Maternal nicotine exposure induces congenital heart defects in the offspring of mice.

Maternal cigarette smoking is a risk factor for congenital heart defects (CHDs). Nicotine replacement therapies are often offered to pregnant women following failed attempts of smoking cessation. However, the impact of nicotine on embryonic heart development is not well understood. In the present study, the effects of maternal nicotine exposure (MNE) during pregnancy on foetal heart morphogenesis were studied. Adult female mice were treated with nicotine using subcutaneous osmotic pumps at 0.75 or 1.5 mg/kg/day and subsequently bred with male mice. Our results show that MNE dose-dependently increased CHDs in foetal mice. CHDs included atrial and ventricular septal defects, double outlet right ventricle, unguarded tricuspid orifice, hypoplastic left ventricle, thickened aortic and pulmonary valves, and ventricular hypertrophy. MNE also significantly reduced coronary artery size and vessel abundance in foetal hearts. Moreover, MNE resulted in higher levels of oxidative stress and altered the expression of key cardiogenic regulators in the developing heart. Nicotine exposure reduced epicardial-to-mesenchymal transition in foetal hearts. In conclusion, MNE induces CHDs and coronary artery malformation in mice. These findings provide insight into the adverse outcomes of foetuses by MNE during pregnancy.

Patterns of cesarean birth among women living with HIV in Ontario: A cross-sectional, population-level study.

BACKGROUND: In Canada, as is found globally, women of reproductive age are a growing demographic of persons living with HIV. Combination antiretroviral therapy (cART) treatment enables women living with HIV (WLWH) to become pregnant without perinatal transmission, and they are increasingly planning to become pregnant. Since 2014, Canadian guidelines no longer recommend routine elective cesarean birth (CB) for women who are virally suppressed and receiving cART. It is unknown whether their obstetric care has changed since this update. Our objective was to describe trends in cesarean births among WLWH in Ontario, Canada, over a 12-year period. METHODS: Our research is co-led and codesigned with WLWH. We conducted a retrospective population-level cohort study using linked health administrative databases at ICES (formally, the Institute for Clinical and Evaluative Sciences). Participants were all women who gave birth in Ontario, between 2006/07 and 2017/18. We assessed their intrapartum characteristics and used multivariable regression to determine an association between HIV status and CB, controlling for sociodemographic and clinical variables. RESULTS: Since 2014, the overall proportion of CB among WLWH remained stable and was higher than among women without HIV (39.9% vs 29.0%, P < 0.001). In addition, the proportion of primary CB decreased between 2006 and 2010 and between 2014 and 2018 (28.5%-19.3%), whereas the proportion of repeat CB increased (13.1%-20.5%, P = 0.013). CONCLUSIONS: Because of decreasing HIV-related indications for CB, more practitioners may be following the guidelines for first-time mothers. Currently, no guidelines exist for care of WLWH with a previous CB, and opportunities for vaginal birth may be missed in this population.

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre-gestational diabetes.

Women with pre-gestational diabetes have a higher risk of producing children with congenital heart defects (CHDs), caused predominantly by hyperglycemia-induced oxidative stress. In this study, we evaluated if exercise during pregnancy could mitigate oxidative stress and reduce the incidence of CHDs in the offspring of diabetic mice. Female mice were treated with streptozotocin to induce pre-gestational diabetes, then mated with healthy males to produce offspring. They were also given access to running wheels 1 week before mating and allowed to exercise voluntarily until E18.5. Heart morphology, gene expression, and oxidative stress were assessed in foetal hearts. Maternal voluntary exercise results in a significantly lower incidence of CHDs from 59.5% to 25%. Additionally, diabetes-induced defects in coronary artery and capillary morphogenesis were also lower with exercise. Myocardial cell proliferation and epithelial-mesenchymal transition at E12.5 was significantly lower with pre-gestational diabetes which was mitigated with maternal exercise. Cardiac gene expression of Notch1, Snail1, Gata4 and Cyclin D1 was significantly higher in the embryos of diabetic mice that exercised compared to the non-exercised group. Furthermore, maternal exercise produced lower reactive oxygen species (ROS) and oxidative stress in the foetal heart. In conclusion, maternal exercise mitigates ROS and oxidative damage in the foetal heart, and results in a lower incidence of CHDs in the offspring of pre-gestational diabetes. Exercise may be an effective intervention to compliment clinical management and further minimize CHD risk in mothers with diabetes.

