Original research publications

Adipose tissue (AT) dysfunction can lead to increased visceral AT (VAT) and metabolic damage. The adiponectin/leptin ratio (ALR) has been proposed as a biomarker of AT functionality. However, its participation in VAT accumulation and the impact of sex on these associations have not been evaluated. In an analytical cross-sectional study, 54 adults (29 male, 25 postmenopausal females, aged 30-70 years, BMI 19-31 kg/m 2 ) were analysed. Anthropometric data, fasting serum samples, and subcutaneous AT (SAT) biopsies were obtained. Morpho-functional AT characteristics included ALR, adipocyte size, macrophage content and AT insulin resistance (ADIPO-IR). Using multivariate and mediation models, we evaluated the associations of SAT characteristics with systemic IR (TyG index), systemic inflammation (C-reactive protein), and VAT area. In postmenopausal females, ALR was inversely associated with adipocyte size, macrophage number, TyG index, CRP, and VAT area. SAT inflammation and ADIPO-IR were independently associated with VAT, and a mediation model suggested ALR as a possible precursor of VAT. Among males, ADIPO-IR and ALR were independently associated with VAT. These findings emphasize the importance of considering sex differences in the prevention and treatment strategies for metabolic diseases among Mexican-Mestizo populations, although these results should be confirmed by prospective studies.

To examine sex differences in care-seeking when afflicted by an acute myocardial infarction (AMI). This was a cross-sectional study in the region of Stockholm, Sweden. All patients from the Swedish national registry SWEDEHEART who were hospitalized due to an acute myocardial infarction in Stockholm, between March and June 2020, were asked to participate. A self-administered questionnaire Patients' appraisal, emotions, and action tendencies preceding care-seeking in acute myocardial infarction' (PA-AMI) including demographical questions, was sent out via mail, which was answered by a total of 326 participants. Additional variables for each participant were obtained from SWEDEHEART. There were no differences between women and men regarding patients' thoughts, feelings, and actions prior to care-seeking, as well as the time from symptom onset to care-seeking, both the patients' own assessed time, and the times reported to SWEDEHEART. However, the results shows that both women and men experience a high degree of uncertainty when afflicted by an AMI. Our results indicate that there are no significant sex differences in care-seeking patterns when afflicted by an AMI. Regardless of sex, AMI is associated with a high level of uncertainty among patients. To address this uncertainty and improve timely care, it is crucial to implement enhanced educational initiatives at both the individual and community levels. These efforts should focus on increasing awareness of the diverse symptom presentation of AMI and emphasize the critical importance of seeking immediate medical attention. Such interventions could help reduce delays in care and improve patient outcomes. The results of this study indicate that there are no significant sex differences in care-seeking patterns when afflicted by an AMIRegardless of sex, AMI is associated with a high level of uncertainty among patientsThis uncertainty is also shown when calling the medical health care service to get advice.

In this retrospective study, we applied unsupervised learning techniques to electronic medical records from the University of California, San Francisco (UCSF) to characterize Alzheimer's disease (AD) comorbidity patterns. Given the well-known female predominance in AD, we performed sex-stratified analyses to explore differences in comorbidity patterns based on sex. Findings were evaluated using an independent UC-wide dataset. Among 8,363 patients in the UCSF dataset, we observed five data-driven comorbidity clusters related to cardiovascular conditions, gastrointestinal disorders, and frailty-related conditions such as pneumonia and pressure ulcers, as well as groups with higher and lower overall comorbidity burden. Sex-stratified analyses within clusters identified variation in comorbidity patterns, including circulatory diseases in males in cluster 2 and bladder stones in females in cluster 3. Key results demonstrate partial consistency in the UC-wide dataset. Our study provides a structured characterization of comorbidity heterogeneity in AD and highlights sex-related differences, though findings should be interpreted as descriptive and hypothesis-generating.

Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male-to-female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry-based proteomics, comprising 47 female and 45 male tumors from treatment-naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex-associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in EAC. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y-chromosome-encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune-related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival specifically in male patients, with no significant association detected in the combined or female-only cohort. Proteome-wide survival analyses further demonstrated distinct sex-specific prognostic landscapes. Our study provides the first comprehensive characterization of sex-associated proteomic differences in EAC. Sex shapes immune-related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex-differential, complement-associated protein with adverse prognostic significance in male patients, highlighting sex as a biologically and clinically relevant variable in EAC.

Binge drinking continues to pose major societal and health challenges. Understanding the molecular mechanisms that drive problematic alcohol use is critical for developing novel therapeutics. Parvalbumin-expressing interneurons (PV-INs), a key subpopulation of interneurons within the prefrontal cortex (PFC) and other brain areas, have been implicated in a variety of alcohol-seeking behaviors. Recent work has identified the metabotropic glutamate 5 (mGlu 5 ) receptor as a critical sex-specific regulator of PV-IN activity. Genetic deletion of mGlu 5 from PV-INs alters PFC-dependent cognitive behaviors and sex-specifically decreases volitional ethanol intake, but its role in motivated drinking remains unknown. Here, we use operant self-administration to examine how disruption of mGlu 5 in PV-INs alters motivated drinking. Under a fixed ratio schedule, PV-mGlu 5 -/- mice show impairments in the acquisition of ethanol self-administration. By contrast, PV-mGlu 5 -/- mice readily acquire sucrose self-administration, suggesting a specific deficit to ethanol reinforcement. With sucrose administration, we found that males produced more active nosepokes and consumed more sucrose than females, an effect attenuated in male PV-mGlu 5 -/- mice. Using a fading procedure, mice were gradually transitioned to respond for 20% ethanol. Following the fade, male wildtypes maintained elevated responding relative to females and to male PV-mGlu 5 -/- mice. Progressive ratio and quinine adulteration suggest that these sex- and genotype-dependent effects reflect differences in motivation rather than altered taste sensitivity. Finally, we found that PV-mGlu 5 -/- mice displayed reduced expression of perineuronal nets and PV protein, with a greater disruption in males than females. Together, these data highlight mGlu 5 receptors and PV-INs as critical regulators of motivated drinking.

