Human Reproduction Research Articles

Advances in stem cell research have enabled the creation of embryo models that challenge existing definitions and regulatory boundaries in embryo research. The scientific community has struggled to establish a coherent nomenclature for these models, leading to confusion and sensationalism about their nature and applications. Moreover, recent publications by the Nuffield Council on Bioethics and the Ethics Committee of the European Society of Human Reproduction and Embryology have argued that embryonic models derived from stem cells are ineligible to be included in the definition of an embryo. However, some countries had already enacted legislation addressing the classification of certain models derived from stem cells as embryos prior to the issuance of these guidelines. This discrepancy engenders considerable tension among the scientific viewpoints of the countries safeguarded by these laws, with suggestions emerging from authoritative agencies. This research seeks to recognise the regulatory and ethical void created by inconsistent definitions of embryo-like entities and to advocate for a framework fostering interdisciplinary agreement in response to recent advancements. Alternatively, we aim to promote a bioethics that not only supports legislative decisions but also guarantees their validation before their implementation. We argue that without a unified interdisciplinary framework, legal structures may become fragmented, jeopardising both research integrity and public trust.

Is there a relationship between the mitochondrial activity and the meiotic progression of oocytes from germinal vesicle (GV) to metaphase II (MII) stages in young and advanced maternal age (AMA) women? Poor mitochondrial metabolism impairs the meiotic progression of human GV oocytes, contributing to a lower oocyte maturation capacity of AMA oocytes. AMA oocytes are characterized by diminished quality, mostly due to the higher rates of chromosomal segregation errors occurring during meiosis I. Another hallmark of AMA oocytes is impaired mitochondrial metabolism. Studies in mice have suggested a link between metabolic dysfunction and meiotic failure, but this relationship has not been fully elucidated in humans. Metabolic dynamics can be visualized by indirect measurements through mitochondrial staining and quantified more directly using fluorescence lifetime imaging microscopy (FLIM). This live-imaging approach can generate metabolic timelapse profiles of oocytes throughout meiosis. In the present study, we explored mitochondrial distribution and functionality in human oocytes at the GV and MII stages, obtained from young and AMA women, to establish the role of mitochondrial metabolism in meiosis progression. A total of 340 GV oocytes from young (≤34 years) and AMA (>37 years) women were included in the study. Denuded GVs were matured in vitro in G2-plus medium for 30 h. Maturation was determined by the presence of the extruded first polar body (PB1). The collected oocytes were processed for mitochondrial protein imaging (n = 80), or for live imaging (n = 171). Moreover, 89 oocytes were used for loss-of-function analysis by treating young GVs with 1 μM trifluoromethoxy-carbonylcyanide-phenylhydrazone (FCCP) for 30 min before in vitro maturation. The proteins dihydrolipoamide-S-acetyltransferase (D-LAT) and translocase-of-outer mitochondrial-membrane (TOMM20) were analyzed in young and AMA oocytes by immunofluorescence to assess mitochondrial activity and localization, respectively. Fluorescence mean intensities (arbitrary-unit, AU) were quantified with ImageJ and compared by t-test; maturation rates were compared by chi-squared test. FLIM comprehensive metabolism (NAD(P)H; FAD+) was taken at GV stage. Different FLIM parameters (fluorescence intensity, fraction bound, short/long lifetime) and the Redox ratio (NAD(P)H intensity/FAD+ intensity) were evaluated. The findings revealed that active mitochondria are specifically localized in the subcortical area, while mitochondria in general are distributed across the whole oocyte. This pattern was substantially maintained in AMA oocytes, which were in turn characterized by a lower mitochondrial activity (D-LAT intensity of 78614 ± 58534 AU in young, 12517 ± 10187 AU in AMA, P = 0.003), while a lower number of mitochondria was observed In AMA patients but the difference did not reach statistical significance (TOMM20 intensity of 61674 ± 24322 AU in young, 32186 ± 33414 AU in AMA, P = 0.195). Using non-invasive FLIM, we assessed the metabolic dynamics of maturing oocytes (Redox ratio in young 2e + 00 ± 0.15, in AMA 1e + 00 ± 0.16, P = 2.969e-05), confirming a similar pattern observed by immunofluorescence. Specifically, FLIM microscopy revealed that GV oocytes from young women slightly increased their metabolism, by 4% on average, after the GV breakdown, and the increase was very consistent across different oocytes. On the contrary, in AMA maturing oocytes, little to no increase in metabolism was observed; they were characterized instead by higher variability, and more AMA oocytes failed to successfully reach the MII stage [AMA oocytes (62.3%; 38/61) compared with young oocytes (86.3%; 63/73; P = 0.002). These differential trends observed in AMA oocytes compared to the young oocytes suggest that impaired metabolic activity significantly compromises maturation capacity, revealing a functional link between adequate metabolic levels and successful meiosis progression. Maturation rates were assessed by the presence of an extruded PB1 and variations in spindle assembly timings may have been overlooked. The quantification of mitochondrial activity in loss-of-function studies was assessed only by immunofluorescence staining. Additionally, the oocytes included in the present study were collected from women who underwent ovarian stimulation and may not faithfully recapitulate physiological maturation. Our findings demonstrate the presence of a functional link between oocyte mitochondrial metabolism and meiosis progression, which may contribute to the decline of oocyte quality with aging. Overall, we provided evidence to understand the biological mechanisms in mitochondrial metabolism that might contribute to driving the decay in oocyte quality in AMA women. This project received intramural funding from the Eugin Group and funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860960. T.S. is a former owner and former stock owner of Optiva Fertility Inc (company closed) and filed two patents for Optiva Fertility Inc (both abandoned). D.S.: Presenter EMD Senoro and Dep. Editor of Human Reproduction. All of the other authors (S.P., M.M., M.B., E.I., M.P., R.V., and F.Z.) have no conflicts of interest to declare. All of the authors contributed substantially to the manuscript and approve its submission. N/A.