Test characteristics of point-of-care ultrasonography in patients with acute kidney injury.

BACKGROUND: Acute kidney injury is a common disorder that is associated with significant morbidity and mortality. Point-of-care ultrasonography (PoCUS) is an imaging modality performed at the bedside and is used to assess for obstructive causes of acute kidney injury. Little is known about the test characteristics of PoCUS in patients with acute kidney injury. OBJECTIVE: Our primary objective was to describe the test characteristics of PoCUS for the detection of hydronephrosis in patients presenting with acute kidney injury at our centre. Our secondary objective was to describe the current rate of use of PoCUS for this indication. RESULTS: In total, 7873 patients were identified between June 1, 2019 and April 30, 2021, with 4611 meeting inclusion criteria. Of these, 94 patients (2%) underwent PoCUS, and 65 patients underwent both PoCUS and reference standard, for a total of 124 kidneys included in our diagnostic accuracy analysis. The prevalence of hydronephrosis in our cohort was 33% (95% CI 25-41%). PoCUS had a sensitivity of 85% (95% CI 71-94%) and specificity of 78% (95% CI 68-87%) for the detection of hydronephrosis. CONCLUSION: We describe the test characteristics of PoCUS for the detection of hydronephrosis in a cohort of patients with acute kidney injury. The low uptake of this test presents an opportunity for quality improvement work to increase its use for this indication.

Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies.

Greater use of umbilical cord blood (UCB) for hematopoietic cell transplantation (HCT) is limited by the number of cells in banked units. Ex vivo culture strategies have been increasingly evaluated in controlled studies, but their impact on transplantation-related outcomes remains uncertain owing to the small patient numbers in these studies, necessitating an updated systematic review and meta-analysis. A systematic literature search was conducted using the MEDLINE, Embase, and Cochrane databases to March 18, 2022. Nine cohort-controlled phase I to III trials were identified, and data of 1146 patients undergoing umbilical cord blood transplantation (UCBT) were analyzed (308 ex vivo expanded and 838 unmanipulated controls). Expansion strategies involved cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and coculture with mesenchymal stromal cells in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 unmanipulated unit (4 studies). The included trials reported a median ex vivo expansion of CD34+ cells from 28-fold to 330-fold. Eight of the 9 studies demonstrated a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT demonstrated long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35% to 78% of double-unit recipients. Our meta-analysis revealed a lower risk of death at the study endpoint in patients who received ex vivo expanded grafts (odds ratio [OR], .66; 95% confidence interval [CI], .47 to .95; P = .02), while the risk of grade II-IV acute graft-versus-host disease was unchanged (OR, .79; 95% CI, .58 to 1.08; P = .14). This review indicates that UCBT following ex vivo expansion can accelerate initial engraftment. Durable donor chimerism can be achieved after transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long term outcomes remain unclear. Larger studies with longer-term outcomes are needed to better understand the merits of specific expansion strategies on survival.

Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes.

Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. In experimental animal models of pregestational diabetes induced-CHDs, upwards of 50% of offspring display congenital malformations of the heart, including septal, valvular, and outflow tract defects. Specifically, the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) signaling is a major driver of the development of CHDs in offspring of mice with pregestational diabetes. NO from endothelial nitric oxide synthase (eNOS) is crucial to cardiogenesis, regulating various cellular and molecular processes. In fact, deficiency in eNOS results in CHDs and coronary artery malformation. Embryonic hearts from diabetic dams exhibit eNOS uncoupling and oxidative stress. Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes.

Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes Mellitus in Mice.

Background Tetrahydrobiopterin is a cofactor of endothelial NO synthase ( eNOS ), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of tetrahydrobiopterin on eNOS uncoupling and congenital heart defects ( CHD s) induced by pregestational diabetes mellitus in mice. Methods and Results Adult female mice were induced to pregestational diabetes mellitus by streptozotocin and bred with normal male mice to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHD s were identified by histological analysis. Cell proliferation, eNOS dimerization, and reactive oxygen species production were assessed in the fetal heart. Pregestational diabetes mellitus results in a spectrum of CHD s in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHD s from 59% to 27%, and major abnormalities, such as atrioventricular septal defect and double-outlet right ventricle, were absent in the sapropterin-treated group. Lineage tracing reveals that pregestational diabetes mellitus results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes mellitus were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered reactive oxygen species levels in the fetal heart. Conclusions Sapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation, and prevents the development of CHD s in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHD s in pregestational diabetes mellitus.