Finite-time synchronization of delayed semi-Markov reaction-diffusion systems: An asynchronous boundary control scheme.

This paper tries to study the problem of finite-time synchronization for delayed semi-Markov reaction-diffusion systems. Based on the spatial and parametric characteristics of the considered systems, a new asynchronous boundary control scheme is proposed to ensure the finite-time synchronization of the drive and response systems. In the asynchronous boundary control scheme, only an actuator should be placed at the spatial boundary, which is more easier to implement and economical than the other non-boundary control strategies. Besides, the system parameters and controller follow two asynchronous semi-Markov chains for jumping, which is more practical than obeying one semi-Markov chain. Moreover, for the considered systems, we proposes a new lemma of finite-time stability, and by employing the inequality methods and variable substitution, we derive the criterion of finite-time synchronization and a correlative corollary. Finally, a numerical example and an application example on secure communication are carried out to support the developed approach.

A secure and highly efficient blockchain PBFT consensus algorithm for microgrid power trading.

There are a series of challenges in microgrid transactions, and blockchain technology holds the promise of addressing these challenges. However, with the increasing number of users in microgrid transactions, existing blockchain systems may struggle to meet the growing demands for transactions. Therefore, this paper proposes an efficient and secure blockchain consensus algorithm designed to meet the demands of large-scale microgrid electricity transactions. The algorithm begins by utilizing a Spectral clustering algorithm to partition the blockchain network into different lower-level consensus set based on the transaction characteristics of nodes. Subsequently, a dual-layer consensus process is employed to enhance the efficiency of consensus. Additionally, we have designed a secure consensus set leader election strategy to promptly identify leaders with excellent performance. Finally, we have introduced an authentication method that combines zero-knowledge proofs and key sharing to further mitigate the risk of malicious nodes participating in the consensus. Theoretical analysis indicates that our proposed consensus algorithm, incorporating multiple layers of security measures, effectively withstands blockchain attacks such as denial of service. Simulation experiment results demonstrate that our algorithm outperforms similar blockchain algorithms significantly in terms of communication overhead, consensus latency, and throughput.

Nanopore sequencing with T2T-CHM13 for accurate detection and preventing the transmission of structural rearrangements in highly repetitive heterochromatin regions in human embryos.

BACKGROUND: Structural rearrangements in highly repetitive heterochromatin regions can result in miscarriage or foetal malformations; however, detecting and preventing the transmission of these rearrangements has been challenging. Recently, the completion of sequencing of the complete human genome (T2T-CHM13) has made it possible to accurately characterise structural rearrangements in these regions. We developed a method based on T2T-CHM13 and nanopore sequencing to detect and block structural rearrangements in highly repetitive heterochromatin sequences. METHODS: T2T-CHM13-based "Mapping Allele with Resolved Carrier Status" was performed for couples who carry structural rearrangements in heterochromatin regions. Using nanopore sequencing and the T2T-CHM13 reference genome, the precise breakpoints of inversions and translocations close to the centromere were detected and haplotypes were constructed using flanking single-nucleotide polymorphisms (SNPs). Haplotype linkage analysis was then performed by comparing consistent parental SNPs with embryonic SNPs to determine whether the embryos carried hereditary inversions or balanced translocations. Based on copy number variation and haplotype linkage analysis, we transplanted normal embryos, which were further verified by an amniotic fluid test. RESULTS: To validate this approach, we used nanopore sequencing of families with inversions and reciprocal translocations close to the centromere. Using the T2T-CHM13 reference genome, we accurately detected inversions and translocations in centromeres, constructed haplotypes and prevented the transmission of structural rearrangements in the offspring. CONCLUSIONS: This study represents the first successful application of T2T-CHM13 in human reproduction and provides a feasible protocol for detecting and preventing the transmission of structural rearrangements of heterochromatin in embryos.

Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility.

