[Influence of different processing methods on volatile components of Atractylodis Rhizoma based on HS-GC-MS technology].

The volatile components of Atractylodis Rhizoma have obvious pharmacological effects and are considered to be the main dry components of Atractylodis Rhizoma. The differences of different processed products of Atractylodis Rhizoma were analyzed from the perspective of volatile oil changes to explain the reasons for dryness reduction and efficacy increase of Atractylodis Rhizoma after processing. HS-GC-MS technology was used to obtain the volatile components of raw Atractylodis Rhizoma, bran-fried Atractylodis Rhizoma, roasted Atractylodis Rhizoma, and rice-water processed Atractylodis Rhizoma under four different processes, and then SIMCA software was used to analyze the volatile oil components of Atractylodis Rhizoma and its different processed products. A total of 87 volatile components were identified in the HS-GC-MS results. A total of 76 volatile components were identified in raw products; 79 volatile components were identified in bran-fried Atractylodis Rhizoma; 70 volatile components were identified in Zhangbang rice-water processed Atractylodis Rhizoma; 81 volatile components were identified in roasted Atractylodis Rhizoma; 78 volatile components were identified in Hunan rice-water processed Atractylodis Rhizoma; 73 volatile components were identified in Jilin rice-water processed Atractylodis Rhizoma, and 77 volatile components were identified in Shanghai rice-water processed Atractylodis Rhizoma. Through multivariate statistical analysis, it was found that there were significant differences between the processed products of Atractylodis Rhizoma. Then, a total of 28 significant differential components between the symbiotic products and the six processed products were established by the OPLS-DA model. Among them, 11 volatile components that generally increased significantly after processing were α-pinene, phellandrene,(1S)-(+)-3-carene, o-isopropyltoluene, D-limonene, α-ocimene, α-isoterpinene, silphiperfol-5-ene,silphinene, γ-alkenyl, and germacrene B, which may be related to their synergistic effect. Five volatile components that generally decreased significantly after processing were ß-elemene, 1-methyl-4-(6-methylhept-5-en-2-yl) cyclohexa-1, 3-diene, ß-selinene,ß-sesquiphellandrene, and atractylon, which may be related to their dryness.

Differences in preimplantation blastocyst chromosomal aberrations between polycystic ovary syndrome women and controls: a multi-center retrospective cohort study.

PURPOSE: Comprehensive chromosomal status of blastocyst from women with polycystic ovary syndrome (PCOS) was limited. This study aimed to identify possible differences in the preimplantation blastocyst chromosome aberrations between PCOS women and controls receiving preimplantation genetic testing (PGT). METHODS: This was a multi-center retrospective cohort study including a total of 707 blastocysts from 147 PCOS women and 3006 blastocysts from 821 control women receiving PGT between 2015 and 2021. Embryonic chromosomal aberration spectrums were compared between PCOS and controls. Mixed effects generalized linear model was conducted to explore possible influence of PCOS-related endocrinological disorders on embryonic chromosomal abnormalities. RESULTS: Blastocysts from PCOS demonstrated significantly lower aneuploidy rate (15.2% vs. 25.2% per women, P < 0.001; 14.7% vs. 25.4% per blastocyst, P < 0.001) but greater mosaicism rate (12.5% vs. 8.0% per women, P = 0.007; 16.5% vs. 8.7% per blastocyst, P < 0.001). Mixed effects generalized linear model identified PCOS as an independent protective factor against embryonic aneuploidy (adjusted odds ratio = 0.68, 95% confidence interval, 0.50-0.93, P = 0.014) but a risk factor for embryonic mosaicism (adjusted odds ratio = 1.52, 95% confidence interval 1.11-2.10, P = 0.009). Further model analysis suggested that insulin resistance could be responsible for the increased risk of embryonic mosaicism among PCOS women (adjusted odds ratio = 2.17, 95% confidence interval, 1.10-4.31, P = 0.026). CONCLUSION: PCOS is associated with a lower aneuploidy risk but an increased mosaicism risk in preimplantation blastocysts, and insulin resistance should be investigated as a potential cause.