Medical research historically underrepresented women, often generalizing findings from men to women. Sex-specific analyses could enhance guideline accuracy and support personalized care. Electroconvulsive therapy (ECT) is highly effective in major depressive disorder (MDD), however research regarding the impact of sex on ECT efficacy is scarce. This study aimed to explore sex differences in ECT outcome and clinical variables associated with ECT outcome to replicate and extend previous research. Clinical data from sites participating in the Dutch ECT Consortium. Remission was defined as a post-ECT Hamilton Depression Rating Scale (HDRS) score of 7 points or below. Clinical variables influencing ECT outcome were selected based on prior research. Data included 1892 MDD patients (N = 1210 women), with a mean age of 59.5 years. Remission rate did not differ among sexes (χ 2 (1) = 2.0, p = 0.17). We observed significant sex-related interaction effects for duration of index episode (χ 2 (1) = 4.36, p = 0.04) and for failed psychotherapy in the current episode (χ 2 (1) = 4.56, p = 0.03). Women's remission rates remained stable regardless of episode duration, while men's remission likelihood decreased with longer episodes. Women treated with prior evidence-based psychotherapy showed lower remission rates than men. This study highlights that ECT is equally effective for both men and women. The tentative sex-related interaction effects are of clinical interest though modest in size. Clinicians must understand sex differences in ECT outcomes and the potential for sex-specific side-effects to make a fully informed decision.

Obesity-related skeletal muscle atrophy poses a significant health burden, with marked sex differences in this condition. However, the mechanisms underlying these sex differences remain poorly understood. This study investigated whether and to what extent skeletal muscle quality was impaired in C57BL/6 mice fed a high-fat, high-cholesterol (HFHC) diet, focusing on sexual dimorphism. Male and female mice were assigned to control or HFHC groups for 40 weeks. The results showed that both sexes fed the HFHC diet developed obesity and dyslipidemia, with males exhibiting a more severe phenotype. Notably, males experienced more pronounced obesity-induced muscle atrophy than females. This study further revealed that HFHC feeding disrupted physiological homeostasis in both sexes, leading to sexual dimorphism in gut microbial composition and short-chain fatty acid levels, with males displaying a diminished capacity to maintain metabolic homeostasis. Furthermore, males exhibited more severe mitochondrial dysfunction and higher oxidative stress levels compared to females, manifesting as reduced muscle strength and upregulated atrophy-related gene expression. Collectively, these findings indicate that long-term HFHC feeding disrupts gut microbiota and glucolipid metabolic homeostasis, further impairing mitochondrial function and exacerbating muscle atrophy preferentially in males, whereas females are relatively protected through superior maintenance of physiological homeostasis, resulting in milder muscle atrophy.

Sex differences in anxiety-like behavior are influenced by gonadal steroids, yet the contribution of early postnatal androgen signaling and testosterone metabolic pathways to the long-term organization of these behaviors remains unclear. Wistar male and female rats received daily s.c. injections from postnatal day (P) 1 to P5 of vehicle, flutamide, letrozole, or finasteride. In young adult animals, locomotor activity and anxiety-like behavior were evaluated via the open field test (OFT) and elevated plus maze (EPM). Females showed higher locomotor activity than males in both tests. Control females showed a less anxiety-like profile than control males in the EPM. Flutamide treatment abolished sex differences in EPM open-arm anxiety-related measures and increased the number of freezing episodes and their duration in the OFT. However, finasteride treatment preserved the sex differences observed in the control groups in anxiety-like measures. Finally, aromatase inhibition abolished sex differences in anxiety-like behavior and induced an anxiolytic-like effect in males, as indicated by increased open-arm entries relative to control males. These findings indicate that androgen-related pathways during early postnatal life shape adult anxiety-like behavior in a sex-dependent and pathway-dependent manner and highlight aromatization as a key mechanism in the organization of EPM behavioral outcomes in males.

Cardiovascular (CV) dysfunction is common in severe acute pancreatitis (AP) and contributes substantially to mortality. Although sex differences in CV diseases are well recognized, with males generally exhibiting higher risk and poorer outcomes, their influence on AP-associated CV responses remains poorly defined. Here, we examined sex-dependent alterations in vascular integrity and cardiac function using cerulein-induced mouse models of AP. Because obesity is associated with more severe forms of AP, cerulein was used to induce mild AP in lean wild-type C57BL/6J mice and a more severe phenotype in obese C57BL/6J mice. Across both models, pancreatic injury was comparable between sexes. A modest sex difference in vascular permeability was observed in the mild but not severe AP model. In mild AP, both males and females showed similar compensatory increases in cardiac systolic function; however, in severe AP, only female mice maintained this adaptive systolic augmentation. Circulating levels of free fatty acids, reflecting systemic tissue lipolysis, were lower in females. Impaired cardiac adaptation in males was accompanied by higher levels of seven different myocardial inflammatory cytokines, as well as elevated circulating levels of angiopoietin-2 (Angpt2). Although Angpt2 levels correlated with the severity of cardiac dysfunction, Angpt2 neutralization did not improve and indeed worsened, cardiac function in males. Together, these findings delineate both sex-dependent and sex-independent CV responses in mild and severe AP and identify Angpt2 as a potential compensatory cardioprotective factor under obesity-associated severe AP. NEW & NOTEWORTHY Cardiovascular responses exhibited both sex-dependent and sex-independent alterations in acute pancreatitis models of differing severity. In cerulein-induced mild acute pancreatitis, both sexes showed enhanced cardiac systolic function with only modest differences in vascular permeability. In severe acute pancreatitis, vascular permeability was similar between sexes, but compensatory cardiac systolic augmentation was preserved only in females. Angiopoietin-2 was identified as a compensatory cardiac mediator in severe disease.

