Diagnostic yield of copy number variation sequencing in fetuses with increased nuchal translucency: a retrospective study.

OBJECTIVE: To assess the efficacy of copy number variation sequencing (CNV-seq) and karyotyping for prenatal detection of chromosomal abnormalities in fetuses with increased nuchal translucency. METHODS: Amniotic fluid samples were extracted from 205 fetuses with increased nuchal translucency (NT ≥ 2.5 mm), diagnosed by ultrasound between gestational ages of 11 and 13 + 6 weeks. Karyotyping and CNV-seq were performed for detecting chromosomal abnormalities. RESULTS: There are 40 fetuses (19.51%) showing increased NT detected with chromosomal abnormalities in karyotyping, and trisomy 21 was found to be the most common abnormalities. There are 50 fetuses (24.39%) identified with chromosomal abnormalities by CNV-seq. The detection of the applied techniques indicated that CNV-seq revealed higher chromosomal aberrations. The risk of chromosomal abnormalities was significantly increased with NT thickening, from 13.64% in the NT group of 2.5-3.4 mm, 38.64% in the NT group of 3.5-4.4 mm, and to 51.72% in the NT group of over 4.5 mm (P < 0.05). The investigated cases with increased NT with presence of soft markers in ultrasound or high risk in non-invasive prenatal testing presented chromosomal abnormalities in higher rates, comparing with those with isolated NT or low risk (P < 0.05). CONCLUSION: The results indicated that the risk of chromosomal abnormalities was associated with the NT thickness, detected by karyotype or CNV-seq. The combination application of two analysis was efficient to reveal the possible genetic defects in prenatal diagnosis. The finding suggested that the detection should be considered with ultrasonographic soft markers, and the NT thickness of 2.5-3.4 mm could be a critical value for detecting chromosomal abnormalities to prevent the occurrence of missed diagnosis.

Anti-thrombotic effects mediated by dihydromyricetin involve both platelet inhibition and endothelial protection.

Classical antithrombotics and antiplatelets are associated with high frequencies of bleeding complications or treatment failure when used as single agents. The platelet-independent fibrin generation by activated endothelium highlights the importance of vascular protection in addition to platelet inhibition in thrombosis prevention. Dihydromyricetin (DHM), the most abundant flavonoid in Ampelopsis grossedentata, has unique vasoprotective effects. This study aims to characterize the antithrombotic potential of DHM. The effects of DHM on the activation of platelets and endothelial cells were evaluated in vitro. Calcium mobilization and activation of mitogen-activated protein kinases (MAPKs) were examined as the potential targets of DHM based on molecular docking analysis. The in vivo effects of DHM were determined in FeCl3-injured carotid arteries and laser-injured cremasteric arterioles. The results showed that DHM suppressed a range of platelet responses including aggregation, secretion, adhesion, spreading and integrin activation, and inhibited exocytosis, phosphatidylserine exposure and tissue factor expression in activated endothelial cells. Mechanistically, DHM attenuated thrombin-induced calcium mobilization and phosphorylation of ERK1/2 and p38 both in platelets and endothelial cells. Intravenous treatment with DHM delayed FeCl3-induced carotid arterial thrombosis. Furthermore, DHM treatment inhibited both platelet accumulation and fibrin generation in the presence or absence of eptifibatide in the laser injury-induced thrombosis model, without prolonging ex vivo plasma coagulation or tail bleeding time. DHM represents a novel antithrombotic agent whose effects involve both inhibition of platelet activation and reduction of fibrin generation as a result of endothelial protection.

Clinical Characteristics and Outcomes of Childbearing-Age Women With COVID-19 in Wuhan: Retrospective, Single-Center Study.

