Joint and Individual Mitochondrial DNA Variation and Cognitive Outcomes in Black and White Older Adults.

BACKGROUND: Mitochondrial dysfunction manifests in neurodegenerative diseases and other age-associated disorders. In this study, we examined variation in inherited mitochondrial DNA (mtDNA) sequences in Black and White participants from two large aging studies to identify variants related to cognitive function. METHODS: Participants included self-reported Black and White adults aged ≥ 70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N=1319) and Health Aging and Body Composition (Health ABC; N=7888) studies. Cognitive function was measured by the digit-symbol substitution test (DSST), and the Modified Mini-Mental State Exam (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined joint effects of multiple variants across 16 functional mitochondrial regions with cognitive function using a sequence kernel association test. Based on these results, we prioritized meta-analysis of common variants in Black and White participants using mixed effects models. A Bonferroni adjusted p-value of <0.05 was considered statistically significant. RESULTS: Joint variation in subunits ND1, ND2, and ND5 of Complex I, 12S RNA, and hypervariable region (HVR) were significantly associated with DSST and 3MSE at baseline. In meta-analyses among Black participants, variant m.4216T>C, ND1 was associated with a faster decline in 3MSE, and variant m.462C>T in the HVR was associated with a slower decline in DSST. Variant m.5460G>C, ND2 was associated with slower and m.182C>T in the HVR was associated with faster decline in 3MSE in White participants. CONCLUSION: Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function.

Complex Patterns of Antihypertensive Treatment Changes in Long-Term Care Residents.

OBJECTIVES: Antihypertensive treatment changes are common in long-term care residents, yet data on the frequency and predictors of changes are lacking. We described the patterns of antihypertensive changes and examined the triggering factors. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: A total of 24,870 Department of Veterans Affairs (VA) nursing home residents aged ≥65 years with long-term stays (≥180 days) from 2006 to 2019. METHODS: We obtained data from the VA Corporate Data Warehouse. Based on Bar Code Medication Administration medication data, we defined 2 types of change events in 180 days of admission: deprescribing (reduced number of antihypertensives or dose reduction of ≥30% compared with the previous week and maintained for at least 2 weeks) and intensification (opposite of deprescribing). Mortality was identified within 2 years after admission. RESULTS: More than 85% of residents were prescribed antihypertensives and 68% of them experienced ≥1 change event during the first 6 months of the nursing home stay. We categorized residents into 10 distinct patterns: no change (27%), 1 deprescribing (11%), multiple deprescribing (5%), 1 intensification (10%), multiple intensification (7%), 1 deprescribing followed by 1 intensification (3%), 1 intensification followed by 1 deprescribing (4%), 3 changes with mixed events (7%), >3 changes with mixed events (10%), and no antihypertensive use (15%). Treatment changes were more frequent in residents with better physical function and/or cognitive function. Potentially triggering factors differed by the type of antihypertensive change: incident high blood pressure and cardiovascular events were associated with intensification, and low blood pressure, weight loss, and falls were associated with deprescribing. Death occurred in 7881 (32%) residents over 2 years. The highest mortality was for those without antihypertensive medication (incidence = 344/1000 person-years). CONCLUSIONS AND IMPLICATIONS: Patterns of medication changes existing in long-term care residents are complex. Future studies should explore the benefits and harms of these antihypertensive treatment changes.

Associations between toxicity-weighted concentrations and dementia risk: Results from the Cardiovascular Health Cognition Study.

