The role of reactive oxygen species (ROS) signaling in the O(2) sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important ...sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses.
We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA).
A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC).
In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in Ca(2+)(i). In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in Ca(2+)(i) of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice.
Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in Ca(2+)(i) that cause acute hypoxic pulmonary vasoconstriction.
Treatment of infants with hypoplastic left heart syndrome (HLHS) remains challenging, and those affected remain with significant risks for mortality and morbidity throughout their lifetimes. The ...maternal–fetal environment (MFE) has been shown to affect outcomes for infants with HLHS after the Norwood procedure. The hybrid procedure, comprised of both catheterization and surgical components, is a less invasive option for initial intervention compared to the Norwood procedure. It is unknown how the MFE impacts outcomes following the hybrid procedure. This is a single-center, retrospective study of infants born with HLHS who underwent hybrid palliation from January 2009 to August 2021. Predictor variables analyzed included fetal, maternal, and postnatal factors. The primary outcome was mortality prior to Stage II palliation. We studied a 144-subject cohort. There was a statistically significant difference in mortality prior to stage II palliation in infants with prematurity, small for gestational age, and aortic atresia subtype (
p
< 0.001,
p
= 0.009, and
p
= 0.008, respectively). There was no difference in mortality associated with maternal diabetes, hypertension, obesity, smoking or illicit drug use, or advanced maternal age. State and national area deprivation index scores were associated with increased risk of mortality in the entire cohort, such that infants born in areas with higher deprivation had a higher incidence of mortality. Several markers of an impaired MFE, including prematurity, small for gestational age, and higher deprivation index scores, are associated with mortality following hybrid palliation. Individual maternal comorbidities were not associated with higher mortality. The MFE may be a target for prenatal counseling and future interventions to improve pregnancy and neonatal outcomes in this population.
Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. ...Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified.
We sought to determine the contribution of HIF-1α in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia.
We used mice with homozygous conditional deletion of HIF-1α combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses.
Tamoxifen-induced smooth muscle-specific deletion of HIF-1α attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures.
These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.
The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants ...who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care).
PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020.
Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori.
Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I2 statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model.
Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2–41.6; 31 studies, 2226 infants; I2=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0–14.3; 10 studies, 374 infants; I2=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6–61.5; 5 studies, 39 infants; I2=45%; Luis Furuya-Kanamori index=−0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported.
The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient–level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.
Early skin-to-skin contact (SSC), beginning in the delivery room, provides myriad health benefits for mother and baby. Early SSC in the delivery room is the standard of care for healthy neonates ...following both vaginal and cesarean delivery. However, there is little published evidence on the safety of this practice in infants with congenital anomalies requiring immediate postnatal evaluation, including critical congenital heart disease (CCHD). Currently, the standard practice following delivery of infants with CCHD in many delivery centers has been immediate separation of mother and baby for neonatal stabilization and transfer to a different hospital unit or a different hospital altogether. However, most neonates with prenatally diagnosed congenital heart disease, even those with ductal-dependent lesions, are clinically stable in the immediate newborn period. Therefore, we sought to increase the percentage of newborns with prenatally diagnosed CCHD who are born in our regional level II–III delivery hospitals who receive mother-baby SSC in the delivery room. Using quality improvement methodology, through a series of Plan-Do-Study-Act cycles we successfully increased mother-baby skin-to-skin contact in the delivery room for eligible cardiac patients born across our city-wide delivery hospitals from a baseline 15% to greater than 50%.
Background
Percutaneous closure of patent ductus arteriosus (PDA) in term neonates is established, but data regarding outcomes in infants born very preterm (<32 weeks of gestation) are minimal, and ...no published criteria exist establishing a minimal weight of 4 kg as a suitable cutoff. We sought to analyze outcomes of percutaneous PDA occlusion in infants born very preterm and referred for PDA closure at weights <4 kg.
Methods and Results
Retrospective analysis (January 2005–January 2014) was done at a single pediatric center. Procedural successes and adverse events were recorded. Markers of respiratory status (need for mechanical ventilation) were determined, with comparisons made before and after catheterization. A total of 52 very preterm infants with a median procedural weight of 2.9 kg (range 1.2–3.9 kg) underwent attempted PDA closure. Twenty‐five percent (13/52) of infants were <2.5 kg. Successful device placement was achieved in 46/52 (88%) of infants. An adverse event occurred in 33% of cases, with an acute arterial injury the most common complication. We observed no association between weight at time of procedure and the risk of an adverse event. No deaths were attributable to the PDA closure. Compared to precatheterization trends, percutaneous PDA closure resulted in improved respiratory status, including less exposure to mechanical ventilation (mixed effects logistic model, P<0.01).
