Identify gestational diabetes mellitus by deep learning model from cell-free DNA at the early gestation stage.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy, which has significant adverse effects on both the mother and fetus. The incidence of GDM is increasing globally, and early diagnosis is critical for timely treatment and reducing the risk of poor pregnancy outcomes. GDM is usually diagnosed and detected after 24 weeks of gestation, while complications due to GDM can occur much earlier. Copy number variations (CNVs) can be a possible biomarker for GDM diagnosis and screening in the early gestation stage. In this study, we proposed a machine-learning method to screen GDM in the early stage of gestation using cell-free DNA (cfDNA) sequencing data from maternal plasma. Five thousand and eighty-five patients from north regions of Mainland China, including 1942 GDM, were recruited. A non-overlapping sliding window method was applied for CNV coverage screening on low-coverage (~0.2×) sequencing data. The CNV coverage was fed to a convolutional neural network with attention architecture for the binary classification. The model achieved a classification accuracy of 88.14%, precision of 84.07%, recall of 93.04%, F1-score of 88.33% and AUC of 96.49%. The model identified 2190 genes associated with GDM, including DEFA1, DEFA3 and DEFB1. The enriched gene ontology (GO) terms and KEGG pathways showed that many identified genes are associated with diabetes-related pathways. Our study demonstrates the feasibility of using cfDNA sequencing data and machine-learning methods for early diagnosis of GDM, which may aid in early intervention and prevention of adverse pregnancy outcomes.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study.

BACKGROUND: Subclinical hypothyroidism (SCH) is linked to dyslipidaemia and adverse pregnancy outcomes. However, the impact of dyslipidaemia on the outcome of pregnancy in SCH is unclear. METHODS: We enrolled 36,256 pregnant women and evaluated their pregnancy outcomes. The following data was gathered during the first trimester (≤ 13+ 6 weeks of gestation): total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), high-density lipoprotein (HDL-C), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations. The reference ranges for lipids were estimated to range from the 5th to the 95th percentile. Logistic regression assessed the relationships between dyslipidaemia and adverse pregnancy outcomes, including abortion, preeclampsia/eclampsia, low birth weight, foetal growth restriction, premature rupture of foetal membranes, gestational hypertension, preterm birth, macrosomia and gestational diabetes mellitus (GDM). Additionally, the best thresholds for predicting adverse pregnancy outcomes based on TSH, FT4, and lipid levels were determined using receiver operating characteristic curves. RESULTS: In the first trimester, LDL-C > 3.24 mmol/L, TG > 1.92 mmol/L, HDL-C < 1.06 mmol/L, and TC > 5.39 mmol/L were used to define dyslipidaemia. In this cohort, 952 (3.56%) patients were diagnosed with SCH, and those who had dyslipidaemia in the first trimester had higher incidences of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%) than did those without dyslipidaemia. However, after adjusting for prepregnancy body mass index (pre-BMI), dyslipidaemia was no longer related to these risks. Furthermore, elevated TG dyslipidaemia in SCH patients was connected to an enhanced potential of gestational hypertension (odds ratio [OR]: 2.687, 95% confidence interval [CI]: 1.074 ~ 6.722), and elevated LDL-C dyslipidaemia correlated with increased preeclampsia/eclampsia risk (OR: 3.172, 95% CI: 1.204 ~ 8.355) after accounting for age, smoking status, alcohol use, pre-BMI, and levothyroxine use. Additionally, the combination of TC, TG, LDL-C, pre-BMI, and TSH exhibited enhanced predictive capabilities for gestational hypertension, preeclampsia/eclampsia, and GDM. Values of 0.767, 0.704, and 0.706 were obtained from the area under the curve. CONCLUSIONS: Among pregnant women with SCH, dyslipidaemia in early pregnancy was related to elevated risks of adverse pregnancy consequences. The combined consideration of age, pre-BMI, TSH, and lipid levels in the first trimester could be beneficial for monitoring patients and implementing interventions to reduce adverse pregnancy outcomes.