BACKGROUND: Air pollution is a modifiable risk factor for dementia. Yet, studies on specific sources of air pollution (i.e., toxic chemical emissions from industrial facilities) and dementia risk are scarce. We examined associations between toxicity-weighted concentrations of industrial pollution and dementia outcomes among a large, multi-site cohort of older adults. METHODS: Participants (n = 2770) were ≥ 65 years old (Mean = 75.3, SD = 5.1 years) from the Cardiovascular Health Cognition Study (1992-1999). Toxicity-weighted concentrations were estimated using the Risk Screening Environmental Indicator (RSEI) model which incorporates total reported chemical emissions with toxicity, fate, and transport models. Estimates were aggregated to participants' baseline census tract, averaged across 1988-1992, and log2-transformed. Dementia status was clinically adjudicated in 1998-1999 and categorized by subtype (Alzheimer's, vascular, mixed). We assessed whether RSEI-estimated toxicity-weighted concentrations were associated with 1) odds of prevalent dementia and 2) incident dementia risk by subtype. RESULTS: After adjusting for individual and census-tract level covariates, a doubling in toxicity-weighted concentrations was associated with 9 % higher odds of prevalent dementia (OR = 1.09, 95 % CI: 1.00, 1.19). In discrete-time survival models, each doubling in toxicity-weighted concentrations was associated with a 16 % greater hazard of vascular dementia (HR = 1.16, 95 % CI: 1.01, 1.34) but was not significantly associated with all-cause, Alzheimer's disease, or mixed dementia (p's > 0.05). DISCUSSION: Living in regions with higher toxicity-weighted concentrations was associated with higher odds of prevalent dementia and a higher risk of incident vascular dementia in this large, community-based cohort of older adults. These findings support the need for additional studies to examine whether toxic chemical emissions from industrial and federal facilities may be a modifiable target for dementia prevention.

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.

Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. Design, Setting, and Participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Exposures: Protein aptamers, measured at study V3 and V5. Main Outcomes and Measures: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. Results: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. Conclusions and Relevance: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

Antihypertensive Medication and Fracture Risk in Older Veterans Health Administration Nursing Home Residents.

Importance: Limited evidence exists on the association between initiation of antihypertensive medication and risk of fractures in older long-term nursing home residents. Objective: To assess the association between antihypertensive medication initiation and risk of fracture. Design, Setting, and Participants: This was a retrospective cohort study using target trial emulation for data derived from 29 648 older long-term care nursing home residents in the Veterans Health Administration (VA) from January 1, 2006, to October 31, 2019. Data were analyzed from December 1, 2021, to November 11, 2023. Exposure: Episodes of antihypertensive medication initiation were identified, and eligible initiation episodes were matched with comparable controls who did not initiate therapy. Main Outcome and Measures: The primary outcome was nontraumatic fracture of the humerus, hip, pelvis, radius, or ulna within 30 days of antihypertensive medication initiation. Results were computed among subgroups of residents with dementia, across systolic and diastolic blood pressure thresholds of 140 and 80 mm Hg, respectively, and with use of prior antihypertensive therapies. Analyses were adjusted for more than 50 baseline covariates using 1:4 propensity score matching. Results: Data from 29 648 individuals were included in this study (mean [SD] age, 78.0 [8.4] years; 28 952 [97.7%] male). In the propensity score-matched cohort of 64 710 residents (mean [SD] age, 77.9 [8.5] years), the incidence rate of fractures per 100 person-years in residents initiating antihypertensive medication was 5.4 compared with 2.2 in the control arm. This finding corresponded to an adjusted hazard ratio (HR) of 2.42 (95% CI, 1.43-4.08) and an adjusted excess risk per 100 person-years of 3.12 (95% CI, 0.95-6.78). Antihypertensive medication initiation was also associated with higher risk of severe falls requiring hospitalizations or emergency department visits (HR, 1.80 [95% CI, 1.53-2.13]) and syncope (HR, 1.69 [95% CI, 1.30-2.19]). The magnitude of fracture risk was numerically higher among subgroups of residents with dementia (HR, 3.28 [95% CI, 1.76-6.10]), systolic blood pressure of 140 mm Hg or higher (HR, 3.12 [95% CI, 1.71-5.69]), diastolic blood pressure of 80 mm Hg or higher (HR, 4.41 [95% CI, 1.67-11.68]), and no recent antihypertensive medication use (HR, 4.77 [95% CI, 1.49-15.32]). Conclusions and Relevance: Findings indicated that initiation of antihypertensive medication was associated with elevated risks of fractures and falls. These risks were numerically higher among residents with dementia, higher baseline blood pressures values, and no recent antihypertensive medication use. Caution and additional monitoring are advised when initiating antihypertensive medication in this vulnerable population.

Effects of residential socioeconomic polarization on high blood pressure among nursing home residents.

