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Abstract Background Recovery from SARS CoV-2 infection is expected within 3 months. Long COVID occurs after SARS-CoV-2 when symptoms are present for more than 3 months that are continuous, relapsing and remitting, or progressive. Better understanding of Long COVID illness trajectories could strengthen patient care and support. Methods We characterized functional impairments, quality of life (QoL), and cognition among patients who recovered from SARS-CoV-2 infection within 3 months (without Long COVID), after 3 months (Recovered Long COVID), or remained symptomatic (Long COVID). Among 7305 patients identified with previous SARS-CoV-2 infection between March 2020 and December 2021, confirmed in the medical record with laboratory test or physician diagnosis, 435 (6%) completed a single self-administered survey between March 2022 and September 2022. Multi-domain QoL and cognitive concerns were evaluated using PROMIS-29 and the Cognitive Change Index-12. Results Nearly half the participants (47.7%) were surveyed more than 2 years from initial infection (median = 23.3 months; IQR = 18.6, 26.7) and 86.7% were surveyed more than 1 year from infection. A significantly greater proportion of the Long COVID (n = 215) group, (Current and Recovered combined), had moderate-to-severe impairment in all health domains assessed compared to those Without Long COVID (n = 220; all p

Abstract Background We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. Methods Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel’s C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer–Lemeshow goodness of fit test along calibration plots. Results Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). Conclusions The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

This study aimed to estimate the incidence rates of post–COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020–February 2021 who were followed for a median of 11.4 (interquartile range 7.8–15.5) months and compared them to data from 9,022 propensity score–matched non–COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non–COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48–1.92) for fatigue and 4.32 (95% CI 2.90–6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

IntroductionCompanion animals offer a unique opportunity to investigate risk factors and exposures in our shared environment. Passive sampling techniques have proven effective in capturing environmental exposures in dogs and humans.MethodsIn a pilot study, we deployed silicone monitoring devices (tags) on the collars of a sample of 15 dogs from the Dog Aging Project Pack cohort for a period of 120 h (5 days). We extracted and analyzed the tags via gas chromatography–mass spectrometry for 119 chemical compounds in and around participants’ homes.ResultsAnalytes belonging to the following chemical classes were detected: brominated flame retardants (BFRs), organophosphate esters (OPEs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), pesticides, phthalates, and personal care products. The types and amounts of analytes detected varied substantially among participants.DiscussionData from this pilot study indicate that silicone dog tags are an effective means to detect and measure chemical exposure in and around pet dogs’ households. Having created a sound methodological infrastructure, we will deploy tags to a geographically diverse and larger sample size of Dog Aging Project participants with a goal of further assessing geographic variation in exposures.

Abstract INTRODUCTION Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain. METHODS We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40% male; and 25% apolipoprotein E (APOE) ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini–Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia. RESULTS Higher plasma levels of sphingomyelin‐d18:1/16:0 (SM‐16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin‐d18:1/22:0 (SM‐22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM‐16 (hazard ration [HR] = 1.24 [95% confidence interval [CI]: 1.08–1.44]) and ceramide‐d18:1/16:0 (Cer‐16) (HR = 1.26 [95% CI: 1.10–1.45]) were associated with higher risk of incident dementia. DISCUSSION Several sphingolipid species appear to be involved in cognitive decline and dementia risk. Highlights Plasma levels of sphingolipids were associated with cognitive decline and dementia risk. Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia. The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

BackgroundSphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.MethodsBrain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.ResultsIn the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction =

Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Abstract Introduction Prior reviews synthesized findings of studies on long-term cardiac complications of COVID-19. However, the reporting and methodological quality of these studies has not been systematically evaluated. Here, we conducted a systematic review and meta-analysis on long-term cardiac complications of COVID-19 and examined patterns of reported findings by study quality and characteristics. Methods We searched for studies examining long-term cardiac complications of COVID-19 that persisted for 4 weeks and over. A customized Newcastle–Ottawa scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed to generate prevalence estimates of long-term cardiac complications across studies. Stratified analyses were further conducted to examine the prevalence of each complication by study quality and characteristics. The GRADE approach was used to determine the level of evidence for complications included in the meta-analysis. Results A total number of 150 studies describing 57 long-term cardiac complications were included in this review, and 137 studies reporting 17 complications were included in the meta-analysis. Only 25.3% (n = 38) of studies were of high quality based on the NOS quality assessment. Chest pain and arrhythmia were the most widely examined long-term complications. When disregarding study quality and characteristics, summary prevalence estimates for chest and arrhythmia were 9.79% (95% CI 7.24–13.11) and 8.22% (95% CI 6.46–10.40), respectively. However, stratified analyses showed that studies with low-quality scores, small sample sizes, unsystematic sampling methods, and cross-sectional design were more likely to report a higher prevalence of complications. For example, the prevalence of chest pain was 22.17% (95% CI 14.40–32.55), 11.08% (95% CI 8.65–14.09), and 3.89% (95% CI 2.49–6.03) in studies of low, medium, and high quality, respectively. Similar patterns were observed for arrhythmia and other less examined long-term cardiac complications. Conclusion There is a wide spectrum of long-term cardiac complications of COVID-19. Reported findings from previous studies are strongly related to study quality, sample sizes, sampling methods, and designs, underscoring the need for high-quality epidemiologic studies to characterize these complications and understand their etiology.

Abstract Background Burden of dementia is expected to substantially increase. Early dementia is underdiagnosed in primary care. Given the benefits of active management of dementia, earlier detection in primary care is imperative. The aim of this study was to understand primary care provider (PCP) perceptions of implementing a cognitive assessment toolkit in primary care. Methods PCPs in a large health system in the US were recruited to a qualitative study utilizing semi-structured interviews. Interviews captured provider perceptions of options for implementing a cognitive assessment toolkit derived from the Gerontological Society of America (GSA) KAER (Kickstart, Assess, Evaluate, Refer) toolkit, including a workflow and adapted clinical tools. A content analysis approach distinguished themes and exemplary quotes. Results Ten PCPs were interviewed. They found the toolkit useful, felt the term Kickstart was not specific to dementia care, and stressed that addressing cognitive evaluation would need to be easy to implement in a clinical workflow. Finally, providers knew many resources for referral but were unsure how to help patients navigate options. Conclusions Providers stressed simplicity, ease, and efficiency for implementation of a cognitive assessment toolkit. Incorporating these findings into the development of clinical tools and workflows may increase cognitive evaluations conducted by PCPs.

The Canine Behavioral Assessment and Research Questionnaire (C-BARQ) is a 100-item owner-completed survey instrument used for assessing behavior and temperament of companion dogs. The shortened version of the C-BARQ (C-BARQ(S)) consists of 42 items of the long C-BARQ. We aimed to validate the shortened C-BARQ(S) by comparing it with the long questionnaire in the same human-dog pair. We examined data from a nationwide cohort of companion dogs enrolled in the large-scale longitudinal Dog Aging Project (DAP) study. Among 435 participating owners who completed both the long and shortened versions of the C-BARQ within 60 days of each other, agreement between individual questions of the long and shortened C-BARQ using an unweighted kappa statistic and percent agreement was examined. Associations between the two questionnaires for mean behavior and temperament domain scores and mean miscellaneous category scores were assessed using Pearson correlation coefficients. Of 435 dogs in the study, the mean (SD) age was 7.3 (4.3) years and 216 (50%) were female. Kappa values between the long and shortened C-BARQ for individual questions within the 14 behavior and temperament domains and a miscellaneous category ranged from fair to moderate (0.23 to 0.40 for 21 items and 0.41 to 0.58 for 26 items, respectively). Pearson correlation coefficients above 0.60 between both questionnaires for 12 of the 14 mean behavior and temperament domain scores and a category of miscellaneous items were observed. Kappa values for individual questions between the long and shortened C-BARQ ranged from fair to moderate and correlations between mean domain scores ranged from moderate to strong.

