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Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = −1.46 (−2.81, −0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [−5.25 (−10.12, −0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [−3.67 (−6.79, −0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.

Fibrates are a medication class prescribed for decades as ‘broad-spectrum’ lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other ‘omes’ in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics.

Objective: Vulnerability indices use quantitative indicators and geospatial data to examine the level of vulnerability to morbidity in a community. The Centers for Disease Control and Prevention (CDC) uses 3 indices for the COVID-19 response: the CDC Social Vulnerability Index (CDC-SVI), the US COVID-19 Community Vulnerability Index (CCVI), and the Pandemic Vulnerability Index (PVI). The objective of this review was to describe these tools and explain the similarities and differences between them. Methods: We described the 3 indices, outlined the underlying data sources and metrics for each, and discussed their use by CDC for the COVID-19 response. We compared the percentile score for each county for each index by calculating Spearman correlation coefficients (Spearman ρ). Results: These indices have some, but not all, component metrics in common. The CDC-SVI is a validated metric that estimates social vulnerability, which comprises the underlying population-level characteristics that influence differences in health risk among communities. To address risk specific to the COVID-19 pandemic, the CCVI and PVI build on the CDC-SVI and include additional variables. The 3 indices were highly correlated. Spearman ρ for comparisons between the CDC-SVI score and the CCVI and between the CCVI and the PVI score was 0.83. Spearman ρ for the comparison between the CDC-SVI score and PVI score was 0.73. Conclusion: The indices can empower local and state public health officials with additional information to focus resources and interventions on disproportionately affected populations to combat the ongoing pandemic and plan for future pandemics.

The application of in vitro biological assays as new approach methodologies (NAMs) to support grouping of UVCB (unknown or variable composition, complex reaction products, and biological materials) substances has recently been demonstrated. In addition to cell-based phenotyping as NAMs, in vitro transcriptomic profiling is used to gain deeper mechanistic understanding of biological responses to chemicals and to support grouping and read-across. However, the value of gene expression profiling for characterizing complex substances like UVCBs has not been explored. Using 141 petroleum substance extracts, we performed dose-response transcriptomic profiling in human induced pluripotent stem cell (iPSC)-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as cell lines MCF7 and A375. The goal was to determine whether transcriptomic data can be used to group these UVCBs and to further characterize the molecular basis for in vitro biological responses. We found distinct transcriptional responses for petroleum substances by manufacturing class. Pathway enrichment informed interpretation of effects of substances and UVCB petroleum-class. Transcriptional activity was strongly correlated with concentration of polycyclic aromatic compounds (PAC), especially in iPSC-derived hepatocytes. Supervised analysis using transcriptomics, alone or in combination with bioactivity data collected on these same substances/cells, suggest that transcriptomics data provide useful mechanistic information, but only modest additional value for grouping. Overall, these results further demonstrate the value of NAMs for grouping of UVCBs, identify informative cell lines, and provide data that could be used for justifying selection of substances for further testing that may be required for registration.

While multiple factors are associated with cardiovascular disease (CVD), many environmental exposures that may contribute to CVD have not been examined. To understand environmental effects on cardiovascular health, we performed an exposome-wide association study (ExWAS), a hypothesis-free approach, using survey data on endogenous and exogenous exposures at home and work and data from health and medical histories from the North Carolina-based Personalized Environment and Genes Study (PEGS) (n = 5015). We performed ExWAS analyses separately on six cardiovascular outcomes (cardiac arrhythmia, congestive heart failure, coronary artery disease, heart attack, stroke, and a combined atherogenic-related outcome comprising angina, angioplasty, atherosclerosis, coronary artery disease, heart attack, and stroke) using logistic regression and a false discovery rate of 5%. For each CVD outcome, we tested 502 single exposures and built multi-exposure models using the deletion-substitution-addition (DSA) algorithm. To evaluate complex nonlinear relationships, we employed the knockoff boosted tree (KOBT) algorithm. We adjusted all analyses for age, sex, race, BMI, and annual household income. ExWAS analyses revealed novel associations that include blood type A (Rh-) with heart attack (OR[95%CI] = 8.2[2.2:29.7]); paint exposures with stroke (paint related chemicals: 6.1[2.2:16.0], acrylic paint: 8.1[2.6:22.9], primer: 6.7[2.2:18.6]); biohazardous materials exposure with arrhythmia (1.8[1.5:2.3]); and higher paternal education level with reduced risk of multiple CVD outcomes (stroke, heart attack, coronary artery disease, and combined atherogenic outcome). In multi-exposure models, trouble sleeping and smoking remained important risk factors. KOBT identified significant nonlinear effects of sleep disorder, regular intake of grapefruit, and a family history of blood clotting problems for multiple CVD outcomes (combined atherogenic outcome, congestive heart failure, and coronary artery disease). In conclusion, using statistics and machine learning, these findings identify novel potential risk factors for CVD, enable hypothesis generation, provide insights into the complex relationships between risk factors and CVD, and highlight the importance of considering multiple exposures when examining CVD outcomes.

The use of palliative care for critically ill hospitalized patients has expanded. However, it is still underutilized in surgical specialties. Postsurgical patients requiring prolonged mechanical ventilation have increased mortality and costs of care; outcomes from adding palliative care services to this population have been poorly investigated. The objective of this study was to determine the impact of palliative medicine consultation on readmission rates and hospitalization costs in postsurgical patients requiring prolonged mechanical ventilation.The Nationwide Readmissions Database was queried for adults (18 years) between the years 2010 and 2014 who underwent a major operation (Healthcare Cost and Utilization Project [HCUP] data element ORPROC = 1), required mechanical ventilation for ≥ 96 consecutive hours (ICD-9-CM V46.1), and survived until discharge. Among these, patients who received a palliative medicine consultation during hospitalization were identified using the ICD-9-CM diagnosis code V66.7.Of 53,450 included patients, 3.4% received a palliative care consultation. Compared to patients who did not receive a palliative care consultation, patients who did receive a consultation had a lower readmission rate (14.8% vs. 24.8%, p0.001) and lower average cost of hospitalization during the initial admission ($109,007 vs. $124,218, p0.001), findings that persisted after multivariable logistic regression.Utilization of palliative care in surgical patients remains low. Palliative care consultation in postsurgical patients requiring prolonged mechanical ventilation was associated with lower cost and rate of readmission. Further work is needed to integrate palliative care services with surgical care.