OBJECTIVE: Neighborhood concentration of racial, income, education, and housing deprivation is known to be associated with higher rates of hypertension. The objective of this study is to examine the association between tract-level spatial social polarization and hypertension in a cohort with relatively equal access to health care, a Veterans Affairs nursing home. METHODS: 41,973 long-term care residents aged ≥65 years were matched with tract-level Indices of Concentration at the Extremes across four socioeconomic domains. We modeled high blood pressure against these indices controlling for individual-level cardiovascular confounders. RESULTS: We found participants who had resided in the most disadvantaged quintile had a 1.10 (95% 1.01, 1.19) relative risk of high blood pressure compared to those in the other quintiles for the joint measuring race/ethnicity and income domain. CONCLUSIONS: We achieved our objective by demonstrating that concentrated deprivation is associated with worse cardiovascular outcomes even in a population with equal access to care. Measures that jointly consider economic and racial/ethnic polarization elucidate larger disparities than single domain measures.

Preoperative GLP-1 Receptor Agonist Use and Risk of Postoperative Respiratory Complications.

This cohort study evaluates the risk of postoperative respiratory complications among patients with diabetes undergoing surgery who had vs those who had not a prescription fill for glucagon-like peptide 1 receptor agonists.

Use of natural language processing method to identify regional anesthesia from clinical notes.

INTRODUCTION: Accurate data capture is integral for research and quality improvement efforts. Unfortunately, limited guidance for defining and documenting regional anesthesia has resulted in wide variation in documentation practices, even within individual hospitals, which can lead to missing and inaccurate data. This cross-sectional study sought to evaluate the performance of a natural language processing (NLP)-based algorithm developed to identify regional anesthesia within unstructured clinical notes. METHODS: We obtained postoperative clinical notes for all patients undergoing elective non-cardiac surgery with general anesthesia at one of six Veterans Health Administration hospitals in California between January 1, 2017, and December 31, 2022. After developing and executing our algorithm, we compared our results to a frequently used referent, the Corporate Data Warehouse structured data, to assess the completeness and accuracy of the currently available data. Measures of agreement included sensitivity, positive predictive value, false negative rate, and accuracy. RESULTS: We identified 27,713 procedures, of which 9310 (33.6%) received regional anesthesia. 96.6% of all referent regional anesthesia cases were identified in the clinic notes with a very low false negative rate and good accuracy (false negative rate=0.8%, accuracy=82.5%). Surprisingly, the clinic notes documented more than two times the number of regional anesthesia cases that were documented in the referent (algorithm n=9154 vs referent n=4606). DISCUSSION: While our algorithm identified nearly all regional anesthesia cases from the referent, it also identified more than two times as many regional anesthesia cases as the referent, raising concerns about the accuracy and completeness of regional anesthesia documentation in administrative and clinical databases. We found that NLP was a promising alternative for identifying clinical information when existing databases lack complete documentation.

Representation of Real-World Adults With Chronic Kidney Disease in Clinical Trials Supporting Blood Pressure Treatment Targets.

BACKGROUND: Little is known about how well trial participants with chronic kidney disease (CKD) represent real-world adults with CKD. We assessed the population representativeness of clinical trials supporting the 2021 Kidney Disease: Improving Global Outcomes blood pressure (BP) guidelines in real-world adults with CKD. METHODS AND RESULTS: Using a cross-sectional analysis, we identified patients with CKD who met the guideline definition of hypertension based on use of antihypertensive medications or sustained systolic BP ≥120 mm Hg in 2019 in the Veterans Affairs and Kaiser Permanente of Southern California. We applied the eligibility criteria from 3 BP target trials, SPRINT (Systolic Pressure Intervention Trial), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and AASK (African American Study of Kidney Disease), to estimate the proportion of adults with a systolic BP above the guideline-recommended target and the proportion who met eligibility criteria for ≥1 trial. We identified 503 480 adults in the Veterans Affairs and 73 412 adults in Kaiser Permanente of Southern California with CKD and hypertension in 2019. We estimated 79.7% in the Veterans Affairs and 87.3% in the Kaiser Permanente of Southern California populations had a systolic BP ≥120 mm Hg; only 23.8% [23.7%-24.0%] in the Veterans Affairs and 20.8% [20.5%-21.1%] in Kaiser Permanente of Southern California were trial-eligible. Among trial-ineligible patients, >50% met >1 exclusion criteria. CONCLUSIONS: Major BP target trials were representative of fewer than 1 in 4 real-world adults with CKD and hypertension. A large proportion of adults who are at risk for cardiovascular morbidity from hypertension and susceptible to adverse treatment effects lack relevant treatment information.

