multi‐ethnic cohort of members of Kaiser Permanente Northern California aged 90 or older. Baseline verbal episodic memory (VEM), semantic memory (SM), and executive function (EF) were evaluated using the Spanish and English Neuropsychological Assessment Scale (SENAS). SuperAgers were individuals who scored above the mean of domain and race‐specific SENAS scores from a reference cohort aged 65‐70 years. The reference group were similar participants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study. To assess the association between age, sex, education, and being a SuperAger, odds ratios (OR) and 95% confidence interval (CI) were calculated using multiple logistic regression. Results: The 617 study participants (236 men and 381 women) had a mean age of 92.9 years (Table1). 53.6% of individuals were SuperAgers in one domain, 22.8% in any two domains, and 7.7% in all three domains. 7.0% of individuals were SuperAgers in SM and EF, 4.5% in VEM and EF, and 3.5% in VEM and SM (Figure1). SuperAgers were younger than non‐SuperAgers. Women were more likely to be SuperAgers in VEM (OR = 2.13; 95%CI: 1.43,3.18) and EF (OR = 2.18; 95%CI: 1.44,3.30) and less likely in SM (OR = 0.49; 95%CI: 0.34,0.71) compared to men. Higher education was related to being a SuperAger in SM (OR = 1.85; 95%CI: 1.28,2.67) and EF (OR = 2.56; 95%CI: 1.74,3.78) but not VEM (Table2). Conclusion: In this diverse cohort of oldest‐old SuperAgers we found that exceptional episodic memory performance does not indicate exceptional performance in other cognitive domains. Education was not a predictor of exceptional performance in all domains. Future work should investigate predictors of exceptional cognitive aging after age 90.

We propose an optical clock based on ultranarrow transitions in neutral titanium, which exhibit small blackbody radiation and quadratic Zeeman shifts and have wavelengths in the S-, C-, and L-telecommunications fiber bands, allowing for integration with robust laser technology. We calculate relevant properties using a high-precision relativistic hybrid method that combines configuration interaction and coupled-cluster approaches. To identify magic wavelengths, we have completed the largest-to-date direct dynamical polarizability calculations. Finally, we identify challenges that arise from magnetic dipole-dipole interactions and describe an approach to overcome them. A telecommunications-band atomic frequency standard will aid the deployment of optical clock networks and clock comparisons over long distances.

ObjectivesIn support of schools restarting during the COVID-19 pandemic, some schools partnered with local experts in academia, education, community, and public health to provide decision-support tools for determining what actions to take when presented with students at risk for spreading infection at school.MethodsThe Student Symptom Decision Tree, developed in Orange County, California, is a flow chart consisting of branching logic and definitions to assist school personnel in making decisions regarding possible COVID-19 cases in schools which was repeatedly updated to reflect evolving evidence-based guidelines. A survey of 56 school personnel evaluated the frequency of use, acceptability, feasibility, appropriateness, usability, and helpfulness of the Decision Tree.ResultsThe tool was used at least 6 times a week by 66% of respondents. The Decision Tree was generally perceived as acceptable (91%), feasible (70%), appropriate (89%), usable (71%) and helpful (95%). Suggestions for improvement included reducing the complexity in content and formatting of the tool.ConclusionsThe data suggest that school personnel found value in the Decision Tree, which was intended to assist them with making decisions in a challenging and rapidly evolving pandemic.

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

ObjectivesWe examined the association of generational status and age at immigration with later life cognitive outcomes in a diverse sample of Latinos and Asian Americans.DesignBaseline data were obtained from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study, and a prospective cohort is initiated in 2017.SettingOlder adults in Northern California.ParticipantsOur cohort consisted of Asians (n = 411) and Latinos (n = 340) who were on average 76 years old (SD = 6.8).MeasurementsWe used multivariable linear regression models to estimate associations between generational status and age at immigration (collapsed into one five-level variable) with measures of verbal episodic memory, semantic memory, and executive function, adjusting for age, gender, race and ethnicity, and own- and parental education.ResultsGenerational status and age at immigration were associated with cognitive outcomes in a graded manner. Compared to third-generation or higher immigrants, first-generation immigration in adulthood was associated with lower semantic memory (β = -0.96; 95% CI: -1.12, -0.81) than immigration in adolescence (β = -0.68; 95% CI: -0.96, -0.41) or childhood (β = -0.28; 95% CI: -0.49, -0.06). Moreover, immigration in adulthood was associated with lower executive function (β = -0.63; 95% CI: -0.78, -0.48) than immigration in adolescence (β = -0.49; 95% CI: -0.75, -0.23). Similarly, compared to third-generation individuals, first-generation immigrants had lower executive functioning scores.ConclusionsOur study supports the notion that sociocontextual influences in early life impact later life cognitive scores. Longitudinal studies are needed to further clarify how immigration characteristics affect cognitive decline.