Studies of anticancer therapies in traditional cell culture models can demonstrate efficacy of direct-acting compounds but lack the 3-dimensional arrangement of the tumor cells and their tissue-specific microenvironments, both of which are important modulators of treatment effects in vivo. Bone cells reside in complex environments that regulate their fate and function. A bioengineered human bone-tumor model has been shown to provide a microphysiological niche for studies of cancer cell behavior. Here, we demonstrate successful transfer between 2 laboratories and utility of this model in efficacy studies using well-established chemotherapeutic agents. The bioengineered human bone-tumor model consisted of Ewing sarcoma (RD-ES) cancer cell aggregates infused into tissue-engineered bone that was grown from human mesenchymal stem cell-derived differentiated into osteoblasts within mineralized bone scaffolds. The tumor model was maintained in culture for over 5 weeks and subjected to clinically relevant doses of linsitinib, doxorubicin, cisplatin, methotrexate, vincristine, dexamethasone, or MAP (methotrexate, doxorubicin, and cisplatin combination). Drug administration cycles were designed to mimic clinical treatment regimens. The bioengineered tumors were evaluated days to weeks after the cessation of treatment to monitor the potential for relapse, using bioengineered bone and ES cell monolayers as controls. Drug binding to the scaffolds and media proteins and gene expression were also evaluated. We show that a bioengineered human bone tumor can be used as a microphysiological model for preclinical studies of anticancer drugs. We found that anticancer efficacy was achieved at concentrations approximating the human Cmax, in contrast to traditional ES cell monolayers. These studies show that the bone-tumor model can be successfully transferred between laboratories and has predictive power in preclinical studies. The effects of drugs on the bone tumors and healthy bone were studied in parallel, in support of the utility of this model for identification of new therapeutic targets.

The RIPK3-MLKL pathway protects epithelial cells from Listeria monocytogenes invasion. Sai et al. find that Listeria infection activates MLKL but does not induce its oligomerization or necroptotic cell death. Instead, Listeria-activated MLKL directly targets intracellular bacteria and suppresses their replication., RIPK3, a key mediator of necroptosis, has been implicated in the host defense against viral infection primary in immune cells. However, gene expression analysis revealed that RIPK3 is abundantly expressed not only in immune organs but also in the gastrointestinal tract, particularly in the small intestine. We found that orally inoculated Listeria monocytogenes, a bacterial foodborne pathogen, efficiently spread and caused systemic infection in Ripk3-deficient mice while almost no dissemination was observed in wild-type mice. Listeria infection activated the RIPK3-MLKL pathway in cultured cells, which resulted in suppression of intracellular replication of Listeria. Surprisingly, Listeria infection–induced phosphorylation of MLKL did not result in host cell killing. We found that MLKL directly binds to Listeria and inhibits their replication in the cytosol. Our findings have revealed a novel functional role of the RIPK3-MLKL pathway in nonimmune cell-derived host defense against Listeria invasion, which is mediated through cell death–independent mechanisms.

Basaloid follicular hamartoma (BFH) is a rare, benign follicular neoplasm which typically presents as brown to skin-colored papules on the face, scalp, and trunk. Histologically, BFH consists of cords and strands of basaloid cells forming cystic structures with scant stroma and should be distinguished from infundibulocystic basal cell carcinoma to avoid overly aggressive treatment. Although BFH has been found to be associated with distinct syndromes, including alopecia, myasthenia gravis, and cystic fibrosis, there is often clinical, histopathologic, and genetic overlap with nevoid basal cell carcinoma syndrome (NBCCS). In this article, we describe a case of a 13-year-old patient with NBCCS who presented with multiple BFHs and propose that it its inclusion into the diagnostic criteria for NBCCS be considered.

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10(−8)). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10(−4), Beta = 3.09, diastolic BP response P = 5 × 10(−3), Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10(−4), odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

While the COVID-19 pandemic presents a global challenge, the U.S. response places substantial responsibility for both decision-making and communication on local health authorities, necessitating tools to support decision-making at the community level.We created a Pandemic Vulnerability Index (PVI) to support counties and municipalities by integrating baseline data on relevant community vulnerabilities with dynamic data on local infection rates and interventions. The PVI visually synthesizes county-level vulnerability indicators, enabling their comparison in regional, state, and nationwide contexts.We describe the data streams used and how these are combined to calculate the PVI, detail the supporting epidemiological modeling and machine-learning forecasts, and outline the deployment of an interactive web Dashboard. Finally, we describe the practical application of the PVI for real-world decision-making.Considering an outlook horizon from 1 to 28 days, the overall PVI scores are significantly associated with key vulnerability-related outcome metrics of cumulative deaths, population adjusted cumulative deaths, and the proportion of deaths from cases. The modeling results indicate the most significant predictors of case counts are population size, proportion of black residents, and mean PMThe COVID-19 PVI Dashboard monitors multiple data streams to communicate county-level trends and vulnerabilities and facilitates decision-making and communication among government officials, scientists, community leaders, and the public to enable effective and coordinated action to combat the pandemic.

Background Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. Objectives In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. Methods In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1β, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. Results After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). Conclusions Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.

Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the

Objectives: The 21st century has seen a rise in racism and xenophobia in the United States. Few studies have examined the health implications of heightened institutional and interpersonal racism. T...

Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses, and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.

Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3,061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher forced expiratory volume in the first second (FEV(1)) (β=49.5ml; 95%CI=2.8,96.1ml; p=0.04) and forced vital capacity (FVC) (β=66.2ml, 95%CI=13.2–119.1ml, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood.

One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (Unknown or Variable composition, Complex reaction products and Biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that animal alternatives new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, can be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data are used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of representative substances in each group for testing when needed, and to fill data gaps by read-across.

