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STUDY QUESTION Is there an efficient and cost-effective detection platform for different genetic conditions about embryos? SUMMARY ANSWER A multifunctional haplotyping-based preimplantation genetic testing platform was provided for detecting different genetic conditions. WHAT IS KNOWN ALREADY Genetic disease and chromosomal rearrangement have been known to significantly impact fertility and development. Therefore, preimplantation genetic testing for aneuploidy (PGT-A), monogenic disorders (PGT-M) and structural rearrangements (PGT-SR), a part of ART, has been presented together to minimize the fetal genetic risk and increase pregnancy rate. For patients or their families who are suffering from chromosome abnormality, monogenic disease, unexplained repeated spontaneous abortion or implantation failure, after accepting genetic counseling, they may be suggested to accept detection from more than one PGT platforms about the embryos to avoid some genetic diseases. However, PGT platforms work through different workflows. The high costliness, lack of material and long-time operation of combined PGT platforms limit their application. STUDY DESIGN, SIZE, DURATION All 188 embryonic samples from 43 families were tested with HaploPGT platform, and most of their genetic abnormalities had been determined by different conventional PGT methods beforehand. Among them, there were 12 families only carrying structural rearrangements (115 embryos) in which 9 families accepted implantation and 5 families had normal labor ART outcomes, 7 families only carrying monogenic diseases (26 embryos) and 3 families carrying both structural rearrangements and monogenic diseases (26 embryos). Twelve monopronucleated zygotes (1PN) samples and 9 suspected triploid samples were collected from 21 families. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Here, we raised a comprehensive PGT method called HaploPGT, combining reduced representation genome sequencing, read-count analysis, B allele frequency and haplotyping analysis, to simultaneously detect different genetic disorders in one single test. MAIN RESULTS AND THE ROLE OF CHANCE With 80 million reads (80M) genomic data, the proportion of windows (1 million base pairs (Mb)) containing two or more informative single nucleotide polymorphism (SNP) sites was 97.81%, meanwhile the genotyping error rate stabilized at a low level (2.19%). Furthermore, the informative SNPs were equally distributed across the genome, and whole-genomic haplotyping was established. Therefore, 80M was chosen to balance the cost and accuracy in HaploPGT. HaploPGT was able to identify abnormal embryos with triploid, global and partial loss of heterozygosity, and even to distinguish parental origin of copy number variation in mosaic and non-mosaic embryos. Besides, by retrospectively analyzing 188 embryonic samples from 43 families, HaploPGT revealed 100% concordance with the available results obtained from reference methods, including PGT-A, PGT-M, PGT-SR and PGT-HLA. LIMITATIONS, REASON FOR CAUTION Despite the numerous benefits HaploPGT could bring, it still required additional family members to deduce the parental haplotype for identifying balanced translocation and monogenic mutation in tested embryos. In terms of PGT-SR, the additional family member could be a reference embryo with unbalanced translocation. For PGT-M, a proband was normally required. In both cases, genomic information from grandparents or parental siblings might help for haplotyping theoretically. Another restriction was that haploid, and diploid resulting from the duplication of a haploid, could not be told apart by HaploPGT, but it was able to recognize partial loss of heterozygosity in the embryonic genome. In addition, it should be noted that the location of rearrangement breakpoints and the situation of mutation sites were complicated, which meant that partial genetic disorders might not be completely detected. WIDER IMPLICATIONS OF THE FINDINGS HaploPGT is an efficient and cost-effective detection platform with high clinical value for detecting genetic status. This platform could promote the application of PGT in ART, to increase pregnancy rate and decrease the birth of children with genetic diseases. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the National Natural Science Foundation of China (81873478, to L.H.), National Key R&D Program of China (2018YFC1003100, to L.H.), the Natural Science Foundation of Hunan Province (Grant 2022JJ30414, to P.X.), Hunan Provincial Grant for Innovative Province Construction (2019SK4012) and the Scientific Research Foundation of Reproductive and Genetic Hospital of China International Trust & Investment Corporation (CITIC)-Xiangya (YNXM-201910). Haplotyping analysis has been licensed to Basecare Co., Ltd. L.K., Y.M., K.K., D.Z., N.L., J.Z. and R.D. are Basecare Co., Ltd employees. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

To investigate the potential role of GXYLT2 (glucoside xylosyltransferase 2) in gastric cancer (GC), the TCGA (The Cancer Genome Atlas) database and Gene Expression Omnibus (GEO) dataset were used to evaluate GXYLT2 mRNA expression, and the standardized mean difference and diagnostic value were comprehensively assessed. Survival analysis and univariate/multivariate cox regression analysis were performed to evaluate the prognostic value of GXYLT2 in GC patients. The correlation between GXYLT2 and tumor immune cells was identified by using the CIBERSORT algorithm. The results showed that GXYLT2 expression level was significantly increased in GC tissues. GXYLT2 expression was significantly correlated with the grade, stage, and invasion depth of gastric cancer. Overall survival was reduced in the high GXYLT2 expression group. Univariate and multivariate Cox regression analyses showed that GXYLT2 was a reliable prognostic factor. GSEA showed that GXYLT2 might participate in the development of GC through tumor-related pathways. The expression of GXYLT2 was positively correlated with 5 tumor-infiltrating immune cells (resting dendritic cells, m2 macrophages, monocytes, active NK cells and resting mast cells), and was negatively correlated with 6 tumor-infiltrating immune cells (plasma cells, activated memory CD4 T cells, resting NK cells, activated dendritic cells, and activated neutrophils and mast cells). Through cell experiment verification, GXYLT2 expression level in gastric cancer cells was found to be high, which verified the results from the bioinformatics analysis. Furthermore, immunohistochemical staining results also showed that GC tissues had positive GXYLT2 expression. In summary, GXYLT2 might be a potential diagnostic and prognostic biomarker for gastric cancer.

Several literature has shown that salinomycin (Sal) is able to kill various types of cancer cells through different signaling pathways. However, its effect on melanoma has seldom been reported. We examined the anti-cancer efficacy of Sal in melanoma cell lines, and found six of eight cell lines were sensitive to Sal. Given the fact that the roles of Sal are diverse in different cancer types, we were eager to figure out the mechanism involved in the current study. We noticed the most sensitive line, SK-Mel-19, showed a typical morphological change after Sal treatment. The autophagy inhibitor, 3-MA, could effectively suppress Sal-induced cell death. It could also facilitate the increase of autophagic markers and reduce the turnover of autophagosomes, which resulted in an aberrant autophagic flux. On the other hand, Sal could stimulate endoplasmic reticulum stress and cause an accumulation of dysfunctional mitochondria. We also discovered a potential correlation between LC3B mRNA level and its sensitivity to Sal in 43 clinical melanoma samples. Overall, our results indicated that Sal could have multiple effect on melanoma cells and induce autophagic cell death in certain kinds of cells, which provided a new insight into the chemotherapy for melanoma.

