BACKGROUND: Split-hand/foot malformation (SHFM) is a rare, genetically heterogeneous, congenital limb defect. Some but not all associated genes are known; therefore, the aim was to identify genes underlying SHFM. METHODS: Buccal cell-derived DNA from 26 children with SHFM and their parents who participated in the National Birth Defects Prevention Study was exome sequenced. Family-based trio analyzes prioritized rare coding variants by inheritance patterns, predicted pathogenicity, and location within putative limb development genes. Copy-number variants in SHFM candidate genomic regions were also examined. Case-control analyzes compared coding variants between case children and 1191 controls (parents of children with non-limb birth defects). Variant validation was by Sanger sequencing or droplet digital polymerase chain reaction. RESULTS: In family-based analyzes, the prioritized and validated variants (each in a single family) included likely damaging variants that were heterozygous and de novo in speckle type BTB/POZ protein (SPOP) and ubiquitin-like modifier activating enzyme 2 (UBA2), X-linked recessive in fibroblast growth factor 13 (FGF13) and RNA binding motif protein 10 (RBM10), and compound heterozygous in interleukin enhancer binding factor 3 (ILF3). Validation assays did not confirm predicted de novo copy-number gains at chromosomes 10q24 and 19p13.11. Case-control analyzes did not identify statistically significant associations. CONCLUSION: Exome analysis nominated new susceptibility genes (FGF13, ILF3, RBM10, SPOP) and detected a variant in a known candidate gene (UBA2). Follow-up investigation is needed to ascertain damaging variants in these genes in additional cases with SHFM and evaluate the impact of the variants on gene expression, protein function, and limb development.

INTRODUCTION: The prevalence of cigarette smoking is high among U.S. Department of Housing and Urban Development (HUD) assistance recipients, putting others at risk for secondhand smoke (SHS) exposure. We evaluated the burden of SHS exposure among HUD-assisted children, adolescents, and adults. AIMS AND METHODS: Using 2007-2018 National Health and Nutrition Examination Survey (NHANES) data linked with HUD administrative data, we assessed SHS exposure prevalence, defined using serum cotinine, among non-tobacco, non-nicotine-using, HUD-assisted children and adolescents (ages 3-17 years, n=955) and adults (ages ≥18 years, n=878) and among low-income, HUD-unassisted children and adolescents (n=5,788) and adults (n=8,027). Time trends were evaluated. Unadjusted and adjusted multivariable logistic regression models were created to assess SHS exposure by HUD assistance status. RESULTS: The prevalence of SHS exposure during 2015-2018 was 73.2% [95% CI: 63.2%-81.7%] among HUD-assisted children and adolescents and 50.1% [40.1%-60.1%] among HUD-assisted adults. Decreases in SHS exposure among HUD-assisted individuals from 2007-2010 through 2015-2018 were significant only for ages 12-17 years (78.6% [68.0%-87.0%] to 64.3% [52.5%-74.9%]; P=0.04). Among low-income individuals, SHS exposure was higher during 2007-2018 among HUD-assisted than HUD-unassisted children and adolescents (Odds Ratio: 3.39 [2.58-4.47]) and adults (2.11 [1.66-2.68]). Results remained significant after adjusting for social, demographic, and housing characteristics. CONCLUSIONS: HUD-assisted children, adolescents, and adults had higher exposure to SHS than those not receiving HUD assistance. SHS exposure among HUD-assisted individuals was high for all years studied, compared to published estimates for the general U.S. population, but did decrease among children and adolescents ages 12-17 years. IMPLICATIONS: This study is the first to provide biomarker-derived prevalence estimates of SHS exposure among recipients of HUD assistance within a nationally representative sample of the United States. The findings suggest that HUD-assisted children, adolescents, and adults are an at-risk population for SHS exposure, independent of known confounding social and demographic factors.

