(Abstracted from JAMA 2022;327:1356–1367) In 2016, gestational diabetes mellitus (GDM) affected 6% of pregnancies in the United States. In 2015, maternal and neonatal adverse outcomes occurred in approximately 33% of pregnancies affected by GDM and in approximately 25% of infants born from pregnancies affected by GDM.
It remains unknown whether SARS-CoV-2 infection specifically increases the risk of serious obstetric morbidity. To evaluate the association of SARS-CoV-2 infection with serious maternal morbidity or mortality from common obstetric complications. Retrospective cohort study of 14 104 pregnant and postpartum patients delivered between March 1, 2020, and December 31, 2020 (with final follow-up to February 11, 2021), at 17 US hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Gestational Research Assessments of COVID-19 (GRAVID) Study. All patients with SARS-CoV-2 were included and compared with those without a positive SARS-CoV-2 test result who delivered on randomly selected dates over the same period. SARS-CoV-2 infection was based on a positive nucleic acid or antigen test result. Secondary analyses further stratified those with SARS-CoV-2 infection by disease severity. The primary outcome was a composite of maternal death or serious morbidity related to hypertensive disorders of pregnancy, postpartum hemorrhage, or infection other than SARS-CoV-2. The main secondary outcome was cesarean birth. Of the 14 104 included patients (mean age, 29.7 years), 2352 patients had SARS-CoV-2 infection and 11 752 did not have a positive SARS-CoV-2 test result. Compared with those without a positive SARS-CoV-2 test result, SARS-CoV-2 infection was significantly associated with the primary outcome (13.4% vs 9.2%; difference, 4.2% [95% CI, 2.8%-5.6%]; adjusted relative risk [aRR], 1.41 [95% CI, 1.23-1.61]). All 5 maternal deaths were in the SARS-CoV-2 group. SARS-CoV-2 infection was not significantly associated with cesarean birth (34.7% vs 32.4%; aRR, 1.05 [95% CI, 0.99-1.11]). Compared with those without a positive SARS-CoV-2 test result, moderate or higher COVID-19 severity (n = 586) was significantly associated with the primary outcome (26.1% vs 9.2%; difference, 16.9% [95% CI, 13.3%-20.4%]; aRR, 2.06 [95% CI, 1.73-2.46]) and the major secondary outcome of cesarean birth (45.4% vs 32.4%; difference, 12.8% [95% CI, 8.7%-16.8%]; aRR, 1.17 [95% CI, 1.07-1.28]), but mild or asymptomatic infection (n = 1766) was not significantly associated with the primary outcome (9.2% vs 9.2%; difference, 0% [95% CI, -1.4% to 1.4%]; aRR, 1.11 [95% CI, 0.94-1.32]) or cesarean birth (31.2% vs 32.4%; difference, -1.4% [95% CI, -3.6% to 0.8%]; aRR, 1.00 [95% CI, 0.93-1.07]). Among pregnant and postpartum individuals at 17 US hospitals, SARS-CoV-2 infection was associated with an increased risk for a composite outcome of maternal mortality or serious morbidity from obstetric complications.