Congenital genetic disorders have traditionally considered to be lifelong. An exception to this long-held view is the reversal of congenital hypogonadotropic hypogonadism (CHH). Approximately 10% of males with CHH undergo reversal with sustained hypothalamic-pituitary-gonadal (HPG) axis activation and/or fertility after discontinuing hormonal treatment. We conducted a structured, systematic literature search to identify relevant articles published on reversal of CHH in males (up to 2025). This mini-review provides a concise overview and synthesizes findings to inform clinical management of CHH. We identified 31 articles reporting reversal of CHH in males including cases of severe GnRH deficiency and individuals harboring pathogenic variants in CHH genes. Reversal is distinct from delayed puberty and olfactory phenotype (i.e., anosmia) does not predict HPG axis recovery. In males, reversal universally occurs after achieving normal serum testosterone levels on hormone therapy. Testicular growth on testosterone replacement is a hallmark of HPG axis activation - yet reversal is not always lasting. Cases exist on a continuum from normosmic individuals with severe GnRH deficiency to milder cases with partial spontaneous puberty (Pasqualini syndrome subtype). Pathogenic variants in GNRHR favor reversal while ANOS1 variants virtually exclude HPG axis recovery. The reversal phenomenon in males has expanded our understanding of the regulation of human reproduction - yet precise mechanism(s) have yet to be elucidated. Clinicians can use clinical signs and genetic testing to identify patients who may benefit from close surveillance of reversal. Insights from reversal of CHH reversal have helped shape the first tailored approach managing CHH.

The growing interest in improving the fertility-rate of livestock species, considering their high economic value, has prompted the development of new methodological approaches using male germline stem cells. Spermatogonial stem cells’ (SSCs) potential to self-renew and differentiate into mature spermatozoa holds promise for their transplantation into testicular tissue and use in new biotechnological methodologies. Moreover, SSCs’ ability to convey genetic information to the next generation is a property that could be exploited for gene targeting. The review provides an update on the main aspects of SSC biology, focusing on the genetic regulators of self-renewal and differentiation processes and different isolation methods. In addition, recent advancement in the cryopreservation of SSCs from domestic animals and their transplantation into recipients’ testes are also discussed. Finally, a section focused on canine SSCs (cSSCs), their biological aspects, and their potential clinical application in the field of reproduction is included. This represents an effective animal model for human reproduction, development, and disease, given that the reproductive anatomy and physiology of canine species and human are similar. We then report on the potential clinical transplantation of SSCs into recipient testicular tissue and suggest future topics to explore for significant advances in fertility preservation.