Plasma proteomic signature of human longevity.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

Evaluating the Sick Quitting Hypothesis for Frailty Status and Reducing Alcohol Use Among People With HIV in a Longitudinal Clinical Cohort Study.

ABSTRACT: "Sick quitting," a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13-2.15]) and reducing (HR: 1.35, 95% CI [1.13-1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20-2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control.

Treatment and Control of Hypertension Among Adults With Chronic Kidney Disease, 2011 to 2019.

BACKGROUND: Hypertension frequently accompanies chronic kidney disease (CKD) as etiology and sequela. We examined contemporary trends in hypertension treatment and control in a national sample of adults with CKD. METHODS: We evaluated 5% cross-sectional samples of adults with CKD between 2011 and 2019 in the Veterans Health Administration. We defined CKD as a sustained estimated glomerular filtration rate value <60 mL/min per 1.73 m2 or a urine albumin-to-creatinine ratio ≥30 mg/g. The main outcomes were blood pressure (BP) control, defined as a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg based on the mean of monthly BP measurements, and prescriptions for antihypertensive medications. RESULTS: The annual samples ranged between n=22 110 and n=33 039 individuals, with a mean age of 72 years, 96% of whom were men. Between 2011 and 2014, the age-adjusted proportion of adults with controlled BP declined from 78.0% to 72.2% (P value for linear trend, <0.001), reached a nadir of 71.0% in 2015, and then increased to 72.9% by 2019 (P value for linear trend, <0.001). Among adults with BP above goal, the age-adjusted proportion who did not receive antihypertensive treatment increased throughout the decade from 18.8% to 21.6%, and the age-adjusted proportion who received ≥3 antihypertensive medications decreased from 41.8% to 36.3%. Prescriptions for first-line antihypertensive agents also decreased. CONCLUSIONS: Among adults with CKD treated in the Veterans Health Administration, the proportion with controlled BP declined between 2011 and 2015 followed by a modest increase, coinciding with fewer prescriptions for antihypertensive medications.

Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10-5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; pprefrailty = 1 × 10-15 , pfrailty = 2 × 10-19 ), transgelin (TAGLN; pprefrailty = 2 × 10-12 , pfrailty = 6 × 10-22 ), and insulin-like growth factor-binding protein 2 (IGFBP2; pprefrailty = 5 × 10-15 , pfrailty = 1 × 10-15 ) and with a lower level of growth hormone receptor (GHR, pprefrailty = 3 × 10-16 , pfrailty = 2 × 10-18 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10-5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

Neighborhood Characteristics and Elevated Blood Pressure in Older Adults.