Abstract Background Although slow gait speed is an established risk factor for falls, few studies have evaluated change in gait speed as a predictor of falls or considered variability in effects by cognitive status. Change in gait speed may be a more useful metric because of its potential to identify decline in function. In addition, older adults with mild cognitive impairment are at an elevated risk of falls. The purpose of this research was to quantify the association between 12-month change in gait speed and falls in the subsequent 6 months among older adults with and without mild cognitive impairment. Methods Falls were self-reported every six months, and gait speed was ascertained annually among 2,776 participants in the Ginkgo Evaluation of Memory Study (2000–2008). Adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for fall risk relative to a 12-month change in gait speed. Results Slowing gait speed over 12 months was associated with increased risk of one or more falls (HR:1.13; 95% CI: 1.02 to 1.25) and multiple falls (HR:1.44; 95% CI: 1.18 to 1.75). Quickening gait speed was not associated with risk of one or more falls (HR 0.97; 95% CI: 0.87 to 1.08) or multiple falls (HR 1.04; 95% CI: 0.84 to 1.28), relative to those with a less than 0.10 m/s change in gait speed. Associations did not vary by cognitive status (pinteraction = 0.95 all falls, 0.25 multiple falls). Conclusions Decline in gait speed over 12 months is associated with an increased likelihood of falls among community-dwelling older adults, regardless of cognitive status. Routine checks of gait speed at outpatient visits may be warranted as a means to focus fall risk reduction efforts.

IntroductionLarge scale data on the prevalence of diverse medical conditions among dog breeds in the United States are sparse. This cross-sectional study sought to estimate the lifetime prevalence of medical conditions among US dogs and to determine whether purebred dogs have higher lifetime prevalence of specific medical conditions compared to mixed-breed dogs.MethodsUsing owner-reported survey data collected through the Dog Aging Project (DAP) Health and Life Experience Survey for 27,541 companion dogs, we identified the 10 most commonly reported medical conditions in each of the 25 most common dog breeds within the DAP cohort. Lifetime prevalence estimates of these medical conditions were compared between mixed-breed and purebred populations. The frequency of dogs for whom no medical conditions were reported was also assessed within each breed and the overall mixed-breed and purebred populations.ResultsA total of 53 medical conditions comprised the top 10 conditions for the 25 most popular breeds. The number of dogs for whom no medical conditions were reported was significantly different (p = 0.002) between purebred (22.3%) and mixed-breed dogs (20.7%). The medical conditions most frequently reported within the top 10 conditions across breeds were dental calculus (in 24 out of 25 breeds), dog bite (23/25), extracted teeth (21/25), osteoarthritis (15/25), and Giardia (15/25).DiscussionPurebred dogs in the DAP did not show higher lifetime prevalence of medical conditions compared to mixed-breed dogs, and a higher proportion of purebred dogs than mixed-breed dogs had no owner-reported medical conditions. Individual breeds may still show higher lifetime prevalence for specific conditions.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P

Over the last few decades, frailty has become a pillar of research and clinical assessment in human gerontology. This complex syndrome, characterized by loss of physiologic reserves leading to decreased resilience to stressors, is of critical importance because it predicts higher risks of poor health outcomes, including mortality. Thus, identifying frailty among the elderly human population has become a key focus of gerontology. This narrative review presents current scientific literature on frailty in both humans and animals. The authors discuss the need for an accessible frailty instrument for companion dogs suitable for general use in veterinary medicine and the advances that would be facilitated by this instrument. A phenotypic frailty instrument for companion dogs, utilizing components that are easily collected by owners, or in the general practice setting, is proposed. The authors elaborate on the domains (physical condition, physical activity, mobility, strength, cognitive task performance, and social behavior), factors that will be included, and the data from the Dog Aging Project that inform each domain.