Background As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. Methods Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. Results Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets—limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. Conclusion Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources–a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

BackgroundReal-world performance of COVID-19 diagnostic tests under Emergency Use Authorization (EUA) must be assessed. We describe overall trends in the performance of serology tests in the context of real-world implementation.MethodsSix health systems estimated the odds of seropositivity and positive percent agreement (PPA) of serology test among people with confirmed SARS-CoV-2 infection by molecular test. In each dataset, we present the odds ratio and PPA, overall and by key clinical, demographic, and practice parameters.ResultsA total of 15,615 people were observed to have at least one serology test 14-90 days after a positive molecular test for SARS-CoV-2. We observed higher PPA in Hispanic (PPA range: 79-96%) compared to non-Hispanic (60-89%) patients; in those presenting with at least one COVID-19 related symptom (69-93%) as compared to no such symptoms (63-91%); and in inpatient (70-97%) and emergency department (93-99%) compared to outpatient (63-92%) settings across datasets. PPA was highest in those with diabetes (75-94%) and kidney disease (83-95%); and lowest in those with auto-immune conditions or who are immunocompromised (56-93%). The odds ratios (OR) for seropositivity were higher in Hispanics compared to non-Hispanics (OR range: 2.59-3.86), patients with diabetes (1.49-1.56), and obesity (1.63-2.23); and lower in those with immunocompromised or autoimmune conditions (0.25-0.70), as compared to those without those comorbidities. In a subset of three datasets with robust information on serology test name, seven tests were used, two of which were used in multiple settings and met the EUA requirement of PPA ≥87%. Tests performed similarly across datasets.ConclusionAlthough the EUA requirement was not consistently met, more investigation is needed to understand how serology and molecular tests are used, including indication and protocol fidelity. Improved data interoperability of test and clinical/demographic data are needed to enable rapid assessment of the real-world performance of in vitro diagnostic tests.

The use of optical interconnects has burgeoned as a promising technology that can address the limits of data transfer for future high-performance silicon chips. Recent pushes to enhance optical communication have focused on developing wavelength-division multiplexing technology, and new dimensions of data transfer will be paramount to fulfill the ever-growing need for speed. Here we demonstrate an integrated multi-dimensional communication scheme that combines wavelength- and mode- multiplexing on a silicon photonic circuit. Using foundry-compatible photonic inverse design and spectrally flattened microcombs, we demonstrate a 1.12-Tb/s natively error-free data transmission throughout a silicon nanophotonic waveguide. Furthermore, we implement inverse-designed surface-normal couplers to enable multimode optical transmission between separate silicon chips throughout a multimode-matched fibre. All the inverse-designed devices comply with the process design rules for standard silicon photonic foundries. Our approach is inherently scalable to a multiplicative enhancement over the state of the art silicon photonic transmitters.

Physiological response to physical exercise through analysis of cardiopulmonary measurements has been shown to be predictive of a variety of diseases. Nonetheless, the clinical use of exercise testing remains limited because interpretation of test results requires experience and specialized training. Additionally, until this work no methods have identified which dynamic gas exchange or heart rate responses influence an individual's decision to start or stop physical activity. This research examines the use of advanced machine learning methods to predict completion of a test consisting of multiple exercise bouts by a group of healthy children and adolescents. All participants could complete the ten bouts at low or moderate-intensity work rates, however, when the bout work rates were high-intensity, 50% refused to begin the subsequent exercise bout before all ten bouts had been completed (task failure). We explored machine learning strategies to model the relationship between the physiological time series, the participant's anthropometric variables, and the binary outcome variable indicating whether the participant completed the test. The best performing model, a generalized spectral additive model with functional and scalar covariates, achieved 93.6% classification accuracy and an F1 score of 93.5%. Additionally, functional analysis of variance testing showed that participants in the 'failed' and 'success' groups have significantly different functional means in three signals: heart rate, oxygen uptake rate, and carbon dioxide uptake rate. Overall, these results show the capability of functional data analysis with generalized spectral additive models to identify key differences in the exercise-induced responses of participants in multiple bout exercise testing.

We evaluated overall and race-specific relationships between social integration and cognition in older adults. Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort participants included 1343 Asian, Black, Latino, or non-Latino White Kaiser Permanente Northern California members. We estimated the effect of social integration on verbal episodic memory, semantic memory, and executive function derived from the Spanish and English Neuropsychological Assessment (SENAS) Scales. Social integration scores included marital status; volunteer activity; and contact with children, relatives, friends, and confidants. We estimated covariate-adjusted linear mixed-effects models for baseline and 17-month follow-up cognition. Social integration was associated with higher baseline cognitive scores (average  β = 0.066 (95% confidence interval: 0.040, 0.092)) overall and in each racial/ethnic group. The association did not vary by race/ethnicity. Social integration was not associated with the estimated rate of cognitive change. In this cohort, more social integration was similarly associated with better late-life cognition across racial/ethnic groups.