Several studies have indicated a protective effect of breastfeeding on reducing the risk of childhood obesity, however, this remains controversial. The aim of this meta-analysis is to clarify the association between breastfeeding and the risk of preschoolers' obesity.Prospective cohort studies published prior to December 1, 2019 were systematically searched in PubMed, EMBASE, the Web of Science and the Cochrane Library databases. Meta-analysis was performed using Stata 15.1.Twenty-six publications involving 332,297 participants were eligible for inclusion.The pooled odds ratio (OR) of the risk of obesity in ever-breastfed preschoolers was 0.83 (95%CI [0.73,0.94]) compared with their never-breastfed counterparts. Random-effects dose-response model revealed a negative correlation between the duration of breastfeeding and risk of obesity (regression coefficient = -0.032, p = .001). Categorical analysis confirmed this dose-response association (1 day to3 months of breastfeeding: OR = 1.07, 95%CI [0.94,1.21]; 3 months to6 months: OR = 0.96, 95%CI [0.60,1.54]; ≥6 months: OR = 0.67, 95%CI [0.58,0.77]). One month of breastfeeding was associated with a 4.0% decrease in risk of obesity (OR = 0.96/month of breastfeeding, 95% CI [0.95, 0.97]). Under the reference of never breastfeeding, the summary OR of exclusive breastfeeding was 0.53 (95%CI [0.45,0.63]).Breastfeeding is inversely associated with a risk of early obesity in children aged two to six years. Moreover, there is a dose-response effect between duration of breastfeeding and reduced risk of early childhood obesity.Clinical nurses' guidance and advice that prolong the duration of breastfeeding and promote exclusive breastfeeding are needed to prevent the development of later childhood obesity.

Hypertension has rapidly increased in the last decades throughout the world. It is an emerging disease. However, limited information is available on secular trends and factors of childhood and adolescents' hypertension in China. In this study, 5-year successive data were derived from a cross-sectional study of the China Health and Nutrition Survey (CHNS) in 2011 and 2015. We used systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) at least 95th percentile on the basis of age, sex, and height percentiles to define hypertension (HBP). A total of 2,827 children and adolescents aged 7–17 years were included. The age-standardized prevalence of hypertension was increased significantly across 5 years: the standardized prevalence of hypertension was increased from 8.08% (2011) to 11.46% (2015) in China (P < 0.01). The mean SBP of boys increased from 101.21 to 102.79 mmHg, while the mean SBP of girls increased from 98.96 to 100.04 mmHg. The mean DBP of boys increased from 61.20 to 67.40 mmHg, while the mean DBP of girls increased from 64.34 to 65.76 mmHg. The prevalence of hypertension grew continuously in both sexes, but the pace of change for boys was more rapid than that for girls. This study confirmed that the association between rural (odds ratio [OR] = 1.394, 95%CI 1.032–1.883), overweight/obesity (OR = 2.621, 95%CI 1.506–4.562), and BP levels was highly correlated (P < 0.05). The possible protecting factors associated with hypertension were being a girl (OR = 0.788, 95%CI 0.595–1.043). There was no association between weekly physical activity, daily sleep duration, and hypertension (P > 0.05). Further in-depth analysis of influencing factors and comprehensive interventions should be urgently implemented to combat the hypertension epidemic among children and adolescents in China.

Breast cancer ranks as the most frequently diagnosed cancer among women worldwide. Elevated cytoplasmic p21 levels are often found in breast cancer tissues and related to a poor prognosis. However, the underlying mechanisms that lead to the stabilization of cytoplasmic p21 protein, which normally has a very short half-life, remain obscure. In this study, we found that there was a strong correlation between p21 and USP11 in the cytoplasm of breast cancer tissues and cells. Furthermore, we revealed that ERK1/2 phosphorylated USP11 at the Ser905 site, which promoted the cytoplasmic localization of USP11. In the cytoplasm, USP11 colocalized and interacted with p21. As a result, USP11 catalyzed the removal of polyubiquitin chains bound to cytoplasmic p21 and resulted in its stabilization. Functionally, USP11-mediated stabilization of cytoplasmic p21 induced breast cancer cell proliferation

Introduction To assess the clinical performance and correlations of automated chemiluminescence assay (CIA) and enzyme-linked immunosorbent assay (ELISA) for detecting antiphospholipid (aPL) antibodies in the diagnosis of antiphospholipid syndrome (APS). Methods The study recruited 505 subjects, including 192 with APS, 193 with connective tissue diseases other than APS, and 120 healthy donors. We measured anticardiolipin (aCL) and anti-β2-glycoprotein I (anti-β2GPI) antibodies IgG, IgM, and IgA in all the samples using both CIA and ELISA. Results Total agreement between the two methods ranged from 83.50% for anti-β2GPI IgG antibodies to 92.76% for anti-β2GPI IgM antibodies in all the groups. Anti-β2GPI and aCL IgG assays showed the highest Spearman's rho coefficients (anti-β2GPI IgG = 0.742, aCL IgG = 0.715). Anti-β2GPI IgG CIA showed the highest sensitivity for diagnosis of APS at 80.21%, which was significantly higher than the sensitivity of anti-β2GPI IgG ELISA (52.08%). For diagnosis of APS, anti-β2GPI IgG CIA had the best discrimination power with the area under the curves (AUC) of 0.922, followed by aCL IgG CIA (AUC of 0.905). While the CIA AUC was slightly higher in all cases, the difference was not statistically significant. Conclusion CIA measurements had a good agreement and correlation with comparative ELISA assays. The CIA anti-β2GPI IgG however was significantly more sensitive for APS diagnosis. The two assay methodologies showed comparable predictive powers and support the value of the CIA method for improved diagnosis and management of patients with APS.

Total fertilization failure (TFF), which is the failure of fertilization in all oocytes, occurs in 1%-3% of intracytoplasmic sperm injection (ICSI) cycles. However, the sperm-related factors that cause fertilization failure in humans are still largely unknown. Here, we identified three novel homozygous variations in the PLCZ1 gene in a recessive inheritance pattern in three consanguineous families, which all located in a key catalytic domain, and predicted to modify its secondary structure and thus impair its hydrolytic activity. Moreover, immunofluorescent staining revealed that PLCζ in mutant sperm exhibited abnormal localization patterns. ICSI-AOA resulted in an increased rate of normal fertilization compared with previous ICSI cycles (75.0% vs 2.2%, P < .001). In summary, we identified three novel homozygous variations in PLCZ1 that led to poor or failed fertilization that could be overcame by ICSI-AOA.

The long-term relative benefit of culprit-only percutaneous coronary intervention (PCI) and staged PCI in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease remains disputable. This study aimed to compare the long-term outcomes of culprit-only PCI and in-hospital staged complete revascularization in real-world patients with STEMI and multivessel coronary artery disease.A total of 452 patients were treated with in-hospital staged complete revascularization (n=133) or culprit-only PCI (n=319) between May 2012 and December 2015 in our center. The primary end point was major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, nonfatal myocardial infarction, stroke, and unplanned revascularization.The median follow-up period was 3.2 years. Overall, treatment with in-hospital staged complete revascularization can reduce the incidence of the primary end point of MACCE in both the overall population [hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.29-0.82] and the propensity-matched cohorts (HR: 0.51; 95% CI: 0.27-0.97). After correction of the possible confounders, staged PCI remained associated with decreased risk of MACCE (HR: 0.56; 95% CI: 0.33-0.96). Besides, the strategy of staged PCI tended to be associated with lower risk of a composite of cardiac death, myocardial infarction, and stroke than culprit-only PCI in multivariable-adjusted analysis (HR: 0.30; 95% CI: 0.09-1.01).In patients with STEMI and multivessel disease undergoing primary PCI, an approach of in-hospital staged complete revascularization was associated with a better 3-year composite outcome compared with culprit-only PCI.

