Incidence, distribution, disease spectrum, and genetic deficits of congenital heart defects in China: implementation of prenatal ultrasound screening identified 18,171 affected fetuses from 2,452,249 pregnancies.

BACKGROUND: Congenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed. METHODS: A national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening-diagnostic centers in China. FINDINGS: A total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383-7·915), 7·839 (CI: 7·680-8·000), 7·647 (CI: 7·383-7·915), 7·562 (CI: 7·225-7·907), 5·618 (CI: 5·337-5·906), and 4·716 (CI: 4·341-5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics. CONCLUSION: Implementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD.

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia.

BACKGROUND: More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. OBJECTIVE: The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. METHODS: We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells. RESULTS: We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5-6 in controls), whereas the number of 3' pure CAG repeats was up to 32 to 87 (4-16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats. CONCLUSIONS: This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Acute and chronic maternal exposure to fine particulate matter and prelabor rupture of the fetal membranes: A nation-wide survey in China.

BACKGROUND: Prelabor rupture of the fetal membranes (PROM) is a major contributor to adverse perinatal outcomes. Some epidemiologic studies explored the association between maternal PM2.5 exposure and PROM but failed to treat the labor induction and prelabor cesarean section as censored observations. OBJECTIVE: We aimed to evaluated whether acute and chronic maternal ambient PM2.5 exposure may increase the risk of PROM in China. METHODS: This study was based on the China Labor and Delivery Survey, a nationwide multicenter investigation. Included in the current analysis were 45,879 singleton spontaneous births in 96 hospitals in mainland China from 2015 to 2017. Outcomes were PROM, preterm PROM (<37 weeks' gestation) and term PROM (≥37 weeks' gestation). Daily concentration of PM2.5 at 1 km spatial resolution was estimated by gap-filling model. Generalized linear mixed model and mixed effects Cox model were applied to assess the associations of acute (from 0 to 4 days before delivery) and chronic (average gestational and trimester-specific) ambient PM2.5 exposure with outcomes, respectively. RESULTS: Significant associations were found between acute PM2.5 exposures (per interquartile range increase) and the risk of preterm PROM (OR = 1.11; 95 % CI: 1.03, 1.19 for PM2.5 on delivery day; OR = 1.10; 95 % CI: 1.02, 1.18 for PM2.5 1 day before delivery) but not for term PROM. An interquartile range increase in PM2.5 during the second trimester was associated with elevated risks of PROM (HR = 1.14; 95 % CI: 1.07, 1.22), preterm PROM (HR = 1.22; 95 % CI: 1.02, 1.45) and term PROM (HR = 1.13; 95 % CI: 1.06, 1.22), respectively. Women who were less educated, obese, or gave birth in a cold season appeared to be more sensitive to ambient PM2.5 exposure. CONCLUSION: Our findings suggest that both acute and chronic maternal exposures to ambient PM2.5 during pregnancy are risk factors for PROM.

Characterization of placental and decidual cell development in early pregnancy loss by single-cell RNA sequencing.

BACKGROUND: Early pregnancy loss (EPL) presents as sporadic or recurrent miscarriage during the first trimester. In addition to chromosomal defects, EPL may result from impairment of the placental-decidual interface at early gestational age due to gene-environmental interactions. METHODS: To better understand the pathogenesis associated with this impairment, cell development in chorionic villi and decidua of different forms of EPL (sporadic or recurrent) was investigated with single-cell RNA sequencing and compared to that of normal first-trimester tissue. RESULTS: Unique gene expression signatures were obtained for the different forms of EPL and for normal tissue and the composition of placental and decidual cell clusters in each form was established. In particular, the involvement of macrophages in the EPL phenotypes was identified revealing an immunoactive state. CONCLUSION: Differential gene expression and unique marker genes among cell clusters from chorionic villi and decidua of miscarried and normal pregnancies, may lead to identification of biomarker for EPL.

Preterm birth update in Australasia: A report of the international symposium of Preterm Birth International Collaborative-Australasia branch.

Preterm birth (PTB) is one of the most important problems that pose dilemmas for both the obstetrician and neonatologist, placing a heavy burden psychologically and financially on the families involved, and triggering high socio-economic costs to the public healthcare. The rate of PTB in Asian countries has been ranked at top globally. To reduce the PTB rate, to promote the prevention and intervention for PTB, and to better understand the pathophysiology underlying PTB, the Preterm Birth International Collaborative Australia branch (PREBIC-AA) was launched in 2017. A series scientific activities including organizing annual research symposiums has been planned and organized among Australasian countries. Here we briefly updated the current progress in clinical management and translational research on PTB in Australasian countries that have been participated in PREBIC-AA.

