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Objective: To evaluate associations between spousal caregiving and mental and physical health among older adults in Mexico., Methods: Data come from the Mexican Health & Aging Study, a national population-based study of adults ≥50 years and their spouses (2001-2015). We compared outcomes for spousal caregivers to outcomes for those whose spouses had difficulty with at least one basic or instrumental activity of daily living (I/ADL) but were not providing care; the control group conventionally includes all married respondents regardless of spouse's need for care. We used targeted maximum likelihood estimation to evaluate the associations with past-week depressive symptoms, lower-body functional limitations, and chronic health conditions., Results: At baseline, 846 women and 629 men had a spouse with ≥1 I/ADL. Of these, 60.9% of women and 52.6% of men were spousal caregivers. Spousal caregiving was associated with more past-week depressive symptoms for men (Marginal Risk Difference (RD): 0.27, 95% confidence internal [CI]: 0.03, 0.51) and women (RD: 0.15, 95% CI: 0.07, 0.23). We could not draw conclusions about associations with lower-body functional limitations and chronic health conditions. On average, all respondents whose spouses had caregiving needs had poorer health than the overall sample., Conclusion: We found evidence of an association between spousal caregiving and mental health among older Mexican adults with spouses who had need for care. However, our findings suggest that older adults who are both currently providing or at risk of providing spousal care may need targeted programs and policies to support health and long-term care needs., (© 2020 John Wiley & Sons Ltd.)

Background and Purpose: Findings from the Framingham Heart Study suggest that declines in dementia incidence rates over recent decades are partially due to decreases in stroke incidence and mortality; however, whether trends of declining dementia rates extend to survivors of incident stroke remains unclear. We investigated evidence for temporal trends in memory change related to incident stroke in a nationally representative cohort., Methods: Adults age 50+ in the HRS (Health and Retirement Study) were followed across three successive 6-year epochs (epoch 1: 1998-2004, n=16 781; epoch 2: 2004-2010, n=15 345; and epoch 3: 2010-2016; n=15 949). Participants were included in an epoch if they were stroke-free at the start of that epoch. Annual rates of change in a composite z-standardized memory score were compared using demographic-adjusted linear regression models for stroke-free participants, those who survived after stroke, and those who died after stroke, considering memory change before stroke, at the time of stroke, and for years following stroke., Results: Crude stroke incidence rates decreased from 8.5 per 1000 person-years in epoch 1 to 6.8 per 1000 person-years in epoch 3. Rates of memory change before and following stroke onset were similar across epochs. Memory decrement immediately after stroke onset attenuated from -0.37 points (95% CI, -0.44 to -0.29) in epoch 1 to -0.26 (95% CI, -0.33 to -0.18) points in epoch 2 and -0.25 (95% CI, -0.33 to -0.17) points in epoch 3 ( P value for linear trend=0.02)., Conclusions: Decreases in stroke-related dementia in recent years may be partially attributable to smaller memory decrements immediately after stroke onset. Findings suggest reductions in stroke incidence and improvements in stroke care may also reduce population burden of dementia. Further investigations into whether temporal trends are attributable to improvements in stroke care are needed.

Evidence for Action (E4A), a signature program of the Robert Wood Johnson Foundation, funds investigator-initiated research on the impacts of social programs and policies on population health and health inequities. Across thousands of letters of intent and full proposals E4A has received since 2015, one of the most common methodological challenges faced by applicants is selecting realistic effect sizes to inform calculations of power, sample size, and minimum detectable effect (MDE). E4A prioritizes health studies that are both (1) adequately powered to detect effect sizes that may reasonably be expected for the given intervention and (2) likely to achieve intervention effects sizes that, if demonstrated, correspond to actionable evidence for population health stakeholders. However, little guidance exists to inform the selection of effect sizes for population health research proposals. We draw on examples of five rigorously evaluated population health interventions. These examples illustrate considerations for selecting realistic and actionable effect sizes as inputs to calculations of power, sample size and MDE for research proposals to study population health interventions. We show that plausible effects sizes for population health interventions may be smaller than commonly cited guidelines suggest. Effect sizes achieved with population health interventions depend on the characteristics of the intervention, the target population, and the outcomes studied. Population health impact depends on the proportion of the population receiving the intervention. When adequately powered, even studies of interventions with small effect sizes can offer valuable evidence to inform population health if such interventions can be implemented broadly. Demonstrating the effectiveness of such interventions, however, requires large sample sizes., Competing Interests: The authors have no competing interests to declare., (© 2021 The Author(s).)

Introduction: Educational attainment is associated with late-life cognitive performance and dementia; few studies have examined diverse racial/ethnic groups to assess whether the association differs by race/ethnicity., Methods: We investigated whether the association between educational attainment and cognition differed between White, Black, Asian, and Latino participants in the Kaiser Healthy Aging and Diverse Life Experiences study (n=1348). Covariate-adjusted multivariable linear regression models examined domains of verbal episodic memory, semantic memory, and executive functioning., Results: We observed significant effect heterogeneity by race/ethnicity only for verbal episodic memory (P=0.0198), for which any schooling between high school and college was beneficial for White, Asian, and Black participants, but not Latino participants. We found no evidence of heterogeneity for semantic memory or executive function., Discussion: With the exception of Latino performance on verbal episodic memory, more education consistently predicted better cognitive scores to a similar extent across racial/ethnic groups, despite likely heterogenous educational and social experiences., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence., Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence., Design, Setting, and Participants: This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020., Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender., Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival., Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women)., Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.

Importance: In the US, dementia risk is higher in non-Hispanic Black individuals than in non-Hispanic White individuals. To evaluate progress toward reducing such disparities, tracking secular trends in racial disparities in dementia prevalence is essential., Objective: To examine whether relative racial disparities in dementia prevalence or incidence have changed in the US from 2000 to 2016., Design, Settings, and Participants: The Health and Retirement Study (HRS) is a nationally representative study of adults 50 years or older. New participants are recruited every 6 years, and study visits occur biennially. Approximately 17 000 to 22 000 respondents have been surveyed at each wave since 2000, achieving response rates of 81% to 89%. Data for this cohort study were obtained from non-Hispanic White and non-Hispanic Black participants aged 70 years and older from the 2000 to 2016 waves. For analyses of secular trends in racial disparities in dementia prevalence, each HRS wave was considered separately (range of participants meeting eligibility criteria in each wave, 6322-7579). For analyses of secular trends in racial disparities in dementia incidence, 7 subcohorts were created (range of participants meeting eligibility criteria in each subcohort, 5322-5961) following up people without dementia for 4 years from subcohort baseline visits in 2000, 2002, 2004, 2006, 2008, 2010, and 2012. Data were analyzed from October 2019 to August 2020., Exposures: Race based on self-response to closed-ended survey questions., Main Outcomes and Measures: Dementia status was determined using 3 algorithms with similar sensitivity and specificity across non-Hispanic White and Black participants. Disparities were characterized using ratio measures., Results: In this study, the mean age and percentage of male participants eligible for inclusion in analyses of racial disparities in dementia prevalence increased over time among non-Hispanic White participants (from 78.2 years and 40% in 2000 to 78.7 years and 44% in 2016) but remained steady in non-Hispanic Black participants during the same period (from 78.0 years and 37% in 2000 to 77.9 years and 38% in 2016). Prevalence ratios comparing Black and White participants ranged from approximately 1.5 to 1.9 across algorithms and years, whereas hazard ratios ranged from approximately 1.4 to 1.8. Although results suggest stable or declining dementia risk overall, there was no evidence suggesting change in relative racial disparities in dementia prevalence or incidence during follow-up., Conclusions and Relevance: This study did not find evidence to suggest that the ratio of dementia risk across Black and White individuals changed in the US between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.