Cementum regeneration is an important and challenging stage in periodontal tissue engineering and regeneration. Pathosis of the periodontium, including cementum, is important in precision diagnosis and obstinate treatment of systemic diseases, such as diabetes, leukemia, and Acquired Immune Deficiency Syndrome. Here, we found that during periodontium development, transcription factor 7-like 2 (Tcf7l2) was widely expressed in the periodontium and dental sac. In mouse cementoblast cell line (OCCM-30), the activation of NF-κB and cementoblast mineralization was significantly reduced when Tcf7l2 gene was silenced. Moreover, Tcf7l2 has a positive effect on NF-κB and cementoblast mineralization. Therefore, Tcf7l2 promotes cementum formation through the NF-κB pathway. In addition, we found a decreased expression of phosphorylated p65 and a thin layer of cementum in Tcf7l2fl/fl mice. These results suggest that Tcf7l2, which accelerates cementum formation by activating NF-κB, has great potential in the treatment of periodontitis and provide guidance for periodontal tissue regeneration.

Objective To investigate the genetic cause of fertilization failure or poor fertilization. Design Genetic analysis. Setting University-affiliated center. Patient(s) Twenty-four Chinese women who underwent assisted reproductive technology (ART) and had repeated fertilization failure or poor fertilization. Intervention(s) None. Main Outcome Measure(s) Twenty-four affected patients were subjected to whole-exome sequencing and candidate mutations were validated by Sanger sequencing. Single-cell reverse transcription was used to analyze the functional characterization of the splice-site mutation in vivo. Evolutionary conservation and molecular modeling analyses were used to predict the impact of missense mutations on secondary protein structure. Immunofluorescence was used to analyze the protein levels of WEE2 and phosphorylated CDC2. Result(s) Biallelic mutations in WEE2 were identified in 5 of 24 (20.8%) Chinese patients with fertilization failure or poor fertilization. Among these individuals we found a novel splice-site mutation, two novel missense mutations, and a previously reported frame-shift mutation. Splicing mutation c.1136-2A>G of WEE2 caused an alteration of the reading frame and introduced a premature stop codon (p.Gly379Glufs*6/p.Asp380Leufs*39). The missense mutations c.585G>C (p.Lys195Asn) and c.1228C>T (p.Arg410Trp) produced obvious changes in secondary protein structures. Immunostaining indicated that mutated WEE2 resulted in the loss of phosphorylated CDC2. The phenotypes of women carrying WEE2 mutations exhibited slight variability, from total fertilization failure to poor fertilization. Conclusion(s) Novel mutations in the known causative gene WEE2 were identified in 5 of 24 women with fertilization failure or poor fertilization, indicating a high prevalence of WEE2 mutations in Chinese women experiencing fertilization failure or poor fertilization.

Background Mosaicism poses challenges for genetic counseling and preimplantation genetic testing for monogenic disorders (PGT‐M). NGS‐based PGT‐M has been extensively used to prevent the transmission of monogenic defects, but it has not been evaluated in the application of PGT‐M resulting from mosaicism. Methods Four women suspected of mosaicism were confirmed by ultra‐deep sequencing. Blastocyst trophectoderm cells and polar bodies were collected for whole genome amplification, followed by pathogenic variants detection and haplotype analysis based on NGS. The embryos free of the monogenic disorders were transplantable. Results Ultra‐deep sequencing confirmed that the four women harbored somatic mosaic variants, with the proportion of variant cells at 1.12%, 9.0%, 27.60%, and 91.03%, respectively. A total of 25 blastocysts were biopsied and detected during four PGT cycles and 5 polar bodies were involved in one cycle additionally. For each couple, a wild‐type embryo was successfully transplanted and confirmed by prenatal diagnosis, resulting in the birth of four healthy infants. Conclusions Mosaic variants could be effectively evaluated via ultra‐deep sequencing, and could be prevented the transmission by PGT. Our work suggested that an NGS‐based PGT approach, involving pathogenic variants detection combined with haplotype analysis, is crucial for accurate PGT‐M with mosaicism., NGS‐based PGT is an effective strategy for the detection of monogenic diseases resulting from mosaicism. Furthermore, NGS‐based PGT combined with PB genetic analysis can improve the accuracy of PGT for monogenic diseases due to maternal mosaicism. This approach will assist clinicians to undertake a more objective assessment of disease recurrence risk for mosaic individuals and obtain an accurate diagnosis of the genotype of embryos for reproductive interventions.

The interaction between psychological stress and immune system may be associated with the cognitive impairment of schizophrenia. To employ machine learning algorithms to examine patterns of stress-immune networks with cognitive impairment in chronic schizophrenia, we selected cortisol, tumor necrosis factor (TNF) - α, interleukin (IL) − 2, IL-6 and IL-8 as biochemical indices reflecting the dysfunctional response to psychological stress and immune system in patients with schizophrenia. Based on 14 kinds of interactions of above five variables, we were able to classify 37 chronic schizophrenia patients and 35 age and gender-matched healthy controls by using decision tree (DT) (Accuracy = 93.1%, Sensitivity = 97.3%, Specificity = 88.6%), random forest (RF) (Accuracy = 94.4%, Sensitivity = 91.9%, Specificity = 97.1%) and support vector machines (SVM) (Accuracy = 98.6%, Sensitivity = 100.0%, Specificity = 97.1%), which indicating that cortisol × TNF-α × IL-8 was the top risk factor for identifying chronic schizophrenia. Furthermore, we found that cortisol × TNF-α × IL-8 was positively correlated with PANSS cognitive subscore. Multiple stepwise linear regression analysis confirmed that PANSS cognitive subscore was correlated with duration of illness and cortisol × TNF-α × IL-8. The results suggest that the glucocorticoid–immune relationship may have an effect on the cognitive impairment of patients.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its lack of treatment options. Patients with TNBC frequently develop resistance to chemotherapy. As epigenetic-based antineoplastic drugs, histone deacetylase inhibitors (HDACis) have achieved particular efficacy in lymphoma but are less efficacious in solid tumors, and the resistance mechanism remains poorly understood. In this study, the GSE129944 microarray dataset from the Gene Expression Omnibus database was downloaded, and fold changes at the transcriptome level of a TNBC line (MDA-MB-231) after treatment with belinostat were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the critical biological processes. Construction and analysis of the protein-protein interaction (PPI) network were performed to screen candidate genes related to cancer prognosis. A total of 465 DEGs were identified, including 240 downregulated and 225 upregulated genes. The cytokine-cytokine receptor pathway was identified as being significantly changed. Furthermore, the expression of CXCL1 was implicated as a favorable factor in the overall survival of breast cancer patients. With in vitro approaches, we also showed that belinostat could induce the expression of CXCL1 in another 2 TNBC cell lines (BT-549 and HCC-1937). We speculate that belinostat-induced CXCL1 expression could be one of the results of the stress clone evolution of cells after HDACi treatment. These findings provide new insights into clone evolution during HDACi treatment, which might guide us to a novel perspective that various mutation-targeted treatments should be implemented during the whole treatment cycle.

