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The construction of bioartificial livers, such as liver organoids, offers significant promise for disease modeling, drug development, and regenerative medicine. However, existing methods for generating liver organoids have limitations, including lengthy and complex processes (taking 6–8 weeks or longer), safety concerns associated with pluripotency, limited functionality of pluripotent stem cell‐derived hepatocytes, and small, highly variable sizes (typically ≈50–500 µm in diameter). Prolonged culture also leads to the formation of necrotic cores, further restricting size and function. In this study, a straightforward and time‐efficient approach is developed for creating rapid self‐assembly mini‐livers (RSALs) within 12 h. Additionally, primary hepatocytes are significantly expanded in vitro for use as seeding cells. RSALs exhibit consistent larger sizes (5.5 mm in diameter), improved cell viability (99%), and enhanced liver functionality. Notably, RSALs are functionally vascularized within 2 weeks post‐transplantation into the mesentery of mice. These authentic hepatocyte‐based RSALs effectively protect mice from 90%‐hepatectomy‐induced liver failure, demonstrating the potential of bioartificial liver‐based therapy. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does the change in endometrial thickness (EMT) from the end of the follicular/estrogen phase to the day of embryo transfer (ET) determine subsequent pregnancy outcomes? SUMMARY ANSWER Endometrial compaction from the late-proliferative to secretory phase is not associated with live birth rate (LBR) and other pregnancy outcomes. WHAT IS KNOWN ALREADY Endometrial compaction has been suggested to be indicative of endometrial responsiveness to progesterone, and its association with ET outcome has been investigated but is controversial. STUDY DESIGN, SIZE, DURATION A systematic review with meta-analysis was carried out. PubMed, EMBASE, and Web of Science were searched to identify relevant studies from inception to 18 November 2022. The reference lists of included studies were also manually screened for any additional publications. PARTICIPANTS/MATERIALS, SETTING, METHODS Cohort studies comparing ET pregnancy outcomes between patients with and without endometrial compaction were included. A review of the studies for inclusion, data extraction, and quality assessment was performed by two independent reviewers. The effect size was synthesized as odds ratio (OR) with 95% CI using a random-effects model. Heterogeneity and publication bias were assessed by the I 2 statistic and Egger's test, respectively. The primary outcome was LBR. Secondary outcomes included biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate (MR), ongoing pregnancy rate (OPR), and ectopic pregnancy rate (EPR). MAIN RESULTS AND THE ROLE OF CHANCE Seventeen cohort studies involving 18 973 ET cycles fulfilled the eligibility criteria. The pooled results revealed that there were no significant differences between endometrial compaction and non-compaction groups in LBR (crude OR (cOR) = 0.95, 95% CI 0.87–1.04; I 2 = 0%; adjusted OR (aOR) = 1.02, 95% CI 0.87–1.19, I 2 = 79%), BPR (cOR = 0.93, 95% CI 0.81–1.06; I 2 = 0%; aOR = 0.88, 95% CI 0.75–1.03, I 2 = 0%), CPR (cOR = 0.98, 95% CI 0.81–1.18; I 2 = 70%; aOR = 0.86, 95% CI 0.72–1.02, I 2 = 13%), MR (cOR = 1.09, 95% CI 0.90–1.32; I 2 = 0%; aOR = 0.91, 95% CI 0.64–1.31; I 2 = 0%), and EPR (cOR = 0.70, 95% CI 0.31–1.61; I 2 = 61%). The OPR was marginally higher in crude analysis (cOR = 1.48, 95% CI 1.01–2.16; I 2 = 81%) among women with compacted endometrium, but was not evident in adjusted results (aOR = 1.36, 95% CI 0.86–2.14; I 2 = 84%). Consistently, the pooled estimate of LBR remained comparable in further subgroup and sensitivity analyses according to the degree of compaction (0%, 5%, 10%, 15%, or 20%), type of ET (fresh, frozen, or euploid only), and endometrial preparation protocol (natural or artificial). No publication bias was observed based on Egger's test. LIMITATIONS, REASONS FOR CAUTION Although the number of included studies is sufficient, data on certain measures, such as EPR, are limited. The inherent bias and residual confounding were also inevitable owing to the observational study design. Furthermore, inconsistent definitions of pregnancy outcomes may affect the accuracy of our pooled analysis. WIDER IMPLICATIONS OF THE FINDINGS Given the lack of prognostic value, assessing endometrial compaction or repeated EMT measurement on the day of ET may not be necessary or warranted. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Natural Science Foundation of Jiangxi Province (20224BAB216025), National Natural Science Foundation of China (82260315), and Central Funds Guiding the Local Science and Technology Development (20221ZDG020071). The authors have no conflicts of interest to declare. REGISTRATION NUMBER CRD42022384539 (PROSPERO). [ABSTRACT FROM AUTHOR]

