A sustained decrease in the systolic/diastolic ratio may be a sign of severe adverse events in the umbilical cord: a report of eight cases.

A high systolic/diastolic (S/D) ratio of umbilical cord blood is a manifestation of intrauterine hypoxia. However, the clinical significance of a persistently decreased S/D ratio of umbilical cord blood has not been reported. We report eight cases of a persistently decreased S/D ratio of umbilical cord blood, with two cases of umbilical thrombus, five cases of excessive torsion, and one case of a true cord knot. Fetuses with a persistently decreased S/D ratio of umbilical cord blood may be at risk, and it may be an important indication of umbilical cord lesions.

Machine learning on cardiotocography data to classify fetal outcomes: A scoping review.

INTRODUCTION: Uterine contractions during labour constrict maternal blood flow and oxygen delivery to the developing baby, causing transient hypoxia. While most babies are physiologically adapted to withstand such intrapartum hypoxia, those exposed to severe hypoxia or with poor physiological reserves may experience neurological injury or death during labour. Cardiotocography (CTG) monitoring was developed to identify babies at risk of hypoxia by detecting changes in fetal heart rate (FHR) patterns. CTG monitoring is in widespread use in intrapartum care for the detection of fetal hypoxia, but the clinical utility is limited by a relatively poor positive predictive value (PPV) of an abnormal CTG and significant inter and intra observer variability in CTG interpretation. Clinical risk and human factors may impact the quality of CTG interpretation. Misclassification of CTG traces may lead to both under-treatment (with the risk of fetal injury or death) or over-treatment (which may include unnecessary operative interventions that put both mother and baby at risk of complications). Machine learning (ML) has been applied to this problem since early 2000 and has shown potential to predict fetal hypoxia more accurately than visual interpretation of CTG alone. To consider how these tools might be translated for clinical practice, we conducted a review of ML techniques already applied to CTG classification and identified research gaps requiring investigation in order to progress towards clinical implementation. MATERIALS AND METHOD: We used identified keywords to search databases for relevant publications on PubMed, EMBASE and IEEE Xplore. We used Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Reviews (PRISMA-ScR). Title, abstract and full text were screened according to the inclusion criteria. RESULTS: We included 36 studies that used signal processing and ML techniques to classify CTG. Most studies used an open-access CTG database and predominantly used fetal metabolic acidosis as the benchmark for hypoxia with varying pH levels. Various methods were used to process and extract CTG signals and several ML algorithms were used to classify CTG. We identified significant concerns over the practicality of using varying pH levels as the CTG classification benchmark. Furthermore, studies needed to be more generalised as most used the same database with a low number of subjects for an ML study. CONCLUSION: ML studies demonstrate potential in predicting fetal hypoxia from CTG. However, more diverse datasets, standardisation of hypoxia benchmarks and enhancement of algorithms and features are needed for future clinical implementation.

Construction of a ferroptosis and hypoxia-related gene signature in cervical cancer to assess tumour immune microenvironment and predict prognosis.

BACKGROUND: This study aimed to investigate the potential role of ferroptosis/hypoxia-related genes in cervical cancer to improve early management and treatment of cervical cancer. METHODS: All data were downloaded from public databases. Ferroptosis/hypoxia-related genes associated with cervical cancer prognosis were selected to construct a risk score model. The relationship between risk score and clinical features, immune microenvironment and prognosis were analysed. RESULTS: Risk score model was constructed based on eight signature genes. Drug prediction analysis showed that bevacizumab and cisplatin were related to vascular endothelial growth factor A. Risk score, as an independent prognostic factor of cervical cancer, had a good survival prediction effect. The two groups differed significantly in degree of immune cell infiltration, gene expression, tumour mutation burden and somatic variation. CONCLUSIONS: We developed a novel prognostic gene signature combining ferroptosis/hypoxia-related genes, which provides new ideas for individual treatment of cervical cancer.

