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Background: Extreme in utero temperatures have been associated with adverse birth outcomes, including preterm birth and low birthweight. However, there is limited evidence on associations with neonatal intensive care unit (NICU) admissions, which reflect a range of poor neonatal health outcomes., Methods: This case-crossover study assesses the associations between ambient temperature changes during the week of delivery and risk of NICU admission. Data from the Consortium on Safe Labor (2002-2008) were linked to ambient temperature at hospital referral regions. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) estimated NICU admission risk with a 1 °C increase on each day of the week of delivery and of the average weekly temperature, adjusted for particulate matter ≤2.5 μm (PM 2.5 ) and relative humidity. We also estimated associations with 1 °C increases and 1 °C decreases in temperatures during weeks of site-specific extreme heat (>90th and 95th percentiles) and cold (<5th and 10th percentiles), respectively., Results: There were 27,188 NICU admissions with median (25th, 75th) temperature of 16.4 °C (5.8, 23.0) during the week before delivery. A 1 °C increase in temperature during the week of delivery was not associated with risk of NICU admission. However, analyses of extreme temperatures found that a 1 °C decrease in weekly average temperatures below the 10th and 5th percentiles was associated with 30 % (aHR = 1.30, 95 % CI 1.28, 1.31) and 47 % (aHR = 1.47, 95 % CI 1.45, 1.50) increased risk of NICU admissions, while a 1 °C increase in weekly average temperatures above the 90th and 95th percentiles was associated with more than two- (aHR = 2.29, 95 % CI 2.17, 2.42) and four-fold (aHR = 4.30, 95 % CI 3.68, 5.03) higher risk of NICU admission, respectively., Conclusions: Our study found temperature extremes in the week before delivery increased NICU admission risk, particularly during extreme heat, which may translate to more adverse neonatal outcomes as extreme temperatures persist., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica L. Gleason reports financial support was provided by National Institute of Child Health and Human Development. Katherine L. Grantz reports financial support was provided by National Institute of Child Health and Human Development. Katherine L. Grantz reports a relationship with National Institute of Child Health and Human Development that includes: employment. Jessica L. Gleason reports a relationship with National Institute of Child Health and Human Development that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Mentorship programs have well-documented benefits to both mentees and mentors. Military medical students face unique challenges in medical school given their service-specific requirements and separate military match process. We therefore aimed to determine whether military medical students' participation in a mentorship program impacts their confidence in applying to obstetrics and gynecology (OB/GYN) residency., Materials and Methods: First, a needs assessment survey regarding the use of a mentorship program was sent to medical students, residents, fellows, and attendings. A structured mentorship program was then developed for military medical students applying to OB/GYN residency based on the survey results. Mentors were randomly paired with mentees and asked to appraise curriculum vitaes, review personal statements, and perform mock interviews. Following completion of these activities, participants were sent a post-intervention questionnaire. This project was exempt by our institution's Institutional Review Board., Results: Our program had 56 participants, with 29 individuals completing our post-intervention survey (response rate 51.8%). After participating in the program, 92.3% of mentors stated they plan to continue a relationship with their mentee. All the mentee respondents stated they would participate in this program again. Before participating in the program, 16.7% of mentees felt "prepared" or "extremely prepared" for the match, compared to 87.6% post-intervention. Most mentee respondents (75%) reported that this program made them a more competitive applicant. Following the mentorship program, 66.7% of participants successfully matched into OB/GYN residency., Conclusions: This reproducible, well-received intervention can be implemented to facilitate mentoring connections regardless of geographic location. As the OB/GYN specialty develops its own application process, civilian medical schools should consider adopting similar programs to aid their students in navigating the match process., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective:  Error in birthweight prediction by sonographic estimated fetal weight (EFW) has clinical implications, such as avoidable cesarean or misclassification of fetal risk in labor. We aimed to evaluate optimal timing of ultrasound and which fetal measurements contribute to error in fetal ultrasound estimations of birth size at the extremes of birthweight., Study Design:  We compared differences in head circumference (HC), abdominal circumference (AC), femur length, and EFW between ultrasound and corresponding birth measurements within 14 ( n  = 1,290) and 7 ( n  = 617) days of birth for small- (SGA, <10th percentile), appropriate- (AGA, 10th-90th), and large-for-gestational age (LGA, >90th) newborns., Results:  Average differences between EFW and birthweight for SGA neonates were: -40.2 g (confidence interval [CI]: -82.1, 1.6) at 14 days versus 13.6 g (CI: -52.4, 79.7) at 7 days; for AGA, -122.4 g (-139.6, -105.1) at 14 days versus -27.2 g (-50.4, -4.0) at 7 days; and for LGA, -242.8 g (-306.5, -179.1) at 14 days versus -72.1 g (-152.0, 7.9) at 7 days. Differences between fetal and neonatal HC were larger at 14 versus 7 days, and similar to patterns for EFW and birthweight, differences were the largest for LGA at both intervals. In contrast, differences between fetal and neonatal AC were larger at 7 versus 14 days, suggesting larger error in AC estimation closer to birth., Conclusion:  Using a standardized ultrasound protocol, SGA neonates had ultrasound measurements closer to actual birth measurements compared with AGA or LGA neonates. LGA neonates had the largest differences between fetal and neonatal size, with measurements 14 days from delivery showing 3- to 4-fold greater differences from birthweight. Differences in EFW and birthweight may not be explained by a single fetal measurement; whether estimation may be improved by incorporation of other knowable factors should be evaluated in future research., Key Points: · Ultrasound measurements may be inadequate to predict neonatal size at birth.. · Birthweight estimation error is higher for neonates >90th percentile.. · There is higher error in AC closer to birth.