Abstract Despite success in hematologic malignancies, chimeric antigen receptor (CAR) T cells have been less effective in solid tumors, in part because of the heterogeneous expression of the CAR-specific target antigen (1° Ag) found within the tumor mass. In combination with a CAR, bispecific T cell engagers (BiTEs) can target additional tumor antigens (2° Ag) while engaging CD3 signaling molecules on T cells, providing a unique way to address tumor heterogeneity, mitigate antigen escape and further potentiate durable effector function. However, in generating off-the-shelf universal CAR-T and NK cells, a combination strategy is not feasible as neither modified cell product is compatible to specifically engage with a BiTE. In developing allogeneic CAR-T cells, the T cell receptor (TCR) surface expression must be eliminated to prevent graft versus host disease, but the absence of surface TCR expression leads to loss of surface CD3 expression and BiTE compatibility. Similarly, NK cells naturally lack TCR expression and have no surface CD3 molecules for BiTE engagement. Here we discuss the development of a novel chimeric CD3ε fusion receptor (CD3-CFR) with a modified transmembrane and endodomain enabling surface expression in TCR-less T or NK cells, allowing for a novel combinatorial solution between universal CAR-T or NK cells with BiTEs in an allogeneic setting. CD3-CFR signal transduction was initially investigated in TRAC knockout NFAT reporter (T-KO) Jurkat cells engineered with CD3-CFR and co-cultured with EpCAM+ target cells. When soluble EpCAM-BiTE was added to the co-culture, the observed 6.9-fold increase in NFAT activity indicated successful engagement associated with the interaction of CD3-CFR, target cells and the BiTE. CD3-CFR T-KO Jurkat cells were further modified to secrete the EpCAM-BiTE and showed increased NFAT activity, demonstrating the feasibility of self-secreting BiTE-mediated targeting through CD3-CFR signaling. We next engineered CD3-CFR expressing iPSC-derived CAR-T (iT) cells to show preserved T cell differentiation kinetics and maintained CAR activity against 1° Ag positive targets (>90% cytolysis). Importantly, while CAR-iT cells showed only background lysis of 1° Ag negative tumor cells, CD3-CFR+ CAR-iT cells were able to lyse ~99% of 1° Ag negative tumor cells with the addition of soluble EpCAM-BiTE targeting the 2° Ag. When CD3-CFR+ CAR-iT cells were further engineered to secrete the EpCAM-BiTE, CD3-CFR+ BiTE+ CAR-iT cells demonstrated superior killing of heterogenous tumors compared to CD3-CFR+ BiTE- CAR-iT cells (70% vs. 5% cytolysis). Taken together these data demonstrate for the first time that CD3 expression and BiTE engagement can be combined in a universal iPSC-derived CAR-iT cell product to overcome antigen heterogeneity and enhance efficacy in solid tumor settings. Citation Format: Eigen Peralta, Dan Lu, Mark Landon, Hui-Yi Chu, Amit Mehta, Philip Chu, Alec Witty, Tom Lee, Bahram Valamehr. Chimeric CD3 fusion receptors expressed on iPSC-derived universal TCR-less CAR-T and -NK cells synergize with bispecific engagers to enhance antitumor activity and limit antigen escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5513.
In Brief OBJECTIVE: To determine if women with a history of a previous preterm cesarean delivery experienced an increased risk of subsequent uterine rupture compared with women who had a previous nonclassic term cesarean delivery. METHODS: A prospective observational study was performed in singleton gestations that had a previous nonclassic cesarean delivery from 1999 to 2002. Women with a history of a previous preterm cesarean delivery were compared with women who had a previous term cesarean delivery. Women who had both a preterm and term cesarean delivery were included in the preterm group. RESULTS: A prior preterm cesarean delivery was significantly associated with an increased risk of subsequent uterine rupture (0.58% compared with 0.28%, P<.001). When women who had a subsequent elective cesarean delivery were removed (remaining n=26,454) women with a previous preterm cesarean delivery were still significantly more likely to sustain a uterine rupture (0.79% compared with 0.46%, P=.001). However, when only women who had a subsequent trial of labor were included, there was still an absolute increased risk of uterine rupture, but it was not statistically significant (1.00% compared with 0.68%, P=.081). In a multivariable analysis controlling for confounding variables (oxytocin use, two or more previous cesarean deliveries, a cesarean delivery within the past 2 years, and preterm delivery in the current pregnancy), patients with a previous preterm cesarean delivery remained at an increased risk of subsequent uterine rupture (P=.043, odds ratio 1.6, 95% confidence interval 1.01–2.50) compared with women with previous term cesarean delivery. CONCLUSION: Women who have had a previous preterm cesarean delivery are at a minimally increased risk for uterine rupture in a subsequent pregnancy when compared with women who have had previous term cesarean deliveries. LEVEL OF EVIDENCE: II Women with a previous nonclassic preterm cesarean delivery are at an increased risk for uterine rupture.
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