The influence of ambient air pollution during folliculogenesis, endometrial development, and spermatogenesis on fertility: A study among patients using vitrified donor oocyte in vitro fertilization.

Oocyte quality declines with age and metabolic stress, largely due to mitochondrial dysfunction and NAD⁺ depletion. Nicotinamide mononucleotide (NMN), a precursor of NAD⁺, has emerged as a potential intervention to restore cellular energy metabolism. This study systematically reviews preclinical evidence on NMN supplementation and integrates transcriptomic analysis of human oocytes to assess its relevance in human fertility. A systematic review was conducted following PRISMA guidelines across Medline, Embase, and Scopus (January 2015-October 2024). Seven high-quality original studies were included after screening and bias assessment. Data were synthesised through thematic analysis and pathway annotation. Additionally, single-oocyte RNA sequencing was performed on 46 human oocytes at germinal vesicle, metaphase I, and metaphase II stages to profile NAD⁺-related gene expression. Across animal models, NMN supplementation has been shown to improve mitochondrial regulation, reduce oxidative stress, and modulate apoptotic and inflammatory pathways in response to metabolic, environmental, and ageing stress. Transcriptomic analysis identified 900 differentially expressed genes between germinal vesicle and metaphase II oocytes, with significant changes in mitochondrial and oxidative stress-related genes (i.e. SIRT3, DNM1L, SOD1), aligned with NMN's known mechanisms of action. NMN supplementation shows improvements for oocyte function across diverse preclinical models. Human transcriptomic data further highlight mitochondrial and oxidative pathways as key regulatory points during oocyte maturation. Standardised protocols and clinical trials are needed to evaluate NMN's translational potential in the context of human reproduction.