Ferroptosis, hypoxia and immune regulation play important roles in cervical cancer progression. In this study, we developed a novel prognostic signature combining ferroptosis and hypoxia-related genes, which provides new ideas for individual treatment of cervical cancer patients. The risk score established by ferroptosis and hypoxia-related gene as an independent prognostic factor of cervical cancer has a good survival prediction effect. High and low risk groups showed significant differences in TIME, prognosis, biological metabolic pathway and tumour mutation burden. In addition, we found drugs associated with signature genes. In short, this study has laid a theoretical foundation for exploring the related molecular mechanisms and prognosis of cervical cancer. It also contributes to the exploration of clinical management and treatment.

Large-scale analysis of interobserver agreement and reliability in cardiotocography interpretation during labor using an online tool.

BACKGROUND: While the effectiveness of cardiotocography in reducing neonatal morbidity is still debated, it remains the primary method for assessing fetal well-being during labor. Evaluating how accurately professionals interpret cardiotocography signals is essential for its effective use. The objective was to evaluate the accuracy of fetal hypoxia prediction by practitioners through the interpretation of cardiotocography signals and clinical variables during labor. MATERIAL AND METHODS: We conducted a cross-sectional online survey, involving 120 obstetric healthcare providers from several countries. One hundred cases, including fifty cases of fetal hypoxia, were randomly assigned to participants who were invited to predict the fetal outcome (binary criterion of pH with a threshold of 7.15) based on the cardiotocography signals and clinical variables. After describing the participants, we calculated (with a 95% confidence interval) the success rate, sensitivity and specificity to predict the fetal outcome for the whole population and according to pH ranges, professional groups and number of years of experience. Interobserver agreement and reliability were evaluated using the proportion of agreement and Cohen's kappa respectively. RESULTS: The overall ability to predict a pH level below 7.15 yielded a success rate of 0.58 (95% CI 0.56-0.60), a sensitivity of 0.58 (95% CI 0.56-0.60) and a specificity of 0.63 (95% CI 0.61-0.65). No significant difference in the success rates was observed with respect to profession and number of years of experience. The success rate was higher for the cases with a pH level below 7.05 (0.69) and above 7.20 (0.66) compared to those falling between 7.05 and 7.20 (0.48). The proportion of agreement between participants was good (0.82), with an overall kappa coefficient indicating substantial reliability (0.63). CONCLUSIONS: The use of an online tool enabled us to collect a large amount of data to analyze how practitioners interpret cardiotocography data during labor. Despite a good level of agreement and reliability among practitioners, the overall accuracy is poor, particularly for cases with a neonatal pH between 7.05 and 7.20. Factors such as profession and experience level do not present notable impact on the accuracy of the annotations. The implementation and use of a computerized cardiotocography analysis software has the potential to enhance the accuracy to detect fetal hypoxia, especially for ambiguous cardiotocography tracings.

EUROPEAN ASSOCIATION OF PERINATAL MEDICINE (EAPM) Position statement: Use of appropriate terminology for situations related to inadequate fetal oxygenation in labor.

In high-resource countries, adverse perinatal outcomes are currently rare in term, non-malformed fetuses, undergoing labor, but they remain a leading cause of medico-legal dispute. Precise terminology is important to describe situations related to inadequate fetal oxygenation in labor, to ensure appropriate communication between healthcare professionals and adequate transmission of information to parents. This position statement provides consensus definitions from European perinatologists and midwives regarding the most appropriate terminology to describe situations related to inadequate fetal oxygenation in labor: suspected fetal hypoxia, severe newborn acidemia, newborn metabolic acidosis, and hypoxic-ischemic encephalopathy. It also identifies terms that are imprecise or nonspecific to this situation, and should therefore be avoided by healthcare professionals: fetal well-being, fetal stress, fetal distress, non-reassuring fetal state, and birth asphyxia.

Fetal monitoring technologies for the detection of intrapartum hypoxia - challenges and opportunities.