BACKGROUND: Since December 2019, an outbreak of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly in Wuhan and worldwide. However, previous studies on pregnant patients were limited. OBJECTIVE: The aim of this study is to evaluate the clinical characteristics and outcomes of pregnant and nonpregnant women with COVID-19. METHODS: This study retrospectively collected epidemiological, clinical, laboratory, imaging, management, and outcome data of 43 childbearing-age women patients (including 17 pregnant and 26 nonpregnant patients) who presented with laboratory-confirmed COVID-19 in Tongji Hospital, Wuhan, China from January 19 to March 2, 2020. Clinical outcomes were followed up to March 28, 2020. RESULTS: Of the 43 childbearing-age women in this study, none developed a severe adverse illness or died. The median ages of pregnant and nonpregnant women were 33.0 and 33.5 years, respectively. Pregnant women had a markedly higher proportion of history exposure to hospitals within 2 weeks before onset compared to nonpregnant women (9/17, 53% vs 5/26, 19%, P=.02) and a lower proportion of other family members affected (4/17, 24% vs 19/26, 73%, P=.004). Fever (8/17, 47% vs 18/26, 69%) and cough (9/17, 53% vs 12/26, 46%) were common onsets of symptoms for the two groups. Abdominal pain (n=4, 24%), vaginal bleeding (n=1, 6%), reduced fetal movement (n=1, 6%), and increased fetal movement (n=2, 13%) were observed at onset in the 17 pregnant patients. Higher neutrophil and lower lymphocyte percent were observed in the pregnant group compared to the nonpregnant group (79% vs 56%, P<.001; 15% vs 33%, P<.001, respectively). In both groups, we observed an elevated concentration of high-sensitivity C-reactive protein, erythrocyte sedimentation rate, aminotransferase, and lactate dehydrogenase. Concentrations of alkaline phosphatase and D-dimer in the pregnant group were significantly higher than those of the nonpregnant group (119.0 vs 48.0 U/L, P<.001; 2.1 vs 0.3µg/mL, P<.001, respectively). Both pregnant (4/10, 40%) and nonpregnant (8/15, 53%) women tested positive for influenza A virus. A majority of pregnant and nonpregnant groups received antiviral (13/17, 76% vs 25/26, 96%) and antibiotic (13/17, 76% vs 23/26, 88%) therapy. Additionally, both pregnant (2/11, 18%) and nonpregnant (2/19, 11%) recovered women redetected positive for SARS-CoV-2 after discharge. CONCLUSIONS: The epidemiology and clinical and laboratory features of pregnant women with COVID-19 were diverse and atypical, which increased the difficulty of diagnosis. Most pregnant women with COVID-19 were mild and moderate, and rarely developed severe pneumonia or severe adverse outcomes.

Maspin impairs the function of endothelial cells: an implying pathway of preeclampsia.

BACKGROUD: Widespread endothelial injury contributes to the occurrence of preeclampsia. Maspin, first identified as a tumor suppressor, plays a critical role in cell invasion and angiogenesis. Our previous studies found that the expression of maspin was increased in preeclampsic placenta. In this research, we studied the function of human umbilical vein endothelial cells (HUVECs) to explore the role and possible mechanism of maspin gene in the pathogenesis of preeclampsia. METHODS: HUVECs were treated with different concentration of recombinant human maspin protein (r-maspin) during normoxia and hypoxia, we detected the proliferation, apoptosis, migration and tube formation of HUVECs. We also assessed nitride oxide (NO) synthesis and the expression of matrix metalloproteinase 2 (MMP2) to further explore the underlying molecular mechanism. RESULTS: There was only slight maspin expression at mRNA level in HUVECs. Treated HUVECs with r-maspin, the proliferation of HUVECs was significantly promoted both under normoxia and hypoxia. The tubes formed by HUVECs were significantly inhibited and NO synthesis was significantly reduced by r-maspin. Meantime, r-maspin also inhibited MMP2 expression and activity in HUVECs. However, there was no significant change in the migration and apoptosis of HUVECs. CONCLUSIONS: Maspin may be an important participant for mediating endothelial function and ultimately leads to the occurence of preeclamsia.

Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level.