Highlights Residential greenspace exposure was found to be associated with moderate cognitive health benefit for older U.S. adults. Dementia subtypes may be differentially impacted by exposure to residential greenspace. Combining multiple greenspace measures may better capture a holistic picture of exposure to greenspace compared to one measure alone.

Air pollution has been linked to Alzheimer’s disease and related dementias (ADRD), but the mechanisms connecting air pollution to ADRD have not been firmly established. Air pollution may cause oxidative stress and neuroinflammation and contribute to the deposition of amyloid beta (Aβ) in the brain. We examined the association between fine particulate matter

Cardiovascular diseases are the leading causes of morbidity and mortality worldwide, but implementation of evidence-based interventions for risk factors such as hypertension is lacking, particularly in low and middle income countries (LMICs). Building implementation research capacity in LMICs is required to overcome this gap. Members of the Global Research on Implementation and Translation Science (GRIT) Consortium have been collaborating in recent years to establish a research and training infrastructure in dissemination and implementation to improve hypertension care. GRIT includes projects in Ghana, Guatemala, India, Kenya, Malawi, Nepal, Rwanda, and Vietnam. We collected data from each site on capacity building activities using the Potter and Brough (2004) model, mapping formal and informal activities to develop (a) structures, systems and roles, (b) staff and infrastructure, (c) skills, and (d) tools. We captured information about sites' needs assessments and metrics plus program adaptations due to the COVID-19 pandemic. All sites reported capacity building activities in each layer of the Capacity Pyramid, with the largest number of activities in the Skills and Tools categories, the more technical and easier to implement categories. All sites included formal and informal training to build Skills. All sites included a baseline needs assessment to guide capacity building activities or assess context and inform intervention design. Sites implementing evidence-based hypertension interventions used common implementation science frameworks to evaluate implementation outcomes. Although the COVID-19 pandemic affected timelines and in-person events, all projects were able to pivot and carry out planned activities. Although variability in the activities and methods used existed, GRIT programs used needs assessments to guide locally appropriate design and implementation of capacity building activities. COVID-19 related changes were necessary, but strong collaborations and relationships with health ministries were maintained. The GRIT Consortium is a model for planning capacity building in LMICs.

Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Summary: Background: It is hypothesized that vitamin D contributes to the aetiology of type 2 diabetes mellitus (diabetes). This study's objective was to examine the relationships between baseline vitamin D status (as measured by plasma 25-hydroxyvitamin D concentration) and both prevalent diabetes and prospective risk of developing diabetes, including prediabetes, in a population with historically low levels of vitamin D. Methods: In this prospective cohort study, data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged ≥50 years residing in Ireland were analysed, including wave 1 (October 2009–June 2011) (n = 5272) and wave 3 (March 2014–October 2015) (n = 3828). Those aged

Abstract Background Cardiovascular diseases (CVDs) are the leading cause of deaths and disability in Nepal. Health systems can improve CVD health outcomes even in resource-limited settings by directing efforts to meet critical system gaps. This study aimed to identify Nepal’s health systems gaps to prevent and manage CVDs. Methods We formed a task force composed of the government and non-government representatives and assessed health system performance across six building blocks: governance, service delivery, human resources, medical products, information system, and financing in terms of equity, access, coverage, efficiency, quality, safety and sustainability. We reviewed 125 national health policies, plans, strategies, guidelines, reports and websites and conducted 52 key informant interviews. We grouped notes from desk review and transcripts’ codes into equity, access, coverage, efficiency, quality, safety and sustainability of the health system. Results National health insurance covers less than 10% of the population; and more than 50% of the health spending is out of pocket. The efficiency of CVDs prevention and management programs in Nepal is affected by the shortage of human resources, weak monitoring and supervision, and inadequate engagement of stakeholders. There are policies and strategies in place to ensure quality of care, however their implementation and supervision is weak. The total budget on health has been increasing over the past five years. However, the funding on CVDs is negligible. Conclusion Governments at the federal, provincial and local levels should prioritize CVDs care and partner with non-government organizations to improve preventive and curative CVDs services.

