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Genetic factors related to pregnancy-related traits are understudied, especially in ancestrally diverse cohorts. To assess maternal contributions to hypertensive disorders of pregnancy (HDP), we performed a multi-ancestry genome-wide association study (GWAS) of HDP in data from the North Carolina-based Personalized Environment and Genes Study (PEGS) cohort with validation in the UK Biobank (UKBB). The GWAS revealed two maternal loci associated with HDP at the genome-wide significance level. The lead independent variants were rs114954125 on chromosome 2 (near LRP1B; odds ratio [OR] [95% confidence interval {CI}]): 2.96 [2.02-4.34]; p = 2.82 × 10 -8 ) and rs61176331 on chromosome 3 (on RARB; OR (95% CI): 3.08 (2.12-4.48); p = 3.52 × 10 -9 ). We validated the associations near RARB with a meta-analysis of PEGS and the UKBB. We also identified cis-expression quantitative trait loci in the candidate region associated with decreased RARB expression in macrophage cells exposed to Salmonella. Chromatin mapping in FUMA identified a significant interaction within chromosome 3's enhancer and open chromatin regions, with strong effects observed for RARB and H3P10 gene regulation in mesendoderm cells, mesenchymal stem cells, and trophoblast-like stem cells. We applied existing polygenic scores (PGS) for preeclampsia and gestational hypertension and found that the scores were significantly associated with HDP in PEGS. The findings demonstrate the power of multi-ancestry studies for genetic discovery and highlight the relationship between immune response, regulation, and HDP and the utility of PGS for risk prediction. (PEGS is registered at ClinicalTrials.gov: NCT00341237.)., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA)., Methods: We studied a prospective cohort of nulliparous women (3968 mother-child pairs). We related maternal and fetal genotype to the adjusted sFLT1 Z score and sFLT1:placental growth factor (PlGF) ratio Z score at each wkGA and the change in the Z score between 28 and 36 wkGA (Δ36-28). We studied genetic variants from a previous fetal genome-wide association study of preeclampsia and an externally defined polygenic score from a maternal genome-wide association study of preeclampsia., Results: Four variants from the fetal preeclampsia genome-wide association study were positively associated with sFLT1 and sFLT1:PlGF Z score at 36 wkGA, and FLT1 enhancer single-nucleotide polymorphisms were associated with increased Δ36-28 of sFLT1. The associations were specific for the fetal genome or stronger for the fetal than the maternal genome. An increased risk of preeclampsia based on the maternal polygenic score for preeclampsia was associated with lower levels of sFLT1 and sFLT1:PlGF ratio in the first trimester and a greater Δ36-28 for sFLT1., Conclusions: The current data are consistent with a causal association between sFLT1 released by the placenta in late pregnancy and the pathophysiology of preeclampsia. The data are also consistent with maternal components to the protective effect of high sFLT1 in the first trimester and the rise in third-trimester sFLT1 levels and preeclampsia.

Vitamin D3, a prohormone, is converted to circulating calcidiol and then to calcitriol, the hormone that binds to the vitamin D receptor (VDR) (a nuclear transcription factor). Polymorphic genetic sequence variants of the VDR are associated with an increased risk of breast cancer and melanoma. However, the relationship between VDR allelic variants and the risk of squamous cell carcinoma and actinic keratosis remains unclear. We examined the associations between two VDR polymorphic sites, Fok1 and Poly-A, and serum calcidiol levels, actinic keratosis lesion incidence, and the history of cutaneous squamous cell carcinoma in 137 serially enrolled patients. By evaluating the Fok1 (F) and (f) alleles and the Poly-A long (L) and short (S) alleles together, a strong association between genotypes FFSS or FfSS and high calcidiol serum levels (50.0 ng/ml) was found; conversely, ffLL patients showed very low calcidiol levels (29.1 ng/ml). Interestingly, the FFSS and FfSS genotypes were also associated with reduced actinic keratosis incidence. For Poly-A, additive modeling showed that Poly-A (L) is a risk allele for squamous cell carcinoma, with an OR of 1.55 per copy of the L allele. We conclude that actinic keratosis and squamous cell carcinoma should be added to the list of squamous neoplasias that are differentially regulated by the VDR Poly-A allele., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults. Methods: We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank. Results: The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14, p = 3.62 × 10 -5 ; OR = 3.05, 95%CI: 1.86 to 4.98, p = 8.85 × 10 -6 ; OR = 19.5, 95%CI: 4.37 to 87.2, p = 9.97 × 10 -5 , respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants. Conclusion: Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Choi, Burkholder, Perera, Mack, Miller, Fessler, Cook, Karmaus, Nakano, Garantziotis, Madenspacher, House, Akhtari, Schmitt, Fargo, Hall and Motsinger-Reif.)