Effects of the Zishen Yutai Pill on live births compared with placebo among infertile women with frozen-thawed embryo transfer cycle: A multicentre double-blind randomized controlled trial.

BACKGROUND: Zishen Yutai Pill exhibited clinical benefit to infertile women undergoing fresh embryo transfer cycles, improving their pregnancy outcomes. However, as the endometrial environment in frozen embryo transfer (FET) is different from fresh cycles, the effects of ZYP on fresh embryo transfer could not be generalized to FET. OBJECTIVE: We aimed to explore the effects of ZYP on live birth rate in women's FET cycles. METHODS: This multicentre, double-blind, placebo-controlled, randomized study was conducted at 11 reproductive medical centres in China. Women were recruited and randomly assigned to ZYP or placebo intervention (5 g once, 3 times per day) around the time of FET. The live birth rate was set as the primary outcome. Secondary outcomes included implantation rate, biochemical pregnancy rate, clinical pregnancy rate, pregnancy loss rates. Data was analyzed based on the intention-to-treat principle, with per protocol analysis as sensitivity analysis. RESULTS: Between December 2017 and April 2019, 934 women were screened, of whom 880 met all eligibility criteria and were allocated to ZYP (n=441) or placebo (n=439). In ITT analysis, the live birth rates were 38.32% (169/441) in ZYP group and 32.57% (143/439) (absolute difference 5.75%, 95%CI [-0.57%, 12.00%], OR 1.29, 95%CI [0.98, 1.70], P=0.08). The intervention of ZYP did not result in significantly differences in all secondary outcomes compared with placebo (all P>0.05). Similar trends were observed in PP analysis. In post hoc analysis, ZYP resulted in higher rates of live birth than placebo among women in specific subgroups, i.e., with miscarriage history (39.23% vs. 26.45%, P=0.01) or advanced maternal age (33.93% vs. 21.85%, P=0.04). CONCLUSION: In infertile women undergoing FET cycle, intervention with ZYP led to a trend of live birth rate increment compared with placebo, but without statistical significance. However, women with miscarriage history and advanced age could experience possible benefits from ZYP intervention. REGISTRATION: ChiCTR-INR-17010809 (http://www.chictr.org.cn).

Biallelic variants in α-tubulin isotypes cause female infertility characterised as recurrent preimplantation embryo arrest.

BACKGROUND: Recurrent preimplantation embryo developmental arrest (RPEA) is the most common phenotype in assisted reproductive technology treatment failure associated with identified genetic abnormalities. Currently known maternal genetic variants explain only a limited number of cases. Variants of the ß-tubulin subunit gene, TUBB8, cause oocyte meiotic arrest and RPEA through a broad spectrum of spindle defects. In contrast, α-tubulin subunit genes are poorly studied in the context of preimplantation embryonic development. METHODS: Whole exome sequencing was performed on the PREA cohort. Functional characterisations of the identified candidate disease-causing variants were validated using Sanger sequencing, bioinformatics, in vitro functional analyses and single-cell RNA-sequencing of arrested embryos. RESULTS: Four homozygous variants were identified in the PREA cohort: two of TUBA1C (p.Gln358Ter and p.Asp444Metfs*42) and two of TUBA4A (p.Arg339Cys and p.Tyr440Ter). These variants cause varying degrees of spindle assembly defects. Additionally, we characterised changes in the human arrested embryo transcriptome carrying TUBA4A variants, with a particular focus on spindle organisation, chromosome segregation and mRNA decay. CONCLUSION: Our findings identified TUBA1C as a novel genetic marker and expanded the genetic and phenotypic spectrum of TUBA4A in female infertility and RPEA, which altogether highlighted the importance of α-tubulin isotypes in preimplantation embryonic development.

Diagnosis and management of heterotopic intramural pregnancy after in vitro fertilization: an eight-case series.