Sex-based differences in chronic obstructive pulmonary disease (COPD) outcomes are well documented, but sex disparities in the delivery of evidence-based, guideline-recommended care remain insufficiently understood. We aimed to compare the receipt of guideline-recommended COPD care between females and males in a national U.S. We performed a retrospective cohort study using national Veterans Health Administration data among individuals with ≥2 encounters with ICD-9 or ICD10 for COPD between 2012 and 2020. We compared receipt of guideline-recommended COPD care among females vs. males. Outcomes included diagnostic confirmation via spirometry, maintenance inhaler prescription and tobacco cessation interventions. Females and males were age-matched at a 1:4 ratio. We used multivariable logistic regression to assess the associations between odds of receiving guideline-recommended COPD care for females vs males, adjusting for age, race/ethnicity, Charlson Comorbidity Index, and Social Vulnerability Index. Among 882,292 individuals with COPD, 34,645 (3.9%) were females. After 1:4 age matching, the final analytic cohort included 173,225 individuals (34,645 females and 138,580 males). In adjusted analyses, females had higher odds of receiving confirmatory spirometry (aOR 1.24 [95%CI: 1.21-1.27]) and tobacco cessation intervention (aOR 1.23 [95%CI: 1.20-1.27]) compared to males; females had lower odds of receiving maintenance inhaler prescriptions (aOR 0.86 [95%CI: 0.84-0.89). Both female and male patients experience suboptimal receipt of guideline-recommended COPD care in this national cohort. However, females more frequently received spirometry and tobacco cessation but less maintenance inhaler therapy than males, underscoring the need for targeted strategies to address these gaps and ensure equitable, guideline-based care for all.

Previous studies have reported sex-based disparities in care, often disadvantaging women. Large registry analyses are limited by incomplete characterization of out-of-hospital cardiac arrest OHCA aetiology and coronary angiography (CAG) findings. We aimed to evaluate sex differences in management and outcomes among patients with angiographically confirmed obstructive coronary artery disease (CAD) following OHCA. We performed a post hoc analysis of consecutive adult OHCA patients with angiographically confirmed obstructive CAD admitted between 2012 and 2023 using a prospective OHCA registry. Obstructive CAD was defined as ≥70% coronary stenosis identified by coronary angiography and considered the most likely cause of OHCA. The primary outcome of this analysis was 30-day survival. The secondary outcome was favourable neurological outcome at hospital discharge. Multivariable logistic regression was used to assess the independent association between sex and 30-day survival. Among 1219 OHCA admissions, 634 (52%) patients had angiographically confirmed CAD, and 580 (91.5%) were included in the final analysis (median age 61 years, 15.3% women). ST-segment elevation myocardial infarction was the predominant aetiology in both groups (64% in women vs. 59.9% in men). Men more frequently had a history of CAD and prior myocardial infarction. No significant sex-related differences were observed in PCI utilization, procedural success, targeted temperature management, or extracorporeal cardiopulmonary resuscitation use. Thirty-day survival was 66.2% in women and 61.5% in men (log-rank p = 0.33), while favourable neurological outcome (Cerebral Performance Category 1-2) occurred in 55.1% and 53.8%, respectively ( p = 0.82). Men more frequently exhibited multivessel CAD, whereas women more often had identifiable culprit lesions. In multivariable analysis, sex was not significantly associated with 30-day survival (adjusted OR 0.75, 95% CI 0.39-1.41, p = 0.37). In this cohort of patients with angiographically confirmed obstructive CAD following OHCA, no statistically significant sex-related differences were observed in management, procedural success, 30-day survival, or neurological outcomes. Men exhibited more extensive CAD.

Central Europe carries a substantial global burden of ischaemic heart disease (IHD). We aimed to quantify sex-specific differences in IHD case-fatality across 13 Central European countries and to examine the contribution of metabolic, behavioural, and dietary risk factors to these disparities. We analysed Global Burden of Disease (GBD) data on IHD from 1990 to 2023 across 13 Central European countries. Population-level case-fatality was assessed using sex-specific age-standardised mortality-to-prevalence ratios (MPRs). Mortality attributable to specific risk factors was normalised to prevalence to derive a case-fatality index (CFI). Z-scores (≥1.96) quantified the significance of sex differences. Associations with gross national income (GNI) per capita were evaluated using Pearson correlation. In 2023, there were 6.71 million prevalent IHD cases in the region, of whom 3.01 million (44.8%) were women. From 2011 to 2023, regional MPRs declined from 4.49% to 4.37% in men (2.6% relative decrease) and from 4.59% to 4.42% in women (3.7% relative decrease). However, statistically significant sex disparities persisted in 2023: women had higher MPRs in Croatia (Z = 5.55), Serbia (Z = 2.55), and Czechia (Z = 2.18), whereas men had higher MPRs in Poland (Z = -2.55). Higher GNI per capita was associated with lower MPRs (r = -0.76; p = 0.003). Elevated systolic blood pressure and physical inactivity were prominent (Z > 1.96) contributors to excess female case-fatality, while tobacco use disproportionately (Z > 2.58) affected men, particularly in Poland. Dietary risks contributed to sex disparities: women demonstrated higher CFIs for low intake of fruits, nuts/seeds, vegetables, and seafood omega-3 in several high-disparity countries, while male excess was limited to high sodium and low whole-grain intake in isolated settings. Despite overall improvements, significant sex inequalities in IHD case-fatality persist in Central Europe. Differential burdens of metabolic, behavioural, and dietary risks are associated with these disparities, underscoring the importance of sex-specific and country-specific prevention approaches to reduce avoidable cardiovascular mortality. None.

The perinatal period is marked by heightened vulnerability to maternal depression and anxiety symptoms, which have been associated with early child socio-emotional development, including difficult temperament. This longitudinal study investigated whether prenatal maternal depression and anxiety symptoms predicted infant difficult temperament at 12 months through parallel mediation by postnatal maternal symptoms and perceived partner support. Given emerging evidence on sex differences in the associations between prenatal maternal distress and early socio-emotional development, exploratory multi-group analyses by child sex were also conducted. Pregnant individuals were recruited (October 2020-September 2022) for the Resilience and Perinatal Stress during the Pandemic (RESPPA) study in Quebec, Canada. Measures included the EPDS, GAD-7, ICQ, and perceived partner support assessed via self-reported online questionnaires. Path analyses (N = 1422) were conducted using data from the third pregnancy trimester (T1), three months postpartum (T2), and 12 months postpartum (T3). Separate models were estimated for depression and anxiety symptoms. Greater prenatal depression symptoms predicted higher infant difficult temperament scores, with postnatal depression symptoms and perceived partner support fully mediating this association. Similar findings emerged for anxiety. No significant sex differences were observed. Findings highlight postnatal maternal depression and anxiety symptoms and perceived partner support as potential screening and intervention targets to promote infant development.