Objective: This study tested the hypothesis that obesity and metabolic abnormalities correlate with background parenchymal enhancement (BPE), the volume and intensity of enhancing fibroglandular breast tissue on dynamic contrast-enhanced magnetic resonance imaging., Methods: Participants included 59 premenopausal women at high risk of breast cancer. Obesity was defined as BMI ≥ 30 kg/m 2 . Metabolic parameters included dual-energy x-ray absorptiometry-quantified body composition, plasma biomarkers of insulin resistance, adipokines, inflammation, lipids, and urinary sex hormones. BPE was assessed using computerized algorithms on dynamic contrast-enhanced magnetic resonance imaging., Results: BMI was positively correlated with BPE (r = 0.69; p < 0.001); participants with obesity had higher BPE than those without obesity (404.9 ± 189.6 vs. 261.8 ± 143.8 cm 2 ; Δ: 143.1 cm 2 [95% CI: 49.5-236.7]; p = 0.003). Total body fat mass (r = 0.68; p < 0.001), body fat percentage (r = 0.64; p < 0.001), visceral adipose tissue area (r = 0.65; p < 0.001), subcutaneous adipose tissue area (r = 0.60; p < 0.001), insulin (r = 0.59; p < 0.001), glucose (r = 0.35; p = 0.011), homeostatic model of insulin resistance (r = 0.62; p < 0.001), and leptin (r = 0.60; p < 0.001) were positively correlated with BPE. Adiponectin (r = -0.44; p < 0.001) was negatively correlated with BPE. Plasma biomarkers of inflammation and lipids and urinary sex hormones were not correlated with BPE., Conclusions: In premenopausal women at high risk of breast cancer, increased BPE is associated with obesity, insulin resistance, leptin, and adiponectin., (© 2023 The Obesity Society.)

Background: The COVID-19 pandemic has caused morbidity and mortality, particularly among vulnerable populations. We aimed to assess social and demographic characteristics associated with COVID-19 severity among symptomatic participants during pregnancy., Methods: The International Registry of Coronavirus Exposure in Pregnancy is a multinational, longitudinal observational cohort study of adult participants tested for SARS-CoV-2 or who received clinical diagnosis of COVID-19 during pregnancy (NCT04366986). Disease severity status of mild, moderate, or severe was determined based on symptoms and healthcare utilization. Stratified by current versus recent pregnancy at enrollment, univariate mixed-effects logistic regression modeling was used to characterize association between social and demographic characteristics with COVID-19 severity, using a cumulative mixed effect model with country as a random effect., Results: The odds of developing more severe COVID-19 (odds ratio [95% confidence interval]) were higher among participants with lower socioeconomic status (poor: 2.72 [2.01,3.69]; lower-middle class: 2.07 [1.62,2.65] vs wealthy), among participants with lower educational attainment (high school: 1.68 [1.39,2.03]; < high school (1.77 [1.25,2.51] vs graduate education). Participants over 25 years of age had lower odds of severe COVID-19 versus participants < 25 years (25-34: 0.69 [0.56,0.85]; 35-50: 0.62 [0.48,0.80]). Employment in food services was also associated with increased odds of more severe COVID-19, whereas employment in healthcare and within home, and primiparity were associated with lower severity., Conclusions: Findings suggest that employment setting and economic status have strong associations with COVID-19 severity, which warrants considering social determinants of health in the context of assessing risk factors of more severe COVID-19 during pregnancy., Trial Registration: IRCEP was registered with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [EUPAS37360] and clinicaltrials.gov [NCT04366986]., (© 2022. The Author(s).)

