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Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

BACKGROUND: The contemporary burden and characteristics of coronary atherosclerosis, assessed using coronary computed tomography angiography (CCTA), is unknown among asymptomatic adults with diabetes and prediabetes in the United States. The pooled cohort equations and coronary artery calcium (CAC) score stratify atherosclerotic cardiovascular disease risk, but their association with CCTA findings across glycemic categories is not well established. METHODS: Asymptomatic adults without atherosclerotic cardiovascular disease enrolled in the Miami Heart Study were included. Participants underwent CAC and CCTA testing and were classified into glycemic categories. Prevalence of coronary atherosclerosis (any plaque, noncalcified plaque, plaque with ≥1 high-risk feature, maximal stenosis ≥50%) assessed by CCTA was described across glycemic categories and further stratified by pooled cohort equations-estimated atherosclerotic cardiovascular disease risk and CAC score. Adjusted logistic regression was used to evaluate the associations between glycemic categories and coronary outcomes. RESULTS: Among 2352 participants (49.5% women), the prevalence of euglycemia, prediabetes, and diabetes was 63%, 30%, and 7%, respectively. Coronary plaque was more commonly present across worsening glycemic categories (euglycemia, 43%; prediabetes, 58%; diabetes, 69%), and similar pattern was observed for other coronary outcomes. In adjusted analyses, compared with euglycemia, prediabetes and diabetes were each associated with higher odds of any coronary plaque (OR, 1.30 [95% CI, 1.05-1.60] and 1.75 [1.17-2.61], respectively), noncalcified plaque (OR, 1.47 [1.19-1.81] and 1.99 [1.38-2.87], respectively), and plaque with ≥1 high-risk feature (OR, 1.65 [1.14-2.39] and 2.53 [1.48-4.33], respectively). Diabetes was associated with stenosis ≥50% (OR, 3.01 [1.79-5.08]; reference=euglycemia). Among participants with diabetes and estimated atherosclerotic cardiovascular disease risk

BackgroundWe report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC).MethodsPatient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test.ResultsFrom September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19.ConclusionsDespite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in

BackgroundWorkplace legal protections are important for perinatal health outcomes. Black birthing people are disproportionally affected by pregnancy discrimination and bias in the employment context and lack of family-friendly workplace policies, which may hinder their participation in the labor force and lead to gender and racial inequities in income and health. We aimed to explore Black pregnant women's experiences of pregnancy discrimination and bias when looking for work, working while pregnant, and returning to work postpartum. Additionally, we explored Black pregnant women's perspectives on how these experiences may influence their health.MethodsUsing an intersectional framework, where oppression is based on intersecting social identities such as race, gender, pregnancy, and socioeconomic status, we conducted an analysis of qualitative data collected for a study exploring the lived experience of pregnancy among Black pregnant women in New Haven, Connecticut, United States. Twenty-four women participated in semi-structured interviews (January 2017-August 2018). Interview transcripts were analyzed using grounded theory techniques.ResultsParticipants expressed their desire to provide a financially secure future for their family. However, many described how pregnancy discrimination and bias made it difficult to find or keep a job during pregnancy. The following three themes were identified: 1) "You're a liability"; difficulty seeking employment during pregnancy; 2) "This is not working"; experiences on the job and navigating leave and accommodations while pregnant and parenting; and 3) "It's really depressing. I wanna work"; the stressors of experiencing pregnancy discrimination and bias.ConclusionBlack pregnant women in this study anticipated and experienced pregnancy discrimination and bias, which influenced financial burden and stress. We used an intersectional framework in this study which allowed us to more fully examine how racism and economic marginalization contribute to the lived experience of Black birthing people. Promoting health equity and gender parity means addressing pregnancy discrimination and bias and the lack of family-friendly workplace policies and the harm they cause to individuals, families, and communities, particularly those of color, throughout the United States.