Preimplantation embryonic arrest is an important pathogenesis of female infertility, but little is known about the genetic factors behind this phenotype. MEI4 is an essential protein for DNA double-strand break formation during meiosis, and Mei4 knock-out female mice are viable but sterile, indicating that MEI4 plays a crucial role in reproduction. To date, MEI4 has not been found to be associated with any human reproductive diseases. Here, we identified six compound heterozygous and homozygous MEI4 variants-namely, c.293C > T, p.(Ser98Leu), c.401C > G, p.(Pro134Arg), c.391C > G, p.(Pro131Ala), c.914A > T, p.(Tyr305Phe), c.908C > G, p.(Ala303Gly), and c.899A > T, p.(Gln300Leu)-in four independent families that were responsible for female infertility mainly characterized by preimplantation embryonic arrest. In vitro, we found that these variants reduced the interaction between MEI4 and DNA. In vivo, we generated a knock-in mouse model and demonstrated that female mice were infertile and were characterized by developmental defects during oogenesis. Our findings reveal the important roles of MEI4 in human reproduction and provide a new diagnostic marker for genetic counseling of clinical infertility patients.

A trusted medical data sharing framework for edge computing leveraging blockchain and outsourced computation.

Traditional cloud-centric approaches to medical data sharing pose risks related to real-time performance, security, and stability. Medical and healthcare data encounter challenges like data silos, privacy breaches, and transmission latency. In response to these challenges, this paper introduces a blockchain-based framework for trustworthy medical data sharing in edge computing environments. Leveraging healthcare consortium edge blockchains, this framework enables fine-grained access control to medical data. Specifically, it addresses the real-time, multi-attribute authorization challenge in CP-ABE through a Distributed Attribute Authorization strategy (DAA) based on blockchain. Furthermore, it tackles the key security issues in CP-ABE through a Distributed Key Generation protocol (DKG) based on blockchain. To address computational resource constraints in CP-ABE, we enhance a Distributed Modular Exponentiation Outsourcing algorithm (DME) and elevate its verifiable probability to "1". Theoretical analysis establishes the IND-CPA security of this framework in the Random Oracle Model. Experimental results demonstrate the effectiveness of our solution for resource-constrained end-user devices in edge computing environments.

Nuclear-cytoplasmic asynchrony in oocyte maturation caused by TUBB8 variants via impairing microtubule function: a novel pathogenic mechanism.

BACKGROUND: TUBB8, a crucial gene encoding microtubule protein, plays a pivotal role in cellular processes. Deleterious TUBB8 variants have been shown to significantly hinder oocyte maturation. In this study, we conducted an in vitro investigation using TUBB8 mutant mouse oocytes to elucidate the pathogenic mechanisms of TUBB8 variants in oocyte nuclear and cytoplasmic maturation. METHODS: A mutant model was successfully established in mouse oocytes via microinjection to further investigate the effects of four novel discovered TUBB8 mutations on the nuclear and cytoplasmic maturation of mouse oocytes. Immunofluorescence and confocal microscopy were performed to observe the cortical polarity and spindle and of mutant oocytes. Active mitochondrial staining was performed to analyze mitochondrial distribution patterns. Endoplasmic reticulum and Ca2+ staining were conducted to assess ER distribution and cytoplasmic calcium ion concentration in oocytes. RESULTS: In mouse oocytes, TUBB8 variants (p.A313V, p.C239W, p.R251Q, and p.G96R) resulted in a reduction of the first polar body extrusion rate, disruption of spindle assembly, and abnormal chromosome distribution. Additionally, these variants induced oocyte organelle abnormalities, including anomalies in mitochondrial redistribution and endoplasmic reticulum stress compared to the wild-type. CONCLUSION: Deleterious TUBB8 variants could disrupt microtubule function, affecting critical processes such as spindle assembly, chromosome distribution, and organelle rearrangement during oocyte meiosis. These disruptions culminate in compromised nuclear-cytoplasmic maturation, consequently giving rise to oocyte maturation defects.

Integrated treatment guided by RNA-seq-based endometrial receptivity assessment for infertility complicated by MEN1.