Does uninterrupted culture in a time-lapse incubator with or without a commercially available machine learning embryo selection algorithm result in comparable obstetric and perinatal outcomes as interrupted culture and morphological embryo selection? The application of uninterrupted culture in a time-lapse incubator with and without the use of an embryo selection algorithm is comparable to interrupted embryo culture and morphological embryo selection in terms of obstetric and perinatal results. There is very limited evidence regarding the safety of time-lapse monitoring (TLM) from prospective randomized controlled trials (RCT). Recent RCTs have demonstrated that the application of TLM does not increase (cumulative) live birth rates or shorten the time to pregnancy within 1year. Although most studies only report pregnancy rates, the safety of this commonly used method is also relevant for decision-making. The obstetric and perinatal outcomes of patients scheduled for Day 3 single embryo transfer who participated in a multicentre RCT on TLM were studied (SelecTIMO trial). Three groups were compared: (i) TLE: embryo selection based on a commercially available Day 3 TLM algorithm, used adjunctively with morphology, and uninterrupted culture. (ii) TLR: routine morphological embryo selection and uninterrupted culture. (iii) CON: routine morphological embryo selection and interrupted culture. In total, 1731 IVF/ICSI patients undergoing their first, second, or third oocyte retrieval cycle were randomized. Obstetric and perinatal data were registered for all pregnancies occurring after fresh and frozen embryo transfers associated with the initial oocyte retrieval cycle as well as natural conceptions within 1year. Serious pregnancy complications and birth weight were considered main safety outcomes. Mean differences (MD) and age-adjusted relative risks (RRadj) and mean differences with 95% CI were calculated for TLE and TLR versus CON. A total of 827 women gave birth to a singleton during the follow-up period (TLE = 275, TLR = 278, CON = 274; P = 0.99). Of the 827 women who gave birth to a singleton, 497 deliveries originated from a fresh embryo transfer (60%), 294 from a frozen embryo transfer (36%), and 36 women conceived naturally (4%), with similar proportions in each study group. The proportion of women with serious pregnancy complications was comparable across the three groups (TLE vs CON: RRadj 0.95, 95% CI 0.65-1.40 and TLR vs CON: RRadj 1.03, 95% CI 0.70-1.50; P = 0.89). Mean (SD) gestational age at birth was 39.4 (1.9) weeks, 39.5 (1.5) weeks, and 39.3 (1.9) weeks, respectively. We found no evidence of differences in preterm and very preterm births between groups. Mean (SD) weight at birth was 3413 (588) g, 3412 (588) g, and 3377 (578) g, respectively (TLE vs CON: MD 34, 95% CI -62 to 129 and TLR vs CON: MD 32, 95% CI -635 to 120; P = 0.70). We did not observe substantial differences in babies with low and very low birth weight. Health problems immediately after delivery were reported for eight babies in the TLE group, 12 in the TLR group, and 11 in the CON group. Major congenital malformations occurred in four children in the TLE group, four in the TLR group, and seven in the CON group. Minor congenital malformations occurred in five children in the TLE group, three in the TLR group, and five in the CON group. This study reports safety outcomes for one type of time-lapse incubator, however, more systems are currently available. Our results suggest that uninterrupted time-lapse culture with and without embryo selection based on machine learning can be regarded as safe compared to interrupted embryo culture and routine morphological selection in terms of obstetric and perinatal risks. The authors received a grant from the Netherlands Organisation for Health Research and Development (ZonMw) for the execution of the SelecTIMO study (Health Care Efficiency Research programme grant 843001602). Merck (Germany and The Netherlands) supplied the six time-lapse incubators, funded the laboratory adjustments, and provided technical support and training to laboratory personnel before and during the study. D.C.K. received the Fertility Society of Australia exchange award. The following declarations of interest were made outside of the submitted work: F.B. reports additional financial support for the LUMO trial from Besins Healthcare Monaco, fellowship grants for ongoing basic research from Merck, consulting fees and payment or honoraria from Merck, Besins, and Ferring, and is member of the DSMB of the POISE study UK. J.M.J.S. has received grants or contracts from Ferring BV and Merck (payments to ETZ in both cases); consulting fees for an advisory board from Ferring BV; speakers fee from Merck BV; and support for conference attendance from Ferring BV, Merck, and Goodlife. M.v.W. is Senior Editor of Cochrane and Editor-in-Chief of Human Reproduction Update. C.B.L. reports a speakers honorarium from Organon (The Netherlands) and was Editor In Chief for Human Reproduction at the time of submitting this manuscript. NTR5423: ICTRP Search Portal (who.int).

Prognostic accuracy of clinical markers of postpartum bleeding in predicting maternal mortality or severe morbidity: a WHO individual participant data meta-analysis

