NIPT-PG: empowering non-invasive prenatal testing to learn from population genomics through an incremental pan-genomic approach.

Non-invasive prenatal testing (NIPT) is a quite popular approach for detecting fetal genomic aneuploidies. However, due to the limitations on sequencing read length and coverage, NIPT suffers a bottleneck on further improving performance and conducting earlier detection. The errors mainly come from reference biases and population polymorphism. To break this bottleneck, we proposed NIPT-PG, which enables the NIPT algorithm to learn from population data. A pan-genome model is introduced to incorporate variant and polymorphic loci information from tested population. Subsequently, we proposed a sequence-to-graph alignment method, which considers the read mis-match rates during the mapping process, and an indexing method using hash indexing and adjacency lists to accelerate the read alignment process. Finally, by integrating multi-source aligned read and polymorphic sites across the pan-genome, NIPT-PG obtains a more accurate z-score, thereby improving the accuracy of chromosomal aneuploidy detection. We tested NIPT-PG on two simulated datasets and 745 real-world cell-free DNA sequencing data sets from pregnant women. Results demonstrate that NIPT-PG outperforms the standard z-score test. Furthermore, combining experimental and theoretical analyses, we demonstrate the probably approximately correct learnability of NIPT-PG. In summary, NIPT-PG provides a new perspective for fetal chromosomal aneuploidies detection. NIPT-PG may have broad applications in clinical testing, and its detection results can serve as a reference for false positive samples approaching the critical threshold.

Disentangling direct from indirect relationships in association networks.

Networks are vital tools for understanding and modeling interactions in complex systems in science and engineering, and direct and indirect interactions are pervasive in all types of networks. However, quantitatively disentangling direct and indirect relationships in networks remains a formidable task. Here, we present a framework, called iDIRECT (Inference of Direct and Indirect Relationships with Effective Copula-based Transitivity), for quantitatively inferring direct dependencies in association networks. Using copula-based transitivity, iDIRECT eliminates/ameliorates several challenging mathematical problems, including ill-conditioning, self-looping, and interaction strength overflow. With simulation data as benchmark examples, iDIRECT showed high prediction accuracies. Application of iDIRECT to reconstruct gene regulatory networks in Escherichia coli also revealed considerably higher prediction power than the best-performing approaches in the DREAM5 (Dialogue on Reverse Engineering Assessment and Methods project, #5) Network Inference Challenge. In addition, applying iDIRECT to highly diverse grassland soil microbial communities in response to climate warming showed that the iDIRECT-processed networks were significantly different from the original networks, with considerably fewer nodes, links, and connectivity, but higher relative modularity. Further analysis revealed that the iDIRECT-processed network was more complex under warming than the control and more robust to both random and target species removal (P < 0.001). As a general approach, iDIRECT has great advantages for network inference, and it should be widely applicable to infer direct relationships in association networks across diverse disciplines in science and engineering.

First-trimester fetal size, accelerated growth in utero, and child neurodevelopment in a cohort study.

BACKGROUND: Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children's neurodevelopment remains to be assessed. This study aimed to explore the association between first-trimester fetal size and children's neurodevelopment and to examine whether intrauterine accelerated growth could compensate for the detrimental effects of first-trimester restricted growth on childhood neurodevelopment. METHODS: The participants were from a birth cohort enrolled from March 2014 to March 2019 in Wuhan, China. A total of 2058 fetuses with crown to rump length (CRL) (a proxy of first-trimester fetal size) measurements in the first trimester and neurodevelopmental assessment at age 2 years were included. We measured the first-trimester CRL and defined three fetal growth patterns based on the growth rate of estimated fetal weight from mid to late pregnancy. The neurodevelopment was assessed using the Bayley Scales of Infant Development of China Revision at 2 years. RESULTS: Each unit (a Z score) increase of first-trimester CRL was associated with increased scores in mental developmental index (MDI) (adjusted beta estimate = 1.19, (95% CI: 0.42, 1.95), P = 0.03) and psychomotor developmental index (PDI) (adjusted beta estimate = 1.36, (95% CI: 0.46, 2.26), P < 0.01) at age 2 years, respectively. No significant association was observed between fetal growth rate and PDI. For children with restricted first-trimester fetal size (the lowest tertile of first-trimester CRL), those with "intrauterine accelerated growth" pattern (higher growth rates) had significantly higher MDI (adjusted beta estimate = 6.14, (95% CI: 3.80, 8.49), P < 0.001) but indistinguishable PDI compared to those with "intrauterine faltering growth" pattern (lower growth rates). Main limitations of this study included potential misclassification of gestational age due to recall bias of the last menstrual period and residual confounding. CONCLUSIONS: The current study suggests that restricted first-trimester fetal size is associated with mental and psychomotor developmental delay in childhood. However, in children with restricted first-trimester fetal size, intrauterine accelerated growth was associated with improved mental development but had little effect on psychomotor development. Additional studies are needed to validate the results in diverse populations.