PURPOSE: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. METHODS: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. RESULTS: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. CONCLUSION: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

BACKGROUND: Depression is a common mental health disorder. OBJECTIVE: The objective of this study was to explore the association between diet quality, as measured by the Healthy Eating Index (HEI-2020), and depression symptoms among US adolescents and young adults, 12-29 years. DESIGN: The study design was a cross sectional secondary data analysis. PARTICIPANTS: Data from the first 24-hour dietary recall for adolescents and young adults 12-29 years in the National Health and Nutrition Examination Survey 2015-March 2020 (n=4750) were analyzed. MAIN OUTCOME: Depression was defined as a score ≥10 from the Patient Health Questionnaire reflecting moderate or severe symptoms in the previous 2 weeks. STATISTICAL ANALYSES PERFORMED: HEI-2020 total (range 0-100) and component scores were calculated for those with and without depression. Predicted HEI-2020 scores were estimated from linear regression models, adjusting for age, gender, race and Hispanic origin, family income, and seeing a mental health professional in the past year. Statistical analyses accounted for the complex sample design. RESULTS: The prevalence of depression among adolescents and young adults was 7.8% (95% confidence interval (CI) 6.3-9.5%). Total HEI-2020 score was 45.9 (95% CI 45.0-46.7) out of 100 on a given day during 2015-March 2020. Among young people with depression, total HEI-2020 score was lower than among those without depression (41.7 versus 46.2, p<0.001). After adjustment for covariates, the difference was attenuated but remained significant. In adjusted analyses, HEI-2020 component scores were lower for those with depression compared to those without depression for the adequacy components: Total Fruits (1.4 vs. 1.7 p=0.03), Whole Fruits (1.2 vs. 1.7 p<0.01), Total Vegetables (2.1 vs. 2.6 p<0.01), Greens and Beans (0.8 vs. 1.2 p<0.01), and Total Protein foods (3.6 vs. 4.0 p=0.02) out of maximum scores of 5. There were no statistically significant differences observed for Whole Grains, Dairy, Seafood and Plant Proteins, Fatty Acids, Saturated Fats, Refined Grains, Sodium, or Added Sugars. CONCLUSION: Overall diet quality is low among young people. Diet quality, especially consumption of fruits, vegetables, and protein foods was lower among young people with depression compared to those without depression.

BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Associations between antenatal SARS-CoV-2 infection and pregnancy outcomes have been conflicting and the role of the immune system is currently unclear. This prospective cohort study investigated the interaction of antenatal SARS-CoV-2 infection, changes in cytokine and HS-CRP levels, birthweight and gestational age at birth. 2352 pregnant participants from New York City (2020-2022) were included. Plasma levels of interleukin (IL)-1β, IL-6, IL-17A and high-sensitivity C-reactive protein (HS-CRP) were quantified in blood specimens obtained across pregnancy. Quantile and linear regression models were conducted to 1) assess the impact of antenatal SARS-CoV-2 infection, overall and by timing of detection of SARS-CoV-2 positivity (< 20 weeks versus ≥ 20 weeks), on birthweight and gestational age at delivery; 2) examine the relationship between SARS-CoV-2 infection and maternal immune changes during pregnancy. All models were adjusted for maternal demographic and obstetric factors and pandemic timing. Birthweight models were additionally adjusted for gestational age at delivery and fetal sex. Immune marker models were also adjusted for gestational age at specimen collection and multiplex assay batch. 371 (15.8%) participants were infected with SARS-CoV-2 during pregnancy, of which 98 (26.4%) were infected at < 20 weeks gestation. Neither SARS-CoV-2 infection in general nor in early or late pregnancy was associated with lower birthweight nor earlier gestational age at delivery. Further, we did not observe cytokine or HS-CRP changes in response to SARS-CoV-2 infection and thus found no evidence to support a potential association between immune dysregulation and the diversity in pregnancy outcomes following infection.

