Early GnRH-agonist therapy does not negatively impact the endometrial repair process or live birth rate.

Study objective: To investigate whether different timings of GnRH-a downregulation affected assisted reproductive outcomes in infertile women with moderate-to-severe intrauterine adhesions (IUAs) accompanied by adenomyosis. Design: A retrospective case series. Setting: An assisted reproductive technology center. Patients: The study reviewed 123 infertile women with moderate-to-severe IUAs accompanied by adenomyosis undergoing their first frozen-thawed embryo transfer (FET) cycles between January 2019 and December 2021. Measurements and main results: The majority of patients had moderate IUA (n=116, 94.31%). The average Basal uterine volume was 73.58 ± 36.50 cm3. The mean interval from operation to the first downregulation was 21.07 ± 18.02 days (range, 1-79 days). The mean duration of hormone replacement therapy (HRT) was 16.93 ± 6.29 days. The average endometrial thickness on the day before transfer was 10.83 ± 1.75 mm. A total of 70 women achieved clinical pregnancy (56.91%). Perinatal outcomes included live birth (n=47, 67.14%), early miscarriage (n=18, 25.71%), and late miscarriage (n=5, 7.14%). The time interval between uterine operation and the first downregulation was not a significant variable affecting live birth. Maternal age was the only risk factor associated with live birth (OR:0.89; 95% CI: 0.79-0.99, P=0.041). Conclusions: The earlier initiation of GnRH-a to suppress adenomyosis prior to endometrial preparation for frozen embryo transfer did not negatively impact repair of the endometrium after resection.

The Degree of Prepregnancy Vitamin D Deficiency Is Not Associated With Gestational Diabetes in Women Undergoing ART.

Context: Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly in women undergoing assisted reproductive technology (ART). An association of GDM with vitamin D in women conceiving naturally has been described; however, studies have yielded heterogeneous results. Objective: To analyze the association between prepregnancy total and free vitamin D and GDM incidence in women undergoing ART. Methods: Post hoc analysis of a prospective study at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China. Total and free vitamin D were measured 1 day before embryo transfer. The patients were screened for GDM using the oral glucose tolerance test. Results: A total of 1593 women were included in the study, among whom 256 (16.1%) developed GDM. According to international guidelines for total 25-hydroxyvitamin D [25(OH)D], 47 (2.9%) patients had sufficient (≥30 ng/mL) levels, while 696 (43.7%) were insufficient (20 to <30 ng/mL) and 850 (54.4%) were deficient (<20 ng/mL). Comparing GDM and non-GDM patients, there was no significant difference in total nor free vitamin D levels (P = .340 and .849). Similarly, analysis of GDM rates by quintiles of total and free 25(OH)D showed no significant association in one-way ANOVA (P = .831 and .799). Multivariate logistic regression, considering age, BMI, and fasting glucose, also did not show a significant influence of the 2 vitamin D forms on GDM incidence (P = .266 and .123 respectively). Conclusion: In this relatively vitamin D deficient/insufficient ART cohort, the degree of neither total nor free vitamin D deficiency before pregnancy was associated with the occurrence of GDM.

Letrozole-stimulated endometrial preparation protocol is a superior alternative to hormone replacement treatment for frozen embryo transfer in women with polycystic ovary syndrome, a cohort study.

BACKGROUND: The current routine endometrial preparation protocol for women with polycystic ovary syndrome (PCOS) is hormone replacement treatment (HRT). Letrozole is rarely used in frozen embryo cycles. Evidence confirming whether letrozole-stimulated (LS) protocol is suitable for frozen embryo transfer in patients with PCOS and for whom is suitable remains lacking. METHODS: This was a retrospective cohort study involving all frozen embryo transfer cycles with LS and HRT for PCOS during the period from Jan 2019 to December 2020 at a tertiary care center. Multivariate Logistic regression was used to analyze the differences in clinical pregnancy rate, live birth rate, miscarriage rate, the incidence of other pregnancy and obstetric outcomes between LS and HRT protocols after adjusting for possible confounding factors. Subgroup analysis was used to explore the population for which LS protocol was suitable. RESULTS: The results of multivariate logistic regression showed that LS was significantly associated with a higher clinical pregnancy rate (70.9% vs. 64.4%;aOR:1.41, 95%CI: 1.18,1.68), live birth rate (60.5% vs. 51.4% aOR:1.49, 95%CI: 1.27,1.76), and a lower risk of miscarriage (14.7% vs. 20.1% aOR: 0.68, 95%CI: 0.53,0.89), hypertensive disorders of pregnancy (6.7% vs. 8.9% aOR: 0.63, 95%CI: 0.42,0.95), and gestational diabetes mellitus (16.7% vs. 20.7% aOR:0.71, 95%CI: 0.53,0.93) than HRT. There were no significant differences in other outcomes such as preterm birth, cesarean delivery, small for gestational age, or large for gestational age between the two endometrial preparation protocols. Subgroup analysis showed that LS had higher live birth rates than HRT in most of the subgroups; in the three subgroups of maternal age ≥ 35 years, menstrual cycle < 35 days, and no insulin resistance, the live birth rates of the two endometrial preparation protocols were comparable. CONCLUSIONS: LS protocol could improve the live birth rate and reduce the incidence of miscarriage, hypertensive disorders of pregnancy and gestational diabetes mellitus in patients with PCOS. LS protocol is suitable for all types of patients with PCOS. LS should be considered the preferred endometrial preparation protocol for women with PCOS.