Associations of prenatal blood pressure trajectory and variability with child neurodevelopment at 2 years old.

BACKGROUND: The patterns of blood pressure (BP) change throughout the pregnancy were related to adverse birth outcomes. However, little is known about the long-term effect of BP change patterns on child neurodevelopment. This study aimed to explore the relationship between the BP trajectory and BP variability during pregnancy and early childhood neurodevelopment. METHOD: A total of 2797 mother-newborn pairs were derived from the Wuhan Healthy Baby Cohort Study. BP was measured during each antenatal visit, and Mental and Psychomotor Development Indexes (MDI and PDI) were assessed using the Bayley Scales of Infant Development (BSID) when the children were 2 years old. Delayed neurodevelopment was defined as scores of PDI or MDI less than - 1SD relative to the mean score of the study population. A group-based multi-trajectory model was adopted to identify multi-trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Visit-to-visit BP variability was assessed by the coefficient of variation (CV), standard deviation (SD), and average real variability (ARV). Generalized linear models and multivariate logistic regressions were used to assess the associations of BP trajectories and variability with BSID scores and delayed neurodevelopment, respectively. RESULTS: Five distinct trajectories for SBP and DBP were identified, namely, "Low-increasing," "Low-stable," "Moderate-decreasing," "Moderate-increasing," and "High-stable" groups. Compared with the "Low-stable" group, the children whose mothers' BP fell into the other four groups had lower PDI scores, and mothers in the "Low-increasing," "Moderate-increasing," and "Moderate-decreasing" groups had 43% (OR: 1.43, 95% CI: 1.01, 2.03), 48% (OR: 1.48, 95% CI: 1.05, 2.08) and 45% (OR:1.45, 95% CI: 1.03, 2.04) higher risk of having offspring with delayed psychomotor neurodevelopment, respectively. High DBP variability was associated with lower BSID scores, and delayed psychomotor neurodevelopment (OR = 1.46, 95% CI: 1.10, 1.92 for DBP-SD; OR = 1.53, 95% CI: 1.16, 2.02 for DBP-CV). CONCLUSION: Our findings suggest that BP change patterns assessed by multi-trajectory and visit-to-visit variability were associated with lower BSID scores and delayed neurodevelopment. Health professionals should be aware of the influence of BP level and its oscillations during pregnancy on the risk of delayed neurodevelopment.

High genetic diversity and different type VI secretion systems in Enterobacter species revealed by comparative genomics analysis.

The human-pathogenic Enterobacter species are widely distributed in diverse environmental conditions, however, the understanding of the virulence factors and genetic variations within the genus is very limited. In this study, we performed comparative genomics analysis of 49 strains originated from diverse niches and belonged to eight Enterobacter species, in order to further understand the mechanism of adaption to the environment in Enterobacter. The results showed that they had an open pan-genome and high genomic diversity which allowed adaptation to distinctive ecological niches. We found the number of secretion systems was the highest among various virulence factors in these Enterobacter strains. Three types of T6SS gene clusters including T6SS-A, T6SS-B and T6SS-C were detected in most Enterobacter strains. T6SS-A and T6SS-B shared 13 specific core genes, but they had different gene structures, suggesting they probably have different biological functions. Notably, T6SS-C was restricted to E. cancerogenus. We detected a T6SS gene cluster, highly similar to T6SS-C (91.2%), in the remote related Citrobacter rodenitum, suggesting that this unique gene cluster was probably acquired by horizontal gene transfer. The genomes of Enterobacter strains possess high genetic diversity, limited number of conserved core genes, and multiple copies of T6SS gene clusters with differentiated structures, suggesting that the origins of T6SS were not by duplication instead by independent acquisition. These findings provide valuable information for better understanding of the functional features of Enterobacter species and their evolutionary relationships.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances and ASD-Related Symptoms in Early Childhood: Mediation Role of Steroids.