Mental health encompasses a range of mental, emotional, social, and behavioral functioning and occurs along a continuum from good to poor. Previous research has documented that mental health among children and adolescents is associated with immediate and long-term physical health and chronic disease, health risk behaviors, social relationships, education, and employment. Public health surveillance of children's mental health can be used to monitor trends in prevalence across populations, increase knowledge about demographic and geographic differences, and support decision-making about prevention and intervention. Numerous federal data systems collect data on various indicators of children's mental health, particularly mental disorders. The 2013-2019 data from these data systems show that mental disorders begin in early childhood and affect children with a range of sociodemographic characteristics. During this period, the most prevalent disorders diagnosed among U.S. children and adolescents aged 3-17 years were attention-deficit/hyperactivity disorder and anxiety, each affecting approximately one in 11 (9.4%-9.8%) children. Among children and adolescents aged 12-17 years, one fifth (20.9%) had ever experienced a major depressive episode. Among high school students in 2019, 36.7% reported persistently feeling sad or hopeless in the past year, and 18.8% had seriously considered attempting suicide. Approximately seven in 100,000 persons aged 10-19 years died by suicide in 2018 and 2019. Among children and adolescents aged 3-17 years, 9.6%-10.1% had received mental health services, and 7.8% of all children and adolescents aged 3-17 years had taken medication for mental health problems during the past year, based on parent report. Approximately one in four children and adolescents aged 12-17 years reported having received mental health services during the past year. In federal data systems, data on positive indicators of mental health (e.g., resilience) are limited. Although no comprehensive surveillance system for children's mental health exists and no single indicator can be used to define the mental health of children or to identify the overall number of children with mental disorders, these data confirm that mental disorders among children continue to be a substantial public health concern. These findings can be used by public health professionals, health care providers, state health officials, policymakers, and educators to understand the prevalence of specific mental disorders and other indicators of mental health and the challenges related to mental health surveillance.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10(-5)), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2(707C>T) and CAPN2(1112C>T) variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