Effect of lifestyle or metformin interventions before IVF/ICSI treatment on infertile women with overweight/obese and insulin resistance: a factorial design randomised controlled pilot trial.

BACKGROUND: For infertile women with overweight/obesity and insulin resistance (IR), it is uncertain whether intervention before infertility treatment can improve live birth rate (LBR). We implemented a factorial-design study to explore the effectiveness of lifestyle and metformin interventions. This pilot study aimed to evaluate the feasibility of a definitive study. METHODS: We randomised 80 women without polycystic ovarian syndrome (PCOS) who planned to start their first or second IVF/ICSI treatment with a body mass index ≥ 25 kg/m2 and IR. Participants were randomised (1:1:1:1) into four groups: (A) lifestyle intervention, (B) metformin intervention, (C) lifestyle + metformin intervention, or (D) no intervention. All interventions were performed before IVF/ICSI treatment. RESULTS: During 10 months, 114 women were screened and eligible; 80 were randomised, and 72 received the assigned treatment. The recruitment rate was 70.18% (80/114, 95% CI 61.65%-78.70%). An average of 10 participants were randomised each month. None of the participants crossed over from one group to another. Approximately 93.15% (68/73) of the participants achieved good intervention compliance. Only 77.78% (56/72) of the recruited participants started infertility treatment after achieving the goal of the intervention. All randomised participants completed the follow-up. Mild adverse events after metformin administration were reported in 43.24% (16/37) of the cases, although no serious adverse events related to the interventions occurred. The LBR for groups A + C and B + D were 33.33% (12/36) and 33.33% (12/36) (RR = 1.00, 95%CI:0.52-1.92) (lifestyle intervention effect). The LBR for groups B + C and A + D were 43.24% (16/37) and 22.86% (8/35) (RR = 1.89, 95% CI:0.93-3.86) (metformin intervention effect). There was no evidence for an intervention interaction between lifestyle and metformin. We cannot yet confirm the effects of lifestyle, metformin, or their interaction owing to the insufficient sample size in this pilot study. CONCLUSIONS: Instituting a 2 × 2 factorial design randomized controlled trial (RCT) is feasible, as the pilot study showed a high recruitment rate and compliance. There is no evidence that lifestyle or metformin improves live birth, and adequately powered clinical trials are required. TRIAL REGISTRATION: clinicaltrials.gov NCT03898037. Registered: April 1, 2019.

The efficacy and safety of cyclosporine in children with systemic lupus erythematosus: A protocol for systematic review and meta-analysis.

BACKGROUND: Childhood-onset systemic lupus erythematosus (SLE) is a rare but severe multisystem autoimmune/inflammatory disease with marked heterogeneity between patients, causing anything from mild to life-threatening disease. We performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of cyclosporine in childhood-onset SLE. METHODS: This systematic review has been registered in PROSPERO (CRD42022377450), which will be conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Only randomized controlled trials will be included.We searched the following databases including PubMed, EMBASE, the Cochrane Library, SinoMed, CNKI, VIP, Wanfang Data and International Clinical Trials Register Search Portal, and Clinical Trials.gov. Two researchers will use the Cochrane systematic evaluation tool to assess the risk of bias independently. Data synthesis will be performed using RevMan V.5.4. RESULTS: This study will comprehensively summarize the high-quality trials to determine the efficacy and safety of cyclosporine in the treatment of childhood-onset SLE. CONCLUSION: This study may be beneficial to health policymakers, clinicians, and patients with regard to the use of cyclosporine in childhood-onset SLE.

