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IntroductionChronic endometritis (CE) is regarded as a potential factor contributing to infertility and embryo implantation failure. The cause of CE remains unclear at present, but it might be associated with intrauterine microbial infections. Empirical antibiotic treatment typically consists of a 2-week course of oral levofloxacin combined with oral metronidazole. Currently, there is no research comparing the efficacy of oral levofloxacin versus vaginal metronidazole suppositories in improving pregnancy outcomes for these patients. This study aims to evaluate the effectiveness of combining oral levofloxacin with metronidazole suppositories in the treatment of CE. The goal is to enhance clinical pregnancy rates and live birth rates among patients undergoing in vitro fertilisation (IVF), while concurrently mitigating the incidence of miscarriages.Methods and analysisThe trial concerning the combination of levofloxacin and metronidazole suppositories for the treatment of CE is a single-centre, randomised controlled clinical trial. We plan to recruit female patients with CE who are planning to undergo IVF. Following informed consent, eligible participants will be randomly assigned in a 1:1 ratio to receive either daily oral levofloxacin combined with oral metronidazole or oral levofloxacin combined with a metronidazole suppository for 2 weeks until the human chorionic gonadotropin trigger day. All IVF procedures will be carried out routinely at this centre. The primary outcome is the live birth rate after embryo transfer, while the secondary pregnancy outcomes include clinical pregnancy rates and miscarriage rates.Ethics and disseminationThis study has been approved by the Ethics Committee of Peking University Third Hospital on 28 June 2024 (Reference No. IRB00006761-M2023857). Written informed consent will be acquired from all participants prior to randomisation. The study findings will be submitted to scientific conferences and peer-reviewed journals.Trial registration numberNCT06650540.

Objective This study aimed to develop a predictive model for secondary infections in patients with severe or critical COVID-19 by analyzing clinical characteristics and laboratory indicators. Method A total of 307 patients with severe or critical COVID-19 admitted to Peking University Third Hospital from December 2022 to February 2023 were retrospectively analyzed, including 156 patients with secondary infection and 151 patients without secondary infection. The Boruta algorithm identified significant variables, and eight machine learning models were evaluated based on area under the curve (AUC) performance. The optimal model selected was further assessed, with model interpretability provided using SHapley Additive exPlanations (SHAP). Result Nine predictive factors were identified: Mechanical Ventilation, Procalcitonin (PCT), Interleukin-8 (IL-8), Interleukin-6 (IL-6), Blood Urea Nitrogen, Glucose, Creatine Kinase, Lactate Dehydrogenase, and Mean Platelet Volume (MPV). The random forest model demonstrated the best performance, with further evaluation showing an average AUC of 0.981 (CI 0.965–0.998) on the training set and 0.836 (CI 0.761–0.912) on the test set. SHAP analysis identified MPV, PCT, and IL-8 as the strongest predictors of secondary infections. Conclusion We developed an effective predictive model for secondary infection risk in severe COVID-19 patients using readily available clinical parameters, enabling early clinical intervention. This machine learning approach demonstrates potential for improving patient management. Clinical trial This study does not involve clinical trial interventions. Therefore, clinical trial registration was not applicable.

Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women and severely impairs fertility. Extant clinical studies can only provide indirect and plausible evidence to support endometrial dysfunction as an ovary-independent contributor to PCOS infertility, considering heterogeneous confounders in their phenotypes, comorbidities, and severities. By strictly controlling embryonic factors and potential confounders, our retrospective cohort study reports an adverse implantation rate in women with PCOS, confirming abnormalities in the endometrium, which are accompanied by excessive ERα and histone lactylation. Next, we validate the cooccurrence of impaired uterine receptivity with elevated ERα and histone lactylation in the PCOS mouse model. Inhibiting histone lactylation could downregulate ERα and estrogen-responsive genes, restore uterine receptivity, and improve the implantation rate in PCOS mice. Here, we show that upregulated ERα and histone lactylation are key indicators of impaired endometrial receptivity in PCOS, providing a potential therapeutic strategy by inhibiting lactate production. It remains unclear whether and how endometrial dysfunction leads to infertility in polycystic ovary syndrome (PCOS), independent of the ovary. Here, the authors show that elevated ERα and histone lactylation impair endometrial receptivity in PCOS and serve as potential therapeutic targets.