PURPOSE: To analyze the ultrasound characteristics, clinical management, and pregnancy outcomes of heterotopic intramural pregnancies (HIMPs) after embryo transfer. METHODS: This was a retrospective observational study of women who were diagnosed with HIMPs. The ultrasound characteristics, clinical treatment, and pregnancy outcomes of patients with HIMPs were evaluated. RESULTS: Eight women with HIMPs were included. Among them, 6 patients were diagnosed by transvaginal sonography, and 2 patients were misdiagnosed with heterotopic interstitial pregnancy. The diagnostic accuracy was 75% (6/8). Five patients with HIMPs were diagnosed at the time of the initial scan (5+6-6+3 weeks). An intramural gestational sac was observed in all 6 patients, and an embryo with cardiac activity was detected in one patient on the follow-up scans. Intrauterine pregnancies (IUPs) were revealed in all 6 patients, and embryo(s) with cardiac activity were observed in 5 patients at the time of the initial diagnosis or later. The patients receiving expectant treatment all presented with bagel signs, while patients with embryos with cardiac activity all underwent surgery. Among the 6 diagnosed women, 1 patient was initially treated medically, 4 were treated expectantly, and 1 was treated surgically. Among the 6 diagnosed patients, the IUPs of 5 patients resulted in live infants. CONCLUSION: Single ET should be recommended to decrease the possibility of HIMP. An accurate diagnosis of HIMP was reached in most cases by detailed ultrasound early in the first trimester. Most IUPs of HIMPs seem to have good outcomes with timely and proper management. Expectant management might be a possible choice for nonviable intramural pregnancies.

Homozygous ACTL9 mutations cause irregular mitochondrial sheath arrangement and abnormal flagellum assembly in spermatozoa and male infertility.

PURPOSE: To identify novel variants in ACTL9 and new phenotypes responsible for male infertility. METHODS: Genomic DNA was extracted from peripheral blood samples for whole-exome sequencing (WES). Computer-assisted sperm analysis (CASA) was used to test the motility of spermatozoa. The ultrastructure of flagella and the mitochondrial sheath were assessed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Immunostaining was used to validate the localization and expression of ACTL9 and ACTL7A. An Actl9-mutated mouse model was used to validate the phenotypes by CASA and TEM. RESULTS: We identified novel homozygous variants in ACTL9 in two independent Chinese families. Spermatozoa with ACTL9 mutations showed decreased CASA parameters and a higher proportion of spermatozoa with abnormal morphology, exhibiting coiled flagella and a thickened midpiece. The spermatozoa were characterized by chaotic or irregular '9+2' structures and irregular mitochondrial sheath arrangements in the flagellum. Actl9 knock-in mice also showed abnormal CASA parameters and irregular '9+2' structures in flagella. CONCLUSIONS: Our study expands the mutation spectrum and phenotypic spectrum of ACTL9.

First-trimester ultrasound diagnosis and risk factor analysis of cesarean scar pregnancy after in vitro fertilization-embryo transfer.

Background: Cesarean scar pregnancy (CSP) is one of the rarest ectopic pregnancies which may be associated with life-threatening complications. Owing to the rarity of CSP, little is known about it. This study aimed to evaluate the value of the first-trimester transvaginal sonography (TVS) diagnosis and the risk factors of CSP after in vitro fertilization-embryo transfer (IVF-ET). Methods: This was a retrospective study of women undergoing IVF-ET between January 2013 and December 2018. Women who were diagnosed with a CSP using TVS and confirmed by surgery and histological examination were included. The clinical data and ultrasound findings were collected and analyzed. Univariate and multivariate logistic regression analyses were performed for evaluation of possible influence factors. Diagnostic parameters including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TVS were calculated for the diagnosis of CSP. Results: Overall, 75,438 consecutive women who underwent IVF-ET had received TVS during this period. Of these, 4,817 women (6.4%) had a history of cesarean section and 83 cases were found to have a CSP. Due to the absence of histological data, 19 cases treated conservatively were excluded. Finally, 64 cases were included, among whom 63 cases were correctly diagnosed [including 17 cases of heterotopic CSP (HCSP)] and 1 case was missed using TVS. Another 1 case of inevitable miscarriage was misdiagnosed as a CSP. The maternal age at the initial scan [34.0 (range, 26.0-44.0) years], the infertility duration [4.0 (range, 1-12) years], and the initial diagnostic time after ET [27 (range, 20-50) days] were recorded. A gestational sac (GS) was observed in all 63 cases during ultrasound examinations, including 28 with fetal pole, 25 with a yolk sac only, and 10 with an empty sac. The sensitivity and specificity of first-trimester TVS in diagnosing CSP were 98.44% and 99.98%, respectively; the PPV and NPV were 98.44% and 99.98%, respectively. Multivariate logistic regression analysis showed thinner endometrial thickness (ET) on transfer day [adjusted odds ratio (aOR): 0.83; 95% confidence interval (CI): 0.76-0.93, P<0.001] and multiple ET (aOR 53.60, 95% CI: 5.31-1,736.00, P=0.008) were independent risk factors for CSP and HCSP, respectively. Conclusions: First-trimester TVS performed by an experienced sonographer has a high sensitivity for making the correct diagnosis of CSP after IVF-ET, which is helpful for clinical intervention and avoiding severe complications. For patients with a history of cesarean section, thinner ET on the transfer day and bigger body mass index (BMI) seem to be risk factors for CSP; single blastocyst transfer should be recommended to decrease the possibility of HCSP. The clinical significance of this study still needs to be considered.