25(OH)VitD and human endocrine and functional fertility parameters in women undergoing IVF/ICSI.

Background: Vitamin D plays an important role in reproduction. Evidence shown that free 25-hydroxyvitamin D (25(OH)VitD) was more accurate than total 25(OH)VitD in reflecting the status of 25(OH)VitD during pregnancy. However, the relationship between free 25(OH)VitD and female fertility parameters has not been reported yet. Therefore, this study aims to compare the correlation of free and total 25(OH)VitD with fertility parameters in infertility females undergoing in vitro fertilization and embryo transfer (IVF-ET) or intracytoplasmic sperm injection (ICSI). Methods: According to the inclusion and exclusion criteria, 2569 infertility patients who received IVF-ET or ICSI treatment for the first time participated in this study. Five milliliter peripheral blood samples of the patients were collected on the day before embryo transfer (ET). Enzyme linked immunosorbent assay (ELISA) kits was used to detect free 25(OH)VitD and total 25(OH)VitD, and clinical information was collected. Spearman's rho was used to evaluate the association between the variables. Results: The median (IQR) of free 25(OH)VitD was 4.71 (4.11-5.31) pg/mL and total 25(OH)VitD was 19.54 (16.52-22.83) ng/m. The correlation between them, however, was week (rho=0.311). Compared to total 25(OH)VitD, free 25(OH)VitD was slightly better correlated with basal follicle-stimulating hormone (FSH) (rho=0.041, P=0.036), basal estradiol (E2) (rho=0.089, P<0.001), anti-Müllerian hormone (AMH) (rho=-0.057, P=0.004), antral follicle count (AFC) (rho=-0.053, P=0.007), E2 (rho=-0.080, P<0.001), number of oocytes retrieval (rho=-0.079, P<0.001) and progesterone (P)/E2 on hCG trigger day (rho=0.081, P<0.001). Conclusions: Overall, there was only a rather weak correlation of free as well as total 25(OH)VitD with human endocrine and functional fertility parameters in women undergoing IVF/ICSI. Neither free nor total 25(OH)VitD seems to play a major role in human embryo implantation.

Non-invasive preimplantation genetic testing for conventional IVF blastocysts.

BACKGROUND: Previous studies suggested that non-invasive preimplantation genetic testing (niPGT) for intracytoplasmic sperm injection (ICSI) blastocysts can be used to identify chromosomal ploidy and chromosomal abnormalities. Here, we report the feasibility and performance of niPGT for conventional in vitro fertilization (IVF) blastocysts. METHODS: This was a prospective observational study. In the preclinical stage, whole genome amplification and NGS were performed using the sperm spent culture medium (SCM). Then, trophectoderm (TE) biopsies and corresponding SCM derived from 27 conventional IVF monopronuclear embryos were collected. In the clinical stage, samples from 25 conventional IVF cycles and 37 ICSI cycles from April 2020-August 2021 were collected for performance evaluation. RESULTS: Preclinically, we confirmed failed sperm DNA amplification under the current amplification system. Subsequent niPGT from the 27 monopronuclear blastocysts showed 69.2% concordance with PGT results of corresponding TE biopsies. In the clinical stage, no paternal contamination was observed in any of the 161 SCM samples from conventional IVF. While maternal contamination was observed in 29.8% (48/161) SCM samples, only 2.5% (4/161) samples had a contamination ratio ≥ 50%. Compared with that of TE biopsy, the performances of NiPGT from 161 conventional IVF embryos and 122 ICSI embryos were not significantly different (P > 0.05), with ploidy concordance rates of 75% and 74.6% for IVF and ICSI methods, respectively. Finally, evaluation of the euploid probability of embryos with different types of niPGT results showed prediction probabilities of 82.8%, 77.8%, 62.5%, 50.0%, 40.9% and 18.4% for euploidy, sex-chromosome mosaics only, low-level mosaics, multiple abnormal chromosomes, high-level mosaics and aneuploidy, respectively. CONCLUSIONS: Our research results preliminarily confirm that the niPGT approach using SCM from conventional IVF has comparable performance with ICSI and might broadening the application scope of niPGT.

Even high normal blood pressure affects live birth rate in women undergoing fresh embryo transfer.