Developmental deficits and staging of dynamics of age associated Alzheimer's disease neurodegeneration and neuronal loss in subjects with Down syndrome.

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21-linked early-onset Alzheimer's disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26-72 years of age were to identify the magnitude of brain region-specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26-41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43-49, 51-59, and 61-72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26-41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43-49 years of age; a 28.0% maximum neuronal loss at 51-59 years of age; and a 11.0% minimum neuronal loss at 61-72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.

Reduced expression in preterm birth of sFLT-1 and PlGF with a high sFLT-1/PlGF ratio in extracellular vesicles suggests a potential biomarker.

Preterm birth may have a pathological impact on intrauterine development of the fetal brain, resulting in developmental disabilities. In this study, we examine the expression of soluble Fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PlGF), which is one of the vascular endothelial growth factors (VEGFs), as these play a key role in angiogenesis; in particular, we examine their effect on the sFLT-1/PlGF ratio in cases of preterm birth as compared to typical pregnancies. Enzyme-linked immunosorbent assay was performed on samples of maternal-derived plasma and extracellular vesicles-exosomes (EVs-EXs) isolated at the third trimester, consisting of 17 samples from cases of preterm birth and 38 control cases. Our results showed that both sFLT-1 (P=0.0014) and PlGF (P=0.0032) were significantly downregulated in cases of preterm birth compared to controls, while the sFLT-1/PIGF ratio was significantly (P=0.0008) increased in EVs-EXs, but not in maternal plasma. Our results suggest that this reduced expression of sFLT-1 and PlGF with an elevated sFLT-1/PlGF ratio in EVs-EXs may represent a potential biomarker for prediction of PTB.

Iatrogenic factors contributed to the high rate of preterm birth in a community hospital.

BACKGROUND: Preterm birth (PTB) rates have been increased significantly in recent years, mostly due to obstetric intervention. This study presents the incidence of PTB in community hospitals by assessing the association between pregnancy complications and iatrogenic PTB. METHODS: A total of 6,693 pregnancies were enrolled in the Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University. They were divided into two groups (<35 and ≥35 years of age) to examine the effect of maternal age on PTB. Binary logistic and multiple linear regression analyses were used to assess the relationship between PTB and pregnancy complications. RESULTS: This study provided the incidence of PTB and found that PP, PROM, and ICP increased the risk of PTB, indicating that pregnancy complications have led to the iatrogenic PTB and contributed to the high rate of PTB, especially in the group of advanced-age pregnant women. The prevalence of PTB was 9.53%. Placenta previa (PP), premature rupture of membranes (PROM), and intrahepatic cholestasis of pregnancy (ICP) were significantly associated with PTB. Among all the risk factors, hypertension, disease in pregnancy, premature PROM, and PP were observed as independent key factors for iatrogenic PTBs. In the advanced-age group, PP and pPROM increased the risk of PTB. CONCLUSIONS: It is often necessary to terminate a pregnancy in community hospitals to balance the safety of the fetus and the maternal comorbid symptoms, which has led to nosocomial premature delivery. Therefore, high-risk pregnancies should be carefully evaluated and comprehensively treated with caution to balance the preterm rate and the safety of the pregnant woman and fetus, and the pros and cons of the outcomes, which has brought a challenge to an obstetrician to reduce the proportion of iatrogenic PTB.

Autism-associated synaptic vesicle transcripts are differentially expressed in maternal plasma exosomes of physiopathologic pregnancies.

BACKGROUND: During intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children. The current study was designed to determine the dynamic profiles of differentially-expressed SVATs in circulating exosomes (EXs) derived from autistic children and pregnant women at different gestational ages. METHODS: Blood samples were collected from autistic children and women with variant physiopathologic pregnancies. EXs were isolated with an ExoQuick Exosome Precipitation Kit and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The expression of lncRNAs and lncRNA-targeted mRNAs were quantified using real-time PCR. RESULTS: SVAT-associated lncRNAs-mRNAs were detected in autistic children and differentially expressed from the first trimester of pregnancy to the term of delivery. Pathologic pregnancies, including spontaneous preterm birth (sPTB), preeclampsia (PE), and gestational diabetes mellitus (GDM), were compared to normal physiologic pregnancies, and shown to exhibit specific correlations between SVAT-lncRNA and SVAT-mRNA of STX8, SLC18A2, and SYP with sPTB; SVAT-lncRNA and SVAT-mRNA of STX8 with PE; and SVAT-lncRNA and SVAT-mRNA of SV2C as well as SVAT-mRNA of SYP with GDM. CONCLUSION: Variant complications in pathologic pregnancies may alter the GEP of SVATs, which is likely to affect the intrauterine development of neural circuits and consequently influence fetal brain development.