Previous studies regarding the associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and autism spectrum disorder (ASD) have yielded inconsistent results, with the underlying mechanisms remaining unknown. In this study, we quantified 13 PFAS in cord serum samples from 396 neonates and followed the children at age 4 to assess ASD-related symptoms. Our findings revealed associations between certain PFAS and ASD-related symptoms, with a doubling of perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) concentrations associated with respective increases of 1.79, 1.62, and 1.45 units in language-related symptoms and PFDA exhibiting an association with higher score of sensory stimuli. Nonlinear associations were observed in the associations of 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES) and 8:2 Cl-PFAES with ASD-related symptoms. Employing weighted quantile sum (WQS) regression, we observed significant mixture effects of multiple PFAS on all domains of ASD-related symptoms, with PFNA emerging as the most substantial contributor. Assuming causality, we found that 39-40% of the estimated effect of long-chain PFAS (PFUnDA and PFDoDA) exposure on sensory stimuli was mediated by androstenedione. This study provides novel epidemiological data about prenatal PFAS mixture exposure and ASD-related symptoms.

Association between mode of delivery and early neurodevelopment: A prospective birth cohort study.

Previous research has assessed the effects of caesarean delivery (CD) on child neurodevelopment; however, whether the effects stem from the surgical procedure itself or its related medical conditions has not been conclusively determined. This study aimed to evaluate the associations among delivery mode, CD-related medical conditions and early childhood neurodevelopment. A total of 3829 maternal-infant pairs from a longitudinal birth cohort in Wuhan City, China, were included in the primary analysis. The neurodevelopment of the children was assessed by the Bayley Scales of Infant Development (BSID), the Conners Comprehensive Behaviour Rating Scale and the Chinese version of the Autism Behavior Checklist. Data on delivery mode and medical conditions were collected via medical records from the study hospital. Among the 3829 children for whom the BSID test was completed at two years of age, 50%, 27%, and 23% were delivered vaginally, by necessary CD, and by elective CD, respectively. Compared with vaginally delivered children, Necessary CD was associated with a 16.67% decrease in Mental Development Index (MDI) scores and a 13.37% decrease in Psychomotor Development Index (PDI) scores, while elective CD showed a 20.63% and 20.99% decrease after FDR correction, respectively. Similarly, among the 2448 children for whom the CBRS was completed, necessary CD was found to be associated with conduct disorders (adjusted ß: 0.06; 95% CI: 0.02, 0.09), hyperactivity (adjusted ß: 0.06; 95% CI: 0.02, 0.11), and hyperactivity index (adjusted ß: 0.07; 95% CI: 0.03, 0.11), while elective CD was significantly associated with hyperactivity problem scores (adjusted ß: 0.08, 95% CI: 0.03, 0.13). However, no significant association was found between CD and symptoms of autism in children, as assessed by the Autism Behavior Checklist (ABC). CONCLUSION: This study suggested that the adverse impact of CD on child neurodevelopment stems from the procedure itself rather than CD-related medical conditions. It is important to minimize the use of CD when there is no medical necessity. WHAT IS KNOWN: • Caesarean delivery (CD) may influence child neurodevelopment and other long-term outcomes. • In China, approximately one-quarter of CD are performed due to maternal request without medical indications. WHAT IS NEW: • The negative impact of CD on the neurodevelopmental outcomes of children may be primarily attributed to the procedure itself, as opposed to related medical conditions. • In the absence of medical indications, unnecessary CD may have adverse impacts on children's neurodevelopment.

Associations between OGTT results during pregnancy and offspring TSH levels: a birth cohort study.