Background: Preimplantation genetic testing (PGT) serves as a tool to avoid genetic disorders in patients with known genetic conditions. However, once a selected embryo is transferred, implantation success is attained independent of embryo quality. Using PGT alone is unable to tackle implantation failure caused by endometrial receptivity (ER) abnormalities in these patients. Methods: We validated our newly developed RNA-seq-based ER test (rsERT) in a retrospective cohort study including 511 PGT cycles and reported experience in treating an infertile female patient complicated by multiple endocrine neoplasia type 1 (MEN1). Results: Significant improvement in the clinical pregnancy rate was found in the performed personalized embryo transfer (pET) group (CR, 69.7%; P = 0.035). In the rare MEN1 case, pET was done according to the prediction of the optimal time of window of implantation after unaffected blastocysts were obtained by PGT-M, which ultimately led to a healthy live birth. However, none of the mRNA variants identified in the patient showed a strong association with the MEN1 gene. Conclusions: Applying the new rsERT along with PGT improved ART outcomes and brought awareness of the importance of the ER examination in MEN1 infertile female patients. MEN1-induced endocrine disorder rather than MEN1 mutation contributes to the ER abnormality. Trial Registration: Reproductive Medicine Ethics Committee of Xiangya Hospital Registry No.: 2022010.

An endometrium of type C along with an endometrial thickness of < 8 mm are risk factors for ectopic pregnancy after stimulated cycles with fresh embryo transfer.

BACKGROUND: The study investigated whether specific ultrasonographically observed endometrial features (including endometrium type and thickness) were linked to ectopic pregnancy after stimulated cycles with fresh embryo transfer. METHOD: Of 6246 pregnancy cycles after fresh embryo transfer, 6076 resulted in intrauterine pregnancy and 170 in ectopic pregnancy. The primary outcome of the study was ectopic pregnancy, with the main variables being endometrium type and endometrial thickness. Univariate and subsequent multiple-stepwise logistic regression analyses were used to identify the risk factors of ectopic pregnancy. RESULTS: 1. Compared with patients with an endometrial thickness ≥ 8 mm, the adjusted odds ratio for those with an endometrial thickness < 8 mm was 3.368 (P < 0.001). The adjusted odds ratio for women with a type-C endometrium was 1.897 (P = 0.019) compared with non-type C. 2. A larger dose of gonadotropin used during controlled ovarian hyperstimulation was a protective factor against ectopic pregnancy (P = 0.008). 3. The GnRH antagonist protocol (P = 0.007) was a risk factor for ectopic pregnancy, compared with the use of GnRH agonists. CONCLUSION: (1) An endometrial thickness < 8 mm coupled with a type C endometrium significantly increased the risk of ectopic pregnancy after fresh embryo transfer. (2) A thin endometrial thickness and a type C endometrium could be further related to an abnormal endometrial receptivity/peristaltic wave. (3) Patients at a high risk of ectopic pregnancy should therefore be given special attention, with early diagnosis during the peri-transplantation period may assist in the prevention of ectopic pregnancy.

Nanopore sequencing for detecting reciprocal translocation carrier status in preimplantation genetic testing.

BACKGROUND: Balanced reciprocal translocation (BRT) is one of the most common chromosomal abnormalities that causes infertility, recurrent miscarriage, and birth defects. Preimplantation genetic testing (PGT) is widely used to select euploid embryos for BRT carriers to increase the chance of a healthy live birth. Several strategies can be used to distinguish reciprocal translocation carrier embryos from those with a normal karyotype; however, these techniques are time-consuming and difficult to implement in clinical laboratories. In this study, nanopore sequencing was performed in two reciprocal translocation carriers, and the results were validated using the next-generation sequencing-based method named, "Mapping Allele with Resolved Carrier Status" (MaReCs). RESULTS: The translocation breakpoints in both reciprocal translocation carriers were accurately identified by nanopore sequencing and were in accordance with the results obtained using MaReCs. More than one euploid non-balanced translocation carrier embryo was identified in both patients. Amniocentesis results revealed normal karyotypes, consistent with the findings by MaReCs and nanopore sequencing. CONCLUSION: Our results suggest that nanopore sequencing is a powerful strategy for accurately distinguishing non-translocation embryos from translocation carrier embryos and precisely localizing translocation breakpoints, which is essential for PGT and aids in reducing the propagation of reciprocal translocation in the population.