Objective: Retirement is a potential trigger for cognitive aging as it may be a stressful life event accompanied by changes in everyday activities. However, the consequences of retirement may differ across institutional contexts which shape retirement options. Comparing memory trajectories before and after retirement in 17 European countries, this study aims to identify cross-national differences in the association between retirement and memory decline., Method: Respondents to the longitudinal Survey of Health, Aging, and Retirement in Europe (SHARE; N = 8,646) aged 50+ who were in paid work at baseline and retired during the observation period completed up to 6 memory assessments (immediate and delayed word recall) over 13 years. Three-level (time points, individuals, and countries) linear mixed models with country-level random slopes for retirement were estimated to evaluate whether memory decline accelerated after retirement and if this association differed between countries., Results: On average, retirement was associated with a moderate decrement in word recall (b = -0.273, 95% CI -0.441, -0.104) and memory decline accelerated after retirement (b = -0.044, 95% CI -0.070, -0.018). Significant between-country heterogeneity in memory decline after retirement existed (variance = 0.047, 95% CI (0.013, 0.168). Memory decline after retirement was more rapid in Italy, Greece, Czech Republic, Poland, Portugal, and Estonia compared to Northern and Central European countries., Discussion: Memory decline postretirement was faster in Mediterranean and eastern European countries, which are characterized by less generous welfare systems with comparatively low pension benefits. Evaluation of resources that could protect retirees from memory decline would be valuable., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The objective of the current study is to investigate whether an area-level measure of racial sentiment derived from Twitter data is associated with state-level hate crimes and existing measures of racial prejudice at the individual-level., Methods: We collected 30,977,757 tweets from June 2015-July 2018 containing at least one keyword pertaining to specific groups (Asians, Arabs, Blacks, Latinos, Whites). We characterized sentiment of each tweet (negative vs all other) and averaged at the state-level. These racial sentiment measures were merged with other measures based on: hate crime data from the FBI Uniform Crime Reporting Program; implicit and explicit racial bias indicators from Project Implicit; and racial attitudes questions from General Social Survey (GSS)., Results: Living in a state with 10% higher negative sentiment in tweets referencing Blacks was associated with 0.57 times the odds of endorsing a GSS question that Black-White disparities in jobs, income, and housing were due to discrimination (95% CI: 0.40, 0.83); 1.64 times the odds of endorsing the belief that disparities were due to lack to will (95% CI: 0.95, 2.84); higher explicit racial bias (β: 0.11; 95% CI: 0.04, 0.18); and higher implicit racial bias (β: 0.09; 95% CI: 0.04, 0.14). Twitter-expressed racial sentiment was not statistically-significantly associated with incidence of state-level hate crimes against Blacks (IRR: 0.99; 95% CI: 0.52, 1.90), but this analysis was likely underpowered due to rarity of reported hate crimes., Conclusion: Leveraging timely data sources for measuring area-level racial sentiment can provide new opportunities for investigating the impact of racial bias on society and health., Competing Interests: Authors declare no conflicts of interest., (© 2021 The Author(s).)

Objectives: Evidence on adverse childhood experiences (ACEs) and late-life cognitive outcomes is inconsistent, with little research among diverse racial/ethnic groups. We investigated whether ACE exposures were associated with worse late-life cognition for all racial/ethnic groups and at different ages of exposure., Design: Covariate-adjusted mixed-effects linear regression models estimated associations of: (1) total number of ACEs experienced, (2) earliest age when ACE occurred and (3) type of ACE with overall cognition., Setting: Kaiser Permanente Northern California members aged 65 years and older, living in Northern California., Participants: Kaiser Healthy Aging and Diverse Life Experiences study baseline participants, aged 65 years and older (n=1661; including 403 Asian-American, 338 Latino, 427 Black and 493 white participants)., Results: Most respondents (69%) reported one or more ACE, most frequently family illness (36%), domestic violence (23%) and parental divorce (22%). ACE count was not adversely associated with cognition overall (β=0.01; 95% CI -0.01 to 0.03), in any racial/ethnic group or for any age category of exposure. Pooling across all race/ethnicities, parent's remarriage (β=-0.11; 95% CI -0.20 to -0.03), mother's death (β=-0.18; 95% CI -0.30 to -0.07) and father's death (β=-0.11; 95% CI -0.20 to -0.01) were associated with worse cognition., Conclusion: Adverse childhood exposures overall were not associated with worse cognition in older adults in a diverse sample, although three ACEs were associated with worse cognitive outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Evaluating the long-term health consequences of migration requires longitudinal data on migrants and non-migrants to facilitate adjustment for time-varying confounder-mediators of the effect of migration on health., Methods: We merged harmonized data on subjects aged 50+ from the US-based Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS). Our exposed group includes MHAS-return migrants (n = 1555) and HRS Mexican-born migrants (n = 924). Our unexposed group includes MHAS-never migrants (n = 16,954). We constructed a lifecourse data set from birth (age 0) until either age at migration to the United States or age at study entry. To account for confounding via inverse probability of treatment weights (IPTW), we modeled the probability of migration at each year of life using time-varying pre-migration characteristics. We then evaluated the effect of migration on mortality hazard estimated with and without IPTW., Results: Mexico to the United States migration was predicted by time-varying factors that occurred before migration. Using measured covariates at time of enrollment to account for selective migration, we estimated that, for women, migrating reduces mortality risk by 13%, although this estimate was imprecise and results were compatible with either large protective or deleterious associations (hazard ratio [HR] =0.87, 95% confidence interval [CI]: 0.60, 1.27). When instead using IPTWs, the estimated effect on mortality was similarly imprecise (HR = 0.98, 95% CI: 0.77, 1.25). The relationship among men was similarly uncertain in both models., Conclusions: Although time-varying social factors predicted migration, IPTW weighting did not affect our estimates. Larger samples are needed to precisely estimate the health effects of migration.

Growing evidence has suggested an association between sleep duration and Alzheimer's disease (AD), but it is unclear if sleep duration is a manifestation of the AD disease process. We studied whether genetic liability for AD predicts sleep duration using a genetic risk score (GRS) for AD (AD-GRS), in 406,536 UK Biobank participants with European ancestry and without dementia at enrollment. Higher AD-GRS score was associated with shorter sleep (b = -0.014, 95% confidence interval [CI] = -0.022 to -0.006), especially in those aged 55+. Using AD-GRS as an instrumental variable for AD diagnosis, incipient AD reduced sleep duration by 1.87 hours (95% CI = 0.96, 2.78). Short sleep duration might be an early marker of AD. ANN NEUROL 2021;89:177-181., (© 2020 American Neurological Association.)