Silver nanoparticles (AgNPs) are widely incorporated into consumer and biomedical products for their antimicrobial and plasmonic properties with limited risk-assessment of low-dose cumulative exposure in humans. To evaluate cellular responses to low-dose AgNP exposures across time, human liver cells (HepG2) were exposed to AgNPs with three different surface charges (1.2 μg mL(−1)) and complete gene expression was monitored across a 24-hour period. Time and AgNP surface chemistry mediate gene expression. In addition, time since cells were fed had marked effects on gene expression that should be considered. Surface chemistry of AgNPs alter gene transcription in a time-dependent manner, with the most dramatic effects in cationic AgNPs. Universal to all surface-coatings, AgNP-treated cells responded by inactivating proliferation and enabling cell cycle checkpoints. Further analysis of these universal features of AgNP cellular response, as well as more detailed analysis of specific AgNP treatments, time points, or specific genes is facilitated with an accompanying application. Taken together, these results provide a foundation for understanding hepatic response to low-dose AgNPs for future risk assessment

The adoption of a new technology into basic research, and industrial and clinical settings requires rigorous testing to build confidence in the reproducibility, reliability, robustness, and relevance of these models. Tissue chips are promising new technology, they have the potential to serve as a valuable tool in biomedical research, as well as pharmaceutical development with regards to testing for efficacy and safety. The principal goals of this study were to validate a previously established proximal tubule tissue chip model in an independent laboratory and to extend its utility to testing of nephrotoxic compounds. Here, we evaluated critical endpoints from the tissue chip developer laboratory, focusing on biological relevance (long-term viability, baseline protein and gene expression, ammoniagenesis, and vitamin D metabolism), and toxicity biomarkers. Tissue chip experiments were conducted in parallel with traditional 2D culture conditions using two different renal proximal tubule epithelial cell sources. The results of these studies were then compared to the findings reported by the tissue chip developers. While the overall transferability of this advanced tissue chip platform was a success, the reproducibility with the original report was greatly dependent on the cell source. This study demonstrates critical importance of developing microphysiological platforms using renewable cell sources.

High-content screening data derived from physiologically-relevant in vitro models promise to improve confidence in data-integrative groupings for read-across in human health safety assessments. The biological data-based read-across concept is especially applicable to bioactive chemicals with defined mechanisms of toxicity; however, the challenge of data-derived groupings for chemicals that are associated with little or no bioactivity has not been explored. In this study, we apply a suite of organotypic and population-based in vitro models for comprehensive bioactivity profiling of twenty E-Series and P-Series glycol ethers, solvents with a broad variation in toxicity ranging from relatively non-toxic to reproductive and hematopoetic system toxicants. Both E-Series and P-Series glycol ethers elicited cytotoxicity only at high concentrations (mM range) in induced pluripotent stem cell-derived hepatocytes and cardiomyocytes. Population-variability assessment comprised a study of cytotoxicity in 94 human lymphoblast cell lines from 9 populations and revealed differences in inter-individual variability across glycol ethers, but did not indicate population-specific effects. Data derived from various phenotypic and transcriptomic assays revealed consistent bioactivity trends between both cardiomyocytes and hepatocytes, indicating a more universal, rather than cell-type specific mode-of-action for the tested glycol ethers in vitro. In vitro bioactivity-based similarity assessment using Toxicological Priority Index (ToxPi) showed that glycol ethers group according to their alcohol chain length, longer chains were associated with increased bioactivity. While overall in vitro bioactivity profiles did not correlate with in vivo toxicity data on glycol ethers, in vitro bioactivity of E-series glycol ethers were indicative of and correlated with in vivo irritation scores.

Longitudinal studies at the level of individuals find that employees who lose their jobs are at increased risk of death. However, analyses of aggregate data find that as unemployment rates increase during recessions, population mortality actually declines. We addressed this paradox by using data from the US Department of Labor and annual survey data (1979–1997) from a nationally representative longitudinal study of individuals—the Panel Study of Income Dynamics. Using proportional hazards (Cox) regression, we analyzed how the hazard of death depended on 1) individual joblessness and 2) state unemployment rates, as indicators of contextual economic conditions. We found that 1) compared with the employed, for the unemployed the hazard of death was increased by an amount equivalent to 10 extra years of age, and 2) each percentage-point increase in the state unemployment rate reduced the mortality hazard in all individuals by an amount equivalent to a reduction of 1 year of age. Our results provide evidence that 1) joblessness strongly and significantly raises the risk of death among those suffering it, and 2) periods of higher unemployment rates, that is, recessions, are associated with a moderate but significant reduction in the risk of death among the entire population.

The potential for cardiotoxicity is carefully evaluated for pharmaceuticals, as it is a major safety liability. However, environmental chemicals are seldom tested for their cardiotoxic potential. Moreover, there is a large variability in both baseline and drug-induced cardiovascular risk in humans, but data are lacking on the degree to which susceptibility to chemically-induced cardiotoxicity may also vary. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an important in vitro model for drug screening. Thus, we hypothesized that a population-based model of iPSC-derived cardiomyocytes from a diverse set of individuals can be used to assess potential hazard and inter-individual variability in chemical effects on these cells. We conducted concentration-response screening of 134 chemicals (pharmaceuticals, industrial and environmental chemicals and food constituents) in iPSC-derived cardiomyocytes from 43 individuals, comprising both sexes and diverse ancestry. We measured kinetic calcium flux and conducted high-content imaging following chemical exposure, and utilized a panel of functional and cytotoxicity parameters in concentration-response for each chemical and donor. We show reproducible inter-individual variability in both baseline and chemical-induced effects on iPSC-derived cardiomyocytes. Further, chemical-specific variability in potency and degree of population variability were quantified. This study shows the feasibility of using an organotypic population-based human in vitro model to quantitatively assess chemicals for which little cardiotoxicity information is available. Ultimately, these results advance in vitro toxicity testing methodologies by providing an innovative tool for population-based cardiotoxicity screening, contributing to the paradigm shift from traditional animal models of toxicity to in vitro toxicity testing methods.

