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Placental extracellular vesicles express active dipeptidyl peptidase IV; levels are increased in gestational diabetes mellitus

ABSTRACTGestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy and is characterized by insulin resistance and decreased circulating glucagon‐like peptide‐1 (GLP‐1). GDM resolves rapidly after delivery implicating the placenta in the disease. This study examines the biological functions that cause this pathology. The placenta releases syncytiotrophoblast‐derived extracellular vesicles (STB‐EVs) into the maternal circulation, which is enhanced in GDM. Dipeptidyl peptidase IV (DPPIV) is known to play a role in type 2 diabetes by breaking down GLP‐1, which in turn regulates glucose‐dependent insulin secretion. STB‐EVs from control and GDM women were analysed. We show that normal human placenta releases DPPIV‐positive STB‐EVs and that they are higher in uterine than paired peripheral blood, confirming placental origin. DPPIV‐bound STB‐EVs from normal perfused placentae are dose dependently inhibited with vildagliptin. DPPIV‐bound STB‐EVs from perfused placentae are able to breakdown GLP‐1 in vitro. STB‐EVs from GDM perfused placentae show greater DPPIV activity. Importantly, DPPIV‐bound STB‐EVs increase eightfold in the circulation of women with GDM. This is the first report of STB‐EVs carrying a biologically active molecule that has the potential to regulate maternal insulin secretion.

Protein Profiling of Placental Extracellular Vesicles in Gestational Diabetes Mellitus

Throughout pregnancy, some degree of insulin resistance is necessary to divert glucose towards the developing foetus. In gestational diabetes mellitus (GDM), insulin resistance is exacerbated in combination with insulin deficiency, causing new-onset maternal hyperglycaemia. The rapid reversal of insulin resistance following delivery strongly implicates the placenta in GDM pathogenesis. In this case–control study, we investigated the proteomic cargo of human syncytiotrophoblast-derived extracellular vesicles (STBEVs), which facilitate maternal–fetal signalling during pregnancy, in a UK-based cohort comprising patients with a gestational age of 38–40 weeks. Medium/large (m/l) and small (s) STBEVs were isolated from GDM (n = 4) and normal (n = 5) placentae using ex vivo dual-lobe perfusion and subjected to mass spectrometry. Bioinformatics were used to identify differentially carried proteins and mechanistic pathways. In m/lSTBEVs, 56 proteins were differently expressed while in sSTBEVs, no proteins reached statistical difference. Differences were also observed in the proteomic cargo between m/lSTBEVs and sSTBEVs, indicating that the two subtypes of STBEVs may have divergent modes of action and downstream effects. In silico functional enrichment analysis of differentially expressed proteins in m/lSTBEVs from GDM and normal pregnancy found positive regulation of cytoskeleton organisation as the most significantly enriched biological process. This work presents the first comparison of two populations of STBEVs’ protein cargos (m/l and sSTBEVs) from GDM and normal pregnancy isolated using placenta perfusion. Further investigation of differentially expressed proteins may contribute to an understanding of GDM pathogenesis and the development of novel diagnostic and therapeutic tools.

Placental small extracellular vesicles from normal pregnancy and gestational diabetes increase insulin gene transcription and content in β cells

Abstract Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from β cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human β cell line, EndoC-βH3, to investigate their effects on β-cell function in vitro. Our results indicate that human β cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the β cells. Moreover, these vesicles up-regulated the expression of Annexin A1, a protein known to increase insulin content. This up-regulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

In vivo evidence of significant placental growth factor release by normal pregnancy placentas