Background: The authors assessed the cross-sectional association of physical function measures with cognition in the Kaiser Healthy Aging and Diverse Life Experiences Cohort., Methods: Analyses included 1369 participants (24% Asian, 26% Black, 18% Latino, 32% White). Grip strength was measured using a hand-held dynamometer (kilograms) and gait speed was measured over a 4-m walk (seconds/meter). The Spanish and English Neuropsychological Assessment Scales was used to evaluate cognitive domains of executive function, semantic memory, and verbal episodic memory. Physical function measures (per SD) were associated with cognitive test z-scores in linear regression models adjusted for demographic, behavioral, and clinical factors. Racial/ethnic differences were tested using interaction terms and stratification., Results: Stronger grip was associated with better executive function [β=0.10 (95% confidence interval, 0.05-0.15)], semantic memory [β=0.13 (0.09-0.18)] and verbal episodic memory [β=0.07 (0.02-0.13)] with no racial/ethnic differences. Faster gait was associated with better executive function [β=0.29 (0.22-0.36)], semantic memory [β=0.23 (0.16-0.30)], and verbal episodic memory [β=0.20 (0.13-0.27)]; however, the association between gait speed and executive function varied by race/ethnicity with the strongest associations in Asians and Whites., Conclusion: Across race/ethnicity, grip strength and gait speed were associated with cognition with racial/ethnic differences in the association of gait speed and executive function., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Among older people living with HIV (PLWH) and comparable individuals without HIV, we evaluated whether associations of HIV and antiretroviral therapy (ART) with disability depend on body mass index (BMI). Methods: We analyzed 4552 participants in the "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa." (HAALSI) We compared prevalence of disability (≥1 impairment in basic activities of daily living) by HIV status, ART use, and BMI category, adjusting for age, sex, education, father's occupation, country of origin, lifetime alcohol use, and primary health-care utilization. Results: Among PLWH, those underweight had 9.8% points (95% confidence interval (CI): 1.2 to 18.4) higher prevalence of disability than those with normal BMI. Among ART users, those underweight had 11.9% points (95% CI: 2.2 to 21.6) higher prevalence of disability than those with normal BMI. Conclusions: We found no evidence that weight improvement associated with ART use is likely to increase disability.

Introduction: We evaluated whether competing risk of death or selective survival could explain the reported inverse association between cancer history and dementia incidence (incidence rate ratio [IRR] ≈ 0.62-0.85)., Methods: A multistate simulation model of a cancer- and dementia-free cohort of 65-year-olds was parameterized with real-world data (cancer and dementia incidence, mortality), assuming no effect of cancer on dementia (true IRR = 1.00). To introduce competing risk of death, cancer history increased mortality. To introduce selective survival, we included a factor (prevalence ranging from 10% to 50%) that reduced cancer mortality and dementia incidence (IRRs ranged from 0.30 to 0.90). We calculated IRRs for cancer history on dementia incidence in the simulated cohorts., Results: Competing risk of death yielded unbiased cancer-dementia IRRs. With selective survival, bias was small (IRRs = 0.89 to 0.99), even under extreme scenarios., Discussion: The bias induced by selective survival in simulations was too small to explain the observed inverse cancer-dementia link, suggesting other mechanisms drive this association., (© 2020 the Alzheimer's Association.)

There is a lack of empirical, prospective human data on the gut microbiome and its relationship with growth, especially in low- and middle-income countries. We prospectively assessed the association between gut microbial diversity and short-term growth in a cohort of preschool children in Burkina Faso to better characterize whether there is any evidence that changes in gut microbial diversity may affect growth. Data were obtained from a randomized controlled trial evaluating the effect of antibiotic administration on gut microbial diversity in preschool children. We followed up the enrolled children for 35 days, with anthropometric measurements at baseline and day 35 and microbial diversity measured at baseline and day 9 (analytic sample, N = 155). We estimated linear mixed-effects regression models with household random intercepts to assess the association of Simpson's and Shannon's alpha diversity with measures of change in anthropometry (e.g., ponderal growth since baseline) and absolute anthropometric measurements (e.g., day 35 weight). We did not find evidence that alpha gut microbial diversity was associated with growth or absolute anthropometric measurements after adjusting for confounding variables. Effect estimates were close to the null ( P ≥ 0.15 for all fully adjusted comparisons), with the association between Simpson's alpha diversity and day 35 height (cm) farthest from the null (coefficient = -0.03, 95% CI: -0.07, 0.01). The change in gut microbial diversity also was not associated with the change in anthropometry in crude or adjusted models. Future research is needed to explore whether gut diversity has an impact on growth over a longer time period, in both healthy and malnourished children.

Mounting evidence reveals considerable racial inequities in coronavirus disease 2019 (COVID-19) outcomes in the United States (US). Area-level racial bias has been associated with multiple adverse health outcomes, but its association with COVID-19 is yet unexplored. Combining county-level data from Project Implicit on implicit and explicit anti-Black bias among non-Hispanic Whites, Johns Hopkins Coronavirus Resource Center, and The New York Times , we used adjusted linear regressions to estimate overall COVID-19 incidence and mortality rates through 01 July 2020, Black and White incidence rates through 28 May 2020, and Black-White incidence rate gaps on average area-level implicit and explicit racial bias. Across 2994 counties, the average COVID-19 mortality rate (standard deviation) was 1.7/10,000 people (3.3) and average cumulative COVID-19 incidence rate was 52.1/10,000 (77.2). Higher racial bias was associated with higher overall mortality rates (per 1 standard deviation higher implicit bias b = 0.65/10,000 (95% confidence interval: 0.39, 0.91); explicit bias b = 0.49/10,000 (0.27, 0.70)) and higher overall incidence (implicit bias b = 8.42/10,000 (4.64, 12.20); explicit bias b = 8.83/10,000 (5.32, 12.35)). In 957 counties with race-specific data, higher racial bias predicted higher White and Black incidence rates, and larger Black-White incidence rate gaps. Anti-Black bias among Whites predicts worse COVID-19 outcomes and greater inequities. Area-level interventions may ameliorate health inequities.

Importance: Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed., Objectives: To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD., Data Sources: All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020., Study Selection: Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history., Data Extraction and Synthesis: Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline., Main Outcomes and Measures: Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis., Results: In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value., Conclusions and Relevance: The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.

Nontraditional education trajectories are common, but their influence on physical health is understudied. We constructed year-by-year education trajectories for 7,501 National Longitudinal Survey of Youth 1979 participants aged 14 to 48 years (262,535 person-years of education data from 1979 to 2014). We characterized trajectory similarity using sequence analysis and used hierarchical clustering to group similar educational trajectories. Using linear regression, we predicted physical health summary scores of the participants at age 50 years from the 12-item Short-Form Survey, adjusting for available confounders, and evaluated effect modification by sex, race/ethnicity, and childhood socioeconomic status. We identified 24 unique educational sequence clusters on the basis of highest level of schooling and attendance timing. General education development credentials predicted poorer health than did high school diplomas (β = -3.07, 95% confidence interval: -4.07, -2.07), and bachelor's degrees attained at earlier ages predicted better health than the same degree attained at later ages (β = 1.66, 95% confidence interval: 0.05, 3.28). Structurally marginalized groups benefited more from some educational trajectories than did advantaged groups (e.g., Black vs. White Americans with some college; those of low vs. high childhood socioeconomic status who received an associate's or bachelor's degree). Both type and timing of educational credentials may influence physical health. Literature to date has likely underestimated the impact of educational trajectories on health., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/objectives: Several longitudinal studies in high-income countries suggest that depression increases stroke risk. However, few prior studies have evaluated this association in low- and middle-income countries (LMICs), where rapidly aging populations may have markedly different vascular risk profiles., Design: Prospective cohort study., Setting: The Mexican Health and Aging Study is a national population-based study of older adults in Mexico., Participants: A total of 10,693 Mexican adults aged 50 and older enrolled in 2001 with no history of prior stroke., Measurements: Depressive symptoms were assessed with a modified 9-item Centers for Epidemiologic Studies Depression Scale (elevated depressive symptom cutoff ≥5) in 2001 and 2003. We evaluated associations between baseline and short-term (2-year) changes in elevated depressive symptoms (categorized as stable low, recently remitted, recent-onset, or stable high symptoms) with incident self-reported or next-of-kin reported doctor-diagnosed stroke through 2015 using Cox proportional hazards models and sensitivity analyses applying inverse probability weights., Results: Over an average follow-up of 11.4 years (standard deviation = 4.2), 10,693 respondents reported 546 incident strokes. Individuals with elevated baseline depressive symptoms experienced a moderately higher hazard of incident stroke (hazard ratio [HR] = 1.13; 95% confidence interval [CI] = .95-1.36) compared with those without elevated baseline depressive symptoms. In analyses of short-term changes in elevated depressive symptoms (n = 8,808; 414 incident stokes), participants with recent-onset (HR = 1.38; 95% CI = 1.06-1.81) or stable high (HR = 1.42; 95% CI = 1.10-1.84) elevated depressive symptoms had a greater hazard of incident stroke compared to those with stable low/no depressive symptoms, whereas recently remitted (HR = 1.01; 95% CI = .74-1.37) symptoms was not associated with stroke hazard., Conclusion: Strategies to reduce depressive symptoms merit evaluation as approaches to prevent stroke in middle-income countries. Findings are similar to those in high-income countries but should be replicated in other LMICs., (© 2020 The American Geriatrics Society.)