BACKGROUND: Limited evidence exists regarding the association between gestational diabetes mellitus (GDM) and elevated levels of thyroid-stimulating hormone (TSH) in newborns. Therefore, this study aimed to investigate the potential risk of elevated TSH levels in infants exposed to maternal GDM, considering the type and number of abnormal values obtained from the 75-gram oral glucose tolerance test (OGTT). METHODS: A population-based, prospective birth cohort study was conducted in Wuhan, China. The study included women who underwent GDM screening using a 75-g OGTT. Neonatal TSH levels were measured via a time-resolved immunofluorescence assay. We estimated and stratified the overall risk (adjusted Risk Ratio [RR]) of elevated TSH levels (defined as TSH > 10 mIU/L or > 20 mIU/L) in offspring based on the type and number of abnormal OGTT values. RESULTS: Out of 15,236 eligible mother-offspring pairs, 11.5% (1,753) of mothers were diagnosed with GDM. Offspring born to women diagnosed with GDM demonstrated a statistically significant elevation in TSH levels when compared to offspring of non-GDM mothers, with a mean difference of 0.20 [95% CI: 0.04-0.36]. The incidence of elevated TSH levels (TSH > 10 mIU/L) in offspring of non-GDM women was 6.3 per 1,000 live births. Newborns exposed to mothers with three abnormal OGTT values displayed an almost five-fold increased risk of elevated TSH levels (adjusted RR 4.77 [95% CI 1.64-13.96]). Maternal fasting blood glucose was independently and positively correlated with neonatal TSH levels and elevated TSH status (TSH > 20 mIU/L). CONCLUSIONS: For newborns of women with GDM, personalized risk assessment for elevated TSH levels can be predicated on the type and number of abnormal OGTT values. Furthermore, fasting blood glucose emerges as a critical predictive marker for elevated neonatal TSH status.

Prenatal phthalate exposure and neurodevelopmental differences in twins at 2 years of age.

BACKGROUND: Previous studies of singletons evaluating prenatal phthalate exposure and early neurodevelopment reported mixed results and the associations could be biased by parental, obstetrical, and genetic factors. METHODS: A co-twin control design was employed to test whether prenatal phthalate exposure was associated with children's neurocognitive development. We collected information from 97 mother-twin pairs enrolled in the Wuhan Twin Birth Cohort between March 2016 and October 2018. Fourteen phthalate metabolites were measured in maternal urine collected at each trimester. Neurodevelopmental differences in twins at the age of two were examined as the outcome of interest. Multiple informant model was used to examine the covariate-adjusted associations of prenatal phthalate exposure with mental development index (MDI) and psychomotor development index (PDI) scores assessed at 2 years of age based on Bayley Scales of Infant Development (Second Edition). This model also helps to identify the exposure window of susceptibility. RESULTS: Maternal urinary levels of mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (ß = 1.91, 95% CI: 0.43, 3.39), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (ß = 1.56, 95% CI: 0.33, 2.79), and the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) (ß = 1.85, 95% CI: 0.39, 3.31) during the first trimester showed the strongest and significant positive associations with intra-twin MDI difference. When stratified with twin chorionicity, the positive associations of monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), individual DEHP metabolites, and ∑DEHP exposure during pregnancy with intra-twin neurodevelopmental differences were more significant in monochorionic diamniotic (MCDA) twins than those in dichorionic diamniotic (DCDA) twins. CONCLUSIONS: Neurodevelopmental differences in MCDA twins were strongly associated with prenatal phthalate exposure. Our findings warrant further confirmation in longitudinal studies with larger sample sizes.

Polyethylene Degradation by a Rhodococcous Strain Isolated from Naturally Weathered Plastic Waste Enrichment.

Polyethylene (PE) is the most widely produced synthetic polymer and the most abundant plastic waste worldwide due to its recalcitrance to biodegradation and low recycle rate. Microbial degradation of PE has been reported, but the underlying mechanisms are poorly understood. Here, we isolated a Rhodococcus strain A34 from 609 day enriched cultures derived from naturally weathered plastic waste and identified the potential key PE degradation enzymes. After 30 days incubation with A34, 1% weight loss was achieved. Decreased PE molecular weight, appearance of C-O and C═O on PE, palmitic acid in the culture supernatant, and pits on the PE surface were observed. Proteomics analysis identified multiple key PE oxidation and depolymerization enzymes including one multicopper oxidase, one lipase, six esterase, and a few lipid transporters. Network analysis of proteomics data demonstrated the close relationships between PE degradation and metabolisms of phenylacetate, amino acids, secondary metabolites, and tricarboxylic acid cycles. The metabolic roadmap generated here provides critical insights for optimization of plastic degradation condition and assembly of artificial microbial communities for efficient plastic degradation.

