Metabolic profiles of children aged 2-5 years born after frozen and fresh embryo transfer: A Chinese cohort study.

BACKGROUND: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. METHODS AND FINDINGS: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. CONCLUSIONS: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.

IVF exposure induced intergenerational effects on metabolic phenotype in mice.

RESEARCH QUESTION: What is the potential transmission of metabolic phenotype from IVF offspring to the subsequent generation? DESIGN: An IVF mouse model was established. The F1 generation mice were produced though IVF or natural mating and the F2 generation was obtained through the mating of F1 generation males with normal females. Their metabolic phenotype, including systemic and hepatic glucolipid metabolism, was examined. RESULTS: It was found that IVF F1 males exhibited metabolic changes. Compared with the control group, the IVF F1 generation showed increased body weight, elevated fasting glucose and insulin, and increased serum triglyceride concentrations. IVF F1 mice also showed an increased expression of hepatic lipogenesis and autophagy genes. Moreover, IVF F1 males transmitted some metabolic changes to their own male progeny (IVF F2) in the absence of a dietary challenge. IVF F2 mice had increased peri-epididymal and subcutaneous fat and decreased insulin sensitivity. Under the 'second hit' of a high-fat diet, IVF F2 mice further showed increased hepatic lipid deposition with unaltered autophagy levels. CONCLUSION: This research demonstrates the impact of IVF on hepatic glucose-lipid metabolism in two successive generations of offspring, highlighting the need for additional investigation. Enhanced understanding of the mechanisms underlying the transmission of multigenerational effects induced by IVF could potentially lead to the advancement of therapeutic interventions for individuals experiencing infertility.

Metabolic Profiles of Offspring Born From Biopsied Embryos from Toddlerhood to Preschool Age.

CONTEXT: Embryo biopsy, which is necessary for preimplantation genetic testing (PGT), has not been fully investigated regarding its potential influences and safety. Previous studies of children born from biopsied embryos (PGT children) have primarily centered around their growth and neuropsychological development, while there remains limited knowledge concerning their endocrine and metabolic parameters. OBJECTIVE: This study aims to examine the effect of trophectoderm (TE) biopsy on metabolic outcomes for PGT children. METHODS: A total of 1267 children from the Center for Reproductive Medicine, Shandong University, who were conceived through in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with and without PGT, were analyzed in this study. Three sets of measurements pertaining to growth and metabolism were taken at each predetermined follow-up time point. The linear regression models within a generalized estimating equation were employed to examine the associations between the PGT and each outcome measure and the approach of false discovery rate was used to correct for multiple comparisons. RESULTS: After controlling for confounding factors and correcting for multiple comparisons, no statistically significant difference was identified in any of the measured variables between the PGT children and children conceived by IVF alone (IVF children) and children conceived through IVF using ICSI (ICSI children). The same is true also for age- or sex-based subgroup analyses. CONCLUSION: Between the ages of 1 and 5 years, there are no clinically adverse metabolic outcomes observed in PGT children, and their metabolic profiles are essentially identical to those of IVF children and ICSI children.

Association between being large for gestational age and cardiovascular metabolic health in children conceived from assisted reproductive technology: a prospective cohort study.

BACKGROUND: To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children. METHODS: This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI). RESULTS: 4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty. CONCLUSIONS: Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty.

Ameliorative effect of total ginsenosides from heat-treated fresh ginseng against cyclophosphamide-induced liver injury in mice.

This study evaluated the effect of heat treatment on the conversion of ginsenoside and the ameliorative effect of heat-treated total ginsenoside (HG) from fresh ginseng on cyclophosphamide (CTX)-induced liver injury. LC-MS analysis revealed that the content of rare ginsenosides increased markedly after heat treatment. HG significantly attenuated CTX-induced hepatic histopathological injury in mice. Western blotting analysis showed that untreated total ginsenoside (UG) and HG regulated the Nrf2/HO-1 and TLR4/MAPK pathways. Importantly, these results may be relevant to the modulation of the intestinal flora. UG and HG significantly increased the short-chain fatty acids (SCFAs)-producing bacteria Lactobacillus and reduced the LPS-producing bacteria Bacteroides and Parabacteroides. These changes in intestinal flora affected the levels of TNF-α, LPS and SCFAs. In short, UG and HG alleviated CTX-induced liver injury by regulating the intestinal flora and the LPS-TLR4-MAPK pathway, and HG was more effective. HG has the potential to be a functional food that can alleviate chemical liver injury.