Abstract STUDY QUESTION Are endometriotic lesions affecting bilateral organs or anatomical structures distributed symmetrically on both sides of the body? SUMMARY ANSWER The left-sided preponderance of pelvic endometriotic lesions, and the right-sided dominance of thoracic and inguinal lesions, suggests that endometriotic lesions exhibit a non-random, asymmetric lateral distribution. WHAT IS KNOWN ALREADY Evaluating the anatomical distribution of endometriotic lesions may elucidate the underlying pathogenic mechanism(s) of the disease. If the coelomic metaplasia or embryonic cell remnant theory is correct, a symmetrical right-left pattern would be expected. Conversely, retrograde menstruation would likely result in asymmetrical distribution, influenced by gravity, peritoneal fluid circulation and anatomical niches. STUDY DESIGN, SIZE, DURATION This systematic review with meta-analysis included full-length, English-language articles published up to 10th June 2024. Literature searches were performed in PubMed/Medline and Embase databases with the keyword ‘endometriosis’, ‘lateral’, ‘distribution’, ‘right’, ‘left’ and ‘asymmetry’. PARTICIPANTS/MATERIALS, SETTING, METHODS The review focused on anatomical structures commonly affected by endometriosis with surgically defined right or left laterality: ovaries, uterosacral ligaments, colon, ureters, inguinal regions, and hemithorax (diaphragm, pleura, lungs). Case reports were excluded. Risk of bias was assessed using ROBINS-I for non-randomised studies and a dedicated tool for case series. Meta-analyses of proportions were conducted in R. Heterogeneity was quantified using the I 2 statistic. Funnel plots for publication bias and Egger tests were performed using Stata. MAIN RESULTS AND THE ROLE OF CHANCE Of 6,356 articles screened, 154 met the inclusion criteria. A statistically significant left-sided preponderance was observed for ovarian (58%; 95% CI : 57–60%; P < 0.001), uterosacral ligament (56%; 95% CI : 54–59%; P < 0.001), ureteral (71%; 95% CI : 67–76%; P < 0.001) and bowel (72%; 95% CI : 64–79%; P < 0.001) lesions, whereas thoracic (98%; 95% CI : 96–100%; P < 0.001) and inguinal (92%; 95% CI : 83–98%; P < 0.001) lesions were predominantly right-sided. These findings were confirmed in the sensitivity analyses. Egger’s test indicated a possible small study effect only for ovarian lesions (P =! 0.012). LIMITATIONS, REASONS FOR CAUTION The preponderance of retrospective studies, the variability in surgical procedures, and the potential difficulties in accurately distinguishing unilateral from bilateral lesions may have influenced the magnitude of the estimated difference. However, the large patient cohorts, geographical diversity and consistent asymmetry across lesion types strengthen the results’ validity and generalisability. WIDER IMPLICATIONS OF THE FINDINGS The pattern of endometriotic lesion distribution, including the opposite asymmetry observed in the pelvis and upper abdomen/thorax, can be explained by factors influencing dissemination and implantation of refluxed endometrial cells. However, it cannot be explained as well by the coelomic metaplasia or embryonic cell remnant theories. This may have important clinical implications, providing a pathogenic basis for secondary prevention strategies. STUDY FUNDING/COMPETING INTEREST(S) The open access facility of this paper was funded by the Italian Ministry of Health, Current research IRCCS Ca’ Granda Ospedale Maggiore Policlinico. P.V. is a member of the Editorial Board of Human Reproduction Open, Journal of Obstetrics and Gynaecology Canada, and International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters in UpToDate. All other authors declare no conflicts of interest. REGISTRATION NUMBER CRD42024511356 (PROSPERO).

Interactive effects of Bisphenol F exposure and TLR4 rs4986790 on unexplained miscarriage.

Disclosure: S. Roberts: None. A. Fontes: None. M. Magnuson: None. H. Kim: None. R. Singh: None. K. Victoria: None. R. Carroll: None. U. Kaiser: None.Background: Transgender and non-binary individuals are presenting at increasing rates for gender-affirming care. Some of these patients desire gender-affirming testosterone therapy, which is standard of care and associated with improved mental health and quality of life. Preclinical models have largely been underutilized in transgender health. We aimed to validate a mouse model of exogenous testosterone (T) therapy in postpubertal wild type (WT) females, recapitulating the treatment paradigm in humans, to characterize the effects on the neuroendocrine control of reproduction and on metabolism. Methods and Results: Thirty WT, gonad-intact, C57BL/6 female mice at age 8 weeks were treated with weekly SC injections of testosterone enanthate, either 0.9 mg/dose (High T) or 0.45 mg/dose (Low T), or sesame oil (Vehicle; V) for 6 weeks (n=10/treatment group). An additional control group of WT, gonad-intact male mice (n=10) receiving sesame oil injections (Male V) were also generated. Weekly peak serum T concentrations were higher in the Female High T group than in the Male V group (p<0.0001); Female Low T and Male V groups were similar (p=0.84); while Female V concentrations were much lower (p<0.0001). After two weeks of treatment, serum LH concentrations were significantly lower in Female High T and Low T compared to Female V mice (p<0.0001). Additionally, mean clitoral length was significantly higher in Female Low T and High T groups, compared to Female V mice (p<0.0001). Female Low T and High T groups entered persistent diestrus by two weeks of treatment for the remainder of the treatment period. Mean body weight and body length were associated significantly with time and treatment (p<0.0001). Female High T mice demonstrated the greatest mean percent change in body weight compared to baseline. In terms of metabolic effects, serum concentrations of the sexually dimorphic adipokines, adiponectin and leptin, declined significantly at six weeks of treatment compared to baseline in Female High T and Low T groups (p<0.0001). Serum resistin concentrations declined with treatment in Female High and Low T groups compared to baseline (p<0.001). Plasminogen activator inhibitor-1 concentrations increased with treatment in Female High T mice (p=0.01). Serum IL-6 and monocyte chemoattractant protein-1 did not differ among treatment groups. Conclusions: These findings indicate, through detailed reproductive phenotyping, that exogenous T exposure in postpubertal female mice recapitulates the human phenotype of increased body weight, lack of menstrual cyclicity and clitoromegaly. The sex steroid responsive adipokines, leptin and adiponectin, decreased to levels similar to male mice. This translational model can serve to help understand mechanisms of action of T on the neuroendocrine control of reproduction in humans, as well as the metabolic consequences of T therapy.Presentation: Sunday, July 13, 2025