Background Chlamydia trachomatis is a common sexually transmitted disease that is associated with considerable morbidity and harmful sequelae, including pelvic inflammatory disease and infertility. Strategies for prevention and treatment of infertility in women with C. trachomatis infection require further investigation. There is evidence suggesting that vitamin D could be a potential treatment. This study aimed to investigate the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels, chlamydia seropositivity, and the risk of infertility in women. Methods We conducted this cross-sectional study using 2013–2016 National Health and Nutrition Examination Survey data. Women aged 18–39 years with complete serum 25(OH)D and chlamydia Pgp3Ab multiplex bead/enzyme-linked immunosorbent assay data available were included. The correlation between 25(OH)D level, chlamydia seropositivity, and infertility was evaluated using the weighted chi-squared test and the t -test with multivariate logistic regression and moderation effect models. Results Among the 1424 women who met our eligibility criteria, the weighted chlamydia seropositivity rate was 36.8%. The 25(OH)D level was significantly lower in the seropositive group compared with seronegative control. ( P  = 0.009). After adjusting for ethnicity, the effect of 25(OH)D was no longer significant ( P =  0.693). Further analysis in the chlamydia-seropositive subset revealed that the vitamin D level was lower in the infertile group ( P  = 0.024). In an interaction model, 25(OH)D was found to antagonizes the positive relationship between chlamydia and infertility (OR = 0.985, 95% CI: 0.971–0.999, P  = 0.040). Conclusion The serum vitamin D level may be more related to the prognosis in terms of infertility than to the risk of chlamydia infection. This finding may reveal a possible treatment strategy for chlamydia infection.

Background While anti-Müllerian hormone (AMH) serves as a well-established biomarker of ovarian reserve, its association with early miscarriage risk remains inconsistently characterized across previous research. To address this evidence gap, our investigation systematically evaluates the relationship between serum AMH concentrations and early miscarriage through a combination of retrospective cohort study and mendelian randomization analysis. Methods The retrospective cohort study enrolled women who achieved intrauterine clinical pregnancies through in vitro fertilization cycles at Peking University Third Hospital between January 2019 and December 2023 ( N  = 19,154). These women were subsequently divided based on their anti-Müllerian hormone levels. Logistic regression and restrictive cubic spline regression models were applied to investigate the association between anti-Müllerian hormone levels and early miscarriage. Additionally, a two-step Mendelian randomization approach was utilized to investigate the causal relationship between anti-Müllerian hormone levels and miscarriage. Exposure traits were extracted from a meta-GWAS dataset ( N  = 9,968), while outcome traits were obtained from three separate GWAS datasets ( N  = 135,962, N  = 360,044, and N  = 150,215, respectively). Results In the in vitro fertilization (IVF) cohort, there were 2,780 women with AMH<1.1ng/ml, 6,666 women with 1.1 < AMH ≤ 2.6 ng/ml, and 9,708 women with AMH ≥ 2.6ng/ml. Compared to women with AMH ≥ 2.6ng/ml, women with AMH < 1.1 ng/mL (17.7% vs. 10.9% reference; aOR = 1.26 [1.11–1.44], p  < 0.001) and women with AMH 1.1–2.6 ng/mL (13.8% vs. 10.9%; aOR = 1.13 [1.02–1.25], p  = 0.018) exhibited significantly higher rates of early miscarriage. The aOR of early miscarriage showed a decreasing trend as AMH levels increased in restrictive cubic spline ( p  < 0.001). MR analysis did not detect a causal relationship between AMH levels and spontaneous miscarriage or recurrent miscarriage. Conclusions Women with low AMH levels who conceive naturally do not need to worry excessively about early miscarriage. However, in the IVF population, low AMH levels warrant caution regarding the risk of early miscarriage. Future studies are necessary to confirm the causal relationship between AMH and early miscarriage in IVF cycles.

