Inflammatory Markers Involved in the Pathogenesis of Dupuytren's Contracture.

Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.

Gender and age differences in the associations between cortical thickness and hand osteoarthritis severity: data from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate gender differences in the association between metacarpal cortical thickness (Tcort)-a surrogate for bone density-and severity of radiographic hand osteoarthritis (HOA) in a longitudinal observational study. METHOD: Hand radiographs of 3575 participants (2039 F/1536 M) from the Osteoarthritis Initiative were assessed at baseline and 48 months. A reader used a semi-automated software tool to calculate Tcort, a measurement of the cortical thickness, for metacarpals 2-4. Average Tcort at baseline and change in Tcort from baseline to 48 months was determined and stratified by gender and age for 7 5-year age groups. Spearman's rank correlation coefficients were calculated for the association of baseline Tcort and 2 measures of baseline HOA severity: the sum of Kellgren-Lawrence (KL) grade and total number of joints with radiographic HOA. Longitudinally, logistic regression was used to assess the relationship of Tcort loss to new finger joint radiographic HOA, increase in KL grades, and incident hand pain. RESULTS: Male Tcort was higher than females. Significant correlations between Tcort and radiographic severity were noted for women but not men, with stronger associations among women >60 years (rho = -0.25; 95% confidence interval (CI) = -0.31 to -0.19). Statistically significant associations were seen between Tcort change and radiographic osteoarthritis change among women but not men, with substantial gender differences for Tcort change, particularly ages 50 to 70 years (p < 0.01; e.g., Tcort change ages 55 to <60: males = -0.182 (0.118), females = -0.219 (0.124)). CONCLUSION: We found significant HOA-related gender differences in Tcort, suggesting the involvement of female bone loss during and after menopause.

Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort.

OBJECTIVE: Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. METHOD: This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n = 1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. RESULTS: Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD = 1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). CONCLUSION: This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.

Knee cartilage change on magnetic resonance imaging: Should we lump or split topographical regions? A 2-year study of data from the osteoarthritis initiative.

OBJECTIVE: We challenge the paradigm that a simplistic approach evaluating anatomic regions (e.g., medial femur or tibia) is ideal for assessing articular cartilage loss on magnetic resonance (MR) imaging. We used a data-driven approach to explore whether specific topographical locations of knee cartilage loss may identify novel patterns of cartilage loss over time that current assessment strategies miss. DESIGN: We assessed 60 location-specific measures of articular cartilage on a sample of 99 knees with baseline and 24-month MR images from the Osteoarthritis Initiative, selected as a group with a high likelihood to change. We performed factor analyses of the change in these measures in two ways: (1) summing the measures to create one measure for each of the six anatomically regional-based summary (anatomic regions; e.g., medial tibia) and (2) treating each location separately for a total of 60 measures (location-specific measures). RESULTS: The first analysis produced three factors accounting for 66% of the variation in the articular cartilage changes that occur over 24 months of follow-up: (1) medial tibiofemoral, (2) medial and lateral patellar, and (3) lateral tibiofemoral. The second produced 20 factors accounting for 75% of the variance in cartilage changes. Twelve factors only involved one anatomic region. Five factors included locations from adjoining regions (defined by the first analysis; e.g., medial tibiofemoral). Three factors included articular cartilage loss from disparate locations. CONCLUSIONS: Novel patterns of cartilage loss occur within each anatomic region and across these regions, including in disparate regions. The traditional anatomic regional approach is simpler to implement and interpret but may obscure meaningful patterns of change.

Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Photosensitizing antihypertensive medication and risk of skin cancer among postmenopausal women.

BACKGROUND: Few prospective studies exist with an evaluation of a dose-response relationship between use of some photosensitizing antihypertensive medications and skin cancer. PATIENT AND METHODS: We used prospective data from the Women's Health Initiative Observational Study to investigate the association between antihypertensive use and risk of non-melanoma skin cancer (NMSC) and melanoma in postmenopausal women aged 50-79 years at baseline (n  =  64,918). Multivariable Cox proportional hazards regression models were used and hazard ratios (HRs) and 95 confidence intervals (CIs) were calculated. RESULTS: 8,777 NMSC and 1,227 melanoma cases were observed. Use of antihypertensives (HR [95% CI]: 1.12 [1.07-1.18]), ACE inhibitors (1.09 [1.01-1.18]), calcium channel blockers (1.13 [1.05-1.22]), diuretics (1.20 [1.12-1.27]), loop diuretics (1.17 [1.07-1.28]), and thiazides (1.17 [1.03-1.33]) were each associated with higher NMSC risk. NMSC risk linearly increased with use of multiple antihypertensives (p-trend  =  0.02) and with longer duration of use (p-trend < 0.01). Antihypertensives (1.15 [1.00-1.31]), angiotensin-II receptor blockers (1.82 [1.05-3.15]), and diuretics (1.34 [1.13-1.59]) were each associated with elevated melanoma risk. Effect modification by solar radiation exposure was found between antihypertensive use and incidence of melanoma (p-interaction  =  0.02). CONCLUSIONS: Use of antihypertensives overall, and several individual classes thereof, were associated with higher incidence of NMSC and melanoma with dose-response relationship.