[An evaluation of carrier detection for Spinal muscular atrophy using digital PCR assay].

OBJECTIVE: To assess the effectiveness and feasibility of carrier detection for Spinal muscular atrophy (SMA) by using digital PCR assay. METHODS: Peripheral blood samples were collected from 214 pregnant women who were routinely screened for SMA carriers, of which 204 were randomly selected samples and 10 were samples with known copy numbers of SMN1 exons 7 and 8. Samples with known copy numbers of SMN1 exons 7 and 8 were randomly mixed into the experiment to validate the performance of the digital PCR assay. RESULTS: The copy numbers of SMN1 exons 7 and 8 and SMN2 exons 7 and 8 in peripheral blood samples were detected by digital PCR assay. The results of SMN1 exons 7 and 8 were compared with those of the quantitative PCR method to assess the reliability and clinical performance of the digital PCR assay. Among the 204 random samples, digital PCR has detected five samples with simultaneous heterozygous deletion of SMN1 exons 7 and 8, three samples with heterozygous deletion of SMN1 exon 8 only, and 196 samples with no deletion of SMN1 exons 7 and 8. Ten samples with known SMN1 exons 7 and 8 copy numbers were detected with the expected values. The digital PCR test results were fully consistent with that of the quantitative PCR. CONCLUSION: The results of digital PCR for the detection of copy number variation of SMN1 exons 7 and 8 were consistent with qPCR. Digital PCR assay was able to clearly distinguish the copy number of the target genes, therefore can be used for SMA carrier screening. Moreover, it can also detect copy number of SMN2 exons 7 and 8, which can provide more information for genetic counseling.

Angiotensin-(1-7) ameliorates intestinal barrier dysfunction by activating the Keap1/Nrf2/HO-1 signaling pathway in acute pancreatitis.

BACKGROUND: Intestinal barrier dysfunction is a serious complication associated with acute pancreatitis (AP). Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier, but the underlying mechanism remains clear. This study investigated the impact of Ang-(1-7) on AP-induced intestinal dysfunction and its involvement in the Keap1/Nrf2/HO-1 pathway. METHODS AND RESULTS: We studied caerulein- and lipopolysaccharide (LPS)-induced AP in mice and an epithelial cell line (IEC-6) from the small intestinal crypt of rats. Ang-(1-7) was administered orally or via the tail vein. IEC-6 cells were divided into five groups: control; LPS; LPS + Ang-(1-7); LPS + Ang-(1-7) + ML385 (an Nrf2 inhibitor); and LPS + ML385. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. The expression of intestinal barrier-associated proteins and Keap1/Nrf2/HO-1 pathway constituents was assessed by RT-PCR and western blotting. The peroxide and antioxidant activities in the IEC-6 cells were measured. Compared to those in AP mice, Ang-(1-7) diminished the intestinal levels of proinflammatory factors (interleukin-1ß and tumor necrosis factor α) and serum levels of intestine permeability (D-lactate). Ang-(1-7) increased the expression of barrier-associated proteins (aquaporin-1, claudin-1, and occludin) compared to those in the AP and LPS group. Moreover, Ang-(1-7) promoted the Keap/Nrf2/HO-1 pathway, which resulted in significantly reduced malondialdehyde and increased superoxide dismutase levels.. However, ML385 abolished the effects of Ang-(1-7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway. CONCLUSIONS: Ang-(1-7) reduces AP-induced intestinal inflammation and oxidative injuries by activating the Keap1/Nrf2/HO-1 pathway.

Potential impact of ambient temperature on maternal blood pressure and hypertensive disorders of pregnancy: A nationwide multicenter study based on the China birth cohort.