Background In May-July 2020 in the New York City area, up to 16% of pregnant women had reportedly been infected with SARS-CoV-2. Prior studies found associations between SARS-CoV-2 infection during pregnancy and certain adverse outcomes (e.g., preterm birth, cesarean delivery). These studies relied on reverse transcription polymerase chain reaction (RT-PCR) testing to establish SARS-CoV-2 infection. This led to overrepresentation of symptomatic or acutely ill cases in scientific studies.Objective To expand our understanding of the effects of SARS-CoV-2 infection during pregnancy on pregnancy outcomes, regardless of symptomatology and stage of infection, by using serological tests to measure IgG antibody levels.Study Design The Generation C Study is an ongoing prospective cohort study conducted at the Mount Sinai Health System. All pregnant women receiving obstetrical care at the Mount Sinai Hospital and Mount Sinai West Hospital from April 20, 2020 onwards are eligible for participation. For the current analysis, we included participants who had given birth to a liveborn singleton infant on or before August 15, 2020. Blood was drawn as part of routine clinical care; for each woman, we tested the latest sample available to establish seropositivity using a SARS-CoV-2 serologic enzyme-linked immunosorbent assay. Additionally, RT-PCR testing was performed on a nasopharyngeal swab taken during labor and delivery. Pregnancy outcomes of interest (i.e., gestational age at delivery, birth weight, mode of delivery, Apgar score, ICU/NICU admission, and neonatal hospital length of stay) and covariates were extracted from electronic medical records. Among all Generation C participants who had given birth by August 15, 2020 (n=708), we established the SARS-CoV-2 seroprevalence. Excluding women who tested RT-PCR positive at delivery, we conducted crude and adjusted linear and logistic regression models to compare antibody positive women without RT-PCR positivity at delivery with antibody negative women without RT-PCR positivity at delivery. We stratified analyses by race/ethnicity to examine potential effect modification.Results The SARS-CoV-2 seroprevalence based on IgG measurement was 16.4% (n=116, 95% CI 13.7-19.3). Twelve women (1.7%) were SARS-CoV-2 RT-PCR positive at delivery (11 of these women were seropositive). Seropositive women were generally younger, more often Black or Hispanic, and more often had public insurance and higher pre-pregnancy BMI compared with seronegative women. SARS-CoV-2 seropositivity without RT-PCR positivity at delivery was associated with decreased odds of caesarean delivery (aOR 0.48, 95%CI 0.27; 0.84) compared with seronegative women without RT-PCR positivity at delivery. Stratified by race/ethnicity, the association between seropositivity and decreased odds of caesarean delivery remained for non-Hispanic Black/African-American and Hispanic women, but not for non-Hispanic White women. No other pregnancy outcomes differed by seropositivity, overall or stratified by race/ethnicity.Conclusion Seropositivity for SARS-CoV-2 without RT-PCR positivity at delivery, suggesting that infection occurred earlier during pregnancy, was not associated with selected adverse maternal or neonatal outcomes among live births in a cohort sample of women from New York City. While non-Hispanic Black and Latina women in our cohort had a higher rate of SARS-CoV-2 seropositivity compared with non-Hispanic White women, we found no increase in adverse maternal or neonatal outcomes among these groups due to infection.Competing Interest StatementMount Sinai has licensed serological assays to commercial entities and has filed for patent protection for serological assays. D.S and F.K. are listed as inventors on the pending patent application. The other authors have nothing to report.Funding StatementThis study is partially funded (contract 75D30120C08186) by the US Centers for Disease Control and Prevention (CDC), who also provided technical assistance related to analysis and interpretation of data and writing the report. The find ngs and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. Initial assay development work in the Krammer laboratory was partially supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract HHSN272201400008C (FK, for reagent generation), Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (FK, for reagent generation), and the generous support of the JPB foundation, the Open Philanthropy Project (#2020-215611) and other philanthropic donations. These funding sources were not involved in the current study.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent per the institutional review board (IRB)-approved study protocol (IRB at the Icahn School of Medicine at Mount Sinai, protocol IRB-20-03352, April 15, 2020).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData not publicly available. Please contact the corresponding author for data requests.

Objective: Dysregulation of the immune system during pregnancy is associated with adverse pregnancy outcomes. Recent studies report cytokine changes during the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We examine whether there is a lasting association between SARS-CoV-2 infection during pregnancy and peripheral blood cytokine levels. Study design: We conducted a case-control study at the Mount Sinai health system in NYC including 100 SARS-CoV-2 IgG antibody positive people matched to 100 SARS-CoV-2 IgG antibody negative people on age, race/ethnicity, parity, and insurance status. Blood samples were collected at a median gestational age of 34 weeks. Levels of 14 cytokines were measured. Result(s): Individual cytokine levels and cytokine cluster Eigenvalues did not differ significantly between groups, indicating no persisting maternal cytokine changes after SARS-CoV-2 infection during pregnancy. Conclusion(s): Our findings suggest that the acute inflammatory response after SARS-CoV-2 infection may be restored to normal values during pregnancy. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Introduction: Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy. Method(s): We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fisher's exact tests, Spearman correlations and linear regression models. Result(s): The median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term (>=37 weeks), and gestational age at delivery did not differ between the SARSCoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants. Discussion(s): SARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Objectives: Information professionals have supported medical providers, administrators and decision-makers, and guideline creators in the COVID-19 response. Searching COVID-19 literature presented new challenges, including the volume and heterogeneity of literature and the proliferation of new information sources, and exposed existing issues in metadata and publishing. An expert panel developed best practices, including recommendations, elaborations, and examples, for searching during public health emergencies. Methods: Project directors and advisors developed core elements from experience and literature. Experts, identified by affiliation with evidence synthesis groups, COVID-19 search experience, and nomination, responded to an online survey to reach consensus on core elements. Expert participants provided written responses to guiding questions. A synthesis of responses provided the foundation for focus group discussions. A writing group then drafted the best practices into a statement. Experts reviewed the statement prior to dissemination. Results: Twelve information professionals contributed to best practice recommendations on six elements: core resources, search strategies, publication types, transparency and reproducibility, collaboration, and conducting research. Underlying principles across recommendations include timeliness, openness, balance, preparedness, and responsiveness. Conclusions: The authors and experts anticipate the recommendations for searching for evidence during public health emergencies will help information specialists, librarians, evidence synthesis groups, researchers, and decision-makers respond to future public health emergencies, including but not limited to disease outbreaks. The recommendations complement existing guidance by addressing concerns specific to emergency response. The statement is intended as a living document. Future revisions should solicit input from a broader community and reflect conclusions of meta-research on COVID-19 and health emergencies. © 2023, Medical Library Association. All rights reserved.