Examining the Relationship Between Multilevel Resilience Resources and Cardiovascular Disease Incidence, Overall and by Psychosocial Risks, Among Participants in the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.

We examined relationships between resilience resources (optimism, social support, and neighborhood social cohesion) and cardiovascular disease (CVD) incidence and assessed potential effect-measure modification by psychosocial risk factors (e.g., stress, depression) among adults without CVD in 3 cohort studies (2000-2018): the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. We fitted adjusted Cox models accounting for within-neighborhood clustering while censoring at dropout or non-CVD death. We assessed for effect-measure modification by psychosocial risks. In secondary analyses, we estimated standardized risk ratios using inverse-probability-weighted Aalen-Johansen estimators to account for confounding, dropout, and competing risks (non-CVD deaths) and obtained 95% confidence intervals (CIs) using cluster bootstrapping. For high and medium (versus low) optimism (n = 6,243), adjusted hazard ratios (HRs) for incident CVD were 0.94 (95% CI: 0.78, 1.13) and 0.90 (95% CI: 0.75, 1.07), respectively. Corresponding HRs were 0.88 (95% CI: 0.74, 1.04) and 0.92 (95% CI: 0.79, 1.06) for social support (n = 7,729) and 1.10 (95% CI: 0.94, 1.29) and 0.99 (95% CI: 0.85, 1.16) for social cohesion (n = 7,557), respectively. Some psychosocial risks modified CVD HRs. Secondary analyses yielded similar findings. For optimism and social support, an inverse relationship was frequently most compatible with the data, but a positive relationship was also compatible. For neighborhood social cohesion, positive and null relationships were most compatible. Thus, specific resilience resources may be potential intervention targets, especially among certain subgroups.

Radiographic joint space width in individuals with hand osteoarthritis: Are their "healthy" joints really healthy?

OBJECTIVES: We aimed to investigate the systemic nature of hand osteoarthritis (OA). We hypothesized that people who suffer from hand OA would display narrower radiographic joint space width (JSW) - not only in joints with apparent radiographic OA but also in their unaffected "healthy" joints. METHOD: We examined 3394 participants from the Osteoarthritis Initiative with available dominant hand radiographs at baseline. Cases were defined as having interphalangeal OA (IPOA) based on a Kellgren and Lawrence (KL) score of ≥2 in two or more finger joints, whereas controls did not have IPOA. We used custom software to make JSW measurements of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints in fingers 2-5 per hand. In joint-level analyses, we included only KL score=0, allowing us to compare all joints without IPOA in cases and controls. We used generalized estimating equation models to compare JSW between both groups, adjusted for age, gender, metacarpal length, and joint type. RESULTS: Finger joints without radiographic OA had significantly narrower JSW in the IPOA group compared to finger joints in the control group (p < 0.001). The differences were significant across all joint types and for both total JSW measurements as well as for central and lateral sub-regions within each joint group (p < 0.001). CONCLUSION: Unaffected finger joints in people with IPOA had narrower joint space than joints of healthy controls. This implies a systemic nature of hand OA, in which people may have a predisposition for general cartilage deterioration.

Comparison of evaluation metrics of deep learning for imbalanced imaging data in osteoarthritis studies.

PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the model's performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.

Hand joints without radiographic osteoarthritis maintain their joint space width over 4 years despite what's happening elsewhere in the hand.