Maternal paraben exposure and intra-pair thyroid-stimulating hormone difference in twin neonates.

Thyroid hormones are essential for fetal growth and neurodevelopment. The recent frequent use of parabens has raised concerns about their endocrine-disrupting potential. However, the effects of maternal paraben exposure on neonatal thyroid hormone levels are still largely unknown. In our study, a co-twin control design was employed to analyze the relationships between maternal paraben exposure and neonatal thyroid-stimulating hormone (TSH) difference. We collected information from 252 mother-twin pairs from a twin birth cohort in Wuhan, China. Concentrations of six parabens were measured in maternal urine samples collected at < 16, 16-28, and > 28 weeks of gestation. Data of neonatal TSH levels were retrieved from medical records. Multiple informant models were applied to explore the time-specific relationships between paraben exposure and intra-twin TSH difference and to determine the susceptible window of exposure. We found that maternal urinary methyl paraben (MeP) during early pregnancy was positively associated with intra-twin TSH difference (%change = 5.96 %; 95 % confidant interval (CI): 0.04 %, 12.2 %). However, no significant differences were observed for exposure to ethyl paraben (EtP) and propyl paraben (PrP), and the associations between parabens and intra-twin TSH difference did not differ materially across pregnancy. Further, a stratified analysis based on twin zygosity and chorionicity and sex types indicated that the positive association between early pregnancy MeP exposure and intra-twin TSH difference was significant in monochorionic diamniotic (MCDA) twins of female-female fetuses and dichorionic diamniotic (DCDA) twins of opposite-sex. The prospective twin study provides first evidence that MeP exposure in early pregnancy was associated with an increased TSH difference in twin neonates, especially in female fetuses.

Development of a Markerless Deletion Mutagenesis System in Nitrate-Reducing Bacterium Rhodanobacter denitrificans.

Rhodanobacter has been found as the dominant genus in aquifers contaminated with high concentrations of nitrate and uranium in Oak Ridge, TN, USA. The in situ stimulation of denitrification has been proposed as a potential method to remediate nitrate and uranium contamination. Among the Rhodanobacter species, Rhodanobacter denitrificans strains have been reported to be capable of denitrification and contain abundant metal resistance genes. However, due to the lack of a mutagenesis system in these strains, our understanding of the mechanisms underlying low-pH resistance and the ability to dominate in the contaminated environment remains limited. Here, we developed an in-frame markerless deletion system in two R. denitrificans strains. First, we optimized the growth conditions, tested antibiotic resistance, and determined appropriate transformation parameters in 10 Rhodanobacter strains. We then deleted the upp gene, which encodes uracil phosphoribosyltransferase, in R. denitrificans strains FW104-R3 and FW104-R5. The resulting strains were designated R3_Δupp and R5_Δupp and used as host strains for mutagenesis with 5-fluorouracil (5-FU) resistance as the counterselection marker to generate markerless deletion mutants. To test the developed protocol, the narG gene encoding nitrate reductase was knocked out in the R3_Δupp and R5_Δupp host strains. As expected, the narG mutants could not grow in anoxic medium with nitrate as the electron acceptor. Overall, these results show that the in-frame markerless deletion system is effective in two R. denitrificans strains, which will allow for future functional genomic studies in these strains furthering our understanding of the metabolic and resistance mechanisms present in Rhodanobacter species. IMPORTANCE Rhodanobacter denitrificans is capable of denitrification and is also resistant to toxic heavy metals and low pH. Accordingly, the presence of Rhodanobacter species at a particular environmental site is considered an indicator of nitrate and uranium contamination. These characteristics suggest its future potential application in bioremediation of nitrate or concurrent nitrate and uranium contamination in groundwater ecosystems. Due to the lack of genetic tools in this organism, the mechanisms of low-pH and heavy metal resistance in R. denitrificans strains remain elusive, which impedes its use in bioremediation strategies. Here, we developed a genome editing method in two R. denitrificans strains. This work marks a crucial step in developing Rhodanobacter as a model for studying the diverse mechanisms of low-pH and heavy metal resistance associated with denitrification.