Transcriptomics-determined chemokine-cytokine pathway presents a common pathogenic mechanism in pregnancy loss and spontaneous preterm birth.

PROBLEM: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear. We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic-environmental factors. The specific objective of the current study is to uncover the common molecular mechanism(s) by identifying the specific transcripts that are present in variant subtypes of pregnancy loss and preterm birth. METHOD OF STUDY: Transcriptomic profiling was performed with RNA expression microarray or RNA sequencing of placentas derived from pregnancy loss (which includes spontaneous miscarriage, recurrent miscarriage, and stillbirth) and spontaneous preterm birth, followed by bioinformatic analysis of multi-omic integration to identify pathogenic molecules and pathways involved in pathological pregnancies. RESULTS: The enrichment of common differentially expressed genes between full-term birth and preterm birth and pregnancy loss of miscarriage and stillbirth revealed different pathophysiological pathway(s), including cytokine signaling dysregulated in spontaneous preterm birth, defense response, graft-versus-host disease, antigen processing and presentation, and T help cell differentiation in spontaneous miscarriage. Thirty-three genes shared between spontaneous preterm birth and spontaneous miscarriage were engaged in pathways of interferon gamma-mediated signaling and of antigen processing and presentation. For spontaneous miscarriage, immune response was enriched in the fetal tissue of chorionic villi and in the maternal facet of the placental sac. The transcript of nerve growth factor receptor was identified as the common molecule that is differentially expressed in all adverse pregnancies: spontaneous preterm birth, stillbirth, spontaneous miscarriage, and recurrent miscarriage. Superoxide dismutase 2 was up-regulated in all adverse outcomes of pregnancy except for recurrent miscarriage. Cytokine-cytokine receptor interaction was the common pathway in spontaneous preterm birth and spontaneous miscarriage. Defense response was enriched in the fetal tissue of miscarriage and in the maternal tissue in spontaneous miscarriage. CONCLUSIONS: Our results indicated that the chemokine-cytokine pathway may play important roles in and function as a common pathogenic mechanism associated with, the different adverse outcomes of pregnancy, which demonstrated that differentially expressed transcripts could result from a common pathogenic mechanism associated with pregnancy loss and spontaneous preterm birth, although individual pregnancy outcomes may differ from each other phenotypically.

(Epi)genetic variants of the sarcomere-desmosome are associated with premature utero-contraction in spontaneous preterm labor.

Spontaneous preterm birth is a syndrome with clinical and genetic heterogeneity. Few studies have focused on the genetic and epigenetic defects and pathogenic mechanisms associated with premature uterine contraction in spontaneous preterm birth. The objective of this study was to investigate the (epi)genetic variations associated with premature uterine contraction of spontaneous preterm birth. A systems biology approach with an integrated multiomic study was employed. Biobanked pregnancy tissues selected from a pregnancy cohort were subjected to genomic, transcriptomic, methylomic, and proteomic studies, with a focus on genetic loci/genes related to uterine muscle contraction, specifically, genes associated with sarcomeres and desmosomes. Thirteen single nucleotide variations and pathogenic variants were identified in the sarcomere gene, TTN, which encodes the protein Titin, from 146 women with spontaneous preterm labor. Differential expression profiles of five long non-coding RNAs were identified from loci that overlap with four sarcomeric genes. Longitudinally, the long non-coding RNA of gene TPM3 that encodes the protein tropomysin 3 was found to significantly regulate the mRNA of TPM3 in the placenta, compared to maternal blood. The majority of genome methylation profiles related to premature uterine contraction were also identified in the CpG promoters of sarcomeric genes/loci. Differential expression profiles of mRNAs associated with premature uterine contraction showed 22 genes associated with sarcomeres and three with desmosomes. The results demonstrated that premature uterine contraction was associated mainly with pathogenic variants of the TTN gene and with transcriptomic variations of sarcomeric premature uterine contraction genes. This association is likely regulated by epigenetic factors, including methylation and long non-coding RNAs.

Analysis of Studies in Tinnitus-Related Gene Research.

