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This study was undertaken to elicit the opinion of experts regarding the management of iatrogenic injury to the carotid artery. A text questionnaire was transmitted by electronic mail to members of the Western Vascular Society concerning management of iatrogenic injury to the cervical carotid artery. Participants were asked to submit information regarding practice status and their preferred choices for the management of different clinical scenarios. The scenarios were: (1) large bore sheath (> 8.5F) cannulation of the carotid artery in anesthetized patients, (2) large bore sheath cannulation of the carotid artery in an awake patient, (3) delayed recognition of a misplaced sheath by > 4 hours, and (4) arterial puncture was recognized after only the entry needle (16-gauge) was introduced but before sheath insertion. Finally, the members were asked to comment on the management of abnormal findings on duplex scanning, such as intimal flap or pseudoaneurysm. A response rate of 42% was obtained (45/106 active members). Eighty-two percent of respondents had been in practice for longer than 10 years. Eighty-nine percent had seen this complication and 29% had cared for patients in whom subsequent neurologic deficit developed. The institutional incidence of such injury was 1-5 cases per year for 82% of respondents. Sixteen-gauge needle injury was managed by immediate removal and applied pressure by 98% of respondents. When large-bore sheath injury is recognized within 1 hour of insertion, 62% of respondents would remove the sheath and hold pressure, with or without obtaining a duplex ultrasound examination. However, if injury recognition was delayed for > 4 hours, 82% would proceed to surgery. Only 26% operated on asymptomatic carotid flap found on ultrasound, while the remaining 74% would base their decision on size and flow characteristics on ultrasound. The management of pseudoaneurysm differed significantly. Whereas 31% of respondents would manage this finding expectantly, 69% would proceed to surgery regardless of size or symptoms. Despite awareness of iatrogenic injury to the cervical carotid artery, the institutional incidence remains high. Two thirds of respondents would manage a misplaced sheath in the carotid artery nonoperatively if the injury was recognized immediately. However, if injury recognition was delayed for > 4 hours, the majority of respondents would remove the sheath surgically. While the management of intimal flap largely depended on size and flow characteristics, 69% of respondents would operate on a pseudoaneurysm regardless of size or symptoms. The results of this survey may serve as a guideline for the management of this potentially devastating injury. [ABSTRACT FROM AUTHOR]

Particulate matter with an aerodynamic diameter of less than 2.5 µm (PM 2.5 ) is one of the criteria air pollutants that (1) serve as an essential carrier of airborne toxicants arising from combustion-related events including emissions from industries, automobiles, and wildfires and (2) play an important role in transient to long-lasting cognitive dysfunction as well as several other neurological disorders. A systematic review was conducted to address differences in study design and various biochemical and molecular markers employed to elucidate neurological disorders in PM 2.5 -exposed humans and animal models. Out of 340,068 scientific publications screened from 7 databases, 312 studies were identified that targeted the relationship between exposure to PM 2.5 and cognitive dysfunction. Equivocal evidence was identified from pre-clinical (animal model) and human studies that PM 2.5 exposure contributes to dementia, Parkinson disease, multiple sclerosis, stroke, depression, autism spectrum disorder, attention deficit hyperactivity disorder, and neurodevelopment. In addition, there was substantial evidence from human studies that PM 2.5 also was associated with Alzheimer's disease, anxiety, neuropathy, and brain tumors. The role of exposome in characterizing neurobehavioral anomalies and opportunities available to leverage the neuroexposome initiative for conducting longitudinal studies is discussed. Our review also provided some areas that warrant consideration, one of which is unraveling the role of microbiome, and the other role of climate change in PM 2.5 exposure-induced neurological disorders.

Policy Points Artificial intelligence (AI) is disruptively innovating health care and surpassing our ability to define its boundaries and roles in health care and regulate its application in legal and ethical ways. Significant progress has been made in governance in the United States and the European Union. It is incumbent on developers, end users, the public, providers, health care systems, and policymakers to collaboratively ensure that we adopt a national AI health strategy that realizes the Quintuple Aim; minimizes race-based medicine; prioritizes transparency, equity, and algorithmic vigilance; and integrates the patient and community voices throughout all aspects of AI development and deployment., (© 2024 The Author(s). The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)

Objectives: To examine if racial differences in cardiovascular health (CVH) are associated with cardiovascular disease (CVD) disparities among women with breast and gynecologic cancers., Sample & Setting: The sample consisted of 252 Black women and 93 White women without a self-reported history of cancer or CVD who developed a breast or gynecologic malignancy. Women who developed CVD before their cancer diagnosis were excluded., Methods & Variables: CVH was classified using metrics of the American Heart Association's Life's Simple 7 framework. Metrics were summed to create a total CVH score (0-7). Associations among race, ideal CVH (score of 5-7), and CVD incidence following cancer diagnosis were estimated with Cox proportional hazards models., Results: Ideal CVH was similar between Black women (33%) and White women (37%). Race and CVH were not associated with CVD incidence., Implications for Nursing: In a small sample of women diagnosed with breast and gynecologic cancers, racial disparities in CVH and CVD incidence were not observed. Additional investigation of potential confounders relating to social determinants of health tied to the construct of race is warranted.

Background: The exposome serves as a popular framework in which to study exposures from chemical and nonchemical stressors across the life course and the differing roles that these exposures can play in human health. As a result, data relevant to the exposome have been used as a resource in the quest to untangle complicated health trajectories and help connect the dots from exposures to adverse outcome pathways., Objectives: The primary aim of this methods seminar is to clarify and review preprocessing techniques critical for accurate and effective external exposomic data analysis. Scalability is emphasized through an application of highly innovative combinatorial techniques coupled with more traditional statistical strategies. The Public Health Exposome is used as an archetypical model. The novelty and innovation of this seminar's focus stem from its methodical, comprehensive treatment of preprocessing and its demonstration of the positive effects preprocessing can have on downstream analytics., Discussion: State-of-the-art technologies are described for data harmonization and to mitigate noise, which can stymie downstream interpretation, and to select key exposomic features, without which analytics may lose focus. A main task is the reduction of multicollinearity, a particularly formidable problem that frequently arises from repeated measurements of similar events taken at various times and from multiple sources. Empirical results highlight the effectiveness of a carefully planned preprocessing workflow as demonstrated in the context of more highly concentrated variable lists, improved correlational distributions, and enhanced downstream analytics for latent relationship discovery. The nascent field of exposome science can be characterized by the need to analyze and interpret a complex confluence of highly inhomogeneous spatial and temporal data, which may present formidable challenges to even the most powerful analytical tools. A systematic approach to preprocessing can therefore provide an essential first step in the application of modern computer and data science methods. https://doi.org/10.1289/EHP12901.

We examined whether resilience modified associations between allostatic load (AL), a physiological indicator of coping with repeated stressors, and cardiovascular disease (CVD) among 2758 African Americans in the Jackson Heart Study. Baseline AL was quantified using biological measures of metabolic, cardiovascular, and immune markers. We constructed a multidimensional resilience measure using validated questionnaires for social support, social networks, religious experiences, and optimism. Participants were followed until 2016 for stroke, coronary heart disease (CHD), and heart failure (HF). We used multivariable-adjusted, sex-stratified Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between dichotomous AL and CVD. High AL was associated with CHD among women (HR = 1.73, 95% CI = 1.00, 2.99) and HF among women (HR = 1.52, 95% CI = 0.98, 2.37) and men (HR = 2.17, 95% CI = 1.28, 3.68). Among women, resilience did not modify the AL-CVD relationship. Among men, we observed higher stroke risk among men with low resilience (HR = 2.21, 95% CI = 0.94, 5.22) and no association among those with high resilience. Counterintuitively, high AL was associated with greater HF (HR = 5.80, 95% CI = 2.32, 14.47) in the subgroup of men with high resilience. Future studies addressing different facets of resilience are needed to elucidate underlying mechanisms for CVD prevention among African Americans., (© 2022. W. Montague Cobb-NMA Health Institute.)