The All of Us Research Program seeks to engage at least one million diverse participants to advance precision medicine and improve human health. We describe here the cloud-based Researcher Workbench that uses a data passport model to democratize access to analytical tools and participant information including survey, physical measurement, and electronic health record (EHR) data. We also present validation study findings for several common complex diseases to demonstrate use of this novel platform in 315,000 participants, 78% of whom are from groups historically underrepresented in biomedical research, including 49% self-reporting non-White races. Replication findings include medication usage pattern differences by race in depression and type 2 diabetes, validation of known cancer associations with smoking, and calculation of cardiovascular risk scores by reported race effects. The cloud-based Researcher Workbench represents an important advance in enabling secure access for a broad range of researchers to this large resource and analytical tools.

Natural patterns of physical activity in youth are characterized by brief periods of exercise of varying intensity interspersed with rest. To better understand systemic physiologic response mechanisms in children and adolescents, we examined five responses [heart rate (HR), respiratory rate (RR), oxygen uptake (V̇O2 ), carbon dioxide production (V̇CO2 ), and minute ventilation (V̇E), measured breath-by-breath] to multiple brief exercise bouts (MBEB). Two groups of healthy participants (early pubertal: 17 female, 20 male; late-pubertal: 23 female, 21 male) performed five consecutive 2-min bouts of constant work rate cycle-ergometer exercise interspersed with 1-min of rest during separate sessions of low- or high-intensity (~40% or 80% peak work, respectively). For each 2-min on-transient and 1-min off-transient we calculated the average value of each cardiopulmonary exercise testing (CPET) variable (Y̅). There were significant MBEB changes in 67 of 80 on- and off-transients. Y̅ increased bout-to-bout for all CPET variables, and the magnitude of increase was greater in the high-intensity exercise. We measured the metabolic cost of MBEB, scaled to work performed, for the entire 15 min and found significantly higher V̇O2 , V̇CO2 , and V̇E costs in the early-pubertal participants for both low- and high-intensity MBEB. To reduce breath-by-breath variability in estimation of CPET variable kinetics, we time-interpolated (second-by-second), superimposed, and averaged responses. Reasonable estimates of τ (

SignificanceGrowing levels of obesity and metabolic syndrome have driven demand for more advanced forms of body composition assessment. While various techniques exist to measure body composition, devices are typically expensive and not portable, involve radiation [in the case of dual-energy x-ray absorptiometry (DXA)], and are limited to analysis of adiposity while metabolic information from blood supply and oxygenation are not considered.AimWe evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used to predict site-specific adiposity and percent fat (whole body) while simultaneously providing information about local tissue hemoglobin levels and oxygenation.ApproachDOSI measures of tissue composition in gastrocnemius, quadriceps, abdomen, and biceps, DXA whole-body composition, and ultrasound-derived skin and adipose tissue thickness (SATT) in the quadriceps were obtained from 99 individuals aged 7 to 34 years old.ResultsVarious DOSI-derived parameters were correlated with SATT and an optical method is proposed for estimating SATT using a newly defined parameter, the optical fat fraction (OFF), which considers all parameters that correlate with SATT. Broadband absorption and scattering spectra from study participants with the thinnest (SATT  ≈  0.25  ±  0.02  cm) and thickest SATT (SATT  ≈  1.55  ±  0.14  cm), representing best estimates for pure in vivo lean and fatty tissue, respectively, are reported. Finally, a trained prediction model is developed which allows DOSI assessment of OFF to predict DXA body-fat percentage, demonstrating that DOSI can be used to quantify body composition.ConclusionsThis study shows that DOSI can be used to assess the adiposity of specific tissues or the entire human body, and the OFF parameter is defined for corroboration and further evaluation in future research.

ImportanceIdentifying the associations between severe COVID-19 and individual cardiovascular conditions in pediatric patients may inform treatment.ObjectiveTo assess the association between previous or preexisting cardiovascular conditions and severity of COVID-19 in pediatric patients.Design, setting, and participantsThis retrospective cohort study used data from a large, multicenter, electronic health records database in the US. The cohort included patients aged 2 months to 17 years with a laboratory-confirmed diagnosis of COVID-19 or a diagnosis code indicating infection or exposure to SARS-CoV-2 at 85 health systems between March 1, 2020, and January 31, 2021.ExposuresDiagnoses for 26 cardiovascular conditions between January 1, 2015, and December 31, 2019 (before infection with SARS-CoV-2).Main outcomes and measuresThe main outcome was severe COVID-19, defined as need for supplemental oxygen or in-hospital death. Mixed-effects, random intercept logistic regression modeling assessed the significance and magnitude of associations between 26 cardiovascular conditions and COVID-19 severity. Multiple comparison adjustment was performed using the Benjamini-Hochberg false discovery rate procedure.ResultsThe study comprised 171 416 pediatric patients; the median age was 8 years (IQR, 2-14 years), and 50.28% were male. Of these patients, 17 065 (9.96%) had severe COVID-19. The random intercept model showed that the following cardiovascular conditions were associated with severe COVID-19: cardiac arrest (odds ratio [OR], 9.92; 95% CI, 6.93-14.20), cardiogenic shock (OR, 3.07; 95% CI, 1.90-4.96), heart surgery (OR, 3.04; 95% CI, 2.26-4.08), cardiopulmonary disease (OR, 1.91; 95% CI, 1.56-2.34), heart failure (OR, 1.82; 95% CI, 1.46-2.26), hypotension (OR, 1.57; 95% CI, 1.38-1.79), nontraumatic cerebral hemorrhage (OR, 1.54; 95% CI, 1.24-1.91), pericarditis (OR, 1.50; 95% CI, 1.17-1.94), simple biventricular defects (OR, 1.45; 95% CI, 1.29-1.62), venous embolism and thrombosis (OR, 1.39; 95% CI, 1.11-1.73), other hypertensive disorders (OR, 1.34; 95% CI, 1.09-1.63), complex biventricular defects (OR, 1.33; 95% CI, 1.14-1.54), and essential primary hypertension (OR, 1.22; 95% CI, 1.08-1.38). Furthermore, 194 of 258 patients (75.19%) with a history of cardiac arrest were younger than 12 years.Conclusions and relevanceThe findings suggest that some previous or preexisting cardiovascular conditions are associated with increased severity of COVID-19 among pediatric patients in the US and that morbidity may be increased among individuals children younger than 12 years with previous cardiac arrest.