Limited evidence exists regarding the association between ambient temperature and blood pressure (BP) level of pregnant women. To investigate the associations of ambient temperature with maternal BP and hypertensive disorders of pregnancy (HDP), we studied 105,063 participants in 38 centers of 17 provinces from November 2017 to December 2021. BP was measured with standardized automated digital sphygmomanometers. Ambient temperature was classified into five classes as very hot, moderate hot, mild, moderate cold, and very cold. Generalized linear mixed models were used to investigate the ambient temperature-BP/HDP associations, controlling for multiple covariates. No significant associations of first-trimester ambient temperature with maternal BP and HDP prevalence were observed. Compared with mild temperature, second-trimester very cold and second-trimester moderate cold were statistically associated with the increase of 1.239 mmHg (95% CI: 0.908, 1.569) and 0.428 mmHg (95% CI: 0.099, 0.757) for second-trimester systolic blood pressure (SBP), respectively. Similar trends were also observed in the association between second-trimester cold exposure and second-trimester diastolic blood pressure (DBP), in the association between second-trimester cold exposure and third-trimester SBP/DBP as well as in the association between third-trimester cold exposure and third-trimester SBP/DBP although some estimates were not statistically significant. Furthermore, in the second and third trimester, very cold [second trimester: adjusted odds ratio (aOR) = 1.298; third trimester: aOR = 1.236) and moderate cold (second trimester: aOR = 1.208; third trimester: aOR = 1.146) exposures also increased the odds of HDP, and these associations were stronger among participants aged ≥35 years or from North China. The second and third trimesters are the critical exposure windows for ambient temperature exposure-BP/HDP associations. During this period, exposure to cold ambient temperature was associated with elevated BP as well as increased HDP prevalence among most Chinese pregnant women, those aged ≥35 years or from North China being more vulnerable.

Effect of the smartphone application on caesarean section in women with overweight and obesity: a randomized controlled trial in China.

BACKGROUND: The rate of caesarean section (CS) is increasing worldwide. While a CS can be life-saving when medically indicated, it can cause adverse health effects for both women and children. This trial aims to evaluate the effect of the smartphone application, which aims to control the gestational weight gain, on the rate of CS in overweight and obese women. METHODS: Overweight and obese primiparas (BMI ≥ 24 kg/m2) with age between 20 and 40 years old were recruited at Beijing Obstetrics and Gynecology Hospital, and randomly assigned into the intervention group (143 cases) and the control group (138 cases). The intervention group applied the smartphone application (App) to control gestational weight gain in addition to the usual care, and the control group received the usual care. Primary outcome was cesarean section (CS) rate. Secondary outcomes included gestational hypertension, preeclampsia and eclampsia, gestational diabetes mellitus, postpartum hemorrhage, neonatal asphyxia, and macrosomia. RESULTS: There was a significant difference in CS rate, with 53.3% in the intervention group and 65.4% in the control group (P = 0.044). The difference still exists in the overweight subgroup (32.6% vs. 55.6%, P = 0.04), but disappears in the obesity subgroup (63.0% vs. 69.1%, P = 0.381). The median of gestational weight gain (GWG) of the intervention group is 8.5 kg (IQR 5.5, 11.0), which is significantly less than that of the control group (median 10.0 kg, IQR [6.0, 14.0], P = 0.008). The intervention group has significantly lower rate of postpartum hemorrhage (5.19%) than the control group (12%) (P = 0.045). There were no significant differences between the groups in gestational hypertension, gestational diabetes mellitus, neonatal asphyxia, and macrosomia. CONCLUSION: The smartphone assisted weight control may help reduce CS rate. The effects of the smartphone application might be via the management of gestational weight gain. TRAIL REGISTRATION: This trial was registered at Chinese Clinical Trial Registry. Registration number is ChiCTR2300068845 (retrospectively registered, 01/03/2023).