Resilience, thriving in the face of adversity, is a critical component of well-being in African American women. However, traditional definitions and approaches to operationalize resilience may not capture race- and gender-related resilience experiences of African American women. A more complete conceptualization of resilience may help facilitate future investigation of the mechanisms through which resilience influences health in this group. Our team conducted a scoping review of the literature published during twenty years, between 2000 and 2019, on resilience and health in African American women. We included a multidisciplinary set of databases (PubMed, CINAHL, PsycINFO, Scopus, Social Work Abstracts, Sociological Abstracts, Academic Search Premier). Using Covidence software a multi-step review process was conducted; 904 abstracts were initially screened for eligibility, 219 full-text studies were screened in stage two, and 22 remaining studies were reviewed for extraction. The studies reviewed revealed limitations of unidimensional approaches to conceptualizing/operationalizing resilience in African American women. The review highlighted culturally-relevant components of resilience including spirituality/religion, strength, survival, active coping, and social support. Findings highlight the importance of operationalizing resilience as a multidimensional construct so it can be optimally included in research designed to investigate the quality of life, cardiovascular risk, and other health outcomes in African American women., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Little is known about whether a breast or gynecologic cancer diagnosis increases long-term cardiovascular disease (CVD) risk among Black females. The purpose of this study was to determine whether a breast or gynecologic cancer diagnosis is associated with CVD risk and identify determinants of subsequent CVD risk among Black females with an incident breast or gynecologic cancer diagnosis., Methods: Using the Southern Community Cohort Study data from 2002-2016, this study was designed to analyze CVD incidence among Black females without cancer or CVD at enrollment. Cox proportional hazards regression models with or without covariates were used to explore the relationship between a breast or gynecologic cancer diagnosis and CVD risk among women without cancer as well as without CVD at enrollment (N=11,486). In addition, Cox proportional hazards regression models, excluding those who developed CVD before breast and gynecologic cancer diagnosis and those with other types of cancers, were used to assess determinants of CVD risk among breast and gynecologic cancer survivors., Results: Of 11,486 Black females, 531 developed a breast or gynecological cancer (4.6%) over a median follow-up of 140 months (interquartile range: 123-159 months). Compared to women without cancer, women with a breast or gynecological cancers had greater than 20% higher risk of incident CVD during the follow-up period. Without adjusting for covariates, positive association between CVD risk and breast cancer was observed (hazard ratio (HR) = 1.24; 95% confidence interval (CI) = 1.11 - 1.39; p < 0.001); as well as between CVD risk and a gynecological cancer (HR = 1.23; 95% CI = 1.03 - 1.46; p = 0.021). Yet, after adjusting for covariates, CVD risk was only significantly associated with breast cancer (p = 0.001) but not gynecologic cancer. In cancer case-only analyses, CVD risk was significantly increasing with age (p < 0.05)., Conclusions: Like study populations of predominantly White females, our results suggest that, adjusting for covariates, Black females possess a higher risk of CVD following a breast cancer diagnosis compared to women who did not develop breast cancer. Our results suggest a need for active CVD surveillance in the cancer survivorship phase., (Copyright © 2023. Published by Elsevier Inc.)

Environmental factors affecting health and vulnerability far outweigh genetics in accounting for disparities in health status and longevity in US communities. The concept of the exposome, the totality of exposure from conception onwards, provides a paradigm for researchers to investigate the complex role of the environment on the health of individuals. We propose a complementary framework, community-level exposomics, for population-level exposome assessment. The goal is to bring the exposome paradigm to research and practice on the health of populations, defined by various axes including geographic, social, and occupational. This framework includes the integration of community-level measures of the built, natural and social environments, environmental pollution-derived from conventional and community science approaches, internal markers of exposure that can be measured at the population-level and early responses associated with health status that can be tracked using population-based monitoring. Primary challenges to the implementation of the proposed framework include needed advancements in population-level measurement, lack of existing models with the capability to produce interpretable and actionable evidence and the ethical considerations of labeling geographically-bound populations by exposomic profiles. To address these challenges, we propose a set of recommendations that begin with greater engagement with and empowerment of affected communities and targeted investment in community-based solutions. Applications to urban settings and disaster epidemiology are discussed as examples for implementation., Competing Interests: Conflict of interest statement None declared.

Columbus, Ohio is one of the more prosperous, well-educated, and progressive cities in the United States. However, it ranks as the second worst life expectancy at birth, has a census tract wealth gap (27-year disparity), and one of the higher infant mortality rates in the country. These data suggest that there are likely several high-risk, vulnerable neighborhoods in Columbus with residents experiencing disparate and adverse outcomes. Illustrative of this fact are studies that have examined the social processes and mechanisms through which neighborhood contexts are at the forefront, including exposures to chemical stressors such as particulate matter (PM 2.5 ) as well as non-chemical stressors including violence, social determinants of health, zoning, and land use policies. It is documented that disparate and adverse outcomes are magnified in the vulnerable neighborhoods on the Near East Side as compared to Columbus city proper, Franklin County and/or the state of Ohio. As such, we developed a nuanced community engagement framework to identify potential environmental hazards associated with adverse pregnancy outcomes in those census tracts. The refined framework uses a blended version of traditional community-based participatory research (CBPR) models and is referred to as E 6 , Enhancing Environmental Endeavors via e-Equity, Education, and Empowerment.

During the 2015-2016 Zika Virus (ZIKV) epidemic in Brazil, the geographical distributions of ZIKV infection and microcephaly outbreaks did not align. This raised doubts about the virus as the single cause of the microcephaly outbreak and led to research hypotheses of alternative explanatory factors, such as environmental variables and factors, agrochemical use, or immunizations. We investigated context and the intermediate and structural determinants of health inequalities, as well as social environment factors, to determine their interaction with ZIKV-positive- and ZIKV-negative-related microcephaly. The results revealed the identification of 382 associations among 382 nonredundant variables of Zika surveillance, including multiple determinants of environmental public health factors and variables obtained from 5565 municipalities in Brazil. This study compared those factors and variables directly associated with microcephaly incidence positive to ZIKV and those associated with microcephaly incidence negative to ZIKV, respectively, and mapped them in case and control subnetworks. The subnetworks of factors and variables associated with low birth weight and birthweight where birth incidence served as an additional control were also mapped. Non-significant differences in factors and variables were observed, as were weights of associations between microcephaly incidence, both positive and negative to ZIKV, which revealed diagnostic inaccuracies that translated to the underestimation of the scope of the ZIKV outbreak. A detailed analysis of the patterns of association does not support a finding that vaccinations contributed to microcephaly, but it does raise concerns about the use of agrochemicals as a potential factor in the observed neurotoxicity arising from the presence of heavy metals in the environment and microcephaly not associated with ZIKV. Summary: A comparative network inferential analysis of the patterns of variables and factors associated with Zika virus infections in Brazil during 2015-2016 coinciding with a microcephaly epidemic identified multiple contributing determinants. This study advances our understanding of the cumulative interactive effects of exposures to chemical and non-chemical stressors in the built, natural, physical, and social environments on adverse pregnancy and health outcomes in vulnerable populations.

