Social Determinants modulate NK cell activity via obesity, LDL, and DUSP1 signaling.

Adverse social determinants of health (aSDoH) are associated with obesity and related comorbidities like diabetes, cardiovascular disease, and cancer. Obesity is also associated with natural killer cell (NK) dysregulation, suggesting a potential mechanistic link. Therefore, we measured NK phenotypes and function in a cohort of African-American (AA) women from resource-limited neighborhoods. Obesity was associated with reduced NK cytotoxicity and a shift towards a regulatory phenotype. In vitro, LDL promoted NK dysfunction, implicating hyperlipidemia as a mediator of obesity-related immune dysregulation. Dual specific phosphatase 1 (DUSP1) was induced by LDL and was upregulated in NK cells from subjects with obesity, implicating DUSP1 in obesity-mediated NK dysfunction. In vitro, DUSP1 repressed LAMP1/CD107a, depleting NK cells of functional lysosomes to prevent degranulation and cytokine secretion. Together, these data provide novel mechanistic links between aSDoH, obesity, and immune dysregulation that could be leveraged to improve outcomes in marginalized populations.

Associations between neighborhood socioeconomic deprivation, IFNγ, and high-density lipoprotein particle size: Data from the Washington, D.C. cardiovascular health and needs assessment.

INTRODUCTION: Neighborhood socioeconomic deprivation is associated with increased cardiovascular risk factors, including inflammation. Inflammation plays an important role in modifying the cardioprotective function of high-density lipoprotein (HDL). Moreover, recent studies suggest that very high HDL is associated with adverse cardiovascular disease (CVD) outcomes. Thus, we sought to explore the relationships between neighborhood socioeconomic deprivation as a marker of chronic stress, inflammation, proprotein convertase subtilisin/kexin type 9 (PCSK9) (a core component of the HDL proteome), HDL characterisitcs, and biological aging as a predictor of CVD and all-cause mortality. METHODS: Sixty African American subjects were recruited to the NIH Clinical Center as part of a community-based participatory research-designed observational study. Neighborhood deprivation index (NDI), a marker of neighborhood socioeconomic deprivation, was measured using US Census data. HDL characteristics (cholesterol, particle number, size, subspecies) were determined from NMR lipoprotein profiling, and plasma cytokines (IL-1ß, IL-6, IL-8, TNFα, IFNγ) were measured using an ELISA-based multiplex technique. Epigenetic clock biomarkers of aging were measured using DNA methylation data obtained from participants' buffy coat samples. We used linear regression modeling adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index (BMI), and lipid-lowering medication use to investigate relationships of interest. RESULTS: NDI directly associated with large HDL particle count (H7P) and IFNγ and trended toward significance with HDL-C and PCSK9. IFNγ and PCSK9 then directly associated with H7P. H7P also directly associated with higher DNA methylation phenotypic age (PhenoAge). CONCLUSION: We highlight associations between neighborhood socioeconomic deprivation, IFNγ, PCSK9, HDL subspecies, and epigenetic biomarkers of aging. Taken together, our findings suggest indirect pathways linking neighborhood deprivation-related stress and inflammation to HDL and immune epigenetic changes. Moreover, these results add to recent work showing the pathogenicity of high HDL levels and underscore the need to understand how chronic stress-related inflammation and lipoprotein subspecies relate to CVD risk across diverse populations.

Neighborhood socioeconomic deprivation and individual-level socioeconomic status are associated with dopamine-mediated changes to monocyte subset CCR2 expression via a cAMP-dependent pathway.