Intrauterine exposure to hyperglycaemia may increase the risk of later-life metabolic disorders. Although the underlying mechanism is not fully understood, epigenetic dysregulation in fetal programming has been implicated. With regard to energy homoeostasis, PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α, encoded by the PPARGC1A gene) plays a regulatory role in several biochemical processes. We hypothesized that maternal gestational glucose levels would positively correlate with DNA methylation of the PPARGC1A promoter in placental tissue. We undertook a cross-sectional study of 58 mothers who underwent uncomplicated Caesarean delivery in a university hospital. Maternal gestational glucose concentration was determined after a 75-g OGTT (oral glucose tolerance test) at 24-28 weeks of gestation. Placenta tissue and cord blood were collected immediately after delivery. Genomic DNA was extracted and thereafter bisulfite conversion was performed. After PCR amplification, the DNA methylation of the PPARGC1A promoter was quantified using a pyrosequencing technique. The protein level of PGC-1α was evaluated by Western blotting. For all participants as a whole, including the GDM (gestational diabetes mellitus) and normoglycaemia groups, the maternal gestational glucose level was positively correlated with placental DNA methylation, and negatively correlated with cord blood DNA methylation of the PPARGC1A promoter in a CpG site-specific manner. In the GDM group alone, the placental CpG site-specific methylation of the PPARGC1A promoter strongly correlated with gestational 2-h post-OGTT glycaemia. Epigenetic alteration of the PPAGRC1A promoter may be one of the potential mechanisms underlying the metabolic programming in offspring exposed to intrauterine hyperglycaemia.

Effectiveness and safety of double-balloon catheter versus intra-amniotic injection of ethacridine lactate for termination of second trimester pregnancy in patients with liver dysfunction.

Severe liver dysfunction in pregnancy (SLDP) is rare but serious complications with high mortality rate. This study compared the effectiveness and safety of double-balloon catheter versus intra-amniotic injection of ethacridine lactate for the termination of second trimester pregnancy in patients with SLD. A total of 55 patients with indications of labor induction were enrolled and analyzed by retrospective control analysis method. Twenty-three cases adopted Cook double balloon dilation as Cook group, and 32 cases received intra-amniotic injection of ethacridine lactate as EL group. The primary outcome was evaluated by successful abortion rate and the difference in the induction-to-abortion interval. Secondary outcomes included liver function recovery and the frequency of adverse events. Both Cook and EL regimens were effective, with successful abortion rate of 87.0% and 93.8%, respectively (P=0.639). The induction-to-delivery interval was similar between Cook group and EL group (38.1 ± 21.5 vs. 41.3 ± 17.4, P=0.543). The liver disease status was more severe in Cook group than in EL group, but it did not show any significant difference after pregnancy termination between the two groups and the improvement rate also did not show any significant difference. Both treatments were safe and there was no significant difference in bleeding and cervical laceration adverse events between the two groups. Our study firstly compared double-balloon catheter and ethacridine lactate for the induction of labor in women with SLD during second trimester pregnancy.

Effects of anti-g and anti-f antibodies on airway function after respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illnesses in infants worldwide. Both RSV-G and RSV-F glycoproteins play pathogenic roles during infection with RSV. The objective of this study was to compare the effects of anti-RSV-G and anti-RSV-F monoclonal antibodies (mAbs) on airway hyperresponsiveness (AHR) and inflammation after primary or secondary RSV infection in mice. In the primary infection model, mice were infected with RSV at 6 weeks of age. Anti-RSV-G or anti-RSV-F mAbs were administered 24 hours before infection or Day +2 postinfection. In a secondary infection model, mice were infected (primary) with RSV at 1 week (neonate) and reinfected (secondary) 5 weeks later. Anti-RSV-G and anti-RSV-F mAbs were administered 24 hours before the primary infection. Both mAbs had comparable effects in preventing airway responses after primary RSV infection. When given 2 days after infection, anti-RSV-G-treated mice showed significantly decreased AHR and airway inflammation, which persisted in anti-RSV-F-treated mice. In the reinfection model, anti-RSV-G but not anti-RSV-F administered during primary RSV infection in neonates resulted in decreased AHR, eosinophilia, and IL-13 but increased levels of IFN-γ in bronchoalveolar lavage on reinfection. These results support the use of anti-RSV-G in the prevention and treatment of RSV-induced disease.

Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand.

BACKGROUND: Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. OBJECTIVES: We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. METHODS: Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. RESULTS: OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. CONCLUSIONS: In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection.

Comparison of Cumulative Live Birth Rates between Flexible and Conventional Progestin-Primed Ovarian Stimulation Protocol in Poor Ovarian Response Patients According to POSEIDON Criteria: A Cohort Study.