There is a well-documented association between ambient fine particulate matter air pollution (PM 2.5 ) and cardiovascular disease (CVD) morbidity and mortality. Exposure to PM 2.5 can cause premature death and harmful and chronic health effects such as heart attack, diabetes, and stroke. The Environmental Protection Agency sets annual PM 2.5 standards to reduce these negative health effects. Currently above an annual average level of 12.0 μg/m is considered unhealthy., Methods: We examined the association of long-term exposure to PM 2.5 and CVD in a cohort of 44,610 individuals who resided in 12 states recruited into the Southern Community Cohort Study (SCCS). The SCCS was designed to recruit Black and White participants who received care from Federally Qualified Health Centers; hence, they represent vulnerable individuals from low-income families across this vast region. This study tests whether SCCS participants who lived in locations exposed to elevated ambient levels of PM 2.5 concentrations were more likely to report a history of CVD at enrollment (2002-2009). Remotely sensed satellite data integrated with ground monitoring data provide an assessment of the average annual PM 2.5 in urban and rural locations where the SCCS participants resided. We used multilevel logistic regression to estimate the associations between self-reported CVD and exposure to elevated ambient levels of PM 2.5 ., Results: We found a 13.4 percent increase in the odds of reported CVD with exposure to unhealthy levels of PM 2.5 exposure at enrollment. The SCCS participants with medical histories of hypertension, hypercholesterolemia, and smoking had, overall, 385 percent higher odds of reported CVD than those without these clinical risk factors. Additionally, Black participants were more likely to live in locations with higher ambient PM 2.5 concentrations and report high levels of clinical risk factors, thus, they may be at a greater future risk of CVD., Conclusions: In the SCCS participants, we found a strong relation between exposures to high ambient levels of PM 2.5 and self-reported CVD at enrollment., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: Non-adherence to antihypertensive medication treatment (AHM) is a complex health behavior with determinants that extend beyond the individual patient. The structural and social determinants of health (SDH) that predispose populations to ill health and unhealthy behaviors could be potential barriers to long-term adherence to AHM. However, the role of SDH in AHM non-adherence has been understudied. Therefore, we aimed to define and identify the SDH factors associated with non-adherence to AHM and to quantify the variation in county-level non-adherence to AHM explained by these factors., Methods: Two cross-sectional datasets, the Centers for Disease Control and Prevention (CDC) Atlas of Heart Disease and Stroke (2014-2016 cycle) and the 2016 County Health Rankings (CHR), were linked to create an analytic dataset. Contextual SDH variables were extracted from the CDC-CHR linked dataset. County-level prevalence of AHM non-adherence, based on Medicare fee-for-service beneficiaries' claims data, was extracted from the CDC Atlas dataset. The CDC measured AHM non-adherence as the proportion of days covered (PDC) with AHM during a 365 day period for Medicare Part D beneficiaries and aggregated these measures at the county level. We applied confirmatory factor analysis (CFA) to identify the constructs of social determinants of AHM non-adherence. AHM non-adherence variation and its social determinants were measured with structural equation models., Results: Among 3000 counties in the U.S., the weighted mean prevalence of AHM non-adherence (PDC < 80%) in 2015 was 25.0%, with a standard deviation (SD) of 18.8%. AHM non-adherence was directly associated with poverty/food insecurity (β = 0.31, P -value < 0.001) and weak social supports (β = 0.27, P -value < 0.001), but inversely with healthy built environment (β = -0.10, P -value = 0.02). These three constructs explained one-third ( R 2 = 30.0%) of the variation in county-level AHM non-adherence., Conclusion: AHM non-adherence varies by geographical location, one-third of which is explained by contextual SDH factors including poverty/food insecurity, weak social supports and healthy built environments.

Obesity, diabetes, and hypertension have increased by epidemic proportions in recent years among African Americans in comparison to Whites resulting in significant adverse cardiovascular disease (CVD) disparities. Today, African Americans are 30% more likely to die of heart disease than Whites and twice as likely to have a stroke. The causes of these disparities are not yet well-understood. Improved methods for identifying underlying risk factors is a critical first step toward reducing Black:White CVD disparities. This article will focus on environmental exposures in the external environment and how they can lead to changes at the cellular, molecular, and organ level to increase the personal risk for CVD and lead to population level CVD racial disparities. The external environment is defined in three broad domains: natural (air, water, land), built (places you live, work, and play) and social (social, demographic, economic, and political). We will describe how environmental exposures in the natural, built, and social environments "get under the skin" to affect gene expression though epigenetic, pan-omics, and related mechanisms that lead to increased risk for adverse CVD health outcomes and population level disparities. We also will examine the important role of metabolomics, proteomics, transcriptomics, genomics, and epigenomics in understanding how exposures in the natural, built, and social environments lead to CVD disparities with implications for clinical, public health, and policy interventions. In this review, we apply an exposome approach to Black:White CVD racial disparities. The exposome is a measure of all the exposures of an individual across the life course and the relationship of those exposures to health effects. The exposome represents the totality of exogenous (external) and endogenous (internal) exposures from conception onwards, simultaneously distinguishing, characterizing, and quantifying etiologic, mediating, moderating, and co-occurring risk and protective factors and their relationship to disease. Specifically, it assesses the biological mechanisms and underlying pathways through which chemical and non-chemical environmental exposures are associated with CVD onset, progression and outcomes. The exposome is a promising approach for understanding the complex relationships among environment, behavior, biology, genetics, and disease phenotypes that underlie population level, Black: White CVD disparities., (Copyright © 2020 Juarez, Hood, Song and Ramesh.)

The Health Opportunity Index (HOI) is a multivariate tool that can be more efficiently used to identify and understand the interplay of complex social determinants of health (SDH) at the census tract level that influences the ability to achieve optimal health. The derivation of the HOI utilizes the data-reduction technique of principal component analysis to determine the impact of SDH on optimal health at lower census geographies. In the midst of persistent health disparities and the present COVID-19 pandemic, we demonstrate the potential utility of using 13-input variables to derive a composite metric of health (HOI) score as a means to assist in the identification of the most vulnerable communities during the current pandemic. Using GIS mapping technology, health opportunity indices were layered by counties in Ohio to highlight differences by census tract. Collectively we demonstrate that our HOI framework, principal component analysis and convergence analysis methodology coalesce to provide results supporting the utility of this framework in the three largest counties in Ohio: Franklin (Columbus), Cuyahoga (Cleveland), and Hamilton (Cincinnati). The results in this study identified census tracts that were also synonymous with communities that were at risk for disparate COVID-19 related health outcomes. In this regard, convergence analyses facilitated identification of census tracts where different disparate health outcomes co-exist at the worst levels. Our results suggest that effective use of the HOI composite score and subcomponent scores to identify specific SDH can guide mitigation/intervention practices, thus creating the potential for better targeting of mitigation and intervention strategies for vulnerable communities, such as during the current pandemic.

(1) Background: Cardio-metabolic diseases (CMD), including cardiovascular disease, stroke, and diabetes, have numerous common individual and environmental risk factors. Yet, few studies to date have considered how these multiple risk factors together affect CMD disparities between Blacks and Whites. (2) Methods: We linked daily fine particulate matter (PM 2.5 ) measures with survey responses of participants in the Southern Community Cohort Study (SCCS). Generalized linear mixed modeling (GLMM) was used to estimate the relationship between CMD risk and social-demographic characteristics, behavioral and personal risk factors, and exposure levels of PM 2.5 . (3) Results: The study resulted in four key findings: (1) PM 2.5 concentration level was significantly associated with reported CMD, with risk rising by 2.6% for each µg/m 3 increase in PM 2.5 ; (2) race did not predict CMD risk when clinical, lifestyle, and environmental risk factors were accounted for; (3) a significant variation of CMD risk was found among participants across states; and (4) multiple personal, clinical, and social-demographic and environmental risk factors played a role in predicting CMD occurrence. (4) Conclusions: Disparities in CMD risk among low social status populations reflect the complex interactions of exposures and cumulative risks for CMD contributed by different personal and environmental factors from natural, built, and social environments., Competing Interests: The authors declare no conflict of interest.

Objective: In clinical practice, the incidence of femoral pseudoaneurysms requiring repair is small, but at a tertiary care center, the repair rate is higher due to referrals. We sought to specifically study patients who suffered postcatheterization pseudoaneurysms requiring thrombin injection or operative repair and compare them to our routine transfemoral endovascular patients to identify predictors of clinically significant pseudoaneurysms. The underlying goal would be to identify what makes these patients that develop pseudoaneurysms different., Methods: A search of our billing records for Current Procedural Technology (CPT) codes of these 2 procedures between January 2008 and April 2018 was combined with our institution's Peripheral Vascular Intervention Vascular Quality Initiative database spanning from January 2013 to December 2017. A comparison was then performed between patients who had the outcome of operative intervention for a pseudoaneurysm complication and those who did not, with the goal of elucidating patient demographics and periprocedural factors that would predict pseudoaneurysm formation using univariate and multivariate analyses., Results: There were 77 patients who required thrombin injection or open repair for access-related pseudoaneurysms and 324 patients who did not. Complications occurred more often in patients who were older than 75 (40.2% vs 21.9%; P = .0009), female (57.1% vs 38.6%; P = .003), obese (59.7% vs 33.3%; P < .001), hypertensive (96.1% vs 79.3%; P = .0005), who received a sheath >6F (32.4% vs 13%; P < .0001), intraoperative and postoperative anticoagulation (77.3% vs 32.7% and 52.1% vs 24.2%, respectively; P < .0001), and periprocedural P2Y12 inhibitors (48.7% vs 28%; P = .0005). Less complications were observed in patients who had a closure device used (42.9% vs 8.45%; P < .0001) and protamine reversal (26.5% vs 13.3%; P = .0163)., Conclusions: Our findings validate published reports that incriminate a larger sheath size, perioperative anticoagulation, and female gender as increasing the rate of access site complications, with the use of a closure device being protective.