OBJECTIVES: We aimed to determine if hand osteoarthritis is characterized by systemic cartilage loss by assessing if radiographically normal joints had greater joint space width (JSW) loss during four years in hands with incident or prevalent osteoarthritis elsewhere in the hand compared with hands without osteoarthritis. METHODS: We used semi-automated software to measure JSW in the distal and proximal interphalangeal joints of 3,368 participants in the Osteoarthritis Initiative who had baseline and 48-month hand radiographs. A reader scored 16 hand joints (including the thumb-base) for Kellgren-Lawrence (KL) Grade. A joint had osteoarthritis if scored as KL ≥ 2. We identified three groups based on longitudinal hand osteoarthritis status: 1) no hand osteoarthritis (KL < 2 in all 16 joints) at the baseline and 48-month visits, 2) incident hand osteoarthritis (KL < 2in all 16 joints at baseline and then ≥1 joint with KL ≥ 2 at 48-months), and 3) prevalent hand osteoarthritis (≥1 joint with KL ≥ 2 at baseline and 48-months). We then assessed if JSW in radiographically normal joints (KL = 0) differed across these three groups. We calculated unpooled effect sizes to help interpret the differences between groups. RESULTS: We observed small differences in JSW loss that are unlikely to be clinically important between radiographically normal joints between those without hand osteoarthritis (n = 1054) and those with incident (n = 102) or prevalent hand osteoarthritis (n = 2212) (effect size range: -0.01 to 0.24). These findings were robust when examining JSW loss dichotomized based on meaningful change and in other secondary analyses. CONCLUSIONS: Hand osteoarthritis is not a systemic disease of cartilage.

Long-term exposure to ambient particulate matter and stroke etiology: Results from the Women's Health Initiative.

BACKGROUND: Ambient particulate matter (PM) air pollution is a leading cause of global disability and accounts for an annual 2.9 million deaths globally. PM is established as an important risk factor for cardiovascular disease, however the evidence supporting a link specifically between long-term exposure to ambient PM and incident stroke is less clear. We sought to evaluate the association of long-term exposure to different size fractions of ambient PM with incident stroke (overall and by etiologic subtypes) and cerebrovascular deaths within the Women's Health Initiative, a large prospective study of older women in the US. METHODS: We studied 155,410 postmenopausal women without previous cerebrovascular disease enrolled into the study between 1993 and 1998, with follow-up through 2010. We assessed geocoded participant address-specific concentrations of ambient PM (fine [PM2.5], respirable [PM10] and coarse [PM10-2.5]), as well as nitrogen dioxide [NO2] using spatiotemporal models. We classified hospitalization events into ischemic, hemorrhagic, or other/unclassified stroke. Cerebrovascular mortality was defined as death from any stroke etiology. We used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for individual and neighborhood-level characteristics. RESULTS: During a median follow-up time of 15 years, participants experienced 4,556 cerebrovascular events. The hazard ratio for all cerebrovascular events was 2.14 (95% CI: 1.87, 2.44) comparing the top versus bottom quartiles of PM2.5. Similarly, there was a statistically significant increase in events comparing the top versus bottom quartiles of PM10 and NO2 (HR: 1.17; 95% CI: 1.03, 1.33 and HR:1.26; 95% CI: 1.12, 1.42). The strength of association did not vary substantially by stroke etiology. There was little evidence of an association between PMcoarse and incident cerebrovascular events. CONCLUSIONS: Long-term exposure to fine (PM2.5) and respirable (PM10) particulate matter as well as NO2 was associated with a significant increase of cerebrovascular events among postmenopausal women. Strength of the associations were consistent by stroke etiology.

Association between race/ethnicity and income on the likelihood of coronary revascularization among postmenopausal women with acute myocardial infarction: Women's health initiative study.

BACKGROUND: Historically, race, income, and gender were associated with likelihood of receipt of coronary revascularization for acute myocardial infarction (AMI). Given public health initiatives such as Healthy People 2010, it is unclear whether race and income remain associated with the likelihood of coronary revascularization among women with AMI. METHODS: Using the Women's Health Initiative Study, hazards ratio (HR) of revascularization for AMI was compared for Black and Hispanic women vs White women and among women with annual income <$20,000/year vs ≥$20,000/year over median 9.5 years follow-up(1993-2019). Proportional hazards models were adjusted for demographics, comorbidities, and AMI type. Results were stratified by revascularization type: percutaneous coronary intervention and coronary artery bypass grafting(CABG). Trends by race and income were compared pre- and post-2010 using time-varying analysis. RESULTS: Among 5,284 individuals with AMI (9.5% Black, 2.8% Hispanic, and 87.7% White; 23.2% <$20,000/year), Black race was associated with lower likelihood of receiving revascularization for AMI compared to White race in fully adjusted analyses [HR:0.79(95% Confidence Interval:[CI]0.66,0.95)]. When further stratified by type of revascularization, Black race was associated with lower likelihood of percutaneous coronary intervention for AMI compared to White race [HR:0.72(95% CI:0.59,0.90)] but not for CABG [HR:0.97(95%CI:0.72,1.32)]. Income was associated with lower likelihood of revascularization [HR:0.90(95%CI:0.82,0.99)] for AMI. No differences were observed for other racial/ethnic groups. Time periods (pre/post-2010) were not associated with change in revascularization rates. CONCLUSION: Black race and income remain associated with lower likelihood of revascularization among patients presenting with AMI. There is a substantial need to disrupt the mechanisms contributing to race, sex, and income disparities in AMI management.

