Cesarean delivery is associated with lower neonatal mortality among breech pregnancies - a systematic review and meta-analysis of preterm deliveries ≤32 weeks of gestation.

OBJECTIVE: To investigate the association between actual and planned modes of delivery, neonatal mortality, and short-term outcomes among preterm pregnancies ≤32 weeks of gestation. DATA SOURCES: A systematic literature search was conducted in three main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 16, 2022. The protocol was registered in advance in the International Prospective Register of Systematic Reviews (CRD42022377870). STUDY ELIGIBILITY CRITERIA: Eligible studies examined pregnancies ≤ 32nd gestational week. All infants received active care, and the outcomes were reported separately by different modes of delivery. Singleton and twin pregnancies at vertex and breech presentations were included. Studies that included pregnancies complicated with preeclampsia and abruptio placentae were excluded. Primary outcomes were neonatal mortality and intraventricular hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random effects model-based odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. ROBINS-I was used to assess the risk of bias. RESULTS: A total of nineteen observational studies were included involving a total of 16,042 preterm infants in this systematic review and meta-analysis. Actual cesarean delivery improves survival (odds ratio, 0.62; 95% confidence interval, 0.42 to 0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57 to 0.85) compared to vaginal delivery. Planned cesarean delivery does not improve the survival of very and extremely preterm infants compared to vaginal delivery (odds ratio, 0.87; 95% confidence interval, 0.53 to 1.44). Subset analysis found significantly lower odds of death for singleton breech preterm deliveries born by both planned (odds ratio, 0.56; 95% confidence interval, 0.32 to 0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13 to 0.88) cesarean delivery. CONCLUSION: Cesarean delivery should be the mode of delivery for preterm ≤32 weeks of gestation breech births due to the higher mortality in preterm infants born via vaginal delivery.

The histologic fetal inflammatory response and neonatal outcomes: systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the prognostic role of concomitant histological fetal inflammatory response with chorioamnionitis on neonatal outcomes through a systematic review and meta-analysis of existing literature. DATA SOURCES: The primary search was conducted on October 17, 2021, and it was updated on May 26, 2023, across 4 separate databases (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Scopus) without using any filters. STUDY ELIGIBILITY CRITERIA: Observational studies reporting obstetrical and neonatal outcomes of infant-mother dyads with histological chorioamnionitis and histological fetal inflammatory response vs infant-mother dyads with histological chorioamnionitis alone were eligible. Studies that enrolled only preterm neonates, studies on neonates born before 37 weeks of gestation, or studies on neonates with very low birthweight (birthweight <1500 g) were included. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42021283448). METHODS: The records were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random-effect model-based pooled odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. RESULTS: Overall, 50 studies were identified. A quantitative analysis of 14 outcomes was performed. Subgroup analysis using the mean gestational age of the studies was performed, and a cutoff of 28 weeks of gestation was implemented. Among neonates with lower gestational ages, early-onset sepsis (pooled odds ratio, 2.23; 95% confidence interval, 1.76-2.84) and bronchopulmonary dysplasia (pooled odds ratio, 1.30; 95% confidence interval, 1.02-1.66) were associated with histological fetal inflammatory response. Our analysis showed that preterm neonates with a concomitant histological fetal inflammatory response are more likely to develop intraventricular hemorrhage (pooled odds ratio, 1.54; 95% confidence interval, 1.18-2.02) and retinopathy of prematurity (pooled odds ratio, 1.37; 95% confidence interval, 1.03-1.82). The odds of clinical chorioamnionitis were almost 3-fold higher among infant-mother dyads with histological fetal inflammatory response than among infant-mother dyads with histological chorioamnionitis alone (pooled odds ratio, 2.99; 95% confidence interval, 1.96-4.55). CONCLUSION: This study investigated multiple neonatal outcomes and found association in the case of 4 major morbidities: early-onset sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity.

Survival and early complications of preterm infants with birthweight less than 500 grams during a 10-year period in Hungary.

