Xiaoting Shen

Background: The rising prevalence of infertility has substantially increased the demand for in vitro fertilization (IVF). While various controlled ovarian stimulation (COS) protocols exist, the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is valued for its efficacy in preventing premature luteinizing hormone (LH) surges. However, it involves high medication costs and requires frequent injections, which impose a significant burden on patients. Clomiphene citrate (CC), a classic oral ovulation induction agent, offers advantages such as low cost and convenient administration. With the widespread adoption of the “freeze-all” strategy, its potential adverse impact on the endometrium can be mitigated. Recent modifications to the CC protocol, combining it with adequate-dose gonadotropins, aim to balance efficacy and cost. However, well-designed studies directly comparing this modified CC protocol with the conventional GnRH-ant protocol in a general IVF population are lacking, particularly those incorporating comprehensive cost-effectiveness analyses. Methods: 3,157 patients undergoing IVF or intracytoplasmic sperm injection (ICSI) cycles using either the CC protocol or the GnRH-ant protocol were matched 1:1 using propensity score matching (PSM) based on female age, basal follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), antral follicle count (AFC), body mass index (BMI), fertilization method, and sperm source. A total of 1,858 patients (929 per group) were included after matching. Embryological parameters and pregnancy outcomes were compared between the two groups, along with cost-effectiveness and sensitivity analyses. Results: Baseline characteristics were well-balanced after PSM (with almost all standardized mean differences (SMD) < 0.1). The clinical pregnancy rate was comparable between the CC group and the GnRH-ant group (46.26% vs. 41.07%, P = 0.113), and the cumulative clinical pregnancy rate was also similar (51.60% vs. 51.79%, P = 1.000). The live birth rate (35.48% vs. 31.95%, P = 0.268) and cumulative live birth rate (35.48% vs. 38.29%, P = 0.398) were also comparable between the two groups. Compared to the GnRH-ant group, the CC group exhibited a higher Day 3 embryo formation rate (66.67% vs. 62.50%, P = 0.012), despite having lower numbers of follicles on the day of hCG trigger and retrieved oocytes (9.00 vs. 10.00 and 6.00 vs. 8.00, P < 0.0001). No significant differences were observed in the oocyte retrieval rate, oocyte maturation rate, fertilization rate, and blastulation rate between two groups. The cost of COS in the CC group was significantly lower than that in the GnRH-ant group (1,414.70 [741.50-2,915.50] CNY [~198 USD] vs. 7,266.24 [5,747.64-9,011.05] CNY [~1,017 USD], P < 0.0001), representing a saving of approximately 5,851.54 CNY (~819 USD; 80.53%). Cost-effectiveness analysis indicated that the CC protocol was superior across all outcome measures, including incremental cost-effectiveness ratios (ICERs) for oocyte, embryo, and clinical pregnancy. One-way sensitivity analysis (OWSA) indicated that the clinical pregnancy rate between the two groups was the most critical factor influencing the ICER for clinical pregnancy. Probabilistic sensitivity analysis (PSA) also suggested that in 98.50% of simulations, the CC protocol was more cost-saving. Conclusions: The modified CC protocol was associated with ovarian stimulation effects and clinical outcomes comparable to those of the GnRH-ant protocol. Furthermore, it represented a more cost-effective ovarian stimulation strategy, significantly reducing treatment costs while maintaining a clinical pregnancy rate comparable to that of the GnRH-ant protocol.

Selective gene expression is pivotal in orchestrating human development. Specifically, trithorax group (TrxG) and polycomb group (PcG) components play crucial roles in transcriptional activation and repression of state-specific stem cell expression programs, yet the mechanisms underlying their selective genomic binding remain poorly understood. In this study, we report that the polycomb repressive complex 1 (PRC1) subunit RYBP co-localizes with TrxG component WDR5 and selectively enriches PcG component RING1B in condensates in murine embryonic stem cells (ESCs). RYBP deficiency impairs the genomic binding of WDR5 and RING1B. Further, STAT3 excludes RING1B binding at RYBP-associated transcriptionally active loci. Additionally, RYBP depletion attenuates WDR5-dependent activation of DNA repair gene expression and facilitates the transition of ESCs to 2-cell-like cells. Finally, RYBP depletion disrupts RING1B deposition at lineage-specific genes, promoting ESC differentiation towards mesendoderm fate. These findings uncover RYBP as a regulator of selective genomic binding of TrxG and PcG components, providing insights into their roles in cell fate determination during development.