Objective: To test the hypothesis that incipient Alzheimer disease (AD) may adversely affect hearing and that hearing loss may adversely affect cognition, we evaluated whether genetic variants that increase AD risk also increase problem hearing and genetic variants that increase hearing impairment risk do not influence cognition., Methods: UK Biobank participants without dementia ≥56 years of age with Caucasian genetic ancestry completed a Digit Triplets Test of speech-in-noise hearing (n = 80,074), self-reported problem hearing and hearing with background noise (n = 244,915), and completed brief cognitive assessments. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related polymorphisms. A genetic risk score for hearing (hearing-GRS) was calculated using 3 previously identified polymorphisms related to hearing impairment. Using age-, sex-, and genetic ancestry-adjusted logistic and linear regression models, we evaluated whether the AD-GRS predicted poor hearing and whether the hearing-GRS predicted worse cognition., Results: Poor speech-in-noise hearing (>-5.5-dB speech reception threshold; prevalence 14%) was associated with lower cognitive scores (ß = -1.28; 95% confidence interval [CI] -1.54 to -1.03). Higher AD-GRS was significantly associated with poor speech-in-noise hearing (odds ratio [OR] 1.06; 95% CI 1.01-1.11) and self-reported problems hearing with background noise (OR 1.03; 95% CI 1.00-1.05). Hearing-GRS was not significantly associated with cognitive scores (ß = -0.05; 95% CI -0.17 to 0.07)., Conclusions: Genetic risk for AD also influences speech-in-noise hearing. We failed to find evidence that genetic risk for hearing impairment affects cognition. AD disease processes or a that shared etiology may cause speech-in-noise difficulty before dementia onset., (© 2020 American Academy of Neurology.)

Previous clinical studies have reported adverse cognitive outcomes for people living with HIV (PLWH), but there are no population-based studies comparing cognitive function between older PLWH and comparators without HIV in sub-Saharan Africa. We analyzed baseline data of 40 + years-old participants in "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) cohort. We measured cognition using a battery of conventional instruments assessing orientation, immediate- and delayed-recall, and numeracy (N = 4560), and the Oxford Cognitive Screen [OCS]-Plus, a novel instrument for low-literacy populations, assessing memory, language, visual-spatial ability, and executive functioning (N = 1997). Linear regression models comparing cognitive scores between participants with and without HIV were adjusted for sex, education, age, country of birth, father's occupation, ever-consumed alcohol, and asset index. PLWH scored on average 0.06 (95% CI 0.01-0.12) standard deviation (SD) units higher on the conventional cognitive function measure and 0.02 (95% CI - 0.07 to 0.04) SD units lower on the OCS-Plus measure than HIV-negative participants. We found higher cognitive function scores for PLWH compared to people without HIV when using a conventional measure of cognitive function but not when using a novel instrument for low-literacy settings.

Background: Anecdotal reports suggest a rise in anti-Asian racial attitudes and discrimination in response to COVID-19. Racism can have significant social, economic, and health impacts, but there has been little systematic investigation of increases in anti-Asian prejudice. Methods: We utilized Twitter's Streaming Application Programming Interface (API) to collect 3,377,295 U.S. race-related tweets from November 2019-June 2020. Sentiment analysis was performed using support vector machine (SVM), a supervised machine learning model. Accuracy for identifying negative sentiments, comparing the machine learning model to manually labeled tweets was 91%. We investigated changes in racial sentiment before and following the emergence of COVID-19. Results: The proportion of negative tweets referencing Asians increased by 68.4% (from 9.79% in November to 16.49% in March). In contrast, the proportion of negative tweets referencing other racial/ethnic minorities (Blacks and Latinx) remained relatively stable during this time period, declining less than 1% for tweets referencing Blacks and increasing by 2% for tweets referencing Latinx. Common themes that emerged during the content analysis of a random subsample of 3300 tweets included: racism and blame (20%), anti-racism (20%), and daily life impact (27%). Conclusion: Social media data can be used to provide timely information to investigate shifts in area-level racial sentiment.

Objective: To examine whether neuropathologic burden is associated with hearing impairment., Methods: We studied 2,755 autopsied participants ≥55 years of age from the National Alzheimer's Coordinating Center database. Participants had at least 1 clinical evaluation at US National Institute on Aging-funded Alzheimer's Disease Center no more than 2 years before death. Patients were classified as hearing impaired by clinician report at baseline. Common dementia neuropathologies included Alzheimer disease pathologic change (Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density, neurofibrillary degeneration Braak stage), Lewy body disease, gross infarcts, and microinfarcts. Logistic regression models predicted impaired hearing with adjustment for age at death, sex, race, education, center, and follow-up time. Relative risks were calculated with the use of marginal standardization., Results: Impaired hearing was common (32%). In participants who were cognitively normal at baseline (n = 580), impaired hearing was associated with higher Braak stage (relative risk [RR] 1.33 per 2-stage increase, 95% confidence interval [CI] 1.06-1.66) but not other pathologies. In participants with dementia (n = 2,175), impaired hearing was positively associated with microinfarcts (RR 1.18, 95% CI 1.00-1.39) and inversely associated with neuritic plaque density (RR 0.91 per score increase, 95% CI 0.85-0.99). Development of impaired hearing in those with cognitive impairment was associated with neocortical Lewy bodies (1.26, 95% CI 1.02-1.55)., Conclusions: Impaired hearing, reported before the onset of cognitive impairment, was associated with increased neurofibrillary tangle burden. Impaired hearing in those with cognitive impairment was associated with microinfarcts and neocortical Lewy bodies but not typical Alzheimer disease pathologic change. Functional hearing problems may be a preclinical marker of neurofibrillary neurodegeneration, although replication is needed., (© 2020 American Academy of Neurology.)