Surgical intervention can effectively treat venous pulsatile tinnitus. To assess the effectiveness of treating of venous pulsatile tinnitus (VPT) by compression reconstruction of sigmoid sinus (SSCR) under local anesthesia. This study retrospectively reviewed 41 patients with VPT in our otolaryngology department between September 2009 and February 2019. Under local anesthesia, all patients were received SSCR. Pre- and postoperative Tinnitus Handicap Inventory (THI) degree and scores were used to evaluate the efficacy of SSCR for VPT. Of the 41 patients, 36 patients were followed up from 9 months to 8 years and 5 patients were lost to follow-up and were excluded from the data analysis. SSCR was clinically effective in 86% of patients with complete disappearance in 18 patients (50%), partial remission in 10 patients (28%), slight alleviation in 3 patients (8%), and no change in 5 patients (14%). The pre- and postoperative THI degree and scores were significantly different (p < .001 and p = .002, respectively). SSCR under local anesthesia is effective for treating patients with VPT. It is critical to perform a rigorous pre-operative clinical and radiological evaluation to reduce intra- and postoperative complications.

Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCζ), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCζ was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCζ. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.

The subcortical maternal complex (SCMC) is an oocyte-to-embryo-specific maternal functional module. Some variants of SCMC genes that contribute to preimplantation embryonic arrest have been identified. However, more novel variants should be identified to broaden the genetic and phenotypic spectrum of SCMC genes and establish their roles in embryonic development. We identified 13 novel variants in the SCMC genes, TLE6, NLRP5, NLRP2, and PADI6, from 10 of a total of 50 infertile females with recurrent preimplantation embryonic arrest. Six variants in TLE6 were found in five patients with embryonic arrest, accompanied by direct cleavage and severe fragmentation at the cleavage stage. Three patients carried NLRP5 variants, and one patient each who carried NLRP2 and PADI6 variants had subsequent poor or failed fertilization and cleavage arrest with a relatively lower ratio of severely fragmented embryos. Our findings expand the genetic and phenotypic spectrum of SCMC genes associated with human embryogenesis and might help lay the foundation for the genetic diagnosis of female infertility.

Aim: The discrimination of renal cell carcinoma from renal angiomyolipoma (RAML) is crucial for the effective treatment of each. Materials & methods: Serum samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and a number of metabolites were further quantified by HPLC–UV. Results: Clear-cell renal carcinoma (ccRCC) was characterized by drastic disruptions in energy, amino acids, creatinine and uric acid metabolic pathways. A logistic model for the differential diagnosis of RAML from ccRCC was established using the combination of serum levels of uric acid, the ratio of uric acid to hypoxanthine and the ratio of hypoxanthine to creatinine as variables with area under the curve of the receiver operating characteristic curve value of 0.907. Conclusion: Alterations in serum purine metabolites may be used as potential metabolic markers for the differential diagnosis of ccRCC and RAML.

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

Aim. To identify the population of patients with high risk of distant metastasis and the poor prognosis before treatment, so as to provide early intervention and better treatment decision. Method. 69 patients with nonmetastatic colorectal cancer (non-mCRC) and 57 with metastatic CRC (mCRC) were enrolled to evaluate the prognostic value of serum albumin (ALB), serum lactate (SLA), and lactate dehydrogenase (LDH) in patients with metastatic CRC. We then followed up the 57 patients with mCRC. The T test, Chi square test, Kaplan-Meier survival analysis model, and Multivariate Cox proportional hazards regression model were applied to assess the prognostic significance of SLA, LDH, and serum ALB on the patients with mCRC. Results. Compared with the non-mCRC group, the patients with mCRC had an elevated level of blood lactate (P=0.01) and LDH (P) and a reduced level of ALB (P). Multivariable analysis showed the elevated LDH combined with elevated SLA (HR=2.922, 95%CI=0.971-8.793, P=0.056), the reduced ALB (HR=0.417, 95%CI=0.230-0.754, P=0.004), and the elevated CA199 (HR=2.072, 95%CI=1.125-3.816, P=0.019) were independent prognostic factors for PFS of patients with mCRC. The elevated LDH (HR=2.204, 95%CI=1.000-4.858, P=0.050), reduced ALB (HR=0.459, 95%CI=0.236-0.892, P=0.022), elevated LDH combined with elevated SLA (HR=3.187, 95%CI=1.019-9.970, P=0.046), and the primary site of tumor (HR=0.359, 95%CI=0.174-0.740, P=0.006) were independent prognostic factors for OS of patients with mCRC. Conclusions. Taken together, our results implicate that the elevated LDH combined with elevated SLA and the reduced ALB are prognostic indicators for patients with mCRC.

Despite an increasing focus on transdiagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a transdiagnostic set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder, and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability. A total of 404 patients with a psychiatric diagnosis were recruited (psychosis, n = 129; unipolar depression, n = 92; post-traumatic stress disorder, n = 91; obsessive-compulsive disorder, n = 92) alongside n = 201 healthy controls and n = 20 unaffected first-degree relatives. We collected structural magnetic resonance imaging scans from each participant, and tested for transdiagnostic alterations using Voxel-based morphometry. Inferences were made at p

Background The contribution of moderate coagulation factor XII (FXII) deficiency to development of thromboembolism is still undetermined. We have tried to show the relevance of FXII deficiency to incidences of venous thrombosis by exploring the prevalence of F12 gene mutations in Chinese patients with thrombotic disorders. Methods One hundred and six patients with venous thromboembolism (VTE) and 220 healthy controls were enrolled in study. The coding region and flanking sequences of F12 gene were amplified and sequenced to identify genetic variances. Patients with F12 mutations were also screened for other thrombotic risk factors. Results Heterozygous F12 gene mutations were identified in 6 individuals with VTE and 10 healthy controls. Q336X and R66W were found in two healthy individuals; D291E was identified in a patient with DVT; and A343P was a recurrent mutation with a prevalence of 4.7% (5/106) in patient group and 3.6%(8/220) in healthy control. The prevalence of heterozygous mutations between the two groups had no significant difference. The association of A343P mutations with VTE was weak with an OR of 1.31 (95% CI 0.42-4.11). No other thrombophilia risk factors screened were positive in patients harboring heterozygous F12 mutations. Conclusions There were conflicting theories about the relationship between FXII deficiency and thrombosis formation. Heterozygous F12 mutation decreases the plasma FXII activity approximately by half and cause moderate FXII deficiency. Although multiple mutations were identified in both groups, the link between F12 heterozygous mutation and development of thrombotic disorders is weak and further studies are warranted to clarify their relationship.

Depressive symptoms are common in first episode schizophrenia. However, the prevalence and its associations of comorbid depressive symptoms with clinical variables are less well characterized in Chinese Han patients with schizophrenia. In this cross-sectional study, we recruited 240 first-episode and drug naive (FEDN) inpatients with schizophrenia. All patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD-17) to measure depressive symptoms, and also on the Positive and Negative Syndrome Scale (PANSS) for psychopathology. Our results showed that 131 patients had a total score of 8 or more points on HAMD-17, making the prevalence of comorbid depressive symptoms 54.6%. Fewer women (48.1%, 62 of 129) than men (62.2%, 69 of 111) had comorbid depressive symptoms. Compared to those patients without depressive symptoms, those with depressive symptoms showed higher PANSS total, general psychopathology, cognitive factor and negative symptom scores (all p