Physicochemical properties and in vitro digestibility of ginseng starches under citric acid-autoclaving treatment.

In this study, the effects of citric acid-autoclaving (CA-A) treatment on physicochemical and digestive properties of the native ginseng starches were investigated. The results showed that ginseng starch exhibited a B-type crystal structure with a low onset pasting temperature of 44.23 ± 0.80 °C, but high peak viscosity and setback viscosity of 5897.34 ± 53.72 cP and 692.00 ± 32.36 cP, respectively. The granular morphology, crystal and short-range ordered structure of ginseng starches were destroyed after CA-A treatment. The more short-chain starches were produced, resulting in the ginseng starches solubility increased. In addition, autoclaving, citric acid (CA) and CA-A treatment promoted polymerization and recrystallization of starch molecules, increased the proportion of amylopectin B1, and B3 chains, and improved molecular weight and resistant starch (RS) content of ginseng starches. The most significant multi-scale structural change was induced by CA-A treatment, which reduced the relative crystallinity of ginseng starch from 28.26 ± 0.24 % to 2.75 ± 0.08 %, and increased the content of RS to 54.30 ± 0.14 %. These findings provided a better understanding of the structure and properties of Chinese ginseng starches and offered new ideas for the deep processing of ginseng foods.

Ginseng Glucosyl Oleanolate from Ginsenoside Ro, Exhibited Anti-Liver Cancer Activities via MAPKs and Gut Microbiota In Vitro/Vivo.

Ginseng is widely recognized for its diverse health benefits and serves as a functional food ingredient with global popularity. Ginsenosides with a broad range of pharmacological effects are the most crucial active ingredients in ginseng. This study aimed to derive ginseng glucosyl oleanolate (GGO) from ginsenoside Ro through enzymatic conversion and evaluate its impact on liver cancer in vitro and in vivo. GGO exhibited concentration-dependent HepG2 cell death and markedly inhibited cell proliferation via the MAPK signaling pathway. It also attenuated tumor growth in immunocompromised mice undergoing heterograft transplantation. Furthermore, GGO intervention caused a modulation of gut microbiota composition by specific bacterial populations, including Lactobacillus, Bacteroides, Clostridium, Enterococcus, etc., and ameliorated SCFA metabolism and colonic inflammation. These findings offer promising evidence for the potential use of GGO as a natural functional food ingredient in the prevention and treatment of cancer.

Associations between Paternal Obesity and Cardiometabolic Alterations in Offspring via Assisted Reproductive Technology.

CONTEXT: Both assisted reproductive technology (ART) and obesity are associated with adverse cardiometabolic alterations in offspring. However, the combined effects of paternal obesity and ART on offspring cardiometabolic health are still unclear. OBJECTIVE: To clarify cardiometabolic changes in offspring of obese fathers conceived using ART. DESIGN: Retrospective cohort study conducted between June 2014 and October 2019. SETTING: Center for reproductive medicine. PATIENTS: A total of 2890 singleton visits aged 4-10 years were followed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age-and sex-specific z-score of body mass index(BMI), blood pressure, insulin resistance and lipid profile were examined. RESULTS: We observed a strong association between paternal BMI categories and offspring BMI, blood pressure, and insulin resistance. Compared to offspring of fathers with normal weight, multivariable-adjusted mean difference for BMI z-score were 0.53 (95%CI: 0.37-0.68) for obese fathers, 0.17 (95%CI: 0.05-0.30) for overweight fathers, and -0.55 (95%CI: -0.95--0.15) for underweight fathers; corresponding values for systolic blood pressure z-score were 0.21(95%CI: 0.07-0.35), 0.10 (95%CI: -0.01-0.21), and -0.24 (95%CI: -0.59-0.11), and corresponding values for HOMA-IR z-score were 0.31(95%CI: 0.16-0.46), 0.09(95%CI: -0.02-0.21), and -0.11 (95%CI: -0.48-0.28), respectively. The mediation analyses suggested that 57.48% to 94.75% of the associations among paternal obesity and offspring cardiometabolic alterations might be mediated by offspring BMI. CONCLUSIONS: Paternal obesity was associated with an unfavourable cardiometabolic profile in ART-conceived offspring. Mediation analyses indicated that offspring BMI was a possible mediator of the association between paternal obesity and the offspring impaired metabolic changes.