Background: An association between education and dementia is well-established but it is unclear whether education is associated with dementia after accounting for early life cognitive ability and whether there is a joint effect, such that the risk associated with one of the exposures depends on the value of the other. We examined separate and joint associations of adolescent cognitive ability and educational attainment with risk of dementia among Danish men born between 1939 and 1959., Methods: Men (N = 477,421) from the Danish Conscription Database were followed for dementia from the age 60 for up to 17 years via patient and prescription registry linkages. Exposure measures included cognitive ability assessed at the conscript board examination around age 18 and highest educational level (low: 0-10 year, medium: 10-13 years, high: ≥13 years) at age 30 from registry records. Associations with dementia diagnosis were estimated in Cox proportional hazards models adjusted for birth year and age at conscript board examination. Interaction was assessed on the multiplicative scale by including a product term between the two exposure measures and on the additive scale by calculating relative excess risk due to interaction (RERI) between different levels of the exposure measures., Results: Compared to men in the high education group hazard ratio [HR] for men in the medium and low group were 1.21 (95% confidence interval [CI]: 1.13, 1.30) and 1.34 (95% CI: 1.24, 1.45), respectively when not adjusting for cognitive ability. Additional adjustment for cognitive ability attenuated the magnitude of the associations, but they remained significant (education medium: HR = 1.10, 95% CI: 1.02, 1.19 and education low: HR = 1.12, 95% CI: 1.02, 1.22). A 10% higher cognitive ability score was associated with a 3.8% lower hazard of dementia (HR = 0.962; 95% CI: 0.957, 0.967), and the magnitude of the association only changed marginally after adjustment for education. Men in the low education group with relatively low cognitive ability were identified as a high-risk subgroup for dementia. The increased risk associated with exposure to both risk factors did, however, not significantly depart from the sum of risk experienced by men only exposed to one of the risk factors (estimates of RERI were not significantly different from 0) and no significant evidence of either additive or multiplicative interactions was found., Conclusions: In conclusion, the results suggest that education and cognitive ability protect against the risk of dementia independently of one another and that increases in educational attainment may at least partially offset dementia risk due to low cognitive ability., Competing Interests: The authors have declared that no competing interests exist.

Introduction: There is limited research on difficulties with activities of daily living (I/ADLs) among older adults living alone with cognitive impairment, including differences by race/ethnicity., Methods: For U.S. Health and Retirement Study (2000-2014) participants aged 55+ living alone with cognitive impairment (4,666 individuals; 9,091 observations), we evaluated I/ADL difficulty and help., Results: Among 4.3 million adults aged 55+ living alone with cognitive impairment, an estimated 46% reported an I/ADL difficulty; 72% reported not receiving help with an I/ADL. Women reported more difficulty than men. Compared to white women, black women were 22% more likely to report a difficulty without help, and Latina women were 36% more likely to report a difficulty with help. Among men, racial/ethnic differences in outcomes were not significant. Patterns of difficulty without help by race/ethnicity were similar among Medicaid beneficiaries., Discussion: Findings call for targeted efforts to support older adults living alone with cognitive impairment., (© 2020 the Alzheimer's Association.)

Cognitive abilities are important predictors of educational and occupational performance, socioeconomic attainment, health, and longevity. Declines in cognitive abilities are linked to impairments in older adults' everyday functions, but people differ from one another in their rates of cognitive decline over the course of adulthood and old age. Hence, identifying factors that protect against compromised late-life cognition is of great societal interest. The number of years of formal education completed by individuals is positively correlated with their cognitive function throughout adulthood and predicts lower risk of dementia late in life. These observations have led to the propositions that prolonging education might (a) affect cognitive ability and (b) attenuate aging-associated declines in cognition. We evaluate these propositions by reviewing the literature on educational attainment and cognitive aging, including recent analyses of data harmonized across multiple longitudinal cohort studies and related meta-analyses. In line with the first proposition, the evidence indicates that educational attainment has positive effects on cognitive function. We also find evidence that cognitive abilities are associated with selection into longer durations of education and that there are common factors (e.g., parental socioeconomic resources) that affect both educational attainment and cognitive development. There is likely reciprocal interplay among these factors, and among cognitive abilities, during development. Education-cognitive ability associations are apparent across the entire adult life span and across the full range of education levels, including (to some degree) tertiary education. However, contrary to the second proposition, we find that associations between education and aging-associated cognitive declines are negligible and that a threshold model of dementia can account for the association between educational attainment and late-life dementia risk. We conclude that educational attainment exerts its influences on late-life cognitive function primarily by contributing to individual differences in cognitive skills that emerge in early adulthood but persist into older age. We also note that the widespread absence of educational influences on rates of cognitive decline puts constraints on theoretical notions of cognitive aging, such as the concepts of cognitive reserve and brain maintenance. Improving the conditions that shape development during the first decades of life carries great potential for improving cognitive ability in early adulthood and for reducing public-health burdens related to cognitive aging and dementia.

Importance: Neighborhood-level residential segregation is implicated as a determinant for poor health outcomes in black individuals, but it is unclear whether this association extends to cognitive aging, especially in midlife., Objective: To examine the association between cumulative exposure to residential segregation during 25 years of young adulthood among black individuals and cognitive performance in midlife., Design, Setting, and Participants: The ongoing prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) Study recruited 5115 black and white participants aged 18 to 30 years from 4 field centers at the University of Alabama, Birmingham; University of Minnesota, Minneapolis; Northwestern University, Chicago, Illinois; and Kaiser Permanente, Oakland, California. Data were acquired from February 1985 to May 2011. Among the surviving CARDIA cohort, 3671 (71.8%) attended examination year 25 of the study in 2010, when cognition was measured, and 3008 (81.9%) of those completed the cognitive assessments. To account for time-varying confounding and differential censoring, marginal structural models using inverse probability weighting were applied. Data were analyzed from April 16 to July 20, 2019., Main Outcomes and Measures: Racial residential segregation was measured using the Getis-Ord Gi* statistic, and the mean cumulative exposure to segregation was calculated across 6 follow-up visits from baseline to year 25 of the study, then categorized into high, medium, and low segregation. Cognitive function was measured at year 25 of the study, using the Digit Symbol Substitution Test (DSST), Stroop color test (reverse coded), and Rey Auditory Verbal Learning Test. To facilitate comparison of estimates, z scores were calculated for all cognitive tests., Results: A total of 1568 black participants with available cognition data were included in the analysis. At baseline, participants had a mean (SD) age of 25 (4) years and consisted of 936 women (59.7%). Greater cumulative exposure to segregated neighborhoods was associated with a worse DSST z score (for high segregation, β = -0.37 [95% CI, -0.61 to -0.13]; for medium segregation, β = -0.25 [95% CI, -0.51 to 0.0002]) relative to exposure to low segregation., Conclusions and Relevance: In this cohort study, exposure to residential segregation throughout young adulthood was associated with worse processing speed among black participants as early as in midlife. This association may potentially explain black-white disparities in dementia risk at older age.