Objective The aim of this study was to explore the prognostic value of the association between systemic inflammation response markers (red blood cell distribution width, neutrophil platelet score, prognostic nutritional index, neutrophil-to-lymphocyte ratio, neutrophil-to-platelet ratio, lymphocyte-to-monocyte ratio, and systemic immune-inflammation index) and poorer body composition conditions (sarcopenia, myosteatosis, and sarcopenic obesity) among patients with gastric cancer who underwent adjuvant chemoradiotherapy after radical gastrectomy. Methods A computed tomography scan was performed within 2 wk of prechemoradiotherapy to identify sarcopenia, myosteatosis and sarcopenic obesity. Tumor and systemic inflammatory response information was recorded. Logistic analysis was used to explore the potential risk factors associated with body composition. Univariate and multivariate Cox analyses were performed for survival analysis. A nomogram was constructed to serve as a prognostic prediction tool for the 3- and 5-y overall survival rates. Results The study included 223 patients (74 women and 149 men) with gastric cancer treated with adjuvant chemoradiotherapy after radical gastrectomy. The incidences of sarcopenia, myosteatosis, and sarcopenic obesity were 30%, 39%, and 16%, respectively. Logistic analysis demonstrated that a low prognostic nutritional index is a risk factor for sarcopenia, myosteatosis, and sarcopenic obesity. Based on survival analysis, stage (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23–0.84; P = 0.01), the neutrophil platelet score (HR, 0.50; 95% CI, 0.31–0.82; P = 0.01), the prognostic nutritional index (HR, 0.40; 95% CI, 0.24–0.68; P = 0.00) and sarcopenic obesity (HR, 0.54; 95% CI, 0.31–0.93; P = 0.03) remained independent prognostic factors for overall survival. Accuracy was improved when systemic inflammation markers were incorporated into the nomogram compared with when they were excluded, and the predicted C indexes of the nomogram with and without systemic inflammatory markers were 0.71 (95% CI, 0.67–0.73) and 0.63 (95% CI, 0.57–0.68), respectively. Conclusion The systemic inflammatory response associated with progressive nutritional conditions and body composition conditions with systemic inflammation markers incorporated presented better prognostic value.

Background The results of recent diffusion tensor imaging (DTI) studies on amyotrophic lateral sclerosis (ALS) are inconclusive and controversial. We performed a voxel-based meta-analysis to identify a statistical consensus among published DTI studies of altered white matter (WM) microarchitecture in ALS. Methods A systematic search was conducted for relevant studies that used voxel-wise analyses of WM microarchitecture in patients with ALS. Anisotropic effect size-signed differential mapping (AES-SDM) was applied to analyze fractional anisotropy (FA) differences between ALS patients and healthy controls. Meta-regression analysis was used to explore the effects of clinical characteristics on WM integrity in patients with ALS. Results A total of 14 studies with 16 datasets that included 396 patients and 360 healthy controls were identified. The pooled meta-analysis revealed that patients with ALS exhibited significant FA reductions in two clusters relative to healthy controls. The largest cluster exhibited a peak coordinate in the left corona radiata, extending to the body and splenium of the corpus callosum, left superior longitudinal fasciculus, posterior limb of the internal capsule, right corona radiata, and bilateral cingulate gyrus. The other cluster exhibited decreased FA in the right corticospinal tract that extended to the right cerebral peduncle. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score was positively correlated with the FA reduction in the left corona radiata. Mean age and illness duration were not linearly correlated with the FA reductions. Conclusions This study provides a thorough profile of WM microarchitecture alterations in patients with ALS and further evidence that the neuronal degeneration is not limited to the corticospinal tract but also includes extra-motor areas, which supports the view that ALS is a multisystem degenerative disorder that involves the white matter., Highlights • To identify statistical consensus between published DTI studies in ALS • Two consistent clusters of FA reductions in patients with ALS. • ALS is a multisystem degenerative disorder involving the WM.

Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder-specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial-identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety.

This study tests whether metformin or diet supplement BR-DIM-induced AMP-activated protein kinase (AMPK) mediated effects on development are more pronounced in blastocysts or 2-cell mouse embryos. Culture mouse zygotes to two-cell embryos and test effects after 0.5–1 h AMPK agonists’ (e.g., Met, BR-DIM) exposure on AMPK-dependent ACCser79P phosphorylation and/or Oct4 by immunofluorescence. Culture morulae to blastocysts and test for increased ACCser79P, decreased Oct4 and for AMPK dependence by coculture with AMPK inhibitor compound C (CC). Test whether Met or BR-DIM decrease growth rates of morulae cultured to blastocyst by counting cells. Aspirin, metformin, and hyperosmotic sorbitol increased pACC ser79P ~ 20-fold, and BR-DIM caused a ~ 30-fold increase over two-cell embryos cultured for 1 h in KSOMaa but only 3- to 6-fold increase in blastocysts. We previously showed that these stimuli decreased Oct4 40–85% in two-cell embryos that was ~ 60–90% reversible by coculture with AMPK inhibitor CC. However, Oct4 decreased only 30–50% in blastocysts, although reversibility of loss by CC was similar at both embryo stages. Met and BR-DIM previously caused a near-complete cell proliferation arrest in two-cell embryos and here Met caused lower CC-reversible growth decrease and AMPK-independent BR-DIM-induced blastocyst growth decrease. Inducing drug or diet supplements decreased anabolism, growth, and stemness have a greater impact on AMPK-dependent processes in two-cell embryos compared to blastocysts.

Although some studies show a positive association between periodontitis and blood pressure (BP) elevation, research on the effect of intensive periodontal treatment on decline in BP levels and endothelial microparticles (EMPs) without any antihypertensive management is lacking. Therefore, the present clinical trial explores whether intensive periodontal therapy would lower BP levels and EMPs of patients with prehypertension with periodontitis.From a total 107 patients, 95 underwent randomization (47 assigned to control-treatment [CT] group and 48 assigned to intensive-treatment [IT] group) and completed the trial. Patients received intervention for 4 consecutive weeks and were followed for 6 months. Levels of BP and EMPs were evaluated at baseline and 1, 3, and 6 months after intervention.Periodontal conditions were significantly improved (P0.05) 6 months after intensive periodontal treatment. In parallel, the primary outcomes including systolic and diastolic BP and EMPs were markedly reduced in the IT group compared with the CT group (absolute difference: 12.57 and 9.65 mm Hg and 581.59/μL, respectively; 95% confidence intervals: 10.45 to 14.69, 7.06 to 12.24, and 348.12 to 815.06, respectively; P0.05). Reduction in BP levels and EMPs was related to improvement in probing depth (r = 0.358, 0.363, and 0.676, respectively, by the Pearson product-moment correlation; P = 0.009, 0.008, and P0.001, respectively).To the best knowledge of the authors, the present study demonstrates for the first time that intensive periodontal intervention without any antihypertensive medication therapy may be an effective means to lower levels of BP and EMPs in patients with prehypertension with periodontitis.

Objective Low-grade serous ovarian cancer (LGSOC) constitutes 5–8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. Methods Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. Results All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. Conclusions Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.

The purpose of this study was to investigate the cause of repeated multipronucleus (MPN) formation in zygotes in a patient after both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). This is a case study. A patient had unexplained primary infertility with recurring total MPN zygotes after IVF and ICSI cycles. Time-lapse monitoring of pronucleus formation was carried out. Embryos developed from MPN zygotes were analyzed by fluorescence in situ hybridization (FISH). Single-cell RNA-seq analysis was used to identify gene expression profiles of the patient’s oocyte and zygote, and these were compared to the data from oocytes and zygotes from donors with normal fertilization (patient, n = 1; donors, n = 4). Oocyte-specific genes with differential expression were selected by the Amazonia! database. From time-lapse analysis, we observed the formation of multiple micronuclei near the site of the second polar body extrusion. These micronuclei migrated, expanded, and juxtaposed with the male pronucleus leading to a multipronucleus. None of these MPN zygotes could develop to the blastocyst stage, and FISH analysis revealed a chaotic chromosomal complement in the arrested embryos. RNA-seq analysis showed 113 differentially expressed genes (DEGs) between the patient and the donor oocytes and zygotes. Moreover, 25 of the 113 DEGs were unique or highly expressed in oocytes and early embryos. From 25 DEGs, three genes, DYNC2LI1, NEK2, and CCNH, which are involved in meiosis and the chromosome separation process, were further validated by real-time PCR. We identified several candidate genes affecting pronucleus formation as a new cause of infertility.