African Americans are at heightened risk for coronary heart disease (CHD), with biologic pathways poorly understood. We examined the role of allostatic load (AL) in the association of depressive symptoms with incident CHD among 2,670 African American men and women in the prospective Jackson Heart Study. Depressive symptoms were quantified using the Center for Epidemiologic Studies Depression Scale (CES-D). Incident CHD was ascertained by self-report, death certificate survey, and adjudicated medical record surveillance. Baseline AL was quantified using biologic parameters of metabolic, cardiovascular, immune, and neuroendocrine subsystems and as a combined meta-factor. Sequential models adjusted for demographic, socioeconomic, and behavioral covariates, stratified to examine differences by sex. Greater depressive symptomatology was associated with greater metabolic, cardiovascular, and immune AL (p-values≤0.036) and AL meta-factor z-scores (p = 0.007), with findings driven by observations among females. Each 1-point increase in baseline depressive symptomatology, and 1-SD increase in metabolic AL, neuroendocrine AL, and AL meta-factor z-scores was associated with 3.3%, 88%, 39%, and 130% increases in CHD risk, respectively (p-values <0.001). Neuroendocrine AL and AL meta-factor scores predicted incident CHD among males but not females in stratified analyses. Metabolic AL partially mediated the association of depressive symptoms with incident CHD (5.79% mediation, p = 0.044), a finding present among females (p = 0.016) but not males (p = 0.840). Among African American adults, we present novel findings of an association between depressive symptomatology and incident CHD, partially mediated by metabolic AL. These findings appear to be unique to females, an important consideration in the design of targeted interventions for CHD prevention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Empirical data on the link between stress and cardiovascular disease (CVD) risk among black women is limited. We examined associations of stressful life events and social strain with incident CVD among black women and tested for effect modification by resilience., Methods and Results: Our analysis included 10 785 black women enrolled in the Women's Health Initiative Observational Study and Clinical Trials cohort. Participants were followed for CVD for up to 23 years (mean, 12.5). Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for associations between stress-related exposures and incident CVD. We included interactions between follow-up time (age) and stressful life events because of evidence of nonproportional hazards. Effect modification by resilience was examined in the sub-cohort of 2765 women with resilience and stressful life events measures. Higher stressful life events were associated with incident CVD at ages 55 (hazard ratio for highest versus lowest quartile=1.80; 95% CI, 1.27-2.54) and 65 (hazard ratio for highest versus lowest quartile=1.40; 95% CI, 1.16-1.68), but not at older ages. Adjustment for CVD risk factors attenuated these associations. Similar associations were observed for social strain. In the sub-cohort of women with updated stressful life events and resilience measures, higher stressful life events were associated with incident CVD in multivariable-adjusted models (hazard ratio=1.61; 95% CI, 1.04-2.51). Resilience did not modify this association nor was resilience independently associated with incident CVD., Conclusions: In this cohort of older black women, recent reports of stressful life events were related to incident CVD. Resilience was unrelated to incident CVD., Clinical Trials Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00000611.

Exposure to chronic stress such as living in disadvantaged neighborhoods has been related to cardiovascular disease (CVD). Chronic stress may increase the risk for CVD by increasing levels of systemic inflammation (e.g., higher levels of pro-inflammatory cytokines). Differential DNA methylation of inflammation-related candidate genes is also related to higher risk for CVD. Thus, the purpose of this review was to examine the association of neighborhood disadvantage with DNA methylation. A search of literature was conducted using Scopus, CINAHL, PubMed, Medline, and Embase databases. The keywords neighborhood, neighborhood disorder, neighborhood crime, neighborhood violence, neighborhood safety, built environment, and housing vacancy were combined with the keywords DNA methylation and epigenetics. Five studies were included in this review (n = 3 adult blood samples and n = 2 fetal blood samples). Four of the five studies reported an association of neighborhood socioeconomic status, social environment, and crime with either global or gene-specific DNA methylation. Only two studies examined the association of neighborhood disadvantage with inflammation-related candidate genes. One of these studies found a significant association of neighborhood socioeconomic disadvantage and social environment with DNA methylation in inflammation-related candidate genes. Thus, data are limited on the association between neighborhood disadvantage and DNA methylation of inflammation-related candidate genes, as well as genes in other potential mechanistic pathways including psychosocial stress, toxin response, and adiposity. Future studies should examine these associations and the potential epigenetic mechanisms by which neighborhood disadvantage increases the risk for CVD.

We report integration of the United States Environmental Protection Agency's (USEPA) United States Environmental Justice Screen (EJSCREEN) database with our Public Health Exposome dataset to interrogate 9232 census blocks to model the complexity of relationships among environmental and socio-demographic variables toward estimating adverse pregnancy outcomes [low birth weight (LBW) and pre-term birth (PTB)] in all Ohio counties. Using a hill-climbing algorithm in R software, we derived a Bayesian network that mapped all controlled associations among all variables available by applying a mapping algorithm. The results revealed 17 environmental and socio-demographic variables that were represented by nodes containing 69 links accounting for a network with 32.85% density and average degree of 9.2 showing the most connected nodes in the center of the model. The model predicts that the socio-economic variables low income, minority, and under age five populations are correlated and associated with the environmental variables; particulate matter (PM 2.5 ) level in air, proximity to risk management facilities, and proximity to direct discharges in water are linked to PTB and LBW in 88 Ohio counties. The methodology used to derive significant associations of chemical and non-chemical stressors linked to PTB and LBW from indices of geo-coded environmental neighborhood deprivation serves as a proxy for design of an African-American women's cohort to be recruited in Ohio counties from federally qualified community health centers within the 9232 census blocks. The results have implications for the development of severity scores for endo-phenotypes of resilience based on associations and linkages for different chemical and non-chemical stressors that have been shown to moderate cardio-metabolic disease within a population health context.

Objectives: To evaluate how frequently elevated soil lead (Pb) hazards (≥400 ppm Pb) were identified in existing blood Pb site investigations in Ohio., Design: This study evaluated 3050 site investigations from the Ohio Department of Health for children with blood Pb levels at or above 10 μg dL that contained bare soil Pb data., Setting: Data were collected from existing databases maintained by the Ohio Department of Health., Participants: All data were de-identified prior to analysis. The data used included blood Pb level test results for children (18 years or younger) in Ohio, with most data coming from children younger than 6 years., Main Outcome Measures: The main outcome measures were blood Pb levels and identified Pb concentrations in environmental media, including soil, paint, and dust., Methods: Data were organized and summarized according to county. Summary statistics were generated on the basis of type of environmental media and county., Results: Soil samples were collected in approximately 5% of all blood Pb cases in Ohio between 1999 and 2015. Median bare soil Pb was 1030 mg Pb kg (range, 0-345 021 mg Pb kg soil). Fifty-six of Ohio's 88 counties had at least 1 soil sample above 10 000 ppm (mg Pb kg). Multiple Pb hazards were identified, including bare soil (74% frequency), deteriorated exterior Pb paint (74%), deteriorated interior Pb paint (72%), and settled Pb dust (72%). Bare soil collected from identified dripline areas contained 2638 ppm Pb above soils collected from bare soil play areas (P = .02). Ninety assessments (3%) contained a bare soil hazard, with no other identified hazards. No trend was found comparing county mean or median Pb with county population. Previously identified high-risk counties for elevated blood Pb levels did not have an elevated prevalence of bare soil Pb hazards compared with other counties (P = .64)., Conclusions: Site investigators should anticipate finding and managing elevated bare soil Pb in locations throughout Ohio. When communicating with the public about bare soil Pb hazards, practitioners and policy makers should emphasize the importance of addressing all potential Pb exposure sources. Findings demonstrate the importance of the individual home environment for exposure, as previously identified high-risk counties for elevated blood Pb levels were not different from other counties.

Objectives: The aim is to identify exposures associated with lung cancer mortality and mortality disparities by race and gender using an exposome database coupled to a graph theoretical toolchain., Methods: Graph theoretical algorithms were employed to extract paracliques from correlation graphs using associations between 2162 environmental exposures and lung cancer mortality rates in 2067 counties, with clique doubling applied to compute an absolute threshold of significance. Factor analysis and multiple linear regressions then were used to analyze differences in exposures associated with lung cancer mortality and mortality disparities by race and gender., Results: While cigarette consumption was highly correlated with rates of lung cancer mortality for both white men and women, previously unidentified novel exposures were more closely associated with lung cancer mortality and mortality disparities for blacks, particularly black women., Conclusions: Exposures beyond smoking moderate lung cancer mortality and mortality disparities by race and gender., Policy Implications: An exposome approach and database coupled with scalable combinatorial analytics provides a powerful new approach for analyzing relationships between multiple environmental exposures, pathways and health outcomes. An assessment of multiple exposures is needed to appropriately translate research findings into environmental public health practice and policy., Competing Interests: Conflicts of interest There are no conflicts of interest.

