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Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Background Very low birthweight (VLBW) infants are at risk for growth failure and poor neurodevelopment. Optimised parenteral nutrition may help promote optimal growth and development, but concerns that provision of enhanced nutrition may contribute to increased early adiposity and later metabolic disease remain.Aim To determine associations between provision of an early enhanced parenteral nutrition protocol or standard parenteral nutrition protocol and growth and body composition for VLBW preterm infants in the neonatal intensive care unit.Subjects This is a secondary analysis of data from a clinical trial aimed at assessing the feasibility and safety of randomising VLBW preterm infants to Standard (n = 45) or Intervention (n = 42) parenteral nutrition groups between August 2017 and June 2019.Methods We evaluated associations between weekly infant growth and body composition measurements from n = 55 infants (Standard = 29, Intervention = 26) that were clinically stable enough to have body composition measurements taken before discharge using mixed effects linear regression models.Result No statistically significant associations between nutrition group and infant growth or body composition measures were observed (p >.05).Conclusion In this pilot trial, enhanced parenteral nutrition in the first week of life was not associated with significant differences in infant growth or body composition during hospitalisation.

The goal of Working Group 1 in the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to outline factors influencing biological processes governing human milk secretion and to evaluate our current knowledge of these processes. Many factors regulate mammary gland development in utero, during puberty, in pregnancy, through secretory activation, and at weaning. These factors include breast anatomy, breast vasculature, diet, and the lactating parent's hormonal milieu including estrogen, progesterone, placental lactogen, cortisol, prolactin, and growth hormone. We examine the effects of time of day and postpartum interval on milk secretion, along with the role and mechanisms of lactating parent-infant interactions on milk secretion and bonding, with particular attention to the actions of oxytocin on the mammary gland and the pleasure systems in the brain. We then consider the potential effects of clinical conditions including infection, pre-eclampsia, preterm birth, cardiovascular health, inflammatory states, mastitis, and particularly, gestational diabetes and obesity. Although we know a great deal about the transporter systems by which zinc and calcium pass from the blood stream into milk, the interactions and cellular localization of transporters that carry substrates such as glucose, amino acids, copper, and the many other trace metals present in human milk across plasma and intracellular membranes require more research. We pose the question of how cultured mammary alveolar cells and animal models can help answer lingering questions about the mechanisms and regulation of human milk secretion. We raise questions about the role of the lactating parent and the infant microbiome and the immune system during breast development, secretion of immune molecules into milk, and protection of the breast from pathogens. Finally, we consider the effect of medications, recreational and illicit drugs, pesticides, and endocrine-disrupting chemicals on milk secretion and composition, emphasizing that this area needs much more research attention.

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Womens Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p

IntroductionEarly life gut microbiomes are important for brain and immune system development in animal models. Probiotic use has been proposed as a strategy to promote health via modulation of microbiomes. In this observational study, we explore if early life exposure to probiotics via the mother during pregnancy and lactation, is associated with decreased inflammation in breastmilk, maternal and infant microbiome variation, and altered infant neurodevelopmental features.MethodsExclusively breastfeeding mother-infant dyads were recruited as part of the “Mothers and Infants Linked for Healthy Growth (MILk) Study.” Probiotic comparison groups were defined by exposure to maternal probiotics (NO/YES) and by timing of probiotic exposure (prenatal, postnatal, total). C-reactive protein (CRP) and IL-6 levels were determined in breastmilk by immunoassays, and microbiomes were characterized from 1-month milk and from 1- and 6-month infant feces by 16S rDNA sequencing. Infant brain function was profiled via electroencephalogram (EEG); we assessed recognition memory using event-related potential (ERP) responses to familiar and novel auditory (1 month) and visual (6 months) stimuli. Statistical comparisons of study outcomes between probiotic groups were performed using permutational analysis of variance (PERMANOVA) (microbiome) and linear models (all other study outcomes), including relevant covariables as indicated.ResultsWe observed associations between probiotic exposure and lower breastmilk CRP and IL-6 levels, and infant gut microbiome variation at 1- and 6-months of age (including higher abundances of Bifidobacteria and Lactobacillus). In addition, maternal probiotic exposure was associated with differences in infant ERP features at 6-months of age. Specifically, infants who were exposed to postnatal maternal probiotics (between the 1- and 6-month study visits) via breastfeeding/breastmilk, had larger differential responses between familiar and novel visual stimuli with respect to the late slow wave component of the EEG, which may indicate greater memory updating potential. The milk of mothers of this subgroup of infants had lower IL-6 levels and infants had different 6-month fecal microbiomes as compared to those in the “NO” maternal probiotics group.DiscussionThese results support continued research into “Microbiota-Gut-Brain” connections during early life and the role of pre- and postnatal probiotics in mothers to promote healthy microbiome-associated outcomes in infants.