Antipsychotics are the mainstay of schizophrenia treatment, but their efficacy and tolerability might differ between females and males, and previous evidence on sex differences has been inconsistent and methodologically limited. We aimed to evaluate sex differences in the efficacy, acceptability, and tolerability of antipsychotics in adults with acute schizophrenia. We performed individual participant data pairwise, dose-response, and network meta-analyses of antipsychotics versus placebo or another antipsychotic, using data from the Vivli and YODA trial data-sharing platforms (inception to April 9, 2025); the main analyses were restricted to fixed-dose trials. The primary outcome was overall symptoms on the Positive and Negative Syndrome Scale at week 6 (or closest). Secondary outcomes included all-cause dropout and other efficacy and tolerability outcomes. We performed one-stage pairwise meta-analyses to quantitatively test sex-treatment interactions, and two-stage sex-stratified dose-response and network meta-analyses to visually examine potential sex differences. Credibility of effect modification was assessed with the Instrument to assess the Credibility of Effect Modification Analyses. People with lived experience were involved in planning and interpretation of the study. This study was registered with PROSPERO, CRD420251022957. We identified 33 eligible trials; 18 fixed-dose trials with 7062 participants (2168 females and 4894 males; of 5161 with race reported, 2954 White, 1187 Black, 752 Asian, and 268 of other or unspecified race; mean age 40·9 years; receiving haloperidol, olanzapine, paliperidone, risperidone, or placebo) were included in the main analyses. There was no evidence of sex differences in drug effects on overall symptoms (difference of standardised mean difference [DoSMD] 0·04, 95% CI -0·09 to 0·18). Dose-response curves were similar in females and males, plateauing at 3-5 mg risperidone equivalents, and the network meta-analysis showed no clear sex-specific treatment effects. Antipsychotics reduced all-cause dropout more in females than in males (ratio of odds ratios 0·74, 95% CI 0·56-0·98; moderate credibility). Prolactin increase was greater in females (DoSMD 0·83, 0·67-0·99; high credibility); other tolerability outcomes showed no clear sex difference. We found no evidence of sex differences in the efficacy or overall adverse event profiles, and no different dose-response relationships, for the drugs studied. However, we found some evidence that, among females, antipsychotics reduce all-cause dropout more, and increase antipsychotic-induced prolactin elevation versus placebo, as compared with males. Overall treatment efficacy estimates from previous meta-analyses are relevant to both sexes. To promote sex and gender equity, female participation in clinical trials and sex-stratified reporting should be encouraged. German Federal Ministry of Research, Technology and Space.

Whether female lifespan advantage is maintained among people with virologically suppressed HIV is unclear. Localized cohorts with demographically similar women and men may reveal associations obscured nationally. We estimated sex differences in life expectancy among people with HIV (PWH) in the Bronx, NY, after first achieving sustained virologic suppression. Among PWH receiving care in Montefiore Health System in the Bronx, NY who achieved sustained virologic suppression for ≥1 year (1997-2021), follow-up began at the end of the earliest qualifying window (index date) and ended at death or 2023. A Poisson model estimated mortality rate ratios by age, sex, race/ethnicity, HIV acquisition category, CD4+ T-cell count, and health insurance at the index date; age-specific mortality rates estimated remaining life-years for a 30-year-old using Chiang's life table method. PWH (n = 9999; 4075 [41%] women, 8392 [84%] Black or Hispanic) were followed for a median of 10.7 years; 2675 (27%) died. Men had 32% higher mortality risk than women (rate ratio: 1.32; 95% CI: 1.21-1.43). Compared to Black (non-Hispanic) PWH, Hispanic PWH had 19% lower mortality risk (RR: 0.81; 95% CI: 0.74-0.88), while those with White or other/unknown race/ethnicity had higher mortality risk. Among PWH with public insurance and CD4+ T-cell count ≥500 cells/μL, remaining life-years at age 30 were 45 and 41 for Hispanic women and men with heterosexual acquisition, 42 and 38 for Black women and men with heterosexual acquisition, and 44 and 41 for Hispanic and Black men with MSM acquisition. Women with HIV in the Bronx after sustained virologic suppression lived approximately 4 years longer than comparable men, approaching sex differences in the general population. Local, disaggregated population analyses may help clarify sex differences in longevity among PWH, thereby informing clinical and public health priorities. NIH.

Fecal microbiota transplantation (FMT) shows potential in promoting hematopoiesis, with efficacy influenced by donor sex. However, its role in radiation-induced thrombocytopenia (RIT) and its sex-specific effects remain unclear. While inulin may enhance FMT efficacy, this has not been explored in the context of RIT. We established an irradiation-induced thrombocytopenia (RIT) model in male and female mice via 4 Gy X-rays exposure. FMT was administered orally as a fecal suspension. Platelet recovery was monitored via hematology analyzer, megakaryopoiesis was assessed by flow cytometry and H&E staining; gut microbiota changes were evaluated by 16S rRNA sequencing. Sex-matched FMT accelerated platelet recovery and promoted megakaryocyte production in the bone marrow and spleen only in female mice, accompanied by an increase in Akkermansia abundance. Furthermore, transplanting feces from female donors also accelerated platelet recovery in irradiated male mice, whereas feces from male donors does not. INU selectively enriched probiotic colonization, thereby fostering a favorable microbial structure that enhanced FMT efficacy. The sexually dimorphic gut microbiota contributes to sex-specific FMT efficacy in alleviating radiation-induced thrombocytopenia, which can be further amplified by inulin. This study offers sex-specific microbial therapy for radiation-induced thrombocytopenia and a prebiotic-based strategy to boost FMT efficacy. What is the context? Radiation‑induced thrombocytopenia (RIT) is a common and dose‑limiting complication in cancer patients undergoing radiation therapy. It increases the risk of bleeding and may interrupt treatment.Current treatments like platelet transfusions or thrombopoietic drugs have limited effectiveness and potential side effects.The gut microbiome influences blood cell production through the “gut-blood axis.” Fecal microbiota transplantation (FMT) has shown promise in modulating immunity and metabolism, but its role in RIT is unclear.Furthermore, the gut microbiome differs between sexes, and the prebiotic inulin may boost FMT efficacy. These aspects have not been systematically studied in the context of RIT. What is the new? In this study, we show for the first time in mice that FMT can alleviate radiation-induced thrombocytopenia, and its effectiveness depends on sex: sex-matched FMT significantly accelerated platelet recovery and promoted megakaryocyte production only in female RIT mice.Female donor FMT accelerates platelet recovery in male RIT mice, whereas male donor FMT does not.The prebiotic inulin enhanced the effect of FMT. It helped beneficial bacteria, such as Akkermansia , to establish in the gut, leading to faster platelet recovery in RIT mice.Analysis of the gut microbiome revealed that Akkermansia might be a key bacterium responsible for the platelet-boosting effects of FMT in RIT mice. What is the impact? This study proposes a novel microbial therapy for radiation‑induced thrombocytopenia that considers biological sex.The results suggest that an FMT strategy combined with inulin could be a more effective treatment, particularly in clinical situations requiring rapid platelet recovery.Future research can explore the mechanism of Akkermansia and its metabolites, advancing personalized microbiome-based therapies for radiation‑induced thrombocytopenia.