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: Antibiotic use is increasing in low- and middle-income countries (LMIC); however, few studies have examined the rates of use in a population. The use of antibiotics for liveborn infants in LMIC was examined., Design: The study, a planned prospective, observational secondary analysis of the A-PLUS randomised controlled trial of azithromycin, was conducted in Global Network sites in seven countries: Bangladesh, Pakistan, India (two sites), Kenya, Zambia, the Democratic Republic of Congo and Guatemala. The analyses included liveborn infants of women planning a vaginal delivery who were enrolled in the A-PLUS trial., Methods: Data were collected on liveborn infants related to non-study antibiotic use in two time-periods: (i) after delivery while in the facility, and (ii) after discharge until 42 days post-partum. Antibiotic use was also examined in preterm and term infants. The most commonly used antibiotics were classified into three groups: penicillins, cephalosporins and aminoglycosides. Antibiotics used in <1% of infants are not presented., Results: Of the 29,354 eligible infants in the study, 2224 (7.6%, 95% CI 7.3-7.9) received non-study antibiotics in the facility after delivery, and 3847 (13.1%, 95% CI 12.7-13.5) received non-study antibiotics after facility discharge until Day 42. In the facility, antibiotics were given to newborns more frequently in sites in Asia and less frequently in sites in Africa and Guatemala. Similarly, after facility discharge, infants were more likely to receive antibiotics in the Asian sites and less so in the African sites and Guatemala. In the facilities, antibiotics were used predominately for prophylaxis (70.7%) but after facility discharge antibiotics were given more often for treatment (56.8%). Preterm infants received more non-study antibiotics than term infants. The antibiotics used varied substantially by time-period and site but, in general, penicillins, cephalosporins and aminoglycosides were the antibiotic categories used more frequently., Conclusions: Across the Global Network sites, which represent a range of LMIC, nearly 8% of infants received non-study antibiotics more often for prophylaxis, with 13% of infants receiving non-study antibiotics following hospital discharge. With concerns about increasing antimicrobial resistance worldwide, further attention should be given to appropriate antibiotic use.

Background: Few studies have prospectively examined whether adverse childhood experiences contribute to suicide or substance-related mortality. Moreover, children are often exposed to multiple adversities making it critical to identify which clusters of adversities are most harmful for these outcomes. Accordingly, we investigated risk for suicide and substance-related mortality based on the number and clusters of adversities children were exposed to., Methods: Identifying information from 49,853 offspring born between 1959 and 1966 to participants in the Collaborative Perinatal Project was linked to the National Death Index to determine vital status by the end of 2016. We examined associations of the total number of adversities and five clusters of adversity (Low Adversity, Parental Harshness & Neglect, Family Instability, Poverty & Crowded Housing, Poverty & Parental Separation) with suicide and substance-related mortality., Results: Of the 45,207 participants in the analysis sample, 267 died by suicide and 338 by substance use. Participants who experienced Family Instability had a higher risk of dying by suicide (hazard ratio [HR] = 1.92, 95%CI:1.32, 2.79) and substance use (HR = 1.50, 95%CI:1.02, 2.19). Participants who experienced Poverty & Parental Separation were at higher risk of dying by substance use (HR = 1.85, 95%CI:1.40, 2.45)., Limitations: Adversities with documented harm including physical and sexual abuse were not assessed in the study., Conclusions: Childhood adversity is associated with self-injury mortality from multiple causes, suggesting shared etiology of risk for suicide and substance-related mortality. Research on interventions that target shared pathways linking childhood vulnerability to multiple causes of death may help reduce the long-term impact of adversities., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Dual-energy x-ray absorptiometry reference data designate Black and non-Black categories, as higher BMD has been documented among Black youth. We examined associations of race, skin tone, and genetic factors with bone mineral density (BMD)., Methods: 557 adolescents were followed longitudinally. Exposures included race, skin tone, and principal components (PC) from genome-wide arrays. Total body BMD Z-score (BMD-Z) was the primary outcome using linear regression., Results: 359 adolescents identified as non-Hispanic White (NHW) and 75, non-Hispanic Black (NHB). BMD-Z was higher in NHB vs. NHW (β: 0.92 units, 95% CI: 0.64, 1.19) or those with darker skin (0.79, 95% CI: 0.49, 1.08 for brown vs. medium). The first genetic PC (PC1) correlated with identification as NHB. PC1 was associated with higher BMD-Z (0.09, 95% CI: 0.06, 0.12), even after