The role of glucose in physiological and pathological heart formation.

Cells display distinct metabolic characteristics depending on its differentiation stage. The fuel type of the cells serves not only as a source of energy but also as a driver of differentiation. Glucose, the primary nutrient to the cells, is a critical regulator of rapidly growing embryos. This metabolic change is a consequence as well as a cause of changes in genetic program. Disturbance of fetal glucose metabolism such as in diabetic pregnancy is associated with congenital heart disease. In utero hyperglycemia impacts the left-right axis establishment, migration of cardiac neural crest cells, conotruncal formation and mesenchymal formation of the cardiac cushion during early embryogenesis and causes cardiac hypertrophy in late fetal stages. In this review, we focus on the role of glucose in cardiogenesis and the molecular mechanisms underlying heart diseases associated with hyperglycemia.

Maternal-Neonatal Dyad Outcomes of Maternal COVID-19 Requiring Extracorporeal Membrane Support: A Case Series.

OBJECTIVE: This study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery. STUDY DESIGN: The clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series. RESULTS: Both women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates. CONCLUSION: This case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period. KEY POINTS: · COVID-19 may present with a more severe course in pregnancy.. · ECMO may be used in pregnant woman with severe COVID-19.. · Delivery can be performed on ECMO without added fetal risk..

Can prenatal ultrasound predict adverse neonatal outcomes in SARS-CoV-2-affected pregnancies?

BACKGROUND: On the basis of available data, at least 1 ultrasound assessment of pregnancies recovering from SARS-CoV-2 infection is recommended. However, reports on prenatal imaging findings and potential associations with neonatal outcomes following SARS-CoV-2 infection in pregnancy have been inconclusive. OBJECTIVE: This study aimed to describe the sonographic characteristics of pregnancies after confirmed SARS-CoV-2 infection and assess the association of prenatal ultrasound findings with adverse neonatal outcomes. STUDY DESIGN: This was an observational prospective cohort study of pregnancies diagnosed with SARS-CoV-2 by reverse transcription polymerase chain reaction between March 2020 and May 2021. Prenatal ultrasound evaluation was performed at least once after diagnosis of infection, with the following parameters measured: standard fetal biometric measurements, umbilical and middle cerebral artery Dopplers, placental thickness, amniotic fluid volume, and anatomic survey for infection-associated findings. The primary outcome was the composite adverse neonatal outcome, defined as ≥1 of the following: preterm birth, neonatal intensive care unit admission, small for gestational age, respiratory distress, intrauterine fetal demise, neonatal demise, or other neonatal complications. Secondary outcomes were sonographic findings stratified by trimester of infection and severity of SARS-CoV-2 infection. Prenatal ultrasound findings were compared with neonatal outcomes, severity of infection, and trimester of infection. RESULTS: A total of 103 SARS-CoV-2-affected mother-infant pairs with prenatal ultrasound evaluation were identified; 3 cases were excluded because of known major fetal anomalies. Of the 100 included cases, neonatal outcomes were available in 92 pregnancies (97 infants); of these, 28 (29%) had the composite adverse neonatal outcome, and 23 (23%) had at least 1 abnormal prenatal ultrasound finding. The most common abnormalities seen on ultrasound were placentomegaly (11/23; 47.8%) and fetal growth restriction (8/23; 34.8%). The latter was associated with a higher rate of the composite adverse neonatal outcome (25% vs 1.5%; adjusted odds ratio, 22.67; 95% confidence interval, 2.63-194.91; P<.001), even when small for gestational age was removed from this composite outcome. The Cochran Mantel-Haenszel test controlling for possible fetal growth restriction confounders continued to show this association (relative risk, 3.7; 95% confidence interval, 2.6-5.9; P<.001). Median estimated fetal weight and birthweight were lower in patients with the composite adverse neonatal outcome (P<.001). Infection in the third trimester was associated with lower median percentile of estimated fetal weight (P=.019). An association between placentomegaly and third-trimester SARS-CoV-2 infection was noted (P=.045). CONCLUSION: In our study of SARS-CoV-2-affected maternal-infant pairs, rates of fetal growth restriction were comparable to those found in the general population. However, composite adverse neonatal outcome rates were high. Pregnancies with fetal growth restriction after SARS-CoV-2 infection were associated with an increased risk for the adverse neonatal outcome and may require close surveillance.