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors that impact health. Neighborhood socioeconomic deprivation (NSD) and low individual-level socioeconomic status (SES) are SDoH that associate with incident heart failure, stroke, and cardiovascular mortality, but the underlying biological mechanisms are not well understood. Previous research has demonstrated an association between NSD, in particular, and key components of the neural-hematopoietic-axis including amygdala activity as a marker of chronic stress, bone marrow activity, and arterial inflammation. Our study further characterizes the role of NSD and SES as potential sources of chronic stress related to downstream immunological factors in this stress-associated biologic pathway. We investigated how NSD, SES, and catecholamine levels (as proxy for sympathetic nervous system activation) may influence monocytes which are known to play a significant role in atherogenesis. First, in an ex vivo approach, we treated healthy donor monocytes with biobanked serum from a community cohort of African Americans at risk for CVD. Subsequently, the treated monocytes were subjected to flow cytometry for characterization of monocyte subsets and receptor expression. We determined that NSD and serum catecholamines (namely dopamine [DA] and norepinephrine [NE]) associated with monocyte C-C chemokine receptor type 2 (CCR2) expression (p < 0.05), a receptor known to facilitate recruitment of monocytes towards arterial plaques. Additionally, NSD associated with catecholamine levels, especially DA in individuals of low SES. To further explore the potential role of NSD and the effects of catecholamines on monocytes, monocytes were treated in vitro with epinephrine [EPI], NE, or DA. Only DA increased CCR2 expression in a dose-dependent manner (p < 0.01), especially on non-classical monocytes (NCM). Furthermore, linear regression analysis between D2-like receptor surface expression and surface CCR2 expression suggested D2-like receptor signaling in NCM. Indicative of D2-signaling, cAMP levels were found to be lower in DA-treated monocytes compared to untreated controls (control 29.78 pmol/ml vs DA 22.97 pmol/ml; p = 0.038) and the impact of DA on NCM CCR2 expression was abrogated by co-treatment with 8-CPT, a cAMP analog. Furthermore, Filamin A (FLNA), a prominent actin-crosslinking protein, that is known to regulate CCR2 recycling, significantly decreased in DA-treated NCM (p < 0.05), indicating a reduction of CCR2 recycling. Overall, we provide a novel immunological mechanism, driven by DA signaling and CCR2, for how NSD may contribute to atherogenesis. Future studies should investigate the importance of DA in CVD development and progression in populations disproportionately experiencing chronic stress due to SDoH.

LDL associates with pro-inflammatory monocyte subset differentiation and increases in chemokine receptor profile expression in African Americans.

BACKGROUND: In the United States, African Americans (AAs) have greater risk for Class III obesity and cardiovascular disease (CVD). Previous reports suggest that AAs have a different immune cell profile when compared to Caucasians. METHODS: The immune cell profile of AAs was characterized by flow cytometry using two experimental setups: ex vivo (N = 40) and in vitro (N = 10). For ex vivo experiments, PBMC were treated with participant serum to understand how lipid contents may contribute to monocyte phenotypic differences. For in vitro experiments, monocytes were low-density lipoprotein (LDL)- or vehicle-treated for four hours and subsequently analyzed by flow cytometry and RT-qPCR. RESULTS: When PBMCs were treated with participant sera, subsequent multivariable regression analysis revealed that serum triglycerides and LDL levels were associated with monocyte subset differences. In vitro LDL treatment of monocytes induced a phenotypic switch in monocytes away from classical monocytes accompanied by subset-specific chemokine receptor CCR2 and CCR5 expression changes. These observed changes are partially translation-dependent as determined by co-incubation with cycloheximide. CONCLUSIONS: LDL treatment of monocytes induces a change in monocyte subsets and increases CCR2/CCR5 expression in a subset-specific manner. Understanding the molecular mechanisms could prove to have CVD-related therapeutic benefits, especially in high-risk populations with hyperlipidemia and increased risk for CVD.

Use of a community advisory board to build equitable algorithms for participation in clinical trials: a protocol paper for HoPeNET.