Chromosomal concordance between babies produced by the preimplantation genetic testing for aneuploidies and trophectoderm biopsies: A prospective observational study.

OBJECTIVES: Contributed to the development of next-generation sequencing (NGS) technology, more and more chromosomally mosaic and aneuploid embryos are discovered during the preimplantation genetic testing for aneuploidy (PGT-A) cycles. Because mosaicism and aneuploidy are routine phenomena throughout human pre- and post-implantation development. The benefit of implanting such mosaicism or aneuploidies detected by precise NGS remains controversial. This study aimed to investigate chromosomal concordance between babies produced by PGT-A and trophectoderm (TE) biopsies, and whether precise NGS resolution would reduce the development of an abnormal embryo in PGT cycles. STUDY DESIGN: Peripheral blood samples from 17 PGT-A babies were collected to compare with TE biopsy results at different NGS resolutions. RESULTS: 16 euploid embryos diagnosed by 10 Mb resolution developed into 16 healthy babies with normal copy number variations (CNVs). One mosaic embryo diagnosed by both 10 Mb and 4 Mb resolution also produced a euploid baby finally. Among them, four euploid embryos diagnosed by 10 Mb NGS, showed segmental aneuploidy at 4 Mb NGS resolution. Four of them developed into euploid babies with normal CNVs finally. CONCLUSIONS: NGS at 10 Mb resolution is accurate enough to diagnose viable embryos. A more precise NGS resolution (e.g., 4 Mb resolution) results in discard of some potentially viable embryos. It is suggested to analyze the TE biopsy at both 10 Mb and 4 Mb resolutions to identify embryos with adverse chromosomal aberrations, but using 10 Mb resolution for guide transfer to increase a development chance of an embryo. TRIAL REGISTRATION: www. CLINICALTRIALS: gov, identifier ChiCTR2100042522.

Arrested Cells/Cellular Debris Expelled from Blastocysts Is Self-Correction Phenomenon During Early Embryonic Development.

Arrested cells/ cellular debris is component left in the zona pellucida after blastocyst hatching. To identify whether expelling arrested cells/cellular debris from blastocysts is a process of human embryo self-correction by eliminating abnormal cells, 21 pairs of trophectoderm (TE) biopsies and the corresponding arrested cells/cellular debris expelled from the blastocysts from July to December 2020 were collected and analyzed using next-generation sequencing (NGS). Then, the NGS results of TE biopsies and the corresponding arrested cells/cellular debris were compared. We identified that 47.6% of blastocysts (10/21) were aneuploidies and mosaicism. A total of 18 groups of arrested cells/cellular debris (85.7%) expelled from blastocysts were abnormal, including nine aneuploid embryos and nine euploid embryos. In the arrested cells/cellular debris, all the chromosomes were affected. In conclusion, mosaicism and aneuploidies are common features of early embryonic development, and the arrested cells/cellular debris expelled from blastocysts provides evidence of early embryonic self-correction.

A novel homozygous nonsense variant of AK7 is associated with multiple morphological abnormalities of the sperm flagella.

