Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported. METHODS AND RESULTS: We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro. CONCLUSION: Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.

Establishment of a canine model of pulmonary arterial hypertension induced by dehydromonocrotaline and ultrasonographic study of right ventricular remodeling.

OBJECTIVE: Pulmonary arterial hypertension (PAH) means high blood pressure in the lungs. We aimed to observe the right ventricular size, wall thickness and characteristic functional changes and their associations with PAH in an established model of beagle dogs, and to explore convenient, reliable and sensitive ultrasound indicators for assessing right ventricular remodeling. METHODS: Twenty healthy beagle dogs (8-10 kg) were randomly divided into control group (N-dimethylformamide, n = 10) and dehydromonocrotaline (DHMCT) group (DHMCT, n = 10). N-dimethylformamide or DHMCT was injected through a catheter into the right atrium, and then right heart catheterization, routine echocardiography and two-dimensional speckle tracking imaging (2D-STI) were performed before modeling (0 weeks) and 8, 14 weeks after modeling. Hemodynamic parameters and right ventricular function-related ultrasound data were acquired. At the end of the experiment, the animals were killed and the lung tissues were taken for HE staining. Left and right ventricular walls were separated and weighed respectively, and right ventricular hypertrophy index (RVHI) was measured. The associations of the routine ultrasound data and 2D-STI data at each time point with hemodynamic parameters and RVHI were analyzed. RESULTS: At 0, 8 and 14 weeks, gradual decreases in the right ventricular global longitudinal strain (RVLS) were found in DHMCT group. RVH occurred in DHMCT group, and DHMCT group had a significantly higher RVHI than that of control group (49.83 ± 4.83% vs. 39.80 ± 1.40%, P < .001) and larger pulmonary artery media thickness. RVLS had significant positive correlations with RVSP (r = 0.74, P < .001), mRVP (r = 0.72, P < .001), PASP (r = 0.75, P < .001), mPAP (r = 0.72, P < .001) and PVR (r = 0.68, P < .001). There was a significant positive correlation between RVLS and RVHI (r = 0.74, P < .001). CONCLUSION: The right ventricular function in PAH can be effectively assessed by echocardiography, and RVLS measured by 2D-STI sensitively reflects right ventricular remodeling following PAH.

Perceived uncertainty stress and its predictors among residents in China during the COVID-19 pandemic.

The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (ß=3.871,P<0.001) and depression symptoms (ß=2.458, P<0.001), family residence (in towns or rural areas) (ß=0.947, P<0.001), lack of support for local epidemic control strategies (ß=1.253, P<0.001), worry about the pandemic (ß=1.191, P<0.001), and symptoms of weakness among family members (ß=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (ß=-0.883, P<0.001) and social networks (ß=-0.726, P<0.001) were negatively, but social participation (ß=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.

Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system.

BACKGROUND: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. METHODS: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. RESULTS: PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. CONCLUSIONS: PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue.

Cord blood vitamin D and neurocognitive development are nonlinearly related in toddlers.

BACKGROUND: Little is known about the relation between vitamin D status in early life and neurodevelopment outcomes. OBJECTIVE: This study was designed to examine the association of cord blood 25-hydroxyvitamin D [25(OH)D] at birth with neurocognitive development in toddlers. METHODS: As part of the China-Anhui Birth Cohort Study, 363 mother-infant pairs with complete data were selected. Concentrations of 25(OH)D in cord blood were measured by radioimmunoassay. Mental development index (MDI) and psychomotor development index (PDI) in toddlers were assessed at age 16-18 mo by using the Bayley Scales of Infant Development. The data on maternal sociodemographic characteristics and other confounding factors were also prospectively collected. RESULTS: Toddlers in the lowest quintile of cord blood 25(OH)D exhibited a deficit of 7.60 (95% CI: -12.4, -2.82; P = 0.002) and 8.04 (95% CI: -12.9, -3.11; P = 0.001) points in the MDI and PDI scores, respectively, compared with the reference category. Unexpectedly, toddlers in the highest quintile of cord blood 25(OH)D also had a significant deficit of 12.3 (95% CI: -17.9, -6.67; P < 0.001) points in PDI scores compared with the reference category. CONCLUSIONS: This prospective study suggested that there was an inverted-U-shaped relation between neonatal vitamin D status and neurocognitive development in toddlers. Additional studies on the optimal 25(OH)D concentrations in early life are needed.

