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Zi-Jiang Chen and Yongyong Shi report a genome-wide association study for polycystic ovary syndrome, a common metabolic and endocrine disorder in women. They identified three susceptibility loci associated with this condition. Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P -value by meta-analysis P meta = 7.55 × 10 −21 , odds ratio (OR) 0.71); 2p21 (rs13429458, P meta = 1.73 × 10 −23 , OR 0.67); and 9q33.3 (rs2479106, P meta = 8.12 × 10 −19 , OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended.

Zi-Jiang Chen and colleagues report a genome-wide association analysis for polycystic ovary syndrome (PCOS) in Han Chinese. They identify eight new susceptibility loci for PCOS in this population. Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10 −8 : 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.

Background Assisted reproductive technology (ART) is the most effective method to treat infertility and the pathogenesis of implantation failure after in vitro fertilization-embryo transfer (IVF-ET) is a challenging filed in infertility. Microbes in the female reproductive tract are considered to be associated with gynecological and obstetric diseases. However, its effects on embryo implantation failure are unsured. Purpose This study aimed to investigate reproductive tract dysbiosis, identify different bacteria in reproductive tract as potential biomarkers of embryo implantation failure and demonstrate the pathogenesis through metabolites analysis. Methods We compared the data from 16S rRNA gene and metagenome in reproductive tracts through QIIME2 and HUMAnN2 by the times of embryo implantation failure on 239 infertile patients and 17 healthy women. Results Our study revealed a strong positive correlation between Lactobacillus abundance and embryo implantation success (IS) after IVF-ET. The microbial community composition and structure in reproductive tract showed substantially difference between the embryo implantation failure (IF) and healthy control. Moreover, we established a diagnostic model through receiver operating characteristic (ROC) with 0.913 area under curve (AUC) in IS and multiple implantation failures (MIF), verified its effectiveness with an AUC = 0.784 demonstrating microbial community alterations could efficiently discriminate MIF patients. Metagenome functional analyses of vaginal samples from another independent infertile patients after IVF-ET revealed the L-lysine synthesis pathway enriched in IF patients, along with ascended vaginal pH and decreased Lactobacillus abundance. Conclusions This study clarifies several independent relationships of bacteria in vagina and endometrial fluid on embryo implantation failure and undoubtedly broadens the understanding about female reproductive health.

Objective To investigate the feasibility of performing frozen-thawed high-quality single blastocyst transfer in women of different ages. Methods A total of 1,279 women were divided into four groups: a 38-40-year-old group ( n  = 147), 35-37-year-old group ( n  = 164), 30-34-year-old group ( n  = 483), and < 30-year-old group ( n  = 485). Intergroup comparisons of baseline characteristics and pregnancy and neonatal outcomes were made. Results The clinical pregnancy rate (47.6%), and live birth rate (34.0%) in the 38-40-year-old group were significantly lower than those in the 30-34-year-old group (64.4%, 50.9%, respectively; all P  < 0.001) and < 30-year-old group (62.9%, 50.7%, respectively; all P  < 0.001). However, the 35-37-year-old group did not differ from the other three groups in these two dimensions (all P  > 0.05). Moreover, there were no differences in the rates of biochemical pregnancy, miscarriage, or obstetric or neonatal complications among the four groups (all P  > 0.05). According to the multivariate logistic regression analysis, the 35-37-year-old group was not associated with non-live birth outcomes, adverse pregnancy outcomes, or obstetric or neonatal complications. However, being 38–40 years of age was a risk factor for non-live birth (OR = 2.121, 95% CI: 1.233–3.647) and adverse pregnancy outcomes (OR = 1.630, 95% CI: 1.010–2.633). Post hoc power analysis showed that the study was sufficiently powered to detect meaningful differences. Conclusion Frozen-thawed high-quality single blastocyst transfer produces the same satisfactory pregnancy outcomes for women aged 35–37 years as younger patients. Future prospective randomized controlled studies with larger populations are needed to verify the feasibility and safety of this method.