The clinical effect of Coronavirus disease 2019 (COVID‐19) on endometrial receptivity and embryo implantation remains unclear. Herein, we aim to investigate whether a COVID‐19 history adversely affect female pregnancy outcomes after frozen‐thawed embryo transfer (FET). This prospective cohort study enrolled 230 women who underwent FET cycles from December 2022 to April 2023 in an academic fertility center. Based on the history of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection before FET, women were divided into the infected group (n = 136) and the control group (n = 94). The primary outcome was the clinical pregnancy rate per cycle. Multivariate logistic regression analysis was conducted to adjust for potential confounders, while subgroup analysis and restricted cubic splines were used to depict the effect of postinfection time interval on FET. The results showed that the clinical pregnancy rate was 59.6% in the infected group and 63.9% in the control group (p = 0.513). Similarly, the two groups were comparable in the rates of biochemical pregnancy (69.1% vs. 76.6%; p = 0.214) and embryo implantation (51.7% vs. 54.5%; p = 0.628). After adjustment, the nonsignificant association remained between prior infection and clinical pregnancy (OR = 0.78, 95% CI: 0.42–1.46). However, the odds for clinical pregnancy were significantly lower in the ≤30 days subgroup (OR = 0.15, 95% CI: 0.03–0.77), while no statistical significance was detected for 31–60 days and >60 days subgroups compared with the uninfected women. In conclusion, our findings suggested that SARS‐CoV‐2 infection in women had no significant effect on subsequent FET treatment overall, but pregnancy rates tended to be decreased if vitrified‐thawed embryos were transferred within 30 days after infection. A 1‐month postponement should be rationally recommended, while further studies with larger sample groups and longer follow‐up periods are warranted for confirmation. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between prior coronavirus disease 2019 (COVID‐19) infection in females and subsequent treatment outcomes of assisted reproductive technology (ART). Methods: A systematic literature review was carried out up to 16 December 2022, in PubMed, Web of Science, EMBASE, and Cochrane Library. Random‐effect models were adopted to estimate the pooled effects as mean differences (MDs) or odds ratios (ORs). I2 statistic and Egger's test were applied to assess heterogeneity and publication bias, respectively. Results: After screening 1480 records, 15 cohort studies totalling 1905 cycles were included in this meta‐analysis. In a comparison of previously COVID‐19‐infected versus uninfected women, no significant differences were observed in the primary outcomes of the retrieved oocytes number (MD = 0.06; 95% confidence interval [CI]: ‐0.75–0.88; I2 = 0) and clinical pregnancy rate (OR = 0.96; 95% CI: 0.74–1.24; I2 = 0). Pooled analyses of other predefined outcomes, which encompassed four cycle characteristics, six laboratory indicators and four pregnancy results, also showed no adverse effects of prior COVID‐19 infection. Most outcomes remained consistent after further sensitivity and subgroup analyses, and no significant publication bias was observed. Conclusions: Our work provides the first systematic evidence that COVID‐19 infection history in females may have no measurable detrimental impact on the subsequent ART cycle. More data are needed to assess the live birth outcome and the optimal time interval from infection to assisted reproduction. [ABSTRACT FROM AUTHOR]

Diet is a critical regulator for physiological metabolism and tissue homeostasis, with a close relation to health and disease. As an important organ for digestion and absorption, the intestine comes into direct contact with many dietary components. The rapid renewal of its mucosal epithelium depends on the continuous proliferation and differentiation of intestinal stem cells (ISCs). The function and metabolism of ISCs can be controlled by a variety of dietary patterns including calorie restriction, fasting, high-fat, ketogenic, and high-sugar diets, as well as different nutrients including vitamins, amino acids, dietary fibre, and probiotics. Therefore, dietary interventions targeting ISCs may make it possible to prevent and treat intestinal disorders such as colon cancer, inflammatory bowel disease, and radiation enteritis. This review summarised recent research on the role and mechanism of diet in regulating ISCs, and discussed the potential of dietary modulation for intestinal diseases. [ABSTRACT FROM AUTHOR]

Background: Previous studies have examined that a range of optimal serum P level during the implantation period was associated with optimal live birth rates. However, those results obtained with vaginal or intramuscular route of progesterone administration for luteal phase support (LPS) alone. Is there a relationship between the serum progesterone (P) on the day of frozen-thawed embryo transfer (FET) with the likelihood of a live birth (LB) in artificial cycles (AC) when using a combination of oral dydrogesterone and vaginal progesterone for LPS? Methods: This was a retrospective study of 3659 FET cycles with artificial endometrial preparation in a Chinese tertiary-care academic medical centre from January 2015 to February 2017. Endometrial preparation was performed using estradiol (E2) valerate (Fematon-red tablets) 8 mg/d beginning on day 3 of the cycle, followed by administration of P both orally (8 mg/d Fematon-yellow tablets) and vaginally (400 mg/d; Utrogestan). The primary endpoint was live birth rate (LBR). The association between the serum P level on the embryo transfer day and pregnancy outcomes was evaluated by univariable and multivariable logistic regression analysis. Results: The LBRs according to the serum P quartiles were as follows: Q1: 35.7%; Q2: 37.4%; Q3: 39.1% and Q4: 38.9%. Logistic regression analysis showed that the odds of a LB were not significantly different between the low (P < 7.9 ng/mL) and high (P ≥ 7.9 ng/mL) progesterone groups before or after adjustment (crude OR = 0.89, 95% CI: 0.76–1.04; adjusted OR = 0.89, 95% CI: 0.75–1.04). Conclusion: The present study suggests that the serum P levels on the day of embryo transfer (ET) do not correlate with the likelihood of a LB in artificial cycles when using a combination of oral dydrogesterone and vaginal progesterone for luteal phase support. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of coronavirus disease 2019 (COVID‐19) vaccination on semen parameters through systematic review and meta‐analysis. PubMed, EMBASE, Web of Science, and Cochrane Library were comprehensively searched by June 2022. Studies were considered eligible if they compared semen parameters before and after COVID‐19 vaccination or between vaccinated and unvaccinated men, with no restrictions on vaccine types or doses. The effect size was calculated as mean difference (MD) with 95% confidence interval (CI) using a random‐effects model. Subgroup and sensitivity analyses were conducted to assess the sources of heterogeneity measured by the I2 statistic, with publication bias evaluated by Egger's test. Twelve cohort studies involving 914 participants fulfilled the inclusion criteria. In a comparison of vaccinated versus unvaccinated group, the pooled data revealed no significant differences in semen volume (MD = 0.18 ml, 95% CI −0.02 to 0.38), sperm concentration (MD = 1.16 million/ml, 95% CI −1.34 to 3.66), total sperm motility (MD = −0.14%, 95% CI −2.84 to 2.56), progressive sperm motility (MD = −1.06%, 95% CI −2.88 to 0.77), total sperm count (MD = 5.92 million, 95% CI −10.22 to 22.05), total motile sperm count (MD = 2.18 million, 95% CI −1.28 to 5.63), total progressively motile sperm count (MD = −3.87 million, 95% CI −13.16 to 5.43), and sperm morphology (MD = 0.07%, 95% CI −0.84 to 0.97). The results also remained similar across messenger ribonucleic acid, viral‐vector, and inactivated COVID‐19 vaccines. Sensitivity analysis identified two individual studies that contributed to heterogeneity, while the effect size was not materially altered. No obvious publication bias was detected among included studies. Our finding suggested that COVID‐19 vaccination had no detrimental impact on semen quality, which could be potentially helpful to reduce male vaccine hesitancy and increase vaccination coverage. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of the long-acting gonadotropin-releasing hormone agonist (GnRH-a) administration before hormone replacement treatment for frozen-thawed embryo transfer in women with different times of embryo implantation failures. Methods: A retrospective cohort study was performed between January 2015 and December 2019. A total of 9263 women who underwent frozen-thawed embryo transfer were included in the study. The study is divided into three parts based on the times of embryo implantation failures. The sample sizes were 4611 for no implantation failure, 3565 for one failure and 1087 for multiple failures. Two endometrium preparation protocols, HRT and HRT with GnRH-a pretreatment (G-HRT), were compared. Confounding factors were treated by propensity score matching and generalized estimation equation. Results: For women with no failure of embryo implantation, the live birth rate was not statistically different when they underwent HRT and G-HRT (HRT: 42.75% [498/1165], G-HRT: 45.24% [527/1165], P=0.2261). Similar outcome also appeared in women with one failure of embryo implantation (HRT: 47.22% [535/1133], G-HRT: 50.31% [570/1131], P=0.1413). For women with multiple failures of embryo implantation, the live birth rate was significantly difference (HRT: 38.74% [117/302], G-HRT: 45.48% [357/785], P=0.0449). When stratified by age, the live birth rate is similar for women older than 37 years. Generalized estimation equation showed that GnRH agonist pretreatment was independently associated with the live birth rate for women with multiple failures (adjust OR: 1.5, 95%CI: [1.12-2.00]). Conclusion: For women with no/one failure of embryo implantation, the live birth rate is similar between HRT and G-HRT protocols. For women with multiple failure of embryo implantation, GnRH agonist pretreatment is beneficial to raise the live birth rate. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of inactivated SARS-CoV-2 vaccination on in vitro fertilization (IVF) outcomes. Patients and Methods: This retrospective cohort study included 2185 patients undergoing fresh IVF cycles from June 1st to September 13th 2021 in a single university-affiliated hospital. Vaccine administration information was collected and ascertained via immunization records. Patients with two dosages of inactivated SARS-CoV-2 vaccines (Sinopharm or Sinovac) were categorized into the vaccinated group (n = 150), while those unvaccinated were classified as control (n = 2035). Propensity score matching was performed to balance the baseline characteristics (14 covariates) between the two groups at a ratio of 1:4. The main outcome measures were the number of oocytes retrieved, good-quality embryo rate and clinical pregnancy rate. Results: There were 146 women in the vaccinated group and 584 in the control group after matching. The number of oocytes retrieved (9.9 ± 7.1 vs 9.9 ± 6.7; P = 0.893), good-quality embryo rate (33.5 ± 29.8% vs 29.9 ± 28.6%; P = 0.184) and clinical pregnancy rate (59.1% vs 63.6%; P = 0.507) were all similar between the two groups. In addition, no significant differences were observed regarding other cycle characteristics, laboratory parameters and pregnancy outcomes. The results were also comparable when vaccinated patients were subdivided into three categories based on the time interval from complete vaccination to cycle initiation: ≤ 1 month, > 1– 2 months, and > 2 months. Conclusion: Our study provided the first-time evidence that inactivated SARS-CoV-2 vaccination in females did not result in any measurable detrimental effects on IVF treatment. Owing to the present limitations, further prospective studies with larger cohort size and longer follow-up are warranted to validate our conclusion. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association of endometrial thickness (EMT) with obstetric and neonatal outcomes in women with polycystic ovary syndrome (PCOS). Methods: A total of 1755 subfertile PCOS women with singleton livebirths after frozen-thawed embryo transfer were included between January 2009 and September 2019. Main obstetric outcomes were hypertensive disorders in pregnancy and abnormal placentation. Main neonatal outcomes were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by univariate and multivariate logistic regression analyses. Results: Each millimeter decrease in EMT was related to a 9% (adjusted OR 1.09, 95% CI 1.00–1.19; P = 0.053), 14% (adjusted OR 1.14, 95% CI 1.02–1.28; P = 0.002) and 22% (adjusted OR 1.22, 95% CI 1.07–1.38; P = 0.003) higher risk of PTB, LBW and SGA, respectively. Compared to women with EMT >13 mm, women with EMT ≤8 mm also had significantly higher risk of PTB (adjusted OR 3.79, 95% CI 1.53–9.39; P = 0.004), LBW (adjusted OR 4.33, 95% CI 1.39–13.50; P = 0.012) and SGA (adjusted OR 6.38, 95% CI 1.78–22.83; P = 0.004). These associations remained consistent in further subgroup analysis by endometrial preparation regimen and in sensitivity analyses among nulligravida women or women without adverse obstetric outcomes. No significant differences were found in the incidence of several pregnancy complications across EMT categories. Conclusion: Decreased EMT was independently associated with increased risk of PTB, LBW and SGA in women with PCOS. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical effect of mild stimulation with letrozole on pregnancy outcomes in ovulatory women undergoing frozen embryo transfer (FET) compared to natural cycle. Design: Retrospective observational study. Setting: Tertiary care academic medical center. Population: A total of 6,874 infertile women with regular menstrual cycles (21-35 days) met the criteria for this study in the period from 2013 to 2020. Methods: All patients who were prepared for and underwent FET were divided into two groups: a modified natural cycle (NC) group (n=3,958) and a letrozole cycle group (n=2,916). Main Outcome Measures: The primary outcome of the study was clinical pregnancy rate. Secondary outcome measures were endometrial thickness, rates of implantation, positive HCG test, live birth, early miscarriage and ectopic pregnancy. Results: The clinical pregnancy rate was not statistically different between the modified NC-FET group and the letrozole-FFT group before (crude OR 0.99, 95% CI 0.90-1.09, P=0.902>0.05) and after propensity score matching (PSM) (crude OR 1.01, 95% CI 0.91-1.12, P=0.870>0.05). After multivariable logistic regression analysis, the clinical pregnancy rate remained insignificant before (adjusted OR 1.00, 95% CI 0.91-1.10, P=0.979>0.05) and after matching (adjusted OR 1.00, 95% CI 0.89-1.11, P=0.936>0.05), respectively. Similarly, in the crude and adjusted analysis, the positive HCG test, implantation, live birth and early miscarriage rates were also comparable in the letrozole-FFT group and modified NC-FET group before and after matching. Furthermore, the endometrial thickness of letrozole-FFT group was similar to that of modified NC-FET group with adjusted analysis. Conclusion: Our observation suggests that mild stimulation with letrozole could produce similar pregnancy outcomes in ovulatory patients who undergo FET when compared with a natural cycle. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis aimed to evaluate the association between adherence to a healthy dietary pattern and outcomes of assisted reproductive techniques (ARTs). PubMed, Embase and Web of Science were searched for eligible studies through December 2019 according to the population, intervention, comparison, outcome and study design (PICOS) criteria. Eight prospective cohort studies (S) reporting pregnancy outcomes (O) of higher vs lower adherence to a healthy dietary pattern (I/C) in women undergoing ART treatment (P) were included, involving a total of 2229 women with 2067 embryo transfer cycles. The pooled odds ratio (OR) for positive pregnancy test, clinical pregnancy and ongoing pregnancy/live birth was 0.82 (95% confidence interval [CI] 0.65-1.03), 0.99 (95% CI 0.68-1.44) and 1.30 (95% CI 0.81-2.09), respectively. In conclusion, greater adherence to a healthy dietary pattern rich in vegetables, fruits, whole grains, legumes and fish, may not be significantly related to ART success. [ABSTRACT FROM AUTHOR]

