Role of SAA1 in endometrial extracellular matrix remodeling in polycystic ovary syndrome: implication for pregnancy loss.

CONTEXT: Abnormal endometrial extracellular matrix (ECM) remodeling compromises endometrial receptivity and diminishes the probability of a successful live birth. Serum amyloid A1 (SAA1), a modulator of inflammation, is elevated in the circulation of polycystic ovary syndrome (PCOS) patients and involved in ECM remodeling during tissue repair. However, the specific role of SAA1 in endometrial ECM remodeling and subsequent risk of pregnancy loss in PCOS patients remains unclear. OBJECTIVE: To examine the role and underlying mechanism of SAA1 in ECM remodeling in the endometrium of PCOS patients. DESIGN: Serum samples from PCOS and control patients were utilized to investigate the relationship between the abundance of SAA1 and pregnancy loss. Human endometrial tissues and primary human endometrial stromal cells were used to examine the role and underlying mechanism of SAA1 in ECM remodeling. RESULTS: Serum SAA1 concentration was elevated and could serve as an independent risk of pregnancy loss in PCOS patients. Increased SAA1 abundance was also observed in endometrium obtained from these patients. Further mechanistic studies showed that SAA1 stimulated collagen I chains synthesis (COL1A1 and COL1A2) in endometrial stromal cells, suggesting excessive SAA1 may contribute to endometrial ECM remodeling, resulting in a non-supportive environment for ongoing pregnancy. This effect was abolished by either a toll-like receptors 2/4 antagonist or a nuclear factor κB inhibitor. CONCLUSIONS: The locally elevated levels of SAA1 in endometrium contribute to ECM over-deposition by inducing collagen I synthesis in PCOS patients, which may hamper embryo implantation and increase the risk of pregnancy loss. These observations highlight the crucial role of heightened SAA1 in orchestrating endometrial dysfunction and shed light on potential therapeutic avenues for improving reproductive outcomes in PCOS patients.

Trophectoderm grade is associated with the risk of placenta previa in frozen-thawed single-blastocyst transfer cycles.

STUDY QUESTION: Do obstetric and perinatal complications vary according to different blastocyst developmental parameters after frozen-thawed single-blastocyst transfer (SBT) cycles? SUMMARY ANSWER: Pregnancies following the transfer of a blastocyst with a grade C trophectoderm (TE) were associated with an increased risk of placenta previa compared to those with a blastocyst of grade A TE. WHAT IS KNOWN ALREADY: Existing studies investigating the effect of blastocyst morphology grades on birth outcomes have mostly focused on fetal growth and have produced conflicting results, while the risk of obstetric complications has rarely been reported. Additionally, growing evidence has suggested that the appearance of TE cells could serve as the most important parameter for predicting implantation and live birth. Given that the TE ultimately develops into the placenta, it is plausible that this independent predictor may also impact placentation. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study at a tertiary-care academic medical center included 6018 singleton deliveries after frozen-thawed SBT cycles between January 2017 and December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singleton pregnancies were grouped into two groups according to blastocyst developmental stage (Days 5 and 6), four groups according to embryo expansion (Stages 3, 4, 5, and 6), three groups according to inner cell mass (ICM) quality (A, B, and C), and three groups according to TE quality (A, B, and C). The main outcomes included pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membrane, placenta previa, placental abruption, placenta accreta, postpartum hemorrhage, preterm birth, low birth weight, small for gestational age, and birth defects. Multivariate logistic regressions were performed to evaluate the effect of blastocyst developmental stage, embryo expansion stage, ICM grade, and TE grade on measured outcomes adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: No association was found between blastocyst developmental stage and obstetric or perinatal outcomes both before and after adjusting for potential confounders, and similar results were found with regard to embryo expansion stage and ICM grade. Meanwhile, the incidence of placenta previa derived from a blastocyst with TE of grade C was higher compared with those derived from a blastocyst with TE of grade A (1.7%, 2.4%, and 4.0% for A, B, and C, respectively, P = 0.001 for all comparisons). After adjusting for potential covariates, TE grade C blastocysts had 2.81 times the likelihood of resulting in placenta previa compared to TE grade A blastocysts (adjusted odds ratio 2.81, 95% CI 1.11-7.09). No statistically significant differences were detected between any other measured outcomes and TE grades both before or after adjustment. LIMITATIONS, REASONS FOR CAUTION: The study is limited by its retrospective, single-center design. Additionally, although the sample size was relatively large for the study group, the sample size for certain subgroups was relatively small and lacked adequate power, particularly the ICM grade C group. Therefore, these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The study extends our knowledge of the potential downstream effect of TE grade on placental abnormalities. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2023YFC2705501, 2023YFC2705505, 2019YFA0802604); National Natural Science Foundation of China (82130046, 82320108009, 82371660, 32300710); Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SHSMU-ZLCX20180401), Shanghai Jiaotong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), and Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Efficacy of endometrial receptivity testing for recurrent implantation failure in patients with euploid embryo transfers: study protocol for a randomized controlled trial.