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.

PurposeThe electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements.MethodsTHEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items).ResultsCenters predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured V̇O2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., V̇O2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET.ConclusionsThe survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application.

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.

Adolescent COVID-19 vaccination has stalled at 53% in the United States. Vaccinating adolescents remains critical to preventing the continued transmission of COVID-19, the emergence of variants, and rare but serious disease in children, and it is the best preventive measure available to return to in-person schooling. We investigated parent-adolescent COVID-19 vaccine decision-making. Between 24 February and 15 March 2021, we conducted surveys and 12 focus groups with 46 parent-adolescent dyads in Southern California. Parents and adolescents completed a survey prior to participation in a focus group discussion, which focused on exploring COVID-19 vaccine acceptance or uncertainty and was guided by the 5C vaccine hesitancy model. Parents uncertain about vaccinating adolescents expressed low vaccine confidence and high COVID-19 disease risk complacency. Parents who accepted COVID-19 vaccination for adolescents expressed high confidence in health authority vaccine recommendations, high perceived COVID-19 risk, and collective responsibility to vaccinate children. Additionally, unique pandemic-related factors of vaccine acceptance included vaccinating for emotional health, resuming social activities, and vaccine mandates. Among parents, 46% were willing to vaccinate their adolescent, 11% were not, and 43% were unsure. Among adolescents, 63% were willing to vaccinate. Despite vaccine availability, 47% of adolescents remain unvaccinated against COVID-19. Factors associated with vaccine uncertainty and acceptability inform health care practitioner, school, community, and public health messaging to reach parents and adolescents.

BackgroundDespite growing research on the association between discrimination and disparities in cognitive aging, an evidence gap remains on how the association varies by racial/ethnic group. This study evaluates the associations of experiences of discrimination with cognitive function and whether these associations varied by race/ethnicity and nativity.MethodUsing the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort (N = 1 712) with approximately equal groups of Black, White, Latino, and Asian community-dwelling older adults aged 65 years and older, we evaluated the associations between self-reported experiences of everyday and major lifetime discrimination with overall cognitive performance and domain-specific cognition (verbal episodic memory, semantic memory, and executive functioning) across race/ethnicity and nativity. Linear regression models examined the cross-sectional association between self-reported experiences of everyday and major lifetime discrimination with z-standardized coefficients for cognition. We tested for effect modification by race and nativity. All models controlled for age, sex, and education.ResultsAmong KHANDLE participants (mean age: 76 years; SD: 6.8), everyday discrimination was not associated with cognitive scores. Major lifetime discrimination was associated with better average cognitive scores among Black participants but not among other racial/ethnic groups. Major lifetime discrimination was associated with better average cognitive scores among U.S.-born but not among non-U.S.-born individuals.ConclusionOur findings do not imply that discrimination improves cognition, but rather suggest that future research should include more detailed measures on discrimination and unfair treatment that could help disentangle the extent to which relationships are causal or reflect some other underlying factor.

ObjectiveTo identify the informatics educational needs of clinical and translational research professionals whose primary focus is not informatics.IntroductionInformatics and data science skills are essential for the full spectrum of translational research, and an increased understanding of informatics issues on the part of translational researchers can alleviate the demand for informaticians and enable more productive collaborations when informaticians are involved. Identifying the level of interest in different topics among various types of of translational researchers will help set priorities for development and dissemination of informatics education.MethodsWe surveyed clinical and translational science researchers in Clinical and Translational Science Award (CTSA) programs about their educational needs and preferences.ResultsResearchers from 23 out of the 62 CTSA hubs responded to the survey. 67% of respondents across roles and topics expressed interest in learning about informatics topics. There was high interest in all 30 topics included in the survey, with some variation in interest depending on the role of the respondents.DiscussionOur data support the need to advance training in clinical and biomedical informatics. As the complexity and use of information technology and data science in research studies grows, informaticians will continue to be a limited resource for research collaboration, education, and training. An increased understanding of informatics issues across translational research teams can alleviate this burden and allow for more productive collaborations. To inform a roadmap for informatics education for research professionals, we suggest strategies to use the results of this needs assessment to develop future informatics education.