Endometriosis (EMT) is a common gynecological disease with a strong genetic component, while its precise etiology remains elusive. This study aims to integrate transcriptome-wide association study (TWAS), Mendelian randomization (MR), and bioinformatics analyses to reveal novel putatively causal genes and potential mechanisms. We obtained summary-level data of the Genotype-Tissue Expression Project (GTEx), v8 expression quantitative loci (eQTL) data, and the genome-wide association study (GWAS) data of EMT and its subtypes from the R11 release results of the FinnGen consortium for analysis. GWAS data of modifiable risk factors were collected from IEU Open GWAS. Cross-tissue TWAS analyses were performed using the unified test for molecular signature (UTMOST), while functional summary-based imputation (FUSION) was employed for single-tissue TWAS analyses. Furthermore, we also conducted multi-marker analysis of genomic annotation (MAGMA) analyses to validate the significant associations. Subsequent Mendelian randomization (MR) and colocalization analysis elucidated the causal associations between the identified genes across various tissues and EMT. To further delve into mechanisms, two-sample network MR analyses were conducted. At last, bioinformatics analyses were employed to enhance our understanding of the functional implications and expression patterns of these identified genes. For EMT, 22 significant gene signals were identified by UTMOST, 615 by FUSION, and 354 by MAGMA. Ultimately, six genes, including CISD2, EFRB, GREB1, IMMT, SULT1E1, and UBE2D3, were identified as candidate susceptibility genes for EMT. Through similar procedures, we identified GREB1, IL1A, and SULT1E1 for EMT of the ovary, and we identified GREB1 for EMT of the pelvic peritoneum, EMT of rectovaginal septum and vagina, and deep EMT. In MR analyses, the expression of IMMT in 21 tissues, EFR3B in the adrenal gland, CISD2 in 17 tissues, and UBE2D3 in 7 tissues demonstrated causal relationships with EMT risk. In addition, CISD2, IMMT, and UBE2D3, across different tissues, exhibited strong colocalization with EMT (PPH4 > 0.7). Two-sample network MR analyses revealed that CISD2, EFR3B, and UBE2D3 could potentially regulate the levels of blood lipids and hip circumference so as to influence the risk of EMT. Furthermore, bioinformatics analyses confirmed our findings and delved into the biological functions of the identified genes. Our study unveiled seven novel candidate genes whose predicted expression was associated with the risk of EMT, providing new insights into the underlying genetic framework of EMT. These findings will facilitate a deeper comprehension of the tissue-specific transcriptional regulatory mechanisms associated with EMT, paving the way for optimizing the management and treatment of EMT.

Abstract Background The sirtuin family is well recognized for its crucial involvement in various cellular processes. Nevertheless, studies on its role in the human endometrium are limited. This study aimed to explore the expression and localization of the sirtuin family in the human endometrium, focusing on sirtuin 3 (SIRT3) and its potential role in the oxidative imbalance of the endometrium in polycystic ovary syndrome (PCOS). Methods Endometrial specimens were collected from both patients with PCOS and controls undergoing hysteroscopy at the Center for Reproductive Medicine, Peking University Third Hospital, from July to August 2015 and used for cell culture. The protective effects of SIRT3 were investigated, and the mechanism of SIRT3 in improving endometrial receptivity of patients with PCOS was determined using various techniques, including cellular bioenergetic analysis, small interfering ribonucleic acid (siRNA) silencing, real-time quantitative polymerase chain reaction, Western blot, immunofluorescence, immunohistochemistry, and flow cytometry analysis. Results The sirtuin family was widely expressed in the human endometrium, with SIRT3 showing a significant increase in expression in patients with PCOS compared with controls (P <0.05), as confirmed by protein and gene assays. Concurrently, endometrial antioxidant levels were elevated, while mitochondrial respiratory capacity was reduced, in patients with PCOS (P <0.05). An endometrial oxidative stress (OS) model revealed that the downregulation of SIRT3 impaired the growth and proliferation status of endometrial cells and reduced their receptivity to day 4 mouse embryos. The results suggested that SIRT3 might be crucial in maintaining normal cellular state by regulating antioxidants, cell proliferation, and apoptosis, thereby contributing to enhanced endometrial receptivity. Conclusions Our findings proposed a significant role of SIRT3 in improving endometrial receptivity in patients with PCOS by alleviating OS and regulating the balance between cell proliferation and apoptosis. Therefore, SIRT3 could be a promising target for predicting and improving endometrial receptivity in this patient population.