Mediterranean diet improves blastocyst formation in women previously infected COVID-19: a prospective cohort study.

Objectives: Our study tries to investigate the effect of the Mediterranean diet (MeDiet) on assisted reproductive treatment outcomes in women after COVID-19 infection. Design: A prospective observational cohort study in the Reproductive and Genetic Hospital of CITIC-Xiangya from February 2023 to August 2023.Subjects: A total of 605 participants previously infected with COVID-19 were enrolled. Exposure: None. Main outcome measurement: The primary outcomes are oocyte and embryo quality. The secondary outcomes are pregnancy outcomes. Results: A majority of participants (n = 517) followed low to moderate MeDiet, and only a small group of them (n = 88) followed high MeDiet. The blastocyst formation rate is significantly higher in MeDiet scored 8-14 points women (46.08%), compared to the other two groups (which is 41.75% in the low adherence population and 40.07% in the moderate adherence population respectively) (p = 0.044). However, the follicle number on hCG day, yield oocytes, normal fertilized zygotes, fertilization rate, day three embryos (cleavage embryos), and embryo quality are comparable among the three groups. For those who received embryo transfer, we noticed an obvious trend that with the higher MeDiet score, the higher clinical pregnancy rate (62.37% vs. 76.09% vs. 81.25%, p = 0.197), implantation rate (55.84% vs. 66.44% vs. 69.23%, p = 0.240) and ongoing pregnancy rate (61.22% vs. 75.00% vs. 81.25%, p = 0.152) even though the p values are not significant. An enlarging sample size study, especially in a high adherence population should be designed to further verify the effects of MeDiet's role in improving IVF performance. Conclusion: High adherence to MeDiet is associated with improved blastocyst formation in women after COVID-19 infection. There is also a trend that high adherence to MeDiet might be beneficial to clinical pregnancy, embryo implantation as well as ongoing pregnancy in these women.

Fluorinated Titanium Oxide (TiO2-xFx) Nanospindles as Ultrasound-Triggered Pyroptosis Inducers to Boost Sonodynamic Immunotherapy.

Pyroptosis is an inflammatory form of programmed cell death associated with the immune system that can be induced by reactive oxygen species (ROS). As a therapeutic strategy with better penetration depth, sonodynamic therapy (SDT) is expected to induce pyroptosis of cancer cells and boost the immune response. However, it is still a limited problem to precisely adjust the structure of sonosensitizers to exhibit satisfactory sono-catalytic properties. Herein, fluorinated titanium oxide (TiO2-xFx) sonosensitizers were developed to induce pyroptosis under ultrasound (US) to boost antitumor immune responses, enabling highly effective SDT. On the one hand, the introduction of F atoms significantly reduced the adsorption energy of TiO2-xFx for oxygen and water, which is conducive to the occurrence of sono-catalytic reactions. On the other hand, the process of F replacing O increased the oxygen vacancies of the sonosensitizer and shortened the band gap, which enabled powerful ROS generation ability under US stimulation. In this case, large amounts of ROS could effectively kill cancer cells by inducing mitochondrial damage and disrupting oxidative homeostasis, leading to significant cell pyroptosis. Moreover, SDT treatment with TiO2-xFx not only suppressed tumor proliferation but also elicited robust immune memory effects and hindered tumor recurrence. This work highlighted the importance of precisely regulating the structure of sonosensitizers to achieve efficient ROS generation for inducing pyroptosis, which sets the stage for the further development of SDT-immunotherapy.

