Birth defects associated with paternal firefighting in the National Birth Defects Prevention Study.

BACKGROUND: Few studies have evaluated birth defects among children of firefighters. We investigated associations between birth defects and paternal work as a firefighter compared to work in non-firefighting and police officer occupations. METHODS: We analyzed 1997-2011 data from the multi-site case-control National Birth Defects Prevention Study. Cases included fetuses or infants with major structural birth defects and controls included a random sample of live-born infants without major birth defects. Mothers of infants self-reported information about parents' occupations held during pregnancy. We investigated associations between paternal firefighting and birth defect groups using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Referent groups included families reporting fathers working non-firefighting and police officer jobs. RESULTS: Occupational groups included 227 firefighters, 36,285 non-firefighters, and 433 police officers. Twenty-nine birth defects were analyzed. In adjusted analyses, fathers of children with total anomalous pulmonary venous return (TAPVR; OR = 3.1; 95% CI = 1.1-8.7), cleft palate (OR = 1.8; 95% CI = 1.0-3.3), cleft lip (OR = 2.2; 95% CI = 1.2-4.2), and transverse limb deficiency (OR = 2.2; 95% CI = 1.1-4.7) were more likely than fathers of controls to be firefighters, versus non-firefighters. In police-referent analyses, fathers of children with cleft palate were 2.4 times more likely to be firefighters than fathers of controls (95% CI = 1.1-5.4). CONCLUSIONS: Paternal firefighting may be associated with an elevated risk of birth defects in offspring. Additional studies are warranted to replicate these findings. Further research may contribute to a greater understanding of the reproductive health of firefighters and their families for guiding workplace practices.

Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines.

Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This "outlier" clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.

Multiple Job Holding, Job Changes, and Associations with Gestational Diabetes and Pregnancy-Related Hypertension in the National Birth Defects Prevention Study.

We used National Birth Defects Prevention Study data to investigate associations between working patterns shortly before and during pregnancy and gestational diabetes and pregnancy-related hypertension. We analyzed working patterns (multiple-job holders, job changers, single-job holders) during the three months before and during pregnancy for 8140 participants who delivered a live-born child without a birth defect. "Multiple-job holders" worked more than one job simultaneously, "job changers" worked more than one job with no overlap, and "single-job holders" (referent) worked one job. We used multivariable logistic regression to estimate associations between working pattern and each outcome, adjusting for maternal age and educational attainment at delivery. We explored effect measure modification by household income, peak weekly working hours, and maternal race/ethnicity. Multiple-job holders had higher odds of gestational diabetes (adjusted odds ratio [aOR]: 1.5; 95% confidence interval [CI]: 1.1-2.1) and pregnancy-related hypertension (aOR: 1.5; 95% CI: 1.0-2.2) compared with single-job holders. Multiple-job holders with a household income of more than 30,000 USD per year, 32-44 peak weekly working hours, and from racial/ethnic minority groups had higher odds of gestational diabetes compared with single-job holders in respective categories. Detailed occupational information is important for studies of occupation and maternal health.

Characteristics of the Moveable Middle: Opportunities Among Adults Open to COVID-19 Vaccination.

INTRODUCTION: Focusing on subpopulations that express the intention to receive a COVID-19 vaccination but are unvaccinated may improve the yield of COVID-19 vaccination efforts. METHODS: A nationally representative sample of 789,658 U.S. adults aged ≥18 years participated in the National Immunization Survey Adult COVID Module from May 2021 to April 2022. The survey assessed respondents' COVID-19 vaccination status and intent by demographic characteristics (age, urbanicity, educational attainment, region, insurance, income, and race/ethnicity). This study compared composition and within-group estimates of those who responded that they definitely or probably will get vaccinated or are unsure (moveable middle) from the first and last month of data collection. RESULTS: Because vaccination uptake increased over the study period, the moveable middle declined among persons aged ≥18 years. Adults aged 18-39 years and suburban residents comprised most of the moveable middle in April 2022. Groups with the largest moveable middles in April 2022 included persons with no insurance (10%), those aged 18-29 years (8%), and those with incomes below poverty (8%), followed by non-Hispanic Native Hawaiian or other Pacific Islander (7%), non-Hispanic multiple or other race (6%), non-Hispanic American Indian or Alaska Native persons (6%), non-Hispanic Black or African American persons (6%), those with below high school education (6%), those with high school education (5%), and those aged 30-39 years (5%). CONCLUSIONS: A sizable percentage of adults open to receiving COVID-19 vaccination remain in several demographic groups. Emphasizing engagement of persons who are unvaccinated in some racial/ethnic groups, aged 18-39 years, without health insurance, or with lower income may reach more persons open to vaccination.