Importance: The local environment remains an understudied contributor to elevated blood pressure among older adults. Untargeted approaches can identify neighborhood conditions interrelated with racial segregation that drive hypertension disparities. Objective: To evaluate independent associations of sociodemographic, economic, and housing neighborhood factors with elevated blood pressure. Design, Setting, and Participants: In this cohort study, the sample included Health and Retirement Study participants who had between 1 and 3 sets of biennial sphygmomanometer readings from 2006 to 2014 or 2008 to 2016. Statistical analyses were conducted from February 5 to November 30, 2021. Exposures: Fifty-one standardized American Community Survey census tract variables (2005-2009). Main Outcomes and Measures: Elevated sphygmomanometer readings over the study period (6-year period prevalence): a value of at least 140 mm Hg for systolic blood pressure and/or at least 90 mm Hg for diastolic blood pressure. Participants were divided 50:50 into training and test data sets. Generalized estimating equations were used to summarize multivariable associations between each neighborhood variable and the period prevalence of elevated blood pressure, adjusting for individual-level covariates. Any neighborhood factor associated (Simes-adjusted for multiple comparisons P ≤ .05) with elevated blood pressure in the training data set was rerun in the test data set to gauge model performance. Lastly, in the full cohort, race- and ethnicity-stratified associations were evaluated for each identified neighborhood factor on the likelihood of elevated blood pressure. Results: Of 12 946 participants, 4565 (35%) had elevated sphygmomanometer readings (median [IQR] age, 68 [63-73] years; 2283 [50%] male; 228 [5%] Hispanic or Latino, 502 [11%] non-Hispanic Black, and 3761 [82%] non-Hispanic White). Between 2006 and 2016, a lower likelihood of elevated blood pressure was observed (relative risk for highest vs lowest tertile, 0.91; 95% CI, 0.86-0.96) among participants residing in a neighborhood with recent (post-1999) in-migration of homeowners. This association was precise among participants with non-Hispanic White and other race and ethnicity (relative risk, 0.91; 95% CI, 0.85-0.97) but not non-Hispanic Black participants (relative risk, 0.97; 95% CI, 0.85-1.11; P = .48 for interaction) or Hispanic or Latino participants (relative risk, 0.84; 95% CI, 0.65-1.09; P = .78 for interaction). Conclusions and Relevance: In this cohort study of older adults, recent relocation of homeowners to a neighborhood was robustly associated with reduced likelihood of elevated blood pressure among White participants but not their racially and ethnically marginalized counterparts. Our findings indicate that gentrification may influence later-life blood pressure control.

Neighborhood factors and survival to old age: The Jackson Heart Study.

Few studies have evaluated environmental factors that predict survival to old age. Our study included 913 African American participants in the Jackson Heart Study (JHS) who resided in the tri-county area of the Jackson, MS metropolitan area and were 65-80 years at baseline. Participants were followed from 2000 through 2019 for the outcome of survival to 85 years old. We evaluated each of the following census tract-level measures of the social/physical environment as exposures: socioeconomic status, cohesion, violence, disorder, healthy food stores, residential land use, and walkability. We assessed mediation by physical activity and chronic conditions. As a complementary ecologic analysis, we used census-tract data to examine factors associated with a greater life expectancy. A total of 501 (55%) JHS participants survived to age 85 years or older. Higher social cohesion and greater residential land use were modestly associated with survival to old age (risk difference = 25%, 95% CI: 0-49%; and 4%, 95% CI: 1-7%, respectively). These neighborhood effects were modestly mediated through leisure time physical activity; additionally, social cohesion was mediated through home and yard activity. In our ecologic analysis, a greater percentage of homeowners and a greater proportion of people living in partnered families were associated with higher census-tract level life expectancy. African American older adults living in residential neighborhoods or neighborhoods with high social cohesion were more likely to survive to old age.

Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.

INTRODUCTION: Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. METHODS: We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. RESULTS: In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. DISCUSSION: Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

Tobacco Smoking and Pack-Years Are Associated With Frailty Among People With HIV.

BACKGROUND: Tobacco smoking increases frailty risk among the general population and is common among people with HIV (PWH) who experience higher rates of frailty at younger ages than the general population. METHODS: We identified 8608 PWH across 6 Centers for AIDS Research Network of Integrated Clinical Systems sites who completed ≥2 patient-reported outcome assessments, including a frailty phenotype measuring unintentional weight loss, poor mobility, fatigue, and inactivity, and scored 0-4. Smoking was measured as baseline pack-years and time-updated never, former, or current use with cigarettes/day. We used Cox models to associate smoking with risk of incident frailty (score ≥3) and deterioration (frailty score increase by ≥2 points), adjusted for demographics, antiretroviral medication, and time-updated CD4 count. RESULTS: The mean follow-up of PWH was 5.3 years (median: 5.0), the mean age at baseline was 45 years, 15% were female, and 52% were non-White. At baseline, 60% reported current or former smoking. Current (HR: 1.79; 95% confidence interval: 1.54 to 2.08) and former (HR: 1.31; 95% confidence interval: 1.12 to 1.53) smoking were associated with higher incident frailty risk, as were higher pack-years. Current smoking (among younger PWH) and pack-years, but not former smoking, were associated with higher risk of deterioration. CONCLUSIONS: Among PWH, smoking status and duration are associated with incident and worsening frailty.