Background There is limited literature investigating the effects of body mass index (BMI) and androgen level on in vitro fertilization (IVF) outcomes with a gonadotropin-releasing hormone (GnRH)-antagonist protocol in polycystic ovary syndrome (PCOS). Androgen-related variation in the effect of body mass index (BMI) on IVF outcomes remains unknown. Methods In this retrospective study, 583 infertile women with PCOS who underwent IVF using the conventional GnRH-antagonist protocol were included. Patients were divided into four groups according to BMI and androgen level: overweight- hyperandrogenism(HA) group, n  = 96, overweight-non-HA group, n  = 117, non-overweight-HA group, n  = 152, and non-overweight-non-HA group, n  = 218. Results A significantly higher number of oocytes were retrieved, and the total Gn consumption as well Gn consumption per day was significantly lower, in the non-overweight groups than in the overweight groups. The number of available embryos was significantly higher in the HA groups than in the non-HA groups. Clinical pregnancy rate was of no significant difference among four groups. Live-birth rates in the overweight groups were significantly lower than those in non-overweight-non-HA group (23.9, 28.4% vs. 42.5%, P <0.05). The miscarriage rate in overweight-HA group was significantly higher than that in non-overweight-non-HA group (45.2% vs. 14.5%, P <0.05). Multivariate logistic regression analysis revealed that BMI and basal androstenedione (AND) both acted as significantly influent factors on miscarriage rate. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis for BMI and basal AND on miscarriage rate were 0.607 ( P  = 0.029) and 0.657 ( P  = 0.001), respectively, and the cut-off values of BMI and basal AND were 25.335 kg/m 2 and 10.95 nmol/L, respectively. Conclusions In IVF cycles with GnRH-antagonist protocol, economic benefits were seen in non-overweight patients with PCOS, with less Gn cost and more retrieved oocytes. BMI and basal AND were both significantly influential factors with moderate predictive ability on the miscarriage rate. The predictive value of basal AND on miscarriage was slightly stronger than BMI.

ObjectiveFetal growth restriction (FGR) is a devastating pregnancy complication that increases the risk of perinatal mortality and morbidity. This study aims to determine the combined and relative effects of genetic and intrauterine environments on neonatal microbial communities and to explore selective FGR-induced gut microbiota disruption, metabolic profile disturbances and possible outcomes.DesignWe profiled and compared the gut microbial colonisation of 150 pairs of twin neonates who were classified into four groups based on their chorionicity and discordance of fetal birth weight. Gut microbiota dysbiosis and faecal metabolic alterations were determined by 16S ribosomal RNA and metagenomic sequencing and metabolomics, and the long-term effects were explored by surveys of physical and neurocognitive development conducted after 2~3 years of follow-up.ResultsAdverse intrauterine environmental factors related to selective FGR dominate genetics in their effects of elevating bacterial diversity and altering the composition of early-life gut microbiota, and this effect is positively related to the severity of selective FGR in twins. The influence of genetic factors on gut microbes diminishes in the context of selective FGR. Gut microbiota dysbiosis in twin neonates with selective FGR and faecal metabolic alterations features decreased abundances of Enterococcus and Acinetobacter and downregulated methionine and cysteine levels. Correlation analysis indicates that the faecal cysteine level in early life is positively correlated with the physical and neurocognitive development of infants.ConclusionDysbiotic microbiota profiles and pronounced metabolic alterations are associated with selective FGR affected by adverse intrauterine environments, emphasising the possible effects of dysbiosis on long-term neurobehavioural development.

The relationship between the intake of artificial sweetener (AS) and adverse pregnancy outcomes is under-researched, and existing studies yield inconsistent conclusions. A Mendelian randomization (MR) approach was employed to investigate the causal relationship between the intake of AS and adverse pregnancy outcomes. Instrumental variables related to the exposure phenotype were selected for analysis. The analysis was conducted using genome-wide association study summary data from public datasets. The inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode methods were used to evaluate the causal relationship between exposure and outcomes. Sensitivity analysis and multivariable Mendelian randomization enrolling body mass index, type 2 diabetes mellitus, and fasting glucose were employed to further validate the consistency and robustness of the results. In univariable MR, the intake of AS added to tea was associated with an increased risk of ectopic pregnancy [OR = 1.821 (1.118–2.967), p = 0.016]. In multivariable MR adjusting for body mass index and type 2 diabetes mellitus, the intake of AS added to cereal was linked to a reduced risk of ectopic pregnancy [OR = 0.361 (0.145–0.895), p = 0.028] and premature rupture of membranes [OR = 0.116 (0.019–0.704), p = 0.019], while the intake of artificial sweetener added to coffee was associated with an increased risk of placenta previa [OR = 1.617 (1.042–2.510), p = 0.032]. No causal relationship was identified between the intake of artificial sweetener and other adverse pregnancy outcomes. The consumption of artificial sweetener during pregnancy warrants careful consideration.