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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 TGFβ 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 messagePrimary 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.

BackgroundCongenital diaphragmatic hernia (CDH) is a cause of significant morbidity. CDH is the most common neonatal diagnosis requiring extracorporeal membrane oxygenation (ECMO).MethodsWe compared the different characteristics of ECMO and non-ECMO patients with CDH in a case-control study. Data were extracted from the Kids’ Inpatient Database. Records from 2006 to 2016 were used. Patients <28 days of age were selected. CDH infants (n=9217) were stratified based on whether they were treated with ECMO (n=348) or not (n=8869). Demographic data and hospital characteristics were collected. Categorical variables were analyzed using χ2 tests to determine associations between the ECMO-treated and non-ECMO-treated infants on demographic and clinical characteristics. Differences in hospitalization costs were analyzed using t-test. Multivariable logistic regression analyses were stratified by clinical and demographic characteristics to identify factors associated with ECMO. Significant variables were included in the model to determine predictors for ECMO.ResultsThe proportion of infants treated with ECMO was higher in White infants, and lower in Hispanics. The cost of hospitalization was higher with ECMO (p<0.0001). ECMO patients were more likely to be treated in their birth hospital (p<0.001), at an urban location (p<0.001) and more likely to have private insurance (p=0.011). After adjusting for confounders, odds of ECMO treatment remained lower in Hispanics (p=0.001) and self-payers (p=0.004).ConclusionThere was a decrease in the proportion of CDH infants needing ECMO use in the USA from 2006 to 2016. Disparities exist in ECMO use and mortality between different ethnic groups and regions of the USA.

Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes.Key messagesDuring perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment.During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs).Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated.Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT).Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.

Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P < 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype.

Hypoglycemia and impaired metabolic transition are frequently observed in neonates during the first 24–48 h after birth [1, 2]. Severe (< 36 mg/dL or 2 mmol/L) and recurrent (3 or more episodes) hypoglycemia can cause neurological injury and developmental delays. The ambiguity regarding a threshold blood glucose concentration remains due to differing values proposed by various professional organizations. This poses a challenge in diagnosing neonatal hypoglycemia in addition to using a single blood glucose value, which in itself is not entirely reflective of various key molecular processes uncovered by in vitro or pre-clinical studies. The symptoms of hypoglycemia can also be present in conditions other than hypoglycemia, e.g., sepsis and polycythemia, and in many cases, hypoglycemia is clinically unrecognized. Therefore, early screening of at-risk and otherwise healthy-appearing neonates is essential. Continuous glucose monitoring and early interventions such as glucose gel, breast and formula feeding, and intravenous glucose administration are utilized to prevent long-term neurological impairments. However, the safe limits of serum glucose that will prevent neuroglycopenia and neural injury are elusive. The impact of early screening and available therapies on neurodevelopmental outcomes remains uncertain due to the absence of a robust clinical design and combining all causes of neonatal hypoglycemia without making further distinctions from other conditions. This review highlights the controversies in definitions and the most recent information on long-term neurodevelopmental outcomes that may impact the early management of NH. Conclusion : Optimizing the definitions and treatment of neonatal dysglycemia is crucial for preventing hypoglycemia-related brain injury. Continuous glucose monitoring technology in neonates offers a promising approach for real-time screening and early intervention.  What is Known: •  There is ongoing debate regarding the optimal glucose threshold for intervention and prevention of  hypoglycemia-induced brain injury. This suggests brain injury may be incurred over a range rather than a single blood glucose concentration. What is New: • Recent studies suggest that glucose concentrations between 36 mg/dL (2 mmol/L) and 47 mg/dL (2.6 mmol/L) are acceptable in asymptomatic neonates. However, neurological injury was observed in early school age with glucose values of <36 mg/dl (<2 mmol/L) and in mid-childhood of <30-36 mg/dL (<1.7 -2 mmol/L). This suggests brain injury may be incurred over a range rather than a single blood glucose concentration. • Continuous glucose monitoring (CGM) highlights real-time glucose measurement and glycemic lability in neonates.  Its use may mitigate long-term neurologic injury by improving early recognition and treatment.

Glucocorticoids might prevent bronchopulmonary dysplasia in extremely preterm infants but have adverse neurodevelopmental effects. In this trial involving preterm infants, there was little difference in survival without bronchopulmonary dysplasia or in the occurrence of neurodevelopmental impairment with hydrocortisone as compared with placebo.

To evaluate the utility of tracheal aspirates in suspected pneumonia in intubated neonates and to measure the burden of antibiotic use associated with a positive tracheal aspirate culture. Retrospective cohort study between January 2016 and December 2017. A level IV neonatal intensive care unit (NICU). Intubated patients with a tracheal aspirate culture. Data on temporally associated clinical measures of illness, laboratory and radiographic testing, and clinical demographic information were analyzed. Positive tracheal aspirate cultures were associated with lower birth weight and a normal immature to total neutrophil ratio (I/T ratio). Positive tracheal aspirates were not significantly associated with clinical, laboratory, or radiographic markers used in clinical practice to screen for infection. Despite the lack of positive clinical associations, a positive tracheal aspirate culture was associated with increased risk of prolonged antibiotic exposure. These findings suggest that positive tracheal aspirates do not always represent clinical infection and may result in unnecessary antibiotic exposure.

ObjectiveTo examine whether changes in survival without moderate or severe neurodevelopmental impairment (NDI) at 18–26 months’ corrected age from 1999 to 2018 differed between male and female infants.DesignThis retrospective cohort study used data from the NICHD Neonatal Research Network hospitals. Robust Poisson regression models were used to estimate adjusted relative risks (aRRs) and 95% CIs for survival without moderate or severe NDI between males and females. Interactions between sex and time were assessed to evaluate temporal differences in the outcome by sex. Variables adjusted for included centre, maternal age, ethnicity/race, gestational age and small for gestational age.PatientsInborn infants with gestational age of 22–26 weeks at NICHD Neonatal Research Network hospitals from 1999 to 2018.Main outcome measureChange over time in survival without moderate or severe NDI at 18–26 months’ corrected age between male and female infants.ResultsOf 26 307 infants, 13 045 (49.6%) were male. Survival without moderate or severe NDI declined for both sexes over time, from 32.9% to 30.6% for males and from 47.4% to 40.0% for females, between 1999–2003 and 2014–2018. Males were less likely than females to survive without moderate or severe NDI (aRR=0.80; 95% CI 0.78 to 0.83). Changes in survival without moderate or severe NDI did not differ between males and females.ConclusionThere were no differential changes in survival without moderate or severe NDI between male and female infants.

ObjectiveTo determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).Study designCohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks’ postmenstrual age was used to produce adjusted odds ratios (aOR).ResultsCompared with infants in the reference group (22–28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50–63 (aOR 1.77, 95% CI 1.03–3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44–6.48). The aOR for NDI did not vary significantly by age of PNS exposure.ConclusionFor infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptome analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provides a high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis.Key messagesGenetic and environmental factors contribute to congenital heart defects (CHDs).How hypoxia contributes to Tetralogy of Fallot (TOF) pathogenesis after birth is unclear.Systems biology-based analysis revealed distinct molecular signature in CHDs.Gene expression modules specifically associated with cyanotic TOF were uncovered.Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.