Yan Zhao’s research while affiliated with Jiangxi Academy of Sciences and other places

Background Prior research showed that elevated serum uric acid (SUA) levels in women with polycystic ovary syndrome (PCOS) before in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) treatment can lead to a lower rate of live birth and an increased risk for low birthweight. Nonetheless, it is not known whether elevated SUA results in similar reproductive outcome in women without PCOS. This study aimed to exploring the relationship between pre-pregnancy SUA levels and reproductive outcomes in non-PCOS women undergoing IVF/ICSI treatment. Methods This single-center, retrospective study included 13,325 women without PCOS undergoing their first IVF/ICSI fresh embryo transfer cycles from January 2014 to December 2022 at a university-affiliated reproductive medicine center in China. The trends for pregnancy, obstetric and perinatal outcomes across quartiles of SUA levels were assessed. A logistic regression analysis was applied to control for baseline and cycle characteristics. Generalized addition model was used to draw spline smoothing plot. Results There was no significant decreasing or increasing trend in the clinical pregnancy rate and live birth rate with the increase in quartiles of SUA levels. For Obstetric and perinatal outcomes following a single live birth, the percentage of hypertensive disorders in pregnancy (1.6–4.1%, Ptrend<0.001), gestational diabetes mellitus (5.9–13.9%, Ptrend<0.001), premature rupture of membranes (0.6–1.5%, Ptrend=0.016), preterm birth (6.3–9.2%, Ptrend=0.009), macrosomia (2.3–5.5%, Ptrend<0.001), large for gestational age (10.8–14.9%, Ptrend=0.002) all increased significantly from the lowest quartile to the highest. Logistic regression results showed that compared with those in quartile 1, the risk of maternal and infant complications mentioned above was still significantly higher in quartile 4 after adjusting for reproductive related factors. When further confounding factors were added, including body mass index (BMI), blood pressure, fasting blood glucose, and blood lipids related indicators, only gestational diabetes mellitus and macrosomia showed a significant increase. Conclusion In women without PCOS, SUA levels before IVF/ICSI treatment do not affect the probabilities of clinical pregnancy and live birth. An elevated SUA level is associated with an increased risk for hypertensive disorders in pregnancy, gestational diabetes mellitus, premature rupture of membranes, preterm birth, macrosomia, and large for gestational age. For gestational diabetes mellitus and macrosomia, the association is independent of BMI, blood pressure, blood glucose, and blood lipid.

Background: Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by insulin resistance and inadequate insulin production. Given the increased frequency of T2DM and the health issues it can cause, there is an increasing need to develop alternative T2DM management strategies. One such approach is Chinese Medicine (CM), a complementary therapy widely used in T2DM treatment. Given the emphasis on gut microbiota in current research, studying CM in the treatment of T2DM via gut microbiota modulation could be beneficial. Scope and approach: The use of various CM methods for managing T2DM via gut microbiota modulation is highlighted in this review. Following an introduction of the gut microbiota and its role in T2DM pathogenesis, we will review the potential interactions between gut microbiota and T2DM. Thereafter, we will review various CM treatment modalities that modulate gut microbiota and provide perspectives for future research. Key findings and discussion: In T2DM, Akkermansia, Bifidobacterium, and Firmicutes are examples of gut microbiota commonly imbalanced. Studies have shown that CM therapies can modulate gut microbiota, leading to beneficial effects such as reduced inflammation, improved metabolism, and improved immunity. Among these treatment modalities, Chinese Herbal Medicine and acupuncture are the most well-studied, and several in vivo studies have demonstrated their potential in managing T2DM by modulating gut microbiota. However, the underlying biomolecular mechanisms of actions are not well elucidated, which is a key area for future research. Future studies could also investigate alternate CM therapies such as moxibustion and CM exercises and conduct large-scale clinical trials to validate their effectiveness in treatment.

Background Diminished ovarian reserve (DOR) is clinically characterized by a decrease in the number of available ovarian follicles and a decline in the quality of oocytes, accompanied by hormonal changes. Low quality of DOR oocyte leads to impaired embryo development, an increased risk of aneuploid pregnancies and miscarriages. However, the specific pathogenic mechanism remains unclear, posing a significant challenge for assisted reproductive technology. Methods For the first time, our study employed single-cell RNA sequencing to reveal the altered transcriptomic landscape of DOR oocytes at GV stage after ovarian stimulation. Differentially expressed genes analysis (DEGs), functional enrichment analysis, weighted gene co-expression network analysis (WGCNA) and protein-protein interactions network analysis were performed. Results We found 132 up-regulated genes and 466 down-regulated genes in DOR oocytes, with the down-regulated genes primarily enriched in mitochondrial function and translation. Hub genes, identified through integrated analysis of WGCNA and DEGs, were further validated in DOR and control oocytes using RT-qPCR. By utilizing hub genes and employing transcription factor enrichment tools, it had been predicted that pleomorphic adenoma gene 1 (PLAG1) played a crucial role as a transcriptional regulatory factor in DOR oocytes. Additionally, we conformed the PLAG1-IGF2 axis was dysregulated in DOR oocytes. Conclusions Transcriptome analysis revealed that DOR oocytes exhibited mitochondrial dysfunction and translational defects, and the PLAG1-IGF2 axis might be a potential contributor for the low quality of DOR oocytes.

