A combined clinical and specific genes' model to predict live birth for in vitro fertilization and embryo transfer patients.

BACKGROUND: We aimed to develop an accurate model to predict live birth for patients receiving in vitro fertilization and embryo transfer (IVF-ET) treatment. METHODS: This is a prospective nested case-control study. Women aged between 18 and 38 years, whose body mass index (BMI) were between the range of 18.5-24 kg/m2, who had an endometrium of ≥ 8 mm at the thickest were enrolled from 2018/9 to 2020/8. All patients received IVF-ET treatment and were followed up until Jan. 2022 when they had reproductive outcomes. Endometrial samples during the window of implantation (LH + 6 to 9 days) were subjected to analyze specific endometrial receptivity genes' expression using real-time PCR (RT-PCR). Patients were divided into live birth group and non-live birth group based on IVF-ET outcomes. Clinical signatures relevant to live birth were collected, analyzed, and used to establish a predictive model for live birth by univariate analysis (clinical model). Specific endometrial receptivity genes' expression was analyzed, selected, and used to construct a predictive model for live birth by The Least Absolute Shrinkage and Selection Operator (LASSO) analysis (gene model). Finally, significant clinical factors and genes were used to construct a combined model for predicting live birth using multivariate logistical regression (combined model). Different models' Area Under Curve (AUC) were compared to identify the most predictive model. RESULTS: Thirty-nine patients were enrolled in the study, twenty-four patients had live births, fifteen did not. In univariate analysis, the odds of live birth for women with ovulation dysfunction was 4 times higher than that for women with other IVF-ET indications (OR = 4.0, 95% CI: 1.125 - 8.910, P = 0.018). Age, body mass index, duration of infertility, primary infertility, repeated implantation failure, antral follicle counting, ovarian sensitivity index, anti-Mullerian hormone, controlled ovarian hyperstimulation protocol and duration, total dose of FSH/hMG, number of oocytes retrieved, regiment of endometrial preparation, endometrium thickness before embryo transfer, type of embryo transferred were not associated with live birth (P > 0.05). Only ovulation dysfunction was used to construct the clinical model and its AUC was 0.688. In lasso analysis, GAST, GPX3, THBS2 were found to promote the risk of live birth. AUCs for GAST, GPX3, THBS2 reached to 0.736, 0.672, and 0.678, respectively. The gene model was established based on these three genes and its AUC was 0.772. Ovulation dysfunction, GAST, GPX3, and THBS2 were finally used to construct the combined model, reaching the highest AUC (AUC = 0.842). CONCLUSIONS: Compared to the single model, the combined model of clinical (Ovulation dysfunction) and specific genes (GAST, GPX3, THBS2) was more accurate to predict live birth for IVF-ET patients.

Prediction model for day 3 embryo implantation potential based on metabolites in spent embryo culture medium.

BACKGROUND: Metabolites in spent embryo culture medium correlate with the embryo's viability. However, there is no widely accepted method using metabolite dada to predict successful implantation. We sought to combine metabolomic profiling of spent embryo culture medium and clinical variables to create an implantation prediction model as an adjunct to morphological screening of day 3 embryos. METHODS: This investigation was a prospective, nested case-control study. Forty-two day 3 embryos from 34 patients were transferred, and the spent embryo culture medium was collected. Twenty-two embryos implanted successfully, and the others failed. Metabolites in the medium relevant to implantation were detected and measured by Liquid Chromatography-Mass Spectrometry. Clinical signatures relevant to embryo implantation were subjected to univariate analysis to select candidates for a prediction model. Multivariate logistical regression of the clinical and metabolomic candidates was used to construct a prediction model for embryo implantation potential. RESULTS: The levels of 13 metabolites were significantly different between the successful and failed groups, among which five were most relevant and interpretable selected by Least Absolute Shrinkage and Selection Operator regression analysis. None of the clinical variables significantly affected day 3 embryo implantation. The most relevant and interpretable set of metabolites was used to construct a prediction model for day 3 embryo implantation potential with an accuracy of 0.88. CONCLUSIONS: Day 3 embryos'implantation potential could be noninvasively predicted by the spent embryo culture medium's metabolites measured by LC-MS. This approach may become a useful adjunct to morphological evaluation of day 3 embryos.

Immunoregulatory Therapy Improves Reproductive Outcomes in Elevated Th1/Th2 Women with Embryo Transfer Failure.

Objective: Immunological disturbance is one of the crucial factors of implantation failure. Limited data exists evaluating immunoregulatory therapy in patients with implantation failures. Methods: This is a retrospective cohort study on patients who had failed embryo transfer cycle and had elevated Th1/Th2 cytokine ratios between 1/2019 and 3/2020. Patients were assigned into two groups based on whether they received immunoregulatory treatment during a frozen transfer cycle. The primary outcome was live birth rate. Secondary outcomes included clinical pregnancy, implantation rate, and neonatal outcomes. Results: Of 71 patients enrolled, 41 patients received immunoregulatory therapy and 30 patients did not. Compared to untreated patients, rate of live birth was significantly elevated in the treated group (41.5% vs. 16.7%, P = 0.026). Rate of biochemical pregnancy, implantation, clinical pregnancy, and ongoing pregnancy between two groups were 56.1% vs. 40% (P = 0.18), 36.5% vs. 23.9% (P = 0.15), 51.2% vs. 30% (P = 0.074), and 41.5% vs. 16.7% (P = 0.03), respectively. Although there was no statistical significance, women receiving treatment also had a tendency of lower frequency of pregnancy loss (19.0% vs. 44.4%, P = 0.20). No adverse events were found between newborns of the two groups. Immunoregulatory therapy, age, infertility type, ovulation induction protocol, number of oocytes retrieved, artificial cycle embryo transfer, and cleavage transfer were associated with live birth in univariate analysis (all P < 0.05). Only immunoregulatory therapy was associated with live birth after adjustment of confounders (OR = 5.02, 95% CI: 1.02-24.8, P = 0.048). Conclusions: Immunoregulatory therapy improves reproductive outcomes in elevated Th1/Th2 cytokine ratio women with embryo transfer failure.