Thin endometrium (TE) severely impairs embryo implantation and pregnancy outcomes in reproductive medicine, while first-line oestrogen-based therapy has marked limitations including receptor insensitivity and systemic side effects. Ejiao (Asini Corii Colla), a classic Traditional Chinese Medicine tonic, is widely used for gynecological disorders, yet its mechanism in endometrial regeneration remains unclear. This study aimed to investigate the therapeutic effect of Ejiao on TE and its regulation of the SDF-1/CXCR4 signalling axis. A TE mouse model was established via intrauterine infusion of 95% ethanol in female C57BL/6J mice. Mice were randomly divided into 4 groups (n = 6 per group): sham operation control group, TE model group, oestradiol positive control group (0.04 mg/kg/d), and Ejiao intervention group (0.2 g/kg/d), with 4 weeks of daily gavage intervention. Oestrous cycle stability was verified by vaginal smears, endometrial morphology was evaluated by HE staining, and SDF-1/CXCR4 mRNA expression in uterine tissues was detected by qPCR. All mice maintained stable oestrous cycling throughout the experiment. Ejiao treatment markedly restored endometrial thickness and glandular density in TE mice, with a superior reparative effect to oestradiol, and significantly upregulated the mRNA expression of SDF-1 and CXCR4 in uterine tissue ( P < 0.05 vs. model and oestradiol groups). Ejiao effectively promotes endometrial regeneration in TE mice via upregulating the SDF-1/CXCR4 signalling axis, providing preclinical mechanistic evidence for its clinical application in TE treatment. For a baby to grow, a fertilised egg must attach to the inside lining of the womb. This lining needs to be thick enough to allow that to happen. In some women, the lining stays too thin, which makes it very hard to become pregnant, even with the help of fertility treatment. The medicines most often used to thicken the womb lining do not work well in all women, and some can cause unwanted side effects.Ejiao is a traditional Chinese medicine that has been used for hundreds of years to support women’s health. It is made by boiling and drying donkey hide into a solid cake, which is then dissolved in water and taken by mouth. Laboratory studies suggest it may help the body heal and repair tissue, but no one had tested whether it could specifically help repair a thin womb lining.In this study, we used mice that had been given a thin womb lining using a simple surgical procedure. The mice were then given Ejiao by mouth every day for four weeks. Afterwards, we examined the womb tissue under a microscope to see how thick the lining had grown and how many small structures, needed for pregnancy, had formed inside it. We also measured how active certain repair-related signals were in the womb tissue.The mice that received Ejiao developed a noticeably thicker womb lining and more of those small internal structures compared with untreated mice. This improvement was greater than what was seen in mice treated with the standard hormone medicine. The body’s own tissue repair signals were also more active in the Ejiao group.These results suggest that Ejiao may help repair a thin womb lining by switching on the body’s own natural healing system. More research, including studies in women, is needed before Ejiao can be recommended as a treatment. However, these findings provide a useful first step in understanding how it might work.

Bacterial vaginosis (BV) is the most common vaginal infection in women of reproductive age and is strongly associated with polymicrobial biofilms, which contribute to antimicrobial tolerance and high recurrence rates. New strategies targeting BV-associated biofilms are therefore needed. This study evaluated the antimicrobial and antibiofilm activity of octenidine dihydrochloride/phenoxyethanol (Octiset®) compared with octenidine dihydrochloride (octenidine) alone in in vitro and ex vivo BV biofilm models. Planktonic cultures and biofilms of BV-associated species ( Gardnerella vaginalis , Fannyhessea vaginae , Prevotella bivia , Peptostreptococcus anaerobius and Mobiluncus curtisii ) were established under anaerobic conditions. Planktonic suspensions were exposed for 24 h to octiset® (50%, 25%) or octenidine (0.1%, 0.05%). Single-species and polymicrobial biofilms were formed for 24 h and treated with octiset® or octenidine up to 12 h. Additionally, polymicrobial biofilms were established on reconstructed human vaginal epithelium (SkinEthic™ HVE) and treated for 8 h. Antimicrobial efficacy was assessed by CFU quantification. Recovery experiments were performed to determine whether residual culturable cells persisted after treatment, by incubating samples in fresh medium for up to 72 h and subsequently quantifying CFUs. Antimicrobial activity was also tested against species associated with healthy vaginal microbiota, by assessing vaginal lactobacilli susceptibility to both compounds. Both compounds showed time- and concentration-dependent activity. Octiset® consistently demonstrated superior killing compared to octenidine, including eradication of several single-species biofilms. Polymicrobial biofilms showed increased tolerance; however, extended exposure (≥8 h) reduced CFUs below detection for both agents, with no regrowth observed after 72 h. In the ex vivo model, both treatments reduced biofilm growth below the limit of detection. All tested lactobacilli also showed susceptibility to both compounds. Octiset® and octenidine exhibited strong antibiofilm activity against BV-associated polymicrobial biofilms in vitro and ex vivo , supporting their potential as biofilm-targeted BV treatment approaches.