The fourth author’s name is incorrect. The correct name is Lawrence C. Brody. The correct citation is: Khoury MJ, Feero WG, Chambers DA, Brody LC, Aziz N, Green RC, et al. (2018) A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health. PLoS Med 15(8): e1002631. https://doi.org/10.1371/journal.pmed.1002631.

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

BACKGROUND: Toxoplasma gondii and Toxocara are common parasites that infect humans globally. Our aim was to examine the relationship between T. gondii and Toxocara infection and cognition. METHODS: Multivariate logistic regression was used to test the association of T. gondii and Toxocara seropositivity on indices of cognitive function (a word list learning trial with delayed recall from the Consortium to Establish a Registry for Alzheimer's Disease, an animal fluency test (AFT) and a digit symbol substitution test (DSST)) among 2643 adults aged 60 years and older in the 2011-2014 National Health and Nutrition Examination Survey. RESULTS: Seropositivity to T. gondii or Toxocara were both associated with lower scores in all three cognitive function measures examined in univariate analyses. Except for the DSST, these associations were not significant after adjustment for age, gender, race and Hispanic origin, poverty level, education, US birth status, depression and hypertension. On stratification to account for significant interactions, Toxocara seropositivity was associated with worse scores on the AFT among those born outside the USA, worse scores on the DSST among those aged 60-69 years, female, Hispanic and with a high school diploma or less. Lower DSST scores with Toxocara infection was greater for adults living below compared with at or above the poverty level. CONCLUSIONS: Seropositivity to these parasites, particularly to Toxocara, may be associated with diminished cognitive performance in certain subgroups of older adults.

INTRODUCTION: Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy. METHODS: We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fisher's exact tests, Spearman correlations and linear regression models. RESULTS: The median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term (≥37 weeks), and gestational age at delivery did not differ between the SARS-CoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants. DISCUSSION: SARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