BACKGROUND: Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of implantation (WOI) displacement, particularly in patients with recurrent implantation failure (RIF). Therefore, a reliable diagnostic tool for identifying the optimal WOI is essential. Previous data has suggested that a novel RNA-Seq-based endometrial receptivity testing (ERT) can diagnose WOI, guide personalized embryo transfer (pET), and improve pregnancy outcomes in patients with RIF compared to standard embryo transfer (sET). However, there is still a lack of evidence from randomized controlled trials (RCT) with sufficient power to determine whether pET based on ERT can increase the rate of live births as the primary outcome. METHODS: This trial is a prospective, single-blind, parallel-group RCT (1:1 ratio of pET versus sET). Infertile women with RIF who intend to undergo frozen-thawed embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) with the availability of at least one euploid blastocyst for transfer will be enrolled and assigned into two parallel groups randomly. Participants in the intervention group will undergo ERT and then pET based on the results of ERT, while those in the control group will undergo sET. The primary outcome is live birth rate. DISCUSSION: The findings of this study will provide evidence for the effect of pET guided by ERT on pregnancy outcomes in patients with RIF. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100049041. Registered on 20 July 2021.

Selenosis in a Woman With Systemic Lupus Erythematosus.

This case report describes hypointensity in the cerebellum and midbrain in a 56-year-old woman with double vision and weakness and ptosis of eyelids.

Effects of SARS-COV-2 infection during the frozen-thawed embryo transfer cycle on embryo implantation and pregnancy outcomes.

STUDY QUESTION: Does severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the frozen-thawed embryo transfer (FET) cycle affect embryo implantation and pregnancy rates? SUMMARY ANSWER: There is no evidence that SARS-CoV-2 infection of women during the FET cycle negatively affects embryo implantation and pregnancy rates. WHAT IS KNOWN ALREADY: Coronavirus disease 2019 (COVID-19), as a multi-systemic disease, poses a threat to reproductive health. However, the effects of SARS-CoV-2 infection on embryo implantation and pregnancy following fertility treatments, particularly FET, remain largely unknown. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study, included women who underwent FET cycles between 1 November 2022 and 31 December 2022 at an academic fertility centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who tested positive for SARS-CoV-2 during their FET cycles were included in the COVID-19 group, while those who tested negative during the same study period were included in the non-COVID-19 group. The primary outcome was ongoing pregnancy rate. Secondary outcomes included rates of implantation, biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy. Multivariate logistic regression models were applied to adjust for potential confounders including age, body mass index, gravidity, vaccination status, and endometrial preparation regimen. Subgroup analyses were conducted by time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) and by level of fever (no fever, fever <39°C, or fever ≥39°C). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 243 and 305 women were included in the COVID-19 and non-COVID-19 group, respectively. The rates of biochemical pregnancy (58.8% vs 62.0%, P = 0.46), clinical pregnancy (53.1% vs 54.4%, P = 0.76), implantation (46.4% vs 46.2%, P = 0.95), early pregnancy loss (24.5% vs 26.5%, P = 0.68), and ongoing pregnancy (44.4% vs 45.6%, P = 0.79) were all comparable between groups with or without infection. Results of logistic regression models, both before and after adjustment, revealed no associations between SARS-CoV-2 infection and rates of biochemical pregnancy, clinical pregnancy, early pregnancy loss, or ongoing pregnancy. Moreover, neither the time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) nor the level of fever (no fever, fever <39°C, or fever ≥39°C) was found to be related to pregnancy rates. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study is subject to possible selection bias. Additionally, although the sample size was relatively large for the COVID-19 group, the sample sizes for certain subgroups were relatively small and lacked adequate power, so these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The study findings suggest that SARS-CoV-2 infection during the FET cycle in females does not affect embryo implantation and pregnancy rates including biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy, indicating that cycle cancellation due to SARS-CoV-2 infection may not be necessary. Further studies are warranted to verify these findings. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2019YFA0802604), National Natural Science Foundation of China (82130046, 82101747), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SSMU-ZLCX20180401), Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai Sailing Program (21YF1425000), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161413). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Histiocytic sarcoma of the spleen without thrombocytopenia.