Objective To examine the racial, ethnic and cultural differences in postpartum participation of women who participated in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) during pregnancy by completing a retrospective analysis of observational data on 35,903 women who enrolled in Minnesota WIC during pregnancy, from April 2018 to March 2020. Methods Descriptive analyses were completed using chi-square tests of association to show differences in postpartum WIC participation by maternal demographics and health risk codes of the WIC participants. Binary logistic regression and multivariate logistic regression were used to obtain odds ratios to compare the likelihood of postpartum WIC participation across different races, ethnicities and cultural groups. Results Asian/Pacific Islander, East African, Hispanic, Hmong, Multigenerational Black, and Other Black pregnant participants were more likely than White participants to return to WIC postpartum (adjusted odds ratio (AOR) 2.54, 95% confidence interval (CI) 1.87-3.46; AOR 3.35, 95% CI 2.40-4.66; 1.30, 95% CI 1.10-1.54; AOR 6.76, 95% CI 4.39-10.42; AOR 1.40, 95% CI 1.11-1.77, AOR 1.52, 95% CI 1.26-1.83, respectively). American Indian pregnant participants were less likely than White participants to return to WIC postpartum (AOR 0.70, 95% CI 0.54-0.92). Conclusions for Practice These findings can help the Minnesota WIC program, as well as other WIC programs, better understand which cultural groups may need more specific outreach strategies to keep women participating in the program after giving birth. Further research is needed to understand why postpartum women choose to participate, or choose not to participate, in WIC., Author(s): Elizabeth (Betsy) Lundmark [sup.1] , Ellen Demerath [sup.1] , Marcia McCoy [sup.2] , Jamie Stang [sup.1] Author Affiliations: (1) https://ror.org/017zqws13, grid.17635.36, 0000 0004 1936 8657, School of Public Health, [...]

This article presents a grounded model of how educators earn students' trust in a high performing U.S. urban high school. This long-term anthropological project set out to understand the beliefs and practices of experienced teachers and staff members nominated by students as helping them feel like they belonged in school. Analysis of study data revealed a process of "mutual discernment" whereby adults and young people were reading one another as they explored the possibilities of entering into learning partnerships. For the educators, study data led us to infer that their trust building strategies were largely based on imagining the student discernment process, and responding to a set of unspoken queries about them that, over time, they seem to have learned were often on the minds of students (e.g. "Why are they here?" "How much do they respect me?"). The grounded model and practice-based evidence presented here summarize the strategies and approaches educators used to respond to these unspoken queries and communicate to students various aspects of their selves and their stance, including their motivation, empathy and respect for students, self-awareness and credibility, their professional ability, and finally, their commitment to helping students and investing emotional labor in them. Throughout, data are also presented regarding how students perceived and experienced these strategies, and ultimately how they interpreted and appraised their relationships with educators, as trusting relationships were developed.

Abstract Brain atrophy associated with valproate therapy is known from single case reports and is frequently accompanied by cognitive deterioration. We present a case series of incidental findings of brain volume loss in children treated with valproate and employed automatic brain volumetry to assess the effect size of volume loss. 3D T1w datasets were automatically segmented into white matter, gray matter, and cerebrospinal fluid using the SPM‐12 algorithm. Respective volumes of cerebrum and cerebellum were read out and normalized to the total intracranial volume. We identified six patients (median age 148.5 [85–178] months) who had received valproate for a median time of 5 (2–23) months prior to MRI in which a loss of brain volume was noted. None had reported the occurrence of new clinical symptoms. Volumetry showed a volume loss of up to 28% for cerebral GM, 25% for cerebellar GM, 10% for cerebral WM, and 20% for cerebellar WM. A volume loss of >5% in at least one of the subvolumes was found in all patients, with the more prominent volume loss in the cerebrum and in gray matter. In one patient, post‐valproate MRI was available and showed normalization of brain volume. Our case series indicates that valproate therapy might be associated with an asymptomatic volume loss of brain parenchyma in children with epilepsy and that this volume loss is assessable with automatic volumetry.