BACKGROUND: There are limited data available on the survival and early complications of preterm infants with less than 500 g birthweight. To estimate the outcomes for these infants, it is important for caregivers to be aware of perinatal factors that may affect survival. OBJECTIVES: We assessed the mortality and certain early complications of preterm infants born with less than 500 g in Hungary between 2006 and 2015. METHODS: We reviewed data of 486 infants from the database of the Hungarian Central Statistical Office and in parallel of 407 infants from the "NICU database." The study period was divided into two epochs: 2006-2010 and 2011-2015. RESULTS: The survival was 27.1% in the first epoch and 39.1% in the second epoch, and the incidence of early complications was slightly higher in the second epoch. In the surviving group (first and second epoch combined), gestational age (25.1 vs 23.7 weeks), birthweight (458 vs 447 g) antenatal steroid treatment (66.3% vs 52.3%), surfactant therapy (95.1% vs 84.3%), median Apgar scores (6 vs 3 and 8 vs 5 at 1 and 5 minutes, respectively) and proportion of caesarean delivery (89.3% versus 68.5%) were higher than in the non-surviving group (first and second epoch combined). The proportion of multiple births was lower in the surviving group (15.7% vs 33.4%). CONCLUSIONS: Survival of infants with less than 500 g improved between 2006-2010 and 2011-2015 in Hungary. The slightly higher occurrence of early complications might be associated with improving survival.

The Prognosis of Preterm Infants Born at the Threshold of Viability: Fog Over the Gray Zone - Population-Based Studies of Extremely Preterm Infants.

The limit of viability for premature newborns has changed in recent decades, but whether to initiate or withhold active care for periviable infants remains a subject of debate because the chances of survival and the extent of severe neurological impairment can be unclear. In our review, we analyzed large population-based studies of periviable infants from the past 2 decades. We compared survival rates and the incidence of early complications among survivors, including bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, and necrotizing enterocolitis. Moreover, we assessed the perinatal factors that may affect the survival of preterm infants. We analyzed 15 studies reporting data on preterm infants born between 22 and 28 gestational weeks. None of these studies reported survival of an infant born before 22 gestational weeks. Survival rates of infants born at 24 weeks' gestation were above 50% in most studies. The incidence of each complication was also higher among infants born at ≤24 weeks. Of the analyzed perinatal factors, antenatal corticosteroid therapy, birth weight, female sex, cesarean delivery, singleton pregnancy, and birth in a tertiary-level Neonatal Intensive Care Unit were found to be associated with improved survival in some studies. The different methodologies of the studies limited comparison of the results. Further investigations are needed to gain up-to-date information on the limit of viability, and standardized methods in future studies would enable more accurate comparisons of findings.

MRTFs- master regulators of EMT.

Recent evidence implicates the myocardin-related transcription factors (MRTFs) as key mediators of the phenotypic plasticity leading to the conversion of various cell types into myofibroblasts. This review highlights the function of MRTFs during development, fibrosis and cancer, and the role of MRTFs during epithelial-mesenchymal transitions (EMTs) underlying these processes. EMT is a sequentially orchestrated process where cells undergo a rearrangement of their cell contacts and activate a fibrogenic and myogenic expression program. MRTFs interact with and regulate the major signaling pathways and the expression of key markers and transcription factors involved in EMT. These functions indicate a central role for MRTFs in controlling the process of EMT. Developmental Dynamics 247:396-404, 2018. © 2017 Wiley Periodicals, Inc.

Trends in Mortality and Morbidity in Infants Under 500 Grams Birthweight: Observations from Our Neonatal Intensive Care Unit (NICU).