One case of histiocytic sarcoma of the spleen is reported. The patient, a 54-year-old female, presented with a huge soft tissue mass with a clear border and pseudo capsule in the splenic parenchyma on CT. The density of the mass was uneven, multifocal cystic necrosis and irregular bleeding were observed inside, but no calcification could be seen. On contrast-enhancement scan, the solid component of tumor exhibited moderate progressive enhancement, and area of cystic necrosis exhibited no enhancement. In MRI, T1WI showed mixed low signal, and T2WI showed mixed slightly high signal. The pathological diagnosis was histiocytic sarcoma.

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7.

BACKGROUND: 3M syndrome is a rare autosomal recessive developmental disorder characterized by pre and postnatal growth deficiency, dysmorphic facial features, and normal intelligence. 3M syndrome should be suspected in a proband with a combination of characteristic or recognizable dysmorphic features. The diagnosis of 3M syndrome could be confirmed by identifying biallelic variants in CUL7, OBSL1, or CCDC8. METHODS: Whole-exome sequencing (WES) was performed to identify genetic causes. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect aberrant splicing events. Haplotypes were constructed using multiplex PCR and sequencing. Variants of the parental haplotype and target likely pathogenic variants were detected by PCR and Sanger sequencing from the embryos. Copy number variant (CNV) detection was performed by next-generation sequencing. RESULTS: We present the case of a nonconsanguineous Chinese couple with one abnormal pregnancy, where the fetus showed 3M phenotypes of shortened long bones. WES identified two novel heterozygous mutations in CUL7: NM_014780.5:c.354del (p.Gln119ArgfsTer52) and NM_014780.5:c.1373-15G>A. RT-PCR from RNA of the mother's peripheral blood leucocytes showed that c.1373-15G>A caused the insertion of a 13-bp extra intron sequence and encoded the mutant p.Leu459ProfsTer25. Both variants were classified as likely pathogenic according to ACMG/AMP guidelines and Clinical Genome Resource specifications. During genetic counseling, the options of prenatal diagnosis through chorionic villus sampling or amniocentesis, adoption, sperm donation, and electing not to reproduce, as well as preimplantation genetic testing for monogenic disorders (PGT-M), were discussed. The couple hopes to conceive a child of their own and refused to accept the 25% risk during the next pregnancy and opted for PGT-M. They finally successfully delivered a healthy baby through PGT-M. CONCLUSION: This study expanded the mutation spectrum of CUL7, detected the aberrant splicing event of CUL7 via RT-PCR, constructed the haplotype for PGT-M, and demonstrated the successful delivery of a healthy baby using PGT-M.

Imaging Characteristics and Pathological Analysis of Primary Hepatic Neuroendocrine Neoplasms.

AIMS: To investigate the radiological characteristics of the PHNENs on CT and MRI and improve the understanding of the image manifestations and preoperative diagnosis of the disease. BACKGROUND: Primary hepatic neuroendocrine neoplasms (PHNENs) are rare diseases, and most of the relevant studies are case reports. Characterized by no specific clinical symptoms, PHNENs not only have a low preoperative diagnosis rate with great difficulty in early diagnosis but are frequently misdiagnosed as primary hepatic cancer. OBJECTIVE: 15 PHNEN patients were enrolled, with 10 cases in the G2 stage and 5 cases in the G3 stage. METHODS: The imaging and clinicopathological information of 15 patients pathologically diagnosed with PHNENs was retrospectively reviewed. RESULTS: The average age of the patients enrolled was 46.14±18.24 years, and the average tumor size was 91.00±61.17 mm. 13 cases showed nodules or masses, 8 cases were located in the periphery of the liver, showing capsule depression and subcapsular effusion signs. CT enhanced scan showed heterogeneous and obvious enhancement in 9 arterial-phase cases, 2 cases in arterial and portal venous phases both saw mild enhancement; the enhancement degree of lesions in the G2 stage in the arterial phase was significantly higher than in the G3 stage. Gd-EOB-DTPA dynamic enhanced MRI was conducted on 3 cases, and scattered lesions with heterogeneous and slight hyperintensity were observed in the hepatobiliaryspecific lesions. Image manifestations showed diffuse lesions in 2 cases, with heterogeneous enhancement in the arterial phase and decreased enhancement in the portal venous phase by the dynamic enhanced scan. CONCLUSION: PHNENs were the imaging characteristics of PHNENs. The CT-enhanced scanning during the arterial phase may provide a certain reference for pathological grading (G2 and G3 grades). Gd-EOB-DTPA-enhanced MRI is helpful for PHNEN diagnosis.