INTRODUCTION: Participation from racial and ethnic minorities in clinical trials has been burdened by issues surrounding mistrust and access to healthcare. There is emerging use of machine learning (ML) in clinical trial recruitment and evaluation. However, for individuals from groups who are recipients of societal biases, utilisation of ML can lead to the creation and use of biased algorithms. To minimise bias, the design of equitable ML tools that advance health equity could be guided by community engagement processes. The Howard University Partnership with the National Institutes of Health for Equitable Clinical Trial Participation for Racial/Ethnic Communities Underrepresented in Research (HoPeNET) seeks to create an ML-based infrastructure from community advisory board (CAB) experiences to enhance participation of African-Americans/Blacks in clinical trials. METHODS AND ANALYSIS: This triphased cross-sectional study (24 months, n=56) will create a CAB of community members and research investigators. The three phases of the study include: (1) identification of perceived barriers/facilitators to clinical trial engagement through qualitative/quantitative methods and systems-based model building participation; (2) operation of CAB meetings and (3) development of a predictive ML tool and outcome evaluation. Identified predictors from the participant-derived systems-based map will be used for the ML tool development. ETHICS AND DISSEMINATION: We anticipate minimum risk for participants. Institutional review board approval and informed consent has been obtained and patient confidentiality ensured.

Spatial Clustering of County-Level COVID-19 Rates in the U.S.

Despite the widespread prevalence of cases associated with the coronavirus disease 2019 (COVID-19) pandemic, little is known about the spatial clustering of COVID-19 in the United States. Data on COVID-19 cases were used to identify U.S. counties that have both high and low COVID-19 incident proportions and clusters. Our results suggest that there are a variety of sociodemographic variables that are associated with the severity of COVID-19 county-level incident proportions. As the pandemic evolved, communities of color were disproportionately impacted. Subsequently, it shifted from communities of color and metropolitan areas to rural areas in the U.S. Our final period showed limited differences in county characteristics, suggesting that COVID-19 infections were more widespread. The findings might address the systemic barriers and health disparities that may result in high incident proportions of COVID-19 clusters.

Geospatial Analysis of Neighborhood Environmental Stress in Relation to Biological Markers of Cardiovascular Health and Health Behaviors in Women: Protocol for a Pilot Study.

BACKGROUND: Innovative analyses of cardiovascular (CV) risk markers and health behaviors linked to neighborhood stressors are essential to further elucidate the mechanisms by which adverse neighborhood social conditions lead to poor CV outcomes. We propose to objectively measure physical activity (PA), sedentary behavior, and neighborhood stress using accelerometers, GPS, and real-time perceived ecological momentary assessment via smartphone apps and to link these to biological measures in a sample of White and African American women in Washington, DC, neighborhoods. OBJECTIVE: The primary aim of this study is to test the hypothesis that living in adverse neighborhood social conditions is associated with higher stress-related neural activity among 60 healthy women living in high or low socioeconomic status neighborhoods in Washington, DC. Sub-aim 1 of this study is to test the hypothesis that the association is moderated by objectively measured PA using an accelerometer. A secondary objective is to test the hypothesis that residing in adverse neighborhood social environment conditions is related to differences in vascular function. Sub-aim 2 of this study is to test the hypothesis that the association is moderated by objectively measured PA. The third aim of this study is to test the hypothesis that adverse neighborhood social environment conditions are related to differences in immune system activation. METHODS: The proposed study will be cross-sectional, with a sample of at least 60 women (30 healthy White women and 30 healthy Black women) from Wards 3 and 5 in Washington, DC. A sample of the women (n=30) will be recruited from high-income areas in Ward 3 from census tracts within a 15% of Ward 3's range for median household income. The other participants (n=30) will be recruited from low-income areas in Wards 5 from census tracts within a 15% of Ward 5's range for median household income. Finally, participants from Wards 3 and 5 will be matched based on age, race, and BMI. Participants will wear a GPS unit and accelerometer and report their stress and mood in real time using a smartphone. We will then examine the associations between GPS-derived neighborhood variables, stress-related neural activity measures, and adverse biological markers. RESULTS: The National Institutes of Health Institutional Review Board has approved this study. Recruitment will begin in the summer of 2021. CONCLUSIONS: Findings from this research could inform the development of multilevel behavioral interventions and policies to better manage environmental factors that promote immune system activation or psychosocial stress while concurrently working to increase PA, thereby influencing CV health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/29191.