STUDY QUESTION: Do differences in blood pressure within the normal range have any impacts on the live birth rate (primary outcome) or biochemical pregnancy rate (beta-hCG positivity), clinical pregnancy rate (heart beating in ultrasound), abortion rate and ectopic pregnancy rate (secondary outcomes) of fresh embryo transfer in women undergoing their IVF/ICSI treatment? SUMMARY ANSWER: Even rather small differences in baseline blood pressure in women with normal blood pressure according to current guidelines undergoing fresh embryo transfer after IVF/ICSI affects substantially the live birth rate. WHAT IS KNOWN ALREADY: Pre-pregnancy hypertension is a well-known risk factor for adverse pregnancy events such as preeclampsia, fetal growth restriction, placental abruption and adverse neonatal events. It is likewise well known that hypertension during pregnancy in women undergoing ART is associated with adverse pregnancy outcomes. However, whether blood pressure at the high end of the normal range has an impact on ART is unknown. STUDY DESIGN, SIZE, DURATION: It is a prospective observational cohort study based on a single IVF center between January 2017 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two thousand four hundred and eighteen women with normal blood pressure undergoing fresh embryo transfer after IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya were enrolled in this study. MAIN RESULTS AND THE ROLE OF CHANCE: Blood pressure was measured at the first visit when women consulted the IVF center due to infertility. In women with a successful pregnancy outcome (1487 live births out of 2418 women undergoing fresh embryo transfer after IVF/ICSI), systolic blood pressure (SBP) (114.1 ± 9.48 mmHg versus 115.4 ± 9.8 mmHg, P = 0.001) and diastolic blood pressure (DBP) (74.5 ± 7.5 mmHg versus 75.3 ± 7.34 mmHg, P = 0.006) were lower than in those who did not achieve live births. Multivariate logistic regression analysis revealed that SBP (OR: 0.987, 95% CI: 0.979-0.996, P = 0.004) and DBP (OR: 0.986, 95% CI: 0.975-0.998, P = 0.016) were negatively associated with live birth. Similarly, SBP was significantly negatively related to clinical pregnancy rate (OR: 0.990, 95% CI: 0.981-0.999, P = 0.033), while for DBP the association was not statistically significant (OR: 0.994, 95% CI: 0.982-1.006, P = 0.343). However, both SBP and DBP were positively associated with miscarriage OR: 1.021 (95% CI: 1.004-1.037, P = 0.013) and OR: 1.027 (95% CI: 1.005-1.049, P = 0.014), respectively. Both SBP and DBP were unrelated to biochemical pregnancy (hCG positivity), implantation and ectopic pregnancy rate. LIMITATIONS, REASONS FOR CAUTION: Whether lowering blood pressure before initiating ART treatment in women with SBP or DBP higher than the thresholds defined in our study will confer a benefit is unknown. Also, we cannot exclude bias due to different ethnicities. Moreover, participants in our study only received fresh embryo transfer, whether the results could apply to frozen embryo transfer is unclear. WIDER IMPLICATIONS OF THE FINDINGS: Our study challenges the current blood pressure goals in women undergoing fresh embryo transfer after IVF/ICSI. Further studies are needed to figure out the mechanism and effective approach to increase IVF/ICSI pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare that there were no conflicts of interest in this study. TRIAL REGISTRATION NUMBER: N/A.

Estrogen valerate pretreatment with the antagonist protocol does not increase oocyte retrieval in patients with low ovarian response: a randomized controlled trial.