Sex-specific and time-dependent effects of prenatal stress on the early behavioral symptoms of ADHD: a longitudinal study in China.

There is increasing evidence that prenatal stressful life events (SLEs) may be a potential risk factor for attention-deficit hyperactivity disorder (ADHD), but the sex-specific and time-dependent effects of prenatal stress on ADHD are less clear. In this prospective longitudinal study, data on prenatal SLEs during different stages of gestation and indicators of buffers against stress, including maternal social support and avoidance coping, were obtained from 1765 pregnant women at 32 weeks of gestation. The behavioral symptoms of ADHD in children aged 48-54 months were evaluated by reports from the parents. There were 226 children (12.8%) above the clinically significant cutoff for ADHD. After adjusting for potential confounders, boys whose mother experienced severe SLEs in the second trimester had a significantly increased risk (OR = 2.41, 95% CI: 1.03-5.66) of developing ADHD symptoms compared with boys whose mothers did not experience severe SLEs at this time. However, no significantly increased risk of ADHD symptoms was observed in girls born to mothers experienced prenatal severe SLEs. Additionally, significant interaction effects of prenatal SLEs, social support and coping style on ADHD symptoms were found in males. Boys whose mothers experienced severe SLEs during the second trimester accompanied by a higher score for avoidance coping (OR = 3.31, 95% CI: 1.13-9.70) or a lower score for social support (OR = 4.39, 95% CI: 1.05-18.31) were likely to be at a higher risk for ADHD symptoms. The epidemiological evidence in this prospective follow-up study suggests that the effect of prenatal SLEs on ADHD symptoms in offspring may depend on the timing of prenatal stress and may vary according to the sex of the offspring.

Does prenatal maternal stress impair cognitive development and alter temperament characteristics in toddlers with healthy birth outcomes?

AIM: The aim of this study was to assess the cognitive and behavioural development of children with healthy birth outcomes whose mothers were exposed to prenatal stress but did not experience pregnancy complications. METHOD: In this prospective study, self-reported data, including the Prenatal Life Events Checklist about stressful life events (SLEs) during different stages of pregnancy, were collected at 32 to 34 weeks' gestation. Thirty-eight healthy females (mean age 27 y 8 mo, SD 2 y 4 mo) who were exposed to severe SLEs in the first trimester were defined as the exposed infant group, and 114 matched comparison participants were defined as the unexposed infant group (1:3). Maternal postnatal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale. The Bayley Scales of Infant Development and the Toddler Temperament Scale were used to evaluate the cognitive development and temperament characteristics of the infants with healthy birth outcomes when they were 16 to 18 months old. RESULTS: A randomized block multivariate analysis of covariance showed that the mental development index scores of the infants of mothers with prenatal exposure to SLEs in the first trimester averaged seven points (95% confidence interval 3.23-10.73 points) lower than those of the unexposed infants. Moreover, the infants in the exposed group achieved higher scores for regularity (adjusted mean [SD] 2.77 [0.65] vs. 2.52 [0.78], F(5,146) =5.27, p=0.023) and for persistence and attention span (adjusted mean 3.61 [0.72] vs. 3.35 [0.52], F(5,146) =5.51, p=0.020). INTERPRETATION: This study provides evidence that lower cognitive ability and less optimal worse behavioural response in infants might independently result from prenatal maternal stress.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

Prenatal Exposure to Air Pollution and Pre-Labor Rupture of Membranes in a Prospective Cohort Study: The Role of Maternal Hemoglobin and Iron Supplementation.