ObjectiveChikungunya virus (CHIKV) causes persistent arthritis, and our prior study showed that approximately one third of CHIKV arthritis patients had exacerbated arthritis associated with exercise. The underlying mechanism of exercise-associated chikungunya arthritis flare (EACAF) is unknown, and this analysis aimed to examine the regulatory T-cell immune response related to CHIKV arthritis flares.MethodsIn our study, 124 Colombian patients with a history of CHIKV infection four years prior were enrolled and 113 cases with serologically confirmed CHIKV IgG were used in this analysis. Patient information was gathered via questionnaires, and blood samples were taken to identify total live peripheral blood mononuclear cells, CD4+ cells, T regulatory cells, and their immune markers. We compared outcomes in CHIKV patients with (n = 38) vs. without (n = 75) EACAF using t-tests to assess means and the Fisher's exact test, chi-squared to evaluate categorical variables, and Kruskal-Wallis tests in the setting of skewed distributions (SAS 9.3).Results33.6% of CHIKV cases reported worsening arthritis with exercise. EACAF patients reported higher global assessments of arthritis disease ranging from 0-100 (71.2 ± 19.7 vs. 59.9 ± 28.0, p=0.03). EACAF patients had lower ratios of T regulatory (Treg)/CD4+ T-cells (1.95 ± 0.73 vs. 2.4 ± 1.29, p = 0.04) and lower percentage of GARP (glycoprotein-A repetitions predominant) expression per Treg (0.13 ± 0.0.33 vs. 0.16 ± 0.24 p= 0.020).ConclusionThese findings suggest relative decreases in GARP expression may indicate a decreased level of immune suppression. Treg populations in patients with CHIKV arthritis may contribute to arthritis flares during exercise, though current research is conflicting.

IntroductionWe examine whether the association between key plasma biomarkers (amyloid β [aβ] 42/40, total tau (t-tau), neurofilament light [NfL]) and cognitive trajectories (executive function [EF] and episodic memory [EM]) is mediated through neurodegeneration.MethodsAll participants were recruited from the University of California, Davis-Alzheimer's Disease Research Center (n = 473; baseline age range = 49-95 years, 60% women). We applied an accelerated longitudinal design to test latent growth models for EF and EM, and path and mediation analyses. Age was centered at 75 years, and all models were adjusted for sex, education, and ethnicity.ResultsHV differentially mediated the association aβ 42/40 and NfL on EF and EM level and change. Hippocampal volume (HV) did not mediate the association between t-tau and cognitive performance.DiscussionNeurodegeneration as represented with HV selectively mediates the association between key non-invasive plasma biomarkers and cognitive trajectories in an ethnoracially and clinically diverse community-based sample.

BackgroundIncreased physical activity (PA) may protect against asthma but PA can trigger asthma symptoms.ObjectiveTo investigate relationships between moderate-to-vigorous PA (MVPA) assessed during routine care visits and incident asthma.MethodsFor this retrospective cohort, 542,486 children between 2 and 17 years from 2010 to 2017 were included who had an MVPA assessment (exercise vital sign) during routine care visits. The association of MVPA and asthma was analyzed using Cox proportional hazards regression models as a function of age, with MVPA and body mass index (BMI) being time-varying factors, adjusted for race and ethnicity, socioeconomic status, and air pollution.ResultsThe mean MVPA was 5.4 (standard deviation: 4.4) hours/week. Crude asthma incidence density rate (IDR) was highest in children with

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer's disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer's disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer's disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer's disease and an association between HDL function, size, and cognitive function.

PurposeWe examined the association of Stroke Belt birth state with late-life cognition in The Study of Healthy Aging in African Americans (STAR).MethodsSTAR enrolled 764 Black Americans ages 50+ who were long-term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check-ups (MHC; 1964-1985) where early-life overweight/obesity, hypertension, diabetes, and hyperlipidemia were measured. At STAR (2018), birth state, self-reported early-life socioeconomic status (SES), and executive function, verbal episodic memory, and semantic memory scores were collected. We used linear regression to examine the association between Stroke Belt birth and late-life cognition adjusting for birth year, gender, and parental education. We evaluated early-life SES and cardiovascular risk factors (CVRF) as potential mechanisms.ResultsTwenty-seven percent of participants were born in the Stroke Belt with a mean age of 69 (standard deviation = 9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β [95% confidence interval]: -0.18 [-0.33, -0.02]) and semantic memory (-0.37 [-0.53, -0.21]), but not verbal episodic memory (-0.04 [-0.20, 0.12]). Adjustment for SES and CVRF attenuated associations of Stroke Belt birth with cognition (executive function [-0.05 {-0.25, 0.14}]; semantic memory [-0.28 {-0.49, -0.07}]).ConclusionsBlack Americans born in the Stroke Belt had worse late-life cognition than those born elsewhere, underscoring the importance of early-life exposures on brain health.

