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Abstract Venom is a remarkable innovation found across the animal kingdom, yet the evolutionary origins of venom systems in various groups, including spiders, remain enigmatic. Here, we investigated the organogenesis of the venom apparatus in the common house spider, Parasteatoda tepidariorum. The venom apparatus consists of a pair of secretory glands, each connected to an opening at the fang tip by a duct that runs through the chelicerae. We performed bulk RNA-seq to identify venom gland-specific markers and assayed their expression using RNA in situ hybridisation experiments on whole-mount time-series. These revealed that the gland primordium emerges during embryonic stage 13 at the chelicera tip, progresses proximally by the end of embryonic development and extends into the prosoma post-eclosion. The initiation of expression of an important toxin component in late postembryos marks the activation of venom-secreting cells. Our selected markers also exhibited distinct expression patterns in adult venom glands: sage and the toxin marker were expressed in the secretory epithelium, forkhead and sum-1 in the surrounding muscle layer, while Distal-less was predominantly expressed at the gland extremities. Our study provides the first comprehensive analysis of venom gland morphogenesis in spiders, offering key insights into their evolution and development.

An interdisciplinary fetal-neonatal neurology (FNN) program over the first 1,000 days teaches perspectives of the neural exposome that are applicable across the life span. This curriculum strengthens neonatal neurocritical care, pediatric, and adult neurology training objectives. Teaching at maternal-pediatric hospital centers optimally merges reproductive, pregnancy, and pediatric approaches to healthcare. Phenotype--genotype expressions of health or disease pathways represent a dynamic neural exposome over developmental time. The science of uncertainty applied to FNN training re-enforces the importance of shared clinical decisions that minimize bias and reduce cognitive errors. Trainees select mentoring committee participants that will maximize their learning experiences. Standardized questions and oral presentations monitor educational progress. Master or doctoral defense preparation and competitive research funding can be goals for specific individuals. FNN principles applied to practice offer an understanding of gene--environment interactions that recognizes the effects of reproductive health on the maternal-placental-fetal triad, neonate, child, and adult. Pre-conception and prenatal adversities potentially diminish life-course brain health. Endogenous and exogenous toxic stressor interplay (TSI) alters the neural exposome through maladaptive developmental neuroplasticity. Developmental disorders and epilepsy are primarily expressed during the first 1,000 days. Communicable and noncommunicable illnesses continue to interact with the neural exposome to express diverse neurologic disorders across the lifespan, particularly during the critical/sensitive time periods of adolescence and reproductive senescence. Anomalous or destructive fetal neuropathologic lesions change clinical expressions across this developmental-aging continuum. An integrated understanding of reproductive, pregnancy, placental, neonatal, childhood, and adult exposome effects offers a life-course perspective of the neural exposome. Exosome research promises improved disease monitoring and drug delivery starting during pregnancy. Developmental origins of health and disease principles applied to FNN practice anticipate neurologic diagnoses with interventions that can benefit successive generations. Addressing health care disparities in the Global South and high-income country medical deserts require constructive dialogue among stakeholders to achieve medical equity. Population health policies require a brain capital strategy that reduces the global burden of neurologic diseases by applying FNN principles and practice. This integrative neurologic care approach will prolong survival with an improved quality of life for persons across the lifespan confronted with neurological disorders. [ABSTRACT FROM AUTHOR]

Integrated fetal, neonatal, and pediatric training constitute an interdisciplinary fetal-neonatal neurology (FNN) program. A dynamic neural exposome concept strengthens curriculum content. Trainees participate in mentoring committee selection for guidance during a proposed two-year program. Prenatal to postnatal clinical learning re-enforces early toxic stressor interplay that influences gene-environment interactions. Maternal-placental-fetal triad, neonatal, or childhood diseases require diagnostic and therapeutic decisions during the first 1,000 days when 80 % of neural connections contribute to lifecourse phenotypic expression. Pediatric follow-up through 3 years adjusts to gestational ages of preterm survivors. Cumulative reproductive, pregnancy, pediatric and adult exposome effects require educational experiences that emphasize a principle-to-practice approach to a brain capital strategy across the lifespan. More rigorous training during fetal, neonatal, and pediatric rotations will be offered to full time trainees. Adult neurology residents, medical students, and trainees from diverse disciplines will learn essential topics during timelimited rotations. Curriculum content will require periodic re-assessments using educational science standards that maintain competence while promoting creative and collaborative problem-solving. Continued career-long learning by FNN graduates will strengthen shared healthcare decisions by all stakeholders. Recognition of adaptive or maladaptive neuroplasticity mechanisms requires analytic skills that identify phenotypes associated with disease pathways. Developmental origins and life-course concepts emphasize brain health across the developmental-aging continuum, applicable to interdisciplinary research collaborations. Social determinants of health recognize diversity, equity, and inclusion priorities with each neurological intervention, particularly for those challenged with disparities. Diagnostic and therapeutic strategies must address resource challenges particularly throughout the Global South to effectively lower the worldwide burden of neurologic disease. Sustainable development goals proposed by the World Health Organization offer universally applicable guidelines in response to ongoing global and regional polycrises. Gender, race, ethnicity, and socio-economic equality promote effective preventive, rescue and reparative neuroprotective interventions. Global synergistic efforts can be enhanced by establishing leadership within academic teaching hubs in FNN training to assist with structure and guidance for smaller healthcare facilities in each community that will improve practice, education and research objectives. Reduced mortality with an improved quality of life must prioritize maternalpediatric health and well-being to sustain brain health across each lifespan with transgenerational benefits. [ABSTRACT FROM AUTHOR]

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and laterlife ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk. [ABSTRACT FROM AUTHOR]

We study the effect of economic conditions early in life on the occurrence of type-2 diabetes in adulthood using contextual economic indicators and withinsibling pair variation. We use data from Lifelines: a longitudinal cohort study and biobank including 51,270 siblings born in the Netherlands from 1950 onward. Sibling fixed-effects account for selective fertility. To identify type-2 diabetes we use biomarkers on the hemoglobin A1c concentration and fasting glucose in the blood. We find that adverse economic conditions around birth increase the probability of type-2 diabetes later in life both in males and in females. Inference based on self-reported diabetes leads to biased results, incorrectly suggesting the absence of an effect. The same applies to inference that does not account for selective fertility. [ABSTRACT FROM AUTHOR]