Lymphoepithelioma-like cholangiocarcinoma mimicking hepatocellular carcinoma.

Lymphoepithelioma like cholangiocarcinoma (LELCC) is a rare low-grade malignancy with a favorable prognosis. This sarcoma has a strong association with Epstein-Barr virus (EBV). Most of these have been benign, with some malignant instances noted as well. In our case, this tumor exhibited imaging characteristics of HCC. When patients showed recurrent tonsillitis at an early age, AFP did not change significantly, and there was no previous history of hepatitis B. In such scenario, diagnosis of LELCC should be considered.

Toxic vascular effects of polystyrene microplastic exposure.

Polystyrene microplastics (PSMPs) are some of the most common microplastic components, and the resulting pollution has become a global problem. Extensive studies have been conducted on the toxic effects of PSMPs on the heart, lungs, liver, kidneys, nerves, intestines and other tissues. However, the impact of PSMPs on vascular toxicity is poorly understood at present. The aim of this study was to reveal the vascular toxicity of microplastics (MPs). Patients were assigned to a calcification group (25 patients) or a non-calcification group (22 patients) based on the presence or absence of calcification in the thoracic aorta wall. We detected 7 polymer types in human feces. Patients with vascular calcification (VC) had higher levels of total MPs, polypropylene (PP) and polystyrene (PS) in feces than patients without VC. The thoracic aortic calcification score was significantly positively correlated with the total MP abundance (Spearman r = 0.8109, p < 0.0001), PP (Spearman r = 0.7211, p = 0.0160) and PS (Spearman r = 0.6523, p = 0.0471) in feces. We then explored the effects of PSMP exposure on normal and vitamin D3 + nicotine (VDN)-treated rats. PSMP exposure induced mild VC in normal rats and aggravated VC in VDN-treated rats. PSMP exposure disturbed the gut microbiota, causing Proteobacteria and Escherichia_Shigella to be the dominant phylum and genus, respectively. It also induced intestinal inflammatory responses in normal rats, aggravated intestinal inflammation in VDN-treated rats, impaired the intestinal mucosal barrier, and increased intestinal permeability. This study provides a theoretical basis for the risk assessment of MP-induced cardiovascular disease.

The effect of peak serum estradiol level during ovarian stimulation on cumulative live birth and obstetric outcomes in freeze-all cycles.

Objective: To determine whether the peak serum estradiol (E2) level during ovarian stimulation affects the cumulative live birth rate (CLBR) and obstetric outcomes in freeze-all cycles. Methods: This retrospective cohort study involved patients who underwent their first cycle of in vitro fertilization followed by a freeze-all strategy and frozen embryo transfer cycles between January 2014 and June 2019 at a tertiary care center. Patients were categorized into four groups according to quartiles of peak serum E2 levels during ovarian stimulation (Q1-Q4). The primary outcome was CLBR. Secondary outcomes included obstetric and neonatal outcomes of singleton and twin pregnancies. Poisson or logistic regression was applied to control for potential confounders for outcome measures, as appropriate. Generalized estimating equations were used to account for multiple cycles from the same patient for the outcome of CLBR. Results: A total of 11237 patients were included in the analysis. Cumulatively, live births occurred in 8410 women (74.8%). The live birth rate (LBR) and CLBR improved as quartiles of peak E2 levels increased (49.7%, 52.1%, 54.9%, and 56.4% for LBR; 65.1%, 74.3%, 78.4%, and 81.6% for CLBR, from the lowest to the highest quartile of estradiol levels, respectively, P<0.001). Such association remained significant for CLBR after accounting for potential confounders in multivariable regression models, whereas the relationship between LBR and peak E2 levels did not reach statistical significance. In addition, no significant differences were noticed in adverse obstetric and neonatal outcomes (gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, placental disorders, preterm birth, low birthweight, and small for gestational age) amongst E2 quartiles for either singleton or twin live births, both before and after adjustment. Conclusion: In freeze-all cycles, higher peak serum E2 levels during ovarian stimulation were associated with increased CLBR, without increasing the risks of adverse obstetric and neonatal outcomes.

Novel mutations in PLCZ1 lead to early embryonic arrest as a male factor.