Association of exposure to ambient particulate matter with maternal thyroid function in early pregnancy.

BACKGROUND: It is known that maternal thyroid dysfunction during early pregnancy can cause adverse pregnancy complications and birth outcomes. This study was designed to examine the association between ambient particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and particulate matter with aerodynamic diameters ≤10 µm (PM10) exposure and maternal thyroid function during early pregnancy. METHODS: This study was based on data from a birth cohort study of 921 pregnant women in China. We estimated associations between ambient PM2.5 and PM10 exposure during the first trimester of pregnancy (estimated with land-use regression models) and maternal thyroid hormone concentrations (free thyroxine (FT4), free tri-iodothyronine (FT3), and thyroid-stimulating hormone (TSH)) collected between weeks 10 and 17 of gestation using linear regression models adjusting for potential confounders. Ambient PM2.5 and PM10 concentrations were modeled per interquartile range (IQR) increment and as tertiles based on the distribution of the exposure levels. RESULTS: An IQR increment (68 µg/m3) in PM2.5 exposure was associated with a significant decrease in maternal FT4 levels (ß = -0.60, 95% CI: -1.07, -0.12); and a significant decrease in FT4/FT3 ratio (ß = -0.13, 95% CI: -0.25, -0.02). Further analyses showed that, relative to the lowest tertile, women in both the middle and highest tertiles of PM2.5 had significantly lower concentrations of maternal FT4 and FT4/FT3 ratio. No significant associations were found between PM2.5 and FT3 or TSH levels. PM10 exposure was not significantly associated with maternal thyroid function. CONCLUSIONS: Our study suggested that higher ambient PM2.5, not PM10, exposed during the first trimester of pregnancy were associated with a significant decrease in maternal serum FT4 concentrations and FT4/FT3 ratio. Studies in populations with different exposure levels are needed to replicate our study results.

Impact of early term and late preterm birth on infants' neurodevelopment: evidence from a cohort study in Wuhan, China.

BACKGROUND: The incidences of early term and late preterm birth have increased worldwide during recent years. However, there is a lack of prospective study about the influence of early term and late preterm birth on infants' neurodevelopment, especially at the early stage. Therefore, we conducted this cohort study to investigate the impact of early term and late preterm birth on infants' neurodevelopment within 6 months. METHODS: This cohort study was conducted in Wuhan, China, between October 2012 and September 2013. A total of 4243 singleton infants born within 34-41 weeks of gestation at Wuhan Children's Hospital were included. The Gesell Developmental Scale (GDS) was utilized to evaluate the neurodevelopment of infants. RESULTS: Among the 4243 included participants, 155 (3.65%) were late preterm infants, 1288 (30.36%) were early term infants, and 2800 (65.99%) were full term infants. After adjusted for potential confounders, significant negative relationship was shown between late preterm birth and development quotient (DQ) in all domains of neurodevelopment: gross motor (ß = - 17.42, 95% CI: - 21.15 to - 13.69), fine motor (ß = - 23.61, 95% CI: - 28.52 to - 18.69), adaptability (ß = - 10.10, 95% CI: - 13.82 to - 6.38), language (ß = - 6.28, 95% CI: - 9.82 to - 2.74) and social behavior (ß = - 5.99, 95% CI: - 9.59 to - 2.39). There was a significant negative trend for early term birth in DQ of fine motor (ß = - 2.01, 95% CI: - 3.93 to - 0.09). Late preterm infants had a significantly elevated risk of neurodevelopmental delay in domains of gross motor (adjusted OR = 3.82, 95% CI: 2.67 to 5.46), fine motor (adjusted OR = 3.51, 95% CI: 2.47 to 5.01), and adaptability (adjusted OR = 1.60, 95% CI: 1.12 to 2.29), whereas early term birth was significantly associated with neurodevelopmental delay of fine motor (adjusted OR = 1.22, 95% CI: 1.05 to 1.42). CONCLUSIONS: This study suggested that late preterm birth mainly elevated the risk of neurodevelopmental delay of gross motor, fine motor, and adaptability, whereas early term birth was associated with the developmental delay of fine motor within 6 months. Further research is needed to determine the effectiveness and necessity of the interventions at the early stage for early term and late preterm infants who had suspected neurodevelopmental delay.