including race (0.07, 95% CI: 0.00, 0.14) or skin tone (0.10, 95% CI: 0.05, 0.15); both race (0.26, 95% CI: -0.49, 1.01 for NHB vs. NHW) and skin tone (-0.08, 95% CI: -0.59, 0.44 for brown vs. medium) no longer predicted BMD-Z after adjustment for PC1., Conclusion: Genetic similarity was robustly associated with BMD, prompting a reevaluation of adolescent BMD reference data to exclude the consideration of race., Impact: Current bone density reference databases include a binary assignment of patients into "Black" and "non-Black" categories, as a higher BMD has been documented among those identifying as Black compared with individuals of other racial and ethnic backgrounds. This study found genetic similarity to be more strongly associated with bone density by dual-energy x-ray absorptiometry than race or skin tone. These data emphasize a need to reevaluate how bone density measurements are interpreted, including exploring reference data that exclude the consideration of race., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To identify differentially methylated regions (DMRs) and assess epigenetic age and instability scores within each cohort of differing income level and educational attainment., Design: Retrospective analysis of epigenetic data., Subjects: 1429 semen samples from participants in the FAZST trial., Exposure: Socio-economic status, approximated by self-reported income, and education level., Main Outcome Measures: Differential sperm DNA methylation, epigenetic age, epigenetic stability RESULTS: There were four significant DMRs associated with the income cohorts and seven associated with the education cohorts, suggesting epigenetic patterns vary with socio-economic status. Adjusted epigenetic age (GLAD values) did not differ significantly in either cohort; however, a higher number of unstable promoters were observed in the lowest education cohort (p-value of 0.006), indicating dysregulation in the epigenome., Conclusion: These findings suggest a biological link between income and education level in sperm epigenetic patterns, which may influence reproductive health. The increase in unstable promoters in the lower education cohorts may contribute to health disparities associated with educational attainment; however, it is important to consider lifestyle factors and environmental exposures as potential underlying causes. Further research is needed to fully elucidate the implications of these epigenetic changes and their relationship to health outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Background: Studies have inconsistently observed that children conceived by IVF or ICSI have higher blood pressure compared to children not conceived by these ARTs., Objective and Rationale: The aim was to perform a systematic review and meta-analysis of blood pressure measures of offspring conceived by ART and those conceived naturally. Resolving the suspicion of ART as a risk factor of higher blood pressure, and therefore of heart disease, has public health and clinical implications., Search Methods: A biomedical librarian searched the Embase, PubMed, and Web of Science databases. Searches were limited to records published in English since 1978. Grey literature was searched. Inclusion criteria were humans born via infertility treatment (vs no treatment) who underwent a blood pressure assessment. Exclusion criteria were non-human participants, non-quantitative studies, absence of a control group, and specialty populations (e.g. cancer patients only). Two reviewers independently screened each record's title and abstract and full text using Covidence, extracted data using Excel, and assessed bias using the National Heart, Lung, and Blood Institute's Quality Assessment Tool for cohort studies., Outcomes: Of 5082 records identified, 79 were included in the systematic review and 36 were included in the meta-analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in ART and non-ART groups. Overall, 34 reports including 40 effect sizes from 25 unique cohorts, compared blood pressure between ART (N = 5229) and non-ART (N = 8509, reference) groups with no covariate adjustment. No standardized mean differences (SMD) in SBP (0.06 per SD of mmHg, 95% CI = -0.05, 0.18) or DBP (0.11, 95% CI = -0.04, 0.25) by treatment were found, but the heterogeneity was considerable (I2=76% for SBP and 87% for DBP). Adjusted analyses were presented in 12 reports, representing 28 effect sizes from 21 unique cohorts (N = 2242 treatment vs N = 37 590 non-treatment). Studies adjusted for varied covariates including maternal (e.g. age, education, body mass index, smoking, pregnancy complications), child (e.g. sex, age, physical activity, BMI, height), and birth characteristics (e.g. birth weight and gestational age). Adjusted results similarly showed no SMD for SBP (-0.03, 95% CI = -0.13, 0.08) or DBP (0.02, 95% CI = -0.12, 0.16), though heterogeneity remained high (I2 = 64% and 86%). Funnel plots indicated a slight publication bias, but the trim and fill approach suggested no missing studies. Removal of five studies which adjusted for birth outcomes (potentially over-adjusting for mediators) made no material difference. Type of treatment (e.g. IVF vs ICSI), period effects by birth year (≤2000 vs >2000), offspring age group (<8, 8-14, 15+), or study location (e.g. Europe) did not modify the results., Wider Implications: In conclusion, conception by ART was not associated with offspring blood pressure in a meta-analysis, although considerable heterogeneity was observed. Given the increasing number of children born using ART, perpetuating a difference in blood pressure would mean unnecessary risk screening for many children/adults on a population level. At a clinical level, couples considering these reproductive technologies have some reassurance that there is no evidence of strong vascular 'programming' due to the techniques used., Registration Number: PROSPERO No. CRD42022374232., (Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology 2024.)