Objectives. We investigated the association between anticipatory stress, also known as racism-related vigilance, and hypertension prevalence in Black, Hispanic, and White adults. Methods. We used data from the Chicago Community Adult Health Study, a population-representative sample of adults (n = 3105) surveyed in 2001 to 2003, to regress hypertension prevalence on the interaction between race/ethnicity and vigilance in logit models. Results. Blacks reported the highest vigilance levels. For Blacks, each unit increase in vigilance (range = 0–12) was associated with a 4% increase in the odds of hypertension (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.00, 1.09). Hispanics showed a similar but nonsignificant association (OR = 1.05; 95% CI = 0.99, 1.12), and Whites showed no association (OR = 0.95; 95% CI = 0.87, 1.03). Conclusions. Vigilance may represent an important and unique source of chronic stress that contributes to the well-documented higher prevalence of hypertension among Blacks than Whites; it is a possible contributor to hypertension among Hispanics but not Whites.

Objectives. Mental health professionals have suggested that widowed persons experience heightened psychological distress on dates that had special meaning for them and their late spouse, such as a wedding anniversary or the late spouse’s birthday. This study examined the effects of such occasions on grief, anxiety, and depressive symptoms in a community sample of older widowed persons. Methods. OLS regression models were estimated using data from the Changing Lives of Older Couples (CLOC) study, a large prospective probability study of late-life widowhood. Participants were interviewed prior to and both 6 and 18 months after spousal loss; married matched controls were interviewed at comparable times. Results. Widowed persons reported heightened psychological distress when interviewed during the month of their late spouse’s birthday, a post-holiday period (January), and in June, a month associated with wedding anniversaries and graduations in the United States. The distressing effects of special occasions on psychological symptoms were evidenced only within the first 6 months postloss, and were not apparent at the 18-month follow-up. Discussion. Our results support the clinical observation that persons in the early stages of spousal bereavement are at increased risk of psychological distress at times with special significance to the couple. We highlight methodological and clinical implications.

Prior longitudinal studies of negative working conditions and depression generally have used a single exposure indicator, such as job strain, and have required consistent availability of the measure across waves and selection of only those working at all measurement points.Up to four waves of the Americans' Changing Lives study (1986 to 2001/2) and item-response theory (IRT) models were used to generate wave-specific measures of negative working conditions. Random-intercept linear mixed models assessed the association between the score and depressive symptoms.Adjusting for covariates, negative working conditions were associated with significantly greater depressive symptoms.A summary score of negative working conditions allowed the use of all available working conditions measures and predicted depressive symptoms in a nationally representative sample of US workers observed for up to 15 years. Linear mixed models also allowed retention of intermittent workers.

David Mechanic has been a principal founder of modern sociological and social science approaches to health, especially in relation to health policy. These approaches have since the 1950s and 1960s resurrected ideas that had currency in the mid-nineteenth century but seemed crucified, dead, and buried by the rise of modern biomedicine from the mid-nineteenth century through the mid-twentieth century. Problems and lacunae in purely biomedical approaches to health in the later twentieth century, along with developments of new biopsychosocial approaches to health, have spawned a return toward ideas of Rudolf Virchow and mid-nineteenth-century social medicine that social determinants and disparities are major drivers of population health. Since individual health and population health constitute the major determinants of health care utilization and expenditures, social determinants and disparities in health are arguably the foundation of a new "demand-side" health policy that can resolve America's paradoxical health policy crisis of spending increasingly more than any nation on health care and insurance yet achieving increasingly worsening health outcomes relative to virtually all developed countries and some developing ones as well, something that current "supply-side" health policy, including Obamacare, cannot do, important as it is for expanding access to health insurance and care.

Background Previous studies, mostly from Europe, suggest that early-life farming exposures protect against childhood asthma and allergy; few data exist on asthma and allergy in adults. Objective We sought to examine associations between early-life farming exposures and current asthma and atopy in an older adult US farming population. Methods We analyzed data from 1746 farmers and 1555 spouses (mean age, 63) from a case-control study nested within the Agricultural Health Study. Current asthma and early-life farming exposures were assessed via questionnaires. We defined atopy based on specific IgE > 0.70 IU/mL to at least 1 of 10 allergens measured in blood. We used logistic regression, adjusted for age, sex, race, state (Iowa or North Carolina), and smoking (pack years), to estimate associations between early-life exposures and asthma (1198 cases and 2031 noncases) or atopy (578 cases and 2526 noncases). Results Exposure to the farming environment in utero and in early childhood had little or no association with asthma but was associated with reduced odds of atopy. The strongest association was seen for having a mother who performed farm activities while pregnant (odds ratio, 0.60; 95% CI, 0.48-0.74) and remained significant in models with correlated early-life exposures including early childhood farm animal contact and raw milk consumption. Conclusions In a large US farming population, early-life farm exposures, particularly maternal farming activities while pregnant, were strongly associated with reduced risk of atopy in adults. These results extend previous work done primarily on childhood outcomes and suggest that protective associations of early-life farming exposures on atopy endure across the life course.

Social networks are typically seen as conduits for the spread of disease and disease risk factors. However, social relationships also reduce the incidence of chronic disease and potentially infectious diseases. Seldom are these opposing effects considered simultaneously. We have shown how and why diarrheal disease spreads more slowly to and in rural Ecuadorian villages that are more remote from the area’s population center. Reduced contact with outside individuals partially accounts for remote villages’ relatively lower prevalence of diarrheal disease. But equally or more important is the greater density of social ties between individuals in remote communities, which facilitates the spread of individual and collective practices that reduce the transmission of diarrheal disease.