BackgroundA disproportionate number of people who are killed by police each year are Black. While much attention rightly remains on victims of police brutality, there is a sparse literature on police brutality and perinatal health outcomes. We aimed to explore how Black pregnant women perceive police brutality affects them during pregnancy and might affect their children.MethodsThis qualitative study involved semi-structured interviews among 24 Black pregnant women in New Haven, Connecticut (January 2017 to August 2018). Interview questions explored neighborhood factors, safety, stressors during pregnancy, and anticipated stressors while parenting. Grounded theory informed the analysis.ResultsParticipants, regardless of socioeconomic status, shared experiences with police and beliefs about anticipated police brutality, as summarized in the following themes: (1) experiences that lead to police distrust - "If this is the way that mommy's treated [by police]"; (2) anticipating police brutality - "I'm always expecting that phone call"; (3) stress and fear during pregnancy - "It's a boy, [I feel] absolutely petrified"; and (4) 'the talk' about avoiding police brutality - "How do you get prepared?" Even participants who reported positive experiences with police anticipated brutality towards their children.ConclusionsInteractions between Black people and police on a personal, familial, community, and societal level influenced how Black pregnant women understand the potential for police brutality towards their children. Anticipated police brutality is a source of stress during pregnancy, which may adversely influence maternal and infant health outcomes. Police brutality must be addressed in all communities to prevent harming the health of birthing people and their children.

Residential racial segregation is a key manifestation of anti-Black structural racism, thought to be a fundamental cause of poor health; evidence has shown that it yields neighborhood disinvestment, institutional discrimination, and targeting of unhealthy products like tobacco and alcohol. Yet research on the long-term impacts of childhood exposure to residential racial segregation is limited. Here, we analyzed data on 1823 Black participants in the Panel Study of Income Dynamics, estimating associations between childhood segregation trajectories and young adult health. Black young adults who consistently lived in high-segregation neighborhoods throughout childhood experienced unhealthier smoking and drinking behaviors and higher odds of obesity compared to other trajectory groups, including children who moved into or out of high-segregation neighborhoods. Results were robust to controls for neighborhood and family poverty. Findings underscore that for Black children who grow up in segregated neighborhoods, the roots of structurally-determined health inequities are established early in life.

BackgroundCardiovascular disease (CVD) disproportionately affects Black adults in the United States. This is increasingly acknowledged to be due to inequitable distribution of health-promoting resources. One potential contributor is inequities in educational opportunities, although it is unclear what aspects of education are most salient. School racial segregation may affect cardiovascular health by increasing stress, constraining socioeconomic opportunities, and altering health behaviors. We investigated the association between school segregation and Black adults' CVD risk.Methods and findingsWe leveraged a natural experiment created by quasi-random (i.e., arbitrary) timing of local court decisions since 1991 that released school districts from court-ordered desegregation. We used the Panel Study of Income Dynamics (PSID) (1991 to 2017), linked with district-level school segregation measures and desegregation court order status. The sample included 1,053 Black participants who ever resided in school districts that were under a court desegregation order in 1991. The exposure was mean school segregation during observed schooling years. Outcomes included several adult CVD risk factors and outcomes. We fitted standard ordinary least squares (OLS) multivariable linear regression models, then conducted instrumental variables (IV) analysis, using the proportion of schooling years spent in districts that had been released from court-ordered desegregation as an instrument. We adjusted for individual- and district-level preexposure confounders, birth year, and state fixed effects. In standard linear models, school segregation was associated with a lower probability of good self-rated health (-0.05 percentage points per SD of the segregation index; 95% CI: -0.08, -0.03; p < 0.001) and a higher probability of binge drinking (0.04 percentage points; 95% CI: 0.002, 0.07; p = 0.04) and heart disease (0.01 percentage points; 95% CI: 0.002, 0.15; p = 0.007). IV analyses also found that school segregation was associated with a lower probability of good self-rated health (-0.09 percentage points; 95% CI: -0.17, -0.02, p = 0.02) and a higher probability of binge drinking (0.17 percentage points; 95% CI: 0.04, 0.30, p = 0.008). For IV estimates, only binge drinking was robust to adjustments for multiple hypothesis testing. Limitations included self-reported outcomes and potential residual confounding and exposure misclassification.ConclusionsSchool segregation exposure in childhood may have longstanding impacts on Black adults' cardiovascular health. Future research should replicate these analyses in larger samples and explore potential mechanisms. Given the recent rise in school segregation, this study has implications for policies and programs to address racial inequities in CVD.