Osteoarthritis (OA) is one of the most prevalent age-related chronic conditions that afflict companion dogs, and multiple joint supplements are available to prevent or treat OA, though the efficacy of these treatments is controversial. While the demographic factors that are associated with OA diagnosis are well established, the factors that are associated with joint supplement use are not as well studied. Using data collected from the Dog Aging Project, we analyzed owner survey responses regarding joint supplement administration and OA diagnosis for 26,951 adult dogs. In this cross-sectional analysis, logistic regression models and odds-ratios (OR) were employed to determine demographic factors of dogs and their owners that were associated with joint supplement administration. Forty percent of adult dogs in our population were given some type of joint supplement. Perhaps not surprisingly, dogs of older age, larger size, and those that were ever overweight were more likely to receive a joint supplement. Younger owner age, urban living, owner education, and feeding commercial dry food were associated with a reduced likelihood of administration of joint supplements to dogs. Interestingly, mixed breed dogs were also less likely to be administered a joint supplement (OR: 0.73). Dogs with a clinical diagnosis of OA were more likely to receive a joint supplement than those without a reported OA diagnosis (OR: 3.82). Neutered dogs were more likely to have a diagnosis of OA, even after controlling for other demographic factors, yet their prevalence of joint supplement administration was the same as intact dogs. Overall, joint supplement use appears to be high in our large population of dogs in the United States. Prospective studies are needed to determine if joint supplements are more commonly administered as a preventative for OA or after an OA clinical diagnosis.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants’ homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4×10−6) and NOX (p = 7.7×10−6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10−8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6×10−8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

Background: Cognitive impairment is a public health burden. Our objective was to investigate associations between work hours and cognitive function. Methods: Multi-Ethnic Study of Atherosclerosis (MESA) participants (n = 2,497; 50.7% men; age range 44–84 years) reported hours per week worked in all jobs in Exams 1 (2000–2002), 2 (2002–2004), 3 (2004–2005), and 5 (2010–2011). Cognitive function was assessed (Exam 5) using the Cognitive Abilities Screening Instrument (version 2), a measure of global cognitive functioning; the Digit Symbol Coding, a measure of processing speed; and the Digit Span test, a measure of attention and working memory. We used a prospective approach and linear regression to assess associations for every 10 hours of work. Results: Among all participants, associations of hours worked with cognitive function of any type were not statistically significant. In occupation-stratified analyses (interaction p = 0.051), longer work hours were associated with poorer global cognitive function among Sales/Office and blue-collar workers, after adjustment for age, sex, physical activity, body mass index, race/ethnicity, educational level, annual income, history of heart attack, diabetes, apolipoprotein E-epsilon 4 allele (ApoE4) status, birth-place, number of years in the United States, language spoken at MESA Exam 1, and work hours at Exam 5 (β = –0.55, 95% CI = –0.99, –0.09) and (β = –0.80, –1.51, –0.09), respectively. In occupation-stratified analyses (interaction p = 0.040), we also observed an inverse association with processing speed among blue-collar workers (adjusted β = –0.80, –1.52, –0.07). Sex, race/ethnicity, and ApoE4 did not significantly modify associations between work hours and cognitive function. Conclusion: Weak inverse associations were observed between work hours and cognitive function among Sales/Office and blue-collar workers.

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology.