Study question Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? Summary answer LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. What is known already Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. Study design, size, duration First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Participants/materials, setting, methods Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia-reoxygenation (H-R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression. Main results and the role of chance LMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4-α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling. Large scale data N/A. Limitations, reasons for caution The primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available. Wider implications of the findings These data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders. Study funding/competing interest(s) This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests.

ObjectiveTo review the research on fear of childbirth, analyze and evaluate the publications by means of bibliometric analysis, and provide suggestions and scopes for future study.Data sourcesWeb of Science, PubMed, Embase and the Cochrane Library databases.Study selectionAll published articles focusing on the fear of childbirth from inception to February 10, 2020.Data extractionA total of 743 articles were included for final analysis. Bibliographic data were exported from databases and then cleaned manually before using Microsoft Excel and VOSviewer to analyze and visualize the findings.Data synthesisIt was found that 743 articles have been cited 31515 times (h-index: 98). The volume of publications increased by 29.3 times in the past two decades. Across the globe, Sweden was the most prolific country having 129 articles (17.4%) with six of its institutions in the top ten most prolific institutions in the world. Fifty-two (7.8%) documents were published in Midwifery journal. The most prolific author was Hildingsson, who published 35 articles (4.7%). "Cesarean section," "experience," and "factor" were the words that appeared most frequently in titles and abstracts of studies. "Point prevalence of psychiatric disorders during the second trimester of pregnancy: A population-based study" was the most cited article and received 525 citations.ConclusionThere is an increasing interest in the research in fear of childbirth during the past two decades. This study has demonstrated that the Swedish authors have a leading role on this topic. Researchers especially in countries with high birth rates, need to promote research projects in this field as it is an important public health issue.

Objective: Defective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation. Approach and Results: In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. Conclusions: In summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.

Background The efficacy of yoga on delivery outcomes remaining controversy. Objectives To evaluate the effects of prenatal yoga on delivery outcomes. Methods The Cochrane Library, PubMed, Embase, Web of Science, CINAHL and Elsevier databases were searched from inception to January 22, 2020, and randomized, quasi-randomized and non-randomized controlled trials evaluating the effect of yoga on the delivery outcomes in pregnant women were included. The methodological quality was assessed by the Cochrane Collaboration's tool. Meta-analysis was performed using Revman 5.3. Results This meta-analysis identified that yoga improved vaginal delivery, decreased premature delivery and birth weight of newborns, shorten the labor duration. Conclusion Prenatal yoga is an effective complementary medicine to improve delivery outcomes and not to increase the risk of fetus, which is worth recommending to pregnant women. But studies involved in this meta-analysis were not all of high quality. The Registration Number in PROSPERO is CRD42019132490.

Background To quantify the dosimetric parameters of different bone marrow sparing strategies and to determine the optimal strategy for cervical cancer patients undergoing postoperative intensity-modulated radiotherapy (IMRT). Methods Fifteen patients with cervical cancer were selected for analysis. The planning target volume (PTV) and the organs at risks (OAR) including small bowel, bladder, rectum, femoral heads, os coxae (OC), lumbosacral spine (LS) and bone marrow (BM) were contoured. For each patient, four IMRT plans with different strategies were generated, including one plan without BM as the dose-volume constraint, namely IMRT (N) plan, and three bone marrow sparing (BMS-IMRT) plans. The three BMS-IMRT plans used the BM, OC, OC and LS respectively, as the BM OAR, namely as IMRT (BM), IMRT (OC) and IMRT (OC + LS) plans. Dose volumes for the target and the OARs were compared using analysis of variance (ANOVA). Results Compared with IMRT (N) plans, the dose to the small bowel, bladder, rectum and femoral heads showed no increase in the three BMS-IMRT plans. However, the irradiated dose to BM, OC and LS significantly decreased. In particular, the mean dose of BM, OC and LS decreased by about 5Gy (p

Congenital factor XI (FXI) deficiency is a rare bleeding disorder with unpredictable bleeding tendency. Few studies in a large cohort have been reported regarding associations between FXI activity (FXI:C) or genotypes and bleeding symptoms currently. This study characterized clinical manifestations and mutation spectrum of 57 subjects with FXI deficiency in China. Clinical data were collected and mutations were identified by direct sequencing and determined by mRNA analysis. The result revealed bleeding symptoms were only found in 12 patients (12/57, 21.1%) with severely reduced FXI:C, and prolonged bleeding post injury/surgery as well as easy bruising were the commonest bleeding manifestations presented in respective 5 cases (5/12, 41.7%). A total number of 37 mutations were identified including 19 missense mutations, 9 nonsense mutations, 6 splice site mutations and 3 small deletions. Among them, 4 missense mutations, 5 splice mutations, 3 small deletions and a nonsense mutation were newly detected. W228*, G400V, Q263* and c.1136-4delGTTG with a total frequency of 48.3% were the most four common mutations in Chinese patients. RT-PCR analysis was carried out and confirmed that both c.596-8T>A and c.1136-4delGTTG were pathogenic due to frameshift resulting in respective truncated proteins. Our findings suggested clinical manifestations had little to do with FXI:C or genotypes, which required further study. This study, the largest investigation of FXI deficiency in China revealed that the F11 mutation spectrum of Chinese population was distinct from those of other populations earlier established.

We investigated the ability of reactive oxygen species (ROS), such as hydrogen peroxide (H(2)O(2)), hydroxyl radical ((·)OH), and hypochlorous acid (HOCl), to overcome the defensive capacity of cumulus cells and elucidate the mechanism through which ROS differentially deteriorate oocyte quality. Metaphase II mouse oocytes with (n = 1634) and without cumulus cells (n = 1633) were treated with increasing concentration of ROS, and the deterioration in oocyte quality was assessed by the changes in the microtubule morphology and chromosomal alignment. Oocyte and cumulus cell viability and cumulus cell number were assessed by indirect immunofluorescence, staining of gap junction protein, and trypan blue staining. The treated oocytes showed decreased quality as a function of increasing concentrations of ROS when compared to controls. Cumulus cells show protection against H(2)O(2) and (·)OH insult at lower concentrations, but this protection was lost at higher concentrations (>50 μmol/L). At higher H(2)O(2) concentrations, treatment dramatically influenced the cumulus cell number and viability with resulting reduction in the antioxidant capacity making the oocyte more susceptible to oxidative damage. However, cumulus cells offered no significant protection against HOCl at any concentration used. In all circumstances in which cumulus cells did not offer protection to the oocyte, both cumulus cell number and viability were decreased. Therefore, the deterioration in oocyte quality may be caused by one or more of the following: a decrease in the antioxidant machinery by the loss of cumulus cells, the lack of scavengers for specific ROS, and/or the ability of the ROS to overcome these defenses.

