Transcutaneous Discrimination of Fetal Heart Rate from Maternal Heart Rate: A Fetal Oximetry Proof-of-Concept.

Intrapartum care uses electronic fetal heart rate monitoring (EFHRM) for over 50 years to indirectly assess fetal oxygenation. However, this approach has been associated with an increase in cesarean delivery rates and limited improvements in neonatal hypoxic outcome. To address these shortcomings, a novel transabdominal fetal pulse oximeter (TFO) is being developed to provide an objective measurement of fetal oxygenation. Previous studies have evaluated the performance of TFO on pregnant ewe. Building on the animal model, this study aims to determine whether TFO can successfully capture human fetal heart rate (FHR) signals during non-stress testing (NST) as a proof-of-concept. Eight ongoing pregnancies meeting specific inclusion criteria (18-40 years old, singleton, and at least 36 weeks' gestation) were enrolled with consent. Each study session was 15 to 20 min long. Reference maternal heart rate (MHR) and FHR were obtained using finger pulse oximetry and cardiotocography for subsequent comparison. The overall root-mean-square error was 9.7BPM for FHR and 4.4 for MHR, while the overall mean-absolute error was 7.6BPM for FHR and 1.8 for MHR. Bland-Altman analysis displayed a mean bias ± standard deviation between TFO and reference of -3.9 ± 8.9BPM, with limits of agreement ranging from -21.4 to 13.6 BPM. Both maternal and fetal heart rate measurements obtained from TFO exhibited a p-value < 0.001, showing significant correlation with the reference. This proof-of-concept study successfully demonstrates that TFO can accurately differentiate maternal and fetal heart signals in human subjects. This achievement marks the initial step towards enabling fetal oxygen saturation measurement in humans using TFO.

Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy.

Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.

Positive predictive value of a single nucleotide polymorphism (SNP)-based NIPT for aneuploidy in twins: Experience from clinical practice.

OBJECTIVE: Twins account for approximately 1 in 30 live births in the United States. However, there are limited clinical experience studies published in noninvasive prenatal testing (NIPT) for detecting aneuploidies in twins. This study reports the performance of an SNP-based NIPT in the largest cohort with known outcomes for high-risk aneuploidy results. METHOD: This is a retrospective analysis of 18,984 results from commercial single-nucleotide polymorphism (SNP)-based NIPT tests performed in twins between October 2, 2017 and December 31, 2019. Follow-up for all 211 high-risk cases was solicited. RESULTS: Follow-up outcomes were obtained in 105 cases. Positive predictive values (PPVs) for high-risk results were 88.7% (63/71, 95% Confidence Interval [CI]: 79.0%-95.0%) for trisomy 21% and 72.7% (8/11, 95% CI: 39.0%-94.0%) for trisomy 18. The results were stratified into monozygotic (MZ) and dizygotic (DZ). The PPVs in MZ were 100% for both trisomy 21 (4/4, 95% CI: 40%-100%) and trisomy 18 (1/1, 95% CI: 2.5%-100%). No trisomy 13 cases were detected in the MZ group. The PPVs in DZ were 88.1% (59/67, 95% CI: 77.8%-94.7%), 70.0% (7/10, 95% CI: 34.8%-93.3%), and 66.7% (2/3, 95% CI: 9.4%-99.2%) for trisomy 21, trisomy 18, and trisomy 13, respectively. CONCLUSION: The performance of SNP-based NIPT in this large twin cohort was comparable to previously reported twin NIPT studies. SNP-based NIPT allows for zygosity-based PPV assessment.

Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation.

OBJECTIVE: This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation. STUDY DESIGN: Retrospective discovery and longitudinal confirmation. SETTING: Maternity units from two US hospitals. PARTICIPANTS: Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation. OUTCOME MEASURES: Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays. RESULTS: Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks' gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation. CONCLUSIONS: Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Obstetrical and perinatal outcomes of patients with methamphetamine-positive drug screen on labor and delivery.