Oxygen Vacancy Enabled Electronic Structure Engineering of Pt-WO3 Nanosheets toward Highly Efficient BTEX Sensing.

A Pt nanoparticle-immobilized WO3 material is a promising candidate for catalytic reactions, and the surface and electronic structure can strongly affect the performance. However, the effect of the intrinsic oxygen vacancy of WO3 on the d-band structure of Pt and the synergistic effect of Pt and the WO3 matrix on reaction performance are still ambiguous, which greatly hinders the design of advanced materials. Herein, Pt-decorated WO3 nanosheets with different electronic metal-support interactions are successfully prepared by finely tuning the oxygen vacancy structure of WO3 nanosheets. Notably, Pt-modified WO3 nanosheets annealed at 400 °C exhibit excellent benzene series (BTEX) sensing performance (S = 377.33, 365.21, 348.45, and 319.23 for 50 ppm ethylbenzene, benzene, toluene, and xylene, respectively, at 140 °C), fast response and recovery dynamics (10/7 s), excellent reliability (σ = 0.14), and sensing stability (φ = 0.08%). Detailed structural characterization and DFT results reveal that interfacial Ptδ+-Ov-W5+ sites are recognized as the active sites, and the oxygen vacancies of the WO3 matrix can significantly affect the d-band structure of Pt nanoparticles. Notably, Pt/WO3-400 with improved surface oxygen mobility and medium electronic metal-support interaction facilitates the activation and desorption of BTEX, which contributes to the highly efficient BTEX sensing performance. Our work provides a new insight for the design of high-performance surface reaction materials for advanced applications.

Identification of novel compound heterozygous ZFP36L2 variants implicated in oocyte maturation defects and female infertility.

PURPOSE: To explore the pathogenesis of oocyte maturation defects. METHODS: Whole exome sequencing was conducted to identify potential variants, which were then confirmed within the pedigree through Sanger sequencing. The functional characterization of the identified variants responsible for the disease, including their subcellular localization, protein levels, and interactions with other proteins, was verified through transient transfection in HeLa cells in vitro. Additionally, we employed real-time RT-PCR and single-cell RNA sequencing to examine the impact of ZFP36L2 pathogenic variants on mRNA metabolism in both HeLa cells and mouse or human oocytes. RESULTS: A novel compound heterozygous variant in ZFP36L2 (c.186T > G, p.His62Gln and c.869 C > T, p.Pro290Leu) was discovered in a patient with oocyte maturation defects. Our findings indicate that these variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes. Furthermore, we characterized the changes in the human oocyte transcriptome associated with ZFP36L2 variants, with a particular emphasis on cell division, mitochondrial function, and ribosome metabolism. CONCLUSIONS: This study broadens the mutation spectrum of ZFP36L2 and constitutes the first report of human oocyte transcriptome alterations linked to ZFP36L2 variants. In conjunction with existing knowledge of ZFP36L2, our research lays the groundwork for genetic counseling aimed at addressing female infertility.

A single-cell transcriptome atlas of human euploid and aneuploid blastocysts.

Aneuploidy is frequently detected in early human embryos as a major cause of early pregnancy failure. However, how aneuploidy affects cellular function remains elusive. Here, we profiled the transcriptomes of 14,908 single cells from 203 human euploid and aneuploid blastocysts involving autosomal and sex chromosomes. Nearly all of the blastocysts contained four lineages. In aneuploid chromosomes, 19.5% ± 1.2% of the expressed genes showed a dosage effect, and 90 dosage-sensitive domains were identified. Aneuploidy leads to prevalent genome-wide transcriptome alterations. Common effects, including apoptosis, were identified, especially in monosomies, partially explaining the lower cell numbers in autosomal monosomies. We further identified lineage-specific effects causing unstable epiblast development in aneuploidies, which was accompanied by the downregulation of TGF-ß and FGF signaling, which resulted in insufficient trophectoderm maturation. Our work provides crucial insights into the molecular basis of human aneuploid blastocysts and may shed light on the cellular interaction during blastocyst development.