Low- and middle-income countries (LMICs) are experiencing rapid aging, a growing dementia burden, and relatively high rates of out-migration among working-age adults. Family member migration status may be a unique societal determinant of cognitive aging in LMIC settings. We aimed to evaluate the association between adult child US migration status and change in cognitive performance scores using data from the Mexican Health and Aging Study, a population-based, national-level cohort study of Mexico adults aged ≥50 years at baseline (2001), with 2-, 12-, and 14-year follow-up waves (2003, 2012, and 2015). Cognitive performance assessments were completed by 5,972 and 4,939 respondents at 11 years and 14 years of follow-up, respectively. For women, having an adult child in the United States was associated with steeper decline in verbal memory scores (e.g., for 9-year change in immediate verbal recall z score, marginal risk difference (RD) = -0.09 (95% confidence interval (CI): -0.16, -0.03); for delayed verbal recall z score, RD = -0.10 (95% CI: -0.17, -0.03)) and overall cognitive performance (for overall cognitive performance z score, RD = -0.04, 95% CI: -0.07, -0.00). There were mostly null associations for men. To our knowledge, this is the first study to have evaluated the association between family member migration status and cognitive decline; future work should be extended to other LMICs facing population aging., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Women with advanced HER2- breast cancer have limited treatment options. Breast MRI functional tumor volume (FTV) is used to predict pathologic complete response (pCR) to improve treatment efficacy. In addition to FTV, background parenchymal enhancement (BPE) may predict response and was explored for HER2- patients in the I-SPY-2 TRIAL., Methods: Women with HER2- stage II or III breast cancer underwent prospective serial breast MRIs during four neoadjuvant chemotherapy timepoints. BPE was quantitatively calculated using whole-breast manual segmentation. Logistic regression models were systematically explored using pre-specified and optimized predictor selection based on BPE or combined with FTV., Results: A total of 352 MRI examinations in 88 patients (29 with pCR, 59 non-pCR) were evaluated. Women with hormone receptor (HR)+HER2- cancers who achieved pCR demonstrated a significantly greater decrease in BPE from baseline to pre-surgery compared to non-pCR patients (odds ratio 0.64, 95% confidence interval (CI): 0.39-0.92, P = 0.04). The associated BPE area under the curve (AUC) was 0.77 (95% CI: 0.56-0.98), comparable to the range of FTV AUC estimates. Among multi-predictor models, the highest cross-validated AUC of 0.81 (95% CI: 0.73-0.90) was achieved with combined FTV+HR predictors, while adding BPE to FTV+HR models had an estimated AUC of 0.82 (95% CI: 0.74-0.92)., Conclusion: Among women with HER2- cancer, BPE alone demonstrated association with pCR in women with HR+HER2- breast cancer, with similar diagnostic performance to FTV. BPE predictors remained significant in multivariate FTV models, but without added discrimination for pCR prediction. This may be due to small sample size limiting ability to create subtype-specific multivariate models., (© Society of Breast Imaging 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We assessed cross-sectional differences in sleep quality and risk factors among Asian, Black, Latino, and White participants in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study., Methods: KHANDLE enrolled community-dwelling adults aged ≥65 years living in northern California. Participants completed a modified Pittsburgh Sleep Quality Index to measure six sleep components and a global sleep score (scored 0-24). Covariates included age, sex, central adiposity, education, income, alcohol consumption, ever smoking, physical activity, and depression. Ordinal logistic regression was used to model sleep component scores across race/ethnic groups. Linear regression was used to assess racial/ethnic differences in global sleep score and the association between risk factors and global sleep score., Results: 1,664 participants with a mean age of 76 (SD=7) and mean global sleep score of 6 (SD=4) were analyzed. Using Latinos as reference (highest average sleep score), Blacks had an average .96 (.37, 1.54) unit higher global sleep score (worse sleep) while Asians [ β : .04 (-.56, .63)] and Whites [ β : .28 (-.29, .84)] did not significantly differ. Compared with Latinos, Blacks and Asians had greater odds of a worse score on the sleep duration component; Blacks and Whites had greater odds of a worse score on the sleep disturbances component; and, Whites had greater odds of a worse score on the medication component. Risk factors for poor sleep did not differ by race/ethnicity except alcohol consumption (interaction P=.04), which was associated with poor sleep in Blacks only., Conclusions: In this cohort, racial/ethnic differences in sleep quality were common., Competing Interests: Competing Interests: None declared., (Copyright © 2020, Ethnicity & Disease, Inc.)

Background: In the United States, racial disparities in birth outcomes persist and have been widening. Interpersonal and structural racism are leading explanations for the continuing racial disparities in birth outcomes, but research to confirm the role of racism and evaluate trends in the impact of racism on health outcomes has been hampered by the challenge of measuring racism. Most research on discrimination relies on self-reported experiences of discrimination, and few studies have examined racial attitudes and bias at the US national level., Objective: This study aimed to investigate the associations between state-level Twitter-derived sentiments related to racial or ethnic minorities and birth outcomes., Methods: We utilized Twitter's Streaming application programming interface to collect 26,027,740 tweets from June 2015 to December 2017, containing at least one race-related term. Sentiment analysis was performed using support vector machine, a supervised machine learning model. We constructed overall indicators of sentiment toward minorities and sentiment toward race-specific groups. For each year, state-level Twitter-derived sentiment data were merged with birth data for that year. The study participants were women who had singleton births with no congenital abnormalities from 2015 to 2017 and for whom data were available on gestational age (n=9,988,030) or birth weight (n=9,985,402). The main outcomes were low birth weight (birth weight ≤2499 g) and preterm birth (gestational age <37 weeks). We estimated the incidence ratios controlling for individual-level maternal characteristics (sociodemographics, prenatal care, and health behaviors) and state-level demographics, using log binomial regression models., Results: The accuracy for identifying negative sentiments on comparing the machine learning model to manually labeled tweets was 91%. Mothers living in states in the highest tertile for negative sentiment tweets referencing racial or ethnic minorities had greater incidences of low birth weight (8% greater, 95% CI 4%-13%) and preterm birth (8% greater, 95% CI 0%-14%) compared with mothers living in states in the lowest tertile. More negative tweets referencing minorities were associated with adverse birth outcomes in the total population, including non-Hispanic white people and racial or ethnic minorities. In stratified subgroup analyses, more negative tweets referencing specific racial or ethnic minority groups (black people, Middle Eastern people, and Muslims) were associated with poor birth outcomes for black people and minorities., Conclusions: A negative social context related to race was associated with poor birth outcomes for racial or ethnic minorities, as well as non-Hispanic white people., (©Thu T Nguyen, Nikki Adams, Dina Huang, M Maria Glymour, Amani M Allen, Quynh C Nguyen. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 06.07.2020.)

Introduction: Small observational studies with short-term follow-up suggest that cancer patients are at reduced risk of Alzheimer's disease (AD) compared to the general population., Methods: A nationwide cohort study using Danish population-based health registries (1980-2013) with cancer patients (n = 949,309) to identify incident diagnoses of AD. We computed absolute reductions in risk attributed to cancer and standardized incidence rate ratios (SIRs) accounting for survival time, comparing the observed to expected number of AD cases., Results: During up to 34 years of follow-up of cancer survivors, the attributable risk reduction was 1.3 per 10,000 person-years, SIR = 0.94 (95% confidence interval 0.92-0.96). SIRs were similar after stratification by sex, age, and cancer stage, and approached that of the general population for those surviving >10 years., Discussion: Inverse associations between cancer and AD were small and diminished over time. Incidence rates in cancer survivors approached those of the general population, suggesting limited association between cancer and AD risk., (© 2020 the Alzheimer's Association.)