RESEARCH QUESTION: Is the novel homozygous nonsense variant of AK7 associated with multiple morphological abnormalities of the sperm flagella (MMAF), a specific type of oligoasthenoteratozoospermia leading to male infertility? DESIGN: Whole-exome sequencing and Sanger sequencing were performed to identify potential gene variants. Immunoblotting and immunofluorescence were applied to confirm the relationship between mutated genes and disease phenotypes. The concentration of reactive oxygen species and the rate of apoptosis were measured to evaluate the mitochondrial function of spermatozoa. Transmission electron microscopy and scanning electron microscopy were employed to observe sperm ultrastructure. RESULTS: A novel homozygous nonsense variant of AK7, c.1153A>T (p. Lys385*), was identified in two infertile siblings with asthenoteratozoospermia through whole-exome sequencing. Both immunoblotting and immunofluorescence assays showed practically complete absence of AK7 in the patient's spermatozoa. Additionally, the individual with the novel AK7 variant exhibited a phenotype characterized by severe oxidative stress and apoptosis caused by mitochondrial metabolic dysfunction of spermatozoa. Notably, remarkable flagellar defects with multiple axonemes in uniflagellate spermatozoa, accompanied by mitochondrial vacuolization, were observed; this has not been reported previously in patients with other AK7 variants. CONCLUSIONS: This study found that a novel identified homozygous nonsense variant of AK7 may be associated with MMAF-related asthenoteratozoospermia. The observed functional associations between mitochondria and sperm flagellar assembly provide evidence for potential mutual regulation between AK7 and flagella-associated proteins during spermatogenesis.

A novel homozygous mutation in the PADI6 gene causes early embryo arrest.

BACKGROUND: It has been proved that mutations in the PADI6 gene can cause early embryo arrest. This study describes a newly discovered mutation in PADI6 that expands the genetic spectrum of early embryo arrest. METHODS: Peripheral blood of a patient diagnosed with early embryo arrest was collected for whole-exome sequencing. Sanger sequencing was performed to confirm this mutation. The effects of the variant were investigated in human embryonic kidney 293T (HEK293T) cells using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. RESULTS: A novel homozygous mutation in PADI6 was identified in the proband. The patient carried a frameshift insertion mutation c.558dupA (p.Thr187Asnfs*48), which was located in the protein arginine deiminase middle domain. The variant destroyed PADI6 protein expression and reduced PADI6 mRNA expression in HEK293T cells. CONCLUSIONS: The newly identified mutation in PADI6 accounts for early embryo arrest. It expands the spectrum of genetic causes and phenotypes of infertility in humans. These findings also provide an additional possible diagnostic marker for patients with recurrent in vitro fertilization/intracytoplasmic sperm injection failure.

Some infertile patients experience multiple in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure owing to recurrent early embryo arrest. However, the underlying mechanisms remain largely unknown. Due to the development of whole-exome sequencing, early embryo arrest has been confirmed as a type of Mendelian disease. This study aimed to identify the genetic cause of early embryo arrest in patients and to expand the genetic spectrum. Furthermore, it can help doctors offer better suggestions to such patients and prevent patients from suffering from multiple IVF/ICSI failures.

An Endometrial Thickness < 8 mm Was Associated With a Significantly Increased Risk of EP After Freeze-Thaw Transfer: An Analysis of 5,960 Pregnancy Cycles.

Introduction: Endometrium characteristics that are most likely to induce ectopic pregnancy were investigated on the basis of the data of 5,960 pregnant freeze-thaw cycles. Methods: A total of 5,960 pregnancy cycles after freeze-thaw embryos transfer were included, with the number of intrauterine and ectopic pregnancies being 5,777 and 183, respectively. Ectopic pregnancy was the primary outcome. Endometrial thickness was the main measured variable. The risk factors of ectopic pregnancy were eventually determined based on univariate analysis and subsequent multiple-stepwise logistic regression analysis. Results: 1. After adjusting for confounders, endometrial thickness could independently predict ectopic pregnancy. The adjusted odd ratios for women with endometrial thickness in the ranges of < 8 mm, 8-9.9 mm, and 10-11.9 mm were 3.270 [95% confidence interval (CI), 1.113-9.605, P = 0.031], 2.758 (95% CI, 0.987-7.707, P = 0.053), and 1.456 (95% CI, 0.502-4.225, P = 0.489), respectively, when compared with those having an endometrial thickness of 12-13.9 mm. 2. Endometrial type and preparation protocol were however not identified as risk factors for ectopic pregnancy. Discussion: 1. After freeze-thaw embryo transfer, risks of ectopic pregnancy were significantly higher when the endometrial thickness was < 8 mm. 2. A thin endometrial thickness could be linked with abnormal endometrial peristaltic waves or abnormal endometrial receptivity. 3. Adequate attention should therefore be paid to patients with a thin endometrial thickness to prevent EP or to achieve early diagnosis during the peri-transplantation period.

