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The London Summit on Family Planning in 2012 inspired the Family Planning 2020 (FP2020) initiative and the 120×20 goal of having an additional 120 million women and adolescent girls become users of modern contraceptives in 69 of the world's poorest countries by the year 2020. Working towards achieving 120 × 20 is crucial for ultimately achieving the Sustainable Development Goals of universal access and satisfying demand for reproductive health. Thus, a performance assessment is required to determine countries' progress. An updated version of the Family Planning Estimation Tool (FPET) was used to construct estimates and projections of the modern contraceptive prevalence rate (mCPR), unmet need for, and demand satisfied with modern methods of contraception among women of reproductive age who are married or in a union in the focus countries of the FP2020 initiative. We assessed current levels of family planning indicators and changes between 2012 and 2017. A counterfactual analysis was used to assess if recent levels of mCPR exceeded pre-FP2020 expectations. In 2017, the mCPR among women of reproductive age who are married or in a union in the FP2020 focus countries was 45·7% (95% uncertainty interval [UI] 42·4–49·1), unmet need for modern methods was 21·6% (19·7–23·9), and the demand satisfied with modern methods was 67·9% (64·4–71·1). Between 2012 and 2017 the number of women of reproductive age who are married or in a union who use modern methods increased by 28·8 million (95% UI 5·8–52·5). At the regional level, Asia has seen the mCPR among women of reproductive age who are married or in a union grow from 51·0% (95% UI 48·5–53·4) to 51·8% (47·3–56·5) between 2012 and 2017, which is slow growth, particularly when compared with a change from 23·9% (22·9–25·0) to 28·5% (26·8–30·2) across Africa. At the country level, based on a counterfactual analysis, we found that 61% of the countries that have made a commitment to FP2020 exceeded pre-FP2020 expectations for modern contraceptive use. Country success stories include rapid increases in Kenya, Mozambique, Malawi, Lesotho, Sierra Leone, Liberia, and Chad relative to what was expected in 2012. Whereas the estimate of additional users up to 2017 for women of reproductive age who are married or in a union would suggest that the 120 × 20 goal for all women is overly ambitious, the aggregate outcomes mask the diversity in progress at the country level. We identified countries with accelerated progress, that provide inspiration and guidance on how to increase the use of family planning and inform future efforts, especially in countries where progress has been poor. The Bill & Melinda Gates Foundation, through grant support to the University of Massachusetts Amherst and Avenir Health.

Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.

Purpose Previous reports suggest that a complex microbiome exists within the female human breast that might contribute to breast cancer etiology. The purpose of this pilot study was to assess the variation in microbiota composition by breast side (left versus right) within individual women and compare the microbiota of normal and breast tumor tissue between women. We aimed to determine whether microbiota composition differs between these groups and whether certain bacterial taxa may be associated with breast tumors. Methods Bilateral normal breast tissue samples ( n  = 36) were collected from ten women who received routine mammoplasty procedures. Archived breast tumor samples ( n  = 10) were obtained from a biorepository. DNA was extracted, amplified, and sequenced. Microbiota data were analyzed using QIIME and RStudio. Results The most abundant phyla in both tumor and normal tissues were Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. There were statistically significant differences in the relative abundance of various bacterial taxa between groups. Alpha diversity (Simpson’s index) was significantly higher in normal compared to tumor samples (0.968 vs. 0.957, p  = 0.022). Based on unweighted UniFrac measures, breast tumor samples clustered distinctly from normal samples ( R 2  = 0.130; p  = 0.01). Microbiota composition in normal samples clustered within women ( R 2  = 0.394; p  = 0.01) and by breast side (left or right) within a woman ( R 2  = 0.189; p  = 0.03). Conclusion Significant differences in diversity between tumor and normal tissue and in composition between women and between breasts of the same woman were identified. These results warrant further research to investigate the relationship between microbiota and breast cancer.

Fentanyl and its analogues are synthetic opioids of varying potencies that are unfortunately heavily abused. Over the last 15 years, fentanyl and its analogues have contributed to the increasing prominence of hospitalisation and numerous deaths due to drug overdose. In this comprehensive literature review, the mechanism of toxicity of the drug in humans is evaluated. A systematic approach was used whereby the relevant literature has been detailed where the toxicity of fentanyl and/or its analogues to different organs/systems were investigated. Furthermore, the review covers the post-mortem toxicological data and demographic information from past fatal cases where fentanyl was believed to be involved. Such insight into fentanyl toxicity is useful as an aid to better understand the toxic doses of the drug and the suspected mechanism of action and the unexpected complications associated with overdose incidences involving the drug. Finally, the review offers an overview of the traditional and emerging test systems used to investigate the adverse effects of fentanyl on human health.

ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs2074192 placental organoids, facilitating mechanistic studies into the role of ACE2 in placental development, and the effect of fetal carriage of ACE2 rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report that ACE2 knockout results in delayed placental cell growth and increased cell death. ACE2 knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression of ACE2 mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides a new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in the carriage of the ACE2 rs2074192 gene variant.