Association between maternal polycystic ovarian syndrome undergoing assisted reproductive technology and pregnancy complications and neonatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is recognized as the most prevalent endocrine disorder among women of reproductive age. While the utilization of assisted reproductive technology (ART) has resulted in favorable outcomes for infertility treatment in PCOS patients, the inherent pathophysiological features of the condition give rise to complications and consequences during pregnancy and delivery for both the mother and offspring. This study was to assess the correlation between maternal PCOS and various pregnancy complications and neonatal outcomes undergone ART. METHODS: A systematic search was conducted on PubMed, EmBase, and the Cochrane Library to identify observational studies that investigated the association between PCOS and the risk of various pregnancy complications and neonatal outcomes, including gestational diabetes mellitus (GDM), hypertension in pregnancy (PIH), preeclampsia (PE), preterm birth, abortion, congenital malformations (CA), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, neonatal intensive care unit (NICU) admission and birth weight. Eligible studies were selected based on predetermined inclusion and exclusion criteria. The meta-analysis was conducted using Review Manager and Stata software, with odds ratios (ORs) or mean difference (MD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The search was conducted up to March 2023. RESULTS: A total of 33 studies with a combined sample size of 92,810 participants were identified. The findings indicate that PCOS is significantly associated with an increased risk of GDM (OR 1.51, 95% CI:1.17-1.94), PIH (OR 1.72, 95% CI:1.25-2.39), PE (OR 2.12, 95% CI:1.49-3.02), preterm birth (OR 1.29, 95% CI:1.21-1.39), and LBW (OR 1.29, 95% CI:1.14-1.47). In subgroup analyses, the risks of GDM (OR 1.80, 95% CI:1.23-2.62) and abortion (OR 1.41, 95% CI:1.08-1.84) were elevated in fresh embryo transferred (ET) subgroup, whereas elevated risk of PE (OR 1.82, 95% CI:1.17-2.83) and preterm birth (OR 1.31, 95% CI:1.21-1.42) was identified in frozen ET subgroup. Whatever with or without hyperandrogenism, patients with PCOS had a higher risk in preterm birth (OR 1.69, 95% CI: 1.31-2.18; OR 1.24, 95% CI:1.02-1.50) and abortion (OR 1.38, 95% CI:1.12-1.71; OR 1.23, 95% CI:1.06-1.43). CONCLUSION: Our findings suggest that individuals with PCOS undergone ART are at a notably elevated risk for experiencing pregnancy complications and unfavorable neonatal outcomes. Nevertheless, to establish a definitive association between PCOS and pregnancy-related outcomes, it is necessary to conduct extensive prospective, blinded cohort studies and effectively control for confounding variables.

The influence of cooperative fermentation on the structure, crystallinity, and rheological properties of buckwheat starch.

The effects of co-fermentation of yeast and Lactiplantibacillus plantarum 104 on buckwheat starch physical properties were investigated by various analytical techniques. To investigate the regulations of starch modification during fermentation and to provide a foundation for improving the performance of modified properties of buckwheat starch food. The pasting properties were decreased by co-fermentation also resulted in a reduction in the relative crystallinity. Scanning electron microscopy (SEM) demonstrated that more holes and a relatively rough granule surface were seen in the co-fermentation group. Fourier transform-infrared spectroscopy (FT-IR) results suggested that co-fermentation fermentation decreased the degree of short-range order (DO) and degree of t1he double helix (DD). The results demonstrated that co-fermentation altered these properties more rapidly than spontaneous fermentation. In conclusion, Lactiplantibacillus plantarum 104 could be used for buckwheat fermentation to improve food quality.

Antitumor Mechanism and Therapeutic Potential of Cordycepin Derivatives.