Homeostatic Model Assessment for Insulin Resistance Is Associated With Late Miscarriage in Non-Dyslipidemic Women Undergoing Fresh IVF/ICSI Embryo Transfer.

Objective: To evaluate the associations between homeostatic model assessment for insulin resistance (HOMA-IR) and pregnancy outcomes in non-dyslipidemic infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Materials and Methods: This is a retrospective study involving 3,615 non-dyslipidemic infertile women who attend to the Reproductive Medicine Center of Xiangya Hospital, Central South University (CSU) between January 2014 and October 2021. Eligible participants were divided into three groups according to the quartiles of HOMA-IR: Group 1 (HOMA-IR <1.46), Group 2 (1.46 to <2.71) and Group 3 (HOMA-IR ≥2.71). Baseline data, clinical characteristics during the assisted reproductive technology (ART) procedure, pregnancy, and neonatal outcomes were compared among the three groups. Subgroup analysis based on presence or absence of the polycystic ovary syndrome (PCOS) status was also performed to analyze the effects of HOMA-IR among non-PCOS populations. Results: The late miscarriage rate and percentage of macrosomia increased with the HOMA-IR group (for late miscarriage rate: 2.23% vs. 3.04% vs. 7.35%, P<0.001; for macrosomia: 0.21% vs. 1.70% vs. 3.23%, P=0.002). Increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.50, 95% CI 1.64-7.47, P=0.001; adjusted OR 3.56, 95% CI 1.56-8.15, P=0.003). In the subgroup analysis, there were 3,165 participants in the non-PCOS group and 450 were assigned to the PCOS group. Late miscarriage rate increased with the HOMA-IR group among non-PCOS populations (2.20% vs. 3.03% vs. 7.67%, P<0.001). Late miscarriage rate of PCOS women were comparable among the three HOMA-IR groups (2.50% vs. 3.06% vs. 5.71%, P=0.634). Among non-PCOS women, increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.71, 95% CI 1.66-8.30, P=0.001; adjusted OR 3.82, 95% CI 1.59-9.17, P=0.003). Conclusions: Late miscarriage rate and prevalence of macrosomia increased with the HOMA-IR index. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET. Controlling insulin resistance before ART might prevent the occurrence of late miscarriage and macrosomia.

Fertilization and neonatal outcomes after early rescue intracytoplasmic sperm injection: a retrospective analysis of 16,769 patients.

PURPOSE: To evaluate the efficacy and safety of short-term insemination and early-rescue intracytoplasmic sperm injection (ICSI), an approach that rescued oocytes with unclear second polar body 6 h after initial insemination by ICSI (early R-ICSI) to avoid total or near-total fertilization failure in conventional in vitro fertilization (IVF). METHODS: We performed a retrospective study in 16,769 patients (short-term IVF, n = 12,094; ICSI, n = 3452; early R-ICSI, n = 1223) who received IVF/ICSI treatment in our hospital from January 2009 to October 2018. Fertilization and clinical outcomes were compared among those three groups. RESULTS: When considering the R-ICSI embryos in the early R-ICSI group independently, the rates of fertilization and day-3 cleaved embryos in 2PN oocytes were comparable, the rates of fertilization (2PN) and high-quality embryos were lower, whereas the multi-PN fertilization rate (3.27%) was significantly higher than the ICSI group (1.26%). The difference of clinical pregnancy rate between the part of transferred R-ICSI embryos (40.81%) and the ICSI group (44.73%) remained nonsignificant. Furthermore, the rate of congenital birth defects in the early R-ICSI group (0.99%) was not significantly different from those in the short-term IVF (0.76%) and ICSI groups (1.07%). CONCLUSION: Despite the multi-PN fertilization rate, our study highlights early R-ICSI as a safe and effective alternative in assisted reproduction to decrease complete IVF fertilization failure and reduce ICSI utilization. Additional large amount and long-term follow-up studies are needed to further validate the use of early R-ICSI.