RESEARCH QUESTION: To compare the cumulative live birth rate (CLBR) per oocyte retrieval cycle of a conventional progestin-primed ovarian stimulation (cPPOS) regimen with a flexible progestin-primed ovarian stimulation (fPPOS) regimen in poor ovarian response patients, according to POSEIDON criteria. DESIGN: Poor ovarian response women, according to POSEIDON criteria, who underwent the first PPOS protocol for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) between January 2018 and December 2020 were included. The fPPOS group involved 113 participants, and the cPPOS group included 1119 participants. In the cPPOS group, medroxyprogesterone acetate (MPA) (10 mg/d) was administrated on the gonadotropin injection the same day as gonadotropin injections in the cPPOS group, while MPA was started either on the day when the leading follicle with mean diameter > 12mm was present and/or serum E2 was >300 pg/mL in the fPPOS protocol group. The primary outcome was CLBR. RESULTS: The fPPOS protocol had higher CLBR per oocyte retrieval cycle compared to the cPPOS group, even without a statistically significant difference (29.6% vs. 24.9%, p = 0.365). The fPPOS group had fewer numbers of retrieved oocytes (2.87 ± 2.03 vs. 3.76 ± 2.32, p < 0.001) but a higher MII oocyte rate (89.8% vs. 84.7%, p = 0.016). In addition, the number of available embryos in the two groups was comparable (1.37 ± 1.24 vs. 1.63 ± 1.38, p = 0.095). There were five women in the fPPOS group, and 86 women in the cPPOS group had a premature LH surge (4.2% vs. 6.8%, p = 0.261). In the fPPOS group, there was one instance of premature ovulation, while in the cPPOS group, there were six occurrences of premature ovulation (0.8 vs. 0.5%, p = 1.000). CONCLUSION(S): The novel fPPOS protocol appears to achieve higher CLBR even without significant differences and with MPA consumption compared with cPPOS protocol in low-prognosis patients.

Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation.

This study introduced whole-exome sequencing (WES) in prenatal diagnosis of fetal bowel dilatation to improve the detection outcome when karyotype analysis and copy number variation sequencing (CNV-seq) were uninformative in detecting pathogenic variants. The work reviewed 28 cases diagnosed with fetal bowel dilatation and analyzed the results of karyotype analysis, CNV-seq, and WES. Among the 28 cases, the detection rate in cases with low risk of aneuploidy was 11.54% (3/26), which is lower than 100% (2/2) in cases with high risk of aneuploidy. Ten low-risk aneuploidy cases with isolated fetal bowel dilatation had normal genetic testing results, while the remaining 16 cases with other ultrasound abnormalities were detected for genetic variants at a rate of 18.75% (3/16). The detection rate of gene variation was 3.85% (1/26) by CNV-seq and 7.69% (2/26) by WES. This study suggested that WES could reveal more genetic risk in prenatal diagnosis of fetal bowel dilatation and has value in prenatal diagnosis to reduce birth defects.

New Interpretation of Neonatal Outcomes by Phenotypically Classified Preterm Syndrome: A Retrospective Cohort Study.

OBJECTIVE: The global aim to lower preterm birth rates has been hampered by the insufficient and incomplete understanding of its etiology, classification, and diagnosis. This study was designed to evaluate the association of phenotypically classified preterm syndromes with neonatal outcomes; to what extent would these outcomes be modified after the obstetric interventions, including use of glucocorticoid, magnesium sulfate, and progesterone. METHODS: This was a retrospective cohort study conducted at Tongji Hospital (composed of Main Branch, Optical Valley Branch and Sino-French New City Branch) in Wuhan. A total of 900 pregnant women and 1064 neonates were retrospectively enrolled. The outcomes were the distribution of different phenotypes among parturition signs and pathway to delivery, the association of phenotypically classified clusters with short-term unfavorable neonatal outcomes, and to what extent these outcomes could be modified by obstetric interventions. RESULTS: Eight clusters were identified using two-step cluster analysis, including premature rupture of fetal membranes (PPROM) phenotype, abnormal amniotic fluid (AF) phenotype, placenta previa phenotype, mixed condition phenotype, fetal distress phenotype, preeclampsia-eclampsia & hemolysis, elevated liver enzymes, and low platelets syndrome (PE-E&HELLP) phenotype, multiple fetus phenotype, and no main condition phenotype. Except for no main condition phenotype, the other phenotypes were associated with one or more complications, which conforms to the clinical practice. Compared with no main condition phenotype, some phenotypes were significantly associated with short-term adverse neonatal outcomes. Abnormal AF phenotype, mixed condition phenotype, PE-E&HELLP phenotype, and multiple fetus phenotype were risk factors for neonatal small-for gestation age (SGA); placenta previa phenotype was not associated with adverse outcomes except low APGAR score being 0-7 at one min; mixed condition phenotype was associated with low APGAR scores, SGA, mechanical ventilation, and grade HI-W intraventricular hemorrhage (IVH); fetal distress phenotype was frequently associated with neonatal SGA and mechanical ventilation; PE-E&HELLP phenotype was correlated with low APGAR score being 0-7 at one min, SGA and neonatal intensive care unit (NICU) admission; multiple fetus phenotype was not a risk factor for the outcomes included except for SGA. Not all neonates benefited from obstetric interventions included in this study. CONCLUSION: Our research disclosed the independent risk of different preterm phenotypes for adverse pregnancy outcomes. This study is devoted to putting forward the paradigm of classifying preterm birth phenotypically, with the ultimate purpose of defining preterm phenotypes based on multi-center studies and diving into the underlying mechanisms.