Migration of cancer cell is a cyclic process, which involves dynamic interaction between extracellular biointerface and cellular responds. In tumors, collagen as extracellular matrix reorganizes biointerface from curl and isotropic fibers to straightened and anisotropic fibers during tumorigenesis, yet how cell migration respond to topography of biointerface is unknown. In this research, we introduced a facile fabrication method on nanofibers of varying topography, which was mimicking the alignment of extracellular nanofibers, to examine the change of cytoskeleton during cell migration. We took advantage of breast carcinoma cell line (MDA-MB-231) for time-lapse imaging analysis. We found that biointerface anisotropy modulated morphology of cell and mediated the pattern of migration. Morphologically, cells on anisotropic nanofiber showed extending spindle shape. The trajectories of migration templated the topographic pattern on biointerface. Besides, aligned nanofiber induced caterpillar-like model of migration through protrusion - retraction cycle, which was indicated by periodical variation of aspect ratio and velocity of cells. The biointerface anisotropy triggered vimentin filaments and microtubule networks preferentially oriented along the alignment of nanofibers. And the velocity of cell mobility by vimentin, β-catenin or CDC42 knockdown was significantly enhanced on aligned nanofibers. Thus, we implied that biointerface anisotropy modulated migration of breast cancer cell and it associated with reorganization of cytoskeleton filaments.

Converging lines of evidence implicate the thalamocortical network in schizophrenia. In particular, the onset of the illness is associated with aberrant functional integration between the medio-dorsal thalamic nucleus (MDN) and widespread prefrontal, temporal and parietal cortical regions. Because the thalamus is also implicated in other psychiatric illnesses including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), the diagnostic specificity of these alterations is unclear. Here, we determined whether aberrant functional integration between the MDN and the cortex is a specific feature of schizophrenia or a trans-diagnostic feature of psychiatric illness. Effective connectivity (EC) between the MDN and rest of the cortex was measured by applying psychophysiological interaction analysis to resting-state functional magnetic resonance imaging data of 50 patients with first episode schizophrenia (FES), 50 patients with MDD, 50 patients with PTSD and 122 healthy controls. All participants were medication-naïve. The only significant schizophrenia-specific effect was increased EC between the right MDN and the right pallidum (p p

Ginseng exhibits multiple medicinal properties, including the improvement of immune function and enhancing disease resistance. In this study, we investigated the inhibitory effects of ginsenoside Rg3 on grass carp reovirus (GCRV) infection of grass carp ovarian (CO) epithelial cells, in order to provide a baseline framework for future high-efficacy antiviral drug screening investigations. Ginsenoside Rg3 was added to GCRV-infected CO cells, and cells were cultured at 27 °C before cell proliferation was measured by MTT assays. Label-free real-time cellular analysis (RTCA) after 72 h of experimentation demonstrated that 100 μg/mL ginsenoside Rg3 treatment had the highest inhibitory effect on GCRV (among 1,10,100 μg/mL treatments). We then measured the capacity for cellular antioxidant ability. Cells treated with 1,10,100 μg/mL ginsenoside Rg3 exhibited increases in Total Antioxidant Capacity activity relative to controls, respectively. Furthermore, Antioxidant assay and reverse transcript quantitative polymerase chain reaction (RT-qPCR) showed that ginsenoside Rg3 were efficient to restrain the replication of GCRV in CO cells. Expression analysis of immune-related genes via RT-qPCR showed that treatment with ginsenoside Rg3 promoted expression of IRF-3 and IRF-7 increases, respectively. Moreover, expression of IFN-1 was induced, which then inhibition the expression of tumor necrosis factor-alpha (TNF-α). In conclusion, we demonstrated that ginsenoside Rg3 promotes CO cell proliferation, inhibits GCRV activity, promotes CO cell immune activities, and thereby enhances the resistance of CO to GCRV infection.

Neuroimaging studies have revealed functional brain network abnormalities in attention deficit hyperactivity disorder (ADHD), but the results have been inconsistent, potentially related to confounding medication effects. Furthermore, specific topological alterations in functional networks and their role in behavioral inhibition dysfunction remain to be established. Resting-state functional magnetic resonance imaging was performed on 51 drug-naive children with ADHD and 55 age-matched healthy controls. Brain functional networks were constructed by thresholding the partial correlation matrices of 90 brain regions, and graph theory was used to analyze network topological properties. The Stroop test was used to assess cognitive inhibitory abilities. Nonparametric permutation tests were used to compare the topological architectures in the two groups. Compared with healthy subjects, brain networks in ADHD patients demonstrated altered topological characteristics, including lower global (FDR q = 0.01) and local efficiency (p = 0.032, uncorrected) and a longer path length (FDR q = 0.01). Lower nodal efficiencies were found in the left inferior frontal gyrus and anterior cingulate cortex in the ADHD group (FDR both q < 0.05). Altered global and nodal topological efficiencies were associated with the severity of inhibitory cognitive control deficits and hyperactivity symptoms in ADHD (p

An increasing number of psychoradiology studies that use tract-based spatial statistics (TBSS) of diffusion tensor imaging have reported abnormalities of white matter in patients with bipolar disorder; however, robust conclusions have proven elusive, especially considering some important clinical and demographic factors. In the present study, we performed a quantitative meta-analysis of TBSS studies to elucidate the most consistent white-matter abnormalities in patients with bipolar disorder.We conducted a systematic search up to May 2017 for all TBSS studies comparing fractional anisotropy (FA) between patients with bipolar disorder and healthy controls. We performed anisotropic effect size-signed differential mapping meta-analysis.We identified a total of 22 data sets including 556 patients with bipolar disorder and 623 healthy controls. We found significant FA reductions in the genu and body of the corpus callosum in patients with bipolar disorder relative to healthy controls. No regions of increased FA were reported. In subgroup analyses, the FA reduction in the genu of the corpus callosum retained significance in patients with bipolar disorder type I, and the FA reduction in the body of the corpus callosum retained significance in euthymic patients with bipolar disorder. Meta-regression analysis revealed that the percentage of female patients was negatively correlated with reduced FA in the body of the corpus callosum.Data acquisition, patient characteristics and clinical variables in the included studies were heterogeneous. The small number of diffusion tensor imaging studies using TBSS in patients with bipolar disorder type II, as well as the lack of other clinical information, hindered the application of subgroup meta-analyses.Our study consistently identified decreased FA in the genu and body of the corpus callosum, suggesting that interhemispheric communication may be the connectivity most affected in patients with bipolar disorder.

To explore the prevalence trends, epidemic characters and relationship of dyslipidemia in Dai and Jingpo ethnics area of Ruili City, Yunnan Province.In 2014, the adult residents( aged from 18 to 89) who were in the random cluster sampling family in Ruili and were enrolled for questionnaire survey, physic examination and biochemical tests. Totally 1551 were in this research.The rate of dyslipidemia was 45. 58%. The standard rate of hypertension was 44. 48%. Along with the age increased, the dyslipidemia prevalence was increased. The dyslipidemia rate of the male was higher than that of the female. And that rate of Han was higher than that of the minority. By the logistic multivariate analysis, the results showed that the abnormal glucose( OR = 2. 799), the over-weight( OR = 1. 079), the fatter( OR = 2. 607), the male( OR = 2. 138), the central obesity( OR = 1. 608), 7- 12 education years( OR = 1. 277), the Han( OR = 1. 269) and the age ≥45( OR = 1. 110) were the independent hazard factors of dyslipidemia. Normal weight and eating grains were the protect factors of dyslipidemia.There was a higher prevalence of dyslipidemia in Dai and Jingpo ethnic area of Yunnan Province. There were quite different characteristics of dyslipidemia prevalence among different population.

