Prenatal Maternal Bereavement and Its Association With Intellectual Disability in the Offspring.

OBJECTIVE: This study aimed to examine the association of a mother's loss of a close relative before or during pregnancy with intellectual disability (ID) in the offspring. METHODS: We performed a nationwide population-based cohort study based on Danish national registries. All live-born singletons born in Denmark during the 1978-2016 period (n = 2,216,601) were followed up starting from birth to 38 years of age. Log-linear Poisson regression was used to estimate the association between maternal bereavement (the death of an older child, a partner, or a parent 1 year before or during pregnancy) and the risk of ID in the offspring. RESULTS: Maternal bereavement during or before pregnancy was associated with an increased risk of ID (incidence rate ratio [IRR] = 1.15; 95% confidence interval [CI] = 1.04-1.28). The risk of ID was increased by 27% when maternal bereavement occurred during pregnancy (IRR = 1.27; 95% CI = 1.08-1.49). When stratifying on the child's sex, we also observed an increased risk of ID associated with maternal bereavement during pregnancy both for male (IRR = 1.25; 95% CI = 1.02-1.53) and for female (IRR = 1.31; 95% CI = 1.02-1.69), respectively. The IRRs for unnatural death of a relative were also elevated (IRR = 1.22; 95% CI = 0.91-1.64) in general, although the difference was not statistically significant. CONCLUSIONS: Our findings suggest that prenatal stress due to maternal loss of a close relative may increase the risk of offspring's ID of both sexes, in particular when the loss happened during pregnancy.

Clinical Value of Predicting Individual Treatment Effects for Intensive Blood Pressure Therapy.

BACKGROUND: The absolute risk reduction (ARR) in cardiovascular events from therapy is generally assumed to be proportional to baseline risk-such that high-risk patients benefit most. Yet newer analyses have proposed using randomized trial data to develop models that estimate individual treatment effects. We tested 2 hypotheses: first, that models of individual treatment effects would reveal that benefit from intensive blood pressure therapy is proportional to baseline risk; and second, that a machine learning approach designed to predict heterogeneous treatment effects-the X-learner meta-algorithm-is equivalent to a conventional logistic regression approach. METHODS AND RESULTS: We compared conventional logistic regression to the X-learner approach for prediction of 3-year cardiovascular disease event risk reduction from intensive (target systolic blood pressure <120 mm Hg) versus standard (target <140 mm Hg) blood pressure treatment, using individual participant data from the SPRINT (Systolic Blood Pressure Intervention Trial; N=9361) and ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure; N=4733) trials. Each model incorporated 17 covariates, an indicator for treatment arm, and interaction terms between covariates and treatment. Logistic regression had lower C statistic for benefit than the X-learner (0.51 [95% CI, 0.49-0.53] versus 0.60 [95% CI, 0.58-0.63], respectively). Following the logistic regression's recommendation for individualized therapy produced restricted mean time until cardiovascular disease event of 1065.47 days (95% CI, 1061.04-1069.35), while following the X-learner's recommendation improved mean time until cardiovascular disease event to 1068.71 days (95% CI, 1065.42-1072.08). Calibration was worse for logistic regression; it over-estimated ARR attributable to intensive treatment (slope between predicted and observed ARR of 0.73 [95% CI, 0.30-1.14] versus 1.06 [95% CI, 0.74-1.32] for the X-learner, compared with the ideal of 1). Predicted ARRs using logistic regression were generally proportional to baseline pretreatment cardiovascular risk, whereas the X-learner observed-correctly-that individual treatment effects were often not proportional to baseline risk. CONCLUSIONS: Predictions for individual treatment effects from trial data reveal that patients may experience ARRs not simply proportional to baseline cardiovascular disease risk. Machine learning methods may improve discrimination and calibration of individualized treatment effect estimates from clinical trial data. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01206062; NCT00000620.

Association between isolated hypothyroxinaemia in early pregnancy and perinatal outcomes.