PurposeEarly age of menopause may increase the risk of fracture, cardiovascular diseases, and all-cause mortality. This study aimed to investigate the relation between early-life undernutrition in the Great Chinese Famine and the risk of early natural menopause.MethodsA famine exposure retrospective cohort was established during 2017–2018. Postmenopausal women who were born on 01 October 1956–30 September 1964 and came to the hospital for routine health examinations were candidates for the study. Famine time was defined from 1 January 1959 to 31 December 1961. Three types of early-life famine exposure status were determined by the participant’s date of birth. Natural menopause age below 45 was defined as early menopause. The association between early-life famine exposure status and the risk of early natural menopause was confirmed by multiple logistic regression.ResultA total of 3,337 participants born around famine were included in this study. The prevalence of early menopause was 13.1, 10.0, and 8.3% for those born before, during, and after the famine, respectively. The multiple logistic regression showed that women born before famine significantly increased the risk of early menopause compared to non-exposure (born after famine) (the fully adjusted OR = 1.463, 95%CI = 1.049–2.042). The fetal famine exposure did not significantly increase the risk of early menopause (the fully adjusted OR = 1.244, 95%CI = 0.878–1.764).ConclusionLong-term early childhood famine exposure, which caused chronic undernutrition at young ages, increased the risk of early menopause. Early lifetime undernutrition can be recognized as an adverse factor in female reproductive development and aging. This cohort study further confirmed the hypothesis of developmental origins of health and disease from the aspect of women’s reproductive health. Further mechanism study is warranted.

The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. In particular, epigenetic marks, including DNA methylation, are thought to be key mechanisms through which environmental exposures programme later-life health. Adequate maternal folate status before and during pregnancy is essential in the protection against neural tube defects, but data are emerging that suggest early-life folate exposures may also influence neurocognitive outcomes in childhood and, potentially, thereafter. Since folate is key to the supply of methyl donors for DNA methylation, we hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n  = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19–21 days) and lactation (mean 22 days) compared with controls (n  = 6, 2 mg folic acid/kg diet). Genes were selected as methylation of their promoters had previously been found to be altered by maternal folate intake in mice and humans across the life course, and because they have potential associations with neurocognitive outcomes. Maternal folate depletion was significantly associated with Art3 gene hypomethylation in subcortical brain tissue of adult mice at 28 weeks of age (mean decrease 6.2%, P  = .03). For the other genes, no statistically significant differences were found between folate depleted and control groups. Given its association with neurocognitive outcomes, we suggest Art3 warrants further study in the context of lifecourse brain health. We have uncovered a potential biomarker that, once validated in accessible biospecimens and human context, may be useful to track the impact of early-life folate exposure on later-life neurocognitive health, and potentially be used to develop and monitor the effects of interventions. [ABSTRACT FROM AUTHOR]

The Asian Indian Beta Cell function (ABCs) in Infants Study examined the associations of maternal weight on infant pancreatic beta cell function across 7 months postpartum. Pregnant women aged 18–35 years were recruited in Hyderabad, India. Women were classified by first trimester weight as underweight (UW), BMI < 18.5 kg/m2; normal weight (NW), BMI 18.5–22.9 kg/m2; or overweight (OW), BMI 23.0 through <28.5 kg/m2. At age > 7 months, infants had an oral glucose tolerance test (OGTT, 1.75 g glucose/kg bodyweight) following a 3 h fast. Infant blood samples were assayed for C-peptide and glucose. Infant beta cell function (HOMA2-B; disposition index, DI) and insulin resistance (HOMA2-IR) were compared across maternal weight groups. Mothers (UW n = 63; NW n = 43; OW n = 29) had similar age at delivery and second trimester 50 g glucose challenge test results. Cord HOMA2-B values were 51% greater for IUW (83.5, SD 55.2) and 44% greater for IOW (79.9, SD 60.8) vs. INW (55.4, SD 51.5), forming a U-shaped relationship between maternal weight and HOMA2-B. No qualitative differences in HOMA2-IR were found at birth. However, at 7 months postpartum, HOMA2-IR changed most within IUW (−64% median reduction) and changed the least in IOW (−7% median reduction). At seven months postpartum, DI was higher in IUW vs. the other groups (geometric mean IUW 1.9 SD 2.5; INW 1.3 SD 2.6 or vs. IOW mean 1.2 SD 3.7), reflecting a +49% difference in DI. Evidence from this study illustrates adaptations in the pancreatic functional response of infants associated with the maternal nutritional environment. [ABSTRACT FROM AUTHOR]

Integrated fetal, neonatal, and pediatric training constitute an interdisciplinary fetal-neonatal neurology (FNN) program. A dynamic neural exposome concept strengthens curriculum content. Trainees participate in mentoring committee selection for guidance during a proposed two-year program. Prenatal to postnatal clinical learning re-enforces early toxic stressor interplay that influences gene–environment interactions. Maternal-placental-fetal triad, neonatal, or childhood diseases require diagnostic and therapeutic decisions during the first 1,000 days when 80 % of neural connections contribute to life-course phenotypic expression. Pediatric follow-up through 3 years adjusts to gestational ages of preterm survivors. Cumulative reproductive, pregnancy, pediatric and adult exposome effects require educational experiences that emphasize a principle-to-practice approach to a brain capital strategy across the lifespan. More rigorous training during fetal, neonatal, and pediatric rotations will be offered to full time trainees. Adult neurology residents, medical students, and trainees from diverse disciplines will learn essential topics during time-limited rotations. Curriculum content will require periodic re-assessments using educational science standards that maintain competence while promoting creative and collaborative problem-solving. Continued career-long learning by FNN graduates will strengthen shared healthcare decisions by all stakeholders. Recognition of adaptive or maladaptive neuroplasticity mechanisms requires analytic skills that identify phenotypes associated with disease pathways. Developmental origins and life-course concepts emphasize brain health across the developmental-aging continuum, applicable to interdisciplinary research collaborations. Social determinants of health recognize diversity, equity, and inclusion priorities with each neurological intervention, particularly for those challenged with disparities. Diagnostic and therapeutic strategies must address resource challenges particularly throughout the Global South to effectively lower the worldwide burden of neurologic disease. Sustainable development goals proposed by the World Health Organization offer universally applicable guidelines in response to ongoing global and regional polycrises. Gender, race, ethnicity, and socio-economic equality promote effective preventive, rescue and reparative neuroprotective interventions. Global synergistic efforts can be enhanced by establishing leadership within academic teaching hubs in FNN training to assist with structure and guidance for smaller healthcare facilities in each community that will improve practice, education and research objectives. Reduced mortality with an improved quality of life must prioritize maternal-pediatric health and well-being to sustain brain health across each lifespan with transgenerational benefits.