Intrapartum fetal hypoxia is related to long-term morbidity and mortality of the fetus and the mother. Fetal surveillance is extremely important to minimize the adverse outcomes arising from fetal hypoxia during labour. Several methods have been used in current clinical practice to monitor fetal well-being. For instance, biophysical technologies including cardiotocography, ST-analysis adjunct to cardiotocography, and Doppler ultrasound are used for intrapartum fetal monitoring. However, these technologies result in a high false-positive rate and increased obstetric interventions during labour. Alternatively, biochemical-based technologies including fetal scalp blood sampling and fetal pulse oximetry are used to identify metabolic acidosis and oxygen deprivation resulting from fetal hypoxia. These technologies neither improve clinical outcomes nor reduce unnecessary interventions during labour. Also, there is a need to link the physiological changes during fetal hypoxia to fetal monitoring technologies. The objective of this article is to assess the clinical background of fetal hypoxia and to review existing monitoring technologies for the detection and monitoring of fetal hypoxia. A comprehensive review has been made to predict fetal hypoxia using computational and machine-learning algorithms. The detection of more specific biomarkers or new sensing technologies is also reviewed which may help in the enhancement of the reliability of continuous fetal monitoring and may result in the accurate detection of intrapartum fetal hypoxia.

Machine Learning to Classify Cardiotocography for Fetal Hypoxia Detection.

Fetal hypoxia can cause damaging consequences on babies' such as stillbirth and cerebral palsy. Cardiotocography (CTG) has been used to detect intrapartum fetal hypoxia during labor. It is a non-invasive machine that measures the fetal heart rate and uterine contractions. Visual CTG suffers inconsistencies in interpretations among clinicians that can delay interventions. Machine learning (ML) showed potential in classifying abnormal CTG, allowing automatic interpretation. In the absence of a gold standard, researchers used various surrogate biomarkers to classify CTG, where some were clinically irrelevant. We proposed using Apgar scores as the surrogate benchmark of babies' ability to recover from birth. Apgar scores measure newborns' ability to recover from active uterine contraction, which measures appearance, pulse, grimace, activity and respiration. The higher the Apgar score, the healthier the baby is.We employ signal processing methods to pre-process and extract validated features of 552 raw CTG. We also included CTG-specific characteristics as outlined in the NICE guidelines. We employed ML techniques using 22 features and measured performances between ML classifiers. While we found that ML can distinguish CTG with low Apgar scores, results for the lowest Apgar scores, which are rare in the dataset we used, would benefit from more CTG data for better performance. We need an external dataset to validate our model for generalizability to ensure that it does not overfit a specific population.Clinical Relevance- This study demonstrated the potential of using a clinically relevant benchmark for classifying CTG to allow automatic early detection of hypoxia to reduce decision-making time in maternity units.

Identification of a prognostic model based on immune and hypoxia-related gene expressions in cervical cancer.

BACKGROUND: Tumour immune microenvironment (TIME) has long been a key direction of tumour research. Understanding the occurrence, metastasis and other processes of cervical cancer (CC) is of great significance in the diagnosis and prognosis of tumours. METHODS: Here, this study applied the univariate Cox regression model to determine the prognostic association of immune and hypoxia signature genes in CC, and used Least Absolute Shrinkage and Selection Operator (LASSO) Cox method to build immune and hypoxia related risk score model to uncover the immune signature of the TIME of CC. Moreover, we used in vitro experiment to validate the expression level of signature genes. Notably, we assessed the predictive effect of anti-PD1/PDL1 immunotherapy using risk score model. RESULTS: Through the LASSO Cox regression model, we obtained 12 characteristic genes associated with the prognosis of CC, and also associated with immunity and hypoxia. Interestingly, the high-risk group had the properties of high hypoxia and low immunity, while the low-risk group had the properties of low hypoxia and high immunity. In the low-risk group, patients lived longer and had a significant therapeutic advantage of anti-PD-1 immunotherapy. CONCLUSIONS: Established risk scores model can help predict response to anti-PD-1 immunotherapy of CC.