BACKGROUND: The effect of isolated maternal hypothyroxinaemia (IMH) on pregnancy complications and neonatal outcomes in human beings is still controversial. METHODS: This was a retrospective cohort study based on the electronic medical register system. The records of women with a singleton pregnancy who sought antenatal examination between January 2014 and December 2015 at Shanghai First Maternity and Infant Hospital were extracted from the electronic medical records system. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and anti-thyroperoxidase autoantibody (TPO-Ab) was measured before 20 gestational weeks, and a multiple logistic regression model was used to estimate the odds ratios of pregnancy complications and neonatal outcomes between euthyroid women and those with isolated hypothyroxinaemia. RESULTS: A total of 8173 women were included in this study, of whom 342 (4.18%) were diagnosed with IMH. Regression analysis showed that IMH diagnosed in the second trimester (13-20 weeks) was associated with an increased risk of hypertensive disorders of pregnancy (OR = 2.66, 95% CI: 1.38-5.10) and placenta abruption (OR = 3.64, 95% CI: 1.07-12.41), but not with preterm delivery (OR = 1.09, 95% CI: 0.50-2.40), small or large gestational age of infant (OR = 0.91, 95% CI: 0.39-2.12; OR = 1.16, 95% CI: 0.72-1.86), macrosomia (OR = 1.71, 95% CI: 0.95-3.07), gestational diabetes mellitus (OR = 1.36, 95% CI: 0.86-2.15) and placenta previa (OR = 1.62, 95% CI: 0.39-7.37). CONCLUSION: IMH could be a risk factor for hypertensive disorders of pregnancy.

Deep learning for chest radiograph diagnosis: A retrospective comparison of the CheXNeXt algorithm to practicing radiologists.

BACKGROUND: Chest radiograph interpretation is critical for the detection of thoracic diseases, including tuberculosis and lung cancer, which affect millions of people worldwide each year. This time-consuming task typically requires expert radiologists to read the images, leading to fatigue-based diagnostic error and lack of diagnostic expertise in areas of the world where radiologists are not available. Recently, deep learning approaches have been able to achieve expert-level performance in medical image interpretation tasks, powered by large network architectures and fueled by the emergence of large labeled datasets. The purpose of this study is to investigate the performance of a deep learning algorithm on the detection of pathologies in chest radiographs compared with practicing radiologists. METHODS AND FINDINGS: We developed CheXNeXt, a convolutional neural network to concurrently detect the presence of 14 different pathologies, including pneumonia, pleural effusion, pulmonary masses, and nodules in frontal-view chest radiographs. CheXNeXt was trained and internally validated on the ChestX-ray8 dataset, with a held-out validation set consisting of 420 images, sampled to contain at least 50 cases of each of the original pathology labels. On this validation set, the majority vote of a panel of 3 board-certified cardiothoracic specialist radiologists served as reference standard. We compared CheXNeXt's discriminative performance on the validation set to the performance of 9 radiologists using the area under the receiver operating characteristic curve (AUC). The radiologists included 6 board-certified radiologists (average experience 12 years, range 4-28 years) and 3 senior radiology residents, from 3 academic institutions. We found that CheXNeXt achieved radiologist-level performance on 11 pathologies and did not achieve radiologist-level performance on 3 pathologies. The radiologists achieved statistically significantly higher AUC performance on cardiomegaly, emphysema, and hiatal hernia, with AUCs of 0.888 (95% confidence interval [CI] 0.863-0.910), 0.911 (95% CI 0.866-0.947), and 0.985 (95% CI 0.974-0.991), respectively, whereas CheXNeXt's AUCs were 0.831 (95% CI 0.790-0.870), 0.704 (95% CI 0.567-0.833), and 0.851 (95% CI 0.785-0.909), respectively. CheXNeXt performed better than radiologists in detecting atelectasis, with an AUC of 0.862 (95% CI 0.825-0.895), statistically significantly higher than radiologists' AUC of 0.808 (95% CI 0.777-0.838); there were no statistically significant differences in AUCs for the other 10 pathologies. The average time to interpret the 420 images in the validation set was substantially longer for the radiologists (240 minutes) than for CheXNeXt (1.5 minutes). The main limitations of our study are that neither CheXNeXt nor the radiologists were permitted to use patient history or review prior examinations and that evaluation was limited to a dataset from a single institution. CONCLUSIONS: In this study, we developed and validated a deep learning algorithm that classified clinically important abnormalities in chest radiographs at a performance level comparable to practicing radiologists. Once tested prospectively in clinical settings, the algorithm could have the potential to expand patient access to chest radiograph diagnostics.