Introduction Studies using voxel-based morphometry report variable and inconsistent abnormalities of gray matter volume (GMV) and white matter volume (WMV) in brains of preterm-born adolescents (PBA). In such circumstances a meta-analysis can help identify the most prominent and consistent abnormalities. Method We identified 9 eligible studies by systematic search of the literature up to October 2017. We used Seed-based d Mapping to analyze GMV and WMV alterations between PBA and healthy controls. Results In the GMV meta-analysis, PBA compared to healthy controls showed: increased GMV in left cuneus cortex, left superior frontal gyrus, and right anterior cingulate cortex; decreased GMV in bilateral inferior temporal gyrus (ITG), left superior frontal gyrus, and right caudate nucleus. In the WMV meta-analysis, PBA showed: increased WMV in right fusiform gyrus and precuneus; decreased WMV in bilateral ITG, and right inferior frontal gyrus. In meta-regression analysis, the percentage of male PBA negatively correlated with decreased GMV of bilateral ITG. Interpretation PBA show widespread GMV and WMV alterations in the default mode network, visual recognition network, and salience network. These changes may be causally relevant to socialization difficulties and cognitive impairments. The meta-regression results perhaps reveal the structural underpinning of the cognition-related sex differences in PBA.

Congenital (hypo)dysfibrinogenemia patients may have obstetric complications during their pregnancies. This study aimed to evaluate thromboelastography (TEG) as a potential tool for assessing the tendency for obstetric complications in those patients in a non-pregnant state. A total of 22 female subjects with congenital (hypo)dysfibrinogenemia were recruited. Nine subjects had histories of obstetric complications and the other 13 subjects had at least one uneventful pregnancy without obstetric complications as yet. Detailed clinical investigation and phenotype/genotype detection were carried out, and both kaolin-activated TEG and functional fibrinogen TEG (FF-TEG) were applied in all subjects. Significant differences were identified in all TEG parameters except for R and angle between these two groups (P < 0.05) by covariance analysis. Receiver operating characteristic (ROC) analysis of discrimination between these two groups of patients was performed for TEG parameters. Significantly high odds ratio (OR) of obstetric complications occurrence were demonstrated in K ≥ 3.8 min, maximum amplitude (MA) ≤ 54.2 mm, comprehensive index (CI) ≤ -3 (11.67, 95% CI 1.527-89.121, P < 0.05 in all), and MA-CFF ≤ 12.1 mm (20.00, 95% confidence interval (95% CI) 1.967-203.322, P = 0.002). Moreover, MA-CFF had better prognostic performance, with a corresponding area under the receiver operating curve of 0.923 (range 0.815-1.031, P = 0.001). This study suggests that (hypo)dysfibrinogenemia patients with values outside of the cut-off values of TEG assays under non-pregnant state may have a higher risk of obstetric complications occurring when they are pregnant. No parameters under non-pregnant state in clinical laboratory have ever been reported to be risk factors for obstetric complication occurrence in (hypo)dysfibrinogenemia patients. This study explored such parameters in TEG assays and found that parameters of TEG assays under non-pregnant status might predict the occurrence of obstetric complications, which could provide physicians with important information about whether fibrinogen replacement therapy is required, so as to prevent the occurrence of obstetric complications, especially for patients who are asymptomatic in daily life.

Hormone replacement therapy has been used as an effective treatment for the prevention of bone loss in postmenopausal women. In our previous study, QiBaoMeiRan formula (QBMR) had estrogenic activity and could relieve symptoms of hot flushes and body weight increase induced by estrogen decline. However, no evidence base links QBMR to preventing bone loss. The aim of this study is to investigate the effect of QBMR on bone loss.The ovariectomized rat model was established, and ovariectomized rats were treated with QBMR at doses of 0.875, 1.75, and 3.5 g/kg per day for 8 weeks. Biochemical parameters, bone mineral density, structural morphometric traits and histological characteristics of trabecular bone were assessed.QBMR treatment significantly decreased the increase in serum alkaline phosphatase, bone Gla-protein and C-telopeptide fragments of type I collagen and decreased the decline of serum calcium and phosphorus in the circulation of ovariectomized rats. QBMR completely corrected the decrease in bone mineral density in lumbar vertebrae (L4-L6) comparable to the sham group. In addition, QBMR treatment also significantly ameliorated the decrease of structural parameters of femur trabecular bone, bone volume fraction, trabecular number, trabecular thickness and bone mineral density as well as the increase in trabecular separation by micro-computerized tomography scanning. These were also confirmed by bone histological results that showed its protective action.Our results indicated that QBMR had a definite anti-bone loss effect and will have potential to be used for the treatment of postmenopausal osteoporosis.

To determine if cardiac axis obtained at an early ultrasound study (11-15 weeks) differs from that obtained at a late ultrasound study (18-22 weeks) in the same fetus and to evaluate the impact of fetal gender and/or maternal body mass index (BMI).Cardiac axes of 324 non-anomalous fetuses at 11-15 weeks gestation were measured, with follow-up measurements obtained at 18-22 weeks. Comparisons were performed based on gestational age period, fetal gender and obese/non-obese maternal status.(1) Mean fetal cardiac axis did not change between 11 and 15 weeks; p = 0.8, (2) mean fetal cardiac axis was more levorotated at 11-15 weeks than measurements obtained at 18-22 weeks; 48.1 ± 7.1° versus 43.7 ± 8.9°; p 0.0001, (3) male fetuses had less levorotated cardiac axis than female fetuses in late ultrasound studies but there was no difference between them at early ultrasound studies; 18-22 weeks male fetus, 42.7 ± 9.3° versus female fetus, 45.2 ± 8.3°; p = 0.02 and 11-15 weeks male fetus, 48.1 ± 7.0° versus female fetus, 48.4 ± 7.4°, p = 0.7, respectively, and (4) similar trends with the overall study population were observed in the comparison between fetuses of obese and non-obese women.Fetal cardiac axis remains stable at 11-15 weeks, becoming less levorotated at 18-22 weeks. This may be attributed to increments in fetal lung volume. The differences in cardiac axis measurements between male and female fetuses examined at 18-22 weeks may also be attributable to differences in increment of fetal lung volume during this gestational age period.

To identify the optimal gestational age (GA) for induction of labor (IOL) at term among patients with gestational diabetes (GDMA) according to perinatal outcomes. The US Natality Database from 2007 to 2010 was reviewed. Inclusion criteria were singleton delivery, IOL at 37 to 42 weeks and GDMA. Exclusion criteria included congenital anomalies, pre-gestational diabetes, hypertensive disorders, previous cesarean, breech presentation and rupture of membranes. Controls were non-GDMA cases delivered in geographic and temporal proximity. Delivery mode, macrosomia and perinatal complications were analyzed. Logistic regression adjusted for confounders was used to calculate odds ratios by GA using 39 weeks non-GDMA as reference. In all, 96 964 cases and 176 079 controls were included. Increased risk for all adverse outcomes among GDMA cases was found. The nadir for intrapartum and neonatal complications was 38 and 40 weeks, respectively, whereas for cesarean and macrosomia was 39 weeks. The optimal timing for IOL at term in GDMA appears to be 39 to 40 weeks.