Abstract Background The burden of sepsis is highest in low- and middle-income countries, though the management of sepsis in these settings is poorly characterized. Therefore, the objective of this study was to assess the early management of sepsis in Thailand. Methods Pre-planned analysis of the Ubon-sepsis study, a single-center prospective cohort study of Thai adults admitted to the general medical wards and medical intensive care units (ICUs) of a regional referral hospital with community-acquired sepsis. Results Between March 2013 and January 2017, 3,716 patients with sepsis were enrolled. The median age was 59 years (IQR 44-72, range 18-101), 58% were male, and 88% were transferred from other hospitals. Eighty-six percent of patients (N = 3,206) were evaluated in the Emergency Department (ED), where median length of stay was less than 1 hour. Within the first day of admission, most patients (83%, N = 3,089) were admitted to the general medical wards, while 17% were admitted to the ICUs. Patients admitted to the ICUs had similar age, gender, and comorbidities, but had more organ dysfunction and were more likely to receive measured sepsis management interventions. Overall, 84% (N = 3,136) had blood cultures ordered and 89% (N = 3,308) received antibiotics within the first day of hospital admission. Among the 3,089 patients admitted to the general medical wards, 38% (N = 1,165) received an adrenergic agent, and 21% (N = 650) received invasive mechanical ventilation. Overall mortality at 28 days was 21% (765/3,716), and 28-day mortality in patients admitted to the ICUs was higher than that in patients admitted to the general medical wards within the first day (42% [263/627] vs. 16% [502/3,089], p < 0.001). Conclusions Sepsis in a regional referral hospital in rural Thailand, where some critical care resources are limited, is commonly managed on general medical wards despite high rates of respiratory failure and shock. Enhancing sepsis care in the ED and general wards, as well as improving access to ICUs, may be beneficial in reducing mortality. Trial registration The Ubon-sepsis study was registered on clinicaltrials.gov (NCT02217592).

Summary: Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Abstract Introduction Plant‐based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained. Methods We measured antioxidants in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow‐up. We measured baseline plasma levels of retinol, α‐, and γ‐tocopherol; zeaxanthin and lutein (combined); beta‐cryptoxanthin; cis‐lycopene; trans‐lycopene; α‐carotene; and trans‐β‐carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist‐adjudicated risks of all‐cause dementia and AD. Results Plasma retinol, α‐, and γ‐tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β‐carotene, or vitamin E supplements. Higher trans‐β‐carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans‐β‐carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α‐carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α‐carotene: 1.15; 95% CI: 1.02, 1.29). Discussion Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

Background: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults. Material and methods: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status. Results: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β = −0.034; SE = 0.015; P = 0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error = 0.016; P = 0.007); for comparison the coefficient for a single year of age in the same model was −0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β = -0.079; SE = 0.029; P = 0.01). Conclusions: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.

BackgroundSubstantial evidence supports the effectiveness of peer educator programs for diabetes management in low- and middle-income countries. However, little is known about peer educators' impact relative to other treatment components such as medication and physician consultation. In Cambodia, the non-governmental organization MoPoTsyo organizes four services for people with diabetes: self-management training through peer educator visits, lab tests, physician consultations, and low-cost medicines. Our aims were to 1) quantify MoPoTsyo participant utilization of each program service and 2) define the relationship between each program service and glycemic control.MethodsWe conducted a retrospective cohort study among 4,210 MoPoTsyo participants, using data collected by MoPoTsyo from 2006-2016. Independent variables assessed were medication adherence, number of peer educator visits, number of physician consultations, and number of lab tests. A multiple logistic regression model was used to evaluate the association between these disease management services and glycemic control-fasting plasma glucose ≤130 mg/dl or post-prandial glucose ≤180 mg/dl-based on most recent glucose level. The model was adjusted for baseline demographic and disease characteristics.FindingsParticipants with 12 or more peer educator visits per year had a 35% higher odds of glycemic control relative to participants with 4 or fewer visits (odds ratio 1.35, 95% CI: 1.08-1.69; p = 0.009), after adjustment for utilization of other treatment components (medication adherence, number of physician visits, number of lab tests), follow-up time, and demographic and disease characteristics. Better adherence to medications and a greater number of lab tests per year were also associated with a higher odds of glycemic control after adjustment. Number of physician consultations was not associated with glycemic control after adjustment.ConclusionsThis study demonstrates a positive association between peer educator utilization and glycemic control incremental to other elements of diabetes management. These results suggest that peer educators may be a valuable addition to comprehensive diabetes management programs in low- and middle-income countries even when other health care services are accessible. The associations identified in this research warrant further prospective studies to explore the causal impact of peer educators on glycemic control relative to other disease management components.