A novel murine model of atrial fibrillation by diphtheria toxin-induced injury.

The treatment of atrial fibrillation (AF) continues to be a significant clinical challenge. While genome-wide association studies (GWAS) are beginning to identify AF susceptibility genes (Gudbjartsson et al., Nature, 2007, 448, 353-357; Choi et al., Circ. Res., 2020, 126, 200-209; van Ouwerkerk et al., Circ. Res., 2022, 127, 229-243), non-genetic risk factors including physical, chemical, and biological environments remain the major contributors to the development of AF. However, little is known regarding how non-genetic risk factors promote the pathogenesis of AF (Weiss et al., Heart Rhythm, 2016, 13, 1868-1877; Chakraborty et al., Heart Rhythm, 2020, 17, 1,398-1,404; Nattel et al., Circ. Res., 2020, 127, 51-72). This is, in part, due to the lack of a robust and reliable animal model induced by non-genetic factors. The currently available models using rapid pacing protocols fail to generate a stable AF phenotype in rodent models, often requiring additional genetic modifications that introduce potential sources of bias (Schüttler et al., Circ. Res., 2020, 127, 91-110). Here, we report a novel murine model of AF using an inducible and tissue-specific activation of diphtheria toxin (DT)-mediated cellular injury system. By the tissue-specific and inducible expression of human HB-EGF in atrial myocytes, we developed a reliable, robust and scalable murine model of AF that is triggered by a non-genetic inducer without the need for AF susceptibility gene mutations.

GLUT1 overexpression enhances glucose metabolism and promotes neonatal heart regeneration.

The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant accumulation of glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites including nucleotides upon injury. Inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level, suggesting that the glucose enhances the cardiomyocyte regeneration through the supply of nucleotides. Our data suggest that the increase in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.

Multi-Institutional Practice-Patterns in Fetal Congenital Heart Disease Following Implementation of a Standardized Clinical Assessment and Management Plan.

Background Prenatal diagnosis of congenital heart disease has been associated with early-term delivery and cesarean delivery (CD). We implemented a multi-institutional standardized clinical assessment and management plan (SCAMP) through the University of California Fetal-Maternal Consortium. Our objective was to decrease early-term (37-39 weeks) delivery and CD in pregnancies complicated by fetal congenital heart disease using a SCAMP methodology to improve practice in a high-risk and clinically complex setting. Methods and Results University of California Fetal-Maternal Consortium site-specific management decisions were queried following SCAMP implementation. This contemporary intervention group was compared with a University of California Fetal-Maternal Consortium historical cohort. Primary outcomes were early-term delivery and CD. A total of 496 maternal-fetal dyads with prenatally diagnosed congenital heart disease were identified, 185 and 311 in the historical and intervention cohorts, respectively. Recommendation for later delivery resulted in a later gestational age at delivery (38.9 versus 38.1 weeks, P=0.01). After adjusting for maternal age and site, historical controls were more likely to have a CD (odds ratio [OR],1.8; 95% CI, 2.1-2.8; P=0.004) and more likely (OR, 2.1; 95% CI, 1.4-3.3) to have an early-term delivery than the intervention group. Vaginal delivery was recommended in 77% of the cohort, resulting in 61% vaginal deliveries versus 50% in the control cohort (P=0.03). Among pregnancies with major cardiac lesions (n=373), vaginal birth increased from 51% to 64% (P=0.008) and deliveries ≥39 weeks increased from 33% to 48% (P=0.004). Conclusions Implementation of a SCAMP decreased the rate of early-term deliveries and CD for prenatal congenital heart disease. Development of clinical pathways may help standardize care, decrease maternal risk secondary to CD, improve neonatal outcomes, and reduce healthcare costs.

Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome.

Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband's dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFß signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. KEY MESSAGE: Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.

The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2.