Chronic inflammation contributes to the onset and progression of cardiovascular disease and other degenerative diseases of aging. But does it have to? This article considers the associations among inflammation, aging, and health through the lens of human population biology and suggests that chronic inflammation is not a normal nor inevitable component of aging. It is commonly assumed that conclusions drawn from research in affluent, industrialized countries can be applied globally; that aging processes leading to morbidity and mortality begin in middle age; and that inflammation is pathological. These foundational assumptions have shifted focus away from inflammation as a beneficial response to infection or injury and toward an understanding of inflammation as chronic, dysregulated, and dangerous. Findings from community-based studies around the world—many conducted in areas with relatively high burdens of infectious disease—challenge these assumptions by documenting substantial variation in levels of inflammation and patterns of association with disease. They also indicate that nutritional, microbial, and psychosocial environments in infancy and childhood play important roles in shaping inflammatory phenotypes and their contributions to diseases of aging. A comparative, developmental, and ecological approach has the potential to generate novel insights into the regulation of inflammation and how it relates to human health over the life course. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades. Methods: Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI. Results: In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio [95% CI per 1 kg increase in birthweight] 0.60 [0.48, 0.75]). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis. Conclusions/interpretation: A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight. [ABSTRACT FROM AUTHOR]

The Asian Indian Beta Cell function (ABCs) in Infants Study examined the associations of maternal weight on infant pancreatic beta cell function across 7 months postpartum. Pregnant women aged 18–35 years were recruited in Hyderabad, India. Women were classified by first trimester weight as underweight (UW), BMI < 18.5 kg/m2; normal weight (NW), BMI 18.5–22.9 kg/m2; or overweight (OW), BMI 23.0 through 2. At age > 7 months, infants had an oral glucose tolerance test (OGTT, 1.75 g glucose/kg bodyweight) following a 3 h fast. Infant blood samples were assayed for C-peptide and glucose. Infant beta cell function (HOMA2-B; disposition index, DI) and insulin resistance (HOMA2-IR) were compared across maternal weight groups. Mothers (UW n = 63; NW n = 43; OW n = 29) had similar age at delivery and second trimester 50 g glucose challenge test results. Cord HOMA2-B values were 51% greater for IUW (83.5, SD 55.2) and 44% greater for IOW (79.9, SD 60.8) vs. INW (55.4, SD 51.5), forming a U-shaped relationship between maternal weight and HOMA2-B. No qualitative differences in HOMA2-IR were found at birth. However, at 7 months postpartum, HOMA2-IR changed most within IUW (−64% median reduction) and changed the least in IOW (−7% median reduction). At seven months postpartum, DI was higher in IUW vs. the other groups (geometric mean IUW 1.9 SD 2.5; INW 1.3 SD 2.6 or vs. IOW mean 1.2 SD 3.7), reflecting a +49% difference in DI. Evidence from this study illustrates adaptations in the pancreatic functional response of infants associated with the maternal nutritional environment.

The role of early life nutrition's impact on relevant health outcomes across the lifespan laid the foundation for the field titled the developmental origins of health and disease. Studies in this area initially concentrated on nutrition and the risk of adverse cardio-metabolic and cancer outcomes. More recently the role of nutrition in early brain development and the subsequent influence of later mental health has become more evident. Scientific breakthroughs have elucidated two mechanisms behind long-term nutrient effects on the brain, including the existence of critical periods for certain nutrients during brain development and nutrient-driven epigenetic modifications of chromatin. While multiple nutrients and nutritional conditions have the potential to modify brain development, iron can serve as a paradigm to understand both mechanisms. New horizons in nutritional medicine include leveraging the mechanistic knowledge of nutrient–brain interactions to propose novel nutritional approaches that protect the developing brain through better timing of nutrient delivery and potential reversal of negative epigenetic marks. The main challenge in the field is detecting whether a change in nutritional status truly affects the brain's development and performance in human subjects. To that end, a strong case can be made to develop and utilise bioindicators of a nutrient's effect on the developing brain instead of relying exclusively on biomarkers of the nutrient's status. [ABSTRACT FROM AUTHOR]

High-quality evidence from prospective longitudinal studies in humans is essential to testing hypotheses related to the developmental origins of health and disease. In this paper, the authors draw upon their own experiences leading birth cohorts with longitudinal follow-up into adulthood to describe specific challenges and lessons learned. Challenges are substantial and grow over time. Long-term funding is essential for study operations and critical to retaining study staff, who develop relationships with participants and hold important institutional knowledge and technical skill sets. To maintain contact, we recommend that cohorts apply multiple strategies for tracking and obtain as much high-quality contact information as possible before the child's 18th birthday. To maximize engagement, we suggest that cohorts offer flexibility in visit timing, length, location, frequency, and type. Data collection may entail multiple modalities, even at a single collection timepoint, including measures that are self-reported, research-measured, and administrative with a mix of remote and in-person collection. Many topics highly relevant for adolescent and young adult health and well-being are considered to be private in nature, and their assessment requires sensitivity. To motivate ongoing participation, cohorts must work to understand participant barriers and motivators, share scientific findings, and provide appropriate compensation for participation. It is essential for cohorts to strive for broad representation including individuals from higher risk populations, not only among the participants but also the staff. Successful longitudinal follow-up of a study population ultimately requires flexibility, adaptability, appropriate incentives, and opportunities for feedback from participants. [ABSTRACT FROM AUTHOR]