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Importance: Malnourished adolescents and young adults with anorexia nervosa (AN) are at high risk for skeletal deficits., Objective: To examine whether low-magnitude mechanical signals (LMMS) could preserve bone mineral density (BMD) throughout 6 months in adolescents and young adults with AN., Design, Setting, and Participants: This double-blind, sham-controlled randomized clinical trial, conducted in a hospital-based specialty clinic, assessed female adolescents and young women without medical comorbidity or medication use that would compromise bone health. A total of 837 female adolescents were screened from January 1, 2012, to December 31, 2019, of whom 317 met the study criteria. Data analysis was performed from 2020 to 2024., Intervention: Platform delivering low-magnitude mechanical signals (LMMS) (0.3 g at 32-37 Hz) or sham (ie, placebo) signals for 10 minutes daily for 6 months., Main Outcomes and Measures: The primary outcome was trabecular volumetric BMD (vBMD) as measured by peripheral quantitative computed tomography of the tibia at baseline and 6 months. Secondary outcomes included cortical vBMD, cross-sectional area (CSA), areal BMD and body composition measured by dual-energy x-ray absorptiometry, and serum bone turnover markers., Results: Forty female adolescents and young women (median [IQR] age, 16.3 [15.1-17.6] years; median [IQR] percentage median BMI for age, 87.2% [81.0%-91.6%]) completed the trial. Total bone vBMD changes were nonsignificant in both groups (95% CI for difference in median change between groups, -57.11 to 2.49): in the LMMS group, vBMD decreased from a median (IQR) of 313.4 (292.9-344.6) to 309.4 (290.4-334.0) mg/cm3, and in the placebo group, it increased from a median (IQR) of 308.5 (276.7-348.0) to 319.2 (309.9-338.4) mg/cm3. Total CSA at the 4% tibia site increased from a median (IQR) of 795.8 (695.0-844.8) mm2 to 827.5 (803.0-839.4) mm2 in the LMMS group, whereas in the placebo group, it decreased from 847.3 (770.5-915.3) mm2 to 843.3 (828.9-857.7) mm2 (95% CI for difference in median change between groups, 2.94-162.53). Median (IQR) trabecular CSA at the 4% tibia site increased from 616.3 (534.8-672.3) mm2 to 649.2 (638.0-661.4) mm2 in the LMMS group but decreased in the placebo group from 686.4 (589.0-740.0) mm2 to 647.9 (637.3-661.9) mm2 (95% CI for difference in median change between groups, 2.80-139.68 mm2). Changes in cortical vBMD, cortical section modulus, and muscle CSA were not significant between groups. The 6-month changes in trabecular and total bone CSA at the tibia 4% site (weight-bearing trabecular bone) were significantly different between groups (these measures increased in the LMMS group but decreased in the placebo group; total bone CSA: 95% CI, 2.94-162.53; P = .01; trabecular CSA: 95% CI, 2.80-139.68; P = .02). Greater increases in body mass index were seen in the placebo group (median [IQR] gain, 0.5 [-0.3 to +2.1]) than in the LMMS group (median [IQR] gain, +0.4 [-0.3 to +2.1]), perhaps due to differences in fat mass accrual. No adverse events occurred related to the LMMS intervention., Conclusions and Relevance: In this randomized clinical trial of female adolescents and young women with AN, a 6-month LMMS intervention did not yield improvement in tibial trabecular vBMD. However, LMMS led to increases in total and trabecular CSA at the tibia. These results suggest an early positive response of increased bone turnover and trabecular bone quantity due to the LMMS intervention. Future studies should use a longer duration of intervention, consider strategies to optimize adherence, and potentially focus on a more profoundly malnourished patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT01100567.