AbstractPlacental growth factor (PlGF) is an angiogenic factor identified in the maternal circulation, and a key biomarker for the diagnosis and management of placental disorders. Furthermore, enhancing the PlGF pathway is regarded as a promising therapy for preeclampsia. The source of PlGF is still controversial with some believing it to be placental in origin while others refute this. To explore the source of PlGF, we undertook a prospective study enrolling normal pregnant women undergoing elective caesarean section. The level of PlGF was estimated in 17 paired serum samples from the uterine vein (ipsilateral or contralateral to the placental insertion) during caesarean section and from a peripheral vein on the same day and second day post-partum. PlGF levels were higher in the uterine than in the peripheral vein with a median difference of 52.2 (IQR 20.1–85.8) pg/mL p = 0.0006. The difference when the sampled uterine vein was ipsilateral to the placenta was 54.8 (IQR 37.1–88.4) pg/mL (n = 11) and 23.7 (IQR −11; 70.5) pg/mL (n = 6) when the sample was contralateral. Moreover, PlGF levels fell by 83% on day 1–2 post-partum. Our findings strongly support the primary source of PlGF to be placental. These findings will be of value in designing target therapies such as PlGF overexpression, to cure placental disorders during pregnancy.

Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Dysmenorrhea: a public health challenge demanding urgent attention

The mHealth clinical decision-making tools for maternal and perinatal health care in Sub-Saharan Africa: A systematic review

Introduction mobile Health (mHealth) refers to use of mobile wireless technologies for health. The potential for mHealth to enhance healthcare delivery is supported by near-universal availability of mobile phones and their expanding coverage in low- and middle-income countries. This systematic review analyses the available evidence on mHealth clinical decision-making tools in maternal and perinatal health, and whether they lead to improved maternal and perinatal health outcomes in Sub-Saharan Africa (SSA). Methods Eligibility criteria: Studies conducted in SSA describing mHealth tools piloted or used for clinical decision-making in maternal or perinatal healthcare. Exclusion criteria included mHealth tools used outside of maternal and perinatal healthcare, publications lacking sufficient detail (where information couldn’t be obtained through contacting authors), articles where tools were used on a laptop or desktop computer, and articles not published in English. Data sources: PubMed, CINAHL, EMBASE, Global Health, and Web of Science were searched for relevant articles following a predetermined search strategy with no date restrictions. A limited grey literature search was conducted. Risk of bias: We assessed the quality of included studies using the Cochrane Risk of bias 2 tool, Newcastle- Ottawa scale and COREQ. This comprehensive approach ensured a rigorous evaluation of bias and validity in our systematic review. Data extraction and synthesis: Two independent reviewers screened articles and extracted data. Results 1119 records were screened, and 36 articles met the inclusion criteria. Fifteen mHealth tools were identified across 11 SSA countries. Conclusion mHealth tools for clinical decision-making in maternal and perinatal care were found to be feasible, usable, and acceptable. They demonstrated adequate user satisfaction, and some demonstrated improvement of pregnancy outcomes. However, technologies lack scalability, with only one scaled up nationally, and few tools interacted with existing health information systems or had plans for sustainability. This review will help establish best practice for developing and scaling up mHealth clinical decision-making tools, helping to improve maternal and perinatal healthcare in SSA.

Measurement, determinants and outcomes of maternal care satisfaction in Nigeria: a systematic review