In this address I identify specific and unique roles anthropology can play in the necessary work of decolonizing education. These include: building anti-racist schools that honor all "ways of being human"; decolonizing school leadership and working towards culture creation for equity and anti-racism; decolonizing teaching and learning and honoring how humans learn best; decolonizing teacher education; decolonizing student-teacher relationships; putting the social in social and emotional learning; and decolonizing education research and policy.

BackgroundBody mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health.ResultsThe discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Introduction Maternal and child health (MCH) services are critical for vulnerable populations. Workforce shortages, poor retention, and gaps in necessary trainings impede the capacity of public health systems to address needs. This manuscript characterizes the current MCH workforce, MCH program applicants and graduates, and describe findings within a national context to devise elements of a recruitment and retention strategy. Methods Data were obtained for public health program applicants, first-destination employment outcomes, and worker perceptions and demographics. Data were stratified according to the MCH and total public health workforce and by local, state, and national totals. Data were characterized by degree type, discipline, demographics, and employment outcomes. Results MCH staff constitute 11% of the state and local governmental public health workforce. MCH staff are approximately as diverse, have higher educational attainment, and are more likely to hold nursing degrees than the rest of the public health workforce. Yet, just 14% of MCH staff hold any type of public health degree. The MCH pipeline from academia appears modestly sized, with approximately 5% of applicants between 2017 and 2021 applying to a MCH master's degree. Discussion The MCH workforce has a lower proportion of formal training or degrees in public health, though trends seem to indicate improvements. However, it is critical that a multi-faceted recruitment and retention strategy be coordinated by a broad range of stakeholders. These efforts will serve to improve the capability and capacity of the public health system to address critical needs of increasingly diverse MCH populations. Significance In order to modernize and reimagine the academic-public health pipeline, it is critical to better understand how many applicants and graduates exist within Maternal and Child Health programs across the US, and their characteristics. This manuscript connects that information with the most recently available public health workforce information on demographics, workplace perceptions, and intent to leave among staff at state and local health departments. Data presented in this paper allow the most comprehensive characterization of the MCH academia->practice pipeline to-date, identifies a fundamental disconnect in those career pathways, and offers options to repair that break., Author(s): Jonathon P. Leider [sup.1] , Jamie Stang [sup.1] , Zobeida E. Bonilla [sup.1] , Jason Orr [sup.1] , Christine M. Plepys [sup.2] , Moriah Gendelman [sup.3] , Ellen W. [...]

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF

Background and purposeThe role of surgery in the treatment of intracerebral haemorrhage (ICH) remains controversial. Whereas open surgery has failed to show any clinical benefit, recent studies have suggested that minimal invasive procedures can indeed be beneficial, especially when they are applied at an early time point. This retrospective study therefore evaluated the feasibility of a free-hand bedside catheter technique with subsequent local lysis for early haematoma evacuation in patients with spontaneous supratentorial ICH.MethodsPatients with spontaneous supratentorial haemorrhage of a volume of >30 mL who were treated with bedside catheter haematoma evacuation were identified from our institutional database. The entry point and evacuation trajectory of the catheter were based on a 3D-reconstructed CT scan. The catheter was inserted bedside into the core of the haematoma, and urokinase (5,000 IE) was administered every 6 h for a maximum of 4 days. Evolution of haematoma volume, perihaemorrhagic edema, midline-shift, adverse events and functional outcome were analyzed.ResultsA total of 110 patients with a median initial haematoma volume of 60.6 mL were analyzed. Haematoma volume decreased to 46.1 mL immediately after catheter placement and initial aspiration (with a median time to treatment of 9 h after ictus), and to 21.0 mL at the end of urokinase treatment. Perihaemorrhagic edema decreased significantly from 45.0 mL to 38.9 mL and midline-shift from 6.0 mm to 2.0 mm. The median NIHSS score improved from 18 on admission to 10 at discharge, and the median mRS at discharge was 4; the latter was even lower in patients who reached a target volume ≤ 15 mL at the end of local lysis. The in-hospital mortality rate was 8.2%, and catheter/local lysis-associated complications occurred in 5.5% of patients.ConclusionBedside catheter aspiration with subsequent urokinase irrigation is a safe and feasible procedure for treating spontaneous supratentorial ICH, and can immediately reduce the mass effects of haemorrhage. Additional controlled studies that assess the long-term outcome and generalizability of our findings are therefore warranted.Clinical trial registration[www.drks.de], identifier [DRKS00007908].