BACKGROUND: Structural racism and pandemic-related stress from the COVID-19 pandemic may increase risk of adverse birth outcomes. OBJECTIVE: Our objective was to examine associations between neighborhood measures of structural racism and pandemic stress with three outcomes: SARS-CoV-2 infection, preterm birth (PTB) and delivering a newborn small-for-gestational-age (SGA). Our secondary objective was to investigate the joint associations of SARS-CoV-2 infection during pregnancy and neighborhood measures on PTB and SGA. STUDY DESIGN: We analyzed data for 967 patients from a prospective cohort of pregnant persons in New York City, comprised of 367 White persons (38%), 169 Black persons (17%), 293 Latina persons (30%), 87 Asian persons (9%), 41 persons of unknown race-ethnicity (4%), and 10 of unknown race-ethnicity (1%). We evaluated structural racism (social/built structural disadvantage, racial-economic segregation) and pandemic-related stress (community COVID-19 mortality, community unemployment rate increase) in quartiles by zip code. SARS-CoV-2 serologic enzyme-linked immunosorbent assay was performed on blood samples from pregnant persons. We ascertained preterm birth (PTB) and small-for-gestational age (SGA) from an electronic medical record database. We used log-binomial regression with robust standard error for clustering by zip code to estimate associations of each neighborhood measure separately with three outcomes: SARS-CoV-2 infection, PTB, and SGA. Covariates included maternal age, parity, insurance status, and BMI. Models with PTB and SGA as the dependent variables additionally adjusted for SARS-CoV-2 infection. RESULTS: 193 (20%) persons were SARS-CoV-2 seropositive, and the overall risk of PTB and SGA were 8.4% and 9.8%, respectively. Among birthing persons in neighborhoods in the highest quartile of structural disadvantage (n=190), 94% were non-White, 50% had public insurance, 41% were obese, 32% were seropositive, 11% delivered preterm, and 12% delivered an infant SGA. Among birthing persons in neighborhoods in the lowest quartile of structural disadvantage (n=360), 39% were non-White, 17% had public insurance, 15% were obese, 9% were seropositive, 6% delivered preterm, and 10% delivered an infant SGA. In adjusted analyses structural racism measures and community unemployment were associated with both SARS-CoV-2 infection and PTB, but not SGA. High vs. low structural disadvantage was associated with an adjusted relative risk (aRR) of 2.6 for infection (95% Confidence Interval (CI)=1.7, 3.9) and 1.7 for PTB (95%CI=1.0, 2.9); high vs. low racial-economic segregation was associated with aRR of 1.9 (95% CI=1.3, 2.8) for infection and 2.0 (95%CI=1.3, 3.2) for PTB; high vs. low community unemployment increase was associated with aRR of 1.7 (95% CI=1.2, 1.5) for infection and 1.6 (95%CI=1.0, 2.8) for PTB. COVID-19 mortality rate was associated with SARS-CoV-2 infection, but not PTB or SGA. SARS-CoV-2 infection was not independently associated with birth outcomes. We found no interaction between SARS-CoV-2 infection and neighborhood measures on PTB or SGA. CONCLUSIONS: Neighborhood measures of structural racism were associated with both SARS-CoV-2 infection and PTB, but these associations were independent and did not have a synergistic effect. Community unemployment rate increases were also associated with an increased risk of PTB independently of SARS-CoV-2 infection. Mitigating these factors might reduce the impact of the pandemic on pregnant people.

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

BACKGROUND: The COVID-19 pandemic is an ongoing global health threat, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Questions remain about how SARS-CoV-2 impacts pregnant individuals and their children. OBJECTIVE: To expand our understanding of the effects of SARS-CoV-2 infection during pregnancy on pregnancy outcomes, regardless of symptomatology, by using serological tests to measure IgG antibody levels. METHODS: The Generation C Study is an ongoing prospective cohort study conducted at the Mount Sinai Health System. All pregnant individuals receiving obstetrical care at the Mount Sinai Healthcare System from 20 April 2020 onwards are eligible for participation. For the current analysis, we included participants who had given birth to a liveborn singleton infant on or before 22 September 2020. For each woman, we tested the latest prenatal blood sample available to establish seropositivity using a SARS-CoV-2 serologic enzyme-linked immunosorbent assay. Additionally, RT-PCR testing was performed on a nasopharyngeal swab taken during labour. Pregnancy outcomes of interest (i.e., gestational age at delivery, preterm birth, small for gestational age, Apgar scores, maternal and neonatal intensive care unit admission, and length of neonatal hospital stay) and covariates were extracted from medical records. Excluding individuals who tested RT-PCR positive at delivery, we conducted crude and adjusted regression models to compare antibody positive with antibody negative individuals at delivery. We stratified analyses by race/ethnicity to examine potential effect modification. RESULTS: The SARS-CoV-2 seroprevalence based on IgG measurement was 16.4% (95% confidence interval 13.7, 19.3; n=116). Twelve individuals (1.7%) were SARS-CoV-2 RT-PCR positive at delivery. Seropositive individuals were generally younger, more often Black or Hispanic, and more often had public insurance and higher pre-pregnancy BMI compared with seronegative individuals. None of the examined pregnancy outcomes differed by seropositivity, overall or stratified by race/ethnicity. CONCLUSION: Seropositivity for SARS-CoV-2 without RT-PCR positivity at delivery (suggesting that infection occurred earlier during pregnancy) was not associated with selected adverse maternal or neonatal outcomes among live births in a cohort sample from New York City.