Introduction: With the growing use of electronic medical records, electronic health records (EHRs), and personal health records (PHRs) for health care delivery, new opportunities have arisen for population health researchers. Our objective was to characterize PHR users and examine sample representativeness and nonresponse bias in a study of pregnant women recruited via the PHR., Design: Demographic characteristics were examined for PHR users and nonusers. Enrolled study participants (responders, n=187) were then compared with nonresponders and a representative sample of the target population., Results: PHR patient portal users (34 percent of eligible persons) were older and more likely to be White, have private health insurance, and develop gestational diabetes than nonusers. Of eligible persons (all PHR users), 11 percent (187/1,713) completed a self-administered PHR based questionnaire. Participants in the research study were more likely to be non-Hispanic White (90 percent versus 79 percent) and married (85 percent versus 77 percent), and were less likely to be Non-Hispanic Black (3 percent versus 12 percent) or Hispanic (3 percent versus 6 percent). Responders and nonresponders were similar regarding age distribution, employment status, and health insurance status. Demographic characteristics were similar between responders and nonresponders., Discussion: Demographic characteristics of the study population differed from the general population, consistent with patterns seen in traditional population-based studies. The PHR may be an efficient method for recruiting and conducting observational research with additional benefits of efficiency and cost-cost-effectiveness.

Etiology of preterm birth (PTB) is multifactorial; therefore, decreasing the incidence of PTB is a major challenge in the field of obstetrics. Epidemiological studies have reported an association between toxicants and PTB. However, there are no studies on the role of benzo[a]pyrene (BaP), an environmental toxicant, in the incidence of PTB. We first assessed the effects of BaP (150 and 300 µg kg(-1) body weight) dosed via gavage from day 14 to 17 of pregnancy on gestation length in Long Evans rats. We further assessed the histopathology of the uterus, expression of inflammatory cytokines, contractile-associated factors, histone deacetylases (HDACs) and NFқB-p65 in myometrium collected on day 22 postpartum versus vehicle-treated controls. In our study, rats exposed to BaP delivered prematurely (P < 0.05) compared to control. Hematoxylin and eosin staining of uterus showed squamous metaplasia, glandular and stromal hyperplasia in BaP-exposed rats versus control. The concentrations of BaP metabolites measured by high-pressure liquid chromatography were higher in uterine myometrium of BaP-exposed rats while they were undetectable in controls. Quantitative real-time polymerase chain reaction showed significant increases in mRNA expression of interleukin-1β and -8, tumor necrosis factor-α, connexin 43, cyclo-oxygenase-2 and prostaglandin F2α receptor as compared to controls (P < 0.05). Western blot analysis revealed that BaP exposure caused decreases in class I HDACs 1 and 3 and increases in class II HDAC 5, cyclo-oxygenase-2 and nuclear translocation of NFκB-p65 relative to controls. Our results suggest that gestational exposure to BaP increases incidence of PTB through epigenetic changes that causes increases in the expression of contractile-associated factors through the NFκB pathway. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

The exposome provides a framework for understanding elucidation of an uncharacterized molecular mechanism conferring enhanced susceptibility of macrophage membranes to bacterial infection after exposure to the environmental contaminant benzo(a)pyrene, [B(a)P]. The fundamental requirement in activation of macrophage effector functions is the binding of immunoglobulins to Fc receptors. FcγRIIa (CD32a), a member of the Fc family of immunoreceptors with low affinity for immunoglobulin G, has been reported to bind preferentially to IgG within lipid rafts. Previous research suggested that exposure to B(a)P suppressed macrophage effector functions but the molecular mechanisms remain elusive. The goal of this study was to elucidate the mechanism(s) of B(a)P-exposure induced suppression of macrophage function by examining the resultant effects of exposure-induced insult on CD32-lipid raft interactions in the regulation of IgG binding to CD32. The results demonstrate that exposure of macrophages to B(a)P alters lipid raft integrity by decreasing membrane cholesterol 25% while increasing CD32 into non-lipid raft fractions. This robust diminution in membrane cholesterol and 30% exclusion of CD32 from lipid rafts causes a significant reduction in CD32-mediated IgG binding to suppress essential macrophage effector functions. Such exposures across the lifespan would have the potential to induce immunosuppressive endophenotypes in vulnerable populations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To characterize behavioral deficits in pre-adolescent offspring exposed in utero to Benzo(a)pyrene [B(a)P], timed-pregnant Long Evans Hooded rats were treated with B(a)P (150, 300, 600, and 1200 µg/kg BW) or peanut oil (vehicle) on E14, 15, 16, and 17. Following birth, during the pre-weaning period, B(a)P metabolites were examined in plasma and whole brain or cerebral cortex from exposed and control offspring. Tissue concentrations of B(a)P metabolites were (1) dose-dependent and (2) followed a time-dependence for elimination with ∼60% reduction by PND5 in the 1200 µg/kg BW experimental group. Spatial discrimination-reversal learning was utilized to evaluate potential behavioral neurotoxicity in P40-P60 offspring. Late-adolescent offspring exposed in utero to 600 and 1200 µg/kg BW were indistinguishable from their control counterparts for ability to acquire an original discrimination (OD) and reach criterion. However, a dose-dependent effect of in utero B(a)P-exposure was evident upon a discrimination reversal as exposed offspring perseverated on the previously correct response. This newly characterized behavioral deficit phenotype for the first reversal was not apparent in either the (1) OD or (2) subsequent reversal sessions relative to the respective control offspring. Furthermore, the expression of activity related-cytoskeletal-associated protein (Arc), an experience-dependent cortical protein marker known to be up-regulated in response to acquisition of a novel behavior, was greater in B(a)P-exposed offspring included in the spatial discrimination cohort versus home cage controls. Collectively, these findings support the hypothesis that in utero exposure to B(a)P during critical windows of development representing peak periods of neurogenesis results in behavioral deficits in later life., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A public participatory geographical information systems (PPGIS) demographic, environmental, socioeconomic, health status portal was developed for the Stambaugh-Elwood (SE) community in Columbus, OH. We hypothesized that soil at SE residences would have metal concentrations above natural background levels. Three aims were developed that allowed testing of this hypothesis. Aim 1 focused on establishing partnerships between academia, state agencies and communities to assist in the development of a community voice. Aim 2 was to design and conduct soil sampling for residents of the SE community. Aim 3 was to utilize our interactive, customized portal as a risk communication tool by allowing residents to educate themselves as to the potential risks from industrial sources in close proximity to their community. Multiple comparisons of means were used to determine differences in soil element concentration by sampling location at p < 0.05. The results demonstrated that eight metals (As, Cd, Cu, Pb, Mo, Se, Tl, Zn) occurred at statistically-significantly greater levels than natural background levels, but most were below risk-based residential soil screening levels. Results were conveyed to residents via an educational, risk-communication informational card. This study demonstrates that community-led coalitions in collaboration with academic teams and state agencies can effectively address environmental concerns.

Objective: The routine measurement of IgA anticardiolipin (aCL) and IgA anti-β 2 glycoprotein I (anti-β 2 GPI) antibodies remain controversial despite several studies demonstrating an association with thromboembolic disease in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This controversy may be a contributing factor for the current under use of IgA antiphospholipid antibodies. We aimed to investigate the nature of discrepant IgA anti-β 2 GPI reactivity to help define the diagnostic value of IgA antiphospholipid antibodies., Material and Methods: Four sera selected from SLE/APS patients and positive for antiphospholipid antibodies but having discrepant IgA anti-β 2 GPI reactivity on two commercial assays were studied. IgA antibodies were affinity purified to investigate anti-β 2 GPI reactivity. Column wash through and eluent fractions were tested on both IgA anti-β 2 GPI assays. Results were normalized to total protein. Assay conjugates and standards from the discrepant assays were interchanged., Results: The diseased samples were strongly positive in one assay [144-388 IgA antiphospholipid (APL) units] and negative or weakly positive in another assay (9.9-53 APL units). IgA eluents from IgA anti-β 2 GPI positive samples reacted 10 times stronger on the reactive assay. When normalized to protein content, the eluents showed no cross-reactivity for IgG or IgM anti-β 2 GPI antibodies, confirming IgA isotype specificity. Conjugate interchange confirmed that both assays bound IgA anti-β 2 GPI antibodies, but the anti-IgA conjugate from the reactive assay was 4 times stronger, suggesting that its ability to detect IgA anti-β 2 GPI antibodies was partially dependent on the anti-IgA conjugate and calibration., Conclusion: These results confirm not only the presence of IgA anti-β 2 GPI antibodies in the selected patient samples but also highlight an IgA conjugate issue for the unreactive assay, causing an underestimation of IgA anti-β 2 GPI. This finding may assist in the ongoing standardization efforts of APS antibody testing. In addition, conclusions from published clinical studies may need to be revised as some assays may understate IgA significance.