BACKGROUND: The incidence of methamphetamine use in reproductive-age women across the United States is increasing. The existing literature on methamphetamine use in pregnancy has indicated an elevated risk of adverse maternal and neonatal health outcomes. OBJECTIVE: This study aimed to investigate pregnancy outcomes in patients with recent methamphetamine use compared with patients who received negative test results for methamphetamine at the time of delivery. STUDY DESIGN: A single-site retrospective cohort study from January to December 2015 was performed. Patients with a documented urine drug screen during the delivery encounter were identified from the electronic medical records. The outcomes of patients with methamphetamine-positive urine drug screens were compared with controls with urine drug screens negative for methamphetamine. Maternal outcomes of interest included placental abruption, hypertensive disorders, premature preterm rupture of membranes, postpartum hemorrhage, and preterm birth. Utilization of prenatal care, social work consults, and child protective services referrals were also recorded. Neonatal outcomes included birthweight, neonatal intensive care unit length of stay, Apgar scores, and perinatal mortality. RESULTS: The 2 groups had similar demographic characteristics (age, multiparity, ethnicity), with the methamphetamine-positive group more likely to have no or limited prenatal care. Both groups engaged in polysubstance use. A methamphetamine-positive urine drug screen at the time of delivery carries an increased risk of abruption (odds ratio, 5.63; confidence interval, 1.21-26.21) but indicated no increased risk of maternal hypertensive disorders. Additional associated risks include preterm birth (odds ratio, 3.10; confidence interval, 1.44-6.68), lower Apgar scores at 1 and 5 minutes (P=.012 and P=.02, respectively), and increased perinatal mortality (odds ratio, 6.9; confidence interval, 1.01-47.4). CONCLUSION: Positive urine drug testing for methamphetamines during labor admission confers considerable maternal and perinatal morbidity and mortality including an increased risk of placental abruption, preterm birth, and perinatal demise. Given the limited treatments for methamphetamine addiction, further research is urgently needed.

Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US.

OBJECTIVES: The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision. STUDY DESIGN: A retrospective cohort study. SETTING: Two medical centres from the USA. PARTICIPANTS: Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms. OUTCOME MEASURES: Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry. RESULTS: A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1 week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=-0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively. CONCLUSIONS: In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.

Large and Dense Organic-Inorganic Hybrid Perovskite CH3NH3PbI3 Wafer Fabricated by One-Step Reactive Direct Wafer Production with High X-ray Sensitivity.

Lead halide perovskites with good optoelectronic properties and high attenuation of high-energy radiation are great candidates for X-ray radiation detectors. Large area, dense, and thick films or wafers are a prerequisite for these applications. In this paper, a one-step heat-assisted high-pressure press method is developed to directly prepare a large (the largest has a diameter of 80 mm) and thickness- and shape-controlled phase-pure organic-inorganic hybrid CH3NH3PbI3 wafer of densely packed large microcrystals from raw powder materials. Meanwhile, this method uses no solvent to achieve essentially 100% material utilization. The obtained wafers show good ambipolar carrier mobilities of ∼20 cm2 V-1 s-1 and a µτ product as high as 3.84 × 10-4 cm2 V-1. Under an X-ray source using an acceleration voltage of 40 kV, the perovskite wafer-based X-ray detector shows an X-ray sensitivity as large as 1.22 × 105 µC Gyair-1 cm-2 under a 10 V bias, the highest reported for any perovskite material. The method provides a convenient strategy for producing large perovskite wafers with good optoelectronic properties, which will facilitate the development of large perovskite devices.

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia.

BACKGROUND: Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms. METHODS: Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice. RESULTS: An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs. CONCLUSIONS: Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

Significance of manganese resistant bacillus cereus strain WSE01 as a bioinoculant for promotion of plant growth and manganese accumulation in Myriophyllum verticillatum.