BACKGROUND: Exposure to air pollution in prenatal period is associated with prelabor rupture of membranes (PROM). However, the sensitive exposure time windows and the possible biological mechanisms underlying this association remain unclear. OBJECTIVE: We aimed to identify the sensitive time windows of exposure to air pollution for PROM risk. Further, we examined whether maternal hemoglobin levels mediate the association between exposure to air pollution and PROM, as well as investigated the potential effect of iron supplementation on this association. METHOD: From 2015 to 2021, 6,824 mother-newborn pairs were enrolled in the study from three hospitals in Hefei, China. We obtained air pollutant data [particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameter ≤10µm (PM10), sulfur dioxide (SO2), and carbon monoxide (CO)] from the Hefei City Ecology and Environment Bureau. Information on maternal hemoglobin levels, gestational anemia, iron supplementation, and PROM was obtained from medical records. Logistic regression models with distributed lags were used to identify the sensitive time window for the effect of prenatal exposure to air pollutant on PROM. Mediation analysis estimated the mediated effect of maternal hemoglobin in the third trimester, linking prenatal air pollution with PROM. Stratified analysis was used to investigate the potential effect of iron supplementation on PROM risk. RESULTS: We found significant association between prenatal exposure to air pollution and increased PROM risk after adjusting for confounders, and the critical exposure windows of PM2.5, PM10, SO2 and CO were the 21th to 24th weeks of pregnancy. Every 10-µg/m3 increase in PM2.5 and PM10, 5-µg/m3 increase in SO2, and 0.1-mg/m3 increase in CO was associated with low maternal hemoglobin levels [-0.94g/L (95% confidence interval (CI): -1.15, -0.73), -1.31g/L (95% CI: -1.55, -1.07), -2.96g/L (95% CI: -3.32, -2.61), and -1.11g/L (95% CI: -1.31, -0.92), respectively] in the third trimester. The proportion of the association between air pollution and PROM risk mediated by hemoglobin levels was 20.61% [average mediation effect (95% CI): 0.02 (0.01, 0.05); average direct effect (95%): 0.08 (0.02, 0.14)]. The PROM risk associated with exposure to low-medium air pollution could be attenuated by maternal iron supplementation in women with gestational anemia. CONCLUSIONS: Prenatal exposure to air pollution, especially in the 21st to 24th weeks of pregnancy, is associated with PROM risk, which is partly mediated by maternal hemoglobin levels. Iron supplementation in anemia pregnancies may have protective effects against PROM risk associated with exposure to low-medium air pollution. https://doi.org/10.1289/EHP11134.

Maternal 25(OH)D attenuates the relationship between ambient air pollution during pregnancy and fetal hyperinsulinism.

Inflammatory responses have been demonstrated to link air pollution with insulin resistance and type 2 diabetes in adults. However, few studies have focused on the relationship between prenatal air pollution and fetal ß-cell function and the mediating effect of systematic inflammation remains elusive. Whether the anti-inflammatory effect of vitamin D could attenuate the ß-cell dysfunction in early life warrants further investigations. We aimed to determine whether maternal blood 25(OH)D attenuates the associations of ambient air pollution during pregnancy with fetal hyperinsulinism mediated by maternal inflammatory response. A total of 8250 mother-newborn pairs were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean air pollution exposure to fine particles (PM2.5 and PM10), SO2, and CO was estimated across pregnancy. Maternal serum samples in the third trimester were used to measure the high-sensitivity c-reactive protein (hs-CRP) and 25(OH)D. Cord blood samples at delivery were collected for the measurement of C-peptide. Fetal hyperinsulinism was based on cord C-peptide >90th centile. An increased fetal hyperinsulinism risk was associated with per 10 µg/m3 increase in PM2.5 [odds ratios (OR): 1.45 (95% confidence interval (CI):1.32, 1.59)], per 10 µg/m3 increase in PM10 [OR = 1.49 (95% CI:1.37, 1.63)], per 5 µg/m3 increase in SO2 [OR = 1.91 (95% CI: 1.70, 2.15)], and per 0.1 mg/m3 increase in CO [OR = 1.48 (95% CI:1.37, 1.61)] across pregnancy. Mediation analysis showed a 16.3% contribution of maternal hsCRP to the relationship between air pollution throughout pregnancy and fetal hyperinsulinism. Air pollution-associated higher levels of hsCRP and risk of fetal hyperinsulinism could be attenuated by higher maternal 25(OH)D levels. Prenatal ambient air pollution exposures were associated with an increased fetal hyperinsulinism risk mediated by maternal serum hsCRP. Higher antenatal 25(OH)D levels could attenuate air pollution-induced inflammatory responses and hyperinsulinism risk.