BackgroundLow socioeconomic status (SES) in early and late life has been associated with lower late-life cognition. Less is known about how changes in SES from childhood to late life are associated with late-life cognition, especially among diverse populations of older adults.MethodsIn a multi-ethnic sample (n = 1353) of older adults, we used linear regression to test associations of change in comprehensive measures of SES (financial, cultural, and social domains) from childhood to late life with semantic memory, episodic memory, and executive function. We tested whether the association between SES trajectory and late-life cognition differed by populations who resided in the U.S. during childhood or immigrated to the U.S. as adults.ResultsParticipants with low childhood/high late-life financial capital had better semantic memory (β = 0.18; 95% CI: 0.04, 0.32) versus those with low financial capital in both childhood and late life, regardless of childhood residence. We observed a significant interaction in the association of verbal episodic memory and cultural capital by childhood residence (p = 0.08). Participants with a foreign childhood residence had higher verbal episodic memory if they had low childhood/high late-life cultural capital (β = 0.32; 95% CI: 0.01, 0.63), but lower verbal episodic memory if they had high childhood/low late-life cultural capital (β = - 0.40; 95% CI: - 0.94, 0.13). Having high lifecourse social capital was associated with better verbal episodic memory scores among those with a U.S. childhood (β = 0.34; 95% CI: 0.14, 0.55), but lower verbal episodic memory among those with a foreign childhood (β = - 0.10; 95% CI: - 0.51, 0.31).ConclusionsHigh financial and cultural capital in late life is associated with better cognition, regardless of early childhood SES or childhood residence.

Persons over the age of 90 are the fastest growing segment of the population in the US, yet there is a dearth of studies investigating the underlying neuropathology of cognitive impairment and dementias, in ethnically diverse, non-white decedents. The Life after 90 study began enrollment in July 2018 and is an ongoing cohort study of members of Kaiser Permanente Northern California aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer's Coordinating Center Neuropathology form v. 10. As of January 2021, 173 (26%) participants enrolled in autopsy (18% Asian, 12% African American, 12% Latino, and 10% as multiracial) with 8 deceased and neuropathological evaluations completed. Average age of death was 96 years (range 91 to 105), 5 (62.5%) were female, 3 Latino, 3 Caucasian, and 2 multiracial. At the final clinical exam, which was on average 4 months before death (range: 2-8), 2 participant had dementia (25%), 3 questionable/mild cognitive impairment (37.5%), and 3 cognitively normal (37.5%). With respect to a neuropathologic diagnosis of Alzheimer's disease (AD), 2 met criteria for intermediate likelihood (25%), 4 low (50%), and 2 were considered not to have AD (25%). Notably, none had high likelihood of AD. All participants had some level of neurofibrillary tangles with Braak stages between II and IV. Two participants lacked plaques (Amyloid-Beta or neuritic types), and the highest Thal phase was 4. Four participants (50%) had Lewy bodies (LBs), 1 in olfactory bulb/tract only, 2 Transitional, and 1 with Diffuse. Hippocampal sclerosis was not seen in any whereas TDP-43 inclusions were detected in 2 participants (25%). Diffuse LB, TDP-43 inclusions, and intermediate AD co-occurred in one (50%) of the dementia participants while all lacking in the other. Preliminary results of the first 8 deaths in this multiethnic cohort of oldest-old individuals indicate that numerous brain pathologies are present with advanced age. Further work with this study will examine the clinical impact of this pathological heterogeneity.

As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. IMPACT: As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk-benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.

BackgroundUnderstanding SARS-CoV-2 infection in children is necessary to reopen schools safely.MethodsWe measured SARS-CoV-2 infection in 320 learners [10.5 ± 2.1 (sd); 7-17 y.o.] at four diverse schools with either remote or on-site learning. Schools A and B served low-income Hispanic learners; school C served many special-needs learners, and all provided predominantly remote instruction. School D served middle- and upper-income learners, with predominantly on-site instruction. Testing occurred in the fall (2020), and 6-8 weeks later during the fall-winter surge (notable for a tenfold increase in COVID-19 cases). Immune responses and mitigation fidelity were also measured.ResultsWe found SARS-CoV-2 infections in 17 learners only during the surge. School A (97% remote learners) had the highest infection (10/70, 14.3%, p

ObjectivesTo characterize the extent to which brief cognitive assessments administered in the population-representative U.S. Health and Retirement Study (HRS) and its International Partner Studies can be considered to be measuring a single, unidimensional latent cognitive function construct.MethodsCognitive function assessments were administered in face-to-face interviews in 12 studies in 26 countries (N = 155,690), including the U.S. HRS and selected International Partner Studies. We used the time point of the first cognitive assessment for each study to minimize differential practice effects across studies and documented cognitive test item coverage across studies. Using confirmatory factor analysis models, we estimated single-factor general cognitive function models and bifactor models representing memory-specific and nonmemory-specific cognitive domains for each study. We evaluated model fits and factor loadings across studies.ResultsDespite relatively sparse and inconsistent cognitive item coverage across studies, all studies had some cognitive test items in common with other studies. In all studies, the bifactor models with a memory-specific domain fit better than single-factor general cognitive function models. The data fit the models at reasonable thresholds for single-factor models in 6 of the 12 studies and for the bifactor models in all 12 of the 12 studies.DiscussionThe cognitive assessments in the U.S. HRS and its International Partner Studies reflect comparable underlying cognitive constructs. We discuss the assumptions underlying our methods, present alternatives, and future directions for cross-national harmonization of cognitive aging data.