Disclosure: G.E. Bentley: None. A. Watanabe: None. H. Ishii: None. I. Sakata: None. S. Aizawa: None.Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that can act in the brain, the pituitary gland, and the gonads to influence reproduction and reproductive behaviors. In the brain, GnIH neurons project to GnRH-I neurons in all vertebrates studied, and GnRH-I neurons express GnIH receptor. In general, GnIH acts to inhibit activity of GnRH-I neurons. Many vertebrates, including humans and non-human primates, additionally express GnRH-II in the brain. GnIH also projects to these GnRH-II neurons, and in birds, GnIH acts on GnRH-II neurons to inhibit sexual activity. However in mammals the functional significance of this neuroanatomical interaction between GnIH and GnRH-II is not clear. The GnRH-II gene is absent or functionally inactivated in many mammals, including rats and mice, making them unsuitable models for studies on the functions of GnRH-II that might be applicable to humans. However, the musk shrew, Suncus murinus, expresses GnRH-II which can modulate food intake and acts as a permissive regulator of female reproductive behavior based on energetic status. In this study, we investigated the relative distributions of GnIH with GnRH-I and -II in musk shrews with the goal of determining whether this species is a tractable model for investigations of the roles of GnIH:GnRH-I and GnRH-II interactions on reproductive physiology and behavior. Using male and female musk shrew brains, we found GnIH immunoreactive (-ir) fibers in putative contact with GnRH-I-ir neurons in the OVLT and pre-optic area, along with putative contact with GnRH-I-ir fibers in the median eminence. Thus, neuroanatomical architecture exists in this species for GnIH to influence GnRH release. In addition, GnIH-II-ir neurons in the midbrain of both sexes receive GnIH-ir fiber input. Thus, based on neuroanatomy, GnIH is likely to influence GnRH-II release and thus sexual behaviors associated with GnRH-II.Presentation: Saturday, July 12, 2025

Abstract Background and objectives Lactation is one of the defining features of mammals, yet many humans struggle with breastfeeding. One reason for this is that humans are unique among mammals in the degree of learning and support that they require to breastfeed successfully. Despite this, we know little about how social learning impacts breastfeeding, particularly outside the influence of biomedical systems. Methodology Qualitative and systematic interviews were conducted with 128 Namibian women on infant feeding norms and practice. Structured statements were analyzed with Cultural Consensus Analysis to determine whether a single cultural model exists and identify variance in individual cultural competencies. Results Cultural consensus analysis revealed a single cultural model for breastfeeding, with strong and consistent norms and a significant role for social learning. Both learning and instinct were invoked in women’s responses, speaking to the necessary and expected role of intensive support in the early postpartum period. Women also noted steep learning curves and clear expectations about infant feeding, which led to universal breastfeeding success and clear paths for troubleshooting difficulties. Conclusions and implications The breastfeeding support that Himba mothers receive is part of the legacy of assisted reproduction in humans. However, the features of intensive teaching and learning shown here are lacking in western models of infant feeding and postpartum care. These data suggest that protracted breastfeeding difficulties may result from a mismatch between the evolved socioecology of breastfeeding and current norms and practices that hinder social learning and impair support pathways.