Cordycepin has good antitumor activity, but its clinical application is limited due to the easy deamination of N6 in structure. In this study, a large lipolysis group was introduced at the cordycepin N6 to improve the problem, cordycepin derivatives (3a-4c) were synthesized, and biological evaluation of compounds was studied. In this study, the vitro antitumor activity of the compounds against MCF7 cells, HepG2 cells and SGC-7901 cells was evaluated by MTT assay. In the results, compound 4a showed the most obvious inhibitory effect on MCF7 cells with an IC50 value of 27.57 ± 0.52 µM, which was much lower than cordycepin. Compound 4a showed high selectivity between MCF7 and normal MCF-10A cells. Further biological evaluation showed that compound 4a promoted apoptosis and blocked the cell cycle in the G0/G1 phase. Then, Western Blot was used to detect related apoptotic proteins. It was found that Compound 4a could down-regulate the expression of Bcl-2 protein and up-regulate the expression of p53, Bax, Caspase-3 and Caspase-9 proteins. The mitochondrial membrane potential decreased continuously and the positive expression rate decreased. It was speculated that compound 4a induced the apoptosis of MCF7 cells through the mitochondrial pathway.

Long-Term Effects of Ecological Restoration Projects on Ecosystem Services and Their Spatial Interactions: A Case Study of Hainan Tropical Forest Park in China.

Ecological restoration projects aim to comprehensively intervene in damaged or deteriorating ecosystems, restore them, improve the provision of ecosystem services, and achieve harmonious coexistence between humans and nature. Implementing ecological restoration projects leads to continuous changes in land use/land cover. Studying the long-term changes in land use/land cover and their impacts on ecosystem services, as well as the trade-off and synergy between these services, helps evaluate the long-term effectiveness of ecological restoration projects in restoring ecosystems. Therefore, this study analyzes the land use/land cover, and ecosystem services of the Hainan Tropical Forest Park in China to address this. Since 2000, the area has undergone multiple ecological restoration projects, divided roughly into two stages: 2003-2013 and 2013-2021. The InVEST model is used to quantify three essential ecosystem services in mountainous regions (water yield, carbon storage, and soil conservation), and redundancy analysis identifies the primary driving factors influencing their changes. We conducted spatial autocorrelation analysis to examine the interplay among ecosystem services under long-term land use/land cover change. The results indicate a decrease in the total supply of water yield (-5.14%) and carbon storage (-3.21%) in the first phase. However, the second phase shows an improvement in ecosystem services, with an increase in the total supply of water yield (11.45%), carbon storage (27.58%), and soil conservation (21.95%). The redundancy analysis results reveal that land use/land cover are the primary driving factors influencing the changes in ecosystem services. Furthermore, there is a shift in the trade-off and synergy between ecosystem services at different stages, with significant differences in spatial distribution. The findings of this study provide more spatially targeted suggestions for the restoration and management of tropical montane rainforests in the future.

Identification and pre-clinical investigation of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid as a drug for external use to treat psoriasis.

BACKGROUND AND PURPOSE: Psoriasis vulgaris is a refractory skin inflammatory disorder with 80% of the cases belonging to the mild-to-moderate type, which can be controlled by topical treatment. Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl-11-keto-beta-boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to improve efficacy and solubility for topical use. EXPERIMENTAL APPROACH: Eleven compounds were synthesized using AKBA as a lead compound, and their effects on Th17 cell differentiation were screened. 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA) potently inhibited Th17 cell differentiation. Its efficacy in a mouse model of psoriasis was assessed along with its pharmacology and safety profile when topically or systemically delivered to several animal species. KEY RESULTS: CKBA inhibited mouse and human Th17 cell differentiation with an IC50 of 3.28 and 3.61 µM, respectively, and directly targeted acetyl-CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high-dose CKBA for 14 days had no dose-associated adverse effects on the CNS, haematopoietic, cardiovascular, respiratory and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose-dependent suppression of imiquimod-induced psoriasis-like skin inflammation with slow absorption and limited bioavailability (<10% in rats and <1% in minipigs). CONCLUSIONS AND IMPLICATIONS: CKBA is safe when topically or systemically delivered to animals. The beneficial effects of CKBA ointment in a mouse model of psoriasis indicate that this is a promising drug candidate for further development as a treatment for psoriasis.

Extended culture may contribute to poor intellectual performance of children born after frozen embryo transfer.