Background: Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine., Methods: We defined treatment as random assignment to sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine before pooling individual participant-level data from 1617 HIV-uninfected pregnant women in Kenya (one trial; n=806) and Uganda (two trials; n=811). We quantified the relative effect of treatment on birthweight (primary outcome) attributed to preventing placental malaria infection (mediator). We estimated antimalarial (indirect) and non-malarial (direct) effects of IPTp on birth outcomes using causal mediation analyses, accounting for confounders. We used two-stage individual participant data meta-analyses to calculate pooled-effect sizes., Findings: Overall, birthweight was higher among neonates of women randomly assigned to sulfadoxine-pyrimethamine compared with women assigned to dihydroartemisinin-piperaquine (mean difference 69 g, 95% CI 26 to 112), despite placental malaria infection being lower in the dihydroartemisinin-piperaquine group (relative risk [RR] 0·64, 95% CI 0·39 to 1·04). Mediation analyses showed sulfadoxine-pyrimethamine conferred a greater non-malarial effect than did dihydroartemisinin-piperaquine (mean difference 87 g, 95% CI 43 to 131), whereas dihydroartemisinin-piperaquine conferred a slightly larger antimalarial effect than did sulfadoxine-pyrimethamine (8 g, -9 to 26), although more frequent dosing increased the antimalarial effect (31 g, 3 to 60)., Interpretation: IPTp with sulfadoxine-pyrimethamine appears to have potent non-malarial effects on birthweight. Further research is needed to evaluate monthly dihydroartemisinin-piperaquine with sulfadoxine-pyrimethamine (or another compound with non-malarial effects) to achieve greater protection against malarial and non-malarial causes of low birthweight., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation, and Worldwide Antimalarial Resistance Network., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Subjective cognitive decline (SCD) may represent a low-burden indicator of dementia risk. The value of SCD as a proxy marker, however, depends on the consistency of associations between subjective and objective cognitive measures across sociodemographic and psychological factors., Methods: We evaluated baseline data from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study (n=1615). SCD was measured using the 12-item Everyday Cognition (ECog) scale. Using linear regression models with interaction terms, we evaluated 6 potential modifiers (age, sex, race/ethnicity, educational attainment, family history of dementia, and depressive symptoms) of the association between cognitive performance (episodic memory, executive function) and SCD., Results: Lower episodic memory and executive function scores were associated with higher log(ECog scores) (more SCD). Older age and elevated depressive symptoms were associated with higher log(ECog scores). Age (interaction P=0.002) and education (interaction P=0.01) modified the association between executive function and log(ECog scores). Specifically, associations between executive function and log(ECog scores) were stronger among participants with more education and less pronounced among older participants., Conclusions: The association between cognitive performance and log(ECog scores) differed little across sociodemographic and psychological factors. SCD as measured by the ECog may be a valuable proxy for cognitive performance in diverse older adults.

Introduction: Leisure time activity is associated with better cognitive function but has not been well studied in racially/ethnically diverse cohorts, who may have different access to activities., Methods: Frequency of participation in 10 leisure time activities (eg, reading, attending cultural events) and cognition (executive function, semantic memory, and verbal episodic memory) were assessed at Wave 1 in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study, a prospective cohort initiated in 2017. Linear regression models adjusted for sociodemographics and depression estimated cross-sectional associations between leisure time activity variety and frequency and cognitive domains overall and by race/ethnicity. Logistic regression models estimated odds of cognitive impairment among those in the lowest quartiles of activity variety and frequency. All models controlled for age, sex, education, income, retirement status, and depression., Results: Higher leisure time activity variety was significantly associated with better cognition for all, except for verbal episodic memory among Asians (β = 0.05, 95% confidence interval [CI]: -0.004, 0.11) and semantic memory among Latinos (β = 0.04, 95% CI: -0.01, 0.08). Low activity variety was associated with nearly three-fold increased odds of cognitive impairment (adjusted odds ratio [OR] = 2.87, 95% CI: 1.77, 4.64). Activity frequency was associated with higher executive function only among whites (β = 0.10, 95% CI: 0.02, 0.18). Patterns by race/ethnicity were not explained by education., Discussion: Engaging in a wider variety of leisure time activities may be more important than frequently participating in fewer activities for cognitive aging in racially/ethnically diverse cohorts., Competing Interests: The authors have no financial interests in the subject matter or findings presented in this study., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

Introduction: To examine associations of history of traumatic brain injuries (TBIs) with loss of consciousness (LOC) with dementia incidence and memory decline., Methods: We studied 2718 participants from the 1992 enrollment cohort of the Health and Retirement Study (HRS) aged 65 years or older in 2000. History of TBI with LOC was self-reported in 1992. Dementia was assessed using four algorithms established in HRS. Participants were followed from 2000 to 2014 with repeated measures of dementia and memory performance. Cox models and linear mixed-effects models were used., Results: In 1992, 11.9% of the participants reported a history of TBI with LOC. In fully adjusted models for all four algorithms, participants with a history of TBI with LOC had no statistically significant difference in dementia incidence nor in memory decline, compared to participants without TBI history., Discussion: Our study did not find evidence of a long-term association between history of TBI with LOC (of unknown frequency and severity) and dementia incidence or memory decline., (© 2020 the Alzheimer's Association.)

Muscle weakness, as measured by handgrip strength, is a primary determinant of physical functioning and disability. There is a high burden of muscle weakness in the United States with close to 50 percent of older Americans meeting criteria for clinical muscle weakness. While previous racial/ethnic disparities have been documented among older adults, the extent to which lifecourse trauma shapes muscle strength trajectories is unknown. Using U.S. Health and Retirement Study (N = 20,472, Mean Age = 63.8 years) data on grip strength (2006-2014, up to 3 assessments) and retrospectively reported traumatic events, we fit gender-stratified growth curve models to investigate whether traumatic events experienced across the lifecourse or at distinct sensitive periods (childhood, early/emerging adulthood or mid-life) predicted later-life trajectories of grip strength. There was no association between cumulative trauma and trajectories of grip strength and the main effects for the life stage models were largely null. However, among White women, our results suggest that traumatic events experienced during childhood (β = -0.012; 95% CI = -0.024, 0.0004) compared to middle adulthood are associated with faster declines in grip strength in later life. Traumatic events reported during childhood was related to a slower decline in grip strength over time among Hispanic women compared to that for White women (β = 0.086, 95% CI = 0.044, 0.128). Among Black men, the association between traumatic events during early/emerging adulthood and age-related declines in grip strength was stronger for Black men than for White men (interaction β = -0.070; 95% CI = -0.138, 0.001). Traumatic events experienced during distinct life stages may influence later life declines in grip strength and exacerbate racial inequalities in later life. This study addresses an important gap by investigating the life course social determinants of later life muscle strength, which is a key driver of physical functioning and mobility., (© 2020 The Authors.)