Previous pregnancy loss and gestational cardiovascular health: A prospective cohort of nulliparous women.

Objectives: To estimate the association of previous pregnancy loss with subsequent cardiovascular health during gestation and to examine the role of high-sensitivity C reactive protein (hs-CRP) in the association. Methods: A total of 2,778 nulliparous pregnant women were recruited between March 2015 and November 2020 in Hefei city, China. Their cardiovascular health (CVH) including prepregnancy body mass index (BMI), blood pressure, total cholesterol, fasting plasma glucose, and smoke status were recorded at 24-28 weeks' gestation, as well as their reproductive history. Multivariate linear and logistic regression were performed to examine the association of pregnancy loss with cardiovascular health. And the role of hs-CRP between pregnancy loss and CVH was assessed by the mediation analysis. Results: Compared with women who have no pregnancy loss, women with a history of spontaneous or induced abortions had higher BMI (ß, 0.72, 95% CI, 0.50 to 0.94) and fasting plasma glucose (ß, 0.04, 95% CI, 0.01 to 0.07), and had lower total CVH scores after adjusting for confounders (ß, -0.09, 95% CI, -0.18 to -0.01). CVH scores were most significantly decreased among women with 3 or more induced abortions (ß, -0.26, 95% CI, -0.49, -0.02). The contribution of pregnancy loss to poorer gestational CVH mediated by increased hs-CRP levels was 23.17%. Conclusion: Previous pregnancy loss was associated with poorer cardiovascular health during gestation, which may be mediated by their gestational inflammatory status. Exposure to miscarriage alone was not a significant predictor of poorer CVH.

Adequate 25(OH)D moderates the relationship between dietary inflammatory potential and cardiovascular health risk during the second trimester of pregnancy.

Background: Pro-inflammatory diets play an important role in developing cardiovascular disease (CVD). Vitamin D has been demonstrated to have an anti-inflammatory effect and promote cardiovascular health (CVH). However, it is unclear whether adequate vitamin D during pregnancy protects against poor CVH caused by pro-inflammatory diets. Objective: To investigate the association of pro-inflammatory diets with the cardiovascular risk (CVR) among pregnant women and whether such association was modified by vitamin D status. Methods: The study was based on a prospective birth cohort that included 3,713 pregnant women between 16 and 23 gestational weeks. In total, 25(OH)D concentrations and high-sensitivity C-reactive protein (hs-CRP) were measured from the collected blood. The dietary inflammatory potential was evaluated using the empirical dietary inflammatory pattern (EDIP) score based on a validated food frequency questionnaire. Gestational CVR was evaluated using the CVR score based on five "clinical" CVR metrics, including body mass index, blood pressure, total cholesterol, glucose levels, and smoking status. Results: The proportion of women with a CVR score >0 was 54.3%. We observed a positive association between the EDIP score and CVR score. Compared with the lowest quartile, the CVR score (ß = -0.114, 95% CI, -0.217, -0.011) and hs-CRP levels (ß = -0.280, 95% CI, -0.495, -0.065) were lower in the highest quartile (P for trend <0.05). Increased CVR connected with high EDIP score was observed only in women with 25(OH)D concentrations <50 nmol/L (RR = 1.85; 95% CI: 1.35, 2.54). Mediation analysis revealed that the proportion of association between the EDIP score and CVR score mediated by 25(OH)D was 28.7%, and the proportion of the association between 25(OH)D and the CVR score mediated by hs-CRP was 21.9%. Conclusion: The higher dietary inflammatory potential was associated with an increased CVR during pregnancy by promoting inflammation. Adequate vitamin D could exert anti-inflammatory effects and modify such association.