ObjectivesFew researchers have evaluated whether school racial segregation, a key manifestation of structural racism, affects child health, despite its potential impacts on school quality, social networks, and stress from discrimination. We investigated whether school racial segregation affects Black children's health and health behaviors.MethodsWe estimated the association of school segregation with child health, leveraging a natural experiment in which school districts in recent years experienced increased school segregation. School segregation was operationalized as the Black-White dissimilarity index. We used ordinary least squares models as well as quasi-experimental instrumental variables analysis, which can reduce bias from unobserved confounders. Data from the Child Development Supplement of the Panel Study of Income Dynamics (1997-2014, n = 1248 Black children) were linked with district-level school segregation measures. Multivariable regressions were adjusted for individual-, neighborhood-, and district-level covariates. We also performed subgroup analyses by child sex and age.ResultsIn instrumental variables models, a one standard deviation increase in school segregation was associated with increased behavioral problems (2.53 points on a 27-point scale; 95% CI, 0.26 to 4.80), probability of having ever drunk alcohol (0.23; 95% CI, 0.049 to 0.42), and drinking at least monthly (0.20; 95% CI, 0.053 to 0.35). School segregation was more strongly associated with drinking behaviors among girls.ConclusionsSchool segregation was associated with worse outcomes on several measures of well-being among Black children, which may contribute to health inequities across the life span. These results highlight the need to promote school racial integration and support Black youth attending segregated schools.

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985-2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18-30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g., for cerebral volume, β = -0.08, 95% confidence interval: -0.15, -0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging.

Background Residential segregation, a geospatial manifestation of structural racism, is a fundamental driver of racial and ethnic health inequities, and longitudinal studies examining segregation's influence on cardiovascular health are limited. This study investigates the impact of segregation on hypertension in a multiracial and multiethnic cohort and explores whether neighborhood environment modifies this association. Methods and Results Leveraging data from a diverse cohort of adults recruited from 6 sites in the United States with 2 decades of follow-up, we used race- and ethnicity-stratified Cox models to examine the association between time-varying segregation with incident hypertension in 1937 adults free of hypertension at baseline. Participants were categorized as residing in segregated and nonsegregated neighborhoods using a spatial-weighted measure. We used a robust covariance matrix estimator to account for clustering within neighborhoods and assessed effect measure modification by neighborhood social or physical environment. Over an average follow-up of 7.35 years, 65.5% non-Hispanic Black, 48.1% Chinese, and 53.7% Hispanic participants developed hypertension. Net of confounders, Black and Hispanic residents in segregated neighborhoods were more likely to develop hypertension relative to residents in nonsegregated neighborhoods (Black residents: hazard ratio [HR], 1.33; 95% CI, 1.09-1.62; Hispanic residents: HR, 1.33; 95% CI, 1.04-1.70). Results were similar but not significant among Chinese residents (HR, 1.20; 95% CI, 0.83-1.73). Among Black residents, neighborhood social environment significantly modified this association such that better social environment was associated with less pronounced impact of segregation on hypertension. Conclusions This study underscores the importance of continued investigations of groups affected by the health consequences of racial residential segregation while taking contextual neighborhood factors, such as social environment, into account.

AIMS: To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). METHODS AND RESULTS: Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning- [WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrells concordance index (C-index) and calibration by the Greenwood-Nam-DAgostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (

ObjectivesThe use of online imagery by non-local observers to conduct remote, centralized collection of streetscape audit data in international studies has the potential to enhance efficiency of collection and comparability of such data for research on built environments and health. The objectives of the study were to measure (1) the consistency in responses between local in-field observers and non-local remote online observers and (2) the reliability between in-country online observers and non-local remote online observers using the Microscale Audit of Pedestrian Streetscapes Global tool to characterize pedestrian-related features along streets in five countries.MethodsConsistency and inter-rater reliability were analyzed between local and non-local observers on a pooled database of 200 routes in five study regions (Melbourne, Australia; Ghent, Belgium; Curitiba, Brazil; Hong Kong, China; and Valencia, Spain) for microscale environmental feature subscales and item-level variables using the intraclass correlation coefficient (ICC).ResultsA local in-field versus remote online comparison had an ICC of 0.75 (95 % CI: 0.68-0.80) for the grand total score. An ICC of 0.91 (95 % CI: 0.88-0.93) was found for the local online versus remote online comparison. Positive subscales yielded stronger results in comparison to negative subscales, except for the similarly poor-performing positive aesthetics/social characteristics.ConclusionsThis study demonstrated remote audits of microscale built environments using online imagery had good reliability with local in-field audits and excellent reliability with local online audits. Results generally supported remote online environmental audits as comparable to local online audits. This identification of low-cost and efficient data acquisition methods is important for expanding research on microscale built environments and physical activity globally.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