Serum uric acid and the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

AIMS: Serum uric acid (SUA) is considered as a risk factor for gestational diabetes mellitus (GDM). However, current studies showed inconsistent results. This study aimed to explore the relationship between SUA levels and GDM risk. METHODS: Eligible studies were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases up to November 1, 2022. The pooled standardized mean difference (SMD) and 95% confidence interval (CI) were used to represent the difference in SUA levels between GDM women and controls. The combined odds ratios (OR) and 95% CI were applied to assess association between SUA levels and GDM risk. Subgroup analyses were conducted on study continents, design, and quality, detection time of SUA, and GDM diagnostic criteria. RESULTS: Totally 11 studies including five case-control and six cohort studies, in which 80,387 pregnant women with 9815 GDM were included. The overall meta-analysis showed that the mean SUA level in GDM group was significantly higher than in controls (SMD = 0.423, 95%CI = 0.019-0.826, p = .040, I2 = 93%). Notably, pregnant women with elevated levels of SUA had a significantly increased risk of GDM (OR = 1.670, 95%CI = 1.184-2.356, p = .0035, I2 = 95%). Furthermore, subgroup analysis performed on the detection time of SUA showed a significant difference in the association between SUA and GDM risk within different trimesters (1st trimester: OR = 3.978, 95%CI = 2.177-7.268; 1st to 2nd trimester: OR = 1.340, 95%CI = 1.078-1.667; p between subgroups <.01). CONCLUSIONS: Elevated SUA was positively associated with GDM risk, particularly in the 1st trimester of pregnancy. Further studies with high quality are required to validate the findings of this study.

Coronavirus Disease 2019 Pandemic-Related Long-Term Chronic Impacts on Psychological Health of Perinatal Women in China.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has caused far-reaching changes in all areas of society. However, limited data have focused on the long-term impacts on perinatal psychological health. This study aims to evaluate long-term impacts of COVID-19 pandemic crisis on psychological health among perinatal women and investigate associated factors. STUDY DESIGN: A multicenter, cross-sectional study, the psychological subproject of China Birth Cohort Study (CBCS), was conducted in 2021. Demographic and obstetric characteristics, pregnancy outcomes, psychological status, and COVID-19-pandemic-related factors were obtained. The symptoms of depression, anxiety, and insomnia of participants were assessed by Patient Health Questionnaire, Edinburgh Postpartum Depression Scale, Generalized Anxiety Disorder Scale, and Insomnia Severity Index, respectively. Multivariate logistic regression was used to identify associated factors of adverse psychological symptoms. RESULTS: Totally, 1,246 perinatal women were enrolled, with the overall prevalence of depression, anxiety, and insomnia symptoms being 63.16, 41.89, and 44.38%, respectively. Perinatal women who needed psychological counseling and were very worried about the COVID-19 pandemic were 1.8 to 7.2 times more likely to report symptoms of depression, anxiety, and insomnia. Unemployment, flu-like symptoms, younger maternal age, and previous diseases before pregnancy were risk factors for depression, anxiety, or insomnia. CONCLUSION: Our study revealed that the prevalence of perinatal depression, anxiety, and insomnia symptoms was at a high level even 1 year after the pandemic outbreak, implying pandemic-associated long-term psychological impacts on perinatal women existed. Government should not only pay attention to the acute effects of psychological health but also to long-term psychological impacts on perinatal women after major social events. KEY POINTS: · The prevalence of perinatal psychological symptoms was at a high level after the COVID-19 outbreak.. · Perinatal women who were very worried about COVID-19 were more often to have psychological symptoms.. · Perinatal women with demands of mental counseling were more likely to report psychological symptoms..

Identification of novel deep intronic PAH gene variants in patients diagnosed with phenylketonuria.

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) gene variants. Previously, 94.21% of variants were identified using Sanger sequencing and multiplex ligation-dependent probe amplification. To investigate the remaining variants, we performed whole-genome sequencing for four patients with PKU and unknown genotypes to identify deep intronic or structural variants. We identified three novel heterozygous variants (c.706+368T>C, c.1065+241C>A, and c.1199+502A>T) in a deep PAH gene intron. We detected a c.1199+502A>T variant in 60% (6/10) of PKU patients with genetically undetermined PKU. In silico predictions indicated that the three deep variants may impact splice site selection and result in the inclusion of a pseudo-exon. A c.1199+502A>T PAH minigene and reverse transcription PCR (RT-PCR) on blood RNA from a PKU patient with biallelic variants c.1199+502A>T and c.1199G>A confirmed that the c.1199+502A>T variant may strengthen the predicted branch point and leads to the inclusion of a 25-nt pseudo-exon in the PAH mRNA. Reverse transcription polymerase chain reaction (RT-PCR) on the minigene revealed that c.706+368T>C may create an SRSF2 (SC35) binding site via a 313-nt pseudo-exon, whereas c.1065+241C>A may produce an 81-nt pseudo-exon that strengthens the predicted SRSF1 (SF2/ASF) binding site. These results augment current knowledge of PAH genotypes and show that deep intronic analysis of PAH can genetically diagnose PKU.