Background: Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the GALT gene. Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with CG due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood., Methods: In this study, we performed single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics on ovary tissue biopsies from prepubertal girls diagnosed with CG to investigate dynamic changes in gene expression and altered signalling pathways in granulosa cells, oocytes, and stromal cells., Results: We generated single-nucleus and spatial transcriptomics atlas of human ovaries from prepubertal girls diagnosed with and without CG. snRNA-seq profiling of the paediatric ovary revealed a diverse ovarian microenvironment with seven distinct major cell types. Our transcriptomic analysis revealed an increase in the expression of several endoplasmic reticulum stress and oxidative stress associated genes, which can promote apoptosis of granulosa cells in CG. PTEN/PI3K/AKT signalling, which is crucial for primordial follicle activation and survival was dysregulated as supported by upregulated PTEN transcripts and a significant reduction in phospho-AKT levels in the granulosa cells and oocytes. We also found a marked increase in expression of phospho-H2A.X, LC3A/B and CASP9 in the primordial follicles of CG ovaries suggesting DNA damage, autophagy, and accelerated follicular atresia. Furthermore, we noticed genes participating in extracellular matrix organisation, integrin and gap junction signalling, essential for structural support of the ovarian stroma were profoundly altered., Conclusions: Our findings provide molecular insights into the dysregulated cellular signalling pathways essential for primordial follicle growth and survival that can explain the etiology of POI in CG patients. This study has implications in the development of future therapeutic interventions to preserve ovarian function and promote female reproductive health., Highlights: Created a comprehensive single-nucleus transcriptomic atlas and spatial landscape of paediatric ovary tissue from prepubertal girls diagnosed with classic galactosemia (CG). Our transcriptomic analysis revealed activation of genes associated with ER-stress signalling, oxidative stress response and ATM signalling/DNA damage response as shown by significant increase in expression of p-EIF2A, p-H2A.X and LC3A/B in the primordial follicles of CG ovary. PTEN/PI3K/AKT signalling pathways was dysregulated evidenced by a significant reduction in phospho-AKT expression in the primordial follicles of CG ovary, suggesting impaired follicle activation and survival., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)., Methods: A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared., Results: Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up., Conclusions: Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the risks of adverse maternal and neonatal outcomes associated with pregnancies complicated by hepatitis C virus (HCV) infection., Methods: This is a secondary analysis of a multicenter prospective cohort study of HCV infection in pregnancy. Participants were screened for HCV infection with serum antibody tests, and each participant with a positive HCV result (case group) was matched with up to two individuals with negative HCV results (control group) prospectively by gestational age (±2 weeks) at enrollment. Maternal outcomes included gestational diabetes, abruption, preeclampsia or gestational hypertension, cholestasis, and preterm delivery. Neonatal outcomes included hyperbilirubinemia, admission to neonatal intensive care (NICU); small-for-gestational-age (SGA) birth weight; and neonatal infection , defined as sepsis or pneumonia. Models were adjusted for maternal age, body mass index, injection drug use, and maternal medical comorbidities., Results: The 249 individuals in the case group were prospectively matched to 486 individuals in the control group who met eligibility criteria. There were significant differences in demographic characteristics between the groups, including race, socioeconomic markers, education, insurance status, and drug and tobacco use. The frequencies of maternal outcomes of gestational diabetes, preeclampsia, and abruption were similar between the case and control groups. Preterm birth was similar between groups, but neonates born to individuals in the case group were more likely to be admitted to the NICU (45.1% vs 19.0%, adjusted odds ratio [aOR] 2.6, 95% CI, 1.8-3.8) and to have SGA birth weights below the 5th percentile (10.6% vs 3.1%, aOR 2.9, 95% CI, 1.4-6.0). There were no increased odds of hyperbilirubinemia or neonatal infection., Conclusion: Despite no increased odds of preterm birth or other adverse maternal outcomes in adjusted analyses, maternal HCV infection was associated with twofold increased odds of NICU admission and nearly threefold increased odds of SGA birth weight below the 5th percentile., Competing Interests: Financial Disclosure Brenna Hughes reports an ongoing financial relationship with UpToDate. Rebecca Clifton reports funding from the University of Arkansas for Medical Sciences for DSMB meetings and from the NIH to her institution. Anna Bartholomew reports money paid to her institution by NICHD and George Washington University. Alan Tita reports money paid to his institution from Pfizer. Torri D. Metz received UpToDate royalties for two topics on trial of labor after cesarean. Money was paid to her institution from Pfizer (site PI for phase III respiratory syncytial virus [RSV] vaccine trial and site PI for a COVID-19 vaccination trial in pregnancy). Geeta Swamy reports receiving past funding from GlaxoSmithKline and ongoing funding from Pfizer, Medscape, UpToDate, Moderna, and Sanofi. The other authors did not disclose any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of Interests T.B. has nothing to disclose. R. Kastury has nothing to disclose. R. Kavarthapu has nothing to disclose. R.B. has nothing to disclose. M.D.L.L.S. has nothing to disclose. H.L. has nothing to disclose. C.A. has nothing to disclose. J.C.Y. has nothing to disclose. V.G.-L. has nothing to disclose.