Frozen embryo transfer (FET) is becoming popular in recent years. However, whether embryos freezing or other factors may affect intellectual performance in offspring is still unknown. We compared the Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV) questionnaire scores between children born after fresh embryo transfer (fresh ET) and FET. They were matched in a 1:1 ratio on their sex and age (±1 month). 326 children were included in each group. We found children born after FET scored lower on the WISC-IV questionnaire (p = 0.002). In subgroup analysis, the full-scale scores are similar between fresh ET and FET in the cleavage-stage transfer group (p = 0.57). In the FET group, the blastocyst-stage transfer group had lower full-scale scores compared with the cleavage-stage transfer group (p = 0.004). Children born after FET scored lower on WISC-IV questionnaire might be linked to extended culture of embryos rather than the freezing process.

Complete genome analysis of type strain of a novel bacterial family Temperatibacteraceae fam. nov., isolated from surface seawater.

Novel bacterial resources are valuable for studying bacterial taxonomy, bacterial evolution, and genome mining of novel antibiotics, antitumor agents, and immune modulators. In this study, we de novo sequenced the type strain of a novel bacterial family, Temperatibacteraceae fam. Nov., belonging to class Alphaproteobacteria of phylum Pseudomonadota. The type strain, Temperatibacter marinus NBRC 110045T, is mesophilic and was isolated from surface seawater around Muroto city of Japan at a depth of 0.5 m. Here, the sequenced complete genome of strain NBRC 110045T is composed of a circular chromosome of 3,184,799 bp with a mean G + C content of 43.71%. Genome analysis was applied to reveal the genetic basis of its cellular activities. Cellular regulation and signaling was analyzed to infer the regulatory mechanism of its limited growth temperature range. Genomic features of the novel family Temperatibacteraceae may expand our knowledge on environmental adaptation, genetic evolution and natural product discovery of marine bacteria.

Who can help me? Understanding the antecedent and consequence of medical information seeking behavior in the era of bigdata.

Introduction: The advent of bigdata era fundamentally transformed the nature of medical information seeking and the traditional binary medical relationship. Weaving stress coping theory and information processing theory, we developed an integrative perspective on information seeking behavior and explored the antecedent and consequence of such behavior. Methods: Data were collected from 573 women suffering from infertility who was seeking assisted reproductive technology treatment in China. We used AMOS 22.0 and the PROCESS macro in SPSS 25.0 software to test our model. Results: Our findings demonstrated that patients' satisfaction with information received from the physicians negatively predicted their behavior involvement in information seeking, such behavior positively related to their perceived information overload, and the latter negatively related to patient-physician relationship quality. Further findings showed that medical information seeking behavior and perceived information overload would serially mediate the impacts of satisfaction with information received from physicians on patient-physician relationship quality. Discussion: This study extends knowledge of information seeking behavior by proposing an integrative model and expands the application of stress coping theory and information processing theory. Additionally, it provides valuable implications for patients, physicians and public health information service providers.

Effects of duration of long-acting GnRH agonist downregulation on assisted reproductive technology outcomes in patients with adenomyosis: a retrospective cohort study.