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

BACKGROUND: The menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time. METHODS: Blood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE). FINDINGS: Macaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV(163P3) infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women. INTERPRETATION: These data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract. FUNDING: This study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]). DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

Since the completion of the Human Genome Project, progress toward translating genomic research discoveries to address population health issues has been limited. Several meetings of social and behavioral scientists have outlined priority research areas where advancement of translational research could increase population health benefits of genomic discoveries. In this review, we track the pace of progress, study size and design, and focus of genomics translational research from 2012 to 2018 and its concordance with five social and behavioral science recommended priorities. We conducted a review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guidelines for Scoping Reviews. Steps involved completing a search in five databases and a hand search of bibliographies of relevant literature. Our search (from 2012 to 2018) yielded 4,538 unique studies; 117 were included in the final analyses. Two coders extracted data including items from the PICOTS framework. Analysis included descriptive statistics to help identify trends in pace, study size and design, and translational priority area. Among the 117 studies included in our final sample, nearly half focused on genomics applications that have evidence to support translation or implementation into practice (Centers for Disease Control and Prevention Tier 1 applications). Common study designs were cross-sectional (40.2%) and qualitative (24.8%), with average sample sizes of 716 across all studies. Most often, studies addressed public understanding of genetics and genomics (33.3%), risk communication (29.1%), and intervention development and testing of interventions to promote behavior change (19.7%). The number of studies that address social and behavioral science priority areas is extremely limited and the pace of this research continues to lag behind basic science advances. Much of the research identified in this review is descriptive and related to public understanding, risk communication, and intervention development and testing of interventions to promote behavior change. The field has been slow to develop and evaluate public health-friendly interventions and test implementation approaches that could enable health benefits and equitable access to genomic discoveries. As the completion of the human genome approaches its 20th anniversary, full engagement of transdisciplinary efforts to address translation challenges will be required to close this gap.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P </= 5 x 10(-8)): rs781716 (P = 4.71 x 10(-9); odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 x 10(-8); OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 x 10(-9); OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 x 10(-8), OR = 0.45; P = 3.31 x 10(-8), OR = 0.45; P = 1.09 x 10(-8), OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 x 10(-8), OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 x 10(-6)). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

In a Policy Forum, Muin Khoury and colleagues discuss research on the clinical application of genome sequencing data.

BACKGROUND: The CDC recommends a targeted strategy for childhood blood lead screening based on participation in federal programs, such as Medicaid and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Yet, there is scarcity of data on blood lead levels (BLLs) among WIC participants. OBJECTIVE: Our objective was to investigate whether children participating in WIC and not enrolled in Medicaid, who have not been targeted in the historical Medicaid-focused screening strategy, have higher BLLs than children in neither of these programs. METHODS: The analysis included 3,180 children 1-5 y of age in the National Health and Nutrition Examination Surveys conducted in 2007-2014. Log-binomial regression, which allows direct estimation of prevalence ratios, was used to examine associations between WIC participation (in conjunction with Medicaid enrollment) and having BLLs >/=5 mug/dL with adjustment for age (1-2 vs. 3-5 y). RESULTS: The percentage of children participating in "WIC only," "Medicaid only," "both WIC and Medicaid," and "neither" were 18.9%, 10.8%, 25.4%, and 44.9%, respectively. "WIC only," "Medicaid only," and "both WIC and Medicaid" children were more likely to have BLLs >/=5 mug/dL than children who were not enrolled in either program, with adjusted prevalence ratios of 3.29 [95% confidence interval (CI): 1.19, 9.09], 4.56 (95% CI: 2.18, 9.55), and 2.58 (95% CI: 1.18, 5.63). CONCLUSIONS: Children participating in WIC but not Medicaid were more likely to have BLLs >/=5 mug/dL than children who were not enrolled in either program. These findings may inform public health recommendations and clinical practice guidelines.