Evidence clearly indicates that the nutritional and non-nutritional environment and level of physical activity during the early-life period from preconception through infancy has a lifelong impact on the child's health. However this message must be communicated effectively to parents and other stakeholders such as grandparents, health professionals, policymakers and the wider community in order for positive change to occur. This systematic review explores how both awareness and understanding of the long-term effects of the early-life environment have been measured in various populations and whether any patterns are evident. Ten articles were retrieved via a search of Embase, Medline and Scopus databases for peer-reviewed studies designed to assess participants' knowledge of the links between early-life exposures and adult health. Eligible articles spanned a wide range of countries, population groups and research methods. Three common themes were identified using thematic analysis: 1. a tendency for researchers to conflate participant understanding of the issue (the WHY) with a knowledge of key phrases and nutrition guidelines (the WHAT); 2. bias in both researchers and participants towards short-term thinking due to difficulty conceptualising long-term risk; and 3. challenges in comprehending the complexity of the evidence resulting in oversimplification and the overemphasis of maternal factors. Taken together these findings underscore the importance of a multi-level, whole-of-society approach to communicating the evidence, with the goal of influencing policy decisions as well as building a foundation of community support for parents and prospective parents to create a healthy early-life environment for the long-term wellbeing of all. [ABSTRACT FROM AUTHOR]

Abstract Introduction Midlife physical capability (PC) is associated with developmental factors in the populations of economically developed countries. As far as we know, there is no information for rural populations of low- and middle-income countries. The aim of the study was to investigate the influence of pre- and postnatal factors on midlife objective measures of PC in a 1966–67 birth cohort from a Mexican rural community. The hypothesis was that adverse developmental conditions are associated with low midlife PC. Methods In 1966–67, a birth cohort of all children from a poor Mexican rural community was assembled. Data on family socioeconomic status (SES), parental health and nutritional status, birth weight, postnatal growth and feeding patterns were registered. In 2018, out of the 336 cohort members, 118 were living in the community, and eighty-two of them underwent a comprehensive clinical evaluation. The evaluation included grip strength, gait velocity and chair-stand PC tests. In multivariable linear models, PC tests were the dependent variables, and prenatal, birth and postnatal factors were the independent variables. Adjustment for confounding was made with adult anthropometric, body composition, clinical and ageing status variables. Results Independent of adult health status and other ageing indicators, lower PC was associated with family organization and SES, parental nutritional status, birth weight, infant postnatal growth velocity, and weaning time. These results indicate that adverse family and environmental conditions that are prevalent in poor rural communities are associated with low midlife PC.

Background: Height growth faltering is associated with less optimal behavioral outcomes and educational achievement. Although catch‐up growth after growth delay may result in developmental gains, it may also present as a double‐edged sword, with consequences for neurocognitive functioning such as symptoms of inattention and hyperactivity. As previously institutionalized (PI) children experience height delays at adoption and catch‐up growth after adoption, they provide a cohort to test associations between catch‐up growth and attention deficit hyperactivity disorder (ADHD) symptoms. Methods: This study used latent growth curve modeling to examine how catch‐up in height‐for‐age growth is related to attention problems in a population of PI youth followed from adoption in infancy through kindergarten. Participants were assessed within three months of arrival into their families (age at entry: 18–36 months). Anthropometrics were measured four times, approximately 7 months apart. Two visits measured behavioral outcomes with parent and teacher reports of ADHD, internalizing, and externalizing symptoms at age 5 and kindergarten. Results: The slope of growth in height z‐scores, but not the intercept, was positively associated with parent‐ and teacher‐reported ADHD symptoms in children. A one standard deviation increase in the slope of height z‐scores across four assessments was associated with a 0.252 standard deviation increase in ADHD symptoms after controlling for internalizing and externalizing problems, iron status, duration of institutional care, sex, and age. The slope of growth was also associated with internalizing but not externalizing symptoms. Conclusions: This study demonstrates that PI children exhibit individual trajectories of height growth postadoption. Higher rates of change in height‐for‐age growth were associated with increased ADHD symptoms. These results suggest that catch‐up growth comes 'at the cost' of poor attention regulation and hyperactive behavior. [ABSTRACT FROM AUTHOR]

Purpose: Early age of menopause may increase the risk of fracture, cardiovascular diseases, and all-cause mortality. This study aimed to investigate the relation between early-life undernutrition in the Great Chinese Famine and the risk of early natural menopause., Methods: A famine exposure retrospective cohort was established during 2017-2018. Postmenopausal women who were born on 01 October 1956-30 September 1964 and came to the hospital for routine health examinations were candidates for the study. Famine time was defined from 1 January 1959 to 31 December 1961. Three types of early-life famine exposure status were determined by the participant's date of birth. Natural menopause age below 45 was defined as early menopause. The association between early-life famine exposure status and the risk of early natural menopause was confirmed by multiple logistic regression., Result: A total of 3,337 participants born around famine were included in this study. The prevalence of early menopause was 13.1, 10.0, and 8.3% for those born before, during, and after the famine, respectively. The multiple logistic regression showed that women born before famine significantly increased the risk of early menopause compared to non-exposure (born after famine) (the fully adjusted OR = 1.463, 95%CI = 1.049-2.042). The fetal famine exposure did not significantly increase the risk of early menopause (the fully adjusted OR = 1.244, 95%CI = 0.878-1.764)., Conclusion: Long-term early childhood famine exposure, which caused chronic undernutrition at young ages, increased the risk of early menopause. Early lifetime undernutrition can be recognized as an adverse factor in female reproductive development and aging. This cohort study further confirmed the hypothesis of developmental origins of health and disease from the aspect of women's reproductive health. Further mechanism study is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Zhang and Qi.)

Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes., (© 2024 Tao et al.; Published by Cold Spring Harbor Laboratory Press.)

Summary: Background: Intrauterine overnutrition has been associated with paediatric nonalcoholic fatty liver disease (NAFLD), but the exact mechanisms involved remain unclear. Objective: To examine whether maternal fuels and metabolic markers during pregnancy are associated with offspring hepatic fat in childhood. Methods: This analysis included 286 mother–child pairs from the Healthy Start Study, a longitudinal pre‐birth cohort in Colorado. Fasting blood draws were collected in early pregnancy (~17 weeks) and mid‐pregnancy (~27 weeks). Offspring hepatic fat was assessed by magnetic resonance imaging (MRI) at ~5 years. Results: In early pregnancy, maternal triglycerides (TGs) and free fatty acids (FFAs) were positively associated with offspring hepatic fat [Back‐transformed β (95% CI): 1.15 (1.05, 1.27) per 1 standard deviation (SD) TGs; 1.14 (1.05, 1.23) per 1 SD FFAs]. Maternal total cholesterol (TC) and low‐density lipoprotein cholesterol (LDL‐C) were also associated with offspring hepatic fat, but only among boys [1.22 (1.08, 1.37) per 1 SD TC; 1.21 (1.07, 1.37) per 1 SD LDL‐C]. In mid‐pregnancy, only maternal TGs remained associated with offspring hepatic fat. Adjusting for potential confounders or mediators did not affect associations. Conclusions: Maternal lipid concentrations, especially in early pregnancy, are associated with higher offspring hepatic fat, and may, therefore, be targeted in future interventions among pregnant women. [ABSTRACT FROM AUTHOR]