OBJECTIVE: Summarize and analyze the current research results of tinnitus-related genes, explore the potential links between the results of each study, and provide reference for subsequent studies. METHODS: Collect and sort out the research literature related to tinnitus genes included in PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform before December 31, 2019. Then the relevant contents of the literature were sorted out and summarized. RESULTS: Fifty-one articles were finally selected for analysis: 31 articles (60.8%) were classified as researches on animal models of tinnitus, and 20 (39.2%) as researches on tinnitus patients. Existing studies have shown that genes related to oxidative stress, inflammatory response, nerve excitation/inhibition, and nerve growth are differentially expressed in tinnitus patients or animal models, and have presented the potential links between genes or proteins in the occurrence and development of tinnitus. CONCLUSION: The research on tinnitus-related genes is still in the exploratory stage, and further high-quality research evidence is needed.

Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.

BACKGROUNDS: Preeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE. The aims of the present study are to explore the effects of TMAO on placental sFlt-1 production and the underlying mechanism in human placenta. METHODS: Human placental explants, human placental primary trophoblasts and the extravillous trophoblasts (EVT) cell line (HRT-8/SVneo) were exposured to various concentrations of TMAO (100, 150, 300, and 600 µM). The mRNA expression and protein secretion of sFlt-1 in placental explants, primary trophoblasts and HRT-8/SVneo cells were determined with qPCR and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production in primary trophoblasts and HRT-8/SVneo cells were measured by peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. RESULTS: Exposure of placental explants, primary trophoblasts and HRT-8/SVneo cells to TMAO significantly enhanced sFlt-1 at both mRNA and protein levels in a dose dependent manner. Moreover, inhibition of NADPH oxidase with apocynin significantly attenuated TMAO-induced ROS production in primary trophoblasts and HRT-8/SVneo, and suppressed sFlt-1 secretion in placental explants, primary trophoblasts and HRT-8/SVneo. CONCLUSIONS: Our findings indicated the NADPH oxidase dependent ROS pathway played a critical role in mediating TMAO-induced sFlt-1 generation in human placenta. TMAO may become a potential novel target for pharmacological or dietary interventions to reduce the risk of developing PE.

Proteomic Study of Fetal Membrane: Inflammation-Triggered Proteolysis of Extracellular Matrix May Present a Pathogenic Pathway for Spontaneous Preterm Birth.

INTRODUCTION: Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5-10% of live births annually. The long-term morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood. Human placenta, the maternal and fetal interface, is an environmental core of fetal intrauterine life, mediates fetal oxygen exchange, nutrient uptake, and waste elimination and functions as an immune-defense organ. In this study, the molecular signature of preterm birth placenta was assessed and compared to full-term placenta by proteomic profiling. MATERIALS AND METHODS: Four groups of fetal membranes (the amniochorionic membranes), with five cases in each group in the discovery study and 30 cases in each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal membranes were dissected and used for proteome quantification study. Maxquant and Perseus were used for protein quantitation and statistical analysis. Both fetal membranes and placental villi samples were used to validate proteomic discovery. RESULTS: Proteomics analysis of fetal membranes identified 2,800 proteins across four groups. Sixty-two proteins show statistical differences between the preterm and full-term groups. Among these differentially expressed proteins are (1) proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and (6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and ACSL3), and energy biosynthesis (ATP6AP1 and CYBB). CONCLUSION: Our molecular signature study of preterm fetal membranes revealed inflammation as a major event, which is inconsistent with previous findings. Proteolysis may play an important role in fetal membrane rupture. Extracellular matrix s have been altered in preterm fetal membranes due to proteolysis. Metabolism was also altered in preterm fetal membranes. The molecular changes in the fetal membranes provided a significant molecular signature for PPROM in preterm syndrome.

Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients.

BACKGROUND: Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients. RESULTS: Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery. CONCLUSIONS: We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

History of the establishment of the Preterm Birth international collaborative (PREBIC).