TBC1D21 is an essential factor for sperm mitochondrial sheath assembly and male fertility‡.

During spermiogenesis, the formation of the mitochondrial sheath is critical for male fertility. The molecular processes that govern the development of the mitochondrial sheath remain unknown. Whether TBC1D21 serves as a GTPase-activating protein (GAP) for GTP hydrolysis in the testis is unclear, despite recent findings indicating that it collaborates with numerous proteins to regulate the formation of the mitochondrial sheath. To thoroughly examine the property of TBC1D21 in spermiogenesis, we applied the CRISPR/Cas9 technology to generate the Tbc1d21-/- mice, Tbc1d21D125A R128K mice with mutation in the GAP catalytic residues (IxxDxxR), and Tbc1d21-3xFlag mice. Male Tbc1d21-/- mice were infertile due to the curved spermatozoa flagella. In vitro fertilization is ineffective for Tbc1d21-/- sperm, although healthy offspring were obtained by intracytoplasmic sperm injection. Electron microscopy revealed aberrant ultrastructural changes in the mitochondrial sheath. Thirty-four Rab vectors were constructed followed by co-immunoprecipitation, which identified RAB13 as a novel TBC1D21 binding protein. Interestingly, infertility was not observed in Tbc1d21D125A R128K mice harboring the catalytic residue, suggesting that TBC1D21 is not a typical GAP for Rab-GTP hydrolysis. Moreover, TBC1D21 was expressed in the sperm mitochondrial sheath in Tbc1d21-3xFlag mice. Immunoprecipitation-mass spectrometry demonstrated the interactions of TBC1D21 with ACTB, TPM3, SPATA19, and VDAC3 to regulate the architecture of the sperm midpiece. The collective findings suggest that TBC1D21 is a scaffold protein required for the organization and stabilization of the mitochondrial sheath morphology.

Angiotensin-(1-7) promotes mitochondrial translocation of human telomerase reverse transcriptase in HUVECs through the TOM20 complex.