Introduction: The association between the mode of previous delivery and subsequent success of assisted reproductive treatment has been poorly understood. By mitigating the detrimental effect of supraphysiologic estradiol levels on endometrial receptivity, a freeze-all strategy provides a novel model to investigate the sole impact of a prior cesarean delivery (CD) on embryo transfer outcomes.Material and Methods: This single-center retrospective cohort study included 2660 patients who underwent their first frozen-thawed embryo transfer cycles after a freeze-all policy from January 2013 to December 2018. Patients with a history of live birth by CD were assigned to the CD group, and those with only vaginal delivery (VD) were categorized into the VD group. The primary outcome measure was live birth. Baseline characteristics of the two groups were balanced by propensity score matching in a ratio of 1:1. Univariate and multivariate logistic regression analyses were performed using the after-matching data.Results: Compared with the VD group, the rates of clinical pregnancy (38.3% vs 44.5%; P = .005) and live birth (27.5% vs 33.4%; P = .003) were significantly lower in women with a history of CD. When adjusted for a number of major confounding factors, the negative association between a prior CD and frozen-thawed embryo transfer success was maintained, with the adjusted odds ratio (OR) being 0.80 (95% CI 0.66-0.96) and 0.78 (95% CI 0.63-0.95) for clinical pregnancy and live birth, respectively. Furthermore, a CD history conferred a marginally increased risk of early miscarriage (crude OR 1.48, 95% CI 1.04-2.11; adjusted OR 1.47, 95% CI 1.01-2.14), whereas the odds of multiple and ectopic pregnancy did not show significant differences before and after adjustment.Conclusions: A prior CD was associated with a decreased chance of live birth and an increased risk of early miscarriage in frozen-thawed embryo transfer cycles. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cell (ADSC) is an alternative and less invasive source of mesenchymal stem cells which can be used to develop biological treatment strategies for tissue regeneration, and their therapeutic applications hinge on an understanding of their physiological characteristics. N6-Methyladenosine (m6A) is the most common chemical modification of mRNAs and has recently been revealed to play important roles in cell lineage differentiation and development. However, the role of m6A modification in the vascular smooth muscle cell (VSMC) differentiation of ADSCs remains unclear. Herein, we investigated the expression of N6-adenosine methyltransferases (Mettl3) and demethylases (Fto and Alkbh5) and found that Mettl3 was upregulated in ADSCs undergoing vascular smooth muscle differentiation induction. Moreover, silence of Mettle3 reduced the expression level of VSMC-specific markers, including α-SMA, SM22α, calponin, and SM-MHC. Meanwhile, Mettl3 knockdown also decreased the expression of paracrine factors, including VEGF, HGF, TGF-β, GM-CSF, bFGF, and SDF-1. In addition, our results suggested that hypoxia stress promotes the ADSC differentiate into VMSCs and regulates the secretion of VEGF, HGF, TGF-β, GM-CSF, bFGF, and SDF-1 by mediating Mettl3 gene expression. These observations might contribute to novel progress in understanding the role of epitranscriptomic regulation in the VSMC differentiation of ADSCs and provide a promising perspective for new therapeutic strategies for tissue regeneration. [ABSTRACT FROM AUTHOR]

Study Question: Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles?Summary Answer: Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles.What Is Known Already: Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles.Study Design, Size, Duration: A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center.Participants/materials, Setting, Methods: Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA).Main Results and the Role Of Chance: The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively.Limitations, Reasons For Caution: The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations.Wider Implications Of the Findings: Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health.Study Funding/competing Interest(s): This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Background: Prior studies have shown that patients with a >10% estradiol (E2) rise after trigger had more oocytes retrieved than plateauing or decreasing E2 responders. However, multiple follicles develop at different stages of maturation during controlled ovarian stimulation (COS) and may exhibit different responses to trigger. The association between the magnitude of E2 increase and oocyte retrieval outcomes is still unclear. Methods: This was a retrospective cohort study of 2,898 women undergoing their first COS cycles with normal response from January 2014 to December 2017 at a tertiary-care academic medical center. Patients were categorized into five groups according to the percentage increase in E2 levels before and after dual trigger: <10.0%, 10.0–19.9%, 20.0–29.9%, 30.0–39.9%, and ≥40.0%. Univariable and multivariable linear regression analysis were performed to explore the association between E2 increase and oocyte/mature oocyte yield, while logistic regression was used to assess its effect on low oocyte/mature oocyte yield (<10th percentile). Results: The post-trigger E2 increase was negatively associated with both oocyte yield (P -trend < 0.001, adjusted P -trend = 0.033) and mature oocyte yield (P -trend < 0.001, adjusted P -trend = 0.002). Compared with a <10.0% E2 increase after trigger, patients with a ≥40.0% rise had fewer mature oocyte yield [adjusted mean absolute difference [MD] = −5.2, 95% confidence interval [CI]: −8.2–−1.8] and higher risk of low mature oocyte yield (adjusted odds ratio [OR] = 1.64, 95% CI: 1.04–2.60), whereas no statistical significance was found in oocyte yield (adjusted MD = −2.7, 95% CI: −6.1–0.8) and low oocyte yield (adjusted OR = 1.48, 95% CI: 0.96–2.28). In addition, the rates of implantation, positive pregnancy test, clinical pregnancy, ongoing pregnancy, pregnancy loss, and live birth were comparable among the 1,942 frozen embryo transfer cycles with embryos originating from different groups of E2 increase (all P > 0.05). Conclusions: A higher E2 rise after dual trigger is independently associated with a lower oocyte and mature oocyte yield in normal responders. Further studies are needed to explore the efficacy of individualized time interval from trigger to oocyte retrieval based on the magnitude of E2 increase after trigger. [ABSTRACT FROM AUTHOR]