The survival rate of cervical cancer (CC) is still low. A prognostic model for CC is urgently needed to improve the prognosis and survival. This study constructed a risk scoring models based on 12 characteristic gene related to hypoxia and immunity, including CX3CL1, CXCL3, GHSR, DLL4, FGFR2, PDF, KLRK1, MAP3K14, RETNLB, PRDX2, P4HA1 and PGK1, which can help predict the prognosis of PD-1 immunotherapy in CC patients. The high-risk group may have the properties of high hypoxia and low immunity, while the low-risk group patients live longer and have obvious therapeutic advantages in anti-PD-1 immunotherapy. Our findings suggest a potential link between hypoxia, immunity, prognosis, tumour immune microenvironment and response to immunotherapy in CC patients.

Identification and verification of genes associated with hypoxia microenvironment in Alzheimer's disease.

As the incidence of Alzheimer's disease (AD) increases year by year, more people begin to study this disease. In recent years, many studies on reactive oxygen species (ROS), neuroinflammation, autophagy, and other fields have confirmed that hypoxia is closely related to AD. However, no researchers have used bioinformatics methods to study the relationship between AD and hypoxia. Therefore, our study aimed to screen the role of hypoxia-related genes in AD and clarify their diagnostic significance. A total of 7681 differentially expressed genes (DEGs) were identified in GSE33000 by differential expression analysis and cluster analysis. Weighted gene co-expression network analysis (WGCNA) was used to detect 9 modules and 205 hub genes with high correlation coefficients. Next, machine learning algorithms were applied to 205 hub genes and four key genes were selected. Through the verification of external dataset and quantitative real-time PCR (qRT-PCR), the AD diagnostic model was established by ANTXR2, BDNF and NFKBIA. The bioinformatics analysis results suggest that hypoxia-related genes may increase the risk of AD. However, more in-depth studies are still needed to investigate their association, this article would guide the insights and directions for further research.

Islet hypoplasia of adult offspring rats caused by intrauterine chronic hypoxia is compensated by up-regulation of INS and PDX-1.

BACKGROUND: Intrauterine chronic hypoxia (ICH) can lead to pancreatic dysmetabolism in offspring. This study aimed to determine the changes in islet function of offspring through a rat ICH model and detect the factors affecting islet function. METHODS: Twenty couples of healthy Sprague - Dawley adult rats were randomly mated, and the pregnant rats were randomly allocated to ICH and normal control (NC) groups. Pregnant rats in the ICH group were placed in a hypoxic chamber with 13% oxygen concentration for hypoxia treatment twice a day for 4 h until delivery at 21 days. NC group is inlet with normal air from beginning to end. After delivery, blood was taken from the heart of pregnant rats for blood gas analysis. The weight of the offspring rats was measured at 12 h after birth and 16 weeks after birth. At 16 weeks, the immunohistochemical results of ß-cell total, islet area, insulin (INS), and glucose transporter 2 (GLUT2) proteins were obtained from the islets. The mRNA data of INS and pancreatic and duodenal homeobox 1 (PDX-1) genes were obtained from pancreas. RESULTS: We found the ß-cell total, islet area, and the positive cell area of INS and GLUT2 of offspring rats in ICH group were lower than those of NC group, while the levels of INS and PDX-1 genes were higher in ICH group than in NC group. CONCLUSIONS: ICH can lead to islet hypoplasia in adult male offspring rats. However, this is within the compensatory range.

Construction and validation of 3-genes hypoxia-related prognostic signature to predict the prognosis and therapeutic response of hepatocellular carcinoma patients.

BACKGROUND: Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment. METHODS: Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints. RESULTS: A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype. CONCLUSIONS: The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.

Identification of hypoxia-related genes and exploration of their relationship with immune cells in ischemic stroke.