Usability of NewSTEPs Data for Assessing the Characteristics of Infants with Newborn Screening Disorders.

Most state newborn screening programs in the U.S. currently contribute case data to the Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs). To assess the usability of these data for research, we examined the completeness of key variables, particularly race and ethnicity. Data included 24,129 cases of 34 newborn screening disorders from 45 states available in NewSTEPs as of 31 August 2020. Birth years of cases ranged between 2006 and 2020. Rates of missing data for sex, gestational age, birth weight, and race/ethnicity were 3.8%, 31.7%, 7.0%, and 39.7%, respectively. After excluding 21 states for which ≥50% of cases had missing data on race and/or ethnicity, 16,010 cases from 24 states remained. The disorders with the highest proportions in which cases were recorded as Hispanic ethnicity/any race were methylmalonic acidemia (48.7%) and maple syrup urine disease (45.7%). Analyses indicated that sex and birth weight data in NewSTEPs are reasonably complete, but missing data are common for gestational age and race/ethnicity. Despite this, our analyses revealed several novel associations between race/ethnicity and newborn screening disorders, such as the high burden of maple syrup urine disease among Hispanic patients. This demonstrates the potential usefulness of NewSTEPs for research if investments in higher-quality data are made.

Geographic Heterogeneity in Behavioral and Social Drivers of COVID-19 Vaccination.

INTRODUCTION: Little is known about how the drivers of COVID-19 vaccination vary across the U.S. To inform vaccination outreach efforts, this study explores geographic variation in correlates of COVID-19 nonvaccination among adults. METHODS: Participants were a nationally representative sample of U.S. adults identified through random-digit dialing for the National Immunization Survey-Adult COVID Module. Analyses examined the geographic and temporal landscape of constructs in the Behavioral and Social Drivers of Vaccination Framework among unvaccinated respondents from May 2021 to December 2021 (n=531,798) and sociodemographic and geographic disparities and Behavioral and Social Drivers of Vaccination predictors of COVID-19 nonvaccination from October 2021 to December 2021 (n=187,756). RESULTS: National coverage with at least 1 dose of COVID-19 vaccine was 79.3% by December 2021, with substantial geographic heterogeneity. Regions with the largest proportion of unvaccinated persons who would probably get a COVID-19 vaccine or were unsure resided in the Southeast and Midwest (Health and Human Services Regions 4 and 5). Both regions had similar temporal trends regarding concerns about COVID-19 and confidence in vaccine importance, although the Southeast had especially low confidence in vaccine safety in December 2021, lowest in Florida (5.5%) and highest in North Carolina (18.0%). The strongest Behavioral and Social Drivers of Vaccination correlate of not receiving a COVID-19 vaccination was lower confidence in COVID-19 vaccine importance (adjusted prevalence ratio=5.19, 95% CI=4.93, 5.47; strongest in the Northeast, Southwest, and Mountain West and weakest in the Southeast and Midwest). Other Behavioral and Social Drivers of Vaccination correlates also varied by region. CONCLUSIONS: Contributors to nonvaccination showed substantial geographic heterogeneity. Strategies to improve COVID-19 vaccination uptake may need to be tailored regionally.

Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette.