Early embryonic arrest is one of the causes of assist reproduction technology (ART) failure. We have previously reported that the first sperm-derived genetic factor, ACTL7a mutations, could lead to early embryonic arrest. However, whether there are other male genetic factors associated with early embryonic arrest remains elusive. Here, we reported bi-allelic mutations in PLCZ1, a well-known causal gene of total fertilization failure, in four infertile males. Among these mutations, p.403_404del, p.I489S, and p.W536X were newly reported in this study. Histological and Western blotting analysis of the patients' sperm indicated these variants as loss-of-function mutations. These patients manifested normal conventional semen parameters and ultra-structures in sperm heads. However, among four in vitro fertilization (IVF) cycles, 81.8% (18/22) of the oocytes were polyspermic fertilized, which was rarely reported in PLCZ1-related male patients. In the following six ICSI cycles, artificial oocyte activation (AOA) was applied and successfully rescued the fertilization failure and polyspermy phenotypes, with 31.3% (15/48) of the MII oocytes normally fertilized. However, 60.0% (9/15) of these normally fertilized zygotes were arrested at 2-5-cell stage, with one failing to cleave, indicating that PLCZ1 was not only necessary for fertilization, but also crucial for early embryonic development. However, these rescued zygotes showed a lower potential in developing into blastocysts when cultured in vitro. Thus, fresh cleavage transfer was tried and two live births were successfully achieved thereafter. In conclusion, this study provided novel mutations in PLCZ1 gene to expand the pathogenic mutational spectrum in male infertility and demonstrated that PLCZ1 was a crucial sperm-related genetic factor for early embryonic arrest. We also proposed that cleavage transfer after ICSI and AOA treatment could be a potential treatment method for male patients carrying bi-allelic mutations in PLCZ1.

Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization: A Randomized Clinical Trial.

Importance: Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate. Objective: To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure. Design, Setting, and Participants: A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021). Interventions: Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy. Main Outcomes and Measures: The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks' gestation with signs of life. Results: Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, -1.0% [95% CI, -8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights. Conclusions and Relevance: Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800018783.

Local glucose elevation activates pyroptosis via NLRP3 inflammasome in ovarian granulosa cells of overweight patients.

Overweight, with an increasing prevalence worldwide, significantly impairs the clinical outcomes following in vitro fertilization (IVF). Hyperglycemia, hyperlipidemia, and metabolic disorders are always accompanied by the majority of overweight patients. The association between granulosa cell function and metabolic alterations in follicular fluid including lipids, proteins, and growth factors has been extensively documented. However, the effects of higher glucose level on ovarian granulosa cells (GCs), remain largely unknown. In this study, we identified that overweight women had elevated follicular glucose level which profoundly activated NLRP3 inflammasome and pyroptosis. An in vitro correlation between follicular high glucose, NLRP3 inflammasome and pyroptosis was also established. More importantly, in granulosa cells of overweight patients, the activation of the NLRP3 inflammasome and pyroptosis induced by high glucose was involved in the dysregulation of estradiol synthesis. Our study may provide new options to interpretate and improve IVF outcomes in overweight women.

CT-measured body composition radiomics predict lymph node metastasis in localized pancreatic ductal adenocarcinoma.

BACKGROUND: To explored the value of CT-measured body composition radiomics in preoperative evaluation of lymph node metastasis (LNM) in localized pancreatic ductal adenocarcinoma (LPDAC). METHODS: We retrospectively collected patients with LPDAC who underwent surgical resection from January 2016 to June 2022. According to whether there was LNM after operation, the patients were divided into LNM group and non-LNM group in both male and female patients. The patient's body composition was measured by CT images at the level of the L3 vertebral body before surgery, and the radiomics features of adipose tissue and muscle were extracted. Multivariate logistic regression (forward LR) analyses were used to determine the predictors of LNM from male and female patient, respectively. Sexual dimorphism prediction signature using adipose tissue radiomics features, muscle tissue radiomics features and combined signature of both were developed and compared. The model performance is evaluated on discrimination and validated through a leave-one-out cross-validation method. RESULTS: A total of 196 patients (mean age, 60 years ± 9 [SD]; 117 men) were enrolled, including 59 LNM in male and 36 LNM in female. Both male and female CT-measured body composition radiomics signatures have a certain predictive power on LNM of LPDAC. Among them, the female adipose tissue signature showed the highest performance (area under the ROC curve (AUC), 0.895), and leave one out cross validation (LOOCV) indicated that the signature could accurately classify 83.5% of cases; The prediction efficiency of the signature can be further improved after adding the muscle radiomics features (AUC, 0.924, and the accuracy of the LOOCV was 87.3%); The abilities of male adipose tissue and muscle tissue radiomics signatures in predicting LNM of LPDAC was similar, AUC was 0.735 and 0.773, respectively, and the accuracy of LOOCV was 62.4% and 68.4%, respectively. CONCLUSIONS: CT-measured body composition Radiomics strategy showed good performance for predicting LNM in LPDAC, and has sexual dimorphism. It may provide a reference for individual treatment of LPDAC and related research about body composition in the future.

Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling.

BACKGROUND: Vascular calcification is a major cause of the high morbidity and mortality of cardiovascular diseases and is closely associated with the intestinal microbiota. Short-chain fatty acids (SCFAs) are derived from the intestinal microbiota and can also regulate intestinal microbiota homeostasis. However, it remains unclear whether exogenous supplementation with propionate, a SCFA, can ameliorate vascular calcification by regulating the intestinal microbiota. This study was conducted to explore the roles of propionate and the intestinal microbiota in the process of vascular calcification. METHODS: In total, 92 patients were enrolled consecutively as the observational cohort to analyse the relationship between SCFAs and vascular calcification in both blood and faecal samples. A rat model of vascular calcification was induced by vitamin D3 and nicotine (VDN) to validate the effect of propionate. Differences in the intestinal microbiota were analysed by 16S ribosomal RNA gene sequencing. Faecal microbiota transplantation and Akkermansia muciniphila transplantation experiments were performed to evaluate the functions of the intestinal microbiota. RESULTS: The results of the observational cohort study revealed that the levels of SCFAs (particularly propionate) in both blood and faecal samples independently correlated negatively with calcification scores (P < 0.01). To verify the activities of propionate, it was provided to VDN-treated rats, and oral or rectal propionate delivery reshaped the intestinal microbiota, resulted in elevated SCFA production, improved intestinal barrier function and alleviated inflammation, ultimately ameliorating vascular calcification. Furthermore, we demonstrated that transplantation of the propionate-modulated intestinal microbiota induced beneficial outcomes similar to those with oral or rectal propionate administration. Interestingly, linear discriminant analysis (LDA) effect size (LEfSe) revealed that oral or rectal propionate administration and propionate-modulated intestinal microbiota transplantation both enriched primarily Akkermansia. Subsequently, we demonstrated that Akkermansia supplementation could ameliorate VDN-induced vascular calcification in rats. CONCLUSIONS: Propionate can significantly ameliorate vascular calcification in VDN-treated rats, and this effect is mediated by intestinal microbiota remodelling. The findings in our study indicate that the intestinal tract-vessel axis is a promising target for alleviating vascular calcification. Video Abstract.

Follicular fluid lipidomic profiling reveals potential biomarkers of polycystic ovary syndrome: A pilot study.

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with multiple metabolic conditions including obesity, insulin resistance, and dyslipidemia. PCOS is the most common cause of anovulatory infertility; however, the molecular diversity of the ovarian follicle microenvironment is not fully understood. This study aimed to investigate the follicular fluid (FF) lipidomic profiles in different phenotypes of PCOS and to explore novel lipid biomarkers. Methods: A total of 25 women with PCOS and 12 women without PCOS who underwent in vitro fertilization and embryo transfer were recruited, and their FF samples were collected for the lipidomic study. Liquid chromatography-tandem mass spectrometry was used to compare the differential abundance of FF lipids between patients with different PCOS phenotypes and controls. Subsequently, correlations between specific lipid concentrations in FF and high-quality embryo rate (HQER) were analyzed to further evaluate the potential interferences of lipid levels with oocyte quality in PCOS. Candidate biomarkers were then compared via receiver operating characteristic (ROC) curve analysis. Results: In total, 19 lipids were identified in ovarian FF. Of these, the concentrations of ceramide (Cer) and free fatty acids (FFA) in FF were significantly increased, whereas those of lysophosphatidylglycerol (LPG) were reduced in women with PCOS compared to controls, especially in obese and insulin-resistant groups. In addition, six subclasses of ceramide, FFA, and LPG were correlated with oocyte quality. Twenty-three lipid subclasses were identified as potential biomarkers of PCOS, and ROC analysis indicated the prognostic value of Cer,36:1;2, FFA C14:1, and LPG,18:0 on HQER in patients with PCOS. Conclusions: Our study showed the unique lipidomic profiles in FF from women with PCOS. Moreover, it provided metabolic signatures as well as candidate biomarkers that help to better understand the pathogenesis of PCOS.