The association of intensive blood pressure treatment and non-fatal cardiovascular or serious adverse events in older adults with mortality: mediation analysis in SPRINT.

AIMS: Randomized clinical trials of hypertension treatment intensity evaluate the effects on incident major adverse cardiovascular events (MACEs) and serious adverse events (SAEs). Occurrences after a non-fatal index event have not been rigorously evaluated. The aim of this study was to evaluate the association of intensive (<120 mmHg) to standard (<140 mmHg) blood pressure (BP) treatment with mortality mediated through a non-fatal MACE or non-fatal SAE in 9361 participants in the Systolic Blood Pressure Intervention Trial. METHODS AND RESULTS: Logistic regression and causal mediation modelling to obtain direct and mediated effects of intensive BP treatment. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cardiovascular (CVM) and non-CV mortality (non-CVM). The direct effect of intensive treatment was a lowering of ACM [odds ratio (OR) 0.75, 95% confidence interval (CI): 0.60-0.94]. The MACE-mediated effect substantially attenuated (OR 0.96, 95% CI: 0.92-0.99) ACM, while the SAE-mediated effect was associated with increased (OR 1.03, 95% CI: 1.01-1.05) ACM. Similar patterns were noted for intensive BP treatment on CVM and non-CVM. We also noted that SAE incidence was 3.9-fold higher than MACE incidence (13.7 vs. 3.5%), and there were a total of 365 (3.9%) ACM cases, with non-CVM being 2.6-fold higher than CVM [2.81% (263/9361) vs. 1.09% (102/9361)]. The SAE to MACE and non-CVM to CVM preponderance was found across all age groups, with the ≥80-year age group having the highest differences. CONCLUSION: The current analytic techniques demonstrated that intensive BP treatment was associated with an attenuated mortality benefit when it was MACE-mediated and possibly harmful when it was SAE-mediated. Current cardiovascular trial reporting of treatment effects does not allow expansion of the lens to focus on important occurrences after the index event.

The benefit of intensive (<120 mmHg) blood pressure (BP) treatment, reduction in all-cause mortality (ACM), was attenuated when mediated through non-fatal major adverse cardiovascular events. This was driven by cardiovascular mortality (CVM). The harm of intensive BP treatment, increase in ACM, was amplified when mediated through serious adverse events. This was driven by non-CVM. Current reporting of treatment effects in cardiovascular trials does not allow for expansion of the lens to focus on important occurrences after the index event.

Regression discontinuity design to evaluate the effect of statins on myocardial infarction in electronic health records.

Regression discontinuity design (RDD) is a quasi-experimental method intended for causal inference in observational settings. While RDD is gaining popularity in clinical studies, there are limited real-world studies examining the performance on estimating known trial casual effects. The goal of this paper is to estimate the effect of statins on myocardial infarction (MI) using RDD and compare with propensity score matching and Cox regression. For the RDD, we leveraged a 2008 UK guideline that recommends statins if a patient's 10-year cardiovascular disease (CVD) risk score > 20%. We used UK electronic health record data from the Health Improvement Network on 49,242 patients aged 65 + in 2008-2011 (baseline) without a history of CVD and no statin use in the two years prior to the CVD risk score assessment. Both the regression discontinuity (n = 19,432) and the propensity score matched populations (n = 24,814) demonstrated good balance of confounders. Using RDD, the adjusted point estimate for statins on MI was in the protective direction and similar to the statin effect observed in clinical trials, although the confidence interval included the null (HR = 0.8, 95% CI 0.4, 1.4). Conversely, the adjusted estimates using propensity score matching and Cox regression remained in the harmful direction: HR = 2.42 (95% CI 1.96, 2.99) and 2.51 (2.12, 2.97). RDD appeared superior to other methods in replicating the known protective effect of statins with MI, although precision was poor. Our findings suggest that, when used appropriately, RDD can expand the scope of clinical investigations aimed at causal inference by leveraging treatment rules from everyday clinical practice.