The lack of progress in reducing health disparities suggests that new approaches are needed if we are to achieve meaningful, equitable, and lasting reductions. Current scientific paradigms do not adequately capture the complexity of the relationships between environment, personal health and population level disparities. The public health exposome is presented as a universal exposure tracking framework for integrating complex relationships between exogenous and endogenous exposures across the lifespan from conception to death. It uses a social-ecological framework that builds on the exposome paradigm for conceptualizing how exogenous exposures "get under the skin". The public health exposome approach has led our team to develop a taxonomy and bioinformatics infrastructure to integrate health outcomes data with thousands of sources of exogenous exposure, organized in four broad domains: natural, built, social, and policy environments. With the input of a transdisciplinary team, we have borrowed and applied the methods, tools and terms from various disciplines to measure the effects of environmental exposures on personal and population health outcomes and disparities, many of which may not manifest until many years later. As is customary with a paradigm shift, this approach has far reaching implications for research methods and design, analytics, community engagement strategies, and research training.

Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual's genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject.

In the US alone, around 60,000 lives/year are lost due to colon cancer. Diet and environment have been implicated in the development of sporadic colon tumors. The objective of this study was to determine how dietary fat potentiates the development of colon tumors through altered B(a)P biotransformation, using the Adenomatous polyposis coli with Multiple intestinal neoplasia mouse model. Benzo(a)pyrene was administered to mice through tricaprylin, and unsaturated (USF; peanut oil) and saturated (SF; coconut oil) fats at doses of 50 and 100 μg/kg via oral gavage over a 60-day period. Blood, colon, and liver were collected at the end of exposure period. The expression of B(a)P biotransformation enzymes [cytochrome P450 (CYP)1A1, CYP1B1 and glutathione-S-transferase] in liver and colon were assayed at the level of protein, mRNA and activities. Plasma and tissue samples were analyzed by reverse phase high-performance liquid chromatography for B(a)P metabolites. Additionally, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the (32)P-postlabeling method using a thin-layer chromatography system. Benzo(a)pyrene exposure through dietary fat altered its metabolic fate in a dose-dependent manner, with 100 μg/kg dose group registering an elevated expression of B(a)P biotransformation enzymes, and greater concentration of B(a)P metabolites, compared to the 50 μg/kg dose group (P<.05). This effect was more pronounced for SF group compared to USF group (P<.05). These findings establish that SF causes sustained induction of B(a)P biotransformation enzymes and extensive metabolism of this toxicant. As a consequence, B(a)P metabolites were generated to a greater extent in colon and liver, whose concentrations also registered a dose-dependent increase. These metabolites were found to bind with DNA and form B(a)P-DNA adducts, which may have contributed to colon tumors in a subchronic exposure regimen., (© 2013.)

The goal of this study was to analyze a 54-item instrument for assessment of perception of exposure to environmental contaminants within the context of the built environment, or exposome. This exposome was defined in five domains to include 1) home and hobby, 2) school, 3) community, 4) occupation, and 5) exposure history. Interviews were conducted with child-bearing-age minority women at Metro Nashville General Hospital at Meharry Medical College. Data were analyzed utilizing DTReg software for Support Vector Machine (SVM) modeling followed by an SPSS package for a logistic regression model. The target (outcome) variable of interest was respondent's residence by ZIP code. The results demonstrate that the rank order of important variables with respect to SVM modeling versus traditional logistic regression models is almost identical. This is the first study documenting that SVM analysis has discriminate power for determination of higher-ordered spatial relationships on an environmental exposure history questionnaire.

Background: The objective of this study is to compare intraoperative endoleak detection by carbon dioxide digital subtraction angiography (CO(2)-DSA) during endovascular aortic aneurysm repair (EVAR) with standard iodinated contrast angiography (ICA)., Methods: Between 2006 and 2010, 76 patients with abdominal aortic aneurysms undergoing EVAR were enrolled in a prospective study. After EVAR, both an ICA and CO(2)-DSA completion study were performed. Two blinded vascular surgeons who were not involved with the EVAR separately interpreted the ICA and CO(2)-DSA results for the presence or absence of an endoleak. Identified endoleaks were classified by types. A third, "tie-breaker" blinded observer was used to resolve differences in interpretations. The sensitivity, specificity, negative predictive value, and positive predictive value were calculated for the ability of CO(2)-DSA to detect endoleaks. Cohen's κ statistic was used to assess interobserver agreement between the 2 initial interpreting surgeons., Results: Of the 76 patients undergoing EVAR, 66 were men with average age of 76 years, a mean aneurysm size of 5.8 cm (range, 4-10 cm), and creatinine of 1 (standard deviation, 0.33). ICA identified 35 type I and 15 type II endoleaks, respectively, while CO(2)-DSA identified 40 type I and 10 type II endoleaks. Overall, CO(2)-DSA had a sensitivity of 0.84, specificity of 0.72, positive predictive value of 0.86, and negative predictive value of 0.69 of intraoperative endoleak detection, with respect to ICA as the criterion standard. The interobserver κ between surgeons for ICA was 0.56, for detection of any endoleak or type I endoleak with CO(2)-DSA was 0.58, and for detection of type II endoleak with CO(2)-DSA was 0.29., Conclusions: Interobserver agreement for the detection of endoleaks is superior with ICA compared to CO(2)-DSA. However, the sensitivity for detecting any endoleak and both the sensitivity and specificity for detecting type I endoleaks using CO(2)-DSA are acceptable. For detecting type II endoleaks using CO(2)-DSA, the sensitivity and positive predictive value are poor. Compared to ICA, CO(2)-DSA provides adequate images for endoleak detection during EVAR and is an acceptable alternative to ICA in patients at risk for contrast-related nephrotoxicity., (Copyright © 2013 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