Neighborhood Environment Associates with Trimethylamine-N-Oxide (TMAO) as a Cardiovascular Risk Marker.

BACKGROUND: Neighborhoods and the microbiome are linked to cardiovascular disease (CVD), yet investigations to identify microbiome-related factors at neighborhood levels have not been widely investigated. We sought to explore relationships between neighborhood deprivation index (NDI) and the microbial metabolite, trimethylamine-N-oxide. We hypothesized that inflammatory markers and dietary intake would be mediators of the relationship. METHODS: African-American adults at risk for CVD living in the Washington, DC area were recruited to participate in a cross-sectional community-based study. US census-based neighborhood deprivation index (NDI) measures (at the census-tract level) were determined. Serum samples were analyzed for CVD risk factors, cytokines, and the microbial metabolite, trimethylamine-N-oxide (TMAO). Self-reported dietary intake based on food groups was collected. RESULTS: Study participants (n = 60) were predominantly female (93.3%), with a mean (SD) age of 60.83 (+/-10.52) years. Mean (SD) NDI was -1.54 (2.94), and mean (SD) TMAO level was 4.99 (9.65) µmol/L. Adjusting for CVD risk factors and BMI, NDI was positively associated with TMAO (ß = 0.31, p = 0.02). Using mediation analysis, the relationship between NDI and TMAO was significantly mediated by TNF-α (60.15%) and interleukin)-1 ß (IL; 49.96%). When controlling for clustering within neighborhoods, the NDI-TMAO association was no longer significant (ß = 5.11, p = 0.11). However, the association between NDI and IL-1 ß (ß = 0.04, p = 0.004) and TNF-α (ß = 0.17, p = 0.003) remained. Neither NDI nor TMAO was significantly associated with daily dietary intake. Conclusion and Relevance: Among a small sample of African-American adults at risk for CVD, there was a significant positive relationship with NDI and TMAO mediated by inflammation. These hypothesis-generating results are initial and need to be confirmed in larger studies.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment.

Background: Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar 18Fluorodeoxyglucose (18FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Methods: Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including 18FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. Results: AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, p = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, p = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (ß = 0.41, p = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. Conclusions: AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings.

Neighborhood environment perceptions associate with depression levels and cardiovascular risk among middle-aged and older adults: Data from the Washington, DC cardiovascular health and needs assessment.

OBJECTIVES: Little is understood about associations between neighborhood characteristics and depression, a cardiovascular disease (CVD) risk factor, in diverse populations. We examined relationships between perceived/objective neighborhood characteristics, depression, and CVD markers within the Washington, DC CV Health/Needs Assessment, an evaluation among predominantly African-American (AA) adults in resource-limited DC communities. METHOD: Factor analysis of overall neighborhood environment perception (NEP) identified three NEP sub-scores:1) violence; 2) physical/social environment; 3) social cohesion (higher score = more favorable perception). Objective neighborhood characteristics were measured by geospatially-derived scores of walkability, transportation, and crime. Depression was defined by the revised Center for Epidemiologic Studies Depression Scale (CESD-R). We used linear-regression modeling to examine neighborhood measures and CESD-R associations. To investigate a subsequent connection with CVD risk, we examined relationships between CESD-R and CVD-associated cytokines in a population subset. RESULTS: Participants (N = 99; mean age = 59.06; 99% AA) had a mean CESD-R score = 5.8(SD = 8.88). In adjusted models, CESD-R scores decreased by 0.20 units (p = 0.01) for every overall NEP unit-increase. Perceived physical/social environment (ß = -0.34, p = 0.04) and social cohesion (ß = -0.82, p = 0.01) were related to CESD-R while perceived violence was not (ß = -0.28, p = 0.1). Of objective neighborhood environment measures (i.e. walk, transit, bike, personal crime, and property crime scores), only property crime score was associated with depression (ß = 4.99, p < 0.03). In population subset (n = 42), higher CESD-R associated with higher IL-1ß (ß = 21.25, p < 0.01) and IL-18 (ß = 0.006, p = 0.01). CONCLUSION: Favorable neighborhood perceptions are related to lower depressive symptoms in a predominantly AA cohort from Washington, DC resource-limited communities. Neighborhood perceptions appear to be strongly associated with depressive symptoms compared to objective characteristics. Increasing CESD-R scores were related to higher pro-inflammatory markers. Improving neighborhood perceptions may be beneficial to psychological well-being and CV health for urban minority residents.