BACKGROUND: Angiotensin (Ang) (1-7) is a vasodilator peptide that ameliorates microcirculation dysfunction, increases telomerase activity in cells, and exerts vasodilatory, anti-inflammatory, antioxidative stress, and antiapoptotic effects. Mitochondrial human telomerase reverse transcriptase (hTERT) plays an important role in the processes of antiapoptosis, antioxidative stress, and immortalization. This study aimed to investigate the effect of Ang(1-7) on the mitochondrial translocation of hTERT. METHODS: An in vitro model of lipopolysaccharide (LPS)-induced inflammation was established in human umbilical vein endothelial cells (HUVECs). Ang(1-7) was added to cells 30 min before LPS stimulation. The Ang(1-7)/Mas receptor antagonist A779 plus Ang(1-7) were added to the cells 30 min before LPS stimulation. The translocase outer membrane (TOM)20-overexpression HUVECs (HUVEC-TOM20OE), TOM20-knockdown HUVECs (HUVEC-TOM20KD), and the corresponding negative control cell lines were constructed by lentiviral transfection of HUVECs. Cells subjected to LPS stimulation alone, LPS plus Ang(1-7), LPS plus Ang(1-7) and A779, vehicle and no treatment were termed the LPS group, LPS + A group, LPS + A + A779 group, Con group and Neg group, respectively. Immunofluorescence staining was used to detect the distribution of hTERT in the nuclei and mitochondria of HUVECs and to locate TOM20, TOM40, and translocase inner membrane (TIM)23 in the mitochondria. The protein expression levels of total hTERT, mitochondrial hTERT, TOM20, TOM40, and TIM23 were measured by Western blot. The mRNA expression levels of hTERT, TOM20, TOM40, and TIM23 were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: hTERT colocalized with TOM40, TOM20 and TIM23 in the mitochondria. The mitochondrial hTERT protein level of the LPS + A group was significantly greater than that of the LPS group (P = 0.001), and the LPS group showed significantly increased expression of mitochondrial hTERT compared with that of the control group (P = 0.001). No significant difference in the level of total hTERT was observed between the LPS + A and LPS groups. The mitochondrial hTERT protein level of the LPS + A + A779 group was significantly lower than that of the LPS + A group (P = 0.021). The protein level of mitochondrial hTERT in HUVEC-TOM20KD treated with or without LPS alone or LPS + A was significantly decreased compared with the corresponding groups of control HUVECs (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.035; HUVEC-TOM20KD-LPS vs. HUVEC-LPS, P = 0.003; HUVEC-TOM20KD-LPS + A vs. HUVEC-LPS + A, P = 0.001), and treatment with Ang(1-7) did not restore the downregulation of mitochondrial hTERT in HUVEC-TOM20KD. HUVEC-TOM20OE showed a significantly increased level of mitochondrial hTERT (HUVEC-TOM20OE-Con vs. HUVEC-Con, P = 0.010), which was further elevated by Ang(1-7) stimulation (HUVEC-TOM20OE-LPS + A vs. HUVEC-TOM20OE-Con, P = 0.011). Lastly, the protein expression levels of TOM40 (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.007) and TIM23 (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.001) were significantly increased in HUVEC-TOM20KD in comparison to HUVECs. CONCLUSIONS: Ang(1-7) effectively promoted mitochondrial translocation of hTERT in HUVECs via TOM20, indicating that hTERT may be transported to the mitochondria through the TOM20 complex. In addition, A779 could block the effects of Ang(1-7) in HUVECs.

The China birth cohort study (CBCS).

The China birth cohort study (CBCS) is a prospective longitudinal, mega-cohort study and the first national-based birth cohort study, aiming to establish a birth cohort covering representative geographical areas of the whole of China to investigate risk factors for birth defects and develop strategies for their reduction. Pregnant women who are of Chinese nationality, are 6-13+6 weeks of gestation, plan to attend the routine antenatal examination and deliver in the study site, and give their informed, written consent are eligible to participate in this study. All participants are followed-up through an in-person interview at 20-23+6 weeks and again at 28-33+6 weeks of gestation, and at delivery, respectively. CBCS has been divided into three phases from 20th November 2017 to 31st December 2021, and the first two phases have now been completed on 29th February 2020, enrolling 120 377 eligible pregnant women during this period. During the same period a total of 40 837 participants had been followed up to the end of pregnancy. Study recruitment will continue until December 2021 to achieve the target of 500 000 participants. Meanwhile, biological samples including peripheral blood, amniocytes, cord blood, placenta, or umbilical cord tissue have been collected from participants according to various conditions. The incidence of birth defects in this group is 2.5% and congenital heart disease is the most common type of birth defect seen so far. A website is in the advanced stages of planning, to allow seamless data transfer and facilitate collaboration with groups around the world.

Significance of levothyroxine treatment on serum lipid in pregnant women with subclinical hypothyroidism.