AbstractIn the United States, 13 million people identify as sexual and gender minorities. The purposes of this article were to (a) examine the associations among sexual orientation concealment and internalized homophobia with HIV knowledge, health literacy, and transactional sex through sexual identity; and (b) assess whether gender expression moderates those relationships in sexual minority men of color. A multigroup mediation path model examined the association between sexual orientation concealment and internalized homophobia on HIV knowledge, health literacy, and transactional sex through sexual identity by gender expression. Results suggest that, among those with a masculine gender expression, as sexual concealment increased, health literacy decreased. The association between sexual orientation concealment and transactional sex varied by participant's gender expression as did the association between internalized homophobia and HIV knowledge. Multiple intersecting identities, when faced with anticipated discrimination and homophobia, can negatively affect health outcomes and increase HIV risk in sexual minority men of color.

Though the transmission of HIV is preventable, there were still 37,968 new documented cases in the United States in 2018. HIV incidence is disproportionate in sexual minority men of color. The purpose of this study was to examine sexual relationship power risk profiles to identify distinct subgroups within the profiles who carry the highest HIV risk. Latent class profile analysis was used to identify subgroups of sexual minority men of color at the highest risk for contracting HIV based on their sexual power profiles. Among 322 sexual minority men, we identified four latent profiles. Profile 1: Low transactional sex and high power (n = 133; 14.3%); Profile 2: Transactional sex, high decision-making in sexual relationships, and low control in sexual relationship (n = 99; 30.7%); Profile 3: Low transactional sex, low decision-making, and moderate control (n = 43; 13.4%); Profile 4: High transactional sex and low power (n = 47; 14.6%). LPA was useful to identify distinct subgroups based on measures of sexual risk and relationship sexual power. Findings carry significant implications for developing tailored strategies to increase HIV knowledge and related HIV prevention and risk reduction services for sexual minority men of color who engage in transactional sex.

ObjectiveTo evaluate the associations between long-term change and variability in glycemia with risk of heart failure (HF) among patients with type 2 diabetes mellitus (T2DM).Research design and methodsAmong participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, variability in HbA1c was assessed from stabilization of HbA1c following enrollment (8 months) to 3 years of follow-up as follows: average successive variability (ASV) (average absolute difference between successive values), coefficient of variation (SD/mean), and SD. Participants with HF at baseline or within 3 years of enrollment were excluded. Adjusted Cox models were used to evaluate the association of percent change (from baseline to 3 years of follow-up) and variability in HbA1c over the first 3 years of enrollment and subsequent risk of HF.ResultsThe study included 8,576 patients. Over a median follow-up of 6.4 years from the end of variability measurements at year 3, 388 patients had an incident HF hospitalization. Substantial changes in HbA1c were significantly associated with higher risk of HF (hazard ratio [HR] for ≥10% decrease 1.32 [95% CI 1.08-1.75] and for ≥10% increase 1.55 [1.19-2.04]; reference

Cardiovascular disease disparities are shaped by differences in risk factors across racial and ethnic groups. Housing remains an important social determinant of health. The objective of this statement is to review and summarize research that has examined the associations of housing status with cardiovascular health and overall health. PubMed/Medline, Centers for Disease Control and Prevention data, US Census data, Cochrane Library reviews, and the annual Heart Disease and Stroke Statistics report from the American Heart Association were used to identify empirical research studies that examined associations of housing with cardiovascular health and overall well-being. Health is affected by 4 prominent dimensions of housing: stability, quality and safety, affordability and accessibility, and neighborhood environment. Vulnerable and underserved populations are adversely affected by housing insecurity and homelessness, are at risk for lower-quality and unsafe housing conditions, confront structural barriers that limit access to affordable housing, and are at risk for living in areas with substandard built environment features that are linked to cardiovascular disease. Research linking select pathways to cardiovascular health is relatively strong, but research gaps in other housing pathways and cardiovascular health remain. Efforts to eliminate cardiovascular disease disparities have recently emphasized the importance of social determinants of health. Housing is a prominent social determinant of cardiovascular health and well-being and should be considered in the evaluation of prevention efforts to reduce and eliminate racial/ethnic and socioeconomic disparities.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

ObjectiveTo develop and validate a novel, machine learning-derived model to predict the risk of heart failure (HF) among patients with type 2 diabetes mellitus (T2DM).Research design and methodsUsing data from 8,756 patients free at baseline of HF, with

AimsThe relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF.Methods and resultsParticipants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI

AimsThe relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF.Methods and resultsParticipants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI

Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4 769 040 deaths among Hispanics (n=382 416) and non-Hispanic whites (n=4 386 624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100 000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100 000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties.

Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics' Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4 769 040 deaths among Hispanics (n=382 416) and non-Hispanic whites (n=4 386 624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100 000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100 000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties.

Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics' Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4 769 040 deaths among Hispanics (n=382 416) and non-Hispanic whites (n=4 386 624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100 000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100 000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties.

Risk factors can drive socioeconomic inequalities in cardiovascular disease (CVD) through differential exposure and differential vulnerability. In this paper, we show how econometric decomposition directly enables simultaneous, policy-oriented assessment of these 2 mechanisms. We specifically estimate contributions of neighborhood environment and proximal risk factors to socioeconomic inequality in CVD incidence via these mechanisms. We followed 5,608 participants in the Multi-Ethnic Study of Atherosclerosis (2000-2012) to their first CVD event (median length of follow-up, 12.2 years). We used a summary measure of baseline socioeconomic position (SEP). Covariates included baseline demographics, neighborhood characteristics, and psychosocial, behavioral, and biomedical risk factors. Using Poisson models, we decomposed the difference (inequality) in incidence rates between low- and high-SEP groups into contributions of 1) differences in covariate means (differential exposure) and 2) differences in CVD risk associated with covariates (differential vulnerability). Notwithstanding large uncertainty in neighborhood estimates, our analysis suggested that differential exposure to poorer neighborhood socioeconomic conditions, adverse social environment, diabetes, and hypertension accounted for most of the inequality. Psychosocial and behavioral contributions were negligible. Further, neighborhood SEP, female sex, and white race were more strongly associated with CVD among low-SEP (vs. high-SEP) participants. These differentials in vulnerability also accounted for nontrivial portions of the inequality and could have important implications for intervention.

Using data from the Multi-Ethnic Study of Atherosclerosis baseline sample from 2000 to 2002 (N=5263; mean age=62) we examined cross-sectional racial/ethnic differences in ideal CVH, defined by the American Heart Association 2020 Impact Goals as a summary measure of ideal levels of blood pressure, fasting glucose, cholesterol, body mass index, diet, physical activity, and smoking. Using three different analytical approaches, we examined differences before and after adjustment for neighborhood socioeconomic, physical, and social environments. Significant racial/ethnic differences were present for all indicators of ideal CVH (excluding physical activity). Additional adjustments for neighborhood factors produced modest reductions in racial/ethnic differences. Future research is necessary to better understand the impact of neighborhood context on health disparities using longitudinal study designs.

UnlabelledWe measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ≥1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8(+) T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4-12 of suppressive ART.Clinical trials registrationNCT00001137.

ObjectiveThe objective of the study was to investigate whether group prenatal care (Centering Pregnancy Plus [CP+]) has an impact on pregnancy weight gain and postpartum weight loss trajectories and to determine whether prenatal depression and distress might moderate these trajectories.Study designThis was a secondary analysis of a cluster-randomized trial of CP+ in 14 Community Health Centers and hospitals in New York City. Participants were pregnant women aged 14-21 years (n = 984). Medical record review and 4 structured interviews were conducted: in the second and third trimesters and 6 and 12 months postpartum. Longitudinal mixed modeling was utilized to evaluate the weight change trajectories in the control and intervention groups. Prenatal distress and depression were also assessed to examine their impact on weight change.ResultsThere were no significant differences between the intervention and control groups in baseline demographics. Thirty-five percent of the participants were overweight or obese, and more than 50% had excessive weight gain by Institute of Medicine standards. CP+ was associated with improved weight trajectories compared with controls (P < .0001): women at clinical sites randomized to group prenatal care gained less weight during pregnancy and lost more weight postpartum. This effect was sustained among women who were categorized as obese based on prepregnancy body mass index (P < .01). Prenatal depression and distress were significantly associated with higher antepartum weight gain and postpartum weight retention. Women with the highest levels of depression and prenatal distress exhibited the greatest positive impact of group prenatal care on weight trajectories during pregnancy and through 12 months postpartum.ConclusionGroup prenatal care has a significant impact on weight gain trajectories in pregnancy and postpartum. The intervention also appeared to mitigate the effects of depression and prenatal distress on antepartum weight gain and postpartum weight retention. Targeted efforts are needed during and after pregnancy to improve weight gain trajectories and overall health.

UnlabelledPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy in need of more effective treatment approaches. One potential therapeutic target is Wnt/β-catenin signaling, which plays important roles in PDAC tumor initiation and progression. Among Wnt inhibitors with suitable in vivo biologic activity is vitamin D, which is known to antagonize Wnt/β-catenin signaling in colorectal cancer and have antitumor activity in PDAC. For this study, the relationship between vitamin D signaling, Wnt/β-catenin activity, and tumor cell growth in PDAC was investigated through the use of calcipotriol, a potent non-hypercalcemic vitamin D analogue. PDAC tumor cell growth inhibition by calcipotriol was positively correlated with vitamin D receptor expression and Wnt/β-catenin activity. Furthermore, vitamin D and Wnt signaling activity were found to be reciprocally linked through feedback regulation. Calcipotriol inhibited autocrine Wnt/β-catenin signaling in PDAC cell lines in parallel with decreased protein levels of the low-density lipoprotein receptor-related protein 6 (LRP6), a requisite coreceptor for ligand-dependent canonical Wnt signaling. Decrease in LRP6 protein seen with calcipotriol was mediated through a novel mechanism involving transcriptional upregulation of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). Finally, changes in LRP6 or LDLRAP1 expression directly altered Wnt reporter activity, supporting their roles as regulators of ligand-dependent Wnt/β-catenin signaling.ImplicationsThis study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/β-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/β-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with β-catenin and inhibit CBP function as a coactivator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G₁ cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/β-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.

BackgroundWe previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1; CD71) to be used as a delivery vector for cancer therapy and showed that ch128.1Av delivers the biotinylated plant toxin saporin-6 into malignant B cells. However, as a result of widespread expression of TfR1, delivery of the toxin to normal cells is a concern. Therefore, we explored the potential of a dual targeted lentiviral-mediated gene therapy strategy to restrict gene expression to malignant B cells. Targeting occurs through the use of ch128.1Av or its parental antibody without avidin (ch128.1) and through transcriptional regulation using an immunoglobulin promoter.MethodsFlow cytometry was used to detect the expression of enhanced green fluorescent protein (EGFP) in a panel of cell lines. Cell viability after specific delivery of the therapeutic gene FCU1, a chimeric enzyme consisting of cytosine deaminase genetically fused to uracil phosphoribosyltransferse that converts the 5-fluorocytosine (5-FC) prodrug into toxic metabolites, was monitored using the MTS or WST-1 viability assay.ResultsWe found that EGFP was specifically expressed in a panel of human malignant B-cell lines, but not in human malignant T-cell lines. EGFP expression was observed in all cell lines when a ubiquitous promoter was used. Furthermore, we show the decrease of cell viability in malignant plasma cells in the presence of 5-FC and the FCU1 gene.ConclusionsThe present study demonstrates that gene expression can be restricted to malignant B cells and suggests that this dual targeted gene therapy strategy may help to circumvent the potential side effects of certain TfR1-targeted protein delivery approaches.

BackgroundWe previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1; CD71) to be used as a delivery vector for cancer therapy and showed that ch128.1Av delivers the biotinylated plant toxin saporin-6 into malignant B cells. However, as a result of widespread expression of TfR1, delivery of the toxin to normal cells is a concern. Therefore, we explored the potential of a dual targeted lentiviral-mediated gene therapy strategy to restrict gene expression to malignant B cells. Targeting occurs through the use of ch128.1Av or its parental antibody without avidin (ch128.1) and through transcriptional regulation using an immunoglobulin promoter.MethodsFlow cytometry was used to detect the expression of enhanced green fluorescent protein (EGFP) in a panel of cell lines. Cell viability after specific delivery of the therapeutic gene FCU1, a chimeric enzyme consisting of cytosine deaminase genetically fused to uracil phosphoribosyltransferse that converts the 5-fluorocytosine (5-FC) prodrug into toxic metabolites, was monitored using the MTS or WST-1 viability assay.ResultsWe found that EGFP was specifically expressed in a panel of human malignant B-cell lines, but not in human malignant T-cell lines. EGFP expression was observed in all cell lines when a ubiquitous promoter was used. Furthermore, we show the decrease of cell viability in malignant plasma cells in the presence of 5-FC and the FCU1 gene.ConclusionsThe present study demonstrates that gene expression can be restricted to malignant B cells and suggests that this dual targeted gene therapy strategy may help to circumvent the potential side effects of certain TfR1-targeted protein delivery approaches.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.