Cranial sutures are complex structures integrating mechanical forces with osteogenesis which are often affected in craniofacial syndromes. While premature fusion is frequently described, rare pathological widening of cranial sutures is a comparatively understudied phenomenon. This narrative review aims to bring to light the biologically variable underlying causes of widened sutures and persistent fontanelles leading to a common outcome. The authors herein present four syndromes, selected from a literature review, and their identified biological mechanisms in the context of altered suture physiology, exploring the roles of progenitor cell differentiation, extracellular matrix production, mineralization, and bone resorption. This article illustrates the gaps in understanding of complex craniofacial disorders, and the potential for further unification of genetics, cellular biology, and clinical pillars of health science research to improve treatment outcomes for patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Infants with neonatal opioid withdrawal syndrome (NOWS) cared for with the Eat, Sleep, Console (ESC) care approach receive less pharmacologic treatment and have shorter hospital stays compared to usual care with the Finnegan Neonatal Abstinence Scoring Tool, but the effects of these approaches on feeding and weight are unknown., Objective: To evaluate feeding practices and weight trajectories in infants cared for with ESC vs usual care., Design, Setting, and Participants: ESC-NOW is a cluster randomized trial of infants with NOWS born at 36 weeks' gestation or later at 26 US hospitals from September 2020 to March 2022. Each site transitioned from usual care to ESC (the study intervention) at a randomized time. Feeding was per site practice and not specified by the intervention. Feeding and weight outcomes were assessed at hospital discharge., Intervention: ESC vs usual care., Main Outcomes and Measures: Outcomes include prospectively identified secondary end points related to feeding and weight. z Scores were used for growth to account for corrected gestational age at the time of measurement. All analyses were intention to treat and adjusted for study design. Maternal/infant characteristics were included in adjusted models., Results: The analyses included 1305 infants (702 in usual care and 603 in ESC; mean [SD] gestational age, 38.6 [1.3] weeks; 655 [50.2%] male and 650 [49.8%] female). Baseline demographic characteristics were similar between groups. The proportion of breastfed infants was higher in the ESC group (52.7% vs 41.7%; absolute difference, 11%; 95% CI, 1.0-20.9). A higher proportion of infants cared for with ESC received exclusive breast milk (15.1% vs 6.7%; absolute difference, 8.4%; 95% CI, 0.9-5.8) or any breast milk (38.8% vs 27.4%; absolute difference, 11.4%; 95% CI, 0.2-23.1) and were directly breastfeeding at discharge (35.2% vs 19.5%; absolute difference, 15.7%; 95% CI, 4.1-27.3). There was no difference in proportion of infants with weight loss greater than 10% or maximum percentage weight loss, although infants cared for with ESC had a lower weight z score on day of life 3 (-1.08 vs -1.01; absolute difference, 0.07; 95% CI, 0.02-0.12). When pharmacologic treatment was added into the model, no breastfeeding outcomes were statistically significant., Conclusions and Relevance: In this study, infants cared for with ESC were more likely to initiate and continue breastfeeding and had no difference in percentage weight loss. The improvement in breastfeeding with ESC may be driven by reduction in pharmacologic treatment and provision of effective nonpharmacologic care., Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Background: Following the results of the ARRIVE trial, which demonstrated a reduction in cesarean delivery with no increase in adverse perinatal outcomes after elective induction of labor (IOL) in low-risk nulliparous patients at 39 weeks' gestation compared with expectant management, the use of induction has increased. Current evidence is insufficient to recommend mid-high-dose over low-dose regimens for routine IOL., Objective(s): We sought to evaluate the association of oxytocin regimen with cesarean delivery and an adverse perinatal composite outcome in low-risk nulliparous patients undergoing IOL at 39 weeks of gestation or greater., Study Design: This is a secondary analysis of the NICHD Maternal-Fetal Medicine Units Network ARRIVE randomized trial. Patients induced with a mid-to high-dose oxytocin regimen (MHD; starting or incremental increase >2 mU/min) were compared with those receiving a low-dose oxytocin regimen (LD; starting and incremental increase ≤2 mU/min). The co-primary outcomes for this secondary analysis were 1) cesarean delivery and 2) composite of perinatal death or severe neonatal complications. Multivariable Poisson regression was used to estimate adjusted