Interactions between ultrasonographic cervical length and placenta accreta spectrum on severe postpartum hemorrhage in women with placenta previa.

OBJECTIVE: To explore the interactions between cervical length (CL) and placenta accreta spectrum (PAS) on severe postpartum hemorrhage (SPPH) in patients with placenta previa. METHODS: A retrospective case-control study was conducted at four medical centers in China, and 588 patients with placenta previa were included. The logistic regression analysis and restricted cubic splines (RCS) were used to evaluate the association between CL and SPPH. Furthermore, the joint effect of CL and PAS on SPPH was assessed, and the additive and multiplicative interactions were calculated. RESULTS: After adjusting for potential confounders, the negative linear dose-response relationship was confirmed by RCS, and the change of odds ratio (OR) was more significant when CL was 2.5 cm or less. The risk of SPPH was significantly higher when CL of 2.5 cm or less co-existed with placenta increta/percreta than when CL of 2.5 cm less, or placenta increta/percreta existed alone (adjusted OR [aOR]CL ≤2.5cm&placenta accreta/non-PAS 3.40, 95% confidence interval [CI] 1.37-8.45; aORplacenta increta/percreta&CL >2.5cm 4.75, 95% CI 3.03-7.47; aORCL ≤2.5cm&placenta increta/percreta 14.51, 95% CI 6.08-34.64), and there might be additive interaction between CL and placenta increta/percreta on SPPH (attributable proportion due to interaction 50.7%, 95% CI 6.1%-95.3%). CONCLUSION: If CL was routinely performed during PAS evaluation, the increased OR of short CL and PAS could allow better patient preparation through counseling.

The Evaluation of Genetic Diagnosis on High-Risk Fetal CAKUT.

Background: It is challenging to make an accurate prenatal diagnosis for congenital anomalies of the kidney and urinary tract (CAKUT) because of its pathologic diversity. This study aims to evaluate the performance of whole-exome sequencing (WES) combined with karyotype analysis and copy number variations (CNVs) in diagnosing high-risk fetal CAKUT. Methods: We conducted a retrospective study on prenatal diagnoses of CAKUT in our hospital from January 2020 to April 2021. The research studied 24 high-risk fetuses with CAKUT who were scanned by ultrasonography at the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were screened for the patients and their parents by multiple approaches, including karyotype analysis, CNVs and WES, and further verified with Sanger sequencing. Results: ①We detected abnormal CNVs in 20.8% (5/24) of the fetuses but only 8.3% (2/24) fetuses had abnormal karyotypes. ②Of the 15 CAKUT fetuses, positive findings (40%) were detected by WES. Of the 9 high-risk fetuses with CAKUT (negative findings in ultrasound scan but with family history), we found abnormal variants (77.8%) through WES. Conclusion: The application of CNVs and WES showed advance in prenatal diagnosis of CAKUT and the pathogenic gene variants were detectable especially for high-risk fetuses with negative ultrasound findings on CAKUT in the preliminary study. The applied strategy could be used to improve the accuracy of prenatal diagnosis for CAKUT in the future.

Immune Deviation in the Decidua During Term and Preterm Labor.