Background Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an “at risk mental state” (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services. Methods In this study information on 338 patients aged ≤37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust. Results Over 2 years, 14 (4.1% of n  = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services. Conclusions In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available.

Estimated Modern Use (EMU) is a novel, service statistics-based indicator designed to complement Couple Years of Protection (CYP) in assessing the scale of family planning use and the first widely used metric since CYPs. Developed by the Track20 project, EMU offers a population-based proportional metric that facilitates cross-country comparisons and temporal trend analysis. By leveraging existing family planning service statistics, EMU provides a more accessible and interpretable measure of contraceptive use.The associated SS-to-EMU tool used to calculate EMU incorporates rigorous data quality review mechanisms, including data visualizations and validated review processes, to enhance the reliability and utility of family planning data for decision-making. The standardization of EMU across countries and projects promotes its integration into routine data review practices, fostering a more comprehensive approach to family planning monitoring and evaluation. Since 2014, all countries that prepare annual estimates for the FP2030 global initiative utilize the SS to EMU tool, to assess data quality and produce EMU estimates.Moreover, the EMU serves as a valuable input for the Family Planning Estimation Tool (FPET), contributing to the refinement of modeled estimates of modern contraceptive prevalence. Since its introduction, EMU has gained widespread adoption at various levels, demonstrating its effectiveness in informing global, regional, and country-level monitoring efforts. Ongoing refinements to the EMU calculation further enhance its accuracy and utility as a supplementary data source for understanding contraceptive use patterns.

Over the past two decades, pregnancy and birth trends have undergone significant shifts across Australia, the United States of America (USA), and the United Kingdom (UK), reflecting changes in societal norms, healthcare advancements, and demographic patterns. Variations in maternal age, birth interventions, and fertility rates highlight the evolving nature of reproductive behaviors and healthcare systems in these nations. The analysis reveals consistent increases in maternal age and gestational diabetes, alongside rising caesarean section rates—particularly in private healthcare settings. While perinatal mortality has declined overall, maternal mortality has increased in the USA and remains disproportionately high among Indigenous women and those in ethnic minorities in all three countries. These findings highlight the influence of structural inequities, healthcare access, and policy differences in maternal health. The review underscores the urgent need for equity-focused, culturally safe, and system-level interventions, as well as improved data collection and international collaboration to reduce preventable maternal and neonatal harms. By comparing these three regions, this review aims to provide insights into the shared challenges and unique approaches shaping childbirth practices in high-income countries in the 21st century.

Solution NMR and functional analyses reveal the 3D structure of a transmembrane reductase, the archeal CcdA, and suggest a mechanism for how these enzymes relay electrons across cell membranes. The mechanism by which transmembrane reductases use a single pair of cysteine residues to relay electrons between protein substrates across biological membranes is a long-standing mystery in thiol-redox biochemistry. Here we show the NMR structure of a reduced-state mimic of archaeal CcdA, a protein that transfers electrons across the inner membrane, by using a redox-active NMR sample. The two cysteine positions in CcdA are separated by 20 Å. Whereas one is accessible to the cytoplasm, the other resides in the protein core, thus implying that conformational exchange is required for periplasmic accessibility. In vivo mixed disulfide–trapping experiments validated the functional positioning of the cysteines, and in vitro accessibility results confirmed conformational exchange. Our NMR and functional data together show the existence of multiple conformational states and suggest a four-state model for relaying electrons from cytosolic to periplasmic redox substrates.

The annual assessment of Family Planning (FP) indicators, such as the modern contraceptive prevalence rate (mCPR), is a key component of monitoring and evaluating goals of global FP programs and initiatives. To that end, the Family Planning Estimation Model (FPEM) was developed with the aim of producing survey-informed estimates and projections of mCPR and other key FP indictors over time. With large-scale surveys being carried out on average every 3–5 years, data gaps since the most recent survey often exceed one year. As a result, survey-based estimates for the current year from FPEM are often based on projections that carry a larger uncertainty than data informed estimates. In order to bridge recent data gaps we consider the use of a measure, termed Estimated Modern Use (EMU), which has been derived from routinely collected family planning service statistics. However, EMU data come with known limitations, namely measurement errors which result in biases and additional variation with respect to survey-based estimates of mCPR. Here we present a data model for the incorporation of EMU data into FPEM, which accounts for these limitations. Based on known biases, we assume that only changes in EMU can inform FPEM estimates, while also taking inherent variation into account. The addition of this EMU data model to FPEM allows us to provide a secondary data source for informing and reducing uncertainty in current estimates of mCPR. We present model validations using a survey-only model as a baseline comparison and we illustrate the impact of including the EMU data model in FPEM. Results show that the inclusion of EMU data can change point-estimates of mCPR by up to 6.7 percentage points compared to using surveys only. Observed reductions in uncertainty were modest, with the width of uncertainty intervals being reduced by up to 2.7 percentage points.