Associations of cord blood meta-inflammation and vitamin D with neurodevelopmental delay: A prospective birth cohort study in China.

Aim: To estimate the associations of cord meta-inflammatory markers with neurodevelopment, including the potential impact of cord blood vitamin D levels. Method: The prospective cohort study comprised 7198 participants based on the Maternal & Infants Health in Hefei study. Cord blood C-peptide, high-sensitive C-reactive protein (hsCRP), high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, triglycerides and 25(OH)D levels were measured. The Gesell Developmental Schedules were used to assess neurodevelopmental outcomes in offspring. Results: After adjusting potential confounders, per quartile increase in cord blood 25(OH)D concentrations was associated with a decreased risk of neurodevelopmental delay [hazard ratios (HR) 0.65 (95% CI 0.57, 0.74)]. Conversely, significant positive associations with cord blood serum C-peptide levels above the 90th percentile [HR 2.38 (95% CI 1.81, 3.13)] and higher levels of cord hsCRP (per quartile increase) [HR 1.18 (95% CI 1.01, 1.37)] with neurodevelopmental delay were observed. These associations could vary by quartiles of cord blood 25(OH)D levels: the adjusted HRs in neurodevelopmental delay comparing children with vs without hyperinsulinemia were 1.28 (95% CI: 1.03, 1.59) for quartiles 1 (lowest), and 1.06 (95% CI: 0.78, 1.44) for quartile 4 (highest). Conclusions: Immune activation and metabolic abnormalities in fetal circulation were associated with neurodevelopmental delay in offspring, which could be attenuated by higher cord blood 25(OH)D levels in a dose-response manner.

Sleep patterns modify the association of 25(OH)D with poor cardiovascular health in pregnant women.

Background: The relationship between vitamin D status and gestational cardiovascular health (CVH) is inconsistent in previous studies. Emerging evidence shows that sleep behaviors are related to vitamin D metabolism. However, no studies evaluate the interaction of vitamin D and sleep behaviors on gestational CVH. Objective: We aimed to estimate the relationship between 25-hydroxyvitamin D [25(OH)D] concentrations and gestational CVH, and whether the relationship was modified by sleep behaviors. Methods: The data of this study was from a multicenter birth cohort study. A total of 9,209 pregnant women at 16-23 weeks of gestation were included. 25(OH)D concentrations were measured from collected blood. Sleep patterns consisted of major sleep behaviors including duration, chronotype, insomnia, snoring, and excessive daytime sleepiness. Data on poor CVH was based on four "clinical" CVH metrics, including body mass index, blood pressure, total cholesterol, and glucose levels. Results: The proportion of women with poor CVH was 25.0%. The relative risk (RR) (95%CI) of poor CVH was 0.67 (0.58-0.76) in women with 25(OH)D ≥ 50 nmol/L after multivariate adjustments. Lower 25(OH)D concentrations were significantly associated with poor CVH. Such association was also evident in subgroups analysis. We found a significant interaction of 25(OH)D (P for interaction = 0.01) with sleep patterns on the risk of poor CVH. A negative dose-response relation was observed between 25(OH)D concentrations and poor CVH risk in healthy or intermediate sleep, not poor sleep. 25(OH)D concentrations were lower and the risk of poor CVH was higher in pregnant women with poor sleep patterns (P < 0.05). Conclusion: Our study suggests that sleep patterns modify the association of 25(OH)D concentrations with the CVH among pregnant women.

Physiological, Genomic and Transcriptomic Analyses Reveal the Adaptation Mechanisms of Acidiella bohemica to Extreme Acid Mine Drainage Environments.