This study evaluated the effect of inhaled BaP on female reproductive function. Rats were exposed to 50, or 75 or 100 μg BaP/m(3), 4 h a day for 14 days via inhalation. Plasma E(2), P(4), LH and FSH concentrations were determined. Ovarian BaP metabolism and aryl hydrocarbon hydrolase (AHH) activity at proestrus were determined and fertility evaluations were conducted. Ovulation rate and number of pups/litter were reduced in rats exposed to 100 μg BaP/m(3) compared with other treatment and control groups. Plasma concentrations of E(2), and LH were significantly reduced at proestrus in BaP-exposed versus those of controls whereas those of P(4) were significantly reduced at diestrus I. The activity of AHH in ovarian and liver tissues and concentrations of BaP 7,8-diol and BaP 3,6-dione metabolites increased in an exposure concentration-dependent manner. These data suggest that exposure of rats to BaP prior to mating contributes to reduced ovarian function and fetal survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In utero exposure of the fetus to benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is thought to dysregulate cardiovascular development. To investigate the effects of in utero B(a)P exposure on cardiovascular development, timed-pregnant Long Evans Hooded (LEH) rats were exposed to diluent or B(a)P (150, 300, 600 and 1200 μg/kg/BW) by oral gavage on embryonic (E) days E14 (the metamorphosing embryo stage) through E17 (the 1st fetal stage). There were no significant effects of in utero exposure to B(a)P on the number of pups born per litter or in pre-weaning growth curves. Pre-weaning profiles for B(a)P metabolite generation from cardiovascular tissue were shown to be dose-dependent and elimination of these metabolites was shown to be time-dependent in exposed offspring. Systolic blood pressure on postnatal day P53 in the middle and high exposure groups of offspring were significantly elevated as compared to controls. Microarray and quantitative real-time PCR results were directly relevant to a biological process pathway in animal models for "regulation of blood pressure". Microarray and quantitative real-time PCR analysis revealed upregulation of mRNA expression for angiotensin (AngII), angiotensinogen (AGT) and endothelial nitric oxide synthase (eNOS) in exposed offspring. Biological network analysis and gene set enrichment analysis subsequently identified potential signaling mechanisms and molecular pathways that might explain the elevated systolic blood pressures observed in B(a)P-exposed offspring. Our findings suggest that in utero exposure to B(a)P predispose offspring to functional deficits in cardiovascular development that may contribute to cardiovascular dysfunction in later life., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The wild-type (WT) Cpr(lox/lox) (cytochrome P(450) oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P(450) enzymes to the metabolic activation and disposition of environmental xenobiotics. In the present study, we examined the effect of in utero exposure to benzo(a)pyrene [B(a)P] aerosol on Sp4 and N-methyl-D-aspartate (NMDA)-dependent systems as well as a resulting behavioral phenotype (object discrimination) in Cpr offspring. Results from in utero exposure of WT Cpr(lox/lox) mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P(450)1B1-associated NADPH oxidoreductase (CYP1B1-associated NADPH oxidoreductase), thus reducing their capacity to produce neural B(a)P metabolites. Subsequent to in utero (E14-E17) exposure to B(a)P (100 μg/m(3)), Cpr(lox/lox) offspring exhibited: (1) elevated B(a)P metabolite and F(2)-isoprostane neocortical tissue burdens, (2) elevated concentrations of cortical glutamate, (3) premature developmental expression of Sp4, (4) decreased subunit ratios of NR2B:NR2A, and (5) deficits in a novelty discrimination phenotype monitored to in utero exposed brain-Cpr-null offspring. Collectively, these findings suggest that in situ generation of metabolites by CYP1B1-associated NADPH oxidoreductase promotes negative effects on NMDA-mediated signaling processes during the period when synapses are first forming as well as effects on a subsequent behavioral phenotype.

Objective: Reports of fatality following carbon dioxide digital subtraction angiography (CO2-DSA) have raised concerns regarding its safety. This study reviews the safety of CO2-DSA., Design: Single-institution retrospective review., Setting: Tertiary care teaching hospital in Los Angeles, California., Patients: A total of 951 patients who underwent 1007 CO2-DSA procedures during a 21-year period., Main Outcome Measures: Preprocedure and postprocedure creatinine values and periprocedural morbidity and mortality., Results: A total of 632 arterial CO2-DSA were performed; 527 were aortograms with or without extremity runoff; 100, extremity alone; and 5, pulmonary. Venous CO2-DSA included 187 inferior vena cavagrams, 182 hepatic or visceral, 5 extremity venograms, and 1 superior vena cavagram. Associated endovascular procedures were performed in 499 cases; 162 were arterial interventions including 62 endovascular aneurysm repairs, 53 visceral or renal percutaneous angioplasty with/without stent, 41 extremity percutaneous angioplasty with or without a stent, and 4 cases of thrombolysis or embolization; 176 caval filters, 98 transjugular intrahepatic portosystemic shunts, 54 transjugular liver biopsies, and 9 other venous interventions. The mean preprocedure creatinine level was 2.1 mg/dL; postprocedure, 2.1 mg/dL (P = .56). There were a total of 61 (6.1%) procedural complications including 4 (0.4%) mortalities. Two were procedure-related complications: 1, suppurative pancreatitis following aortogram; and 2, hepatic bleed following failed transjugular intrahepatic portosystemic shunts. Two were attributable to patient disease; 1, metastatic adenocarcinoma; and 2, refractory, end-stage cardiomyopathy., Conclusion: Carbon dioxide digital subtraction angiography is a versatile technique that can be safely used for diagnostic and therapeutic endovascular procedures. Morbidity and mortality are acceptable with preservation of renal function. Thus, CO2-DSA is a safe alternative to iodinated contrast.

Objectives: For patients with end-stage critical limb ischemia (CLI) who have already suffered over an extended period of time, a major amputation that is free of wound complications remains paramount. Utilizing data from the American College of Surgeons, National Surgical Quality Improvement Program (ACS-NSQIP), the objective of this report was to determine critical factors leading to wound complications following major amputation., Methods: ACS-NSQIP was used to identify patients ≥ 50 years, with CLI, and having an ipsilateral below-(BKA) or above-knee amputation (AKA). The primary outcome was wound occurrence (WO) defined by affirmative findings of superficial infection, deep infection, and/or wound disruption. The secondary outcome was 30-day mortality. Following univariate analyses, a multiple logistic regression was performed to identify predictive factors., Results: Between January 1, 2005 and December 31, 2008, 4250 patients fulfilled inclusion criteria (2309 BKAs and 1941 AKAs). WOs were 10.4% for BKAs and 7.2% for AKAs. For BKAs, increasing elevation in international normalized ratio (INR) predicted more WOs (P = .008, odds ratio [OR] 1.5 for every integral increase in INR) as did age 50 to 59 compared with older patients (P = .002, OR 1.9). For AKAs, being a current smoker predicted more WOs (P = .0008, OR 1.8) as did an increasing body mass index (BMI) (P = .02, OR 1.3 for every 10 kg/m(2) increase in BMI). Mortality was 7.6% for BKAs and 12% for AKAs. Complete functional dependence was most predictive of mortality following AKA (P < .0001, OR 2.5). Medical comorbidities such as history of myocardial infarcation (MI) (OR 1.8), congestive heart failure (CHF, OR 1.6), and chronic obstructive pulmonary disease (COPD, OR 1.6) predicted mortality following BKA, while dialysis use (OR 2.4), CHF (OR 2.3), and COPD (OR 2.1) predicted mortality following AKA., Conclusions: Wound occurrences and mortality rates after major amputation for CLI continue to be a prevalent problem. Normalization of the INR prior to BKA should decrease WOs. Heightened awareness in higher risk patients with improved preventive measures, earlier disease recognition, better treatments, and increased education remain critical to improving outcomes in an already stressed patient cohort., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Gene by environment interactions (G × E) are thought to underlie neurodevelopmental disorder, etiology, neurodegenerative disorders, including the multiple forms of autism spectrum disorder. However, there is limited biological information, indicating an interaction between specific genes and environmental components. The present study focuses on a major component of airborne pollutants, polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene [B(a)P], which negatively impacts cognitive development in children who have been exposed in utero. In our study, prenatal exposure of Cpr(lox/lox) timed-pregnant dams to B(a)P (0, 150, 300, and 600 μg/kg body weight via oral gavage) on embryonic day (E14-E17) consistent with our susceptibility-exposure paradigm was combined with the analysis of a replicated autism risk gene, the receptor tyrosine kinase, Met. The results demonstrate a dose-dependent increase in B(a)P metabolite generation in B(a)P-exposed Cpr(lox/lox) offspring. Additionally, a sustained persistence of hydroxy metabolites during the onset of synapse formation was noted, corresponding to the peak of Met expression. Prenatal B(a)P exposure also downregulated Met RNA and protein levels and dysregulated normal temporal patterns of expression during synaptogenesis. Consistent with these data, transcriptional cell-based assays demonstrated that B(a)P exposure directly reduces human MET promoter activity. Furthermore, a functional readout of in utero B(a)P exposure showed a robust reduction in novel object discrimination in B(a)P-exposed Cpr(lox/lox) offspring. These results confirm the notion that common pollutants, such as the PAH B(a)P, can have a direct negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes.

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.

Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase., (2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Toxic environmental emissions have the potential to harm already susceptible populations living in close proximity to industries with pollutant emissions such as coal-fired electrical power plants. The organized dissemination of information in communities that find themselves susceptible to occupation by industries with pollutant emissions is a crucial step in the long and arduous process of preventing such harm. Here, we present a blueprint that can be used by community organizations to prevent industries that pollute the environment from locating in communities that are already disproportionately exposed to pollution (referred to here as environmental justice communities). We base this blueprint on a specific case in Taylor County, Florida, where the steps outlined successfully prevented the Taylor Energy Center (TEC) consortium from obtaining the necessary permits for the operation of a proposed coal-fired electrical power plant, thereby minimizing the risks of additional toxicant exposure to the affected community.