Objectives: To elucidate the relationship between long-acting GnRH agonist (GnRHa) downregulation and assisted reproductive technology (ART) outcomes and identify the optimal duration of downregulation in patients with adenomyosis. Design: Retrospective cohort study. Participants: The study was designed to evaluate ART outcomes in adenomyosis patients with and without GnRHa downregulation between January 2016 and December 2020. A total of 374 patients with adenomyosis (621 cycles) were included with 281 cycles in downregulation group versus 340 cycles in non-downregulation group. After 1:1 propensity score matching (PSM), a sample size of 272 cycles in each group was matched. The matched downregulation group was further divided into 1-month (147 cycles), 2-months (72 cycles), and ≥3 months downregulation (53 cycles) subgroups. Stratification analysis was conducted on pregnancy outcomes in 239 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. Results: The downregulation group had larger mean diameter of initial uterus and higher proportion of severer dysmenorrhea compared to non-downregulation group. The pregnancy-related parameters in GnRHa downregulation group were similar to those in non-downregulation group, except for higher late miscarriage rate (MR) (13.4% vs. 3.1%, P = 0.003). The subgroup comparisons in fresh ET cycles indicated that implantation rate (75.0% vs. 39.2%, P = 0.002), biochemical pregnancy rate (91.7% vs. 56.0%, P = 0.036) and clinical pregnancy rate (83.3% vs. 47.0%, P = 0.016) could be improved by prolonged GnRHa downregulation (≥3 months), whereas late MR was difficult to be reversed (30.0% vs. 3.2%, P = 0.017). In FET cycles, higher MR (53.6% vs. 29.9%, P = 0.029; 58.8% vs. 29.9%, P = 0.026) and lower live birth rate (18.8% vs. 34.1%, P = 0.023; 17.1% vs. 34.1%, P = 0.037) were observed in the 1-month and ≥3 months downregulation group, while no differences were found in the 2-months downregulation group compared to the non-downregulation group. Conclusion: In patients with severer adenomyosis, long-acting GnRHa downregulation might be correlated with improved ART outcomes. In fresh ET cycles, prolonged downregulation (≥3 months) might be beneficial to improve live birth rate, which needed to be verified by further study with larger sample. In FET cycles, the optimal duration of downregulation was not certain and still needed further exploration.

Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology.

STUDY QUESTION: What are the factors influencing the occurrence of monozygotic (MZ) twins in offspring conceived by assisted reproductive technology (ART)? SUMMARY ANSWER: Parental ages, the transfer of fresh versus frozen embryos, and the grade of blastocysts are all related to MZ twinning in ART offspring. WHAT IS KNOWN ALREADY: Offspring conceived by ART have significantly increased risk of MZ twins, which may be due to the characteristics of the infertile population. The objective of this study was to explore the incidence of monozygotic (MZ) twins after ART and to clarify the risk factors for MZ twinning. STUDY DESIGN SIZE DURATION: A total of 255 monozygotic twins were enrolled in this cohort study, and then matched with singletons at a ratio of 1:4 randomly (with 1020 in the control group). All offspring were conceived by single embryo transfer. PARTICIPANTS/MATERIALS SETTING METHODS: The collected data were divided into the following three aspects for analysis: characteristics of the infertile population, gamete or embryo manipulations, and factors related to embryo development. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of MZ twins was 1.638% (255 out of 15 567 pregnancies after single embryo transfers). Compared to singleton births, a significantly lower rate of frozen embryo transfers (FET; 78.0% vs 86.1% P = 0.002) was seen amongst the MZ twins. Amongst fresh ETs, the rate of blastocyst transfers in the MZ twins group was higher compared to that in the control group (92.9% vs 75.4%, P = 0.005). We also found that certain grades of blastocysts in terms of trophectoderm (TE) development, inner cell mass + TE development and the classification of 'top-quality' embryos were associated with the incidence of MZ twinning (P = 0.025, P = 0.012, P = 0.020, respectively). Logistic regression analysis revealed that higher paternal age (odds ratio (OR) = 0.94, 95% CI = 0.89-1.00, P = 0.029) and FET (OR = 0.48, 95% CI = 0.33-0.68, P = 0.001) may be protective factors against MZ twinning. However, higher maternal age (OR = 1.07, 95% CI = 1.01-1.13, P = 0.027) and the transfer of blastocysts (OR = 4.31, 95% CI = 1.46-12.73, P = 0.008) appeared to be associated with an increased risk of MZ twinning. Amongst blastocyst transfers, a C grade TE may be protective factor against MZ twinning (B: OR = 1.90, 95% CI = 1.18-3.07, P = 0.009; A: OR = 1.58, 95% CI = 0.93-2.67, P = 0.089). LIMITATIONS REASONS FOR CAUTION: First, our definition of MZ twins was based on twins' birth after single embryo transfers (SET), rather than ultrasound examination during early pregnancy. Second, the parental characteristics of the two groups were homogenous, so it was difficult to find any associations between infertility factors and the incidence of MZ twins. WIDER IMPLICATIONS OF THE FINDINGS: This multifaceted analysis of the risk factors for MZ twinning provides some information for clinical interventions in high-risk populations. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Key Technology Research and Developmental Program of China (2022YFC2704404), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201909195), the Basic Science Center Program (31988101), and the Shandong Provincial Key Research and Development Program (2020ZLYS02). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Cyclophosphamide induced early remission and was superior to rituximab in idiopathic membranous nephropathy patients with high anti-PLA2R antibody levels.