relative risks (aRR) and 97.5% confidence intervals (CI) for the co-primary endpoints, 95% CI for binomial outcomes and multinomial logistic regression was used to estimate adjusted odds ratios (aOR) and 95% CIs for multinomial outcomes., Results: Of 6,106 participants enrolled in the primary trial, 2,933 underwent induction with oxytocin: 861 in the MHD group and 2,072 in the LD group. The lower frequency of cesarean delivery in the MHD group compared with the LD group (20.3% vs. 25.2%, RR 0.81, 95%CI (0.69-0.94)) was not significant after adjustment (aRR 0.90, 97.5%CI (0.76-1.07)). The composite of perinatal death or severe neonatal complications was more frequent in the MHD group compared with the LD group (6.7% vs. 4.3%, RR 1.55, 95%CI (1.13-2.14)) and remained significant after adjustment (aRR 1.61, 97.5%CI (1.11-2.35)). The majority of the cases in the composite were from the respiratory support (5.2% vs. 3.1%) component with an increase in transient tachypnea of the newborn (3.8% vs. 2.5%, aRR 1.63, 95% CI (1.04-2.54)). The duration of neonatal respiratory support for one day was significantly higher in the MHD group compared with the LD group (3.5% vs. 1.4%, aRR 2.59, 95%CI (1.52-4.39)); however, support beyond one day was not different between the two groups. The MHD group, when compared with the LD group had a higher operative vaginal delivery rate (10.0% vs. 7.0%, aRR 1.54, 95%CI (1.18-2.00)) and shorter duration of time from start of oxytocin to delivery [crude median (interquartile range) 12 (8-17) vs. 13 (9-19) hours, adjusted median difference -2 (-2 to -1), p<0.001], respectively., Conclusion(s): Mid-high-dose oxytocin regimen use for IOL in nulliparas at ≥ 39 weeks' gestation was not associated with improved maternal or neonatal outcomes compared with low-dose regimens. Although mid-high-dose oxytocin regimen use was associated with a shorter duration of labor, there was an increase in self-limited neonatal respiratory support and no difference in cesarean rates. More evidence is needed to define the magnitude of potential maternal and neonatal benefits and risks associated with oxytocin regimens., (Copyright © 2024. Published by Elsevier Inc.)

Background: Parental education is linked to child development and wellbeing, but unique and combined contributions of maternal and paternal education have rarely been studied., Aims: This study assessed the individual and joint associations of maternal and paternal education on children's odds of a probable developmental delay., Methods and Procedures: Mothers (N = 3566) from the Upstate KIDS cohort study reported on theirs and the father's highest level of education and completed the Ages and Stages Questionnaires up to 7 times when the child was 4- to 36-months-old. A nonparametric constrained inference technique assessed the association between education and probable developmental delays., Outcomes and Results: Higher levels of maternal and paternal education were protective against child probable developmental delays in years 2 (18, 24 months; p-trends<.001) and 3 (30, 36 months; p-trends<.001), but not year 1 (4, 8, 12 months; p-trend=.486-.832). Trends held adjusting for parental age and race. When adjusting for the other parent's education, only maternal education had unique associations with delays. Among parents with the same or similar education levels, when both parents had one level higher education it was also protective., Conclusions and Implications: Both maternal and paternal education may protect against children's developmental delays in toddlerhood, but maternal education may be particularly important., (Published by Elsevier Ltd.)

Iron regulatory proteins (IRP1 and IRP2) play a pivotal role in maintaining cellular iron homeostasis by binding to iron-responsive elements (IREs) of target mRNAs and regulating the expression of these iron-related genes. Mice and humans that lack functional IRP1 develop erythrocytosis due to erythropoietin overproduction, whereas those that lack IRP2 develop microcytic anemia believed to result from iron deficiency of erythroblasts. Here, we discovered that IRP2 deficiency reduced the expression of hypoxia inducible factor 2 alpha (HIF2a) and its transcriptional target, erythropoietin (EPO), thereby compromising the stress erythropoiesis response to generate RBCs upon anemia. The distinct consequences of IRP2 and IRP1 on EPO result from the higher binding affinity of the HIF2a IRE for IRP1 compared to IRP2. This difference in binding affinity arises from a bulge uridine in the upper stem of HIF2a IRE that impairs the ability of IRP2 to bind the IRE. These results reveal that IRP1 and IRP2 play distinct roles in erythropoiesis and unveil an unsuspected IRE binding preference that contributes to the divergent phenotypes observed in IRP1 and IRP2 deficient mammals., (Copyright © 2024 American Society of Hematology.)