CRISPR-Staphylococcus aureus Cas9 (CRISPR-SaCas9) has been harnessed as an effective in vivo genome-editing tool to manipulate genomes. However, off-target effects remain a major bottleneck that precludes safe and reliable applications in genome editing. Here, we characterize the off-target effects of wild-type (WT) SaCas9 at single-nucleotide (single-nt) resolution and describe a directional screening system to identify novel SaCas9 variants with desired properties in human cells. Using this system, we identified enhanced-fidelity SaCas9 (efSaCas9) (variant Mut268 harboring the single mutation of N260D), which could effectively distinguish and reject single base-pair mismatches. We demonstrate dramatically reduced off-target effects (approximately 2- to 93-fold improvements) of Mut268 compared to WT using targeted deep-sequencing analyses. To understand the structural origin of the fidelity enhancement, we find that N260, located in the REC3 domain, orchestrates an extensive network of contacts between REC3 and the guide RNA-DNA heteroduplex. efSaCas9 can be broadly used in genome-editing applications that require high fidelity. Furthermore, this study provides a general strategy to rapidly evolve other desired CRISPR-Cas9 traits besides enhanced fidelity, to expand the utility of the CRISPR toolkit.

Background Approximately 50% of the women with polycystic ovary syndrome (PCOS) are overweight or obese and obesity can significantly impair reproductive function. This study aimed to investigate the association between body mass index (BMI) and embryonical/clinical outcomes in PCOS patients undergoing ultralong gonadotrophin-releasing hormone agonist (GnRH-a) protocol and to establish evidence-based management strategies for obese women with PCOS. Method A total of 1704 PCOS patients aged 20–42 years were treated with an ultralong GnRH-a protocol during a single oocyte retrieval cycle, followed by blastocyst transfer between 2016 and 2023. Participants were stratified according to BMI criteria into four groups: underweight ( n  = 125), normal weight ( n  = 845), overweight ( n  = 517) and obese ( n  = 217). Baseline characteristic and reproductive outcomes were compared across BMI categories. Results PCOS patients with obesity exhibited a significant reduction in both the number of retrieved oocytes and mature oocytes. In fresh blastocyst transfer cycles, no statistical differences in live birth rates were observed across the four BMI groups ( p  = 0.246). However, in frozen-thawed blastocyst transfer cycles, the obese group had the lowest live birth rate among all BMI categories. Multivariate logistic regression analysis identified several key predictors of live birth. The number of high-quality blastocysts transferred was a dominant favorable factor (OR = 1.480, 95% CI 1.251–1.751). Conversely, obesity independently predicted a reduced likelihood of live birth (OR = 0.437, 95% CI 0.298–0.641). Further analysis of cumulative live birth outcomes in a complete oocyte retrieval cycle confirmed that obesity remained a negative predictor (OR = 0.438, 95% CI 0.312–0.615), while the number of high-quality blastocysts transferred (OR = 1.269, 95% CI 1.132–1.423) and a shorter duration of infertility (OR = 0.927, 95% CI 0.885–0.972) were associated with improved success rates. Conclusions PCOS patients with obesity presented poorer embryonical and clinical outcomes. Obesity emerged as a significant independent predictor of nonlive birth in both frozen-thawed blastocyst transfer cycles and complete in vitro fertilization (IVF) cycles. This study underscores the clinical importance of incorporating pre-IVF interventions, particularly weight management strategies, for obese PCOS patients to optimize reproductive outcomes.