ObjectiveTo investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.MethodsData from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.ResultsAfter adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.InterpretationThe results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.

Abstract Introduction Hearing and vision loss are independently associated with dementia, but the impact of dual sensory impairment (DSI) on dementia risk is not well understood. Methods Self‐reported measures of hearing and vision were taken from 2051 participants at baseline from the Gingko Evaluation of Memory Study. Dementia status was ascertained using standardized criteria. Cox models were used to estimate risk of dementia associated with number of sensory impairments (none, one, or two). Results DSI was significantly associated with higher risk of all‐cause dementia (hazard ratio [HR] = 1.86; 95% confidence interval [CI] = 1.25‐2.76) and Alzheimer's disease (HR = 2.12; 95% CI = 1.34‐3.36). Individually only visual impairment was independently associated with an increased risk of all‐cause dementia (HR = 1.32; 95% CI = 1.02‐1.71). Discussion Older adults with DSI are at a significantly increased risk for dementia. Further studies are needed to evaluate whether treatments can modify this risk.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Abstract Introduction Apolipoproteins of demonstrated importance to brain cholesterol and ß‐amyloid metabolism may serve as novel risk markers for Alzheimer's pathology. Methods We measured apolipoproteins (apoE, apoJ, apoA‐I, and apoC‐III and their uniquely defined subspecies) by enzyme‐linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia‐free participants of the Ginkgo Evaluation of Memory Study and related these to ß‐amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009. Results Higher apoE was associated with lower ß‐amyloid deposition. Despite apoA‐I being unrelated to hippocampal volume, subspecies of apoA‐I containing or lacking apoJ or apoC‐III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE ε4 noncarrier and when analyzing apolipoproteins in 2000–2002. Discussion Apolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.

Abstract Background There is evidence to suggest that frontline community health workers in Malawi are under-referring children to higher-level facilities. Integrating a digitized version of paper-based methods of Community Case Management (CCM) could strengthen delivery, increasing urgent referral rates and preventing unnecessary re-consultations and hospital admissions. This trial aims to evaluate the added value of the Supporting LIFE electronic Community Case Management Application (SL eCCM App) compared to paper-based CCM on urgent referral, re-consultation and hospitalization rates, in two districts in Northern Malawi. Methods/design This is a pragmatic, stepped-wedge cluster-randomized trial assessing the added value of the SL eCCM App on urgent referral, re-consultation and hospitalization rates of children aged 2 months and older to up to 5 years, within 7 days of the index visit. One hundred and two health surveillance assistants (HSAs) were stratified into six clusters based on geographical location, and clusters randomized to the timing of crossover to the intervention using simple, computer-generated randomization. Training workshops were conducted prior to the control (paper-CCM) and intervention (paper-CCM + SL eCCM App) in assigned clusters. Neither participants nor study personnel were blinded to allocation. Outcome measures were determined by abstraction of clinical data from patient records 2 weeks after recruitment. A nested qualitative study explored perceptions of adherence to urgent referral recommendations and a cost evaluation determined the financial and time-related costs to caregivers of subsequent health care utilization. The trial was conducted between July 2016 and February 2017. Discussion This is the first large-scale trial evaluating the value of adding a mobile application of CCM to the assessment of children aged under 5 years. The trial will generate evidence on the potential use of mobile health for CCM in Malawi, and more widely in other low- and middle-income countries. Trial registration ClinicalTrials.gov, ID: NCT02763345 . Registered on 3 May 2016.