BACKGROUND In our previous study, some changes were presented in obstetric care and we studied the morbidity and mortality trends of infants with <500 grams birth weight. Several neonatal protocol changes occurred during the study period. The aim of this study was to analyze the changes in mortality and morbidity of premature infants in light of changing neonatal protocols. MATERIAL AND METHODS We performed a retrospective study of premature infants with <500 grams birth weight, born at our department between 2006 and 2015. We divided the study period into two 5-year epochs and compared mortality and morbidity rates. We calculated the duration of mechanical ventilation and non-invasive respiratory support, and also investigated the potential impact of the differences in clinical practice. RESULTS The survival rate was 30.8% during first epoch, which was significantly lower than the 70.4% survival rate during second epoch. There was no difference in the rate of complications between the 2 epochs. The total number of ventilator and non-invasive ventilation days was significantly lower in the second epoch. CONCLUSIONS We found significant differences in survival rates but no change in the incidence of morbidities between the 2 epochs. Therefore, although the number of neonates surviving with morbidities has increased, so did the number of those with intact survival. The increased survival of infants born with <500 grams birth weight is not associated with increased rate of morbidities. Protocol changes may have contributed to these findings; however, in a retrospective study it is not possible to separate the impact of individual changes.

When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition.

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.

Characterization and role of SCAI during renal fibrosis and epithelial-to-mesenchymal transition.

During progressive tubulointerstitial fibrosis, renal tubular epithelial cells transform into α-smooth muscle actin (SMA)-expressing myofibroblasts via epithelial-to-mesenchymal transition (EMT). SMA expression is regulated by transforming growth factor (TGF)-ß1 and cell contact disruption, through signaling events targeting the serum response factor-myocardin-related transcription factor (MRTF) complex. MRTFs are important regulators of fibrosis, tumor cell invasion, and metastasis. Consistent with the role of MRTFs in tumor progression, suppressor of cancer cell invasion (SCAI) was recently identified as a negative regulator of MRTF. Herein, we studied the role of SCAI in a fibrotic EMT model established on LLC-PK1 cells. SCAI overexpression prevented SMA promoter activation induced by TGF-ß1. When co-expressed, it inhibited the stimulatory effects of MRTF-A, MRTF-B or the constitutive active forms of RhoA, Rac1, or Cdc42 on the SMA promoter. SCAI interfered with TGF-ß1-induced SMA, connective tissue growth factor, and calponin protein expression; it rescued TGF-ß1-induced E-cadherin down-regulation. IHC studies on human kidneys showed that SCAI expression is reduced during fibrosis. Kidneys of diabetic rats and mice with unilateral ureteral obstruction depicted significant loss of SCAI expression. In parallel with the decrease of SCAI protein expression, diabetic rat and mouse kidneys with unilateral ureteral obstruction showed SMA expression, as evidenced by using Western blot analysis. Finally, TGF-ß1 treatment of LLC-PK1 cells attenuated SCAI protein expression. These data suggest that SCAI is a novel transcriptional cofactor that regulates EMT and renal fibrosis.

The Effect of Additional Whole-Body Vibration on Musculoskeletal System in Children with Cerebral Palsy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Nowadays, whole-body vibration (WBV) has become increasingly popular as an additional therapy in the intervention of patients with cerebral palsy (CP). However, the impact of WBV remains a subject of debate. Consequently, a systematic review and meta-analysis were undertaken to evaluate the effects of WBV on the musculoskeletal system in children with CP. Randomized controlled trials (RCTs) were sought in the most frequent databases. The intervention studied was WBV combined with conventional physiotherapy (PT) compared with conventional PT as the control; the main outcomes were changes in the musculoskeletal system. Weighted mean differences with 95%CIs were calculated. A random-effects model was applied, and the publication bias was checked using funnel plots. On the basis of the inclusion and exclusion criteria, 16 articles, including 414 patients, were considered in the final analysis. The improvement in walking performance (speed and step length) was statistically significant (p < 0.05), and although there were no significant differences in the further outcomes, a clear positive tendency was visible in the case of improved muscle strength, decreased spasticity, enhanced gross motor functions, and overall stability. Based on the findings, a clear assessment of the usefulness of this intervention cannot be made; nonetheless, due to the promising results, it would be worthwhile to conduct additional RCTs to enhance the available evidence in this field. Due to the wide range of vibration configurations, including varying durations and intensities, it is suggested to establish guidelines and a strategy for the incorporation of this additional treatment.