Impact of the 2017 ACC/AHA Guideline for High Blood Pressure on Evaluating Gestational Hypertension-Associated Risks for Newborns and Mothers.

RATIONALE: In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) released a new hypertension guideline for nonpregnant adults, using lower blood pressure values to identify hypertension. However, the impact of this new guideline on the diagnosis of gestational hypertension and the associated maternal and neonatal risks are unknown. OBJECTIVE: To estimate the impact of adopting the 2017 ACC/AHA guideline on detecting gestational blood pressure elevations and the relationship with maternal and neonatal risk in the perinatal period using a retrospective cohort design. METHODS AND RESULTS: This study included 16 345 women from China. Systolic and diastolic blood pressures of each woman were measured at up to 22 prenatal care visits across different stages of pregnancy. Logistic and linear regressions were used to estimate associations of blood pressure categories with the risk of preterm delivery, early-term delivery, and small for gestational age, and indicators of maternal liver, renal, and coagulation functions during pregnancy. We identified 4100 (25.1%) women with gestational hypertension using the 2017 ACC/AHA guideline, compared with 4.2% using the former definition. Gestational hypertension, but not elevated blood pressure (subclinical blood pressure elevation), was significantly associated with altered indicators of liver, renal, and coagulation functions during pregnancy for mothers and increased risk of adverse birth outcomes for newborns; adjusted odds ratios (95% CIs) for gestational hypertension stage 2 were 2.23 (1.18-4.24) for preterm delivery, 2.05 (1.67-2.53) for early-term delivery, and 1.43 (1.13-1.81) for small for gestational age. CONCLUSIONS: Adopting the 2017 ACC/AHA guideline would result in a substantial increase in the prevalence of gestational hypertension; subclinical blood pressure elevations during late pregnancy were not associated with increased maternal and neonatal risk in this cohort. Therefore, the 2017 ACC/AHA guideline may improve the detection of high blood pressure during pregnancy and the efforts to reduce maternal and neonatal risk. Replications in other populations are required.

The associations of birth outcome differences in twins with prenatal exposure to bisphenol A and its alternatives.

BACKGROUND: Bisphenol A (BPA) and its alternatives, including BPF and BPS, exhibit endocrine disruption activities. However, the effects of bisphenols on fetal growth in twins remain unclear. OBJECTIVE: To explore the associations of prenatal BPA, BPF, and BPS exposure with birth outcome differences in twins. METHODS: We recruited 289 twin pregnant women who visited the hospital for prenatal examination during the first trimester from 2013 to 2016. Urinary bisphenol levels were determined during the first, second, and third trimesters. The associations of maternal exposure to bisphenols with birth outcome differences in twins were analyzed after stratification by different trimesters. We applied the multiple informant model to estimate trimester-specific associations between urinary bisphenol concentrations and birth outcome differences in twins. RESULTS: We found low reproducibility (ICC<0.40) for maternal urinary BPA and moderate reproducibility (0.40 < ICC<0.75) for BPF and BPS. Urinary BPA concentrations were positively associated with within-pair twin birth weight difference when comparing the third vs. the first tertile in each of the three trimesters (i.e., 133.06 g, 95% CI: 68.19, 197.94; 144.5 g, 95%CI: 81.82-207.18 g; and 135.04 g, 95%CI: 71.37-198.71 g for the 1st, 2nd, and 3rd trimester, respectively). The effect of urinary BPA concentration on increased birth length difference within-pair twins were also observed across different trimesters (All P for trends < 0.05). Urinary BPA levels were positively associated with the within-pair birth weight and birth length differences across pregnancy trimesters (All of Type 3 P for values < 0.05). CONCLUSION: Maternal BPA exposure appeared to influence birth wight and birth length differences in twins. Our results warrant further confirmation.

Association between early-term birth and delayed neurodevelopment at the age of 2 years: results from a cohort study in China.