Corrigendum: An endometrial receptivity scoring system evaluated by ultrasonography in patients undergoing frozen-thawed embryo transfer: a prospective cohort study.

[This corrects the article DOI: 10.3389/fmed.2024.1354363.].

Vitamin D binding protein correlate with estrogen increase after administration of human chorionic gonadotropin but do not affect ovulation, embryo, or pregnancy outcomes.

Background: Vitamin D binding protein (DBP) might increase substantially after ovarian stimulation and hence could be associated with IVF/ICSI outcomes because it determines the fraction of free bioavailable 25(OH) vitamin D. In this study, we aim to determine whether DBP is associated with E2 level after ovarian stimulation and IVF/ICSI outcomes. Design: Post-hoc analysis of a prospective observational cohort. Setting: Single-center study. Participants: 2569 women receiving embryo transfer. Intervention: None. Main outcome measures: The main outcomes were oocyte and embryo quality as well as pregnancy outcomes. Results: DBP concentration correlates with E2 on hCG day (=day of inducing ovulation with hCG; correlation coefficient r = 0.118, P<0.001) and E2 x-fold change to baseline level (r = 0.108, P<0.001). DBP is also positively correlated with total 25(OH)D (r = 0.689, R2 = 0.475, P<0.001) and inversely with free 25(OH)D (r=-0.424, R2=0.179, P<0.001), meaning that E2-stimulated DBP synthesis results in a decrease of free 25(OH)D during ovarian stimulation. However, such alteration does not affect IVF/ICSI outcomes when considering confounding factors, such as the number and quality of oocytes nor embryo quality as well as pregnancy outcomes. Conclusion: DBP concentration correlates with the degree of E2 increase after ovarian stimulation. DBP is also positively correlated with total 25(OH)D and inversely with free 25(OH)D, suggesting that the proportion of free 25(OH)D decreases during ovarian stimulation caused by E2-stimulated DBP synthesis. However, such alteration does not affect clinical IVF/ICSI outcomes.

Comparison of stimulation protocols for dose determination of gonadotropins: A systematic review and Bayesian network meta-analysis based on randomized controlled trials.

BACKGROUND: To date, evidence regarding the effectiveness and safety of individualized controlled ovarian stimulation (COS) compared with standard dose COS has been inadequate. OBJECTIVES: To evaluate the updated evidence from published randomized controlled trials (RCTs) about the efficacy and safety of individualized COS with different ovarian reserve test biomarkers or clinical experience versus standard dose COS. SEARCH STRATEGY: Terms and descriptors related to COS, individualized or standard, and RCT were combined to search, and only English language studies were included. Conference abstracts and comments were excluded. SELECTION CRITERIA: RCTs with comparison between different individualized COS strategies and standard starting dose strategy were included. DATA COLLECTION AND ANALYSIS: Two reviews independently assessed the eligibility of retrieved citations in a predefined standardized manner. Relative risk (RRs) and the weighted mean difference (WMD) with 95% confidence intervals (CIs) were pooled using a random-effects model on R software version 4.2.2. MAIN RESULTS: Compared with the standard dose COS strategy in pairwise meta-analysis, the individualized COS strategy was associated with a notable lower risk of ovarian hyperstimulation syndrome (OHSS; 174/2384 [7.30%] vs 114/2412 [4.73%], RR 0.66, 95% CI: 0.47-0.93, I2 = 46%), a significantly lower risk of hyperresponse to stimulation (hyperresponse; 476/2402 [19.82%] vs 331/2437 [13.58%], RR 0.71, 95% CI: 0.57-0.90, I2 = 61%), and a slightly longer ovarian stimulation days (duration of stimulation; WMD 0.20, 95% CI: 0.01-0.40, I2 = 66%). Bayesian network meta-analysis also found that biomarker-tailored strategy had a significantly lower risk of OHSS than standard dose strategy (OHSS; RR 0.63, 95% CI: 0.41-0.97, I2 = 47.5%). CONCLUSION: Compared with standard dose COS strategy, individualized COS strategy could significantly reduce the risks of OHSS and hyperresponse to stimulation, but the duration of stimulation was slightly longer. TRIAL REGISTRATION: PROSPERO: CRD42023358439.