While pregnancy increases the risk for severe COVID-19, the clinical and immunological implications of COVID-19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID-19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1,400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID-19 show increased inflammation and unique IFN-λ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery, altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, and ESM1 and reducing BGN and CD209. Finally, COVID-19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3, and CCL21), while some undergo IL-1ß/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID-19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.

Most, but not all, yeast strains in the deletion library contain the [PIN(+)] prion.

The yeast deletion library is a collection of over 5100 single gene deletions that has been widely used by the yeast community. The presence of a non-Mendelian element, such as a prion, within this library could affect the outcome of many large-scale genomic studies. We previously showed that the deletion library parent strain contained the [PIN(+)] prion. [PIN(+)] is the misfolded infectious prion form of the Rnq1 protein that displays distinct fluorescent foci in the presence of RNQ1-GFP and exists in different physical conformations, called variants. Here, we show that over 97% of the library deletion strains are [PIN(+)]. Of the 141 remaining strains that have completely (58) or partially (83) lost [PIN(+)], 139 deletions were able to efficiently maintain three different [PIN(+)] variants despite extensive growth and storage at 4 degrees C. One strain, cue2Delta, displayed an alteration in the RNQ1-GFP fluorescent shape, but the Rnq1p prion aggregate shows no biochemical differences from the wild-type. Only strains containing a deletion of either HSP104 or RNQ1 are unable to maintain [PIN(+)], indicating that 5153 non-essential genes are not required for [PIN(+)] propagation.

Perinatal Maternal-Fetal/Neonatal Transmission of COVID-19: A Guide to Safe Maternal and Neonatal Care in the Era of COVID-19 and Physical Distancing.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is highly contagious and can cause serious respiratory illness and other clinical manifestations. The aim of this review is to summarize the clinical presentation, diagnosis, and outcomes of COVID-19 in pregnant women and neonates, who may be especially vulnerable to the effects of COVID-19, and to discuss what is known about potential maternal-fetal and maternal-neonatal transmission of SARS-CoV-2.

Modelo ecológico y sistemas de regulación moral, cultural y legal como factores de riesgo y protección frente al consumo de sustancias ilícitas en estudiantes de la Universidad de Nariño / Ecological model and systems of moral, cultural and legal regulation as risk and protection factors against substance abuse among students of the University of Nariño

Objetivo: El propósito del presente estudio fue analizar los factores de riesgo y protección frente al consumo de sustancias ilícitas en los estudiantes de la Universidad de Nariño desde la perspectiva del modelo ecológico y las características de la regulación moral, cultural y legal de este fenómeno. Método: El estudio se desarrolló desde el paradigma cuantitativo, enmarcado en los estudios analíticos, específicamente de corte transversal. Resultados: Los datos demuestran que dos de las variables que hacen parte del microsistema de los estudiantes se comportan como factores de riesgo para el consumo de sustancias psicoactivas ilícitas, específicamente: fumar más de tres cigarrillos diarios y observar a padres o padrastros agredirse físicamente. Por otra parte, la regulación moral es el único factor que se identificó como protector. Conclusión: Los resultados del estudio resaltan la importancia de las variables que hacen parte del contexto más cercano a la persona (incluyendo sus propios hábitos y reglas), como determinantes de conductas de riesgo que comprometen el bienestar individual y colectivo y la percepción de la regulación moral como factor protector.

Objective: The purpose of this study was to analyze risk and protection factors against substance abuse among students of the University of Nariño from the perspective of the ecological model and the characteristics of moral, cultural and legal regulation of this phenomenon. Method: The study was conducted from the quantitative paradigm which is framed in analytical studies, specifically a cross-sectional study. Results: The data show that two of the variables that are part of the students' microsystem behave as risk factors for substance abuse. These are: smoking more than three cigarettes a day and watching parents or stepparents physically attacking themselves. Moreover, moral regulation is the only factor that was identified as the protector one. Conclusion: The results of the study highlight the importance of the variables that are part of the nearest context to the person (including their own habits and rules) as determinants of risk behaviors that compromise the individual and collective welfare and perception of moral regulation as a protective factor.