When growing older, many people are faced with cognitive deterioration, which may even amount to a form of dementia at some point in time. Although neuropathological signs of dementia disorders can often be demonstrated in brains of patients, the degree to which clinical symptoms are present does mostly not accurately reflect the amount of neuropathology that is present. Sometimes existent pathology even goes without any obvious clinical presentation. An explanation for this phenomenon may be found in the concept of reserve capacity. Reserve capacity refers to the ability of the brain to effectively buffer changes that are associated with normal aging processes and to cope with pathological damage. A larger reserve capacity has been suggested to increase resilience against age-associated cognitive deterioration and dementia disorders. Traditionally, a division has been made between brain reserve, which is based on morphological characteristics of the brain, and cognitive reserve, which is based on functional characteristics of the brain. The present review discusses the premises that brain and cognitive reserve capacity are shaped by prenatal and early postnatal factors. Evidence is accumulating that circumstances during the first 1,000 days of life are of the utmost importance for the lifelong health of an individual. Cognitive deterioration and dementia disorders may also have their origin in early life and a potentially important pathway by which the early environment affects the risk for neurodegenerative diseases is by developmental programming of the reserve capacity of the brain. The basic idea behind developmental programming of brain and cognitive reserve is explained and an overview of studies that support this idea is presented. The review is concluded by a discussion of potential mechanisms, synthesis of the evidence and relevance and future directions in the field of developmental origins of reserve capacity. [ABSTRACT FROM AUTHOR]

We use newly collected individual‐level hunger recall information from the China Family Panel Survey to estimate the causal effect of undernourishment on later‐life health. We develop a two‐sample instrumental variable (TSIV) estimator that can deal with heterogeneous samples. We find a nonlinear relationship between mortality rates, a commonly used famine indicator, and the individual hunger experience. The nonlinearity in famine exposure may explain the variation in the famine's effect on later‐life health found in previous studies. We also find that exposure to hunger early in life leads to worse health among females 50 years later. This effect is much larger than the reduced‐form effect found in previous studies. For males, we find no impact. [ABSTRACT FROM AUTHOR]

When growing older, many people are faced with cognitive deterioration, which may even amount to a form of dementia at some point in time. Although neuropathological signs of dementia disorders can often be demonstrated in brains of patients, the degree to which clinical symptoms are present does mostly not accurately reflect the amount of neuropathology that is present. Sometimes existent pathology even goes without any obvious clinical presentation. An explanation for this phenomenon may be found in the concept of reserve capacity. Reserve capacity refers to the ability of the brain to effectively buffer changes that are associated with normal aging processes and to cope with pathological damage. A larger reserve capacity has been suggested to increase resilience against age-associated cognitive deterioration and dementia disorders. Traditionally, a division has been made between brain reserve, which is based on morphological characteristics of the brain, and cognitive reserve, which is based on functional characteristics of the brain. The present review discusses the premises that brain and cognitive reserve capacity are shaped by prenatal and early postnatal factors. Evidence is accumulating that circumstances during the first 1,000 days of life are of the utmost importance for the lifelong health of an individual. Cognitive deterioration and dementia disorders may also have their origin in early life and a potentially important pathway by which the early environment affects the risk for neurodegenerative diseases is by developmental programming of the reserve capacity of the brain. The basic idea behind developmental programming of brain and cognitive reserve is explained and an overview of studies that support this idea is presented. The review is concluded by a discussion of potential mechanisms, synthesis of the evidence and relevance and future directions in the field of developmental origins of reserve capacity.

Rates of chronic kidney disease (CKD) are disproportionately increased in Indigenous peoples. The focus has traditionally been on adults, as they experience the highest rates of kidney failure requiring kidney replacement therapy. The impacts of colonization, systemic racism, and sociodemographic marginalization however impact the health of Indigenous peoples across the lifespan. This review presents the social context within which Indigenous children develop and the impact relevant to kidney health across the developmental stages. In utero exposures impact nephron endowment which can manifest in glomerular hyperfiltration and sclerosis as well as an increased risk of congenital anomalies of the kidney and urinary tract. Young children are at increased risk of autoimmune conditions, secondary to infectious and environmental exposures, and are also exposed to the impacts of a Western lifestyle manifesting early onset overweight/obesity. Adolescents begin to manifest more severe metabolic complications such as type 2 diabetes. The impacts of early onset diabetes are associated with aggressive kidney complications and high rates of kidney failure in young adulthood. Finally, the key elements of successful prevention and treatment strategies are discussed including the importance of screening for asymptomatic, modifiable early disease, linked with clinical primary and tertiary care follow-up, and culturally relevant and safe care. [ABSTRACT FROM AUTHOR]

Abstract Background Males and females may experience different effects of early-life adversity on life-long health. One hypothesis is that male foetuses invest more in foetal growth and relatively less in placental growth, and that this makes them susceptible to poor nutrition in utero, particularly if nutrition is reduced part-way through gestation. Objectives Our objectives were to examine whether (1) food and/ or protein restriction in rats and mice has consistent sex-dependent effects, (2) sex-dependency differs between types of outcomes, and (3) males are more severely affected when restriction starts part-way through gestation. Data sources PubMed and Web of Science were searched to identify eligible studies. Study eligibility criteria Eligible studies described controlled experiments that restricted protein or food during gestation in rats or mice, examined physiological traits in offspring from manipulated pregnancies, and tested whether effects differed between males and females. Results Our search identified 292 articles, of which the full texts of 72 were assessed, and 65 were included for further synthesis. A majority (50) used Wistar or Sprague-Dawley rats and so these were the primary focus. Among studies in which maternal diet was restricted for the duration of gestation, no type of trait was consistently more severely affected in one particular sex, although blood pressure was generally increased in both sexes. Meta-analysis found no difference between sexes in the effect of protein restriction throughout gestation on blood pressure. Among studies restricting food in the latter half of gestation only, there were again few consistent sex-dependent effects, although three studies found blood pressure was increased in males only. Meta-analysis found that food restriction in the second half of gestation increased adult blood pressure in both sexes, with a significantly greater effect in males. Birthweight was consistently reduced in both sexes, a result confirmed by meta-analysis. Conclusions We found little support for the hypotheses that males are more affected by food and protein restriction, or that effects are particularly severe if nutrition is reduced part-way through gestation. However, less than half of the studies tested for sex by maternal diet interactions to identify sex-dependent effects. As a result, many reported sex-specific effects may be false positives.