Purpose Current embryo selection is limited by fragmented morphological assessments, high resource demands of image-based Artificial Intelligence, and inadequate integration of clinical factors. This study aims to establish a unified multi-day assessment framework by developing an Improved Numerical Embryo Quality scoring index (INEQsi) and to provide a lightweight and robust tool for predicting embryo quality and pregnancy outcomes by integrating these standardized scores with clinical data through machine learning. Methods This study developed a multidimensional embryo scoring system based on established embryo grading standards and integrated other clinical variables to build a machine learning prediction model. By systematically evaluating and comparing multiple algorithms for predicting embryo quality scores and post-implantation pregnancy outcomes, the best prediction model was ultimately determined. Results The random forest model with INEQsi achieved high accuracy in predicting embryo quality for both cleavage-stage (RMSE: 1.26) and blastocyst-stage embryos (RMSE: 1.11–1.13), extending its predictive capability to Day 3. It outperformed NEQsi in pregnancy prediction, with a sensitivity of 0.99–1.00 (95% CI) on Day 5 and 93% accuracy on Day 6. Conclusion This study proposed a multitage embryo scoring system and combines it with machine learning to form a lightweight analytical framework. In this single-center retrospective analysis, the approach showed reasonable performance in assessing embryo quality and predicting clinical pregnancy outcomes, suggesting its potential as a supplementary tool in IVF decision-making where advanced imaging systems are not routinely used.

Unexplained miscarriage (UM) remains challenge due to unclear pathogenesis and biological mechanisms. BPB (Bisphenol B), an extensively used endocrine disrupting chemical, has been widely detected out in human. Migrasomes are newly identified cellular organelles with a large number of unknown functions. However, whether and how BPB exposure may suppress migrasome formation (MF) to induce miscarriage are completely unknown. In this study, it is found that higher urinary BPB levels are associated with the suppressed MF in villous tissues and unexplained miscarriage. It is further confirmed that BPB exposure suppresses MF in the mouse placenta and thus induces miscarriage. Supplement with Pkca or Tspan4, two essential proteins for migration/invasion (MI) and MF, can efficiently treat against BPB‐induced miscarriage. In biological mechanisms, BPB up‐regulates ER levels, enhances its interactions with the lnc‐HZ04 promoter region, and thus promotes ER‐mediated lnc‐HZ04 transcription. Subsequently, lnc‐HZ04 suppresses TCF4‐mediated PKCA transcription and subsequently suppresses MI and MF. Collectively, this study not only identifies BPB as a novel risk factor for unexplained miscarriage, discovers novel pathogenesis and biological mechanisms in BPB‐induced miscarriage, but also provides potential targets for treatment against unexplained miscarriage.

The issues of uncontrolled global population growth and unintended pregnancies are severe, and the existing contraceptive methods have numerous limitations, making the development of novel contraceptive technologies urgent. Contraceptive vaccines offer a promising alternative to traditional contraception methods. This article reviews the three developmental stages of contraceptive vaccines, including early exploration, technical bottlenecks, and innovative development directions in the new era. This article also summarizes the targets of immunocontraception, covering the current research status of contraceptive vaccines targeting sperm production, sperm antigens, oocyte zona pellucida, and gamete outcomes. Furthermore, this article explores the advantages of contraceptive vaccines in terms of efficiency, non-invasiveness, reversibility, and the promotion of gender equality. Challenges associated with clinical translation and real-world implementation are also critically analyzed.