Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019.Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed agespecific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. FindingsThe global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66-2•79) in 2000 to 2•31 (2•17-2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5-137•8) in 2000 to a peak of 139•6 million (133•0-146•9) in 2016. Global livebirths then declined to 135•3 million (127•2-144•1) in 2019. Of the 204 countries and territories included in...

BackgroundThe causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has been poorly investigated.ObjectivesThe aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning.MethodsPregnant Sprague-Dawley rats had access to drinking water containing 1 mg/L BPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet.ResultsGestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-α (CAAT enhancer binding protein alpha), PPAR-γ (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex- and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet.ConclusionsPerinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors.

The primary event in mammalian sexual development is the differentiation of the bipotential gonads into either testes or ovaries. Our understanding of the molecular pathways specifying gonadal differentiation is still incomplete. To identify the initial molecular changes accompanying gonadal differentiation in mice, we have performed a large-scale transcriptional analysis of XX and XY Sf1-positive gonadal cells during sex determination. In both male and female genital ridges, a robust genetic program is initiated pre-dating the first morphological changes of the differentiating gonads. Between E10.5 and E13.5, 2306 genes were expressed in a sex-specific manner in the somatic compartment of the gonads; 1223 were overexpressed in XX embryos and 1083 in XY embryos. Although sexually dimorphic genes were scattered throughout the mouse genome, we identified chromosomal regions hosting clusters of genes displaying similar expression profiles. The cyclin-dependent kinase inhibitors Cdkn1a and Cdkn1c are overexpressed in XX gonads at E11.5 and E12.5, suggesting that the increased proliferation of XY gonads relative to XX gonads may result from the overexpression of cell cycle inhibitors in the developing ovaries. These studies define the major characteristics of testicular and ovarian transcriptional programs and reveal the richness of signaling processes in differentiation of the bipotential gonads into testes and ovaries.

The function of pancreatic β-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ERα and ERβ, are important molecules involved in glucose metabolism, yet their role in pancreatic β-cell physiology is still greatly unknown. In this report we show that both ERα and ERβ are present in pancreatic β-cells. Long term exposure to physiological concentrations of 17β-estradiol (E2) increased β-cell insulin content, insulin gene expression and insulin release, yet pancreatic β-cell mass was unaltered. The up-regulation of pancreatic β-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ERα and ERβ agonists as well as ERαKO and ERβKO mice suggests that the estrogen receptor involved is ERα. The up-regulation of pancreatic insulin content by ERα activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

Background Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings An estimated 1•57 billion (95% uncertainty interval 1•51-1•64) people globally had hearing loss in 2019, accounting for one in five people (20•3% [19•5-21•1]). Of these, 403•3 million (357•3-449•5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430•4 million (381•7-479•6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127•1 million people [112•3-142•6]). Of all people with a hearing impairment, 62•1% (60•2-63•9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65•8% of the variation in national agestandardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2•45 billion (2•35-2•56) people will have hearing loss, a 56•1% (47•3-65•2) increase from 2019, despite stable age-standardised prevalence. Interpretation As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings. Funding Bill & Melinda Gates Foundation and WHO.