Term Delivery in a Woman with Severe Uterine Dehiscence After a Previous Cesarean Section: A Case Report.

Background: Cesarean section is the most frequently performed obstetrics operation. It can be associated with short- and long-term risks, one of which is uterine scar dehiscence. Women with uterine scar dehiscence often fear pregnancy because they are advised it may increase the risk of uterine rupture. It is generally recommended that women undergo transvaginal or laparoscopic repair of the uterine dehiscence before any future pregnancies. Case: A 32-year-old woman with a previous transverse lower-segment cesarean section complicated by severe uterine dehiscence, diagnosed by MRI before pregnancy, was treated with expectant management during a subsequent pregnancy. She was asymptomatic during pregnancy until term delivery with expectant management. Conclusion: We recommend that patients with severe uterine dehiscence undergo transvaginal or laparoscopic repair before attempting another pregnancy. However, if they become pregnant without repair of the dehiscence, they can be managed conservatively with routine surveillance and intermittent monitoring by ultrasound to term unless there is an emergency.

MiR-495 suppresses mesendoderm differentiation of mouse embryonic stem cells via the direct targeting of Dnmt3a.

Embryonic stem cells (ESCs) are promising resources for clinical therapies due to their potential to generate multiple cell types. The dynamic expression of de novo methyltransferases (Dnmt3a and Dnmt3b) is essential to ESCs; however, the regulatory mechanism of Dnmt3a or Dnmt3b expression in ESCs is still poorly understood. Here, we reported that decreased expression of microRNA-495 (miR-495) in the first 2days of embryoid body (EB) formation was required for mouse embryonic stem cell (mESC) differentiation because repressed mesoderm and endoderm lineages were detected in ectopic miR-495 expression mESCs. This effect was reversed by the function blockade of miR-495. We identified Dnmt3a as a functional target of miR-495 and showed that endogenous miR-495 repressed the expression of Dnmt3a in mESCs. Furthermore, the effect of miR-495 on mESCs could be eliminated by Dnmt3a overexpression. Moreover, miR-495 had no effect on the expression of Dnmt3b despite the findings obtained from previous studies that mainly focused on the common characteristics of the regulatory mechanisms of Dnmt3a and Dnmt3b expression. Thus, our studies not only uncovered a previously uncharacterized function of miR-495 in mESC differentiation but also generated a new idea to explore the mechanisms governing the functional difference between Dnmt3a and Dnmt3b.

Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas.

BACKGROUND/AIMS: In this study, a subpopulation of stem-like cells in human high grade serous ovarian carcinomas (ovarian cancer stem cells; OCSCs) were isolated and characterized. METHODS: Primary high-grade serous ovarian carcinoma (HGSC) fresh biopsies were cultured under serum-free conditions to produce floating spheres. Sphere formation assay, including self-renewal, differentiation potential, chemo-resistance, and tumorigenicity were determined in vitro or in vivo. RESULTS: OCSCs overexpressed stem cell genes (Oct-4, Nanog, Sox-2, Bmi-1, Nestin, CD133, CD44, CD24, ALDH1, CD117, and ABCG2). Immunostaining of spheres showed overexpressed Oct-4, Nanog, and Sox-2. These isolated tumor cells expanded as spheroid colonies for more than 30 passages. In contrast, adherent cells expressed high levels of CA125 and CK7. Flow cytometry analysis showed increased CSC markers (CD44, CD24, CD117, CD133, ABCG2, and ALDH1) in the spheroid cell population. OCSCs displayed higher chemoresistance to cisplatin or paclitaxel compared to adherent cells. Moreover, subcutaneous injection of 1 × 104 sphere-forming cells into NOD/SCID mice gave rise to new tumors similar to the original human tumors and could be passaged in mice. CONCLUSION: These results revealed that HGSCs are created and propagated by a small number of undifferentiated tumorigenic cells, and therapeutic targeting of these cells could be beneficial for treatment of HGSCs.