Fungi in acid mine drainage (AMD) environments are of great concern due to their potentials of decomposing organic carbon, absorbing heavy metals and reducing AMD acidity. Based on morphological analysis and ITS/18S high-throughput sequencing technology, previous studies have provided deep insights into the diversity and community composition of fungi in AMD environments. However, knowledge about physiology, metabolic potential and transcriptome profiles of fungi inhabiting AMD environments is still scarce. Here, we reported the physiological, genomic, and transcriptomic characterization of Acidiella bohemica SYSU C17045 to improve our understanding of the physiological, genomic, and transcriptomic mechanisms underlying fungal adaptation to AMD environments. A. bohemica was isolated from an AMD environment, which has been proved to be an acidophilic fungus in this study. The surface of A. bohemica cultured in AMD solutions was covered with a large number of minerals such as jarosite. We thus inferred that the A. bohemica might have the potential of biologically induced mineralization. Taking advantage of PacBio single-molecule real-time sequencing, we obtained the high-quality genome sequences of A. bohemica (50 Mbp). To our knowledge, this was the first attempt to employ a third-generation sequencing technology to explore the genomic traits of fungi isolated from AMD environments. Moreover, our transcriptomic analysis revealed that a series of genes in the A. bohemica genome were related to its metabolic pathways of C, N, S, and Fe as well as its adaptation mechanisms, including the response to acid stress and the resistance to heavy metals. Overall, our physiological, genomic, and transcriptomic data provide a foundation for understanding the metabolic potential and adaptation mechanisms of fungi in AMD environments.

Plasma Small Extracellular Vesicle-Carried miRNA-501-5p Promotes Vascular Smooth Muscle Cell Phenotypic Modulation-Mediated In-Stent Restenosis.

Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation. sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation. Plasma sEV in ISR patients are elevated markedly and decrease the expression of VSMC contractile markers α-SMA and calponin and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then, we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis (R 2 = 0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α-SMA and calponin and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p. Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3.

[Effect of intrahepatic cholestasis of pregnancy on the functions of hypothalamic-pituitary-adrenocortical axis and adrenal cortex in normal neonates].

OBJECTIVE: To study the effect of intrahepatic cholestasis of pregnancy (ICP) on the functions of the hypothalamic-pituitary-adrenocortical (HPA) axis and adrenal cortex in normal neonates. METHODS: Demographic characteristics, prenatal anxiety and depression, and perceived stress during delivery were investigated in 32 ICP women and 32 controls. The cord blood levels of cortisal, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS) were measured by the radioimmunity technique in normal neonates immediately after birth. RESULTS: The scores of prenatal anxiety and depression in ICP women were significantly higher than those in controls (p<0.05 and p<0.01, respectively). There were no significant differences in the perceived stress during delivery between the two groups. The cord blood levels of cortisol and ACTH in neonates from ICP women were significantly lower (p<0.01), while the DHEAS level was significantly higher (p<0.01) than in neonates from controls. The DHEAS/ACTH ratio was significantly higher (p<0.01), while the cortisol/DHEAS ratio was significantly lower in the ICP group (p<0.01) than in the control group. The glycocholic acid level in ICP women was positively correlated with the DHEAS level in neonatal cord blood (r=0.47, p<0.01). CONCLUSIONS: There may be a dissociation between cortisol and DHEAS in neonates with normal birth outcome from ICP women. ICP may result in a decreased responsiveness of HPA axis and an increased secretion of DHEAS by adrenal cortex in these neonates. This suggests that there might be dysfunction of the fetal zones of the adrenal cortex.

The association of vitamin D status and supplementation during pregnancy with gestational diabetes mellitus: a Chinese prospective birth cohort study.