Genetics-based studies of women with polycystic ovary syndrome (PCOS) implicate >20 PCOS risk genes that collectively account for 90% of PCOS cases. Animal models convincingly demonstrate excess fetal testosterone exposure in females as a reliable, epigenetic, developmental origin for PCOS-like traits. In particular, nonhuman primates (NHPs) provide the most faithful emulation of PCOS-like pathophysiology, likely because of close similarities to humans in genomic, developmental, reproductive and metabolic characteristics, as well as aging. Recent appreciation of potential molecular mechanisms contributing to enhanced LH action in both PCOS women (GWAS-based) and PCOS-like monkeys (DNA methylation-based) suggest commonality in pathogenic origins. This review examines the translational relevance of NHP studies to PCOS, identifying characteristics of newborn females at risk for PCOS-like traits and potential prepubertal treatment interventions to ameliorate PCOS onset.

Introduction: Midlife physical capability (PC) is associated with developmental factors in the populations of economically developed countries. As far as we know, there is no information for rural populations of low- and middle-income countries. The aim of the study was to investigate the influence of pre- and postnatal factors on midlife objective measures of PC in a 1966-67 birth cohort from a Mexican rural community. The hypothesis was that adverse developmental conditions are associated with low midlife PC.Methods: In 1966-67, a birth cohort of all children from a poor Mexican rural community was assembled. Data on family socioeconomic status (SES), parental health and nutritional status, birth weight, postnatal growth and feeding patterns were registered. In 2018, out of the 336 cohort members, 118 were living in the community, and eighty-two of them underwent a comprehensive clinical evaluation. The evaluation included grip strength, gait velocity and chair-stand PC tests. In multivariable linear models, PC tests were the dependent variables, and prenatal, birth and postnatal factors were the independent variables. Adjustment for confounding was made with adult anthropometric, body composition, clinical and ageing status variables.Results: Independent of adult health status and other ageing indicators, lower PC was associated with family organization and SES, parental nutritional status, birth weight, infant postnatal growth velocity, and weaning time. These results indicate that adverse family and environmental conditions that are prevalent in poor rural communities are associated with low midlife PC. [ABSTRACT FROM AUTHOR]

While research into the developmental origins of health and disease (DOHaD) has highlighted the potential of healthy early-life environments for later noncommunicable disease risk reduction, such research is lacking in developing contexts. This study is set in Rarotonga, Cook Islands, a small island developing state in the Pacific—population 17 434. Adult overweight/obesity rates are 89.5%/69.8% and raised blood glucose affects 23.5%. This study investigates early-life associations with later-life health by matching birth weight and adolescent health indicators in Rarotongan-born students from 2016 to 2018. Of 195 students, median age 13 years, 67.7% were overweight/obese, 45.7% had central obesity, and 42.7% had raised blood pressure. A significant inverse association was found between birth weight and central obesity (P =.043). This is the first DOHaD study in a Pacific Island country and demonstrates the importance of prioritizing investment in the early-life environment to optimize later-life health and contribute to reducing the global noncommunicable disease burden. [ABSTRACT FROM AUTHOR]

Research into associations between early life nutritional exposures and vulnerability to adult non-communicable disease (NCD) highlights the importance of maternal diet. A booklet outlining evidence-based dietary guidelines for the first 1000 days of life was first published in 2016 by early life nutrition experts for distribution to pregnant women in Australia and New Zealand. First-time New Zealand mothers' (n=9) perceptions of the booklet and its relevance for the future health of their child were explored via semi-structured focus groups and interviews. Recruitment took place via social media channels and antenatal classes around Auckland. Three major themes were identified using thematic analysis: 1. A difference in the ways mothers related to the booklet depending on their apparent level of health literacy and communication preferences; 2. A tendency for women to outsource decision-making to nutrition 'rules', rather than interpreting information to suit personal circumstances; 3. Intense pressure to comply, resulting in feelings of shame or guilt when the 'rules' were not followed. In this study, first-time mums expressed feeling under pressure to 'get it right' and identified a desire for more support from healthcare providers and society. Nutrition education is essential; however, a booklet should provide a starting point for conversation rather than a stand-alone list of recommendations. Further exploration is needed to develop a resource that can be used by health professionals working alongside women and their partners to support healthy child development. [ABSTRACT FROM AUTHOR]

Dr. Dante Cicchetti's pioneering theory and research on developmental psychopathology have been fundamental to the proliferation of research on intergenerational transmission over the last 40 years. In part due to this foundation, much has been learned about continuities and discontinuities in child maltreatment, attachment, parenting, and psychopathology across generations. Looking towards the future, we propose that this field stands to benefit from a prospective, three-generation approach. Specifically, following established prospective, longitudinal cohorts of children over their transition to parenting the next generation will afford the opportunity to investigate the developmental origins of intergenerational transmission. This approach also can address key outstanding questions and methodological limitations in the extant literature related to the confounding of retrospective and prospective measures; examination of mediators and moderators; and investigation of the roles of biology, environment, and their interplay. After considering these advantages, we offer several considerations and recommendations for future research, many of which are broadly applicable to the study of two or more generations. We hope that this discussion will inspire the leveraging of existing prospective cohorts to carry forward Dr. Cicchetti's remarkable contributions, with the ultimate aim to inform the development of preventions and interventions that disrupt deleterious intergenerational cycles.