The development of methods to achieve efficient reprogramming of human cells while avoiding the permanent presence of reprogramming transgenes represents a critical step toward the use of induced pluripotent stem cells (iPSC) for clinical purposes, such as disease modeling or reconstituting therapies. Although several methods exist for generating iPSC free of reprogramming transgenes from mouse cells or neonatal normal human tissues, a sufficiently efficient reprogramming system is still needed to achieve the widespread derivation of disease-specific iPSC from humans with inherited or degenerative diseases. Here, we report the use of a humanized version of a single lentiviral "stem cell cassette" vector to accomplish efficient reprogramming of normal or diseased skin fibroblasts obtained from humans of virtually any age. Simultaneous transfer of either three or four reprogramming factors into human target cells using this single vector allows derivation of human iPSC containing a single excisable viral integration that on removal generates human iPSC free of integrated transgenes. As a proof of principle, here we apply this strategy to generate >100 lung disease-specific iPSC lines from individuals with a variety of diseases affecting the epithelial, endothelial, or interstitial compartments of the lung, including cystic fibrosis, α-1 antitrypsin deficiency-related emphysema, scleroderma, and sickle-cell disease. Moreover, we demonstrate that human iPSC generated with this approach have the ability to robustly differentiate into definitive endoderm in vitro, the developmental precursor tissue of lung epithelia.

Independent and joint contributions of economic, social and physical environmental characteristics to mortality in the Detroit Metropolitan Area: A study of cumulative effects and pathways.

OBJECTIVE: Previous studies have demonstrated associations between race-based residential segregation, neighborhood socioeconomic and physical environmental characteristics, and mortality. Relatively few studies have examined independent and joint effects of these multiple neighborhood characteristics and mortality, including potential mediating pathways. In this study we examine the extent to which associations between race-based residential segregation and all-cause mortality may be explained by multiple socioeconomic indicators and exposure to air pollutants. METHODS: Drawing on data from multiple sources, we assessed bivariate associations between race-based residential segregation (operationalized as percent non-Hispanic Black), education (percent with graduate equivalency degree), poverty (percent below poverty), income inequality (GINI coefficient) and air pollution (ambient PM2.5) and age adjusted all-cause, all race mortality (henceforth all cause mortality) at the census tract level in the Detroit Metropolitan Area. We used inequality curves to assess the (in)equitable distribution of economic and environmental characteristics by census tract racial composition. Finally, we used generalized estimating equations (GEE) to examine independent and joint associations among percent NHB, education, income inequality, and air pollution to all-cause mortality, and test for mediating effects. RESULTS: Bivariate associations between racial composition, education, poverty, income inequality, PM2.5 and all-cause mortality were statistically significant. Census tracts with higher concentrations of NHB residents had significantly lower educational attainment, higher poverty, and greater exposure to PM2.5. In multivariate models, education, income inequality and PM2.5 fully attenuated associations between racial composition and all-cause mortality. CONCLUSIONS: Results are consistent with the hypothesis that race-based residential segregation is associated with heightened all-cause mortality, and that those effects are mediated by education, income inequality, and exposure to air pollution at the census tract level. Public health and cross-sector interventions to eliminate race-based residential segregation or to eliminate the maldistribution of educational and economic resources, and environmental exposures, across census tracts could substantially reduce regional inequities in all-cause mortality.

Jedi Public Health: Co-creating an Identity-Safe Culture to Promote Health Equity.

The extent to which socially-assigned and culturally mediated social identity affects health depends on contingencies of social identity that vary across and within populations in day-to-day life. These contingencies are structurally rooted and health damaging inasmuch as they activate physiological stress responses. They also have adverse effects on cognition and emotion, undermining self-confidence and diminishing academic performance. This impact reduces opportunities for social mobility, while ensuring those who "beat the odds" pay a physical price for their positive efforts. Recent applications of social identity theory toward closing racial, ethnic, and gender academic achievement gaps through changing features of educational settings, rather than individual students, have proved fruitful. We sought to integrate this evidence with growing social epidemiological evidence that structurally-rooted biopsychosocial processes have population health effects. We explicate an emergent framework, Jedi Public Health (JPH). JPH focuses on changing features of settings in everyday life, rather than individuals, to promote population health equity, a high priority, yet, elusive national public health objective. We call for an expansion and, in some ways, a re-orienting of efforts to eliminate population health inequity. Policies and interventions to remove and replace discrediting cues in everyday settings hold promise for disrupting the repeated physiological stress process activation that fuels population health inequities with potentially wide application.

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics.

Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na(+) channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na(+) channel current (I(NaL)) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of I(NaL) such that increasing the pacing rate markedly reduces I(NaL) and, in addition, increases its inhibition by the Na(+) channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband's iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.

Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors.

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.