Inverse association of prepregnancy systolic blood pressure and live birth rate in normotensive women undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To explore whether maternal baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) affect pregnancy outcomes particularly in normotensive women (SBP, 90-139 mm Hg; DBP, 60-89 mm Hg) and hypertensive women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Maximum care hospital for reproductive medicine. PATIENT(S): This study included 73,462 patients who underwent IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya between January 1, 2016, and November 30, 2020, selected on the basis of pre-established criteria. Analysis was limited to the first transfer cycle of the first stimulation cycle. INTERVENTION: Baseline SBP and DBP. MAIN OUTCOME MEASURE(S): The primary outcome focused on the live birth rate (LBR), with the secondary outcomes including clinical pregnancy rate, ectopic pregnancy rate, first-trimester miscarriage rate, second- or third-trimester fetal loss, and delivery/neonatal/maternal outcomes. Analytic methods included Poisson regression, linear regression, linear mixed-effect model, and restricted cubic spline analysis as appropriate. RESULT(S): For normotensive women, a 10-mm Hg increase in SBP was associated with an adjusted relative risk of 0.988 (95% confidence interval, 0.981-0.995) for live birth likelihood. However, DBP was not significantly associated with LBR after adjustments. The secondary outcomes indicated that increases in SBP and DBP were associated with higher risks of first-trimester miscarriage, gestational diabetes mellitus, and gestational hypertension in the normotensive subset. Sensitivity analyses confirmed these associations between SBP/DBP and LBR, consistent with the main findings even under stricter guidelines and after adjusting for multiple confounders. Subgroup analyses showed variation in the impact of blood pressure on LBR across different demographics and conditions. Consistent with earlier studies on blood pressure and birth outcomes, we found a 10-mm Hg increase in SBP was associated with a 5.4% (adjusted relative risk per 10 mm Hg, 0.946; 95% confidence interval, 0.907-0.986) reduction in LBR in the hypertensive subgroup. CONCLUSION(S): Systolic blood pressure impacted LBR outcomes in normotensive women who underwent IVF/ICSI, which suggests the need for reconsidering blood pressure management guidelines for reproductive-age women, focusing on reproductive health in addition to cardiovascular risk.

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.

Immunological Indicators of Recurrent Pregnancy Loss: A Mendelian Randomization Study.

Recurrent pregnancy loss (RPL) is thought to be related to maternal-fetal immune tolerance disorders. Immune monitoring of RPL patients mainly involves two aspects: inflammatory factors and immune cells. However, most observational studies have reported controversial findings. This study aimed to confirm whether abnormal inflammatory factors and immune cells in peripheral blood may lead to RPL, and guide clinical immune monitoring. We demonstrated causality using two-sample Mendelian randomization. Sensitivity analysis, reverse Mendelian randomization and meta-analysis were used to enhance the effectiveness of the results. There was a causal relationship between the level of IL-12 (OR = 1.78, 95% CI = 1.25-2.55; P = 0.00149) and RPL for 41 inflammatory factors. We screened 5 groups of immune cell subtypes that were causally associated with RPL: switched memory B-cell absolute count (OR = 0.66, 95% CI = 0.49-0.87, P = 0.00406), IgD + CD24 + B-cell absolute count (OR = 0.69, 95% CI = 0.53-0.88, P = 0.00319), CD39 + resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.86, 95% CI = 0.78-0.95, P = 0.00252), activated & resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.89, 95% CI = 0.82-0.97, P = 0.00938) and CD45 RA + CD28-CD8 + T-cell %CD8 + T-cell (OR = 0.99, 95% CI = 0.98-1.00, P = 0.01231). In terms of inflammatory factors, a causal relationship between IL-12 and RPL in peripheral blood was confirmed. We also identified five immune cell phenotypes that play a protective role. This suggests that there may be protective B cells and CD8 + T-cell subsets in peripheral blood, and the protective effect of Tregs was proved again. Immune monitoring of peripheral blood in patients with RPL seems to be necessary and the foundation for precision medicine.