INTRODUCTION: The primary aim of PREBIC is to assess the underlying mechanisms and developing strategies for preterm birth (PTB) prevention. MATERIALS AND METHODS: We used concept mapping and logic models to track goals. This paper reviews our progress over 13 years using working group activities, research developments, guest speakers, and publications. RESULTS: Using interactions between genetics, environment, and behaviors we identified complex interactions between biological systems. PREBIC determined that epidemiology and biomarkers should be an initial focus. In 2005, we initiated presentations by young investigators, yearly satellite meetings, working groups including nutrition and inflammation, assessment of clinical trials, and accepted an invitation by the WHO to begin yearly meetings in Geneva. DISCUSSION: PREBIC used epidemiology to identify PTB factors and complex pathways. Candidate genes are associated with the environment, behavior (stress), obesity, inflammation and insulin resistance. Epigenetic changes and production of proteins can be used as biomarkers to define risk. Subsequently, we found risk factors for PTB that were also associated with the risk of cardiovascular disease (CVD) of the mother. Tanz et al. (2017) found that a history of PTB is independently predictive of CVD later in life and suggested that a modest proportion of PTB-CVD association was accounted by CVD risk factors, many of which have been identified in this paper. CONCLUSION: Our findings support a relationship between genes, environment, behaviors and risk of CVD in women. The next several years must assess which factors are modifiable early in life and before pregnancy to prevent PTB.

Down-regulation of DKK1 and Wnt1/ß-catenin pathway by increased homeobox B7 resulted in cell differentiation suppression of intrauterine fetal growth retardation in human placenta.

OBJECTIVE: This study aimed to test the influence of homeobox B7 (HoxB7) on the proliferation, invasion, and migration of human trophoblast cells and to reveal the down-regulation of HoxB7 on the transcriptional suppression of Dick Kopf-related protein1 (DKK1) and of Cysteine-rich glycosylated wingless protein 1 (Wnt1)/ß-catenin in intrauterine fetal growth retardation (FGR). METHODS: Quantitative measurement of HoxB7, DKK1, Wnt1, and ß-catenin was performed in human placentas collected from normal pregnancies and from FGR with quantitative real time PCR (qRT-PCR). Cultured HTR-8/SVneo cells, transfected with a lentiviral plasmid that in-frame expresses human HoxB7 gene, were applied to functional assessment to study the biological impact of HoxB7 gene on DKK1, Wnt1, and ß-catenin. Counting Kit-8, Transwell invasion assays, and flow cytometry were applied for the functional measurements. RESULTS: The expression of HoxB7 was significantly increased, and of DKK1, Wnt1, and ß-catenin was decreased, in FGR placenta tissues and in HTR-8/SVneo cells. Function studies revealed that overexpression of HoxB7 inhibited proliferation, migration, and invasion in HTR-8/SVneo cells. DKK1, Wnt1, and ß-catenin were down-regulated in HTR-8/SVneo cells, inversely correlated with HoxB7 expression. Overexpression of HoxB7 showed a suppressive effect on proliferation, migration, and invasion in the HTR-8/SVneo cells. CONCLUSIONS: Our results indicate that HoxB7 inhibited human trophoblast cell differentiation by down-regulating DKK1 expression and that it may affect transcription of Wnt1/ß-catenin. The activation of HoxB7 might suppress the cell differentiation in HTR-8/SVneo cell cultures. The Wnt/ß-catenin signaling pathway may play a significant role in the pathogenesis of FGR by regulating the invasion and proliferation of trophoblasts.

Maternal obesity and risk of cerebral palsy in children: a systematic review and meta-analysis.

AIM: Several studies have examined the links between maternal obesity and the risk of cerebral palsy (CP) in children, with inconsistent results. The aim of our study was to investigate whether maternal obesity is associated with increased risk of CP in offspring by using meta-analysis. METHOD: PubMed and Web of Science were searched until August 2017. Observational studies relevant to the maternal obesity and risk of CP in children were extracted and compiled. Meta-analyses were performed for different obesity levels and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were reported. RESULTS: A total of five cohort studies involving 12 324 cases and 7 919 288 participants were included in our meta-analysis. The pooled crude and adjusted ORs (95% CIs) were 1.65 (1.38-1.98) and 1.51 (1.24-1.84) respectively. Additionally, the pooled OR (95% CI) for CP in offspring in relation to maternal obesity class I (body mass index [BMI] 30.0-34.9), class II (BMI 35.0-39.9), and class III (BMI≥40.0) compared with normal weight during prepregnancy or pregnancy was 1.31 (1.15-1.50), 1.65 (1.34-2.02), and 2.37 (1.91-2.94) respectively. INTERPRETATION: This meta-analysis demonstrated that increasing grades of maternal obesity are associated with a higher risk of CP in offspring. WHAT THIS PAPER ADDS: Meta-analysis demonstrates a significant positive association between maternal obesity and the risk of cerebral palsy (CP) in children. Subgroup analysis indicates that higher grades of maternal obesity are associated with increasing risk of CP.