Ischemic stroke (IS) is a major threat to human health, and it is the second leading cause of long-term disability and death in the world. Impaired cerebral perfusion leads to acute hypoxia and glucose deficiency, which in turn induces a stroke cascade response that ultimately leads to cell death. Screening and identifying hypoxia-related genes (HRGs) and therapeutic targets is important for neuroprotection before and during brain recanalization to protect against injury and extend the time window to further improve functional outcomes before pharmacological and mechanical thrombolysis. First, we downloaded the GSE16561 and GSE58294 datasets from the NCBI GEO database. Bioinformatics analysis of the GSE16561 dataset using the limma package identified differentially expressed genes (DEGs) in ischemic stroke using adj. p. values < 0.05 and a fold change of 0.5 as thresholds. The Molecular Signature database and Genecards database were pooled to obtain hypoxia-related genes. 19 HRGs associated with ischemic stroke were obtained after taking the intersection. LASSO regression and multivariate logistic regression were applied to identify critical biomarkers with independent diagnostic values. ROC curves were constructed to validate their diagnostic efficacy. We used CIBERSORT to analyze the differences in the immune microenvironment between IS patients and controls. Finally, we investigated the correlation between HRGs and infiltrating immune cells to understand molecular immune mechanisms better. Our study analyzed the role of HRGs in ischemic stroke. Nineteen hypoxia-related genes were obtained. Enrichment analysis showed that 19 HRGs were involved in response to hypoxia, HIF-1 signaling pathway, autophagy, autophagy of mitochondrion, and AMPK signaling pathway. Because of the good diagnostic properties of SLC2A3, we further investigated the function of SLC2A3 and found that it is closely related to immunity. We have also explored the relevance of other critical genes to immune cells. Our findings suggest that hypoxia-related genes play a crucial role in the diversity and complexity of the IS immune microenvironment. Exploring the association between hypoxia-related critical genes and immune cells provides innovative insights into the therapeutic targets for ischemic stroke.

Optimizing the management of acute, prolonged decelerations and fetal bradycardia based on the understanding of fetal pathophysiology.

Any acute and profound reduction in fetal oxygenation increases the risk of anaerobic metabolism in the fetal myocardium and, hence, the risk of lactic acidosis. On the contrary, in a gradually evolving hypoxic stress, there is sufficient time to mount a catecholamine-mediated increase in the fetal heart rate to increase the cardiac output and redistribute oxygenated blood to maintain an aerobic metabolism in the fetal central organs. When the hypoxic stress is sudden, profound, and sustained, it is not possible to continue to maintain central organ perfusion by peripheral vasoconstriction and centralization. In case of acute deprivation of oxygen, the immediate chemoreflex response via the vagus nerve helps reduce fetal myocardial workload by a sudden drop of the baseline fetal heart rate. If this drop in the fetal heart rate continues for >2 minutes (American College of Obstetricians and Gynecologists' guideline) or 3 minutes (National Institute for Health and Care Excellence or physiological guideline), it is termed a prolonged deceleration, which occurs because of myocardial hypoxia, after the initial chemoreflex. The revised International Federation of Gynecology and Obstetrics guideline (2015) considers the prolonged deceleration to be a "pathologic" feature after 5 minutes. Acute intrapartum accidents (placental abruption, umbilical cord prolapse, and uterine rupture) should be excluded immediately, and if they are present, an urgent birth should be accomplished. If a reversible cause is found (maternal hypotension, uterine hypertonus or hyperstimulation, and sustained umbilical cord compression), immediate conservative measures (also called intrauterine fetal resuscitation) should be undertaken to reverse the underlying cause. In reversible causes of acute hypoxia, if the fetal heart rate variability is normal before the onset of deceleration, and normal within the first 3 minutes of the prolonged deceleration, then there is an increased likelihood of recovery of the fetal heart rate to its antecedent baseline within 9 minutes with the reversal of the underlying cause of acute and profound reduction in fetal oxygenation. The continuation of the prolonged deceleration for >10 minutes is termed "terminal bradycardia," and this increases the risk of hypoxic-ischemic injury to the deep gray matter of the brain (the thalami and the basal ganglia), predisposing to dyskinetic cerebral palsy. Therefore, any acute fetal hypoxia, which manifests as a prolonged deceleration on the fetal heart rate tracing, should be considered an intrapartum emergency requiring an immediate intervention to optimize perinatal outcome. In uterine hypertonus or hyperstimulation, if the prolonged deceleration persists despite stopping the uterotonic agent, then acute tocolysis is recommended to rapidly restore fetal oxygenation. Regular clinical audit of the management of acute hypoxia, including the "the onset of bradycardia to delivery interval," may help identify organizational and system issues, which may contribute to poor perinatal outcomes.