Background: The ability of anti-Müllerian hormone (AMH) to predict ovarian response has been studied extensively in gonadotropin-releasing hormone agonist and antagonist treatments, but no information is available regarding its value in progestin-primed ovarian stimulation (PPOS) protocol. Methods: This retrospective data analysis included 523 patients without polycystic ovary syndrome who underwent their first in vitro fertilization/intracytoplasmic sperm injection cycle with PPOS protocol at our center between Jan. 2015 and Jul. 2018. Serum AMH measurements were acquired within 12 months prior to ovarian stimulation using the automated Access AMH assay. Results: AMH exhibited a significantly positive correlation with the number of retrieved oocytes (r = 0.744, P < 0.001). For the prediction of poor (<4 oocytes) and high (>15 oocytes) response, AMH had an area under the receiver operating characteristic curve (AUC) of 0.861 and 0.773, corresponding with an optimal cutoff point of 1.26 and 4.34 ng/mL, respectively. When stratified according to the dose of medroxyprogesterone acetate (MPA) (4 mg vs. 10 mg per day), AMH retained its similarly high predictive value for poor (AUC = 0.829 and 0.886, respectively) and high response (AUC = 0.770 and 0.814, respectively) in both groups. Amongst the 314 women who received their first frozen embryo transfer (FET) following PPOS protocol, no significant differences were observed on the rates of biochemical pregnancy, clinical pregnancy, implantation, early miscarriage, multiple pregnancy and ectopic pregnancy (all P > 0.05) across AMH quartiles (≤1.43, 1.44-2.55, 2.56–4.35, >4.35 ng/mL). In a multivariable logistic regression model, age was suggested to be the only independent risk factor for clinical pregnancy (P = 0.011). Conclusions: Our data demonstrated that AMH is an adequate predictor of both high and poor ovarian response in PPOS protocol regardless of MPA dose, but it does not associate with pregnancy outcomes in the first FET cycles in a freeze-all strategy. [ABSTRACT FROM AUTHOR]

We read with great interest the recent study by Moon et al.,[1] which demonstrated no significant differences in the delivery outcomes of pregnant women in a set of acupuncture and control groups. As a result of the potential adverse effects of these disorders on pregnancy outcomes,[2] a direct comparison between these two populations could be affected by the patient characteristics and so fail to fully reflect the effects of the acupuncture treatment itself. Given the benefits of acupuncture on maternal symptoms, a comprehensive safety validation for neonates would further promote the widespread use of this complementary therapy. [Extracted from the article]

The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.

Background: Observational studies have reported that Helicobacter pylori ( H. pylori ) infection is associated with a series of pregnancy and neonatal outcomes. However, the results have been inconsistent, and the causal effect is unknown., Methods: A two-sample Mendelian randomization (MR) study was performed using summary-level statistics for anti- H. pylori IgG levels from the Avon Longitudinal Study of Parents and Children Cohort. Outcome data for pregnancy (miscarriage, preeclampsia-eclampsia, gestational diabetes mellitus, placental abruption, premature rupture of membranes, postpartum hemorrhage) and neonates (birthweight, gestational age, and preterm birth) were sourced from genome-wide association meta-analysis as well as the FinnGen and Early Growth Genetics Consortium. Causal estimates were calculated by five methods including inverse variance weighted (IVW). The heterogeneity of instrumental variables was quantified by Cochran's Q test, while sensitivity analyses were performed via MR-Egger, MR-PRESSO, and leave-one-out tests., Results: IVW estimates suggested that genetically predicted anti- H. pylori IgG levels were significantly associated with increased risks of preeclampsia-eclampsia (odds ratio [OR] = 1.12, 95% confidence interval [CI] 1.01-1.24, P = 0.026) and premature rupture of membranes (OR = 1.17, 95% CI 1.05-1.30, P = 0.004). Similar results were obtained for preeclampsia-eclampsia from the MR-Egger method (OR = 1.32, 95% CI 1.06-1.64, P = 0.027) and for premature rupture of membranes from the weighted median method (OR = 1.22, 95% CI 1.06-1.41, P = 0.006). No significant causal effects were found for other outcomes. There was no obvious heterogeneity and horizontal pleiotropy across the MR analysis., Conclusion: Our two-sample MR study demonstrated a causal relationship of H. pylori infection with preeclampsia-eclampsia and premature rupture of membranes. The findings confirm the epidemiological evidence on the adverse impact of H. pylori in pregnancy. Further studies are needed to elucidate the pathophysiological mechanisms and assess the effectiveness of pre-pregnancy screening and preventive eradication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Liu, Xu, Chen, Xie, Chen, Xia, Yu, Wu, Li, Wang and Tian.)