Background Few previous studies have addressed the impact of COVID-19 infection status on assisted reproductive technology outcomes. The purpose of this study was to assess whether COVID-19 infection affects ovulation induction outcomes and the laboratory outcomes of women undergoing assisted reproductive technology treatment. Methods In total, 363 patients were divided into three groups: the COVID-19 infection group (group A, n  = 49), the COVID-19 recovery group (group B, n  = 119) and the COVID-19 non-infection group (group C, n  = 195). Intergroup comparisons of baseline characteristics, stimulation characteristics and laboratory outcomes were performed. Results The Gn dosage in group A was significantly higher than those in groups B and C. The duration of Gn treatment was longer in group A than in group B. In group B, the number of high-quality blastocysts was lower than that in group C. The rates of blastocyst formation (42.56%) and high-quality blastocyst formation (12.05%) in group B were significantly lower than those in group A (51.51%; P  = 0.003, 16.58%; P  = 0.026) and C (48.20%; P  = 0.005, 16.49%; P  = 0.002). The high-quality blastocyst rate in group C (34.20%) was the highest and was different from that in group B (28.33%). The main risk factor for high-quality blastocyst formation according to multivariate logistic regression analysis was recovery from COVID-19 (0.599, 95% CI: 0.360–0.996; P  = 0.048). Conclusion Asymptomatic or mild COVID-19 infection prior to oocyte retrieval may not has a significant negative effect on ovulation induction outcomes or laboratory outcomes, although the number of Gn days and dose of Gn may increase. In addition, we should pay attention to infertile women recovering from COVID-19 infection and be aware of the significant reduction in the number of high-quality blastocysts in this population.

Background This study was designed to evaluate pregnancy outcomes between morulae transferred on day 4 (D4) and blastocysts transferred on day 5 (D5). Methods From September 2017 to September 2020, 1963 fresh transfer cycles underwent early follicular phase extra-long protocol for assisted conception in our fertility center were divided into D4 (324 cases) and D5 (1639 cases) groups, and the general situation and other differences of patients in both groups were compared. To compare the differences in pregnancy outcomes, the D4 and D5 groups were further divided into groups A and B based on single and double embryo transfers. Furthermore, the cohort was divided into two groups: those with live births (1116 cases) and those without (847 cases), enabling a deeper evaluation of the effects of D4 or D5 transplantation on assisted reproductive outcomes. Results In single embryo transfer, there was no significant difference between groups D4A and D5A ( P  > 0.05). In double embryo transfer, group D4B had a lower newborn birthweight and a larger proportion of low birthweight infants ( P  < 0.05). The preterm delivery rate, twin delivery rate, cesarean delivery rate, and percentage of low birthweight infants were lower in the D5A group than in the D5B group ( P  < 0.05). Analysis of factors influencing live birth outcomes further confirmed the absence of a significant difference between D4 and D5 transplantation in achieving live birth ( P  > 0.05). Conclusion When factors such as working life and hospital holidays are being considered, D4 morula transfer may be a good alternative to D5 blastocyst transfer. Given the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) success rate and risk of twin pregnancy, D4 morula transfer requires an adapted decision between single and double embryo transfer, although a single blastocyst transfer is recommended for the D5 transfer in order to decrease the twin pregnancy rate. In addition, age, endometrial thickness and other factors need to be taken into account to personalize the IVF program and optimize pregnancy outcomes.