Remnant cholesterol is prospectively associated with cardiovascular disease events and all-cause mortality in kidney transplant recipients: the FAVORIT study.

BACKGROUND: The cholesterol content of circulating triglyceride-rich lipoproteins is characterized as remnant cholesterol, although little is known about its role in the development of cardiovascular disease (CVD) outcomes, all-cause mortality or transplant failure in kidney transplant recipients (KTRs). Our primary aim was to investigate the prospective association of remnant cholesterol and the risk of CVD events in renal transplant recipients with secondary aims evaluating remnant cholesterol and renal graft failure and all-cause mortality among participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial. METHODS: Among 4110 enrolled participants, 98 were excluded for missing baseline remnant cholesterol levels and covariates. Nonfasting remnant cholesterol levels were calculated based on the lipid profiles in 3812 FAVORIT trial participants at randomization. A Wilcoxon-type test for trend was used to compare baseline characteristics across remnant cholesterol quartiles. Cox proportional hazards regression was used to evaluate the association of baseline remnant cholesterol levels with time to primary and secondary study outcomes. RESULTS: During a median follow-up of 4.0 years we documented 548 CVD incident events, 343 transplant failures and 452 all-cause deaths. When comparing the highest quartile (quartile 4) to quartile 1, proportional hazard modeling revealed a significant increase in CVD risk {hazard ratio [HR] 1.32 [95% confidence interval (CI) 1.04-1.67]} and all-cause mortality risk [HR 1.34 (95% CI 1.01-1.69)]. A nonsignificant increase in transplant failure was seen as well [HR 1.20 (95% CI 0.87-1.64)]. CONCLUSIONS: Remnant cholesterol is associated with CVD and all-cause mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of remnant cholesterol-lowering therapy on these outcomes may be warranted.

Increased risk of incident knee osteoarthritis in those with greater work-related physical activity.

OBJECTIVE: Occupations involving greater physical activity may increase risk for knee osteoarthritis (OA). Existing studies have not evaluated work-related physical activity before OA onset. Hence, we aimed to evaluate the association between work-related physical activity and knee OA incidence. METHODS: We performed a person-based longitudinal study using Osteoarthritis Initiative (OAI) data among people who volunteered or worked for pay without baseline radiographic knee OA or knee pain. Bilateral knee radiographs were obtained at baseline and annual follow-ups. We defined radiographic OA as Kellgren-Lawrence grade ≥2. Questions from the Physical Activity Scale for the Elderly at baseline and annual OAI visits provided information about work-related physical activity level and hours. We performed logistic regression with work-related physical activity level ( mainly sitting , standing and some walking , walking while handling some materials ) and hours as predictors. The outcome was incident person-based radiographic OA within the ensuing 12 months, over 48 months. RESULTS: Among 951 participants (2819 observations), higher work-related physical activity levels had greater adjusted ORs for incident radiographic OA (people with jobs with standing and some walking : 1.11 (0.60-2.08), and walking while handling some materials : 1.90 (1.03-3.52), when compared with those with mainly sitting work-related activity ). There was no association between number of hours worked and incident radiographic OA. CONCLUSIONS: People performing work that require walking while handling some materials have greater odds of incident knee OA than those with jobs mostly involving sitting. Strategies are needed to mitigate risk factors predisposing them to radiographic OA.

Physical activity modifies the relation between gestational perfluorooctanoic acid exposure and adolescent cardiometabolic risk.