Background It has been recognized that the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol has a detrimental effect on clinical outcomes compared to the GnRH agonist (GnRH-a) protocol during in vitro fertilization-fresh embryo transfer (IVF-ET) cycles. However, the related mechanisms were unclear. Methods A total of 18,561 patients, who underwent fresh IVF-ET cycles in the Center for Assisted Reproduction of Jiangxi Maternal and Child Health Hospital from January 2014 to September 2021, were retrospectively analyzed. The propensity score matching (PSM) technique was used to control for confounding factors between the GnRH-ant and GnRH-a groups. Human endometrial stromal cells (hESCs) were collected for primary culture and treated with relevant receptor antagonists and activators. RT-PCR, Western Blot, immunofluorescence staining, cell migration and adhesion assays, and animal experiments were employed to elucidate the molecular mechanism by which GnRH antagonist affects the migration and adhesion ability of hESCs. Results There was no statistical difference between the two groups in terms of baseline characteristics after matching basal status by propensity score matching. The result showed that the endometrial thickness (10.4 ± 2.35 vs. 11.03 ± 2.61 mm, p < .001) on trigger day was significantly lower in the GnRH-ant group. Compared with the GnRH-a protocol, the implantation rate (39.71% vs. 50.36%, p < .001), biochemical pregnancy rate (64.26% vs. 72.7%, p < .001), clinical pregnancy rate (56.39% vs. 65.24%, p < .001), live birth rate (45.25% vs. 56.1%, p < .001) in the GnRH-ant group were significantly decreased. Contrarily, the rate of early miscarriage in the GnRH-ant group (13.95% vs. 9.04%, p < .001) was higher than in the GnRH-a group. Furthermore, after treating with GnRH-ant, hESCs showed a reduced expression of HOXA10 and MMP-9 proteins, and a weakened migration ability. Subsequently, by establishing the co-culture system of hESCs and JAR trophoblast spheroids, we found that GnRH-ant inhibited the adhesion and invasion ability of trophoblast cells. Moreover, we also found a decreased expression and phosphorylation of c-kit receptor in decidualized hESCs after treating with GnRH-ant. Similar results as observed above were also confirmed when inhibiting the activation of c-kit receptor by imatinib. Conclusions GnRH-ant could reduce the motility of hESCs by inhibiting the expression and activation of the C-kit receptor, which impaired the process of embryo implantation.

Background The cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations. Methods This retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation. Results Predictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05. Conclusions This study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator (https://h5.eheren.com/hcyc/pc/index.html#/home). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

Background Trophectoderm (TE) cell biopsy at the blastocyst stage is currently the predominant method used in preimplantation genetic testing for monogenic disorders (PGT-M). However, this approach may result in the discarding of genetically unaffected embryos due to the fact that not all embryos progress to the blastocyst stage. This study aimed to investigate the advantages of utilizing polar body (PB) biopsy in females with disease-causing mutations and a limited number of oocytes undergoing PGT-M. Methods Three couples with females carrying autosomal dominant or X-linked mutations in IRF6, FMR1, and EDA were recruited. The number of retrieved oocytes was no more than six per cycle. The first and second PBs (PB1 and PB2) of each oocyte were individually biopsied and subjected to multiple displacement amplification (MDA). The genotype of each embryo was deduced by analyzing the MDA products of corresponding PB1 and PB2 using a novel strategy that combined direct mutation testing and single nucleotide polymorphism linkage analysis. Mutation-free embryos cryopreserved before the blastocyst stage were selected to transfer. Results In total, four cycles were conducted resulting in the retrieval of 15 oocytes for the three couples. The genotype of each embryo was successfully determined. Seven mutation-free embryos were identified. Three of them were transferred and resulted in two clinical pregnancies, culminating in the birth of two healthy babies. The accuracy of the embryo genotypes was validated through genetic testing of the fetuses in the second trimester or at birth. Conclusions The PB-based strategy is feasible and effective to detect the mutation carrier statuses of embryos in PGT-M for maternal mutations. Compared with blastocyst stage detection, this method may preserve a higher number of genetically unaffected embryos for the patients. Further clinic trials are warranted to verify whether PB biopsy offers greater benefits than TE cell biopsy for females with disease-causing mutations and a limited number of oocytes in PGT-M.

Background This study aimed to investigate the rates and causality of patient-reported adverse events (AEs) associated with concomitant Chinese Herbal Medicine (CHM) and Western Medicine prescription drug (WMPD) consumption through active surveillance in Singapore’s Traditional Chinese Medicine (TCM) clinics. Methods A cross-sectional study was conducted at five TCM clinics across Singapore from 8th May till 8th July 2023. Patients were screened to determine rates of CHM and WMPD consumption, and then interviewed if an AE was reported. An expert committee assessed the AE reports to determine causality. Along with descriptive statistics, odds ratios were calculated to determine AE occurrence likelihoods for patients who consumed both CHM and WMPD compared to CHM consumption alone. Results 1028 patients were screened and 62.65% of them reported concurrent CHM-WMPD consumption. Patients who consumed CHM and WMPD were 3.65 times more likely to experience an AE as compared to CHM consumption alone. 18 AE reports were adjudicated, with most AEs deemed unlikely due to CHM consumption. Conclusions A large proportion of patients consumed CHM and WMPD concurrently, thus increasing their risk of experiencing AEs compared to those consuming CHM only. Active surveillance is applicable for detecting AEs, collecting data for causality assessment, and analysis.

Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24–74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m ² intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43–79%) and 68% (95%CI, 47–84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45–83%) and 86% (95%CI, 63–95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.