Uterine massage to reduce blood loss after vaginal delivery: a randomized controlled trial.

OBJECTIVE: To evaluate whether sustained transabdominal uterine massage can reduce blood loss after vaginal delivery. METHODS: In this multicenter randomized controlled trial, eligible women who had delivered vaginally were randomly assigned to receive 10 units oxytocin intramuscularly immediately after delivery of the shoulder plus 30 minutes of sustained transabdominal uterine massage after delivery of the placenta or to 10 units oxytocin intramuscularly alone. The primary outcome was blood loss of 400 mL or more in the 2 hours after delivery of the neonate. Secondary outcomes included blood loss of 1,000 mL or more, blood loss in the 2 hours after delivery, use of therapeutic uterotonics or other hemostatic procedures, hemoglobin of lower than 80 g/L before discharge, and need for blood transfusion. Analysis was by intent to treat. With a one-sided α of 0.05 and a power of 0.8, a sample size of 1,061 women per group was calculated to detect a 3% absolute decrease in the primary outcome. RESULTS: Of 2,340 eligible women, 1,170 were randomized to oxytocin plus uterine massage and 1,170 to the oxytocin-only group. Baseline characteristics were similar in both groups. The incidence of blood loss of 400 mL or more in the 2 hours after delivery was not significantly different between the two groups (143/1,170 [12.2%] compared with 144/1,170 [12.3%]; relative risk 0.99, 95% confidence interval 0.88-1.13) according to intent-to-treat analysis with a power of more than 0.8. No significant differences were found in the secondary outcomes. CONCLUSION: In patients delivered vaginally, transabdominal uterine massage after delivery of the placenta in addition to oxytocin does not reduce blood loss when compared with administration of oxytocin alone. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, www.chictr.org, ChiCTR-TRC-11001763. LEVEL OF EVIDENCE: I.

Possible role of the 'IDO-AhR axis' in maternal-foetal tolerance.

The induction and maintenance of immunologic tolerance at the feto-maternal interface is necessary for a successful pregnancy. The most accepted hypothesis for the mechanism underlying this tolerance is that pregnancy-induced foetal antigen-specific maternal T regulatory (T(reg) ) cells mediate maternal tolerance to the foetus. The aryl hydrocarbon receptor (AhR), which is highly expressed in the placenta, is widely studied in female reproductive biology and immunology. Activation of AhR can promote immune tolerance by controlling the differentiation of T(reg) cells in some autoimmune disorders. However, the specific mechanisms underlying tolerance are poorly understood. Indoleamine 2,3-dioxygenase (IDO) is the initial and rate-limiting enzyme of tryptophan catabolism in human placental trophoblasts. IDO produces kynurenine, an endogenous AhR ligand that directly activates AhR and is proposed to be central to the establishment and maintenance of immunologic tolerance at the maternal-foetal interface. We propose that kynurenine activates AhR, leading to the AhR-dependent T(reg) cells generation, which in turn critically regulates immunological tolerance at the feto-maternal interface. This hypothesis must be tested and the proof of this hypothesis may provide a potential therapeutic target for the treatment of infertility and other adverse pregnancy outcomes resulted from inadequate immunological tolerance at the feto-maternal interface.

Application of a NotI subtraction and methylation­specific genome subtractive hybridization technique in the detection of genomic DNA methylation differences between hydatidiform moles and villi.