BACKGROUND: High fractional exhaled nitric oxide (FeNO) is an indicator of poor asthma control and has been proposed as a non-invasive assessment tool to guide asthma management. OBJECTIVE: We aimed to describe the prevalence of and factors associated with high FeNO among US youth with asthma. METHODS: Data from 716 children and adolescents with asthma ages 6-19 years who participated in the 2007-2012 National Health and Nutrition Examination Survey were analyzed. Using American Thoracic Society guidelines, high FeNO was defined as >50 ppb for ages 12-19 years and >35 ppb for ages 6-11 years. Multivariate logistic regression examined associations between high FeNO and age, sex, race/Hispanic origin, income status, weight status, tobacco smoke exposure, and other factors associated with asthma control (recent use of inhaled corticosteroids, recent respiratory illness, asthma-related respiratory signs/symptoms, and spirometry). RESULTS: About 16.5% of youth with asthma had high FeNO. The prevalence of high FeNO was higher among non-Hispanic black (27%, P < 0.001) and Hispanic (20.2%, P = 0.002) youth than non-Hispanic white (9.7%) youth. Differences in high FeNO prevalence by sex (girls < boys), weight status (obese < normal weight), tobacco smoke exposure (smokers < home exposure < no exposure), and FEV1/FVC (normal < abnormal) were also observed. No differences were noted between categories for the remaining covariates. CONCLUSION: High FeNO was observed to be associated with sex, race/Hispanic origin, weight status, tobacco smoke exposure, and abnormal FEV1/FVC, but was not associated with asthma-related respiratory symptoms. These findings may help inform future research and clinical practice guidelines on the use of high FeNO in the assessment of asthma control.

Early recognition of acute myocardial infarction (MI), followed by prompt emergency care, improves patient outcomes. Among rural American Indian (AI) populations there are disparities in access to care for MI and processes of care, resulting in poor MI-related health outcomes compared to the general population. We sought to gain an understanding of barriers related to MI time-to-treatment delays using a qualitative approach. We conducted semi-structured interviews and focus groups with AI key informants and community members in three Indian Health Service regions. Major barriers to care included long travel distance to care and lack of supporting infrastructure; distrust of the health care system; low overall literacy and basic health literacy; priority of family care-giving; and lack of specialized medical facilities and specialists. Findings suggest that improved time-to-treatment facilitators include educating the local community about the causes and consequences of MI and culturally-sensitive health communication, as well as addressing the quality of local systems of care and the community's perception of these systems. Pursuing these strategies may improve quality of care and reduce MI-related morbidity and mortality in rural AI populations.

In 2014, Ebola virus disease (EVD) in West Africa was first reported during March in 3 southeastern prefectures in Guinea; from there, the disease rapidly spread across West Africa. We describe the epidemiology of EVD cases reported in Guinea's capital, Conakry, and 4 surrounding prefectures (Coyah, Dubreka, Forecariah, and Kindia), encompassing a full year of the epidemic. A total of 1,355 EVD cases, representing approximately 40% of cases reported in Guinea, originated from these areas. Overall, Forecariah had the highest cumulative incidence (4x higher than that in Conakry). Case-fatality percentage ranged from 40% in Conakry to 60% in Kindia. Cumulative incidence was slightly higher among male than female residents, although incidences by prefecture and commune differed by sex. Over the course of the year, Conakry and neighboring prefectures became the EVD epicenter in Guinea.