Bioactive Layered Double Hydroxides for Synergistic Sonodynamic/Cuproptosis Anticancer Therapy with Elicitation of the Immune Response.

Sonodynamic therapy (SDT) has promising application prospects in tumor therapy. However, SDT does not eradicate metastatic tumors. Herein, Cu-substituted ZnAl ternary layered double hydroxide nanosheets (ZCA NSs) were developed as both sonosensitizers and copper nanocarriers for synergistic SDT/cuproptosis cancer therapy. An optimized electronic structure more conducive to the sonodynamic process was obtained from ZCA NSs via the Jahn-Teller effect induced by the introduction of Cu2+, and the synthesized ZCA NSs regulated the intricate tumor microenvironment (TME) by depleting endogenous glutathione (GSH) to amplify oxidative stress for further enhanced SDT performance. Furthermore, cuproptosis was evoked by intracellular overload of Cu2+ and amplified by SDT, leading to irreversible proteotoxicity. In vitro results showed that such synergetic SDT/cuproptosis triggered immunogenic cell death (ICD) and promoted the maturation of dendritic cells (DCs). Furthermore, the as-synthesized ZCA NS-mediated SDT/cuproptosis thoroughly eradicated the in vivo solid tumors and simultaneously elicited antitumor immunity to suppress lung and liver metastasis. Overall, this work established a nanoplatform for synergistic SDT/cuproptosis with a satisfactory antitumor immunity.

[Genetic analysis and assisted reproductive guidance for two infertile patients with rare small supernumerary marker chromosomes].

OBJECTIVE: To carry out cytogenetic and molecular genetic analysis for two infertile patients carrying rare small supernumerary marker chromosomes (sSMC). METHODS: Two infertile patients who received reproductive and genetic counseling at CITIC Xiangya Reproductive and Genetic Hospital on October 31, 2018 and May 10, 2021, respectively were selected as the study subjects. The origin of sSMCs was determined by conventional G banding, fluorescence in situ hybridization (FISH) and copy number variation sequencing (CNV-seq). Microdissection combined with high-throughput whole genome sequencing (MicroSeq) was carried out to determine the fragment size and genomic information of their sSMCs. RESULTS: For patient 1, G-banded karyotyping and FISH revealed that he has a karyotype of mos47,XY,del(16)(p10p12),+mar[65]/46,XY,del(16)(p10p12)[6]/48,XY,del(16)(p10p12),+2mar[3].ish mar(Tel 16p-,Tel 16q-,CEP 16-,WCP 16+). CNV analysis has yielded a result of arr[GRCh37]16p12.1p11.2(24999364_33597595)×1[0.25]. MicroSeq revealed that his sSMC has contained the region of chromosome 16 between 24979733 and 34023115 (GRCh37). For patient 2, karyotyping and reverse FISH revealed that she has a karyotype of mos 47,XX,+mar[37]/46,XX[23].rev ish CEN5, and CNV analysis has yielded a result of seq[GRCh37]dup(5)(p12q11.2)chr5:g(45120001_56000000)dup[0.8]. MicroSeq results revealed that her sSMC has contained the region of chromosome 5 between 45132364 and 55967870(GRCh37). After genetic counseling, both couples had opted in vitro fertilization (IVF) treatment and preimplantation genetic testing (PGT). CONCLUSION: For individuals harboring sSMCs, it is vital to delineate the origin and structural characteristics of the sSMCs for their genetic counseling and reproductive guidance. Preimplantation genetic testing after microdissection combined with high-throughput whole genome sequencing (MicroSeq-PGT) can provide an alternative treatment for carrier couples with a high genetic risk.