BACKGROUND: There is no consensus reference range for serum lipid levels during pregnancy. The benefit of levothyroxine (L-T4) on serum lipid levels are unclear among pregnant women with subclinical hypothyroidism (SCH). OBJECTIVE: To determine the recommended reference ranges for serum lipid concentrations during pregnancy and effects of L-T4 treatment on serum lipids in pregnant women with SCH. DESIGN: Cohort study. METHODS: A analysis of 20,365 women in the first trimester was conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University during 2018-2020. After excluding women with adverse pregnancy outcomes, we determined the reference range of serum lipid in the first and third trimesters of pregnancy by using median and quartile to determine appropriate percentiles. Next, we divided into three groups as follows: SCH L-T4 treatment group (n = 319), SCH non-intervention group (n = 103) and the control group(n = 9598). RESULTS: The recommended reference range for serum lipids in the first trimester of pregnancy should be: TC < 5.33 mmol/L, TG < 1.73 mmol/L, LDL-C < 3.12 mmol/L and HDL-C > 1.1 mmol/L, and in third trimester of pregnancy should be: TC < 8.47 mmol/L, TG < 4.86 mmol/L, LDL-C < 5.3 mmol/L and HDL-C > 1.34 mmol/L. There are significant differences in TC and LDL-C levels between SCH treatment group and SCH non-intervention Group (P = 0.043, P = 0.046; respectively). CONCLUSIONS: We determine the recommended reference ranges for serum lipid concentrations during pregnancy. TC and LDL-C levels in pregnant women with SCH could improve after L-T4 treatment.

Acute pancreatitis in pregnancy: a 10-year, multi-center, retrospective study in Beijing.

OBJECTIVE: Acute pancreatitis in pregnancy (APIP) is a rare and serious complication during pregnancy. It has acute onset and is difficult to diagnose and treat. The aim of the present study was to describe the etiology, clinical manifestations, and maternofetal outcomes of APIP. METHODS: We retrospectively reviewed 32 pregnant women who were treated at three tertiary care hospitals in Beijing, China. The correlation between the causes of APIP, severity, laboratory indices, and outcomes was analyzed. RESULTS: The most common causes of APIP were hypertriglyceridemia (56.2%,18/32) and gallstones (28.1%, 9/32). Hypertriglyceridemia-induced APIP was associated with a higher rate of severe acute pancreatitis (P = 0.025). Serum level of triglycerides showed a positive correlation with the severity of APIP (P = 0.039). The most frequent presentation of APIP was abdominal pain (93.7%, 30/32). There were no maternal or fetal deaths in our study. Apgar scores at 1 min, 5 min, and 10 min of the premature neonates was correlated with the severity of APIP of the mother (P = 0.022; 0.002; 0.002). CONCLUSION: High level of triglycerides may serve as a useful marker of the severity of APIP. The severity of APIP was associated with higher risk of neonate asphyxia. Appropriate timing of termination of pregnancy is a key imperative for APIP patients.

Dynamics of gut microbiota during pregnancy in women with TPOAb-positive subclinical hypothyroidism: a prospective cohort study.

BACKGROUND: Anti-thyroid peroxidase antibody (TPOAb) positivity can contribute to inhibit thyroxine synthesis. Gut microbiota can interact with metabolic or immune diseases. However, dynamics of gut microbiota from the second (T2) to the third trimester (T3) in women with TPOAb-positive/negative subclinical hypothyroidism (TPOAb+/TPOAb- SCH) have not been reported. Therefore, we aimed to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. METHODS: In this single-center prospective cohort study, we observed gut microbiota dynamics by sequencing 16S rRNA from fecal samples collected in T2 (20-23+ 6 weeks) and T3 (28-33+ 6 weeks). TPOAb+/TPOAb- SCH were stratified depending on whether or not they used levothyroxine (LT4) during the pregnancy (LT4+/LT4-). Microbiome bioinformatics analyses were performed using QIIME2. The linear discriminant analysis effect size (LEfSe) was used for the quantitative analysis of biomarkers. Functional profiling was performed with PICRUSt2. RESULTS: Distinct gut microbiota dynamics from T2 to T3 were noted in the TPOAb- (n = 68) and TPOAb+ (n = 64) SCH groups. The TPOAb+ LT4- group was characterized by enriched bacterial amplicon sequence variants (ASVs) of Prevotella in T2 and Bacteria, Lachnospirales, Lachnospiraceae, Blautia, and Agathobacter in T3 and by depleted ASVs of Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae in T2 and Actinobacteriota, Coriobacteriia, Actinobacteria, Coriobacteriales, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Dorea formicigenerans, and Bifidobacterium longum in T3. The TPOAb+ LT4+ group was characterized by enriched bacterial ASVs of Blautia, Streptococcus salivarius, and Bifidobacterium longum in T3 and by depleted ASVs of Bacteroidota, Bacteroidia, Bacteroidales, and Prevotella in T2 and Agathobacter in T3. Moreover, we identified 53 kinds of metabolic functions that were mainly involved in sugar, lipid, and amino acid metabolism. CONCLUSIONS: Our results indicated that low dynamics of gut microbiota composition and high dynamics of its metabolic function from T2 to T3 were associated with TPOAb+ SCH. We concluded that gut microbiota could be new targets for treatment of TPOAb+ SCH during pregnancy. TRIAL REGISTRATION: This study was retrospectively registered at the Chinese Clinical Trial Registry (registration number ChiCTR2100047175 ) on June 10, 2021.