Background: Poor oocyte quality remains one of the major challenges for polycystic ovary syndrome (PCOS) patients during in vitro fertilization (IVF) treatment. Granulosa cells (GCs) in PCOS display altered functions and could cause an unfavorable microenvironment for oocyte growth and maturation. Ferroptosis is a new form of programmed cell death, but its role in PCOS has been largely unclarified., Methods: Ferroptosis-related differentially expressed genes (DEGs) of GCs in women with PCOS were identified by bioinformatic analyses of GSE155489 and GSE168404 datasets. Functional enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Core ferroptosis-related genes were further screened by random forest, and evaluated for diagnostic value by receiver operating characteristic curve analyses. Gene expression was validated by real-time quantitative polymerase chain reaction of collected GC samples, and analyzed for association with oocyte quality. In addition, gene regulatory network was constructed based on predicted RNA interactions and transcription factors, while potential therapeutic compounds were screened through molecular docking with crystallographic protein structures., Results: A total of 14 ferroptosis-related DEGs were identified. These DEGs were mainly enriched in reactive oxygen species metabolic process, mitochondrial outer membrane, antioxidant activity as well as ferroptosis and adipocytokine signaling pathways. Eight core ferroptosis-related genes (ATF3, BNIP3, DDIT4, LPIN1, NOS2, NQO1, SLC2A1 and SLC2A6) were further selected in random forest model, which showed high diagnostic performance for PCOS. Seven of them were validated in GC samples, and five were found to be significantly and positively correlated with one or more oocyte quality parameters in PCOS patients, including oocyte retrieval rate, mature oocyte rate, normal fertilization rate, and good-quality embryo rate. Gene regulatory network revealed JUN and HMGA1 as two important transcription factors, while dicoumarol and flavin adenine dinucleotide were predicted as small molecules with therapeutic potential., Conclusions: This is the first comprehensive report to study the differential expression of ferroptosis-related genes in GCs of PCOS and their clinical relevance with oocyte quality. Our findings could provide novel insights on the potential role of GC ferroptosis in PCOS pathogenesis, diagnosis, and targeted treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Fan, Li, Yang, Xiong, Xiong, Feng, Chen, Wang, Su, Xu, Yang, Wang and Zhu.)

Introduction: The clinical impact of SARS-CoV-2 infection on human reproduction remains controversial. This prospective cohort study aimed to assess the effect of prior female SARS-CoV-2 infection on subsequent in vitro fertilization (IVF) outcomes., Materials and Methods: A total of 451 women who underwent fresh IVF treatment between December 1, 2022 and April 30, 2023 were included from an academic fertility center. Participants were divided into the infected group if they had a prior COVID-19 history before cycle initiation (n = 252), while the control group were those uninfected (n = 199). The primary outcomes were the number of oocytes retrieved and clinical pregnancy rate after fresh embryo transfer. Multivariate linear and logistic regression analyses were conducted to control for potential confounders., Results: The number of oocytes retrieved (11.4 ± 8.3 vs. 11.6 ± 7.7; P = 0.457) and clinical pregnancy rate (70.3% vs. 73.7%; P = 0.590) were similar between infected and uninfected groups, with a fully adjusted β coefficient of 0 (95% confidence interval [CI]: -0.14-0.13) and odds ratio of 0.64 (95% CI: 0.20-2.07), respectively. Consistently, the two groups were comparable in cycle characteristics as well as other laboratory and pregnancy parameters. In both subgroup analyses and restricted cubic splines, different post-infection time intervals to IVF cycle initiation showed no significant associations with treatment outcomes., Conclusion: Prior SARS-CoV-2 infection in females had no adverse influence on subsequent IVF treatment, regardless of the time interval following infection. Our findings provide reassurance for infected women planning for assisted reproduction. Additional prospective cohort studies with larger datasets and longer follow-up are required to confirm the conclusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Liu, Xia, Zhao, Tian, Xu, Su, Hu, Xie, Chen, Li, Ai, Wang and Wu.)