The basal luteinizing hormone (LH) and the prior LH to follicle-stimulating hormone (FSH) ratio (LH/FSH) in polycystic ovarian syndrome (PCOS) are generally higher than those in non-PCOS patients and the general population. The potential negative effects of elevated LH on human reproductive function are highly controversial, as are the effects of down-regulation of LH on reproductive function. The purpose of this study was to evaluate the effect of the basal LH/FSH ratio on the live birth rate of PCOS patients undergoing fertilization (IVF) cycles. A retrospective analysis was conducted on 698 patients with polycystic ovary syndrome undergoing IVF treatments with a mild stimulation protocol ( = 95) and a gonadotropin-releasing hormone (GnRH) agonist protocol ( = 603). The basal LH/FSH ratio of 2 was used as the cut-off value for further subgroup analysis. The demographic properties, controlled ovarian hyperstimulation (COH) processes, and clinical pregnancy outcomes were compared between groups under each ovulation stimulation protocol. The live birth rate for patients with a LH/FSH ratio ≥ 2 group (56.38%, = 149) was not statistically different from that of the ones with a ratio < 2 (53.74%, = 454) in the GnRH agonist protocol ( = 0.576). Correspondingly, the live birth rate for the LH/FSH ratio ≥ 2 group (43.48%, = 23) also showed no statistical difference from the ratio < 2 group (48.61%, = 72) in the mild stimulation protocol ( = 0.668). Additionally, LH/FSH ratios had no significant effect on the live birth rate after adjusting for confounders both in the GnRH agonist protocol (adjusted OR: 1.111; 95% CI [0.467-2.642], = 0.812) and in the mild stimulation protocol (adjusted OR: 4.057; 95% CI [0.431-38.195], = 0.221). Furthermore, there was no significant difference in the live birth rate between different ovulation stimulation protocols in PCOS patients with the LH/FSH ratio ≥ 2. The live birth rate in IVF outcomes was not affected by an elevated basal LH/FSH ratio in patients with polycystic ovary syndrome. The choice of the GnRH agonist protocol or mild stimulation protocol for ovulation stimulation does not affect the final clinical outcomes either for PCOS patients with a basal LH/FSH ratio ≥ 2.

To investigate transfer strategies in the frozen-thawed embryo transfer (FET) cycle. The clinical data of 1,652 FET patients were divided into five groups according to the number and quality of the transferred blastocyst: high-quality single blastocyst group (group A,  = 558), high-quality plus poor-quality double blastocyst group (group B,  = 435), poor-quality double blastocyst group (group C,  = 241), high-quality double blastocyst group (group D,  = 298), and poor-quality single blastocyst group (group E,  = 120). Inter-group comparison analyses of primary conditions, pregnancy outcomes and neonatal outcomes were then performed. Group A had the highest embryo implantation rate (67.38%), significantly different from the implantation rates of the other four groups. The gemellary pregnancy rate (1.60%), preterm birth rate (5.58%), neonatal birth weight (3,350g [3,000g, 3,650g]), neonatal birth age (39.57 weeks [38.71, 40.34]), and incidence of low birth weight (7.02%) in group A were different from those in groups B, C, and D, but did not significantly differ from those in group E. Moreover, the proportions of male infants born in groups A (56.86%) and D (59.41%) were significantly higher than those in the other three groups. Double blastocyst transfer (0.528, 95% CI [0.410-0.680],  < 0.001) and high-quality blastocyst transfer (0.609, 95% CI [0.453-0.820],  = 0.001) were found to be protective factors for live birth. In addition, double blastocyst transfer was also the largest risk factor for pregnancy complications (3.120, 95% CI [2.323-4.190],  < 0.001) and neonatal complications (2.230, 95% CI [1.515-3.280],  < 0.001), especially for gemellary pregnancy (59.933, 95% CI [27.298-131.58],  < 0.001) and preterm birth (3.840, 95% CI [2.272-6.489],  < 0.001). Based on the ROC curves, a double blastocyst transfer could predict gemellary pregnancy reliably with a high area under the curve (AUC = 78.53%). Additionally, a double blastocyst transfer could effectively predict a high risk of pregnancy complications (AUC = 65.90%), neonatal complications (AUC = 64.80%) and preterm birth (AUC = 66.20%). The live birth rate of frozen-thawed high-quality single blastocyst transfer is lower than that of double high-quality blastocyst transfer, which can significantly increase the embryo implantation rate. High-quality single blastocyst transfer also significantly lowers the risk of gemellary pregnancy, preterm birth, and low birth weight, and can significantly improve maternal and infant outcomes. After weighing the pros and cons of live birth with pregnancy and neonatal complications, the authors believe that high-quality single blastocyst transfer is the optimal FET strategy for young women and is worthy of further clinical application. Despite this recommendation, high-quality single blastocyst transfer can increase the risk of monozygotic twins, as well as significantly increase the proportion of male infants born.