STUDY QUESTION: Does luteal phase estrogen valerate pretreatment improve oocyte yield and clinical outcomes in patients with low ovarian response during ovarian stimulation with the antagonist protocol? SUMMARY ANSWER: Pretreatment with oral estrogen valerate from Day 7 after ovulation to Day 2 of the next menstrual cycle did not increase oocyte yield in patients with a low ovarian response compared to no pretreatment. WHAT IS KNOWN ALREADY: Previous studies showed that patients with a normal ovarian response can obtain better clinical outcomes after pretreatment with estrogen in the antagonist protocol. For patients with advanced age and low ovarian response, it remains unclear if estrogen valerate pretreatment with the antagonist protocol yields more oocytes and improves pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: This non-blinded randomized controlled trial (RCT) was conducted between November 2017 and March 2021. Participants were 552 women with low response who requested IVF treatment. The primary endpoint was comparison of the total number of retrieved oocytes between the two groups. The secondary endpoints were the total number of retrieved metaphase II (MII) oocytes, duration and total dosage of recombinant FSH (rFSH), good-quality embryo rate and clinical pregnancy rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a reproductive center. The RCT enrolled 552 infertile women with a low ovarian response (according to the Bologna criteria) who were undergoing IVF. In the study group, on Day 7 after ovulation patients were administered oral estrogen valerate (2 mg twice a day) until Day 2 of their next menstruation. Ovary stimulation was performed using rFSH, and a GnRH antagonist (0.25 mg/day) was started when a dominant follicle had a mean diameter ≥13 mm. MAIN RESULTS AND THE ROLE OF CHANCE: No significant difference was observed in the number (mean [SD]) of oocytes retrieved from the estrogen valerate pretreatment and control group (3.2 [2.8] versus 3.4 [2.6], respectively). The treatment difference was -0.18 (95% CI -0.67, 0.32, P = 0.49). No significant differences were observed in the number of MII oocytes (2.9 [2.5] versus 3.1 [2.4], mean difference -0.23, 95% CI (-0.69, 0.23), P = 0.16) and good-quality embryos (1.0 [1.3] versus 1.20 [1.6], mean difference -0.23, 95% CI (-0.50, 0.04), P = 0.19) between the two groups. The duration of rFSH treatment was significantly longer in the estrogen valerate pretreatment group than in the control group (10.3 [2.2] versus 8.6 [2.1] days, mean difference 1.7, 95% CI (1.3, 2.2), P = 0.00), and the total rFSH dosage was significantly higher in the estrogen valerate pretreatment group than in the control group (3081 [680] versus 2548 [649] IU, mean difference 553.7, 95% CI (405.8, 661.6), P = 0.00). The clinical pregnancy rate in the pretreatment group (19.3% [23/119]) was not significantly different from that in the control group (28.7% [43/150]). The mean difference was -0.09, 95% CI (-0.20, 0.01), P = 0.08. LIMITATIONS, REASONS FOR CAUTION: The major limitation was the high dropout rate of patients. Some patients did not return to the hospital for treatment because of predicted low success rates and for economic reasons. In addition, it is possible that the fixed dose of 300 IU rFSH was not sufficient to see differences in oocyte yield between the groups. WIDER IMPLICATIONS OF THE FINDINGS: Estrogen valerate pretreatment with an antagonist protocol did not increase oocyte yield in patients with low ovarian response. Similar to the number of retrieved oocytes, there was no significant difference in clinical pregnancy rate between estrogen pretreatment group and control group. More research is needed on whether patients with low ovarian response need pretreatment and which pretreatment is more appropriate. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by a research grant from the Investigator-Initiated Studies Program of MSD (China) Holding Co., Ltd. and Organon (Shanghai) Pharmaceutical Technology Co., Ltd. (Grant number: IIS 56284). The authors declare that they have no competing interests regarding authorship or publication of this study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03300518. TRIAL REGISTRATION DATE: 28 September 2017. DATE OF FIRST PATIENT'S ENROLMENT: 15 November 2017.

Impact of body mass index (BMI) on the success rate of fresh embryo transfer in women undergoing first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment.

OBJECTIVE: To investigate the impact of body mass index (BMI) on the success rate and prenatal outcomes of fresh embryo transfer in women undergoing their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. METHODS: It is a post-hoc analysis of a prospective observational cohort study. 2569 Chinese women were grouped in quintiles of BMI and according to the official Chinese classification of body weight. IVF/ICSI and pregnancy outcomes were compared between groups. RESULTS: BMI was not associated with IVF/ICSI pregnancy outcomes including hCG positive rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, ongoing pregnancy rate, early miscarriage rate, and live birth rate. However, it was negatively related to some pregnancy complications such as gestational diabetes mellitus (GDM) and hypertension. Additionally, the proportion of Cesarean-section was increased with BMI. As for prenatal outcomes, the current results showed no statistical difference in the number of male and female newborn, the proportion of low live birth weight (<2500 g), macrosomia (≥4000 g) (both in all live birth and full-term live birth), and premature delivery (<37 weeks). CONCLUSIONS: The current study showed that BMI was not associated with embryo transfer outcomes after fresh embryo transfer in women undergoing their first IVF/ICSI treatment, whereas BMI was associated with GDM and gestational hypertension.

Blastocyst Transfer: A Risk Factor for Gestational Diabetes Mellitus in Women Undergoing In Vitro Fertilization.