One species-general life history (LH) principle posits that challenging childhood environments are coupled with a fast or faster LH strategy and associated behaviors, while secure and stable childhood environments foster behaviors conducive to a slow or slower LH strategy. This coupling between environments and LH strategies is based on the assumption that individuals' internal traits and states are independent of their external surroundings. In reality, individuals respond to external environmental conditions in alignment with their intrinsic vitality, encompassing both physical and mental states. The present study investigated attachment as an internal mental state, examining its role in mediating and moderating the association between external environmental adversity and fast LH strategies. A sample of 1169 adolescents (51% girls) from 9 countries was tracked over 10 years, starting from age 8. The results confirm both mediation and moderation and, for moderation, secure attachment nullified and insecure attachment maintained the environment-LH coupling. These findings suggest that attachment could act as an internal regulator, disrupting the contingent coupling between environmental adversity and a faster pace of life, consequently decelerating human LH.

Background: Growing evidence supports changes in the gastrointestinal microbiome over the course of pregnancy may have an impact on the short- and long-term health of both the mother and the child., Objective: Our objective was to explore the association of diet quality, as measured by the Healthy Eating Index (HEI), with the composition and gene ontology (GO) representation of microbial function in the maternal gastrointestinal microbiome during pregnancy., Methods: We conducted a retrospective, observational analysis of n = 185 pregnant participants in the Pregnancy Eating Attributes Study. Maternal dietary intake was assessed in the first trimester using the automated self-administered 24-h recall method, from which the HEI 2015 was calculated. Rectal swabs were obtained in the second trimester and sequenced using the NovaSeq 6000 system shotgun platform. We used unsupervised clustering to identify microbial enterotypes representative of maternal taxa and GO functional term composition. Multivariable linear models were used to identify associations between taxa, functional terms, and food components while controlling for relevant covariates. Multinomial regression was then used to predict enterotype membership based on a participant's HEI food component score., Results: Those in the high diet quality tertile had a lower early pregnancy BMI [mean (M) = 23.48 kg/m 2 , SD = 3.38] compared with the middle (M = 27.35, SD = 6.01) and low (M = 27.49, SD = 6.99) diet quality tertiles (P < 0.01). There were no statistically significant associations between the HEI components or the total HEI score and the 4 alpha diversity measures. Differences in taxa and GO term enterotypes were found in participants with, but not limited to, a higher saturated fat component score (β = 1.35, P = 0.01), added sugar HEI component (β = 0.07, P < 0.001), and higher total dairy score (β = 1.58, P = 0.01)., Conclusions: Specific dietary components are associated with microbial composition and function in the second trimester of pregnancy. These findings provide a foundation for future testable hypotheses., Competing Interests: Conflict of interest AMS-R reports financial support was provided by National Institute of Child Health and Human Development and a relationship with International Food Information Council that includes: board membership and travel reimbursement. The authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. All rights reserved.)

Background: Although diet quality during pregnancy and postpartum is important for multiple parent and child outcomes, within-person changes in diet quality throughout these periods have not been extensively examined., Objectives: This study investigated diet quality from early pregnancy through 1 y postpartum and examined differences by sociodemographic characteristics in participants receiving obstetric care in Chapel Hill, North Carolina, United States., Methods: Participants completed 24-h dietary recalls at 6 study visits (each pregnancy trimester and 6 wk, 6 mo, and 1 y postpartum) (n = 383). Between-visit mean Healthy Eating Index-2015 (HEI) scores (min = 0, max = 100) were compared using the population ratio (PR) method. The NCI usual intakes method estimated the distribution of HEI scores in pregnancy and postpartum; unpaired t-tests compared usual mean HEI scores by covariates; paired t-tests compared differences between mean pregnancy and postpartum., Results: The total HEI mean ± standard error scores (NCI method) were 61.4 ± 0.8 in pregnancy and 61.7 ± 0.9 in postpartum. Mean HEI scores differed by sociodemographic characteristics, particularly education, marital status, and federal assistance participation. The highest scores were observed in participants with at least a bachelor's degree (64.1 ± 0.9 in pregnancy, 64.5 ± 1.0 in postpartum, n = 257) and those with other non-Hispanic White race/ethnicity (64.7 ± 1.8 in pregnancy, 66.4 ± 2.2 in postpartum). There were no between-visit differences in mean total HEI scores (PR). Although differences were observed in some mean HEI component scores between pregnancy and postpartum visits, they were small (mostly <1 point) in magnitude and in inconsistent directions., Conclusions: Stable total HEI mean scores suggest that adherence to dietary guidelines was consistent throughout pregnancy and postpartum in this sample. Although some sociodemographic characteristics may identify individuals at greater risk of diet-related pregnancy complications, low diet quality was pervasive throughout all subgroups and reflects an urgent need for widespread improvement., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Published by Elsevier Inc.)