Yellow Fever (YF), a disease typically transmitted to humans by infected mosquitoes, is endemic to regions such as South America. Climate change plays a crucial role in exacerbating the spread of YF. We formulate a mathematical model of YF transmission with a case study of the region in the southeastern Brazil with a well documented 2017/2018 outbreak. We validate the model using historical data, then run simulations to generate projections of future outbreaks under different climate scenarios in 2050. We also evaluate the outcomes of different mitigation measures such as emergency vaccination programs. Our results suggest that under all projected climate scenarios, increasing temperatures will yield a marked increase in the total number of cases. Under RCP 8.5, the basic human infection reproduction number will increase by 11.4%, and the cumulative infections will increase by 8.1%. The model predicts a similar increase under a moderate radiative forcing scenario. The introduction of additional emergency vaccination, at a rate of 8.0% (equivalent to 60% vaccination coverage over the course of 15 weeks) of the susceptible population per week, can reduce this increase of cumulative cases to approximately 4.9%. This effect of emergency vaccines will be equivalent to alternative public health interventions to reduce the mosquito-to-human disease transmission effective contact by approximately 23.0%. Increasing temperatures and rainfall due to climate change are projected to increase YF cases. Vaccination can be an important part of integrative mitigating measures.

ABSTRACT High incidence of recurrent miscarriage (RM, recurrent abnormal early embryo loss) largely limits global human reproduction. However, it is unclear how the pathogenesis greatly restricts its effective clinical treatment. In our previous studies, we have identified a group of novel long non-coding RNAs (lncRNAs), which might regulate the occurrence of RM through unknown biological mechanisms. In this study, we confirm that a novel lncRNA, lnc-HZ14, which is highly expressed in unexplained RM vs healthy control (HC) villous tissues, is associated with RM using a new RM case-control group (n = 50). In trophoblast cellular assays, lnc-HZ14 suppresses trophoblast cell proliferation by specifically downregulating SPHK1 (sphingosine kinase 1) protein levels. In terms of mechanism, lnc-HZ14 upregulates SQSTM1/p62 protein levels, enhances its protein interactions with polyubiquitin-modified SPHK1, promotes the formation of SQSTM1-SPHK1 bodies through liquid-liquid phase separation (LLPS), and accelerates SPHK1 aggrephagy degradation. Meanwhile, lnc-HZ14 also promotes autophagy by activating ETV4-mediated transcription of ATG101 and PPP1R15A/GADD34. The cellular mechanisms are consistent with those in villous tissues of RM patients and in placental tissues of a mouse miscarriage model, excepting that there is no lnc-HZ14 homolog in mouse. As for miscarriage treatment, therapeutic upregulation of SPHK1 by treatment with phorbol 12-myristate 13-acetate (PMA), an SPHK1 agonist recovers mouse placental proliferation and alleviates mouse miscarriage. Collectively, this study shows for the first time the regulatory roles of lnc-HZ14, LLPS, and aggrephagy degradation of SPHK1 in unexplained recurrent miscarriage, uncovering novel pathogenesis and biological mechanisms of unexplained RM and also providing potential targets for treatment against miscarriage.

Endometriosis is a common estrogen-dependent inflammatory disease, yet its complex etiology is not fully understood. Endocrine Disrupting Chemicals (EDCs) exposure disrupts human reproduction, but studies on mixed EDCs and endometriosis risk are Limited. The study Analyzed 2,644 women, assessing 12 phthalates, 8 polycyclic aromatic hydrocarbons, And 6 phytoestrogens in a representative US population. Various statistical models (generalized linear model, partial least squares discriminant analysis, weighted quantile sum, quantile g-computation, restricted cubic spline) were used to explore the link between EDC exposure and endometriosis risk, with mediating effects of lipid metabolism and inflammatory biomarkers examined. Biological mechanisms were identified through an integrated strategy involving target analysis of key chemicals and endometriosis intersections, network establishment, pathway analysis, and target validation. Various statistical models revealed that the gut microbiota metabolite enterolactone (ENL) was negatively associated with endometriosis, while the PAH metabolite 1-Hydroxyphenanthrene (1-OHPHE) was positively associated. Mediation analysis showed that uric acid (UA) and ferritin (Fer) were associated with mediating pathways in the relationships between ENL And decreased risk, And 1-OHPHE and increased risk, respectively. Network and target analysis indicated that ENL affects risk via ESR1, while 1-OHPHE disturbs it through GRB2. ENL can bind to XDH, inhibiting UA production. ENL supplementation may mitigate PAH-induced risks through the PI3K-Akt pathway. In conclusion, higher ENL levels were associated with reduced endometriosis risk, while 1-OHPHE was associated with increased prevalence. Inflammatory mediators UA And Fer demonstrated potential mediating associations in these relationships. ENL levels may be associated with attenuation of 1-OHPHE associations with endometriosis, potentially through gut microbiota-related pathways. These findings emphasize the role of environmental and microbiome interactions in modulating endometriosis risk.