We used differences in state school policies as natural experiments to evaluate the joint influence of educational quantity and quality on late-life physical and mental health. Using US Census microsample data, historical measures of state compulsory schooling and school quality (term length, student-teacher ratio, and attendance rates) were combined via regression modeling on a scale corresponding to years of education (policy-predicted years of education (PPYEd)). PPYEd values were linked to individual-level records for 8,920 black and 14,605 white participants aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke study (2003-2007). Linear and quantile regression models estimated the association between PPYEd and Physical Component Summary (PCS) and Mental Component Summary (MCS) from the Short Form Health Survey. We examined interactions by race and adjusted for sex, birth year, state of residence at age 6 years, and year of study enrollment. Higher PPYEd was associated with better median PCS (β = 1.28, 95% confidence interval (CI): 0.40, 1.49) and possibly better median MCS (β = 0.46, 95% CI: -0.01, 0.94). Effect estimates were higher among black (vs. white) persons (PCS × race interaction, β = 0.22, 95% CI: -0.62, 1.05, and MCS × race interaction, β = 0.18; 95% CI: -0.08, 0.44). When incorporating both school quality and duration, this quasiexperimental analysis found mixed evidence for a causal effect of education on health decades later., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Directed acyclic graphs (DAGs), a prominent tool for expressing assumptions in epidemiologic research, are most useful when the hypothetical data generating structure is correctly encoded. Understanding a study's data generating structure and translating that data structure into a DAG can be challenging, but these skills are often glossed over in training. Campbell and Stanley's framework for causal inference has been extraordinarily influential in social science training programs but has received less attention in epidemiology. Their work, along with subsequent revisions and enhancements based on practical experience conducting empirical studies, presents a catalog of 37 threats to validity describing reasons empirical studies may fail to deliver causal effects. We interpret most of these threats to study validity as suggestions for common causal structures. Threats are organized into issues of statistical conclusion validity, internal validity, construct validity, or external validity. To assist epidemiologists in drawing the correct DAG for their application, we map the correspondence between threats to validity and epidemiologic concepts that can be represented with DAGs. Representing these threats as DAGs makes them amenable to formal analysis with d-separation rules and breaks down cross-disciplinary language barriers in communicating methodologic issues.

Background: Research documenting the relevance of neighbourhoods for the health of older adults has focused on global physical functioning outcomes, such as disability, rather than physiologic impairments that lead to disability. Muscle weakness is an age-related impairment and a central mechanism of disability. Evaluating neighbourhood effects on muscle weakness may offer insight into physiologic mechanisms of disability. We examined the association between perceived neighbourhood disorder and muscle strength in a nationally representative sample of US adults aged 51+., Methods: Among 11 277 participants (57% women; mean age: 66.6 years) in the Health and Retirement Study (2012-2014), we investigated whether self-reported neighbourhood physical disorder (1-7 scale, mean=2.61, SD=1.45); presence of vandalism/graffiti, litter, deserted houses, feeling safe walking alone) was associated with mean hand grip strength using linear regression models with sampling weights. We tested whether the association between neighbourhood disorder and grip strength differed by age and gender., Results: After adjusting for demographic characteristics, marital status, education and household wealth, residence in neighbourhoods with high perceived physical neighbourhood disorder was associated with lower muscle strength for men (β=-1.95 kg; 95% CI, 2.68 to -1.22) and to a lesser extent, for women (β=-0.64 kg, 95% CI, -1.11 to -0.19), (p for interaction <0.0001). For both men and women, associations between neighbourhood physical disorder and grip strength were more adverse among the middle aged (51-64 years) than for older (ages 65+) adults., Discussion: Perceived neighbourhood disorder was associated with lower muscle strength. Future studies should more rigorously evaluate causality and evaluate potential interventions., Competing Interests: Competing interests: PMC reports consultation to BioAge Labs, and grants to her institution from Abbott and Nestle, all for work outside of this project., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The effect of education on late life cognition has attracted substantial attention in lifecourse epidemiology, in part because of its relevance for understanding the effect of education on dementia. Although numerous studies document an association between education and later life cognition, these studies are potentially confounded by early life socioeconomic position and cognition. Good measures of these early life constructs are rarely available in data sets assessing cognition in late life. A further body of evidence has taken advantage of compulsory schooling law (CSL) instrumental variables (IV), although these estimates have been criticized based on questions about the validity of CSL IVs. In this issue of the Journal, Zhang et al. took advantage of the Wisconsin Longitudinal Study to control for both prospectively measured adolescent IQ and early life socioeconomic status in an analysis evaluating the effect of education on cognitive scores in late middle age (Zhang et al., 2019; IN THIS ISSUE). Their results indicate a moderate effect of each additional year of education on later life cognition, of approximately 0.1-0.15 standard deviations per year of schooling. These estimates are remarkably aligned with findings from prior observational designs and from the CSL IV studies. Although criticisms of any individual study are plausible, this new study complements the body of prior evidence to provide compelling evidence for the benefits of education on late life cognition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In the United States whites are more likely to misuse opioid pain relievers (OPRs) than blacks, and blacks are less likely to be prescribed OPRs than whites. Our objective is to determine whether racial discrimination in medical settings is protective for blacks against OPR misuse, thus mediating the black-white disparities in OPR misuse., Methods: We used data from 3528 black and white adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing multi-site cohort. We employ causal mediation methods, with race (black vs white) as the exposure, lifetime discrimination in medical settings prior to year 2000 as the mediator, and OPR misuse after 2000 as the outcome., Results: We found black participants were more likely to report discrimination in a medical setting (20.3% vs 0.9%) and less likely to report OPR misuse (5.8% vs 8.0%, OR = 0.71, 95% CI = 0.55, 0.93, adjusted for covariates). Our mediation models suggest that when everyone is not discriminated against, the disparity is wider with black persons having even lower odds of reporting OPR misuse (OR = 0.63, 95% CI = 0.45, 0.89) compared to their white counterparts, suggesting racial discrimination in medical settings is a risk factor for OPR misuse rather than protective., Conclusions: These results suggest that racial discrimination in a medical setting is a risk factor for OPR misuse rather than being protective, and thus could not explain the seen black-white disparity in OPR misuse., Competing Interests: The authors have declared that no competing interests exist.

Population health researchers from different fields often address similar substantive questions but rely on different study designs, reflecting their home disciplines. This is especially true in studies involving causal inference, for which semantic and substantive differences inhibit interdisciplinary dialogue and collaboration. In this paper, we group nonrandomized study designs into two categories: those that use confounder-control (such as regression adjustment or propensity score matching) and those that rely on an instrument (such as instrumental variables, regression discontinuity, or differences-in-differences approaches). Using the Shadish, Cook, and Campbell framework for evaluating threats to validity, we contrast the assumptions, strengths, and limitations of these two approaches and illustrate differences with examples from the literature on education and health. Across disciplines, all methods to test a hypothesized causal relationship involve unverifiable assumptions, and rarely is there clear justification for exclusive reliance on one method. Each method entails trade-offs between statistical power, internal validity, measurement quality, and generalizability. The choice between confounder-control and instrument-based methods should be guided by these tradeoffs and consideration of the most important limitations of previous work in the area. Our goals are to foster common understanding of the methods available for causal inference in population health research and the tradeoffs between them; to encourage researchers to objectively evaluate what can be learned from methods outside one's home discipline; and to facilitate the selection of methods that best answer the investigator's scientific questions., Competing Interests: The authors have no competing interests to declare., (© 2019 The Authors.)

Introduction: Systematic disparities in misdiagnosis of dementia across racial/ethnic groups have implications for health disparities. We compared the risk of dementia under- and overdiagnosis in clinical settings across racial/ethnic groups from 2000 to 2010., Methods: We linked fee-for-service Medicare claims to participants aged ≥70 from the nationally representative Health and Retirement Study. We classified dementia status using an algorithm with similar sensitivity and specificity across racial/ethnic groups and assigned clinical dementia diagnosis status using ICD-9-CM codes from Medicare claims. Multinomial logit models were used to estimate relative risks of clinical under- and overdiagnosis between groups and over time., Results: Non-Hispanic blacks had roughly double the risk of underdiagnosis as non-Hispanic whites. While primary analyses suggested a shrinking disparity over time, this was not robust to sensitivity analyses or adjustment for covariates. Risk of overdiagnosis increased over time in both groups., Discussion: Our results suggest that efforts to reduce racial disparities in underdiagnosis are warranted., (© 2019 The Authors.)

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Burgess S et al.)