Conclusions
Among infants born very preterm, percutaneous PDA closure at weights <4 kg is generally safe and may improve respiratory health, but risk of arterial injury is noteworthy. Randomized clinical trials are needed to assess clinically relevant differences in outcomes following percutaneous PDA closure versus alternative (surgical ligation) management strategies.
Critical congenital heart disease (cCHD) has neurodevelopmental sequelae that can carry into adulthood, which may be due to aberrant brain development or brain injury in the prenatal and ...perinatal/neonatal periods and beyond. Health disparities based on the intersection of sex, geography, race, and ethnicity have been identified for poorer pre- and postnatal outcomes in the general population, as well as those with cCHD. These disparities are likely driven by structural racism, disparities in social determinants of health, and provider bias, which further compound negative brain development outcomes. This review discusses how aberrant brain development in cCHD early in life is affected by reduced access to quality care (ie, prenatal care and testing, postnatal care) due to divestment in non-White neighbourhoods (eg, redlining) and food insecurity, differences in insurance status, location of residence, and perceived interpersonal racism and bias that disproportionately affects pregnant people of colour who have fewer economic resources. Suggestions are discussed for moving forward with implementing strategies in medical education, clinical care, research, and gaining insight into the communities served to combat disparities and bias while promoting cultural humility.
La cardiopathie congénitale critique (CCC) a des séquelles neurodéveloppementales qui peuvent se prolonger jusqu’à l’âge adulte, ce qui pourrait s’expliquer par un développement cérébral aberrant ou des lésions cérébrales survenant pendant les périodes pré, péri ou néonatale au-delà. Des disparités en matière de santé basées sur les chevauchements de facteurs comme le sexe, la région géographique, la race et l’origine ethnique ont été mises en lumière dans des cas d’issues pré ou postnatales négatives au sein de la population générale ainsi que parmi les sujets atteints de CCC. Ces disparités sont probablement attribuables au racisme structurel, aux inégalités sur le plan des déterminants sociaux de la santé et aux préjugés des prestataires de soins, qui aggravent encore les résultats négatifs du développement cérébral. Cet article de synthèse examine comment un développement cérébral aberrant survenant en début de vie dans un contexte de CCC dépend de divers facteurs, à savoir l’accès limité à des soins de qualité (c.-à-d. soins et examens prénataux, soins postnataux) en raison du désinvestissement dans les quartiers non blancs (p. ex. une exclusion systématique), l’insécurité alimentaire, les différences en matière d’assurabilité, le lieu de résidence de même que la perception du racisme et des préjugés interpersonnels affectant de manière disproportionnée les femmes de couleur enceintes moins bien nanties. Nous suggérons des stratégies à mettre en œuvre en matière d’éducation médicale, de soins cliniques, de recherche et d’information sur les communautés desservies dans le but de lutter contre les disparités et les préjugés tout en favorisant l’humilité culturelle.
Display omitted
To examine whether racial disparities in access to pediatric mental health care were affected during the COVID-19 telemedicine transition at both The Children's Hospital of Philadelphia (CHOP) and ...Boston Children's Hospital (BCH).
Electronic health records were queried for all unique outpatient visits from a pre-pandemic period in 2019 and a within-pandemic period in 2020. Changes in the proportion of patients were compared based on insurance status, clinic location, and racial identification. Hypotheses were tested via logistic regression analyses.
At CHOP, from 2019 to 2020, the proportion of racially minoritized patients significantly declined within a 1-month period from 62% to 51%, whereas the proportion of White-identifying patients increased from 38% to 49% (β = 0.47; z = 3.60; p =.0003), after controlling for insurance status and clinic location. At BCH, the proportion of racially minoritized patients significantly declined within a longer 6-month period between 2019 and 2020, from 62% to 59%, whereas the proportion of White-identifying patients increased from 38% to 41% (β = 0.13; z = 2.8; p = .006), after controlling for insurance status.
At CHOP and BCH, the COVID-19 telemedicine transition exacerbated pre-existing racial disparities in pediatric mental health services. Our findings suggest that racially minoritized patients receiving services in urban areas may be particularly at risk for losing access when telemedicine is implemented. Although there are limitations to this racial dichotomization, examining differences between White and racially minoritized patients can highlight ways in which White-identifying individuals have disproportionately received enhanced access to healthcare resources.
PDF