BACKGROUND: The risk of developing gestational diabetes mellitus (GDM) is higher in women undergoing assisted reproductive treatment than in women conceiving spontaneously. OBJECTIVES: To determine whether the GDM risk after day-3 embryo transfer differs from the GDM risk after day-5 blastocyst transfer. METHODS: Prospective observational study in women becoming pregnant after first fresh embryo or blastocyst transfer. RESULTS: A total of 1579 women got pregnant and had live birth; 1300 women got day-3 embryo transfer only, whereas 279 women received at least 1 blastocyst. Of 1579 women, 252 developed GDM. Age, body mass index, baseline estradiol, baseline high-density lipoprotein, and progesterone on the day of human chorionic gonadotropin injection were not different in women receiving day-3 embryos only vs women receiving at least 1 blastocyst. The number and quality of retrieved oocytes were not different in women receiving day-3 embryo transfer from those receiving blastocysts. Our study confirmed already established GDM risk factors such as age and body mass index, baseline estradiol, and high-density lipoprotein, as well as progesterone after ovarian stimulation. We furthermore demonstrate that the GDM incidence in women receiving day-5 blastocyst transfer was significantly higher than those who received day-3 embryo transfer (21.15% vs 14.85%; P = 0.009). Considering confounding factors, we likewise saw that blastocyst transfer was an independent procedure-related GDM risk factor [P = 0.009, Exp (B): 1.56, 95% CI: 1.12-2.18]. CONCLUSION: Blastocyst transfer after in vitro fertilization/intracytoplasmic sperm injection increases the risk of developing GDM.

Case Report: A Novel Heterozygous ZP3 Deletion Associated With Empty Follicle Syndrome and Abnormal Follicular Development.

Background: Empty follicle syndrome (EFS) is defined as the complete failure to retrieve oocytes after ovarian stimulation. Although several mutations in ZP1, ZP2, ZP3, and LHCGR have been identified as genetic causes of EFS, its pathogenesis is still not well-understood. Methods: Whole-exome sequencing (WES) was employed to identify the candidate pathogenic mutations, which were then verified by Sanger sequencing. A study in CHO-K1 cells was performed to analyze the effect of the mutation on protein expression. Additionally, immunohistochemistry (IHC) staining was used to examine follicular development and zona pellucida (ZP) assembly in the ovary of an EFS patient. Results: A novel heterozygous deletion in ZP3 (c.565_579del[p.Thr189_Gly193del]) was identified in the EFS patient. It was inherited dominantly and resulted in significant degradation of the ZP3 protein. Oocytes with degenerated cytoplasm and abnormal ZP assembly were observed in follicles up to the secondary stage, and many empty follicle-like structures were present. Conclusion: We identified a novel ZP3 mutation that expands the mutational spectrum associated with human EFS. We also showed the abnormal follicular development and ZP assembly of the EFS patient with the heterozygous ZP3 mutation, which provides new insights into the pathogenesis of EFS.

Age-related differences in clinical characteristics of Kawasaki disease.

This study aimed to examine and summarize clinical characteristics of Kawasaki disease (KD) at different ages to further strengthen clinicians understanding of children with KD, improving the level of diagnosis, and reducing coronary artery complications of KD. A total of 398 patients with KD who were diagnosed between January 2016 and December 2017 were reviewed retrospectively. These participants were allocated into three groups according to age: group A (<1 year, n=62), group B (≥1 and <5 years, n=286), and group C (≥5 years, n=50). Clinical manifestations, laboratory results, and echocardiographic findings were compared among the groups. Most (71.86%) patients with KD were aged 1-5 years. The prevalence of cervical lymphadenopathy was lowest in group A. The duration of fever before admission was longest in group A. The rate of cervical lymphadenopathy and laboratory data were different among the groups. Group A had higher frequencies of gastrointestinal involvement, neurological symptoms, and redness at the Bacillus Calmette-Guerin inoculation site than the other groups. Infants aged <1 year with KD often have a longer duration of fever before admission, a lower prevalence of cervical lymphadenopathy, and a higher prevalence of gastrointestinal and neurological symptoms.

Impact of vitamin D on human embryo implantation-a prospective cohort study in women undergoing fresh embryo transfer.