A growing body of research demonstrates that having multiple adverse biological risk factors – such as hypertension, obesity, high blood sugar, and elevated cholesterol – increases the risk of morbidity, functional and cognitive decline, and mortality (1-16). Such research also suggests that racial/ethnic minority groups and people with lower levels of education and income tend to accumulate more biological risk factors (4, 6, 9, 10, 17-20), making the cumulative toll of such “wear and tear” to the body a potentially critical, though not yet widely recognized, facet of health disparities in the United States. In an influential essay on the pathways from stress to disease, McEwen and Stellar (21) coined the term allostatic load to describe the harmful effects of physiological response patterns that can ensue from prolonged exposure to stressful environments or being highly reactive to stressors. They described a process in which the body responds to physical, psychosocial, and environmental stressors by producing hormones and neurotransmitters that help the body respond to stress by coordinating physiological responses across multiple biological systems, thus achieving stability through change (22). In the face of severe or prolonged stress, dysfunctions can result from physiological systems being activated too frequently, not having a chance to return to their setpoints, or ceasing to activate adequately. Moreover, dysfunctions of one physiological system can spillover into related systems. For example, exposure to stress can trigger surges in blood pressure, which in turn can accelerate atherosclerosis or interact with metabolic processes to produce Type II diabetes (22). Thus, the theory of allostatic load offers a framework for understanding not only the pathways between stress and disease but also how physiological pathologies can spread across systems and cumulatively affect health. There is a growing literature on how to measure allostatic load in population-based research. Most studies of this kind create indices of allostatic load from biomarkers of metabolic, inflammatory, cardiovascular, and neuroendocrine processes. There is substantial variation across studies in how many biomarkers are included in such indices, which physiological systems are represented, and how the indices are formulated [for a comprehensive review, see Juster, McEwen, and Lupien (23)]. In this study we follow an approach similar to prior studies but use the term “cumulative biological risk” (CBR) rather than allostatic load to describe indices of this kind to acknowledge that they are indirect indicators (at best) of the underlying processes that generate allostatic load. That is, like other studies, we do not have measures of primary stress mediators and instead have secondary outcomes that reflect adaptive physiological responses to stress and other adverse stimuli but which also can arise from other etiologies. Although some scholars use the term “allostatic load” in reference to similar measures, we did not want to give readers the impression that we were directly operationalizing the concept of allostatic load and thus preferred the term CBR. It is worth noting that metabolic syndrome describes a cluster of risk factors that overlaps considerably with those in our measure of CBR, although conceptually allostatic load addresses a broader array of systems in dysregulation. Both of these concepts describe a potentially interrelated set of physiological conditions that may have cumulative and interactive effects on health. Several studies show that racial/ethnic minorities and/or people of lower social status experience a greater accumulation of biological risk factors (11, 24). For example, in an analysis of the Normative Aging Study (24), Kubzansky and colleagues found that respondents with lower levels of education experienced higher levels of cumulative biological risk. In Weinstein and colleagues’ study using both the MacArthur Study of Successful Aging and Taiwan Social Environment and Biomarkers of Aging Study (SEBAS) cohorts (25), income and education were inversely related to CBR. Likewise, higher levels of education and income were associated with lower CBR in Seeman and colleagues’ (26) analysis of the National Health and Nutrition Examination Study (NHANES III). Respondents with a poverty-income ratio less than 1.85 were more likely than the non-poor to have high CBR in Geronimus and colleagues’ analysis of NHANES III, and they also found racial differences in CBR, with higher risks for respondents in the non-poor black category compared to poor whites (6). Several other studies have also shown that blacks (6, 9, 19, 26) and Hispanics (9, 19) have significantly more risks than whites, independent of education and income. Neighborhood environments are often invoked as a possible explanation for social disparities in health. In their study of NHANES III, Bird and colleagues (27) found that neighborhood socioeconomic status was associated with a higher count of biological risks after adjustment for age, gender, race/ethnicity, marital status, nativity, education, and an income to poverty ratio. Merkin and colleagues (28) expanded on the analysis by Bird and colleagues, using models stratified by race/ethnicity to show that the relationship between neighborhood disadvantage and CBR is strongest among blacks and, to a lesser extent, Mexican Americans. Neither study assessed the degree to which neighborhood factors explain racial/ethnic differences in CBR; Merkin and colleagues cite insufficient overlap in the distribution of neighborhood disadvantage between blacks and whites as an obstacle to such an analysis using the NHANES data (28). Thus, to date, no study has provided a systematic account of how much individual-level disparities are a function of or conditioned by neighborhood context (29). This paper (1) assesses the contribution of neighborhood environments to racial/ethnic and socioeconomic disparities in CBR, using data from a population-based study of adults in Chicago, and (2) shows that the relationship between neighborhood socioeconomic position and CBR may be driven less by the factors that indicate neighborhood disadvantage (e.g., aggregate income levels and rates of poverty, unemployment, public assistance) and more by factors that may be more indicative of relative neighborhood affluence (e.g., aggregate education levels, occupational composition, and home values).

To examine whether the psychological traits of hopelessness and depressive symptoms are related to endothelial dysfunction.Data are derived from a subsample of 434 respondents in the 2001 to 2003 Chicago Community Adult Health Study, a population-based survey designed to study the impact of psychological attributes, neighborhood environment, and socioeconomic circumstances on adults aged ≥18 years. Circulating biomarkers of endothelial dysfunction, including e-selectin, p-selectin, and soluble intercellular adhesion molecule-1 (s-ICAM1) were obtained from serum samples. Hopelessness was measured by responses to two questions, and depressive symptoms were measured by an 11-item version of the Center for Epidemiological Studies Depression scale. Multivariate regression models tested whether continuous levels of the biomarkers (natural log transformed) were associated with levels of hopelessness and depressive symptoms separately and concurrently.In age- and sex-adjusted models, hopelessness showed significant positive linear associations with s-ICAM1. In contrast, there was no significant linear association between hopelessness and e-selectin and p-selectin. Adjustment for clinical risk factors, including systolic pressure, chronic health conditions, smoking, and body mass index, did not substantively alter these associations. Results from similar models for depressive symptoms did not reveal any association with the three biomarkers of endothelial dysfunction. The associations between hopelessness and e-selectin and s-ICAM1 were robust to the inclusion of adjustments for depressive symptoms.Negative psychosocial traits may influence cardiovascular outcomes partially through their impact on the early stages of atherosclerosis, and specific psychosocial traits, such as hopelessness, may play a more direct role in this process than overall depressive symptoms.