Comparing Methods to Identify Wear-Time Intervals for Physical Activity With the Fitbit Charge 2.

There is no established method for processing data from commercially available physical activity trackers. This study aims to develop a standardized approach to defining valid wear time for use in future interventions and analyses. Sixteen African American women (mean age = 62.1 years and mean body mass index = 35.5 kg/m2) wore the Fitbit Charge 2 for 20 days. Method 1 defined a valid day as ≥10-hr wear time with heart rate data. Method 2 removed minutes without heart rate data, minutes with heart rate ≤ mean - 2 SDs below mean and ≤2 steps, and nighttime. Linear regression modeled steps per day per week change. Using Method 1 (n = 292 person-days), participants had 20.5 (SD = 4.3) hr wear time per day compared with 16.3 (SD = 2.2) hr using Method 2 (n = 282) (p < .0001). With Method 1, participants took 7,436 (SD = 3,543) steps per day compared with 7,298 (SD = 3,501) steps per day with Method 2 (p = .64). The proposed algorithm represents a novel approach to standardizing data generated by physical activity trackers. Future studies are needed to improve the accuracy of physical activity data sets.

Multilevel mobile health approach to improve cardiovascular health in resource-limited communities with Step It Up: a randomised controlled trial protocol targeting physical activity.

INTRODUCTION: Although physical activity (PA) reduces cardiovascular disease (CVD) risk, physical inactivity remains a pressing public health concern, especially among African American (AA) women in the USA. PA interventions focused on AA women living in resource-limited communities with scarce PA infrastructure are needed. Mobile health (mHealth) technology can increase access to PA interventions. We describe the development of a clinical protocol for a multilevel, community-based, mHealth PA intervention for AA women. METHODS AND ANALYSIS: An mHealth intervention targeting AA women living in resource-limited Washington, DC communities was developed based on the socioecological framework for PA. Over 6 months, we will use a Sequential Multi-Assignment, Randomized Trial approach to compare the effects on PA of location-based remote messaging (named 'tailored-to-place') to standard remote messaging in an mHealth intervention. Participants will be randomised to a remote messaging intervention for 3 months, at which point the intervention strategy will adapt based on individuals' PA levels. Those who do not meet the PA goal will be rerandomised to more intensive treatment. Participants will be followed for another 3 months to determine the contribution of each mHealth intervention to PA level. This protocol will use novel statistical approaches to account for the adaptive strategy. Finally, effects of PA changes on CVD risk biomarkers will be characterised. ETHICS AND DISSEMINATION: This protocol has been developed in partnership with a Washington, DC-area community advisory board to ensure feasibility and acceptability to community members. The National Institutes of Health Intramural IRB approved this research and the National Heart, Lung, and Blood Institute provided funding. Once published, results of this work will be disseminated to community members through presentations at community advisory board meetings and our quarterly newsletter. TRIAL REGISTRATION NUMBER: NCT03288207.

Geospatial Analysis of Neighborhood Deprivation Index (NDI) for the United States by County.