Colorectal cancer, responsible for 50,000 deaths per year, is a contributing factor for considerable mortalities in the United States. Consumption of well-done red meat and saturated fats rich in polycyclic aromatic hydrocarbons may be one of the causative factors for sporadic colon cancer. The objective of this study was to investigate whether the formation of colon tumors in adult Apc(Min) mice was influenced by the ingestion of different types of fat containing benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon compound. Treatment consisted of 50 and 100 microg B(a)P/kg body weight dissolved in peanut or coconut oil (representatives of unsaturated and saturated fats, respectively) administered daily to six-week-old male Apc(Min) mice via oral gavage for sixty days. At the end of exposure, mice were sacrificed; jejunum and colons were retrieved and preserved in 10% formalin for observation for gross pathological changes. An increased prevalence of adenomas in colons of mice that ingested B(a)P through saturated dietary fat compared to unsaturated fat and controls (p < .05) was noticed. Interestingly, we also observed adenomas with high-grade dysplasia in the B(a)P + saturated fat group, and these incidences were frequent at the 100 microg/kg B(a)P dose. On the other hand, the B(a)P-alone and unsaturated-fat groups did not show significant differences in the numbers of adenomas and invasive tumors in the both jejunum and the colon. Our studies established that dietary fat, especially saturated fat, potentiates the development of colon tumors caused by B(a)P in the Apc(Min) mouse.

Histone deacetylase 5 (HDAC5) represses expression of nuclear genes that promote cardiac hypertrophy. Agonism of a variety of G protein coupled receptors (GPCRs) triggers phosphorylation-dependent nuclear export of HDAC5 via the CRM1 nuclear export receptor, resulting in derepression of pro-hypertrophic genes. A cell-based high-throughput screen of a commercial compound collection was employed to identify compounds with the ability to preserve the nuclear fraction of GFP-HDAC5 in primary cardiomyocytes exposed to GPCR agonists. A hit compound potently inhibited agonist-induced GFP-HDAC5 nuclear export in cultured neonatal rat ventricular myocytes (NRVMs). A small set of related compounds was designed and synthesized to evaluate structure-activity relationship (SAR). The results demonstrated that inhibition of HDAC5 nuclear export was a result of compounds irreversibly reacting with a key cysteine residue in CRM1 that is required for its function. CRM1 inhibition by the compounds also resulted in potent suppression of cardiomyocyte hypertrophy. These studies define a novel class of anti-hypertrophic compounds that function through irreversible inhibition of CRM1-dependent nuclear export.

Prenatal exposure to environmental contaminants, such as benzo(a)pyrene [B(a)P] has been shown to impair brain development. The overarching hypothesis of our work is that glutamate receptor subunit expression is crucial for cortical evoked responses and that prenatal B(a)P exposure modulates the temporal developmental expression of glutamatergic receptor subunits in the somatosensory cortex. To characterize prenatal B(a)P exposure on the development of cortical function, pregnant Long Evans rats were exposed to low-level B(a)P (300 microg/kg BW) by oral gavage on gestational days 14-17. At this exposure dose, there was no significant effect of B(a)P on (1) the number of pups born per litter, (2) the pre-weaning growth curves and (3) initial and final brain to body weight ratios. Control and B(a)P-exposed offspring were profiled for B(a)P metabolites in plasma and whole brain during the pre-weaning period. No detectable levels of metabolites were found in the control offspring. However, a time-dependent decrease in total metabolite concentration was observed in B(a)P-exposed offspring. On PND100-120, cerebrocortical mRNA expression was determined for the glutamatergic NMDA receptor subunit (NR2B) in control and B(a)P-exposed offspring. Neural activity was also recorded from neurons in primary somatic sensory (barrel) cortex. Semiquantitative PCR from B(a)P-exposed offspring revealed a significant 50% reduction in NR2B mRNA expression in B(a)P-exposed offspring relative to controls. Recordings from B(a)P-exposed offspring revealed that N-methyl-d-aspartate (NMDA) receptor-dependent neuronal activity in barrel cortex evoked by whisker stimulation was also significantly reduced (70%) as compared to controls. Analysis showed that the greatest deficit in cortical neuronal responses occurred in the shorter latency epochs from 5 to 20 ms post-stimulus. The results suggest that in utero exposure to benzo(a)pyrene results in diminished mRNA expression of the NMDA NR2B receptor subunit to result in late life deficits in cortical neuronal activity in the offspring. The findings from this study lead to a strong prediction that in utero exposure to benzo(a)pyrene at a time when synapses are first formed and adjusted in strength by activity in the sensory pathways will produce a strong negative effect on brain function in offspring progeny.

The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 rats to inhaled benzo(a)pyrene (BaP). Rats were assigned randomly to a treatment or control group. Treatment consisted of sub-chronic exposure of rats via inhalation to 75microgBaP/m(3), 4h daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately after the cessation of exposures (time 0) and subsequently at 24, 48, and 72h, to assess the effect of bioavailable BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Rats were sacrificed after the last blood collection. Testes were harvested, weighed and prepared for histology and morphometric analysis, and cauda epididymides were isolated for the determination of progressive motility and density of stored spermatozoa. BaP exposure reduced testis weight compared with UNC (mean+/-SE; 2.01+/-0.11 versus 3.04+/-0.16g; P<0.025), and caused significant reductions in the components of the steroidogenic and spermatogenic compartments of the testis. Progressive motility and mean density of stored spermatozoa were reduced (P<0.05). Plasma testosterone concentrations were decreased by two-thirds in BaP-exposed rats throughout the time periods studied compared with those of their UNC counterparts (P<0.05), concomitant with increased concentrations of LH in BaP-exposed rats (P<0.05). These data suggest that sub-chronic exposure to inhaled BaP contribute to reduced testicular and epididymal function in exposed rats.

The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of Polycyclic Aromatic Hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fisher-344 rats were given single oral doses of 25 and 50 microg/kg FLA in tricaprylin, peanut oil, cod liver oil, Tween 80/isotonic saline (1:5) and 2% Alkamuls-EL620 through gavage. After administration, the rats were housed individually in metabolic cages and sacrificed at 2, 4, 6, 8, 10 and 12 hours post FLA exposure. Blood, lung, liver, small intestine, adipose tissue samples, urine, and feces were collected at each time point. Samples were subjected to a liquid-liquid extraction using methanol, chloroform, and water. The extracts were analyzed by a reverse-phase HPLC, equipped with a fluorescence detector. The results revealed a dose-dependent increase in FLA concentrations in plasma and tissues for all the vehicles used. Plasma and tissue FLA concentrations were greater for peanut oil; cod liver oil, and tricaprylin vehicles compared to Alkamuls (p < 0.05), and Tween 80/isotonic saline (1:5). Most of the FLA administered through peanut oil, cod liver oil and tricaprylin was cleared from the body by 8 hours (90%) and 12 hours (80%) post administration for the 25 microg/kg and 50 microg/kg dose groups, respectively. With both doses employed, the metabolism of FLA was highest when cod liver oil was used as a vehicle and lowest in vehicles containing detergent/water [cod liver oil > peanut oil > tricaprylin > alkamuls > Tween 80/isotonic saline (1:5)]. These findings suggest that uptake and elimination of FLA is accelerated when administered through oil-based vehicles. The low uptake of FLA from Alkamuls and Tween 80/isotonic saline may have been a result of the poor solubility of the chemical. In summary, our findings reiterate that absorption characteristics of FLA were governed by the dose as well as the dosing vehicle. The vehicle-dependent bioavailability of FLA suggests a need for the judicious selection of vehicles in evaluating oral toxicity studies for risk assessment purposes.

The impact of racial background on the outcome of lower extremity revascularization is unknown because a majority of studies have a preponderance of white patients. The charts of patients between 1988 and 2004 requiring infrapopliteal lower extremity revascularization were reviewed. Life-table analyses, the Cox proportional hazards model, and log-rank test were used to calculate graft patency and limb salvage. Bypasses were performed on 236 limbs in 225 patients. Mean follow-up was 18 +/- 1.5 months. Twenty-eight (12%) bypasses were performed on whites, 43 (18%) on African Americans, 148 (63%) on Hispanics, and 17 (7.2%) on patients of other races. African American race negatively correlated with primary-assisted patency (hazard ratio 2.9, P = .03), secondary patency (hazard ratio 3.64, P = .02), and limb salvage (hazard ratio 8, P = .006) compared with whites. African American race has a negative impact on the long-term outcome of infrapopliteal revascularization, regardless of disease stage or associated risk factors.