Many demographic, socioeconomic, and behavioral risk factors predict mortality in the United States. However, very few population-based longitudinal studies are able to investigate simultaneously the impact of a variety of social factors on mortality. We investigated the degree to which demographic characteristics, socioeconomic variables and major health risk factors were associated with mortality in a nationally-representative sample of 3,617 U.S. adults from 1986-2005, using data from the 4 waves of the Americans’ Changing Lives study. Cox proportional hazard models with time-varying covariates were employed to predict all-cause mortality verified through the National Death Index and death certificate review. The results revealed that low educational attainment was not associated with mortality when income and health risk behaviors were included in the model. The association of low-income with mortality remained after controlling for major behavioral risks. Compared to those in the “normal” weight category, neither overweight nor obesity was significantly associated with the risk of mortality. Among adults age 55 and older at baseline, the risk of mortality was actually reduced for those were overweight (hazard rate ratio=0.83, 95% C.I. = 0.71 – 0.98) and those who were obese (hazard rate ratio=0.68, 95% C.I. = 0.55 – 0.84), controlling for other health risk behaviors and health status. Having a low level of physical activity was a significant risk factor for mortality (hazard rate ratio=1.58, 95% C.I. = 1.20 – 2.07). The results from this national longitudinal study underscore the need for health policies and clinical interventions focusing on the social and behavioral determinants of health, with a particular focus on income security, smoking prevention/cessation, and physical activity.

Studying the relation between the residential environment and health requires valid, reliable, and cost-effective methods to collect data on residential environments. This 2002 study compared the level of agreement between measures of the presence of neighborhood businesses drawn from 2 common sources of data used for research on the built environment and health: listings of businesses from commercial databases and direct observations of city blocks by raters. Kappa statistics were calculated for 6 types of businesses—drugstores, liquor stores, bars, convenience stores, restaurants, and grocers—located on 1,663 city blocks in Chicago, Illinois. Logistic regressions estimated whether disagreement between measurement methods was systematically correlated with the socioeconomic and demographic characteristics of neighborhoods. Levels of agreement between the 2 sources were relatively high, with significant (P < 0.001) kappa statistics for each business type ranging from 0.32 to 0.70. Most business types were more likely to be reported by direct observations than in the commercial database listings. Disagreement between the 2 sources was not significantly correlated with the socioeconomic and demographic characteristics of neighborhoods. Results suggest that researchers should have reasonable confidence using whichever method (or combination of methods) is most cost-effective and theoretically appropriate for their research design.

Background: Observational studies and controlled experiments have provided evidence that airborne particulate matter (PM) is capable of acutely increasing blood pressure (BP) in certain scenarios. The goal of this study was to evaluate whether and to what extent obesity and community location affect relationships between fine particulate matter (PM2.5) and blood pressure (BP) measures. Methods: Using data from a stratified random sample survey of adults conducted in 2002–3 in Detroit, Michigan, we tested body mass index (BMI) and waist circumference (WCIR) in separate models as effect modifiers of the relationship between PM2.5 exposure and BP. We also tested interactions with community location. Models were adjusted for covariates with established prohypertensive effects. Results: PM2.5 exposure was positively associated with increased pulse pressure (PP) for those categorised as obese (BMI>30) across lags 2 (b 4.16, p,0.05) and 3 days (b 2.55, p,0.05) prior to BP measure. WCIR similarly modified the effect of exposure to PM2.5 on PP (b 4.34, p,0.003). The observed effects were enhanced in the community with closer proximity to local emissions of PM2.5, and for residents classified as obese (BMI>30) or with WCIR above high-risk cuts points. Conclusions: This community-based study suggests that positive associations between PM2.5 exposure and PP and systolic BP are enhanced in areas proximate to sources of PM 2.5 emissions. These patterns were observed for all residents, but were more visible and consistent among those who were obese. Research is needed to examine the mechanistic pathways by which air particles interact with obesity and location to affect BP, and inform community interventions to reduce the population burden of hypertension and related co-morbidities.

Economic recessions, the industrial shift from manufacturing toward service industries, and rising global competition have contributed to uncertainty about job security, with potential consequences for workers’ health. To address limitations of prior research on the health consequences of perceived job insecurity, we use longitudinal data from two nationally-representative samples of the United States population, and examine episodic and persistent perceived job insecurity over periods of about three years to almost a decade. Results show that persistent perceived job insecurity is a significant and substantively important predictor of poorer self-rated health in the American’s Changing Lives (ACL) and Midlife in the United States (MIDUS) samples, and of depressive symptoms among ACL respondents. Job losses or unemployment episodes are associated with perceived job insecurity, but do not account for its association with health. Results are robust to controls for sociodemographic and job characteristics, negative reporting style, and earlier health and health behaviors.

Research on the effects of the built environment in the pathway from impairment to disability has been largely absent. Using data from the Chicago Community Adult Health Study (2001–2003), the authors examined the effect of built environment characteristics on mobility disability among adults aged 45 or more years (n = 1,195) according to their level of lower extremity physical impairment. Built environment characteristics were assessed by using systematic social observation to independently rate street and sidewalk quality in the block surrounding each respondent's residence in the city of Chicago (Illinois). Using multinomial logistic regression, the authors found that street conditions had no effect on outdoor mobility among adults with only mild or no physical impairment. However, among adults with more severe impairment in neuromuscular and movement-related functions, the difference in the odd ratios for reporting severe mobility disability was over four times greater when at least one street was in fair or poor condition (characterized by cracks, potholes, or broken curbs). When all streets were in good condition, the odds of reporting mobility disability were attenuated in those with lower extremity impairment. If street quality could be improved, even somewhat, for those adults at greatest risk for disability in outdoor mobility, the disablement process could be slowed or even reversed.

We sought to develop and optimize a hybridoma-based technology for generating human hybridomas that secrete virus-specific monoclonal antibodies for clinical diagnosis and therapy. We developed a novel electrofusion protocol for efficiently fusing Epstein-Barr virus (EBV)-transformed human B cells with myeloma partners. We tested seven myeloma cell lines and achieved highest efficiency when the HMMA 2.5 line was used. We optimized the electrofusion process by improving cell treatments before and after electrofusion as well as varying cell ratios, fusion medium and other experimental parameters. Our fusion efficiency increased remarkably to 0.43%, a significant improvement over the efficiency of previous PEG-based or other electrofusion methods. Using the optimized protocol, we obtained human hybridomas that secrete fully human monoclonal antibodies against two major human respiratory pathogens: respiratory syncytial virus (RSV) and an influenza H3N2 vaccine virus strain. In conclusion, we have developed an efficient and routine approach for the generation of human hybridomas secreting functional human virus-specific monoclonal antibodies.