A growing body of evidence indicates that early-term births (37-38 weeks of gestational age) have an increased risk of short-term and long-term complications. Here, we sought to explore the association between early-term births and the risk of delayed neurodevelopment at age 2 years. Pregnant women and their live singleton birth were recruited from a single tertiary hospital between October 2013 and February 2017. Mental and Psychomotor Development Indexes (MDI and PDI) were assessed using the Bayley Scales of Infant Development (BSID). Delayed neurodevelopment was defined as scores of PDI or MDI less than -1SD relative to the mean score of the study population. In total, 1678 full-term infants and 727 early-term infants were assessed when they were 2 years old. After adjustment for potential confounders, early-term birth was related to 43% increased odds of neurodevelopmental delay in the PDI domain as compared with full-term birth (OR: 1.43; 95% CI: 1.12, 1.82). The observed associations were more prominent among those infants born by cesarean (OR: 1.44; 95% CI: 1.03, 2.00) and among males (OR: 1.66; 95% CI: 1.20, 2.28). No statistical difference in the MDI domain was found between early-term and full-term births.Conclusions: Our findings suggest that early-term birth was associated with increased odds of delayed neurodevelopment in the PDI domain as measured by BSID assessments at age 2 years. Health professionals should be aware of the influence of early-term birth on the risk of delayed neurodevelopment. What is Known: • Evidence indicates that early-term births have an increased risk of short-term and long-term complications. • The association between early-term births and delayed neurodevelopment at their early childhood has not been widely studied. What is New: • Early-term birth was associated with increased odds of delayed neurodevelopment in PDI domain as measured by BSID assessments at age 2 years. • The observed associations were more prominent among infants born by cesarean section and among male infants.

Associations between prenatal and postnatal lead exposure and preschool children humoral and cellular immune responses.

Studies have shown that lead exposure affected the immune function, but few studies have examined the relationships between in utero lead exposure, a sensitive period that is important for immune development, and later immune responses. To investigate the effects of prenatal and childhood lead exposure on the preschool-aged children's immune responses, a prospective birth cohort study was established in Wuhan, China, in which lead concentrations were analyzed in maternal urine during the third trimester and in plasma samples from children aged about 3 years. We assessed immune responses by measuring immune cytokines in the children's plasma (n = 326) and peripheral blood T lymphocyte subsets (n = 394) at 3 years of age. Each unit increase in maternal urinary lead concentration (µg/g creatinine) was associated with reduced IL-10 (ß = -5.93%, 95%CI: -11.82%, -0.03%) and reduced IL-4 levels (ß = -5.62%, 95%CI: -10.44%, -0.80%). Lead in children's plasma (µg/L) was associated with significant increase in TNF-α (ß = 10.78%, 95%CI: 3.97%, 17.59%). No statistically significant relationship of childhood lead exposure with T lymphocyte subsets was observed. The study suggested prenatal and childhood lead exposure was associated with changes in preschool children's plasma cytokine levels.

Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study.

OBJECTIVE: Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life. Newborn TL is sensitive to maternal metals concentrations, while study about the association between maternal manganese (Mn) concentrations and newborn TL was not found. Our study aimed to investigate whether newborn TL is related to maternal Mn concentrations. METHODS: Data were collected from a birth cohort study of 762 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. We measured the Mn concentrations in spot urine samples collected during three trimesters by inductively coupled plasma mass spectrometry (ICP-MS) and relative cord blood TL by quantitative real-time polymerase chain reaction (qPCR). We applied multiple informant models to investigate the associations between maternal Mn concentrations and cord blood TL. RESULTS: The geometric mean of creatinine-corrected urinary Mn concentrations were 1.58 µg/g creatinine, 2.53 µg/g creatinine, and 2.62 µg/g creatinine in the first, second, and third trimester, respectively. After adjusting for potential confounders, a doubling of maternal urinary Mn concentration during the second trimester was related to a 2.10% (95% CI: 0.25%, 3.99%) increase in cord blood TL. Mothers with the highest tertile of urinary Mn concentrations during the second trimester had a 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL than those with the lowest tertile. This association was more evident in male infants. No relationship was found between maternal urinary Mn concentrations and cord blood TL during the first and third trimesters in our study. CONCLUSIONS: Our findings suggested that maternal Mn concentration during the second trimester was positively associated with newborn TL. These results might provide an epidemiology evidence on the protective role of maternal Mn for newborn TL and offer clues for the early prevention of telomere shortening related diseases.

CircPSMC3 alleviates the symptoms of PCOS by sponging miR-296-3p and regulating PTEN expression.

Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.