Mutation analysis of the TUBB8 gene in primary infertile women with oocyte maturation arrest.

BACKGROUND: Oocyte maturation arrest at metaphase I leads to fertilization failure in humans. In early embryos, the tubulin beta 8 class VIII (TUBB8) encodes a ß-tubulin isotype and aids in the assembling of the human oocyte spindle. Mutations in the TUBB8 potentially interfere with human oocyte maturation-a crucial prerequisite for fertilization and subsequent embryonic development. This study aims to investigate the novel mutations in TUBB8 and their prevalence. RESULTS: Hundred fertile women (controls) and eleven infertile women with oocyte maturation arrest were chosen for the study. A total of five TUBB8 heterozygous/homozygous mutations were found in eleven infertile females (p.A313V, p.C239W, p.R251Q, p.P358L, and p.G96R). The Exome Aggregation Consortium (ExAC), SIFT, and PolyPhen-2 analyses revealed that p. A313V has unknown pathogenicity and p.C239W, p.R251Q, p.P358L, and p.G96R have possible pathogenicity. The wild-type (WT) and four mutant gene constructs were transfected to Hela cells. The Western blot analysis indicates that the TUBB8 expression of the p.C239W, p.R251Q, and p.G96R mutations was significantly decreased than that of WT. The immunofluorescence assay showed that the Hela cells transfected with either p.C239W, p.R251Q, or p.G96R mutations exhibited the disrupted microtubule structure, revealing a significant difference in the organization of the microtubule network compared to the WT. CONCLUSIONS: We identified three novel variants and two reported variants out of 11 infertile women with oocyte metaphase I arrest. According to the present data, TUBB8 gene variants account for 31.96% of all participants (109/341) with oocyte maturation arrest.

Associations between dyslipidaemia and pregnancy outcomes in the first complete cycle of IVF/ICSI: a real-world analysis.

RESEARCH QUESTION: Are there associations between dyslipidaemia and pregnancy outcomes in the first complete cycle of IVF/intracytoplasmic sperm injection (ICSI)? DESIGN: This long-term, retrospective real-world analysis involved 5030 infertile women who underwent a first complete IVF/ICSI cycle between January 2015 and October 2020. They were categorized into dyslipidaemia (n = 1903) and control (n = 3127) groups according to serum lipid concentrations before ovarian stimulation. Propensity score matching and multivariable logistic regression were used to control for confounding variables. RESULTS: In the raw cohort, women with dyslipidaemia had a significantly increased late miscarriage rate (P = 0.039), decreased term birth rate (P = 0.002) and decreased live birth rate (P = 0.005) compared with non-dyslipidaemic women. In the propensity score-matched cohort, the term birth rate (P = 0.038) and live birth rate (P = 0.044) were significantly lower in the dyslipidaemia group (n = 1686) than the controls (n = 1686). Multivariable logistic regression indicated that infertile women with dyslipidaemia (P = 0.026) and elevated serum total cholesterol concentrations (total cholesterol ≥5.20 mmol/l; P = 0.028) were significantly less likely to have a live birth. Rates of late miscarriage (P = 0.027), term birth (P = 0.003) and live birth (P = 0.010) differed significantly among women with normal, borderline increased and increased serum lipid concentrations. Compared with controls, women with increased serum lipid concentrations had a significantly higher late miscarriage rate, lower term birth rate and lower live birth rate. Women with increased serum lipid concentrations were significantly less likely than controls to have a live birth. CONCLUSIONS: Dyslipidaemia, total cholesterol ≥5.20 mmol/l and degrees of elevated serum lipid concentrations are negatively associated with live birth rate in the first complete IVF/ICSI cycle in infertile women.