Rituximab (RTX) and cyclophosphamide (CYC) based treatments are both recommended as first-line therapies in idiopathic membranous nephropathy (IMN) by KDIGO 2021 guideline. However, the efficacy of RTX vs. CYC-based treatments in IMN is still controversial. We performed this systemic review and meta-analysis registered in PROSPERO (CRD 42,022,355,717) by pooling data from randomized controlled trials or cohort studies in IMN patients using the EMBASE, PubMed, and Cochrane libraries (till Orc 1, 2022). The primary outcomes were the complete remission (CR) rate + partial remission (PR) rate. CR rate, immunologic response rate, relapse rate, and the risk of serious adverse events (SAE) were secondary outcomes. Eight studies involving 600 adult patients with IMN were included with a median follow-up duration of 12 to 60 months. RTX induced a similar overall remission rate compared with CYC (RR 0.88, 95% CI: 0.71, 1.09, P = 0.23). At the follow-up time of 6 months, RTX was associated with a lower CR + PR rate compared with CYC (RR 0.67, 95% CI: 0.52, 0.88, P = 0.003). Moreover, RTX might be less effective in inducing CR + PR than CYC treatment in IMN patients with high antiPLA2R antibody levels (RR 0.67, 95% CI: 0.48, 0.94, P = 0.02). The occurrences of CRs, relapse rates, immunologic response rates, and SAE were not significantly different between RTX and CYC, respectively. In conclusion, although the long-term efficacy and safety of CYC compared to RTX were comparable, CYC might respond faster and be more advantageous in IMN patients with high antiPLA2R antibody titers.

Effects of ovarian stimulation protocols on outcomes of assisted reproductive technology in adenomyosis women: a retrospective cohort study.

Objective: To evaluate the effects of different ovarian stimulation protocols on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes in infertile women with adenomyosis. Methods: We carried out a retrospective cohort study among infertile women with adenomyosis receiving IVF/ICSI treatment, including 257 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. In fresh ET cycles, ultra-long, long, short, and antagonist protocols were adopted. In FET cycles, patients received long-acting GnRH agonist (GnRHa) pretreatment or not. The primary outcome was clinical pregnancy rate (CPR), and the secondary outcomes included implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR). Results: In fresh ET cycles, compared with ultra-long and long protocols, IR (49.7%, 52.1% versus 28.2%, P=0.001) and CPR (64.3%, 57.4% versus 35.6%, P=0.004) significantly decreased in the short protocol. Similarly, compared with ultra-long and long protocols, a decreased inclination of IR (49.7%, 52.1% versus 33.3%) and CPR (57.4%, 64.3% versus 38.2%) existed in the antagonist protocol, although no statistical significance was detected because of strict P adjustment of Bonferroni method (Padj=0.008). Compared with long protocol, LBR in short protocol decreased obviously (48.2% versus 20.3%, P<0.001). In FET cycles, no matter which origin of embryos, there were no statistical differences in IR, CPR, and LBR. For women ≥35 years receiving fresh ET, CPR was higher in ultra-long and long protocols (52.1%, 50.0% versus 20.0%, 27.5%, P=0.031) compared to antagonist and short protocols. For women ≥35 years receiving FET, compared with ultra-long and antagonist protocols, cycles with embryos originating from long and short protocols had higher proportions of long-acting GnRHa pretreatment (30.4%,30.00 versus 63.9%, 51.4%, P=0.009). IR (61.1%, 48.6% versus 32.6%, 25.0%, P=0.020) and CPR (58.3%, 48.6% versus 30.4%, 25.0%, P=0.024) in long and short protocols were higher than rates of ultra-long and antagonist protocols, but no statistical differences were supported because of strict Bonferroni method (Padj=0.008). Conclusion: In infertile women with adenomyosis, if a fresh embryo was planned for transfer, an ultra-long or long protocol might be beneficial. If antagonist and short protocols were used, whole embryos frozen followed by FET was recommended. In FET cycles, embryos derived from different protocols had no impact on pregnancy outcomes.