IntroductionMaternal mortality rates are unacceptably high in Nigeria. Understanding women’s satisfaction with the maternity health system is fundamental, as perceived quality of care is a determinant of service utilisation and improved birth outcomes.ObjectivesThis systematic review aims to explore patients’ satisfaction with maternal healthcare in Nigeria, examining the measurement, determinants, and outcomes of satisfaction.DesignA systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.Data sourcesSearches were conducted in Embase, Maternity and Infant Care, Global Health, Ovid, Africa Journals Online, Cochrane Central Register of Controlled Trials, MEDLINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus and Google Scholar, alongside citation searches of relevant studies.Eligibility criteriaOriginal studies assessing patient satisfaction with maternal health services in Nigeria were included. There were no restrictions on study design types. Studies were excluded if they did not clearly define how satisfaction was measured or did not focus on the maternal health service domains under review (ie, antenatal, delivery, and/or postnatal care).Data extraction and synthesisKey information relevant to this study was extracted into an Excel spreadsheet and narratively synthesised. The Quality Assessment for Diverse Studies tool was used to appraise the quality of the selected literature.ResultsMaternal care satisfaction (MCS) ratings are high in Nigeria, but this may either indicate genuine positive experiences or be influenced by measurement-related biases. Several factors determine women’s satisfaction with maternity services. Key factors influencing MCS in Nigeria are positive client-provider relationships, a favourable hospital environment with easy accessibility and affordable care costs. While our study demonstrated a correlation between MCS and socioeconomic and demographic factors, there is no complete consensus within the literature about this correlation. Furthermore, patient satisfaction was associated with women’s future health-seeking behaviour and willingness to recommend care to others.ConclusionUnderstanding the multifaceted nature of MCS determinants and outcomes can better equip us to provide the support and care that mothers need to thrive. The findings from this study can inform policy, improve health responsiveness and ensure that women are provided with satisfactory and patient-centred maternity care, hence leading to a decline in poor pregnancy outcomes in Nigeria. It also highlights the need for robust methodologies that accurately measure women’s experiences, which is essential for enhancing the quality of maternal health services.PROSPERO registration numberA protocol was developed for this study and published on PROSPERO, the International Prospective Register of Systematic Reviews (CRD42023414771).

PatchCTG: A Patch Cardiotocography Transformer for Antepartum Fetal Health Monitoring

Antepartum Cardiotocography (CTG) is a biomedical sensing technology widely used for fetal health monitoring. While the visual interpretation of CTG traces is highly subjective, with the inter-observer agreement as low as 29% and a false positive rate of approximately 60%, the Dawes–Redman system provides an automated approach to fetal well-being assessments. However, it is primarily designed to rule out adverse outcomes rather than detect them, resulting in a high specificity (90.7%) but low sensitivity (18.2%) in identifying fetal distress. This paper introduces PatchCTG, an AI-enabled biomedical time series transformer for CTG analysis. It employs patch-based tokenisation, instance normalisation, and channel-independent processing to capture essential local and global temporal dependencies within CTG signals. PatchCTG was evaluated on the Oxford Maternity (OXMAT) dataset, which comprises over 20,000 high-quality CTG traces from diverse clinical outcomes, after applying the inclusion and exclusion criteria. With extensive hyperparameter optimisation, PatchCTG achieved an AUC of 0.77, with a specificity of 88% and sensitivity of 57% at Youden’s index threshold, demonstrating its adaptability to various clinical needs. Its robust performance across varying temporal thresholds highlights its potential for both real-time and retrospective analysis in sensor-driven fetal monitoring. Testing across varying temporal thresholds showcased it robust predictive performance, particularly with finetuning on data closer to delivery, achieving a sensitivity of 52% and specificity of 88% for near-delivery cases. These findings suggest the potential of PatchCTG to enhance clinical decision-making in antepartum care by providing a sensor-based, AI-driven, objective tool for reliable fetal health assessment.

FIGO position statement on postpartum intrauterine devices (PPIUD)

AbstractPostpartum contraception is a critical intervention to address the unmet need for family planning, which affects over 218 million women globally, predominantly in low‐ and middle‐income countries (LMICs). Immediate postpartum family planning (PPFP) offers a unique opportunity to provide contraception during a crucial health‐seeking encounter, particularly given the rise in institutional births worldwide. Short inter‐pregnancy intervals are associated with increased maternal and neonatal morbidity and mortality, making timely postpartum contraception essential. The postpartum intrauterine device (PPIUD), a long‐acting reversible contraceptive (LARC), is a highly cost‐effective, non‐hormonal method with a low failure rate. It can be safely inserted immediately after vaginal or cesarean delivery, offering women a reliable and accessible option. However, successful implementation of PPIUD services requires overcoming barriers such as fragmented health services, provider bias, sociocultural misconceptions, and supply chain challenges. FIGO advocates for integrating PPFP, including PPIUD, into routine maternity care and emphasizes task sharing, community engagement, and comprehensive counseling as critical strategies. By incorporating postpartum contraception into standard maternal care, particularly in LMICs, health systems can improve maternal and child health outcomes, advance Sustainable Development Goals (SDGs), and empower women to make informed reproductive choices.