Effects of Gestational Hypoxia on PGC1α and Mitochondrial Acetylation in Fetal Guinea Pig Hearts.

Chronic intrauterine hypoxia is a significant pregnancy complication impacting fetal heart growth, metabolism, and mitochondrial function, contributing to cardiovascular programming of the offspring. PGC1α (peroxisome proliferator-activated receptor γ co-activator 1α) is the master regulator of mitochondrial biogenesis. We investigated the effects of hypoxia on PGC1α expression following exposure at different gestational ages. Time-mated pregnant guinea pigs were exposed to normoxia (NMX, 21% O2) or hypoxia (HPX, 10.5% O2) at either 25-day (early-onset) or 50-day (late-onset) gestation, and all fetuses were extracted at term (term = ~65-day gestation). Expression of nuclear PGC1α, sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and mitochondrial sirtuin 3 (SIRT3) was measured, along with SIRT3 activity and mitochondrial acetylation of heart ventricles of male and female fetuses. Early-onset hypoxia increased (P<0.05) fetal cardiac nuclear PGC1α and had no effect on mitochondrial acetylation of either growth-restricted males or females. Late-onset hypoxia had either no effect or decreased (P<0.05) PCC1α expression in males and females, respectively, but increased (P<0.05) mitochondrial acetylation in both sexes. Hypoxia had variable effects on expression of SIRT1, AMPK, SIRT3, and SIRT3 activity depending on the sex. The capacity of the fetal heart to respond to hypoxia differs depending on the gestational age of exposure and sex of the fetus. Further, the effects of late-onset hypoxia on fetal heart function impose a greater risk to male than female fetuses, which has implications toward cardiovascular programming effects of the offspring.

Dissecting the contributions of the peripheral chemoreflex and myocardial hypoxia to fetal heart rate decelerations in near-term fetal sheep.

Brief repeated fetal hypoxaemia during labour can trigger intrapartum decelerations of the fetal heart rate (FHR) via the peripheral chemoreflex or the direct effects of myocardial hypoxia, but the relative contribution of these two mechanisms and how this balance changes with evolving fetal compromise remain unknown. In the present study, chronically instrumented near-term fetal sheep received surgical vagotomy (n = 8) or sham vagotomy (control, n = 11) to disable the peripheral chemoreflex and unmask myocardial hypoxia. One-minute complete umbilical cord occlusions (UCOs) were performed every 2.5 min for 4 h or until arterial pressure fell below 20 mmHg. Hypotension and severe acidaemia developed progressively after 65.7 ± 7.2 UCOs in control fetuses and 49.5 ± 7.8 UCOs after vagotomy. Vagotomy was associated with faster development of metabolic acidaemia and faster impairment of arterial pressure during UCOs without impairing centralization of blood flow or neurophysiological adaptation to UCOs. During the first half of the UCO series, before severe hypotension developed, vagotomy was associated with a marked increase in FHR during UCOs. After the onset of evolving severe hypotension, FHR fell faster in control fetuses during the first 20 s of UCOs, but FHR during the final 40 s of UCOs became progressively more similar between groups, with no difference in the nadir of decelerations. In conclusion, FHR decelerations were initiated and sustained by the peripheral chemoreflex at a time when fetuses were able to maintain arterial pressure. After the onset of evolving hypotension and acidaemia, the peripheral chemoreflex continued to initiate decelerations, but myocardial hypoxia became progressively more important in sustaining and deepening decelerations. KEY POINTS: Brief repeated hypoxaemia during labour can trigger fetal heart rate decelerations by either the peripheral chemoreflex or myocardial hypoxia, but how this balance changes with fetal compromise is unknown. Reflex control of fetal heart rate was disabled by vagotomy to unmask the effects of myocardial hypoxia in chronically instrumented fetal sheep. Fetuses were then subjected to repeated brief hypoxaemia consistent with the rates of uterine contractions during labour. We show that the peripheral chemoreflex controls brief decelerations in their entirety at a time when fetuses were able to maintain normal or increased arterial pressure. The peripheral chemoreflex still initiated decelerations even after the onset of evolving hypotension and acidaemia, but myocardial hypoxia made an increasing contribution to sustain and deepen decelerations.