Endophytic bacteria are generally helpful for plant growth and protection. Strain WSE01, which was identified as bacillus cereus, was isolated from the stem of Myriophyllum verticillatum and it displayed a high tolerance to Mn (1500 mg/L). The strain was found to be able to produce indole-3-acetic acid (IAA) and siderophores, fix the atmospheric nitrogen and dissolve potassium from insoluble K-bearing minerals. In hydroponic culture experiments, the inoculation of strain WSE01 significantly promoted the growth and increased the leaf enzyme activity in the inoculated plant M. verticillatum. Furthermore, the manganese content was increased by 36.4% in stems and by 54.7% in leaves of the inoculated plant under Mn stress at 400 mg/L, compared to the non-inoculated group. This study suggests that the strain WSE01 has the potential to be used as biocontrol and/or biofertilizing agents for application in macrophyte M. verticillatum and conduces to achieving more effective phytoremediation of metal-contaminated waters.

Emerging pollutants in water environment: Occurrence, monitoring, fate, and risk assessment.

The occurrence of emerging pollutants (EPs) is continuously reported worldwide. Nevertheless, only few of these compounds are toxicologically evaluated due to their vast numbers. Reliable analytical methods and toxicity assessment methods are the basis of either the management or the elimination of EPs. In this paper, literature published in 2018 on EPs were reviewed with special regard to their occurrence, detection methods, fate in the environment, and ecological toxicity assessment. Particular focus was placed on practical considerations, novel processes, and new solution strategies. PRACTITIONER POINTS: Literature published in 2018 on emerging pollutants were reviewed. This review article is with special regard to the occurrence, detection methods, fate and toxicity assessment of emerging pollutants. Particular focus was placed on practical considerations, novel processes and new solution strategies.

Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.

Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.

Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78.

Patients with ovarian cancer are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane ((mem)GRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied the effects of ascites on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased (mem)GRP78 levels compared with ID8 cells from normal culture. We hypothesized that these ascites-associated (mem)GRP78(+) cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that (mem)GRP78(+) cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared with (mem)GRP78(-) cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more (mem)GRP78 and increased self-renewing ability compared with those cultured in medium alone. Moreover, compared with their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: (i) reduce self-renewing ability of murine and human ovarian cancer cells preincubated with ascites and (ii) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that (mem)GRP78 is a logical therapeutic target for late-stage ovarian cancer.

Changes in oligosaccharide chains of autoantibodies to GRP78 expressed during progression of malignant melanoma stimulate melanoma cell growth and survival.

A correlation between expression of the glucose-regulated protein of 78 kDa (GRP78) in malignant melanoma tumors and poor patient survival is well established. In this study, in addition to demonstrating the expression of GRP78 in tumor tissue, we investigated the immune response against GRP78 in a group of patients with different progression stages of malignant melanoma. Furthermore, we analyzed the glycosylation status of GRP78 immunoglobulin (Ig) G autoantibodies at these stages and evaluated their capacities to affect the protein B-dependent protein kinase signaling pathway and unfolded protein response signaling mechanisms, all known to promote malignant melanoma cell proliferation and survival. We found that progression of disease correlates not only with enhanced expression of GRP78 in the tumor but also with an increase in GRP78 autoantibody serum titers in these patients. We also found that the glycosylation status of anti-GRP78 IgG changes as the disease progresses. The anti-GRP78 IgG is abnormally glycosylated in the Fc region and asymmetrically glycosylated in the Fab region. We demonstrate that hyperglycosylated anti-GRP78 IgGs stimulate cell proliferation through protein B-dependent protein kinase signaling pathways. They also mimic the effects of α2-macroglobulin on the upregulation of GRP78 and X-box binding protein 1, activating transcription factor 6 α, and serine/threonine-protein kinase/endoribonuclease precursor α as endoplasmic reticulum stress biomarkers and show no effect on expression or activation of caspases 3, 9, or 12. In conclusion, the anti-GRP78 IgG autoantibodies downregulate apoptosis and activate unfolded protein response mechanisms, which are essential to promote melanoma cell growth and survival.