This article draws together science and technology studies (STS) and queer- and transfeminist theory. I argue that queer- and transfeminist STS is about more than simply adding ‘queer and trans people’ to the agenda of STS – just as feminist STS encompasses more than women* and their exclusion from, marginalization within and exploitation through science, technology and biomedicine. Through the lens of queer- and transfeminist STS, I demonstrate the potential of queering and transing assisted reproductive technologies (ART). By challenging the norms of who can reproduce and how, as well as challenging intelligible forms of life and kin-making, queer- and transfeminist STS has already produced new research perspectives and insights on ART. Taken them further with alliances and solidarities, these perspectives open up opportunities for reproduction, future technologies, policies and politics for queer and trans communities.

Caspase 1-deficient humans survive into late adulthood despite dramatically lower canonical inflammasome activity.

Background: Homocysteine (Hcy) plays a pivotal role in human reproduction, influencing gamete quality, embryo development, implantation, and pregnancy outcomes. It is central to folate and methionine metabolism and supports methylation-dependent epigenetic processes. Hyperhomocysteinemia (HHcy) exerts diverse biological effects and is associated with reproductive impairments in both sexes, affecting both spontaneous fertility and the outcome of assisted reproduction, including In Vitro Fertilization (IVF). Although the mechanisms of HHcy toxicity in reproduction are not fully understood, significant progress has been made in elucidating its effects. The emerging picture is complex, as Hcy and its metabolites impact biomolecules and cellular processes in a tissue- and sex-specific manner. Results: In men, HHcy compromises sperm deoxyribonucleic acid (DNA) integrity, methylation, and testicular microcirculation, reducing fertility potential. In women, HHcy disrupts follicular growth, oocyte competence, embryo quality, and endometrial receptivity, increasing the risk of implantation failure, miscarriage, and pregnancy complications. In assisted reproduction, HHcy and 5,10-methylenetetrahydrofolate reductase (MTHFR) variants may lower oocyte yield and embryo quality, although folate and B-vitamin supplementation can mitigate these effects. Conclusions: These effects largely reflect oxidative, inflammatory, vascular and epigenetic mechanisms, highlighting Hcy as a modifiable factor for improving natural fertility, optimizing IVF outcomes, and supporting healthy offspring development.

This study is a comprehensive review of English-language academic literature on donor anonymity in assisted reproductive technology (ART) procedures. It systematically examines arguments for and against anonymity, explores the risks associated with de-anonymization, and analyzes the motivations of recipients and donors in choosing either anonymity or openness. Psychological aspects related to these decisions, as well as the consequences of concealing a donor’s identity, are also addressed. The review highlights how technological developments, particularly the increasing accessibility of genetic testing, are reshaping social and legal attitudes toward donor anonymity. Findings indicate that absolute anonymity is no longer feasible, a trend likely to drive many countries toward adopting the principle of openness. This shift necessitates careful review of mechanisms for informing donors (and, where applicable, recipients) while safeguarding their privacy. The study provides a foundation for future empirical research to confirm or challenge these conclusions and to formulate newresearch objectives. Additionally, by synthesizing current knowledge, this review offers valuable insights for legislative bodies, regulatory agencies, medical institutions, and other stakeholders involved in ART, supporting evidence-based policymaking and practice.