OBJECTIVE: Exposure to per- and polyfluoroalkyl substances (PFAS) - endocrine disrupting chemicals - may increase cardiometabolic risk. We evaluated whether adolescent lifestyle factors modified associations between gestational PFAS exposure and cardiometabolic risk using a prospective cohort study. METHODS: In 166 mother-child pairs (HOME Study), we measured concentrations of four PFAS in maternal serum collected during pregnancy. When children were age 12 years, we calculated cardiometabolic risk scores from visceral adiposity area, blood pressure, and fasting serum biomarkers. We assessed adolescent physical activity and Healthy Eating Index scores using the Physical Activity Questionnaire for Older Children (PAQ-C), actigraphy, and 24-h diet recalls. Using multivariable linear regression and weighted quantile sum regression, we examined whether physical activity or diet modified covariate-adjusted associations of PFAS and their mixture with cardiometabolic risk scores. RESULTS: Physical activity modified associations between perfluorooctanoic acid (PFOA) and cardiometabolic risk scores. Each doubling of PFOA was associated with worse cardiometabolic risk scores among children with PAQ-C scores < median (ß:1.4; 95% CI:0.5, 2.2, n = 82), but not among those with PAQ-C scores ≥ median (ß: 0.2; 95% CI: 1.2, 0.7, n = 84) (interaction p-value = 0.01). Associations were most prominent for insulin resistance, leptin-adiponectin ratio, and visceral fat area. We observed results suggesting that physical activity modified the association of PFAS mixture with cardiometabolic risk scores, insulin resistance, and visceral fat area (interaction p-values = 0.17, 0.07, and 0.10, respectively); however, the 95% CIs of the interaction terms included the null value. We observed similar, but attenuated patterns for PFOA and actigraphy-based measures of physical activity. Diet did not modify any associations. Physical activity or diet did not modify associations for other PFAS. CONCLUSIONS: Childhood physical activity modified associations of prenatal serum PFOA concentrations with children's cardiometabolic risk in this cohort, indicating that lifestyle interventions may ameliorate the adverse effects of PFOA exposure.

Examining relationships between perceived neighborhood social cohesion and ideal cardiovascular health and whether psychosocial stressors modify observed relationships among JHS, MESA, and MASALA participants.

BACKGROUND: Psychosocial stressors increase the risks for cardiovascular disease across diverse populations. However, neighborhood level resilience resources may protect against poor cardiovascular health (CVH). This study used data from three CVH cohorts to examine longitudinally the associations of a resilience resource, perceived neighborhood social cohesion (hereafter referred to as neighborhood social cohesion), with the American Heart Association's Life's Simple 7 (LS7), and whether psychosocial stressors modify observed relationships. METHODS: We examined neighborhood social cohesion (measured in tertiles) and LS7 in the Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America study. We used repeated-measures, modified Poisson regression models to estimate the relationship between neighborhood social cohesion and LS7 (primary analysis, n = 6,086) and four biological metrics (body mass index, blood pressure, cholesterol, blood glucose; secondary analysis, n = 7,291). We assessed effect measure modification by each psychosocial stressor (e.g., low educational attainment, discrimination). RESULTS: In primary analyses, adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) for ideal/intermediate versus poor CVH among high or medium (versus low) neighborhood social cohesion were 1.01 (0.97-1.05) and 1.02 (0.98-1.06), respectively. The psychosocial stressors, low education and discrimination, functioned as effect modifiers. Secondary analyses showed similar findings. Also, in the secondary analyses, there was evidence for effect modification by income. CONCLUSION: We did not find much support for an association between neighborhood social cohesion and LS7, but did find evidence of effect modification. Some of the effect modification results operated in unexpected directions. Future studies should examine neighborhood social cohesion more comprehensively and assess for effect modification by psychosocial stressors.

Accelerometer-Measured Daily Steps, Physical Function, and Subsequent Fall Risk in Older Women: The Objective Physical Activity and Cardiovascular Disease in Older Women Study.

Steps per day were measured by accelerometer for 7 days among 5,545 women aged 63-97 years between 2012 and 2014. Incident falls were ascertained from daily fall calendars for 13 months. Median steps per day were 3,216. There were 5,473 falls recorded over 61,564 fall calendar-months. The adjusted incidence rate ratio comparing women in the highest versus lowest step quartiles was 0.71 (95% confidence interval [0.54, 0.95]; ptrend across quartiles = .01). After further adjustment for physical function using the Short Physical Performance Battery, the incidence rate ratio was 0.86 ([0.64, 1.16]; ptrend = .27). Mediation analysis estimated that 63.7% of the association may be mediated by physical function (p = .03). In conclusion, higher steps per day were related to lower incident falls primarily through their beneficial association with physical functioning. Interventions that improve physical function, including those that involve stepping, could reduce falls in older adults.

Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly.

BACKGROUND: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Gestational perfluoroalkyl substance exposure and body mass index trajectories over the first 12 years of life.

BACKGROUND/OBJECTIVES: Gestational exposure to perfluoroalkyl substances (PFAS), a ubiquitous class of persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disease. However, it is unclear if gestational PFAS exposure is associated with adiposity trajectories related to adult obesity and cardiometabolic health. SUBJECTS/METHODS: We measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid, and perfluorohexanesulfonic acid (PFHxS) concentrations in maternal serum collected between 16 weeks gestation and delivery in a cohort of 345 mother-child pairs in Cincinnati, OH (enrolled 2003-06). From age 4 weeks to 12 years, we measured weight and length or height up to eight times and calculated child body mass index (BMI) (1865 repeated measures). Using covariate-adjusted linear mixed models and splines to account for repeated BMI measures and nonlinear BMI patterns, respectively, we estimated the age/magnitude of infancy BMI zenith (~1 year) and childhood BMI nadir (~5 years), BMI accrual from 8 to 12 years, and BMI at age 12 years by PFAS terciles. RESULTS: BMI trajectories varied by PFOA concentrations (age × PFOA interaction p value = 0.03). Children born to women with higher PFOA concentrations had lower infancy and early childhood BMI, earlier BMI nadir, accelerating BMI gains in mid-childhood and adolescence, and higher BMI at age 12 years. Some of these associations were non-monotonic. PFOS and PFHxS were not associated with alterations in BMI trajectories, but were monotonically associated with lower BMI across infancy, childhood, and adolescence. Compared to children in the first PFOS tercile, those in the second (ß: -0.83; 95% confidence interval (CI): -2.11, 0.51 kg/m2), and third (ß: -1.41; 95% CI: -2.65, -0.14 kg/m2) had lower BMI at age 12 years. CONCLUSIONS: These results suggest that gestational PFOA exposure may be associated with BMI trajectories related to adult obesity and cardiometabolic disease, while PFOS and PFHxS exposure is associated with lower BMI in the first 12 years of life.

When the At-Risk Do Not Develop Heart Failure: Understanding Positive Deviance Among Postmenopausal African American and Hispanic Women.

BACKGROUND: African American and Hispanic postmenopausal women have the highest risk for heart failure compared with other races, but heart failure prevalence is lower than expected in some national cohorts. It is unknown whether psychosocial factors are associated with lower risk of incident heart failure hospitalization among high-risk postmenopausal minority women. METHODS AND RESULTS: Using the Women's Health Initiative Study, African American and US Hispanic women were classified as high-risk for incident heart failure hospitalization with 1 or more traditional heart failure risk factors and the highest tertile heart failure genetic risk scores. Positive psychosocial factors (optimism, social support, religion) and negative psychosocial factors (living alone, social strain, depressive symptoms) were measured using validated survey instruments at baseline. Adjusted subdistribution hazard ratios of developing heart failure hospitalization were determined with death as a competing risk. Positive deviance indicated not developing incident heart failure hospitalization with 1 or more risk factors and the highest tertile for genetic risk. Among 7986 African American women (mean follow-up of 16 years), 27.0% demonstrated positive deviance. Among high-risk African American women, optimism was associated with modestly reduced risk of heart failure hospitalization (subdistribution hazard ratio 0.94, 95% confidence interval 0.91-0.99), and social strain was associated with modestly increased risk of heart failure hospitalization (subdistribution hazard ratio 1.07, 95% confidence interval 1.02-1.12) in the initial models; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses. Among 3341 Hispanic women, 25.1% demonstrated positive deviance. Among high-risk Hispanic women, living alone was associated with increased risk of heart failure hospitalization (subdistribution hazard ratio 1.97, 95% confidence interval 1.06-3.63) in unadjusted analyses; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses. CONCLUSIONS: Among postmenopausal African American and Hispanic women, a significant proportion remained free from heart failure hospitalization despite having the highest genetic risk profile and 1 or more traditional risk factors. No observed psychosocial factors were associated with incident heart failure hospitalization in high-risk African Americans and Hispanics. Additional investigation is needed to understand protective factors among high-risk African American and Hispanic women.