OBJECTIVE: To measure free and total 25-hydroxyvitamin D [25(OH)D] immediately before embryo transfer and analyze its association with early pregnancy outcome parameters such as biochemical pregnancy, implantation rate, and clinical pregnancy rates in women undergoing fresh embryo transfer after their first ovarian hyperstimulation. DESIGN: Prospective cohort study. SETTING: Academically affiliated private fertility center. PATIENT(S): A total of 2,569 women undergoing fresh embryo transfer after ovarian hyperstimulation. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The study end points were biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate. Free and total 25(OH)D concentrations were measured 1 day before embryo transfer. RESULT(S): Total 25(OH)D correlated with free 25(OH)D. Total and free 25(OH)D serum concentrations were similar in those patients reaching and not reaching the study outcomes (biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate). There was likewise no statistical difference when analyzing the frequency of all study outcomes in quintiles of either total or free 25(OH)D. In addition, the study population was divided into three groups according to the total vitamin D status based on clinical practice guideline. All outcomes were similar in women with adequate, insufficient, and deficient total 25(OH)D. Multiple linear regression analysis considering confounding likewise indicated no association of free or total vitamin D with any of the study outcomes. CONCLUSION(S): Neither free nor total 25(OH)D concentration at embryo transfer was associated with successful embryo implantation in women undergoing fresh transfer after ovarian hyperstimulation.

Age-related differences in clinical characteristics of Kawasaki disease

This study aimed to examine and summarize clinical characteristics of Kawasaki disease (KD) at different ages to further strengthen clinicians understanding of children with KD, improving the level of diagnosis, and reducing coronary artery complications of KD. A total of 398 patients with KD who were diagnosed between January 2016 and December 2017 were reviewed retrospectively. These participants were allocated into three groups according to age: group A (<1 year, n=62), group B (≥1 and <5 years, n=286), and group C (≥5 years, n=50). Clinical manifestations, laboratory results, and echocardiographic findings were compared among the groups. Most (71.86%) patients with KD were aged 1-5 years. The prevalence of cervical lymphadenopathy was lowest in group A. The duration of fever before admission was longest in group A. The rate of cervical lymphadenopathy and laboratory data were different among the groups. Group A had higher frequencies of gastrointestinal involvement, neurological symptoms, and redness at the Bacillus Calmette-Guerin inoculation site than the other groups. Infants aged <1 year with KD often have a longer duration of fever before admission, a lower prevalence of cervical lymphadenopathy, and a higher prevalence of gastrointestinal and neurological symptoms.

Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility.

Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them-c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)-resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for female infertility.

Cumulative Live Birth Rates in Low Prognosis Patients According to the POSEIDON Criteria: An Analysis of 26,697 Cycles of in vitro Fertilization/Intracytoplasmic Sperm Injection.

Objective: The POSEIDON criteria are used to stratify patients with low prognosis after assisted reproductive technology (ART) treatment. Since its introduction, there has been no large study about the prognosis of the POSEIDON population. We used the POSEIDON criteria in Chinese women who underwent repeated ART treatment and analyzed the association between POSEIDON criteria and the cumulative live-birth rate (CLBR). Methods: This was a retrospective cohort study of 62,749 women (97,388 cycles) who underwent ART treatment at the Reproductive and Genetic Hospital of CITIC-XIANGYA between January 2014 and June 2017. Among them, 19,781 (31.52%) women fulfilled the POSEIDON criteria, including 26,697 cycles. The optimal and conservative CLBRs within a complete IVF/ICSI treatment cycle were calculated, as well as the CLBRs following repeated ovarian stimulation cycles. Results: In POSEIDON groups 1, 2, 3, and 4, the optimal and conservative CLBRs of three complete consecutive in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were 83.87 and 66.06%, 53.67 and 37.72%, 44.24 and 27.98%, and 14.20 and 9.68%, respectively. The POSEIDON stratification [group 2: odds ratio (OR) = 2.319, 95% confidence interval (CI): 2.131-2.525, P < 0.001; group 3: OR = 1.356, 95% CI: 1.005-1.828, P = 0.046; group 4: OR = 3.525, 95% CI: 2.774-4.479, P < 0.001; all vs. group 1] and ovarian stimulation protocol [gonadotropin-releasing hormone (GnRH) antagonist protocol: OR = 1.856, 95% CI: 1.640-2.100, P < 0.001; other protocols: OR = 1.651, 95% CI: 1.155-2.361, P = 0.006; both vs. long GnRH agonist protocol] were associated with live birth in the first stimulation cycle. For the second stimulation cycle, the POSEIDON stratification (except POSEIDON group 3) and ovarian stimulation protocol were associated with live birth. A change in ovarian stimulation protocol was not associated with an improvement in the live birth rate. Conclusions: More than 30% of women who undergo IVF/ICSI treatment may be classified as low prognosis. Different reproductive outcomes were observed among the four POSEIDON groups. The most optimal outcomes after three successive cycles of IVF/ICSI treatment were observed in groups 1, 2, and 3.