BackgroundLow physical fitness (PF) levels during childhood affect healthy growth and development, and increase the risk of cardiovascular diseases. Physical education standards exist for nearly all states in the United States, but evaluation of PF in youth has yet to be systematic, reproducible, and harmonized. The purpose of this project was to describe publicly available data of school-based PF testing (SB-PFT).MethodsA list of state-mandated SB-PFT programs published by SHAPE 2016 was confirmed by contacting appropriate authorities. SB-PFT data were obtained through each state's department of education.ResultsSixteen states mandate SB-PFT, with 10 states providing publicly available data; 92% to 100% of states perform the pacer/mile, curl-up, and push-up; 54.2% to 78.5% of elementary and 44% to 66.5% of high-school youth are in the "healthy fitness zone" for aerobic capacity.ConclusionsSB-PFT provided PF data in children across the United States. The variability and inconsistency in reporting and in the values, however, raises questions about the current status of SB-PFT data and its utility in assessing PF in children. The critical nature of PF assessments is highlighted in the current COVID-19 pandemic, during which physical education has been curtailed, and emerging data demonstrate worsening of the already low levels of PF in youth.

BackgroundMidlife cardiovascular risk factors (CVRF) increase risk of dementia. Black Americans experience an elevated prevalence of CVRF and dementia. However, little is known of how CVRF prior to midlife affect late-life cognition. We examined CVRF in adolescence, young adulthood, and midlife with late-life cognition in The Study of Healthy Aging in African Americans (STAR).MethodsSTAR assesses cognitive aging among 764 Black Americans ages ≥50 (mean age=69;SD=9;range 53-95). Participants' body mass index, blood pressure, glucose, and total cholesterol were collected during Multiphasic Health Check-ups (MHC;1964-1985). At STAR baseline (2018-2019), executive function, verbal episodic memory, and semantic memory were measured using the Spanish and English Neuropsychological Assessment Scales. Linear regression models examined associations between CVRF and cognition adjusting for demographics and years since MHC.ResultsAt MHC, 36% of participants had 1 CVRF and 26% had ≥2. Twenty-two percent of participants were adolescents (ages:12-20), 62% young adults (ages:21-34), and 16% midlife adults (ages:35-56). Overweight/obesity was not associated with cognition. Hypertension was associated with worse executive function [β(95%CI):-0.14(-0.28,-0.0003)] and verbal episodic memory [β(95%CI):-0.22(-0.37,-0.07)] compared to normotension. Diabetes was associated with worse executive function [β(95%CI):-0.43(-0.83,-0.03)]. Having ≥2 CVRF (versus 0) was associated with worse executive function [β(95%CI):-0.19(-0.34,-0.03)] and verbal episodic memory [β(95%CI):-0.25(-0.41,-0.08)]. Adolescents with hypertension had lower late-life executive function compared to normotensive adolescents [β(95%CI):-0.39(-0.67,-0.11)]. Young adulthood hypertension [β(95%CI):-0.29(-0.49,-0.09)] and midlife hyperlipidemia [β(95%CI):-0.386(-0.70,-0.02)] were associated with lower verbal episodic memory.ConclusionsAmong Black Americans, lifecourse CVRF were associated with poorer executive function and verbal episodic memory emphasizing the importance of cardiovascular health on the aging brain.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

BackgroundMidlife cardiovascular risk factors (CVRF) increase dementia risk. Less is known about whether CVRF identified before midlife impact late-life cognition in diverse populations.MethodsLinear regression models examined hypertension, hyperlipidemia, and overweight/obesity at ages 30 to 59 with late-life executive function, semantic memory, verbal episodic memory, and global cognition in a cohort of Asians, blacks, Latinos, and whites (n=1127; mean age=75.8, range=65 to 98). Models adjusted for age at CVRF, age at cognitive assessment, sex, race/ethnicity, participant education, and parental education.ResultsOverall, 34% had 1 CVRF at ages 30 to 59; 19% had 2+. Blacks (26%) and Latinos (23%) were more likely to have 2+ CVRF than Asians (14%) or whites (13%). Having 2+ CVRF was associated with lower global cognition [β=-0.33; 95% confidence interval (CI)=-0.45, -0.21], executive function (β=-0.26; 95% CI=-0.39, -0.13), verbal episodic memory (β=-0.34; 95% CI=-0.48, -0.20), and semantic memory (β=-0.20; 95% CI=-0.33, -0.07). Interaction by age (P=0.06) indicated overweight/obesity was negatively associated with executive function at ages 30 to 39 but not at ages 40 to 59. Race/ethnic-specific effects showed disparities in CVRF prevalence impact population disparities in late-life cognition.ConclusionBeing overweight/obese in early adulthood and having 2+ CVRF in early adulthood/midlife are modifiable targets to redress racial/ethnic disparities in cognitive impairment and dementia.