Context: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function.Objective: To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults.Design: Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991.Setting: King Edward Memorial Hospital, Perth, Western Australia, Australia.Participants: A total of 917 participants aged 18 years from Gen2 of the Raine Study.Main Outcome Measures: Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test.Results: In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships.Conclusion: We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship. [ABSTRACT FROM AUTHOR]

Almost 2 billion adults in the world are overweight, and more than half of them are classified as obese, while nearly one-third of children globally experience poor growth and development. Given the vast amount of knowledge that has been gleaned from decades of research on growth and development, a number of questions remain as to why the world is now in the midst of a global epidemic of obesity accompanied by the "double burden of malnutrition," where overweight coexists with underweight and micronutrient deficiencies. This challenge to the human condition can be attributed to nutritional and environmental exposures during pregnancy that may program a fetus to have a higher risk of chronic diseases in adulthood. To explore this concept, frequently called the developmental origins of health and disease (DOHaD), this review considers a host of factors and physiological mechanisms that drive a fetus or child toward a higher risk of obesity, fatty liver disease, hypertension, and/or type 2 diabetes (T2D). To that end, this review explores the epidemiology of DOHaD with discussions focused on adaptations to human energetics, placental development, dysmetabolism, and key environmental exposures that act to promote chronic diseases in adulthood. These areas are complementary and additive in understanding how providing the best conditions for optimal growth can create the best possible conditions for lifelong health. Moreover, understanding both physiological as well as epigenetic and molecular mechanisms for DOHaD is vital to most fully address the global issues of obesity and other chronic diseases. [ABSTRACT FROM AUTHOR]

Aim: The main objective is to review the available evidence in the literature for developmental origins of neuropsychiatric diseases and their underlying mechanisms. We also probe emerging cutting-edge prenatal MR imaging tools and their future role in advancing our understanding the prenatal footprints of neuropsychiatric disorders.Observations: Both human and animal studies support early intrauterine origins of neuropsychiatric disease, particularly autism spectrum disorders (ASD), attention and hyperactivity disorders, schizophrenia, depression, anxiety and mood disorders. Specific mechanisms of intrauterine injury include infection, inflammation, hypoxia, hypoperfusion, ischaemia polysubstance use/abuse, maternal mental health and placental dysfunction.Conclusions and Relevance: There is ample evidence to suggest developmental vulnerability of the foetal brain to intrauterine exposures that increases and individual's risk for neuropsychiatric disease, especially the risk of ASD, depression and anxiety. Elucidating the exact timing and mechanisms of injury can be difficult and require novel, non-invasive approaches to the study emerging structural and functional brain development of the foetus. Clinical care should both emphasise maternal health during pregnancy, as well as close, continued monitoring for at risk offspring throughout young adulthood for the early identification and treatment of neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL. [Display omitted] • Single-cell network analyses define gene activity changes during B cell maturation • Systems pharmacology links B-ALL developmental origins to asparaginase sensitivity • Single-cell multi-omics reveals intra-leukemia heterogeneity in drug response • Asparaginase cooperates with venetoclax to kill B-ALL via modulating mTOR signaling Network-based analyses of single-cell transcriptomes delineate B cell differentiation and its impact on leukemia drug sensitivity. Huang et al. uncover a correlation between developmental states and asparaginase response in B cell acute lymphoblastic leukemia, highlighting intra-leukemia heterogeneity. Targeting BCL2 enhances asparaginase efficacy, suggesting a systems pharmacology approach to rational combination therapy design. [ABSTRACT FROM AUTHOR]

Abstract Background Maternal nutrition during pregnancy has life-long consequences for offspring. However, the effects of maternal overnutrition and/ or obesity on fetal growth remain poorly understood, e.g., it is not clear why birthweight is increased in some obese pregnancies but not in others. Maternal obesity is frequently studied using rodents on high-fat diets, but effects on fetal growth are inconsistent. The purpose of this review is to identify factors that contribute to reduced or increased fetal growth in rodent models of maternal overnutrition. Methods We searched Web of Science and screened 2173 abstracts and 328 full texts for studies that fed mice or rats diets providing ~ 45% or ~ 60% calories from fat for 3 weeks or more prior to pregnancy. We identified 36 papers matching the search criteria that reported birthweight or fetal weight. Results Studies that fed 45% fat diets to mice or 60% fat diets to rats generally did not show effects on fetal growth. Feeding a 45% fat diet to rats generally reduced birth and fetal weight. Feeding mice a 60% fat diet for 4–9 weeks prior to pregnancy tended to increase in fetal growth, whereas feeding this diet for a longer period tended to reduce fetal growth. Conclusions The high-fat diets used most often with rodents do not closely match Western diets and frequently reduce fetal growth, which is not a typical feature of obese human pregnancies. Adoption of standard protocols that more accurately mimic effects on fetal growth observed in obese human pregnancies will improve translational impact in this field.

Sleep-disordered breathing (SDB) worsens over pregnancy, and obstructive sleep apnea is associated with serious maternal complications. Intrauterine exposures that provoke insulin resistance (IR), inflammation, or oxidative stress may have long-term offspring health consequences. In obesity, worsening maternal SDB appears to be an exposure that increases the risk for both small- or large-for-gestational-age (SGA, LGA, respectively), suggesting distinct outcomes linked to a common maternal phenotype. The aim of this paper is to systematically review and link data from both mechanistic rodent models and descriptive human studies to characterize the impact of maternal SDB on fetal development. A systematic review of the literature was conducted using PubMed, Embase, and CINAHL (01/2000–09/2019). Data from rodent (9 studies) and human models (48 studies, 5 meta-analyses) were included and reviewed using PRISMA guidelines. Evidence from rodent models suggests that intermittent maternal hypoxia results in mixed changes in birth weight (BW) followed by accelerated postnatal growth, while maternal sleep fragmentation results in normal BW followed by later metabolic derangement. Human studies support that maternal SDB is associated with both SGA and LGA, both of which may predispose offspring to later obesity. Evidence also suggests a link between SDB, inflammation, and oxidative stress that may impact maternal metabolism and/or placental function. SDB is common in pregnancy and affects fetal growth and development. Given that SDB has significant potential to adversely influence the intrauterine metabolic environment, larger, prospective studies in humans are urgently needed to fully elucidate the effects of this exposure on offspring metabolic risk. [ABSTRACT FROM AUTHOR]