Forward Genetic Screens as Tools to Investigate Role and Mechanisms of EMT in Cancer.

Epithelial-mesenchymal transition (EMT) is a process of cellular plasticity regulated by complex signaling networks. Under physiological conditions, it plays an important role in wound healing and organ repair. Its importance for human disease is given by its central role in chronic fibroproliferative diseases and cancer, which represent leading causes of death worldwide. In tumors, EMT is involved in primary tumor growth, metastasis and therapy resistance. It is therefore a major requisite to investigate and understand the role of EMT and the mechanisms leading to EMT in order to tackle these diseases therapeutically. Forward genetic screens link genome modifications to phenotypes, and have been successfully employed to identify oncogenes, tumor suppressor genes and genes involved in metastasis or therapy resistance. In particular, transposon-based insertional mutagenesis screens and CRISPR-based screens are versatile and easy-to-use tools applied in recent years to discover and identify novel cancer-related mechanisms. Here, we review the contribution of forward genetic screens to our understanding of how EMT is regulated and how it is involved in various aspects of cancer. Based on the current literature, we propose these methods as additional tools to investigate EMT.

Therapeutic Targeting of Fibrotic Epithelial-Mesenchymal Transition-An Outstanding Challenge.

Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that "fibroblasts in some cases arise from the local conversion of epithelium." In the following years, epithelial-mesenchymal transition was in the spotlight of fibrosis research, especially in the kidney. However, the hypothesis came under scrutiny following some discouraging findings from lineage tracing experiments and clinical observations. In this review, we provide a timely overview of the current position of the epithelial-mesenchymal transition hypothesis in the context of fibrosis (with a certain focus on renal fibrosis) and highlight some of the potential hurdles and pitfalls preventing therapeutic breakthroughs targeting fibrotic epithelial-mesenchymal transition.

Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer.

Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms' tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-ß1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer.

Morbidity and mortality trends in very-very low birth weight premature infants in light of recent changes in obstetric care.

OBJECTIVE: In this study, we describe trends in morbidity and mortality of preterm infants with less than 500mg birth weight in the changing landscape of obstetric and neonatal care. STUDY DESIGN: During a ten year study period between 2006 and 2016 we assessed outcome data for all neonates with less than 500mg birth weight born at our Neonatal Intensive Care Unit. We divided study subjects into two groups based on whether their birth date fell in the first half (2006-2010; n=39) versus the second half (2011-2015; n=27) of the study period comparing clinical outcomes in the two groups. We also assessed several clinical parameters for association with postnatal survival by comparing relative frequencies for each clinical parameter among surviving infants versus mortality cases. RESULTS: Survival rate for preterm neonates with less than 500mg birth weight born between 2006 and 2010 was 30.8%. This survival rate rose to 70.4% in the second half of the study period between 2011 and 2015 (p<0.05). Among surviving babies premature birth was found to be predominantly associated with maternal hypertension or intrauterine growth restriction while in those who died premature birth due to premature rupture of membranes and spontaneous preterm labor were significantly more common. All surviving infants with less than 500mg birth weight were born via cesarean section whereas among those who died cesarean section had been performed in only 80% and vaginal delivery in 20% representing a significant difference between the groups (p<0.05). The majority (90.3%) of surviving infants with less than 500mg birth weight had received surfactant therapy while the proportion of neonates receiving surfactant therapy among mortality cases was significantly lower (65.2%; p<0.05). DISCUSSION: Our findings suggest that among premature neonates with less than 500mg birth weight preterm delivery due to premature rupture of membranes and intrauterine infections represents the worse mortality risk. Steroid prophylaxis and measures to prevent and treat intrauterine infections with appropriate use of antibiotics can markedly improve survival in these cases. In premature neonates with less than 500mg birth weight survival is more favorable after cesarean section compared to vaginal delivery.

Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation.

Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-ß, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-ß1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, ß1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-ß signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-ß-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-ß-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.

Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation.

Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-ß, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-ß1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, ß1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-ß signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-ß-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-ß-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.