Background and purpose: External drainage represents a well-established treatment option for acute intracerebral hemorrhage. The current standard of practice includes post-operative computer tomography imaging, which is subjectively evaluated. The implementation of an objective, automated evaluation of postoperative studies may enhance diagnostic accuracy and facilitate the scaling of research projects. The objective is to develop and validate a fully automated pipeline for intracerebral hemorrhage and drain detection, quantification of intracerebral hemorrhage coverage, and detection of malpositioned drains. Materials and methods: In this retrospective study, we selected patients (n = 68) suffering from supratentorial intracerebral hemorrhage treated by minimally invasive surgery, from years 2010–2018. These were divided into training (n = 21), validation (n = 3) and testing (n = 44) datasets. Mean age (SD) was 70 (±13.56) years, 32 female. Intracerebral hemorrhage and drains were automatically segmented using a previously published artificial intelligence-based approach. From this, we calculated coverage profiles of the correctly detected drains to quantify the drains' coverage by the intracerebral hemorrhage and classify malpositioning. We used accuracy measures to assess detection and classification results and intraclass correlation coefficient to assess the quantification of the drain coverage by the intracerebral hemorrhage. Results: In the test dataset, the pipeline showed a drain detection accuracy of 0.97 (95% CI: 0.92 to 0.99), an agreement between predicted and ground truth coverage profiles of 0.86 (95% CI: 0.85 to 0.87) and a drain position classification accuracy of 0.88 (95% CI: 0.77 to 0.95) resulting in area under the receiver operating characteristic curve of 0.92 (95% CI: 0.85 to 0.99). Conclusion: We developed and statistically validated an automated pipeline for evaluating computed tomography scans after minimally invasive surgery for intracerebral hemorrhage. The algorithm reliably detects drains, quantifies drain coverage by the hemorrhage, and uses machine learning to detect malpositioned drains. This pipeline has the potential to impact the daily clinical workload, as well as to facilitate the scaling of data collection for future research into intracerebral hemorrhage and other diseases. [ABSTRACT FROM AUTHOR]

Background High pre-pregnancy body mass index (BMI) and excessive gestational weight gain (GWG) are significant risk factors for maternal and neonatal health. Aim To assess pre-pregnancy BMI and GWG during pregnancy and their association with different maternal and neonatal characteristics in the transitional Mediterranean population from the Eastern Adriatic islands. Subjects and methods Two hundred and sixty-two mother–child dyads from the CRoatian Islands’ Birth Cohort Study (CRIBS) were included in the study. Chi-square test, ANOVA, and regression analysis were used to test the association between selected characteristics. Results In total, 22% of women entered pregnancy as overweight/obese and 46.6% had excessive GWG. Pre-pregnancy overweight and obesity were significantly associated with elevated triglycerides uric acid levels, and decreased HDL cholesterol in pregnancy. Excessive GWG was associated with elevated fibrinogen and lipoprotein A levels. Women with high pre-pregnancy BMI and GWG values were more likely to give birth to babies that were large for gestational age (LGA), additionally confirmed in the multiple logistic regression model. Conclusion High maternal pre-pregnancy BMI and excessive GWG were both significantly associated with deviated biochemical parameters and neonatal size. More careful monitoring of maternal nutritional status can lead to better pre- and perinatal maternal healthcare.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.