New zaogong erteng decoction (NZGETD) is a compound Chinese medicine modified from the Zaogong Erteng Decoction. Previous clinical observations suggested its potential efficacy against endometritis, an inflammatory condition that adversely impacts endometrial receptivity and embryo implantation. In this study, the role and mechanism of NZGETD in improving embryo implantation were investigated in a mouse model of lipopolysaccharide-induced endometritis. Female mice were treated with 2.5 mg/mL lipopolysaccharide in the endometrium for 24 h to induce endometritis and were subsequently gavaged with NZGETD for 8 days. Pathological changes, inflammatory cytokine levels, uterine index, endometrial decidualization, microangiogenesis and hormone levels were assessed. Network pharmacology analysis was employed to identify potential active components and targets. The expression of key proteins related to endometrial receptivity and implantation was confirmed by western blotting. NZGETD attenuated lipopolysaccharide-induced pathological changes and downregulated uterine levels of IL-1β, IL-6 and TNF-α, indicating its anti-inflammatory effect in this endometritis model. NZGETD significantly increased the uterine index, promoted endometrial decidualization and microangiogenesis (upregulated CD31 on gestational day 4.5). Additionally, NZGETD significantly elevated uterine levels of estrogen and progesterone and increased the number of implantation sites on gestational day 8.5. Network pharmacology analysis screened beta-sitosterol, quercetin, kaempferol and stigmasterol as the common active components of NZGETD. Western blotting confirmed that NZGETD up-regulated ESR, PGR, Hoxa10, integrin β3, LIF, HIF1α and VEGF during embryo implantation. In a mouse model of lipopolysaccharide-induced endometritis, NZGETD promoted decidualization and microangiogenesis of the endometrium, enhanced endometrial receptivity and facilitated embryo implantation.

With rising global temperatures, the detrimental effects of heat stress on the reproductive performance of female animals have received increasing attention. In this study, we investigated the effects of heat stress on reproductive function in female mice and explored the therapeutic potential of probiotics in alleviating uterine damage through repair of the intestinal barrier. Seven-week-old female ICR mice were used to establish a systemic heat stress model. Mice in the treatment groups received Enterococcus faecium or Clostridium butyricum during heat stress. The results showed that heat stress induced systemic inflammation, oxidative stress, and elevated endotoxin (LPS) levels, leading to downregulation of tight junction proteins (ZO-1, occludin, and claudin-1) in the colon and uterine tissues. Systemic inflammation increased the levels of the pro-inflammatory cytokines IL-1β and IL-2 while decreasing the levels of the anti-inflammatory cytokines IL-4 and IL-10 in uterine tissue, resulting in uterine inflammatory damage and reproductive hormone dysregulation, thereby exacerbating placental injury and increasing the risk of fetal growth restriction. Treatment with E. faecium or C. butyricum repaired the intestinal barrier and inhibited the TLR4-MyD88 signaling pathway, thereby protecting the uterus from heat stress-induced injury and effectively alleviating uterine inflammation and fetal growth restriction. The 16S rRNA sequencing results demonstrate the regulatory effects of Enterococcus faecium and Clostridium butyricum on intestinal microbiota. Fecal microbiota transplantation (FMT) experiments further demonstrated that oxidative stress and uterine inflammatory damage in heat-stressed mice were alleviated following transplantation of intestinal microbiota from mice treated with E. faecium or C. butyricum. These findings suggest that E. faecium and C. butyricum have potential applications in reducing heat stress-induced reproductive damage in female animals.

Despite extensive investigations over the last few decades, molecular mechanisms underlying the pathogenesis of preeclampsia remain incompletely understood. Emerging evidence suggests that microRNAs (miRNAs) regulate key pathological processes in preeclampsia including endothelial dysfunction, inflammation, and oxidative stress. However, a comprehensive profiling of miRNA expression has not been previously carried out. Thus, using reduced uterine perfusion pressure (RUPP) model of preeclampsia, we performed placental miRNA sequencing to identify functional relevance of abnormally expressed miRNAs. Blood pressure was measured via carotid catheterization on gestational day (GD)19. Placental small-RNA sequencing was performed using Illumina NextSeq2000 sequencer. Our analysis identified 142 differentially regulated miRNAs (40 up- and 102 down-regulated) in placenta from RUPP rats. The top upregulated miRNAs included miR-211-3p, miR-628, miR-6324, miR-363-5p, and miR-6329, while miR-3587, miR-29b-3p, miR-3556a, miR-29a-3p, and miR-21-3p were the most downregulated. Functional annotation revealed associations with immune response (miR-363, miR-21, miR-29), B-cell differentiation (miR-628), T-cell activation (miR-21), adipogenesis, and lipid metabolism (miR-211, miR-29, miR-21), and angiogenesis (miR-363, miR-21). Further, gene ontology analysis revealed significant enrichment in biological processes; regulation of transport, cell-cell signaling, and calcium-dependent exocytosis, cellular components; synaptic vesicles, perinuclear cytoplasm, and clathrin-coated vesicles, and molecular functions; glycoprotein binding, protein dimerization, and myosin binding. These findings suggest that robust miRNA dysregulation in RUPP rats may underlie disease pathogenesis.

Intrauterine adhesion (IUA) is a common complication of endometrial injury. Bone marrow mesenchymal stem cells (BMSCs) have been implicated in endometrial repair, but strategies to enhance their therapeutic efficacy remain to be optimized. The C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis plays a pivotal role in BMSC homing. This study aimed to test the hypothesis that ATI-2341, a functionally selective allosteric regulator of CXCR4, enhances the therapeutic efficacy of BMSCs in a rat IUA model. After establishing the endometrial injury model, rat BMSCs were extracted and treated with ATI-2341 TFA (100 ng/mL). IUA model rats were randomly divided into model control group, BMSCs group, BMSCs+ATI-2341 TFA group, BMSCs+PBS group and Positive control group (n=10 each). Endometrial thickness was assessed by hematoxylin and eosin (HE) staining; cell proliferation by the methyl thiazolyl tetrazolium (MTT) assay; matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expression by Western blot; and cytokeratin and vimentin expression by immunohistochemistry. ATI-2341 TFA-pre-treated BMSCs significantly increased endometrial thickness compared to untreated BMSCs (P < 0.05) or estrogen (P < 0.05). ATI-2341 TFA enhanced BMSC proliferation at 48 h (P < 0.05) and 72 h (P < 0.05). BMSCs exposed to ATI-2341 TFA or estrogen exhibited strong cytokeratin positivity and vimentin negativity. MMP-9 was downregulated (P < 0.05) and TIMP-1 upregulated (P < 0.05) in the ATI-2341 TFA group relative to controls. ATI-2341 TFA promotes acquisition of epithelial-like immunophenotype in BMSCs within the injured endometrial microenvironment and is associated with improved endometrial morphology in IUA rats. These findings provide preliminary evidence for the functional modulation of BMSCs by CXCR4-targeted therapy in endometrial repair.