The maternal-fetal immune disorder is considered to be an important factor of preterm birth (PTB); however, the underlying mechanism is still not fully understood. This study was designed to explore the innate and adaptive immune features in the decidua during term and preterm labor. Women delivered at term or preterm were classified into four groups: term not in labor (TNL, N=19), term in labor (TL, N=17), preterm not in labor (PNL, N=10), and preterm in labor (PIL, N=10). Decidua basalis and parietalis were collected and analyzed for macrophage subtypes (M1 and M2) as well as T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells by flow cytometry and immunohistochemistry. Our results demonstrated significantly decreased frequencies of M2 cells and elevated M1/M2 ratio in the PIL group compared to that in the PNL group in both decidua basalis and parietalis, whereas no significant differences were found between the above two groups in both sites in terms of the polarization status of Th cells. On the contrary, macrophage subsets were comparable in the TL and TNL groups, whereas elevated Th1 percentages and Th1/Th2 ratio were observed in TL women compared to that in TNL women in the decidua. Interestingly, although the frequencies and ratios of Th17 and Treg were comparable among the four groups, the Th17/Treg ratios of these groups were significantly increased in decidua basalis than that in decidua parietalis. Collectively, the M1/M2 imbalance is associated with the breakdown of maternal-fetal immune tolerance during PTB, whereas the aberrant Th1/Th2 profile plays an important role in immune disorder during term labor. Moreover, Th17/Treg deviation is more remarkable in decidua basalis than in decidua parietalis.

Systematic external evaluation of four preoperative risk prediction models for severe postpartum hemorrhage in patients with placenta previa: A multicenter retrospective study.

AIM: To compare and evaluate the validity of the existing risk prediction models for severe postpartum hemorrhage (SPPH) in patients with placenta previa. METHODS: We conducted a systematic literature review to collect the existing risk prediction models for SPPH in patients with placenta previa, and recruited patients with placenta previa who underwent cesarean section in Tongji Hospital (Wuhan, China) and 4 cooperative hospitals from January 2018 to June 2021. We defined SPPH as total blood loss ≥1500 mL or transfusion packed red blood cell ≥4 U. The risk of SPPH of each patient was predicted by the collected models, respectively. Then we calculated the sensitivity, specificity, coincidence rate (CCR), positive predictive value (PPV), negative predictive value (NPV) and drawn the receiver operating characteristic (ROC) curve and decision curve analysis (DCA) curve of each model. RESULTS: This external cohort contained 1172 patients of whom 284 patients (24.23%) experienced SPPH, and 4 risk prediction models were collected in this study. After evaluated by this external cohort, the area under the ROC curve (AUC), sensitivity, specificity, CCR, PPV and NPV of the four models ranged from 0.644 to 0.755, 38.38% to 86.31%, 42.75% to 86.49%, 56.23% to 74.83%, 38.68% to 47.60%, 81.15% to 87.45%, respectively. The model established by Kim JW et al. had the highest sensitivity, NPV, AUC and net benefit, the model established by Lee JY et al. had the highest specificity, CCR and PPV. CONCLUSIONS: The four prediction models showed moderate predictive performance, the discrimination indicators and benefit indicators of each model were not simultaneously ideal in this population. The prediction models should be further optimized to improve the discrimination ability and benefit, and prospective external validation studies should also be carried out before they are applied to clinical practice.

B cell-T cell interplay in immune regulation: A focus on follicular regulatory T and regulatory B cell functions.

B cells are the core components of humoral immunity. A mature B cell can serve in multiple capacities, including antibody production, antigen presentation, and regulatory functions. Forkhead box P3 (FoxP3)-expressing regulatory T cells (Tregs) are key players in sustaining immune tolerance and keeping inflammation in check. Mounting evidence suggests complex communications between B cells and Tregs. In this review, we summarize the yin-yang regulatory relationships between B cells and Tregs mainly from the perspectives of T follicular regulatory (Tfr) cells and regulatory B cells (Bregs). We discuss the regulatory effects of Tfr cells on B cell proliferation and the germinal center response. Additionally, we review the indispensable role of B cells in ensuring homeostatic Treg survival and describe the function of Bregs in promoting Treg responses. Finally, we introduce a new subset of Tregs, termed Treg-of-B cells, which are induced by B cells, lake the expression of FoxP3 but still own immunomodulatory effects. In this article, we also enumerate a sequence of research from clinical patients and experimental models to clarify the role of Tfr cells in germinal centers and the role of convention B cells and Bregs to Tregs in the context of different diseases. This review offers an updated overview of immunoregulatory networks and unveils potential targets for therapeutic interventions against cancer, autoimmune diseases and allograft rejection.

Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion.

Previous studies have reported the involvement of γδ T cells in recurrent spontaneous abortion (RSA); however, both pathogenic and protective effects were suggested. To interrogate the role of γδ T cells in RSA, peripheral blood from RSA patients and healthy women with or without pregnancy were analyzed for γδ T cells by flow cytometry (n = 9-11 for each group). Moreover, the decidua from pregnant RSA patients and healthy controls (RSA-P and HC-P group, respectively) was simultaneously stained for γδ T cells by immunohistochemistry (IHC) and bulk sequenced for gene expression. Our results demonstrated that the frequencies of peripheral γδ T cells and their subpopulations in RSA patients were comparable to that in healthy subjects, but the PD1 expression on Vδ2+ cells was increased in pregnant patients. Furthermore, peripheral Vδ2+ cells in RSA-P patients demonstrated significantly increased expression of CD107a, as compared to that in pregnant healthy controls. In addition, RSA-P patients had higher proportion of IL-17A-secreting but not IL-4-secreting Vδ2+ cells compared to the control groups. In decidua, an inflammatory microenvironment was also evident in RSA-P patients, in which CCL8 expression and the infiltration of certain immune cells were higher than that in the HC-P group, as revealed by transcriptional analysis. Finally, although the presence of γδ T cells in decidua could be detected during pregnancy in both RSA patients and healthy subjects by multicolor IHC analysis, the expression of CD107a on γδ T cells was markedly higher in the RSA-P group. Collectively, our results indicated that the increased activation, cytotoxicity, and inflammatory potential of peripheral and/or local γδ T cells might be responsible for the pathogenesis of RSA. These findings could provide a better understanding of the role of γδ T cells in RSA and shed light on novel treatment strategies by targeting γδ T cells for RSA patients.

Developing and Validating Nomogram to Predict Severe Postpartum Hemorrhage in Women With Placenta Previa Undergoing Cesarean Delivery: A Multicenter Retrospective Case-Control Study.

OBJECTIVE: Developing and validating nomogram to predict severe postpartum hemorrhage (SPPH) in women with placenta previa (PP) undergoing cesarean delivery. METHODS: We conducted a multicenter retrospective case-control study in five hospitals. In this study, 865 patients from January, 2018 to June, 2020 were enrolled in the development cohort, and 307 patients from July, 2020 to June, 2021 were enrolled in the validation cohort. Independent risk factors for SPPH were obtained by using the multivariate logistic regression, and preoperative nomogram and intraoperative nomogram were developed, respectively. We compared the discrimination, calibration, and net benefit of the two nomograms in the development cohort and validation cohort. Then, we tested whether the intraoperative nomogram could be used before operation. RESULTS: There were 204 patients (23.58%) in development cohort and 80 patients (26.06%) in validation cohort experienced SPPH. In development cohort, the areas under the receiver operating characteristic (ROC) curve (AUC) of the preoperative nomogram and intraoperative nomogram were 0.831 (95% CI, 0.804, 0.855) and 0.880 (95% CI, 0.854, 0.905), respectively. In validation cohort, the AUC of the preoperative nomogram and intraoperative nomogram were 0.825 (95% CI, 0.772, 0.877) and 0.853 (95% CI, 0.808, 0.898), respectively. In the validation cohort, the AUC was 0.839 (95% CI, 0.789, 0.888) when the intraoperative nomogram was used before operation. CONCLUSION: We developed the preoperative nomogram and intraoperative nomogram to predict the risk of SPPH in women with PP undergoing cesarean delivery. By comparing the discrimination, calibration, and net benefit of the two nomograms in the development cohort and validation cohort, we think that the intraoperative nomogram performed better. Moreover, application of the intraoperative nomogram before operation can still achieve good prediction effect, which can be improved if the severity of placenta accreta spectrum (PAS) can be accurately distinguished preoperatively. We expect to conduct further prospective external validation studies on the intraoperative nomogram to evaluate its application value.