Little is known about the spatial clustering of neighborhood deprivation across the United States (U.S.). Using data from the 2010 U.S. Census Bureau, we created a neighborhood deprivation index (NDI: higher NDI indicates higher deprivation/ lower neighborhood socioeconomic status) for each county within the U.S. County level scores were loaded into ArcGIS 10.5.1 where they were mapped and analyzed using Moran's I and Anselin Local Moran's I. Ultimately, NDI varies spatially across the US. The highest NDI scores were found in the Southeastern and Southwestern U.S. states, and inland regions of Southern California. This information is critical for public health initiative development as planners may need to tailor the scale of their efforts based on the higher NDI neighborhoods of the county or geographic region with potentially greater chronic disease burden.

Time to listen: a mixed-method study examining community-based views of mobile technology for interventions to promote physical activity.

INTRODUCTION: A mixed-method, co-design approach to studying the adoption of mobile health (mHealth) technology among African-American (AA) women has not been fully explored. Qualitative data may contextualise existing knowledge surrounding perceptions of mHealth among AA women as part of formative work for designing a physical activity application (app). METHODS: A convenience sample of 16 AA women completed an informatics survey prior to participating in focus groups exploring their use of mobile technology and health apps. Survey responses provided frequency data, while iterative transcript analysis of focus groups identified themes. RESULTS: The majority of participants (mean age=62.1 years, SD=6.6) felt comfortable using a tablet/smartphone (75.0%). Most (68.8%) reported using health-related apps, primarily focused on physical activity and nutrition. Focus groups revealed four overarching concepts, including (1) user attachment, (2) technology adoption, (3) potential facilitators and (4) potential barriers. Important features which may serve as facilitators or barriers to future adoption of a mobile app for an mHealth intervention include individual app tailoring and software concerns, respectively. DISCUSSION: Thematic analysis revealed high user attachment to smartphones and described participants' process for adopting new mHealth technology. CONCLUSION: Early engagement of target end users as a part of a broader co-design and community-based participatory research process for developing mHealth technologies may be useful for sustained adoption of these tools in future mHealth behavioural interventions.

Digital Food Records in Community-Based Interventions: Mixed-Methods Pilot Study.

BACKGROUND: A pressing need exists to understand and optimize the use of dietary assessment tools that can be used in community-based participatory research (CBPR) interventions. A digital food record, which uses a mobile device to capture the dietary intake through text and photography inputs, is a particularly promising mobile assessment method. However, little is understood about the acceptability and feasibility of digital food records in CBPR and how to best tailor dietary assessment tools to the needs of a community. OBJECTIVE: The objective of our study was to evaluate the acceptability and feasibility of digital food records among church-based populations in resource-limited wards of Washington, DC, USA, using a mixed-methods approach. METHODS: This community-based pilot study was conducted as part of the Washington, DC Cardiovascular Health and Needs Assessment. Participants (n=17) received a mobile device (iPod Touch) to photodocument their dietary intake for a 3-day digital food record using a mobile app, FitNinja (Vibrent Health). The acceptability of the digital food record was explored through the thematic analysis of verbatim transcripts from a moderated focus group (n=8). In addition, the feasibility was evaluated by the percentage of participants complying with instructions (ie, capturing both before and after meal photos for at least 2 meals/day for 3 days). RESULTS: Qualitative themes identified were related to (1) the feasibility and acceptability of the mobile device and app, including issues in recording the dietary information and difficulty with photodocumentation; (2) suggestions for additional support and training experiences; and (3) comparisons with other mobile apps. Overall, the participants accepted the digital food record by demonstrating satisfaction with the tool and intent to continue the use (eg, participants recorded an average of 5.2, SD 7, consecutive days). Furthermore, of the 17 participants, 15 photodocumented at least 1 meal during the study period and 3 fully complied with the digital food record instructions. CONCLUSIONS: This study demonstrated digital food records as an acceptable tool in CBPR and identified contributors and barriers to the feasibility of digital food records for future research. Engaging community members in the implementation of novel assessment methods allows for the tailoring of technology to the needs of the community and optimizing community-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927783; https://www.clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/70WzaFWb6).