Previous studies indicate that epigenetic modifications play an important role in transcriptional regulation and contribute to the pathogenesis of gestational trophoblastic disease, including complete hydatidiform moles (CHMs). However, the underlying mechanisms and the critical genes have not been clearly identified. In the present study, we developed a novel technique, NotI subtraction and methylation-specific genome subtractive hybridization (MS-G-SH), as a method of screening for methylation changes between hydatidiform moles and villi. Following NotI subtraction and hybridization, three different positive DNA clones were found in 110 random clones of DNA samples. Most importantly, two DNA clones having long CpG islands and high homology with exons of insulin-like growth factor 2 (IGF2) and transforming growth factor-ß (TGF-ß) were identified using bioinformatic tools. After bisulfite treatment and methylation-specific PCR, the specific methylation of certain exons of IGF2 and TGF-ß was identified. In addition, the mRNA expression levels of these two genes were markedly different. In conclusion, this novel MS-G-SH technique is an alternative and effective approach for the detection of specific DNA methylation.

Retinoic acid regulates germ cell differentiation in mouse embryonic stem cells through a Smad-dependent pathway.

Murine embryonic stem cells (ESCs) are pluripotent cells that differentiate into multiple cell lineages. It was recently observed that all-trans retinoic acid (RA) provides instructive signals for the commitment of the germ cell lineage from ESCs. However, little is known about the molecular mechanisms by which RA signals lead to germ cell commitment. In this study, we determined if RA induced ESC differentiation to the germ lineage through modulation of the (bone morphogenetic protein) BMP/Smad pathway activity. In a monolayer culture, RA significantly induced both the expression of the early germ-specific genes, Stra8, Dazl and Mvh, and prolonged activation of Smad1/5 (for at least 24h). Meanwhile, dorsomorphin (a BMP-Smad1/5 specific inhibitor) significantly reduced the RA-induced germ-specific gene expression and completely blocked the RA-induced activation of Smad1/5. Moreover, RA-induced germ-specific gene expression was significantly increased by treatment with the potential activator of Smad1/5, SB431542. Furthermore, the biochemical manipulation of Smad1/5 expression through shRNA knockdown significantly reduced RA-mediated up-regulation of germ-specific gene expression. Our results clearly demonstrate that the Smad1/5 pathway is specifically required at an early stage of germ cell differentiation, corresponding to the RA-dependent commitment of ESCs.

The possible role of AhR in the protective effects of cigarette smoke on preeclampsia.

Although smoking during pregnancy may lead to many adverse effects, such as fetal growth restriction, placental abruption, stillbirth, and preterm labor, smoking is the only environmental exposure known to consistently reduce the risk of preeclampsia and gestational hypertension. The exact mechanisms through which cigarette smoke reduces the risk of preeclampsia are not yet understood. Aryl hydrocarbon receptor (AhR), as the most abundant expression protein in the placenta, was widely studied in the human reproduction. We propose that cigarette smoke decreases the risk of developing preeclampsia via direct activation of AhR system in placenta. In this review we will address, and provide evidence for, our specific hypotheses that: cigarette significantly enhance trophoblast invasion and decrease placental oxidative damage through activation of AhR. This mechanism of suppression must be further investigated as they may provide valuable clues to novel therapeutic design in the realm of preeclampsia research.

Quantitative fluorescent polymerase chain reaction to detect chromosomal anomalies in spontaneous abortion.

OBJECTIVES: To evaluate the value of short tandem repeats (microsatellites) in the study of numerical chromosomal anomalies in spontaneous abortion. METHOD: Multiplex quantitative fluorescent polymerase chain reaction (QF-PCR) was carried out on 61 spontaneous abortion samples and 48 controls using microsatellite markers from 8 chromosomes where aneuploids are commonly found. RESULTS: Of the 61 samples, 65.6% were successfully karyotyped, and the call rate of the QF-PCR was 98.3%. The correspondence between PCR and karyotyping was 95%. The success rate of karyotyping in the inevitable abortion group was 79.6%, higher than for the missed abortion group (8.3%), P<0.001. The call rate of QF-PCR showed no difference between these 2 groups (100% vs 91.7%, P=0.197). CONCLUSION: Microsatellite-based QF-PCR is a helpful and reliable tool to diagnose numerical chromosomal anomalies in spontaneous abortion. It also provides a diagnosis for necrotic tissue.