The role of transcriptomic biomarkers of endometrial receptivity in personalized embryo transfer for patients with repeated implantation failure.

BACKGROUND: Window of implantation (WOI) displacement is one of the endometrial origins of embryo implantation failure, especially repeated implantation failure (RIF). An accurate prediction tool for endometrial receptivity (ER) is extraordinarily needed to precisely guide successful embryo implantation. We aimed to establish an RNA-Seq-based endometrial receptivity test (rsERT) tool using transcriptomic biomarkers and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with RIF. METHODS: This was a two-phase strategy comprising tool establishment with retrospective data and benefit evaluation with a prospective, nonrandomized controlled trial. In the first phase, rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 IVF patients with normal WOI timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n = 56; control group, n = 86). pET guided by rsERT was performed in the experimental group and conventional ET in the control group. RESULTS: The rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using tenfold cross-validation. The intrauterine pregnancy rate (IPR) of the experimental group (50.0%) was significantly improved compared to that (23.7%) of the control group (RR, 2.107; 95% CI 1.159 to 3.830; P = 0.017) when transferring day-3 embryos. Although not significantly different, the IPR of the experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of the control group (RR, 1.562; 95% CI 0.898 to 2.718; P = 0.111) when transferring blastocysts. CONCLUSIONS: The rsERT was developed to accurately predict the WOI period and significantly improve the pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Trial registration Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx.

Association of ABO blood groups with ovarian reserve, and outcomes after assisted reproductive technology: systematic review and meta-analyses.

BACKGROUND: There has been an interest in the relationship between ABO blood groups and infertility. Many studies have investigated the association of ABO blood groups with diminished ovarian reserve (DOR), ovarian hyperstimulation syndrome (OHSS), and outcomes of assisted reproductive technology (ART), with controversial results. METHODS: A systematic review and meta-analysis was conducted to evaluating the association of ABO blood groups with DOR, OHSS, and outcomes of ART. RESULTS: Thirteen studies performed between 2010 and 2018 were included in this meta-analysis. DOR, OHSS, live birth rate (LBR), clinical pregnancy rate (CPR), miscarriage rate (MR) were reported in 9, 2, 4, 3, 2 studies, respectively. The combined results showed similar risk of DOR among individuals with blood group A (RR, 0.98; 95% confidence interval [CI], 0.85, 1.13), B (RR, 0.96; 95% CI, 0.76, 1.20), AB (RR, 1.00; 95% CI, 0.76, 1.30), and non-O (RR, 0.94; 95% CI, 0.79, 1.11) as compared to those with blood group O. Meta-analysis showed that the incidences of OHSS were similar in women with blood group A (RR, 1.05; 95% CI, 0.66, 1.66), B (RR, 1.04; 95% CI, 0.46, 2.35), AB (RR, 0.51; 95% CI, 0.10, 2.56), non-O (RR, 1.02; 95% CI, 0.65, 1.57) with blood group O. As to the clinical outcomes, meta-analysis showed no difference in LBR among individuals with blood group A (RR, 1.27; 95% CI, 0.74, 2.17), B (RR, 1.47; 95% CI, 0.95, 2.29), AB (RR, 1.48; 95% CI, 0.76, 2.90), non-O (RR, 1.28; 95% CI, 0.83, 1.98) when compared to those with blood group O. Similarly, the results also found that there were no difference in CPR and MR between women with blood A (CPR: RR, 1.12), B (CPR: RR, 1.08), AB (CPR: RR, 1.05), non-O (CPR: RR, 1.05; MR: RR, 0.94) and blood group O. CONCLUSIONS: ABO blood groups may not be associated with DOR, OHSS, LBR, CPR, and MR of ART. Infertility and ART outcomes are influenced by multiple factors. Blood groups should not be taken into account excessively during diagnosis and treatment of infertile women.