To conduct the first nationwide spatio-temporal analysis of vulvar cancer mortality in Spain, identifying geographical inequalities and temporal trends over 25 years. A population-based ecological study analyzed mortality data (1999-2023) across 52 Spanish provinces and autonomous cities. Expected deaths were calculated via indirect standardization. Hierarchical Bayesian spatio-temporal models were implemented using Integrated Nested Laplace Approximation (INLA). Spatial heterogeneity accounted for 68.8% of the total posterior variance, whereas the national temporal trend explained only 8.2%. Nationally, mortality risk showed a modest downward trend, with the RR decreasing from 1.054 (95% CrI 0.981-1.133) in 1999 to 0.954 (95% CrI 0.890-1.022) in 2023. However, areas with a high posterior probability (PP(RR > 1) > 0.95) of excess mortality were consistently identified in southwestern Spain (Badajoz RR 1.25, Cádiz 1.21, Huelva 1.20, Sevilla 1.18) and Lugo (RR 1.16), while lower risks were observed in Madrid and Barcelona (RR 0.85). Vulvar cancer mortality in Spain shows persistent geographical disparities rather than a uniform national trend. These ecological findings do not allow causal interpretation, but they may reflect underlying contextual factors, such as socioeconomic inequalities, heterogeneous access to early diagnosis, variability in access to specialized gynecologic oncology services, and differences in the detection and management of precursor conditions. These results highlight the need for further research incorporating incidence, clinical stage, and healthcare access data, as well as public health strategies aimed at ensuring equitable access to multidisciplinary care and strengthening coordinated early detection pathways across regions.

Endometrial carcinoma (EC) presents commonly with abnormal uterine bleeding, and definitive diagnosis requires invasive endometrial biopsy. Haematological inflammatory markers-including the neutrophil-to-lymphocyte ratio (NLR), platelet distribution width (PDW), and the systemic immune-inflammation index (SII)-have been proposed as adjuncts in the differential diagnosis of endometrial pathologies. We evaluated whether these markers can independently discriminate EC from endometrial hyperplasia with atypia/endometrial intraepithelial neoplasia (EHA/EIN), endometrial hyperplasia without atypia (EH), and normal endometrium, after adjustment for age and other confounders. Data from 238 patients who underwent endometrial biopsy for abnormal uterine bleeding between 2015 and 2020 were retrospectively analysed. Patients were categorised as EC ( n = 74), EHA/EIN ( n = 28), EH without atypia ( n = 66), and controls with normal endometrium ( n = 70). Haematological parameters, NLR, platelet-to-lymphocyte ratio (PLR), and SII were derived from preoperative complete blood count results. Univariable comparisons used the Kruskal-Wallis test with Dunn's post-hoc pairwise comparisons. Hierarchical multivariable logistic regression models were fitted, adjusting sequentially for age, menopausal status, and (where available) diabetes mellitus and hypertension. Receiver operating characteristic (ROC) analysis was performed for markers showing significant univariable discrimination, and PDW was analysed in inverted form (1-PDW direction) to reflect its inverse association with malignancy. NLR and SII were significantly elevated, and PDW was significantly reduced, in EC patients compared with controls (all p < 0.05). After adjustment for age and menopausal status, NLR (adjusted OR [aOR] 2.06, 95% CI 1.04-4.09; p = 0.037), SII per 100 units (aOR 1.49, 95% CI 1.09-2.04; p = 0.014) and PDW (aOR 0.93, 95% CI 0.89-0.96; p < 0.001) remained independently associated with EC versus controls. By contrast, after adjustment for age, NLR and SII no longer independently discriminated EC from EH (NLR aOR 1.27, p = 0.245; SII aOR 1.14, p = 0.165), suggesting that age accounts for a substantial proportion of the apparent univariable differences. In ROC analysis with PDW values inverted, AUCs were 0.79 (95% CI 0.72-0.87) for PDW, 0.68 (95% CI 0.59-0.76) for NLR, and 0.62 (95% CI 0.52-0.70) for SII against the control group. No marker-adjusted or unadjusted-significantly distinguished EC from EHA/EIN. NLR, SII, and (low) PDW are independently associated with EC compared with normal endometrium, even after age and menopausal status adjustment, but their performance is modest and they do not independently discriminate EC from premalignant endometrial lesions. Histopathological evaluation remains indispensable. These markers may inform risk stratification but are not sufficient as standalone tests. Endometrial cancer is the most common gynaecological cancer in many European countries. It usually presents with abnormal vaginal bleeding, and diagnosis currently requires a small biopsy from the lining of the womb. Telling cancer apart from precancerous changes (endometrial hyperplasia) and from normal tissue is clinically important.In this study we asked whether simple blood test results—already taken before biopsy—could help distinguish these conditions. Specifically, we looked at three measurements that reflect inflammation: the neutrophil-to-lymphocyte ratio (NLR), platelet distribution width (PDW), and the systemic immune-inflammation index (SII).We studied 238 women who had an endometrial biopsy. NLR and SII were higher, and PDW was lower, in women with cancer than in those with normal tissue. When we accounted for the fact that women with cancer were on average older and more likely to have diabetes and high blood pressure, NLR, SII, and low PDW were still linked with cancer compared with normal tissue, but they could not separate cancer from the precancerous changes (atypical hyperplasia). They also did not reliably tell cancer apart from simple hyperplasia once age was taken into account.These results suggest that these blood tests may add some useful information when combined with other clinical findings, but they cannot replace a biopsy and they are not strong enough on their own to decide who needs further investigation. They should be seen as adjuncts to standard clinical evaluation, not as a screening test.