The relationship between maternal anemia and electronic fetal monitoring patterns.

BACKGROUND: Anemia is a commonly diagnosed comorbidity in pregnancy that is associated with increased risk of maternal and neonatal complications. Recent data demonstrate that maternal anemia is associated with higher umbilical artery and umbilical vein O2 content at the time of delivery. OBJECTIVE: This study aimed to examine the relationship between maternal anemia and electronic fetal monitoring patterns associated with fetal hypoxia. STUDY DESIGN: This is a secondary analysis of a prospective cohort study of singleton term deliveries with cord gases and universal complete blood count collected on admission between 2010 and 2014. Maternal anemia was defined as hemoglobin ≤11.0 g/dL on admission. The primary outcome was a composite of high-risk category 2 electronic fetal monitoring features in the last 60 minutes before delivery (recurrent late and/or variable decelerations, minimal variability, tachycardia, or >1 prolonged deceleration); secondary outcomes were total deceleration area and total deceleration area >90th percentile. Of the 8580 patients in the original study, 8196 were included in the analysis. Outcomes were compared between patients with and without anemia. Multivariable logistic regression was used to adjust for potentially confounding factors, including hypertensive disorders of pregnancy and induction of labor. RESULTS: Of the 8196 patients with complete blood count on admission and fetal monitoring data, 2672 (32.6%; 2672/8196) were anemic and 5524 (67.4%; 5524/8196) were not. Patients with anemia were significantly less likely to have composite high-risk category 2 features on electronic fetal monitoring (34.2% vs 32.0%; adjusted risk ratio, 0.93; 95% confidence interval, 0.86-0.99). Women with anemia also had decreased total deceleration area and were less likely to have total deceleration area >90th percentile (18.7% vs 16.2%; adjusted risk ratio, 0.85; 95% confidence interval, 0.77-0.94). CONCLUSION: Patients with anemia are less likely to have high-risk category 2 electronic fetal monitoring features associated with fetal hypoxia. This finding is consistent with the association between maternal anemia and increased umbilical cord O2 content, and suggests that maternal anemia may be protective against intrapartum fetal hypoxia.

OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

A comparative study of smart nanoformulations of diethyldithiocarbamate with Cu4O3 nanoparticles or zinc oxide nanoparticles for efficient eradication of metastatic breast cancer.

Metastatic tumor is initiated by metastatic seeds (cancer stem cells "CSCs") in a controlled redox microenvironment. Hence, an effective therapy that disrupts redox balance with eliminating CSCs is critical. Diethyldithiocarbamate (DE) is potent inhibitor of radical detoxifying enzyme (aldehyde dehydrogenase "ALDH"1A) causing effective eradication of CSCs. This DE effect was augmented and more selective by its nanoformulating with green synthesized copper oxide (Cu4O3) nanoparticles (NPs) and zinc oxide NPs, forming novel nanocomplexes of CD NPs and ZD NPs, respectively. These nanocomplexes exhibited the highest apoptotic, anti-migration, and ALDH1A inhibition potentials in M.D. Anderson-metastatic breast (MDA-MB) 231 cells. Importantly, these nanocomplexes revealed more selective oxidant activity than fluorouracil by elevating reactive oxygen species with depleting glutathione in only tumor tissues (mammary and liver) using mammary tumor liver metastasis animal model. Due to higher tumoral uptake and stronger oxidant activity of CD NPs than ZD NPs, CD NPs had more potential to induce apoptosis, suppress hypoxia-inducing factor gene, and eliminate CD44+CSCs with downregulating their stemness, chemoresistance, and metastatic genes and diminishing hepatic tumor marker (α-fetoprotein). These potentials interpreted the highest tumor size reduction with complete eradicating tumor metastasis to liver in CD NPs. Consequently, CD nanocomplex revealed the highest therapeutic potential representing a safe and promising nanomedicine against the metastatic stage of breast cancer.