IntroductionEducational attainment is associated with late-life cognitive performance and dementia; few studies have examined diverse racial/ethnic groups to assess whether the association differs by race/ethnicity.MethodsWe investigated whether the association between educational attainment and cognition differed between White, Black, Asian, and Latino participants in the Kaiser Healthy Aging and Diverse Life Experiences study (n=1348). Covariate-adjusted multivariable linear regression models examined domains of verbal episodic memory, semantic memory, and executive functioning.ResultsWe observed significant effect heterogeneity by race/ethnicity only for verbal episodic memory (P=0.0198), for which any schooling between high school and college was beneficial for White, Asian, and Black participants, but not Latino participants. We found no evidence of heterogeneity for semantic memory or executive function.DiscussionWith the exception of Latino performance on verbal episodic memory, more education consistently predicted better cognitive scores to a similar extent across racial/ethnic groups, despite likely heterogenous educational and social experiences.

We measure and analyze the isotope shifts in the multiplet of transitions between the metastable a5F and excited y5Go terms of neutral titanium by probing a titanium vapor in a hollow cathode lamp using saturated absorption spectroscopy. We resolve the five J→J+1 and the four J→J transitions within the multiplet for each of the three I=0 stable isotopes (Ti46, Ti48, and Ti50). The isotope shifts on these transitions allow us to determine the isotope-dependent variation in the fine-structure splitting of the a5F and y5Go levels themselves. Combined with existing knowledge of the nuclear charge radii of titanium nuclei, we derive the specific mass and field shifts, which arise from correlated electronic motion and electronic density at the nucleus respectively, and further observe a strong J-dependent variation in each. Our results yield insight into the electronic and nuclear structure of transition metal atoms like titanium and also characterize optical transitions that may allow for optical manipulation of ultracold gases of transition-metal species.

ObjectivesEvidence on adverse childhood experiences (ACEs) and late-life cognitive outcomes is inconsistent, with little research among diverse racial/ethnic groups. We investigated whether ACE exposures were associated with worse late-life cognition for all racial/ethnic groups and at different ages of exposure.DesignCovariate-adjusted mixed-effects linear regression models estimated associations of: (1) total number of ACEs experienced, (2) earliest age when ACE occurred and (3) type of ACE with overall cognition.SettingKaiser Permanente Northern California members aged 65 years and older, living in Northern California.ParticipantsKaiser Healthy Aging and Diverse Life Experiences study baseline participants, aged 65 years and older (n=1661; including 403 Asian-American, 338 Latino, 427 Black and 493 white participants).ResultsMost respondents (69%) reported one or more ACE, most frequently family illness (36%), domestic violence (23%) and parental divorce (22%). ACE count was not adversely associated with cognition overall (β=0.01; 95% CI -0.01 to 0.03), in any racial/ethnic group or for any age category of exposure. Pooling across all race/ethnicities, parent's remarriage (β=-0.11; 95% CI -0.20 to -0.03), mother's death (β=-0.18; 95% CI -0.30 to -0.07) and father's death (β=-0.11; 95% CI -0.20 to -0.01) were associated with worse cognition.ConclusionAdverse childhood exposures overall were not associated with worse cognition in older adults in a diverse sample, although three ACEs were associated with worse cognitive outcomes.

IntroductionDuring the COVID-19 pandemic, some K-12 schools resumed in-person classes with varying degrees of mitigation plans in the fall 2020. Physical distancing and face coverings can minimize SARS-CoV-2 spread, the virus that causes COVID-19. However, no research has focused on adherence to mitigation strategies during school days. Thus, we sought to develop a systematic observation protocol to capture COVID-19 mitigation strategy adherence in school environments: The Systematic Observation of COVID-19 Mitigation (SOCOM).MethodsWe extended previously validated and internationally used tools to develop the SOCOM training and implementation protocols to assess physical-distancing and face-covering behaviors. SOCOM was tested in diverse indoor and outdoor settings (classrooms, lunchrooms, physical education [PE], and recess) among diverse schools (elementary, secondary, and special needs).ResultsFor the unique metrics of physical-distancing and face-covering behaviors, areas with less activity and a maximum of 10-15 students were more favorable for accurately capturing data. Overall proportion of agreement was high for physical distancing (90.9%), face covering (88.6%), activity type (89.2%), and physical activity level (87.9%). Agreement was lowest during active recess, PE, and observation areas with ≥20 students.ConclusionsMillions of children throughout the USA are likely to return to school in the months ahead. SOCOM is a relatively inexpensive research tool that can be implemented by schools to determine mitigation strategy adherence and to assess protocols that allow students return to school safely and slow the spread of COVID-19.