Normal myofibroblast differentiation is critical for proper skin wound healing. Neoexpression of α-smooth muscle actin (α-SMA), a marker for myofibroblast differentiation, is driven by transforming growth factor (TGF)-β receptor-mediated signaling. Hyaluronan and its three synthesizing enzymes, hyaluronan synthases (Has 1, 2, and 3), also participate in this process. Closure of skin wounds is significantly accelerated in Has1/3 double-knockout (Has1/3-null) mice. Herein, TGF-β activity and dermal collagen maturation were increased in Has1/3-null healing skin. Cultures of primary skin fibroblasts isolated from Has1/3-null mice had higher levels of TGF-β activity, α-SMA expression, and phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182, compared with wild-type fibroblasts. p38α mitogen-activated protein kinase was a necessary element in a noncanonical TGF-β receptor signaling pathway driving α-SMA expression in Has1/3-null fibroblasts. Myocardin-related transcription factor (MRTF), a cofactor that binds to the transcription factor serum response factor (SRF), was also critical. Nuclear localization of MRTF was increased, and MRTF binding to SRF was enhanced in Has1/3-null fibroblasts. Inhibition of MRTF or SRF expression by RNA interference suppresses α-SMA expression at baseline and diminished its overexpression in Has1/3-null fibroblasts. Interestingly, total matrix metalloproteinase activity was increased in healing skin and fibroblasts from Has1/3-null mice, possibly explaining the increased TGF-β activation., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Interprofessional experiences during medical school are often delivered during pre-clinical years, but less is known about the value of clinical students. Our institution implemented a specialty-specific interprofessiona curriculum during Residency Preparation Courses (RPCs) for senior students including didactics, clinical experiences, and a simulated paging curriculum. Our aim was to determine whether this intervention improved perceptions of interprofesiona roles. We distributed anonymous surveys before (pre-survey) and after (post-survey, collected within 2 weeks of course completion) the RPC to 90 students with questions related to interprofessional roles using a 5-point scale (1 =  strongly disagree , 5 =  strongly agree ). Three months after the start of residency, we sent follow-up surveys inquiring about the usefulness of RPC components (1 =  not at all useful , 5 =  extremely useful ). Response rates were 84.4% pre-survey, 63.3% post-survey, and 41.1% follow-up survey. Post-surveys indicated improvement in self-reported ability in all domains: understanding one's contributions to interprofessional teams (3.9 to 4.4, p < .0001), understanding other team members' contributions (3.9 to 4.4, p < .0001), learning from interprofessional team members (4.2 to 4.6, p = .0002), accounting for interprofessional perspectives (4.2 to 4.6, p < .0001), and co-developing effective care plans (3.9 to 4.4, p < .0001). Follow-up surveys rated clinical experiences as slightly-to-moderately useful (2.3 ± 1.0) and paging curriculum very-to-extremely useful (4.3 ± 1.0). This study demonstrates the value of interprofessional education for advanced students.

Building on nascent literature examining the health-related effects of vicarious structural racism, we examined indirect exposure to the Flint Water Crisis (FWC) as a predictor of birth outcomes in Michigan communities outside of Flint, where residents were not directly exposed to lead-contaminated water. Using linear regression models, we analyzed records for all singleton live births in Michigan from 2013 to 2016, excluding Flint, to determine whether birth weight (BW), gestational age (GA), and size-for-gestational-age (SzGA) decreased among babies born to Black people, but not among babies born to White people, following the highly publicized January 2016 emergency declaration in Flint. In adjusted regression models, BW and SzGA were lower for babies born to both Black and White people in the 37 weeks following the emergency declaration compared to the same 37-week periods in the previous 3 years. There were no racial differences in the association of exposure to the emergency declaration with BW or SzGA. Among infants born to Black people, GA was 0.05 weeks lower in the 37-week period following the emergency declaration versus the same 37-week periods in the previous 3 years (95% CI: -0.09, -0.01; p = 0.0177), while there was no change in GA for infants born to White people following the emergency declaration (95% CI: -0.01, 0.03; p = 0.6962). The FWC, which was widely attributed to structural racism, appears to have had a greater impact, overall, on outcomes for babies born to Black people. However, given the frequency of highly publicized examples of anti-Black racism over the study period, it is difficult to disentangle the effects of the FWC from the effects of other racialized stressors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EC declared a shared affiliation with the authors KA, JM, NF, and BN to the handling editor at the time of review., (Copyright © 2022 Allgood, Mack, Novak, Abdou, Fleischer and Needham.)

In this paper, we provide a brief overview of the history, organizational structure, and current operational state of our blended academic and community-model breast service. We review the challenges inherent to governance and management of a "matrix" organization practice model such as ours, and discuss the ways in which the leadership of our evolving blended practice are addressing those challenges collaboratively., (Copyright © 2021 Elsevier Inc. All rights reserved.)