To generate the evidence base, using national cohort data, to design a clinical trial evaluating whether cesarean section (CS) or vaginal birth (VB) offers better outcomes for very preterm infants. Severe intraventricular hemorrhage (IVH) remains a major cause of death and brain injury amongst very preterm infants. Observational studies have suggested CS may reduce the risk, but it is not known which infants might benefit and whether a randomized trial, to generate robust evidence to guide clinical decisions, would be feasible. We examined births in England and Wales between 22 + 0 and 31 + 6 weeks' gestation (2012-2022; n = 74,423) and identified the infants that could take part in a trial. Three emulated target trials (ETTs) were constructed examining intended mode of birth (iVB vs iCS), across different populations, with confounding controlled by inverse probability weighting. One in four(25.2%) very preterm infants could be considered for participation in a future trial. Infants born by CS had lower rates of severe IVH or death than those born by VB (4,319 (9.6%) vs 5,542 (18.7%)) ( p < 0.001), although in the adjusted analyses using intended mode of birth the difference did not persist (e.g. ETT#1: 13.3% vs 13.0%, p = 0.609); except for non‑cephalic (breech) infants. Infants in a non-cephalic presentation in the iCS group had a significantly lower chance of death or sIVH in all three emulated trials (ETT#1, OR 0.73 (0.64-0.83); ETT#2, OR 0.65 (0.56-0.76); ETT#3, OR 0.81 (0.70-0.94). Only a minority of very preterm births are realistically randomisable in a future trial, particularly babies in breech presentation who may benefit from a CS. An international multi-centre trial is needed to examine this question.

Solitary fibrous tumor (SFT) is a rare fibroblastic neoplasm that may occur at various anatomic sites, whereas vulvar involvement is exceptional. The myxoid variant of SFT, defined by extensive myxoid stromal change, is exceedingly uncommon and may present diagnostic challenges due to atypical radiologic and histologic features. We report a case of a 35-yr-old woman with a slowly enlarging vulvar mass radiologically interpreted as a benign cystic lesion. Histologic examination revealed a predominantly myxoid spindle cell tumor with staghorn vascular features in its periphery. Immunohistochemistry showed diffuse nuclear STAT6 and CD34 positivity, and molecular analysis confirmed a NAB2:::STAT6 fusion. This case highlights the diagnostic pitfalls associated with myxoid change in vulvar mesenchymal tumors and underscores the importance of immunohistochemical and molecular confirmation.

To evaluate the feasibility of sentinel lymph node detection using a combined technique with superparamagnetic iron oxide tracer and patent blue dye in patients with vulvar cancer. This retrospective observational study included patients with vulvar cancer who underwent sentinel lymph node biopsy at a Portuguese oncological center between 2021 and 2025. Sentinel lymph node mapping was performed in patients with clinically negative groins. The procedure was also performed in selected cases of carcinoma in situ in which stromal invasion could not be preoperatively excluded. Five patients were included. The median age was 68 years (range 56-86), and all tumors were located in the midline. Final histopathology confirmed squamous cell carcinoma in all cases, including two in situ lesions and three invasive tumors. Sentinel lymph node detection was achieved in all patients (100%), with bilateral detection in four patients (80%) and a detection rate per groin of 90% (9/10). The mean number of sentinel lymph nodes retrieved per patient was 3.4 (range 1-5). In two groins, sentinel lymph nodes were identified exclusively by the magnetic tracer, with no progression of patent blue dye. No metastatic involvement was identified. The median follow-up was 20 months (range 8-51), and no inguinal recurrences were observed. Sentinel lymph node biopsy using a combined magnetic and dye technique was feasible in this series of patients with vulvar cancer and may represent a useful approach in selected patients, although further studies are needed. Résumé. Évaluer la faisabilité du repérage du ganglion sentinelle à l'aide d'un traceur à base d'oxyde de fer superparamagnétique combiné à un colorant bleu breveté chez les patientes atteintes d'un cancer de la vulve. MéTHODOLOGIE: La présente étude observationnelle rétrospective a été menée auprès de patientes atteintes d'un cancer de la vulve qui ont subi une biopsie du ganglion sentinelle dans un centre oncologique portugais entre 2021 et 2025. Une cartographie du ganglion sentinelle a été réalisée pour les patientes dont l'examen clinique des aines s'est avéré négatif. Une cartographie a également été réalisée pour certains cas de carcinome in situ, dans lesquels l'invasion stromale ne pouvait être exclue avant l'intervention chirurgicale. RéSULTATS: Cinq patientes ont été incluses dans l'étude. L'âge médian était de 68 ans (intervalle : 56 à 86 ans), et toutes les tumeurs se trouvaient à la ligne médiane. Dans tous les cas, l'histopathologie finale a confirmé la présence d'un carcinome épidermoïde, dont deux lésions in situ et trois tumeurs invasives. Un ganglion sentinelle a été repéré chez toutes les patientes (100 %); un ganglion sentinelle a été repéré aux deux aines chez quatre d'entre elles (80 %), et un ganglion sentinelle a été trouvé dans 9 des 10 aines examinées (9/10, donc 90 %). Le nombre moyen de ganglions sentinelles retirés par patiente s'élevait à 3,4 (intervalle : 1 à 5). Dans deux cas, les ganglions sentinelles ont été repérés exclusivement grâce au traceur magnétique, le colorant bleu ne s'étant pas propagé. Aucune atteinte métastatique n'a été constatée. La période médiane de suivi était de 20 mois (intervalle : 8 à 51 mois); aucune récidive inguinale n'a été observée. Le repérage du ganglion sentinelle à l'aide d'un traceur à base d'oxyde de fer superparamagnétique combiné à un colorant bleu breveté s'est avéré faisable chez ce groupe de patientes atteintes d'un cancer de la vulve. Cette méthode pourrait être utile chez certaines patientes, mais d'autres études sont nécessaires pour le confirmer.

Uterine adenosarcoma is an uncommon biphasic neoplasm composed of malignant stroma and benign non-neoplastic epithelium. Most adenosarcomas show canonical low-grade morphology, which must be distinguished from various benign uterine polyps. A subset of adenosarcomas shows sarcomatous overgrowth, myometrial invasion, vascular invasion, heterologous differentiation, or marked nuclear atypia. These findings are prognostically adverse and may raise the differential with other uterine sarcomas. This article provides an overview of the clinicopathologic features of uterine adenosarcoma, with a particular focus on challenging presentations and histologic mimics.