Previous research has shown that involuntary job loss may have negative health consequences, but existing analyses have not adequately adjusted for health selection or other confounding factors that could reveal the association to be spurious. Using two large, population-based longitudinal samples of U.S. workers from the Americans' Changing Lives Study and the Wisconsin Longitudinal Study, this analysis goes further by using respondents' self-reports of the reasons for job loss and information about the timing of job losses and acute negative health shocks to distinguish health-related job losses from other involuntary job losses. Results suggest that even after adjustment for numerous social background characteristics and baseline health, involuntary job loss is associated with significantly poorer overall self-rated health and more depressive symptoms. More nuanced analyses reveal that among involuntary job losers, those who lose their jobs for health-related reasons have, not surprisingly, the most precipitous declines in health. Job losses for other reasons have substantive and statistically significant effects on depressive symptoms, while effects on self-rated poor health are relatively small.

Objectives. This article overviews previously published and ongoing research from the Americans’ Changing Lives (ACL) Study, a longitudinal study of a nationally representative sample of 3,617 adults aged 25 years and older when first interviewed in 1986, focusing on socioeconomic disparities in the way health changes with age during middle and later life, especially in terms of compression of morbidity/functional limitations. Methods. A variety of descriptive and multivariate regression and growth curve analyses are done on the ACL sample, now surveyed over four waves spanning 15.5 years between 1986 and 2001/2002 with continuing mortality ascertainment via the National Death Index, death certificate searches, and informant reports. Results. Both cross-sectional and longitudinal analyses indicate that socioeconomic disparities in health are small in early adulthood, increase through middle and early old age, and then lessen again in later old age. In other terms, compression of morbidity/functional limitations into the later stages of the life course is realized to a much greater degree among the better educated compared with the less educated. Cross-sectional evidence suggests that this reflects differential exposure to or experience of a wide range of psychosocial, environmental, and biomedical risk factors for health (and perhaps their differential impact at different ages and life stages), as well as variations in biological robustness and frailty and also perhaps in the strength of social welfare supports for health at different life stages. Longitudinal analyses reveal several new insights: (a) The flow of causality is much greater from socioeconomic position to health than vice versa; (b) education plays a greater role relative to income in the onset of functional limitations, whereas income has much stronger effects on their progression or course; and (c) educational disparities in the onset and hence of compression of functional limitations over the life course have increased strikingly in later middle and early old age (ages 55‐84 years) since 1986. Discussion. The results indicate that understanding and alleviating social disparities in health are both theoretically and methodologically quintessential problems of life course analysis and research.

It has been hypothesized that exposure to stress and negative life events is related to poor health outcomes, and that differential exposure to stress plays a role in socioeconomic disparities in health. Data from three waves of the Americans' Changing Lives study (n = 3,617) were analyzed to investigate prospectively the relationship among socioeconomic indicators, five measures of stress/negative life events, and the health outcomes of mortality, functional limitations, and self-rated health. The results revealed that (1) life events and other types of stressors are clearly related to socioeconomic position; (2) a count of negative lifetime events was positively associated with mortality; (3) a higher score on a financial stress scale was predictive of severe/moderate functional limitations and fair/poor self-rated health at wave 3; and (4) a higher score on a parental stress scale was predictive of fair/poor self-rated health at wave 3. The negative effects of low income on functional limitations attenuated to insignificance when waves 1 and 2 stress/life event measures were controlled for, but other socioeconomic disparities in health change remained sizable and significant when adjusted for exposure to stressors. The results support the hypothesis that differential exposure to stress and negative life events is one of many ways in which socioeconomic inequalities in health are produced in society.

Research and theory increasingly suggest that attendance at religious services is protective against premature mortality. However, prior studies are limited and do not extensively explore potential explanations for the relationship, especially in terms of religious beliefs and behaviors associated with service attendance. This study estimates the impact of service attendance on mortality in a national probability sample and provides the most extensive empirical examination of potential explanations. Individuals who report attending religious services once a month or more (just over 50 percent of the population) have a 30–35 percent reduced risk of death over a 7.5 year follow-up period after adjusting for potential confounding factors. Consistent with prior research, 20–30 percent of this effect may be explained by better health behaviors (especially physical activity) among regular service attendees. Surprisingly, other religious beliefs and behaviors do not explain, and often tend to suppress, the association between service attendance and mortality.

Background Although a robust association between socioeconomic status and health has been shown in past research, the processes that explain the connection are not well understood. This paper seeks to advance such understanding in two ways, first by attending to the distinction between onset of a functional health problem and its progression, and second by addressing whether and how education and income relate differently to the onset versus progression of functional health problems. Methods Data come from the Americans' Changing Lives survey (n = 3617). The baseline was conducted in 1986 and outcome status measured in 1994. Activity limitations are categorized into none, mild, moderate, severe. Onset is defined as having no limitation at origin and a limitation at outcome. Progression is defined as limitation of a particular severity at origin and improving, staying the same, or getting worse with respect to the severity. Multinomial regressions determine transition probabilities related to onset and progression. Results Those with higher income and education are less likely to experience an onset. Only income associates with progression. Those with the highest income are most likely to improve and least likely to get worse in comparison to those with the lowest income. Conclusions Education, being determined early in life and influencing psychosocial mechanisms throughout life, may have a greater impact on prevention of activity and functional disorders. Income's role may be both as a prevention factor and as a mechanism for management of health problems.

Previous research has shown parental warmth to have mixed effects on individuals in violent families. While positively associated with psychological health in some victims, parental warmth has also been positively associated with measures of psychological distress in other victims. The current study examined two models (the “buffering” and “inconsistency” theories) to clarify the effects of parental warmth. The current study also sought to clarify the role of parental warmth within the context of exposure to different types of family violence (i.e., witnessing versus victimization). Results differed depending on the type of violence exposure. Both mother and father warmth were negatively associated with secure attachment and self-esteem in combined victims and witnesses of violence, whereas, mother warmth was positively associated with self-esteem in witnesses of violence. Father warmth did not significantly impact either outcome for witnesses. Parental warmth did not influence either outcome for those who had only experienced victimization.

Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung resistance and also increased methacholine-induced airway hyperresponsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitive to serotonin-induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS.—House, J. S., Li, H., DeGraff, L. M., Flake, G., Zeldin, D. C., London, S. J. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse.

Background— The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4 . Methods and Results— We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P −4 ) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene ( ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant ( ADAM19 rs13155908, minor allele frequency=0.12; P =1.56×10 −4 ). Analysis of rare variants (minor allele frequency Conclusions— Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4 .

This study investigated the hypothesis that socioeconomic differences in health status change can largely be explained by the higher prevalence of individual health-risk behaviors among those of lower socioeconomic position. Data were from the Americans' Changing Lives study, a longitudinal survey of 3,617 adults representative of the US non-institutionalized population in 1986. The authors examined associations between income and education in 1986, and physical functioning and self-rated health in 1994, adjusted for baseline health status, using a multinomial logistic regression framework that considered mortality and survey nonresponse as competing risks. Covariates included age, sex, race, cigarette smoking, alcohol consumption, physical activity, and Body Mass Index. Both income and education were strong predictors of poor health outcomes. The four health-risk behaviors under study statistically explained only a modest portion of the socioeconomic differences in health at follow-up. For example, after adjustment for baseline health status, those in the lowest income group at baseline had odds of moderate/severe functional impairment in 1994 of 2.11 (95% C.I.: 1.40, 3.20) in an unadjusted model and 1.89 (95% C.I.: 1.23, 2.89) in a model adjusted for health-risk behaviors. The results suggest that the higher prevalence of major health-risk behaviors among those in lower socioeconomic strata is not the dominant mediating mechanism that can explain socioeconomic disparities in health status among US adults.

Neutralizing antibodies (Abs) are the principal protective mechanism against disease caused by reinfection with viruses. Ab-mediated neutralization of viruses is a complex process comprising multiple mechanisms. Every structural aspect of Abs is potentially capable of modulating the level of neutralizing activity or the mechanisms of neutralization. The focus of our laboratory is to understand the genetic and structural basis of Ab-mediated neutralization of human viral pathogens. We demonstrated the unexpected finding that virus antigen-binding fragments of Abs (Fabs) mediate potent virus neutralizing effects in vivo. This work has led to a broad investigation of the importance of the genetics, chemistry, and structure of the combining site to the neutralizing activity of antiviral Abs. Ongoing work in our laboratory reveals that effect or functions specified by the Ab isotype such as polymer formation, interactions with complement, interactions with Fc receptors, and the ability to transcytose mucosal epithelia, also modulate the mechanism and level of neutralizing effects mediated by antiviral Abs.

OBJECTIVES: The goals of this study were to estimate prospective mortality risks of city residence, specify how these risks vary by population subgroup, and explore possible explanations. METHODS: Data were derived from a probability sample of 3617 adults in the coterminous United States and analyzed via cross-tabular and Cox proportional hazards methods. RESULTS: After adjustment for baseline sociodemographic and health variables, city residents had a mortality hazard rate ratio of 1.62 (95% confidence interval [CI] = 1.21, 2.18) relative to rural/small-town residents; suburbanites had an intermediate but not significantly elevated hazard rate ratio. This urban mortality risk was significant among men (hazard rate ratio: 2.25), especially non-Black men, but not among women. Among Black men, and to some degree Black women, suburban residence carried the greatest risk. All risks were most evident for those younger than 65 years. CONCLUSIONS: The mortality risk of city residence, at least among men, rivals that of major psychosocial risk factors such as race, low income, smoking, and social isolation and merits comparable attention in research and policy.

Objectives. This study examined whether psychological adjustment to widowhood is affected by three aspects of marital quality—warmth, conflict, and instrumental dependence—assessed prior to the loss. Methods. The Changing Lives of Older Couples (CLOC) is a prospective study of a two-stage area probability sample of 1,532 married individuals aged 65 and older. The CLOC includes baseline data on marital quality and mental health and data on grief, anxiety, and depression collected 6, 18, and 48 months after spousal loss. Results. Widowhood was associated with elevated anxiety among those who were highly dependent on their spouses and lower levels of anxiety among those who were not dependent on their spouses. Levels of yearning were lower for widowed persons whose relationships were conflicted at baseline and higher for those reporting high levels of marital closeness and dependence on their spouses. Women who relied on their husbands for instrumental support had significantly higher levels of yearning than men who depended on their wives. Discussion. The findings contradict the widespread belief that grief is more severe if the marriage was conflicted and suggest a more complex relationship between bereavement and characteristics of the marriage.

Studies on the health effects of income inequality have generated great interest. The evidence on this association between countries is mixed,1–4 but income inequality and health have been linked within the United States,5–11 Britain,12 and Brazil.13 Questions remain over how to interpret these findings and the mechanisms involved. We discuss three interpretations of the association between income inequality and health: the individual income interpretation, the psychosocial environment interpretation, and the neo-material interpretation. #### Summary points Income inequality has generally been associated with differences in health A psychosocial interpretation of health inequalities, in terms of perceptions of relative disadvantage and the psychological consequences of inequality, raises several conceptual and empirical problems Income inequality is accompanied by many differences in conditions of life at the individual and population levels, which may adversely influence health Interpretation of links between income inequality and health must begin with the structural causes of inequalities, and not just focus on perceptions of that inequality Reducing health inequalities and improving public health in the 21st century requires strategic investment in neo-material conditions via more equitable distribution of public and private resources We reviewed the literature through traditional and electronic means and supplemented this with correlational analyses of gross domestic product and life expectancy and of income inequality and mortality trends based on data from the World Bank,14 the World Health Organization,15 and two British sources.16 17 According to the individual income interpretation, aggregate level associations between income inequality and health reflect only the individual level association between income and health. The curvilinear relation between income and health at the individual level 18 19 is a sufficient condition to produce health differences between populations with the same average income but different distributions of income.3 20 This interpretation assumes that determinants …