Review: The potential role of placental extracellular vesicles in blood-brain barrier disruption and neuroinflammation in preeclampsia

Preeclampsia is a complex pregnancy disorder characterized by hypertension and multisystem organ damage, notably affecting the liver, kidneys, and brain. Eclampsia, a severe form of preeclampsia, is marked by the sudden onset of generalized tonic-clonic seizures. Brain complications, including eclampsia, are responsible for 60–70 % of preeclampsia-related maternal deaths, particularly in low-income regions. Despite the significant impact of brain complications in preeclampsia, their underlying pathophysiology remains unclear. Evidence suggests that brain edema in preeclampsia and eclampsia results from disruption of the blood-brain barrier (BBB). Although direct analysis of the BBB is challenging, in vitro studies indicate that plasma from women with preeclampsia can compromise the BBB, with the specific circulating factors involved still unidentified. Among the potential culprits, recent findings highlight placental-derived small extracellular vesicles (PDsEVs) as key players in BBB disruption observed in preeclampsia. This review examines the role of PDsEVs in the pathophysiology of brain edema associated with preeclampsia, emphasizing areas for future research, including neuroinflammation and neuron dysfunction. Additionally, we discuss the protective role of magnesium sulfate in these processes.

Towards Multi-resolution Spatiotemporal Graph Learning for Medical Time Series Classification

Spectrum of congenital anomalies detected through anatomy ultrasound at a referral hospital in Ghana

Protocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect)

Endometriosis affects 10% of women worldwide and is one of the most common causes of chronic pelvic pain and infertility. However, causal mechanisms of this disease remain unknown due to its heterogeneous presentation. In order to successfully study its phenotypic variation, large sample sizes are needed. Pooling of data across sites is not always feasible given the large variation in the complexity and quality of the data collected. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) have developed an endometriosis participant questionnaire (EPQ) to harmonize non-surgical clinical participant characteristic data relevant to endometriosis research, allowing for large-scale collaborations in English-speaking populations. Although the WERF EPHect EPQs have been translated into different languages, no study has examined the cross-cultural translation and adaptation for content and face validity. In order to investigate this, we followed the standard guidelines for cross-cultural adaptation and translation of the minimum version of the EPQ (EPQ-M) using 40 patients who underwent laparoscopic surgery in Turkey and 40 women in Northern Cyprus, aged between 18 and 55. We assessed the consistency by using cognitive testing and found the EPHect EPQ-M to be comprehensive, informative, and feasible in these two Turkish-speaking populations. The translated and adapted questionnaire was found to be epidemiologically robust, taking around 30–60 min to complete; furthermore, participants reported a similar understanding of the questions, showing that common perspectives were explored. Results from the cognitive testing process led to minor additions to some items such as further descriptive and/or visuals in order to clarify medical terminology. This paper illustrates the first successful cross-cultural translation and adaptation of the EPHect EPQ-M and should act as a tool to allow for further studies that wish to use this questionnaire in different languages. Standardized tools like this should be adopted by researchers worldwide to facilitate collaboration and aid in the design and conduction of global studies to ultimately help those affected by endometriosis and its associated symptoms.

Impact of Endometriosis in Women of Arab Ancestry on: Health-Related Quality of Life, Work Productivity, and Diagnostic Delay.

