Silencing P38 MAPK reduces cellular senescence in human fetal chorion trophoblast cells.

PROBLEM: Amniochorion senescence generates mechanistic signals to initiate parturition. Activation of p38 mitogen-activated kinase (MAPK) in fetal amnion cells is a key mediator of senescence as well as epithelial-mesenchymal transition (EMT) of amnion cells. However, the impact of p38 MAPK in chorion trophoblast cells (CTCs) is unclear. We tested if eliminating p38 will reduce oxidative stress (OS) induced cell fates like cellular senescence, EMT, and inflammation induced by these processes in CTCs. METHODS: p38MAPK in CTCs was silenced using CRISPR/Cas9. OS was evoked by cigarette smoke extract (CSE) exposure. EMT was evoked by transforming growth factor (TGF)-ß treatment. Cell cycle, senescence, EMT, and inflammation were analyzed. RESULTS: CSE-induced changes in the cell cycle were not seen in p38KO CTCs compared to WT cells. OS induced by CSE evoked senescence and senescence-associated secretory phenotype (SASP as indicated by IL-6 and IL-8 increase) in WT but not in p38MAPK KO CTCs. No changes were noted in HLA-G expression regardless of the status of p38MAPK. Neither CSE nor TGF-ß evoked EMT in either WT or p38 KO CTCs. CONCLUSION: Senescence and senescence-associated inflammation in human fetal CTCs are mediated by p38MAPK. Compared to amnion epithelial cells, CTCs are resistant to EMT. This refractoriness may help them to maintain the barrier functions at the choriodecidual interface.

Stress signaler p38 mitogen-activated kinase activation: a cause for concern?

Oxidative stress (OS) induced activation of p38 mitogen-activated kinase (MAPK) and cell fate from p38 signaling was tested using the human fetal membrane's amnion epithelial cells (AEC). We created p38 KO AEC using the CRISPR/Cas9 approach and tested cell fate in response to OS on an AEC-free fetal membrane extracellular matrix (ECM). Screening using image CyTOF indicated OS causing epithelial-mesenchymal transition (EMT). Further testing revealed p38 deficiency prevented AEC senescence, EMT, cell migration, and inflammation. To functionally validate in vitro findings, fetal membrane-specific conditional KO (cKO) mice were developed by injecting Cre-recombinase encoded exosomes intra-amniotically into p38αloxP/loxP mice. Amnion membranes from p38 cKO mice had reduced senescence, EMT, and increased anti-inflammatory IL-10 compared with WT animals. Our study suggested that overwhelming activation of p38 in response to OS inducing risk exposures can have an adverse impact on cells, cause cell invasion, inflammation, and ECM degradation detrimental to tissue homeostasis.

Outpatient Compared With Inpatient Preinduction Cervical Ripening Using a Synthetic Osmotic Dilator: A Randomized Clinical Trial.

OBJECTIVE: To assess whether outpatient cervical ripening with a synthetic osmotic dilator shortens the length of hospital stay in term pregnancies undergoing labor induction. METHODS: Pregnant participants scheduled for labor induction at term with unfavorable cervix (less than 3-cm dilated and less than 60% effaced) and not requiring inpatient maternal or fetal monitoring were consented, and synthetic osmotic dilator rods were inserted on the day of scheduled induction. After reassuring fetal heart tracing, patients randomized to the outpatient group were asked to return 12 hours after insertion or sooner if needed. Those randomized to the inpatient group remained in the hospital. After the first round of ripening, additional ripening, oxytocin, and labor management were left up to the clinical health care professionals. The primary outcome was the proportion of participants with hospital stays longer than 48 hours. We estimated that a sample size of 338 would provide 85% power to detect a 30% difference between groups. RESULTS: From November 2018 to November 2021, 339 participants were randomized (171 inpatient, 167 outpatient, one withdrawal). Four patients in the outpatient group were admitted before12 hours for suspected labor and rupture of membranes, and 19 in the inpatient group had the device removed before 12 hours. The proportion of participants with hospital stays longer than 48 hours was lower in the outpatient group compared with the inpatient group (89 [53%] vs 152 [89%], relative risk [RR] 0.60, 95% CI 0.52-0.70). Patients in the outpatient group had a shorter total length of stay and time from admission to active labor. They were more likely to have a vaginal delivery within 24 hours of admission and were less likely to receive analgesics during ripening. Route of delivery and other maternal and neonatal outcomes were not significantly different between groups. CONCLUSION: Outpatient cervical ripening with a cervical osmotic dilator decreased hospital stay compared with inpatient ripening, without significant adverse outcomes. FUNDING SOURCE: Medicem Technology s.r.o., Czech Republic. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03665688.

Quality Improvement Initiative to Reduce Time from Regional Anesthesia Placement to Delivery for Cesarean Delivery.

OBJECTIVE: Our objective was to evaluate the impact of a quality improvement (QI) initiative on the regional anesthesia placement-to-infant delivery time during cesarean delivery (CD). STUDY DESIGN: We performed a quality improvement trial. Before June 18, 2018, the preoperative protocol was as follows: the anesthesiologist administered regional anesthesia in the operating room then the nurse placed the Foley's catheter, clipped pubic hair, precleaned the abdomen, and abdominal preparation. On June 18, 2018, the protocol changed and all the preoperative preparation (Foley's clip and preclean) were performed prior to the arrival in the operating room. The records of patients who underwent scheduled or nonemergency CD between May 1 and July 15, 2018, were reviewed. Our primary outcome was time between the placements of regional anesthesia to infant delivery at the time of CD. Bivariate and multivariable analyses were performed. RESULTS: A total of 194 patients were included, 124 before and 70 after the process change. The change in process leads to a significant reduction in anesthesia-to-delivery time, even after adjusting for number of prior CD and body mass index (BMI). Other times were also significantly impacted by the change. CONCLUSION: Our QI initiative significantly decreased the time from anesthesia placement to delivery of the fetus. Performing preoperative preparation activities, such as Foley's placement and shaving, after regional anesthesia for CD, increase the risk of fetal exposure to maternal hypotension. We evaluated the impact of a QI initiative on regional anesthesia placement to infant delivery time during CD.