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review.

BACKGROUND: Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD. METHODS: Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis's five-class evidence grade. RESULTS: A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as "Moderate". One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed. CONCLUSION: The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.

Effect on the cardiovascular independent risk factor lipoprotein(a) in overweight or obese PCOS patients with ethinyl-estradiol/drospirenone alone or plus orlistat.

OBJECTIVE: This study aimed to assess the effect on the cardiovascular independent risk factor Lipoprotein(a) [Lp(a)] in overweight or obese polycystic ovary syndrome (PCOS) patients with ethinyl-estradiol/drospirenone (EE/DRSP) alone or plus orlistat. METHODS: In this randomized controlled prospective study, 66 PCOS patients with overweight or obesity were matched according to age and BMI. All participants were randomly divided into two groups to receive EE/DRSP plus Orlistat (n = 33) or EE/DRSP alone (n = 33) for 3 months. Changes in cardiovascular risk factors including Lp(a), CRP, LDL-C, anthropometric assessments, variations in sex hormones related parameters, and in glucolipid metabolic index were evaluated after the intervention. RESULTS: Lp(a) and CRP were significantly decreased at 3 months only in the EE/DRSP plus Orlistat group. There were significant reductions in LDL-C, weight, BMI, waist circumference (WC), body fat percentage (BFP), FT in both groups compared to baseline. However, these reductions were significantly greater in EE/DRSP plus Orlistat group. The levels of HDL-C, TG, and SHBG significantly increased, while TT and LH significantly decreased in both groups over time. TC, FINS, FPG were not significantly changed in both groups after the intervention. CONCLUSIONS: This is the first study found that EE/DRSP plus Orlistat could significantly decrease Lp(a) in overweight or obese PCOS patients. This result can be assessed as particularly important, because Lp(a) is well-known as an independent risk factor predicting an increased risk of cardiovascular diseases (CVDs).

Extensive serum biomarker analysis in the prethrombotic state of recurrent spontaneous abortion.

The prethrombotic state (PTS) is a possible cause of recurrent spontaneous abortion (RSA). The aim of this study was to identify serum biomarkers for the detection of RSA with PTS (PSRSA). A Quantibody array 440 was used to screen novel serum-based biomarkers for PSRSA/NRSA (RSA without PTS). Proteins differentially expressed in PSRSA were analysed using bioinformatics methods and subjected to a customized array and enzyme-linked immunosorbent assay (ELISA) validation. We used receiver operating characteristic to calculate diagnostic accuracy, and machine learning methods to establish a biomarker model for evaluation of the identified targets. 20 targets were selected for validation using a customized array, and seven targets via ELISA. The decision tree model showed that IL-24 was the first node and eotaxin-3 was the second node distinguishing the PSRSA and NRSA groups (an accuracy rate of 100% and an AUC of 1). Epidermal growth factor (EGF) as the node distinguished the PSRSA and NC groups (an accuracy rate of 100% and an AUC of 1). EGF as the node distinguished the NRSA and NC groups (an accuracy rate of 96.5% and an AUC of 0.998). Serum DNAM-1, BAFF, CNTF, LAG-3, IL-24, Eotaxin-3 and EGF represent a panel of promising diagnostic biomarkers to detect the PSRSA.