Introduction: Endometriosis has a negative effect on health-related quality of life (HRQoL), wellbeing and daily functioning. Endometriosis is an under-researched condition within non-western populations. Cultural representations are needed to understand the relative roles of societal norms, traditional factors, and religious sensitivities on the impact of endometriosis on HRQoL in various populations. In particular, there is a lack of emphasis placed in understanding the association of HRQoL on endometriosis in Arab women. Method: In this prospective case-control study, 2,610 Arab ancestry women in the United Arab Emirates were recruited to investigate the impact of endometriosis on HRQoL, diagnostic delay, psychological co-morbidities, work productivity, and physical activity. Participants completed the following standardized, validated questionnaires: Short Form-36 version 2 questionnaire, the World Endometriosis Research Foundation EPHect minimum clinical questionnaire version, and Work Productivity and Activity Impairment questionnaire. Translations to the Arabic language, validated using the forward-backward translation method, of the questionnaires were utilized. Results: HRQoL scores were significantly impaired in women with endometriosis, as demonstrated in the Physical Composite Scores and Mental Composite Scores in the symptomatic control group (p = 0.001; p = 0.003, respectively) and the asymptomatic control group (p < 0.001; p < 0.001, respectively). Susceptibility and severity of multiple pain syndromes and infertility in women with endometriosis was the main indicator of lower HRQoL. Anxiety (p = 0.007) and depression (p = 0.005) were significantly associated with endometriosis, in comparison to symptomatic controls. The average diagnostic delay was 11.61 years, however single women experience 15.81 years of diagnosis delay, with approximately 18% (n = 15) of the single women experiencing more than a 20-year delay in diagnosis. The intensity of physical activity was not associated with endometriosis, when compared to symptomatic (p = 0.405) or asymptomatic controls (p = 0.144). Conclusion: For the first time, we provide evidence from a combined hospital, clinic, and population-based study that Arab women with endometriosis experience significant impacts on HRQoL, substantial diagnostic delay after the onset of symptoms, significant association to psychological disorders (anxiety and depression), and a negative impact on work productivity. Future research must focus on understanding the personal and culturally centered beliefs of Arab women to ensure a positive HRQoL trajectory by improving diagnosis and management strategies.

Predictors and trends of Caesarean section and breastfeeding in the Eastern Mediterranean region: Data from the cross-sectional Cyprus Women’s Health Research (COHERE) Initiative

Introduction Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population. Methods Using self-reported data from the representative Cyprus Women’s Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration. Results C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14–2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06–1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length. Conclusion Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

The phenotypic and genetic association between endometriosis and immunological diseases

Abstract STUDY QUESTION Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk? SUMMARY ANSWER Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis. WHAT IS KNOWN ALREADY The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank. STUDY DESIGN, SIZE, DURATION Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64 620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493–77 052 cases) were conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30–80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P = 3.25 × 10−15), rheumatoid arthritis (rg = 0.27, P = 1.5 × 10−5) and multiple sclerosis (rg = 0.09, P = 4.00 × 10−3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR = 1.16, 95% CI = 1.02–1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1). LIMITATIONS, REASONS FOR CAUTION We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results. WIDER IMPLICATIONS OF THE FINDINGS Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions. STUDY FUNDING/COMPETING INTEREST(S) We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

Pre-oviposition development of the brown anole (Anolis sagrei).

BACKGROUND: The brown anole, Anolis sagrei, has emerged as a representative squamate species for developmental studies during the past decades. Novel functional tools have been established to manipulate embryogenesis through genome editing or the introduction of small molecule inhibitors, and their effective use requires a thorough understanding of early anole embryogenesis. To enable precise and reproducible staging of anole embryos, we need knowledge of the progression of anole embryogenesis and morphogenesis. While post-oviposition development has been described, the pre-oviposition period remains to be explored. RESULTS: We provide the first staging series of pre-oviposition development for the brown anole. Analyzing the follicles and embryos through brightfield imaging, SEM, STEM, histology, and DAPI staining, we define 26 distinct developmental stages. Furthermore, we followed heart development, neural crest cell migration, and central nervous system development using immunofluorescence analyses and provide new comparative insights into the morphogenesis of each of these organ systems. CONCLUSIONS: Our dataset reveals that peri-gastrulation morphogenesis up to the initiation of neurulation diverges significantly from chick, the common representative model of reptile embryogenesis. With this study, we establish the brown anole as a squamate model organism for cross-clade evolutionary studies of early embryogenesis.