BACKGROUND: Previous studies have shown conflicting findings regarding the relation of vitamin D status and supplementation during pregnancy with gestational diabetes mellitus (GDM). Most of these studies hypothesized that 25-hydroxyvitamin D [25(OH)D] concentrations were associated with GDM risk and glucose metabolism based on linear association models. OBJECTIVES: We aimed to estimate the associations of 25(OH)D concentrations and vitamin D supplementation with GDM risk and glucose metabolism and determine the threshold concentrations of 25(OH)D that could significantly affect glucose metabolism and GDM risk. METHODS: In a prospective birth cohort study, we collected information about sociodemographic characteristics, health status, and lifestyle from 4984 pregnant women. Vitamin D supplementation and 25(OH)D concentrations were assessed in the second trimester. Data from the 75-g oral-glucose-tolerance test were obtained at 24-28 weeks of gestation. RESULTS: A total of 922 (18.5%) women were diagnosed with GDM. Compared with women with 25(OH)D concentrations <25 nmol/L, the GDM risk was significantly lower in women with 25(OH)D concentrations ranging from 50 to 75 nmol/L (RR: 0.74; 95% CI: 0.58, 0.95) and >75 nmol/L (RR: 0.40; 95% CI: 0.22, 0.70). The curve-fitting models suggested a significant large reduction in GDM risk, fasting plasma glucose, and area under the curve of glucose with increasing 25(OH)D concentrations only for concentrations >50 nmol/L. Consistently, GDM risk was significantly reduced only in women who took 400-600 IU vitamin D/d (RR: 0.83; 95% CI: 0.70, 0.97) with a mean 25(OH)D concentration of 50 nmol/L but not in women taking vitamin D sometimes with a mean 25(OH)D concentration of 40 nmol/L. CONCLUSIONS: GDM risk was significantly reduced only in pregnant women with 25(OH)D concentrations >50 nmol/L. Pregnant women taking 400-600 IU vitamin D/d with mean 25(OH)D concentrations of 50 nmol/L had a lower risk of GDM.

[Effect of dexmedetomidine on inflammatory factors level and cognitive function after femoral head replacement in elderly patients].

OBJECTIVE: To analyze the effect of dexmedetomidine on the inflammatory factors level and cognitive function after femoral head replacement in elderly patients. METHODS: From January 2016 to December 2017, 60 elderly patients(more than 60 years old, and Grade I to II of ASA) treated with femoral head replacement were divided into three groups, and 20 in each group. All patients received midazolam, fentanyl, etomidate, cisatracurium anesthesia induction and sevoflurane inhalation anesthesia maintenance. The patients in group B and group C were first given 1.0 µg·kg⁻¹ of dexmedetomidine 10 minutes during the operation. The maintenance volume was 0.3 µg·kg⁻¹·h⁻¹ of dexmedetomidine(in group B) and 0.6 µg·kg⁻¹·h⁻¹ of dexmedetomidine(in group C) by pumping. The same amount of saline was given to the patients in group A in the same way. The time of extubation, wakefulness and recovery, the simple intelligent mental state score (MMSE), the incidence of postoperative cognitive dysfunction (POCD) and the levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and S100ß protein expression in the 3 groups were compared. RESULTS: There were significant differences in the time of spontaneous breathing recovery, eye opening tome and the time of extubation, as well as the dosage of propofol among the three groups(P<0.05). On the 1st, 3rd and 7th day after operation, there was a significant difference in MMSE score of group B and group C compared with that of group A(P<0.05), and MMSE score in group C was significantly higher than that of group B(P<0.05). The incidence of POCD was 0.0% (0/20) and the incidence of adverse reactions was 30%(6/20) in group C, but those were 25% (5/20) and 0.0% (0/20) in group A and 5% (1/20) and 10% (2/20) respectively in group B. The difference was statistically significant (P<0.05). Before induction of anesthesia, there was no significant difference in the levels of IL-6, IL-10 and S100ß protein among the three groups(P>0.05); but one hour after the operation, the levels of IL-6 IL-10 and S100ß protein in group B and group C was statistically different from those in group A(P<0.05). The IL-6 and S100ß protein in group C were significantly lower than those in group B (P<0.05), and IL-10 was significantly higher than that in group B (P<0.05). CONCLUSIONS: For elderly patients operated for femoral head replacement, dexmedetomidine can reduce the level of inflammatory factors level and propofol consumption, and the incidence of postoperative POCD is low, indicating a dose dependence of dexmedetomidine. But it is necessary to choose the right dose according to the patient's condition.