Summary: Background: Maternal obesity is associated with offspring cardiometabolic risk. UPBEAT was a randomised controlled trial of an antenatal diet and physical activity intervention in 1555 women with obesity. The intervention was associated with lower gestational weight gain, healthier diet and metabolic profile in pregnancy, and reduced infant adiposity at six months. Objective: We have investigated whether the UPBEAT intervention influenced childhood cardiometabolic outcomes or was associated with sustained improvements in maternal lifestyle 3‐years after delivery. Methods: In UPBEAT mother‐child dyads at the 3‐year follow‐up, we assessed childhood blood pressure, resting pulse rate, and adiposity (body mass index, skinfold thicknesses, body fat, waist and arm circumferences) and maternal diet, physical activity, and anthropometry. Results: 514 three‐year‐old children attended the appointment (49% intervention, 51% standard care). There was no difference in the main outcome of interest, subscapular skinfold thickness, between the trial arms (−0.30 mm, 95% confidence interval: −0.92, 0.31). However, the intervention was associated with a lower resting pulse rate (−5 bpm [−8.41, −1.07]). There was also a non‐significant lower odds of overweight/obesity (OR 0.73; 0.50, 1.08). Maternal dietary improvements observed in the UPBEAT trial, including glycaemic load and saturated fat were maintained 3‐years postpartum. Conclusion: This study has demonstrated that an antenatal dietary and physical activity intervention in women with obesity is associated with lower offspring pulse rate and sustained improvement in maternal diet. Whilst larger than previous cohorts, there remains potential for bias from attrition and these findings require validation in future cohorts. [ABSTRACT FROM AUTHOR]

Background: Males and females may experience different effects of early-life adversity on life-long health. One hypothesis is that male foetuses invest more in foetal growth and relatively less in placental growth, and that this makes them susceptible to poor nutrition in utero, particularly if nutrition is reduced part-way through gestation. Objectives: Our objectives were to examine whether (1) food and/ or protein restriction in rats and mice has consistent sex-dependent effects, (2) sex-dependency differs between types of outcomes, and (3) males are more severely affected when restriction starts part-way through gestation. Data sources: PubMed and Web of Science were searched to identify eligible studies. Study eligibility criteria: Eligible studies described controlled experiments that restricted protein or food during gestation in rats or mice, examined physiological traits in offspring from manipulated pregnancies, and tested whether effects differed between males and females. Results: Our search identified 292 articles, of which the full texts of 72 were assessed, and 65 were included for further synthesis. A majority (50) used Wistar or Sprague-Dawley rats and so these were the primary focus. Among studies in which maternal diet was restricted for the duration of gestation, no type of trait was consistently more severely affected in one particular sex, although blood pressure was generally increased in both sexes. Meta-analysis found no difference between sexes in the effect of protein restriction throughout gestation on blood pressure. Among studies restricting food in the latter half of gestation only, there were again few consistent sex-dependent effects, although three studies found blood pressure was increased in males only. Meta-analysis found that food restriction in the second half of gestation increased adult blood pressure in both sexes, with a significantly greater effect in males. Birthweight was consistently reduced in both sexes, a result confirmed by meta-analysis. Conclusions: We found little support for the hypotheses that males are more affected by food and protein restriction, or that effects are particularly severe if nutrition is reduced part-way through gestation. However, less than half of the studies tested for sex by maternal diet interactions to identify sex-dependent effects. As a result, many reported sex-specific effects may be false positives. [ABSTRACT FROM AUTHOR]

Objectives: Microchimerism is the presence of a small quantity of cells or DNA from a genetically distinct individual. This phenomenon occurs with bidirectional maternal‐fetal exchange during pregnancy. Microchimerism can persist for decades after delivery and have long‐term health implications. However, little is known about why microchimerism is detectable at varying levels in different individuals. We examine the variability and the following potential determinants of maternal‐origin microchimerism (MMc) in young women in the Philippines: gestational duration (in utero exposure to MMc), history of being breastfed (postpartum exposure to MMc), maternal telomere length (maternal cells' ability to replicate and persist), and participant's pregnancies in young adulthood (effect of adding fetal‐origin microchimerism to preexisting MMc). Materials and Methods: Data are from the Cebu Longitudinal Health and Nutrition Survey, a population‐based study of infant feeding practices and long‐term health outcomes. We quantified MMc using quantitative PCR (qPCR) in 89 female participants, ages 20–22, and analyzed these data using negative binomial regression. Results: In a multivariate model including all predictors, being breastfed substantially predicted decreased MMc (detection rate ratio = 0.15, p = 0.007), and there was a trend of decreasing MMc in participants who had experienced more pregnancies (detection rate ratio = 0.55, p = 0.057). Discussion These results might be explained by breastfeeding having lasting impact on immune regulatory networks, thus reducing MMc persistence. MMc may also decrease in response to the introduction of fetal‐origin microchimerism with pregnancies experienced in adulthood. [ABSTRACT FROM AUTHOR]

Background: Previous researched has demonstrated potent health and survival advantages across three-generations in longevity-enriched families. However, the survival advantage associated with familial longevity may manifest earlier in life than previously thought., Methods: We conducted a matched cohort study comparing early health trajectories in third-generation grandchildren (n = 5,637) and fourth-generation great-grandchildren (n = 14,908) of longevity-enriched sibships to demographically matched births (n = 41,090) in Denmark between 1973 and 2018., Results: Lower risk was observed across a range of adverse early life outcomes in the grandchildren, including infant mortality (Hazard Ratio (HR) = 0.53, 95% CI [0.36, 0.77]), preterm birth (Odds Ratio (OR) = 0.82, [0.72, 0.93]), small for gestational age (OR = 0.83, [0.76, 0.90]) and neonatal respiratory disorders (OR = 0.77, [0.67, 0.88]). Relative advantages in parental education and maternal smoking were observed in both generations to a similar degree. However, a much smaller reduction in infant mortality was observed in the great-grandchildren (HR = 0.90, [0.70, 1.17]) and benefits across other outcomes were also less consistent, despite persisting socioeconomic and behavioural advantages. Lastly, maternal, and paternal lines of transmission were equipotent in the transmission of infant survival advantages., Conclusions: Descendants of longevity-enriched sibships exhibit a broad health advantage manifesting as early the perinatal period. However, this effect is strongly diluted over successive generations. Our findings suggest that exceptional health and survival may have early developmental components and implicate heritable genetic and or epigenetic factors in their specific transmission., Competing Interests: Competing Interests: No competing interests declared.