A core outcome set for future male infertility research: development of an international consensus

A core outcome set for future male infertility research: development of an international consensus

Abstract STUDY QUESTION Can a core outcome set be developed through a global consensus to standardize outcome selection, collection, comparison, and reporting in future male infertility trials? SUMMARY ANSWER A minimum dataset, known as a ‘core outcome set’, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential interventions for male infertility. WHAT IS KNOWN ALREADY Numerous factors, including a failure to consider the perspectives of men with lived experiences of infertility or their partners when developing and conducting RCTs can limit their clinical utility. Selection of outcomes, variations in outcome definitions, and the selective reporting of outcomes based on statistical analysis make the results of infertility research challenging to interpret, compare, and implement. For male infertility, this is further compounded by there being potentially three participants, the male, their female partner, and any offspring born, all with outcomes to be reported. This has led to significant heterogeneity in trial design and reporting. While a core outcome set for general infertility trials has been developed, there is no such outcome set for male infertility trials. STUDY DESIGN, SIZE, DURATION A two-round Delphi survey (334 participants from 39 countries) and consensus development workshops (44 participants from 21 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, researchers, and men and women with infertility were brought together in a transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE The core outcome set for male infertility trials has been developed by the inclusion of specific male-factor outcomes in addition to the general infertility core outcome set. These outcomes include assessment of semen using the World Health Organization recommendations for semen analysis; viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancies); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Although not a requirement as part of the core outcome set, other outcomes were identified as potentially useful in certain study settings. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods in this work, which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes, which are inconsistently reported at present. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set for male infertility trials. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by The Urology Foundation, Small Project Fund awarded to Michael P Rimmer at the University of Edinburgh, UK. RTM was supported by a United Kingdom Research and Innovation (UKRI) Future Leaders Fellowship (MR/Y011783/1). C.L.R.B. is the co-editor in chief of Human Reproduction and recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. R.P.B. receives royalties from Flow diagnósticos. M.L.E. is an advisor to the companies Hannah, Illumicell, Next, Legacy, Doveras, Vseat and received a consultancy fee for this. B.W.M. is a paid consultant for Norgine and Organon and has received research funding from Ferring and Merck, he also receives consultancy and travel support from Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. has been an associate editor with Human Reproduction Open. K.Mc.E. received funding to attend Fertility 2025 by the British Fertility Society and is the Chair of the British Fertility Society. He is a member of the HFEA’s Scientific and Clinical Advances Advisory Committee and a Committee Member of the NICE Fertility Problems Guideline Group. M.H.V.L. receives consultation fees for the WHO Manual Spanish translation, and travel expenses for the ESHRE MRHI meeting in Budapest. She is a member of the editorial board for Fertility & Sterility, F&S Science, Human Reproduction, and Frontiers in Endocrinology. She is also a panel member of the World Health Organization (WHO) Human Reproduction Programme (HRP) Research Project Review Panel. R.S.M. is a member of the NICE Guideline Committee on Fertility and former chair of the British Fertility Society. A. Perheentupa receives an honoraria for lecturing from Merck for the Tackling Infertility manifest, Gedeon Richter & Ferring. A. Perheentupa declares lecture honoraria from Merck, Gideon Richter, and Ferring; and payment from Merck for the Tackling Infertility manifesto. A. Pacey receives consultancy fees for Carrot Fertility and Cryos International as well as lecturing for IBSA Institut Biochimique SA and Mealis Group—all fees paid to The University of Manchester. He is also a Trustee of Progress Educational. Trust (Charity Number 1139856) and Chairman of UKNEQAS Reproductive Sciences Advisory Committee. F.T. is the recipient of a Bayer research grant, as well as DFG Clinical Research Unit ‘Male Germ Cells’ (CRU326, project number 329621271) and BMBF Junior Scientist Research Centre ‘ReproTrack.MS’ (grant 01GR2303), he has received travel support from IBSA and Organon. M.v.W. is the Editor-in-Chief of Human Reproduction Update. R.W. is a former Deputy Editor of Human Reproduction and is currently a Deputy Editor of Human Reproduction Update. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586.