Free 25-Vitamin D Is Correlated with Cardiovascular Events in Prevalent Hemodialysis Patients but Not with Markers of Renal Mineral Bone Disease.

Free vitamin D is the biologically active form of vitamin D. Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. The goal of our current study was to investigate the relation between blood concentrations of free 25-hydroxyvitamin D with cardiovascular events in end-stage chronic kidney disease patients on hemodialysis, because this is unknown so far. We measured free vitamin D levels in 117 stable consecutive prevalent patients in September as a surrogate of vitamin D exposure during the past 6 months, and recorded the number of cardiovascular events during the previous 6 months defined as hospitalization due to heart failure, episodes of acute coronary syndrome, and stroke. Fourteen events occurred during the observation period. In patients without any cardiovascular events the free vitamin D levels were significantly higher as compared to those with cardiovascular events (patients without events: 5.68 [4.37-9.27] pg/mL; patients with events: 4.74 [3.46-5.37] pg/mL, p = 0.015). This finding remained stable after multiple regression analysis considering confounding factors such as age, time on dialysis, preexisting diabetes, hypertension, and coronary heart disease. In conclusion, our study shows that free vitamin D serum concentrations are independently associated with major cardiovascular events in chronic kidney disease patients on dialysis.

Prevalence and characteristics of arthritis in Kawasaki disease: a Chinese cohort study.

Arthritis is a major complication of Kawasaki disease (KD). The aims of this study were to define the frequency and the clinical characteristics of arthritis in KD in China and to analyze the relation between arthritis and coronary outcome in KD. We included 1420 KD patients followed at Jiangxi Children's Hospital from January 2014 to December 2017. Demographic, clinical and laboratory features of KD were analyzed. Among the 1420 patients enrolled, 151 had arthritis. The median age of KD patients with arthritis was 29 months and older than those without arthritis (20 months). Of the 151 patients developed arthritis, 101 patients (66.9%) had oligoarticular involvement and 50 patients (33.1%) had polyarticular involvement. Early-onset and late-onset arthritis were, respectively, observed in 123 (81.45%) and 28 (18.54%) patients. The KD patients with arthritis had significantly increased levels of inflammatory markers, and we observed a higher incidence rate of coronary artery aneurysms among those with arthritis (7.28%) compared to those without arthritis (2.75%) (p = 0.003), but the prevalence of coronary artery lesions (CALs) was similar in the two groups. The arthritis in KD was self-limited, left no sequelae and did not require additional medications. KD patients with arthritis were more likely to get coronary artery aneurysms than the patients without arthritis, so examination of joints in KD was necessary.

ZP2 pathogenic variants cause in vitro fertilization failure and female infertility.

PURPOSE: The oocyte-borne genetic causes leading to fertilization failure are largely unknown. We aimed to identify novel human pathogenic variants (PV) and genes causing fertilization failure. METHODS: We performed exome sequencing for a consanguineous family with a recessive inheritance pattern of female infertility characterized by oocytes with a thin zona pellucida (ZP) and fertilization failure in routine in vitro fertilization. Subsequent PV screening of ZP2 was performed in additional eight unrelated infertile women whose oocytes exhibited abnormal ZP and similar fertilization failure. Expression of ZP proteins was assessed in mutant oocytes by immunostaining, and functional studies of the wild-type and mutant proteins were carried out in CHO-K1 cells. RESULTS: Two homozygous s PV (c.1695-2A>G, and c.1691_1694dup (p.C566Wfs*5), respectively) of ZP2 were identified in the affected women from two unrelated consanguineous families. All oocytes carrying PV were surrounded by a thin ZP that was defective for sperm-binding. Immunostaining indicated a lack of ZP2 protein in the thin ZP. Studies in CHO cells showed that both PV resulted in a truncated ZP2 protein, which might be intracellularly sequestered and prematurely interacted with other ZP proteins. CONCLUSION: We identified loss-of-function PV of ZP2 causing a structurally abnormal and dysfunctional ZP, resulting in fertilization failure and female infertility.