Purpose: To explore the impact of inactivated COVID-19 vaccination on ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) concentration., Methods: A total of 3160 women were included in this single-center retrospective cohort study between June 2021 and October 2022. Vaccination information were collected from official immunization records available in personal mobile apps. Serum AMH was qualified by electrochemiluminescence immunoassay and compared with previous measurement data within three years. Women were categorized to the vaccinated group if they received two doses of inactivated COVID-19 vaccines (Sinopharm or Sinovac) between AMH tests ( n = 488), and to the control group if not vaccinated ( n = 2672). Propensity score matching and multivariate linear regression were performed to control for potential confounders. The main outcome measures were the numeric AMH change and percentage AMH change between the two tests., Results: There were 474 women left in each group after matching all baseline characteristics. The mean interval from the first to second AMH measurement was 508.0 ± 250.2 and 507.5 ± 253.6 days for vaccinated and unvaccinated women, respectively ( P = 0.680). Both groups had a significant AMH decrease in the second test compared with the first test ( P = 0.001). However, the second AMH level remained comparable between groups (3.26 ± 2.80 vs. 3.24 ± 2.61 ng/mL, P = 0.757). Similarly, no significant differences were observed in numerical (-0.14 ± 1.32 vs. -0.20 ± 1.56 ng/mL, P = 0.945) and percentage (2.33 ± 58.65 vs. 0.35 ± 48.42%, P = 0.777) AMH changes. The results were consistent in sub-analyses for women aged <35 and ≥35 years. There were also no significant differences when vaccinated women were divided according to the time interval after vaccination: ≤30, 31-60, 61-90, and ≥91 days., Conclusion: Our study provides the first evidence that inactivated COVID-19 vaccination has no measurable detrimental effect on ovarian reserve, regardless of female age and vaccination interval. This reassuring finding adds to the safety evidence of COVID-19 vaccine in fertility, and should be useful to promote vaccine acceptance. Multicenter prospective cohort studies are needed to validate our conclusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Guan, Tian, Xia, Xu, Wu, Huang, Chen, Fang, Xiong, Nie, Wang, Li, Zhao and Wu.)

Background: Thin endometrial tissue is a leading cause of embryo transfer failure, potentially contributing to sustained infertility and associated adverse outcomes. The application of exosomes derived from autologous or allogeneic bone marrow-derived stem cells (BMSCs) has been used to promote uterine repair following injury, and there is also prior evidence that stem cell transplantation can bolster fertility. Genetic modifications represent a primary approach to enhancing exosomal therapy strategies. The present study thus explored the effects of Cardiotrophin-1 (CTF1)-modified BMSCs-exo on fertility-related outcomes. Methods: An adenoviral vector was used to generate CTF1-overexpressing BMSCs (C-BMSCs), after which exosomes were isolated from control BMSCs (BMSC-exos) and C-BMSCs (C-BMSC-exos). The angiogenic effects of C-BMSC-exo treatment were assessed through analyses of endothelial cell proliferation and tube formation. Model rats exhibiting endometrial thinning were administered C-BMSCs-exo, after which the effects of such treatment were assessed through H&E staining, Masson's trichrome staining, and immunofluorescence analyses. The mechanistic basis for the proangiogenic effects of CTF1 as a driver of endometrial regeneration was additionally explored. Results: C-BMSC-exo treatment of HUVECs was associated with enhanced neovascularization, as evidenced by improved in vitro proliferation, migration, and tube formation. Importantly, such treatment was also linked to tissue regeneration, neovascularization, and the suppression of localized tissue fibrosis in vivo . Regenerated endometrial tissue exhibited higher embryo receptivity and was associated with higher birth rates in treated rats. The upregulation of the JAK/PI3K/mTOR/STAT3 signaling pathways in C-BMSC-exo-treated rats may underscore the mechanistic basis whereby CTF1 can positively impact endometrial angiogenesis and regeneration. Conclusion: Our data suggest that exosomes produced by CTF1-modified BMSCs can more effectively promote the regeneration of endometrial and myometrial tissues, driving neovascularization in a manner that improves endometrial receptivity in a rat model system, highlighting the therapeutic promise of this approach for patients diagnosed with endometrial thinning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Tang, Zhu, Chen, Huang and Lin.)

Background: Peak endometrial thickness (EMT), measured on the end of follicular phase or early luteal phase, is the most widely used marker for endometrial receptivity during infertility treatment. However, the clinical significance of follicular-to-luteal EMT change remains unclear. We aimed to study whether the change of EMT between the day of human chorionic gonadotrophin (hCG) triggering and the day of frozen-thawed embryo transfer (FET) has any influence on pregnancy outcomes in modified natural cycles (mNCs)., Methods: This was a retrospective cohort study of 2,768 regular ovulatory women who underwent their first mNC-FET cycles from January 2011 to June 2015. Patients were divided into three groups according to the percentage change of EMT from the hCG triggering day to the FET day: >5% decrease (n=405), ±5% plateau (n=1,259) and >5% increase (n=1,104). The main outcome measure was live birth rate., Results: Live birth rates were 41.9%, 39.8% [crude odds ratio (cOR) 0.91, 95% CI, 0.73-1.15) and 42.4% (cOR 1.02, 95% CI, 0.87-1.20) in the EMT plateau, decrease and increase groups, respectively (P=0.649). Multiple regression analysis did not alter the finding after controlling for a variety of confounders. Compared with the post-trigger EMT plateau group, the adjusted OR of live birth was 0.88 (95% CI, 0.69-1.12) in the decrease group and 1.05 (95% CI, 0.88-1.25) in the increase group. Similarly, no significant associations were observed before or after adjustment between EMT change and other pregnancy outcomes including positive hCG test, clinical pregnancy, early miscarriage and ongoing pregnancy., Conclusions: EMT change from hCG triggering to embryo transfer was not associated with pregnancy chances in mNC-FET cycles. This reassuring finding should provide guidance for physicians and patients when confronted with EMT decrease on the transfer day., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1459). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)