Epidural analgesia during labor and its optimal initiation time-points: A real-world study on 400 Chinese nulliparas.

ABSTRACT: Recent research has suggested that 6 cm of cervical dilation should be the threshold for the active labor phase, and it has confirmed that epidural analgesia (EA) is a safe method of pain relief during labor. However, the evidence provided for these findings comes mainly from randomized controlled clinical trials (RCTs), which suffer from the limitation of real-world generalizability.To test the generalizability of the conclusions from these previous RCTs, we conducted a prospective cohort, real-world study (RWS) on 400 Chinese term nulliparas. A total of 200 of the participants (the EA group) received EA upon request. The participants in the EA group were further subdivided as follows according to their cervical dilation when the EA administration was initiated (CDE): [EA1 group (CDE < 3 cm), EA2 group (3 cm ≤ CDE < 6 cm), and EA3 group (CDE ≥ 6 cm)]. We compared the labor duration of the EA group versus the non-EA (NEA) group, and the NEA group versus the 3 EA subgroups. We also compared delivery outcomes between the EA and NEA groups.The median total labor duration for the EA group [676 (511-923) minutes] was significantly longer than that of the NEA group [514 (373-721) minutes] (P < 0.001). The median durations of both the first- and second-stages of labor for the EA group [600 (405-855) minutes, 68 (49-97) minutes] were longer than those of the NEA group [420 (300-630) minutes, 50 (32-85) minutes] (P < .001, P < .001)]. In addition, the median total labor durations in both the EA1 [720 (548-958) minutes] and EA2 groups [688 (534-926) minutes] were longer than in the NEA group (P < .001 and P < .001, respectively), and the first- and second-stage labor durations of these subgroups were similar to their total labor durations. A Cox regression analysis showed that EA was associated with longer first-stage labor [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.42-0.71, P < .001] and longer second-stage labor (HR 0.66, 95% CI 0.51-0.85, P = .001). The delivery modes and neonatal outcomes between the EA and NEA groups were not statistically different, however.Our findings suggest that EA administered before a cervical dilation of 6 cm may be associated with longer total, first-, and second-stage labor durations compared with no EA, while later EA administration is not. In addition, though EA prolongs labor duration, it does not impact delivery outcomes. These results confirm the significance of a 6 cm cervical dilation threshold in real-world labor settings.

Sex-specific associations of prenatal exposure to bisphenol A and its alternatives with fetal growth parameters and gestational age.

BACKGROUND: Bisphenol A (BPA) can cause detrimental effects on fetal growth. However, the effects of BPA alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), on fetal growth are less known. OBJECTIVE: To investigate the relationships of prenatal BPA, BPF, and BPS exposures with fetal growth parameters and gestational age. METHODS: Urinary BPA, BPF, and BPS were measured in 1,197 pregnant women before delivery in a Chinese cohort. The associations of prenatal exposure to BPA, BPF, and BPS with fetal growth parameters and gestational age were examined, and associations stratified by fetal sex were also conducted. We used a restricted cubic splines (RCS) model to examine the dose-response associations between exposures and outcomes. RESULTS: Maternal urinary BPA and BPF were negatively related to birth length (-0.30 cm, 95% CI: -0.44, -0.15 and -0.21 cm, 95% CI: -0.36, -0.07 comparing the extreme exposure groups, respectively, both p for trends < 0.01). These associations were more pronounced in girls with inverted U-shaped dose-response relationships. Maternal urinary BPA and BPF were positively related to ponderal index (0.05 g/cm3 × 100, 95% CI: 0.01, 0.09 and 0.04 g/cm3 × 100, 95% CI: 0.01, 0.08 comparing the extreme exposure groups, respectively, both p for trends = 0.02), and maternal urinary BPS was associated with shorter gestational age (-0.20 weeks, 95% CI: -0.37, -0.03 comparing the extreme exposure groups, p for trend = 0.02). These associations were only observed in girls and exhibited a linear dose-response relationship. CONCLUSIONS: Prenatal BPA, BPF, and BPS exposures were associated with detrimental effects on fetal growth parameters, and stronger effects were noted in female infants.