The outcomes of pregnant and postpartum patients with cerebral venous sinus thrombosis after anticoagulant therapy.

BACKGROUND: To describe the outcome of the patients with cerebral venous sinus thrombosis (CVST) during pregnancy and postpartum treated with anticoagulant therapy. METHODS: This is a retrospective cohort study and patients with CVST were collected from October 2009 to March 2018. Patients were divided into pregnancy-related (occurred during pregnancy and postpartum) group and non-pregnancy-related. Recovery rate at 12 months after anticoagulant therapy, adverse events, characteristics of patients with poor outcomes were statistically analyzed. RESULTS: Fifty-eight pregnancy-related CVST patients (17 pregnancy and 41 postpartum) as study group and 76 non-pregnancy-related CVST women as control group were enrolled. Study group was statistically different to control group in several baseline variables. More pregnancy-related patients had modified rankin scale (mRS) = 5 (15.5% vs 11.8%, P = 8.1×10-3) before anticoagulant therapy. At 12 months heparinization, difference in recovery rate was not statistically significant (80% vs 87.5%, P = .29) between 2 groups. No differences were found of adverse events between 2 groups. Patients with poor outcomes had less sigmoid sinus thrombosis (16.7% vs 61.5%, P = .14), more coma (41.2% vs 17.2%, P = 5.2×10-7), more mRS = 4 (33.3% vs 19.2%, P = 1.63 × 10-4), more mRS = 5 (66.7% vs 9.6%, P = 1.63 × 10-4) before treatment. CONCLUSION: Pregnancy-related CVST patients had severer condition before treatment, but can achieve comparable recovery rate at 12 months after anticoagulant therapy with non-pregnancy-related women. Pregnancy-related patients with poor prognosis had less sinus sigmoid occlusion, more coma, high mRS at admission.

Abnormal IL-10 levels were related to alanine aminotransferase abnormalities during postpartum in HBeAg positive women with chronic hepatitis B.

Alanine transaminase (ALT) abnormalities are common in chronic hepatitis B (CHB) carriers during postpartum period. Disturbances in cytokines are considered to be associated with hepatitis Flares. There are limited data on cytokines changes in HBeAg positive patients with ALT abnormalities.This is an observational study. Pregnant patients with hepatitis B e-antigen (HBeAg) positive were enrolled from January 2014 to September 2018. Patients were assigned into three groups based on ALT levels in postpartum 6 to 8 weeks: ALT in normal range, ALT in 1 to 2-fold upper limits of normal (ULN) and ALT >2-fold ULN. Serum cytokines, ratios of regulatory T cells, and the concentration of cortisol were collected and compared among the three groups.Of the 135 mothers enrolled, 80.7% (109/135) completed the postpartum 6-week study. 13.8% (15/109) patients had postpartum ALT higher than 2ULN, 27.5% (30/109) patients had ALT in 1 to 2ULN and 58.7% (64/109) patients had ALT in normal range. Compared to control group, patients with ALT >2ULN had a higher IL-10 level (P < .05). No differences of IL-10 levels were found in the comparison of other inter comparison among three groups. No differences were found in the levels of other collected serum cytokines, cortisol, and regulatory T cells among three groups. On multivariate analysis, abnormal IL-10 level was independent risk factor for postpartum ALT elevating >2ULN. At the same time, the incidence of postpartum ALT elevated >2ULN were higher in patients with abnormal elevation IL-10 level than in patients with normal IL-10 level (14/68 vs 1/41, P = .008).CHB patients with postpartum ALT abnormalities show higher IL-10 level and postpartum ALT abnormalities were mainly occurred in patients with abnormal IL-10 level. IL-10 may be an underlying predictor and treatment target of hepatitis B, and further studies are needed.

E2F1-directed activation of nc886 mediates drug resistance in cervical cancer cells via regulation of major vault protein.

Non-coding RNAs are critical regulators of tumor biology. nc886, a recently identified non-coding RNA, is overexpressed in some tumors, but undetected in others. However, the precise role of nc886 remains unclear in cervical cancers. In this study, we found that nc886, major vault protein (MVP), and E2F1 exhibited coordinate expression as they were silenced in normal tissues but overexpressed in cervical cancer tissues. We subsequently demonstrate that nc886 upregulation was a critical response to chemotherapy treatment of cervical cancer cells. Mechanistically, inhibition of nc886 increased chemosensitivity, induced apoptosis, and suppressed the protein expression of MVP, a critical regulator of drug resistance. Furthermore, we identify E2F1 as a key transcription regulator of nc886 that directly interacts and modulates promoter activity. Taken together, we demonstrate that E2F1 sufficiently promotes nc886 transcription and in turn MVP expression to drive drug resistance in cervical cancer cells.