Context: Nepal is currently experiencing a rapid growth in noncommunicable diseases (NCDs). Depression has previously been associated with NCDs in South Asia; however, data regarding its prevalence and risk factors are lacking in Nepal. Aims: This study aims to describe the prevalence of and risk factors for depressive symptoms in a suburban population of adults within Nepal. Setting and Design: We conducted a cross-sectional analysis of baseline data collected from participants enrolled in the Dhulikhel Heart Study, a population-based, longitudinal cohort study investigating cardiovascular risk factors in Dhulikhel, a suburban town outside Kathmandu. Subjects and Methods: Baseline questionnaire data from 1073 adults age 18 years and older included the Center for Epidemiologic Studies Depression Scale (CES-D). A score of 16 or greater on the CES-D has been shown to indicate major depressive symptomatology. Statistical Analysis: Using STATA 13, we conducted Pearson's Chi-square tests and multiple logistic regressions to examine associations between the binary CES-D score and gender, age, education, marital status, body mass index, physical activity, and hypertensive status. Results: The mean CES-D score in the sample was 11.7 (standard deviation: 5.3), with 21.3% scoring 16 or greater. Age over 60 and lack of formal education were associated with increased risk of depressive symptoms. Being physically active was associated with decreased risk of depressive symptoms. Conclusions: The estimated prevalence of depression among adults in Dhulikhel was 21.3%. Significant risk factors for increased depressive symptoms included lack of formal education, age over 60, and physical inactivity.

Abstract Background We examined whether changes in metabolic factors over 10 years were associated with cognitive performance. Methods Participants from the Multi‐Ethnic Study of Atherosclerosis were followed since baseline (2000–2002) with five clinical examinations. At exam 5 (2010–2012), they received a short cognitive battery (Cognitive Abilities Screening Instrument [CASI], Digit Symbol Coding [DSC], and Digit Span [DS]). We examined associations between baseline metabolic factors and their changes over time before cognitive testing. Results Among 4392 participants, baseline metabolic disorders (fasting glucose, systolic and diastolic blood pressures) were significantly associated with poorer CASI, DSC, and DS scores measured 10 years later. Increases in blood pressure were associated with lower cognitive performance. Results did not differ by race/ethnicity and were stronger among those without the APOE ε4 allele. Conclusions Cognitive performance was associated with antecedent abnormalities in glucose metabolism and blood pressure increases. Findings appeared stronger among APOE ε4‐negative participants.

Background: Viet Nam is experiencing a health transition from infectious to chronic disease. Data on cardiovascular diseases, including strokes, are limited. Methods: Data were randomly collected from six communities in Da Nang, Viet Nam, on participant demographics, medical history, blood pressure, anthropometrics and health behavior using World Health Organization (WHO) guidelines. Stroke symptoms were collected by self-report with the standardized Questionnaire for Verifying Stroke Free Status. Multivariate logistic regression was used to identify factors associated with the presence of stroke symptoms. Results: One thousand six hundred and twenty one adults were examined with a mean age of 52.0 years (±12.5 years), of which 56.1% were women. 27.3% of the participants were found to have hypertension, 26.2% used tobacco, and 16.1% were overweight. More than two-thirds of the participants with hypertension were unaware of their condition. Almost one fourth of the participants were identified by the questionnaire as previously experiencing at least one stroke symptom. Age, rural residence, and education were associated with the presence of stroke symptoms. Models adjusted for demographics found hypertension, high cholesterol, reported severe chest pain, former smoking, and being overweight to be associated with a higher prevalence of stroke symptoms. Conclusions: The high frequency of stroke symptoms in Da Nang calls for further evaluation and interventions to reduce hypertension and other risk factors for chronic disease in Viet Nam and other health transition countries.