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The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice (Dll4+/lacz). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at P14. Vascular defects coincided with polarization of lung EC expression toward JAG1-NICD-HES1 signature and decreased tip cell-like (Car4) markers. Dll4+/lacZ mice had impaired terminal bronchiole development at the canalicular stage and impaired alveolarization upon lung maturity. We discovered that alveolar type I cell (Aqp5) markers progressively decreased in Dll4+/lacZ mice after birth. Moreover, in human lung EC, DLL4 deficiency programmed a hypersprouting angiogenic phenotype cell autonomously. In conclusion, DLL4 is expressed from the canalicular to alveolar stage in mice and humans, and Dll4 haploinsufficiency programs dysmorphic microvascularization, impairing alveolarization. Our study reveals an obligate role for DLL4-regulated angiogenesis in distal lung morphogenesis.

To identify factors leading to readmission for tracheostomized, ventilator-dependent infants2 years of age.Retrospective cohort study of 117 tracheostomized, ventilator-dependent infants followed through 2 years of age.Home ventilator use (at hospital discharge, 6 and 12 months of age), inhaled steroid use (at 12 and 24 months of age), oxygen dependence (at 6 and 12 months of age) and tracheostomy (at discharge, 6 and 12 months of age) were increased risks for rehospitalization. Equipment malfunction throughout the first 2 years also contributed to readmissions. Viral infection, with rhinovirus/enterovirus the most commonly identified pathogen, was the most common etiology for rehospitalization. Diuretic use and initial comorbid diagnoses were not associated with increased risk of rehospitalization.The risk for rehospitalization for infants requiring tracheostomy and ventilator support was affected by prolonged oxygen use, prolonged ventilator dependence, inhaled steroid use and equipment malfunction, and was equally distributed throughout the first 2 years of life.

In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsis-induced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)–mediated inflammation and alveolar remodeling. Six-day-old NOX2+/+ and NOX2−/− mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2+/+ mice was decreased by >50% in NOX2−/− mice. LPS-induced TLR4 signaling evident by inhibitor of NF-κB kinase-β and mitogen-activated protein kinase phosphorylation, and nuclear factor-κB/AP-1 translocation were attenuated in NOX2−/− mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX2+/+ mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX2−/− mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2−/− mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.

OBJECTIVE To determine the association of timing of steroid therapy for bronchopulmonary dysplasia (BPD) and outcomes. METHODS Retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD. Infants treated with steroids at day of life (DOL) 14-28 (moderately late group) were compared to infants treated at DOL 29-42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge. RESULTS Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified. The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high frequency ventilation (96% vs 47%, P

Objective This article aimed to identify readmission risk factors through 2 years of life for infants with severe bronchopulmonary dysplasia (BPD) who do not require tracheostomy and ventilatory support after neonatal intensive care unit (NICU) discharge. It also aimed to identify if clinical differences exist between the subcategories of severe BPD. Study Design A retrospective chart review was performed on 182 infants with severe BPD born between 2010 and 2015. A total of 130 infants met the inclusion criteria and were stratified into three groups based on their respiratory status at 36 weeks of gestational age: group A—oxygen (O2), group B—assisted ventilation (AV), group C—both O2 and AV. NICU clinical risk factors for readmission were assessed at set time points (6/12/18/24 months). Reasons for readmission were assessed for the entire cohort and severe BPD subgroups. Conclusion An NICU diagnosis of neurologic abnormality, necrotizing enterocolitis, invasive NICU infection, dysphagia, and O2 at NICU discharge differed between the three subgroups of severe BPD. The most common cause of readmission was viral respiratory tract infection. Inhaled steroid use remained stable over time, while oxygen use and diuretic use declined over time. Risk factors for readmission in the entire cohort included g-tube, O2 use, and diuretic use at 12 months. There was no significant difference in readmission rates between the three BPD subgroups.

Objective To report on the population of infants receiving a tracheostomy, identify acute post-tracheostomy clinical decompensations, and seek predictive markers associated with acute complications following the placement of a tracheostomy. Study Design Retrospective deidentified clinical data was provided by the Infant Pulmonary Data Repository at Children's Mercy Hospital, Kansas City. Data from infants undergoing tracheostomy from January 1, 2008 through September 30, 2016 were divided into one of two study groups based on clinical correlations: (1) no acute decompensations within 72 hours post-tracheostomy or (2) acute clinical decompensation defined as sustained escalation of respiratory care within the 72 hours following tracheostomy. Results Thirty-four percent of infants undergoing tracheostomy during this period developed acute post-tracheostomy clinical decompensations. Elevated pre-tracheostomy positive end expiratory pressure, mean airway pressure, and echocardiogram findings suggestive of pulmonary hypertension (PH) or ventricular dysfunction were associated with acute post-tracheostomy clinical decompensations. Additionally acute post-tracheostomy clinical decompensation was associated with higher rate of death prior to discharge. Conclusion Infants requiring higher respiratory support and infants with PH or ventricular dysfunction are at risk of acute post-tracheostomy clinical decompensation, thus identifying these patients may lead to better pre-tracheostomy counseling and potentially targeted treatments to decrease this risk.

Objective The objective of this study was to assess the outcomes of preterm infants who failed to extubate following initial treatment with steroids. Materials and Methods This is a retrospective cohort study of ventilator-dependent preterm infants treated with first course of systemic steroids to facilitate extubation. Outcomes of infants who successfully extubated were compared with infants who failed to extubate. Results In this study, 74 infants (mean gestation 25.4 ± 1.4 weeks and mean birth weight 764 ± 163 g) met inclusion criteria. Of these, 41 (55%) were successfully extubated and 33 (45%) were not. Baseline demographics were similar between the two groups. The primary outcome of severe bronchopulmonary dysplasia (BPD) or death at 36 weeks was higher among infants who failed to extubate (94 vs. 63%, p = 0.002). Severe BPD remained significantly higher even after adjustment for potential confounders (odds ratio: 12.2, 95% confidence interval: 2.1–70.5, p = 0.005). Extubation failure was also associated with substantially higher rate of tracheostomy (32 vs. 5%, p = 0.003) and gastrostomy tube placement (61 vs. 22%, p = 0.001), as well as longer days of hospitalization (179 ± 72 vs. 129 ± 44 days, p = 0.001) and mechanical ventilation (112 ± 89 vs. 52 ± 42 days, p Conclusion Failure to extubate after first course of systemic steroids for BPD is associated with poor prognostic implications.

Objective: Assess the impact of intercurrent respiratory infections in infants

To assess pulmonary outcomes of infants

Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?

OBJECTIVE This study aims to determine risk factors for rehospitalization in extremely premature infants. STUDY DESIGN A retrospective cohort study of 157 infants born

We present an unusual case of hyperbilirubinemia with rapid early progression leading to bilirubin encephalopathy in a term neonate. Despite early recognition and intervention, the total serum bilirubin reached a maximum level of 39 mg/dL at 32 hours of life. Prior to an emergent exchange transfusion, the patient’s diagnostic evaluation was significant for Coombs-negative microangiopathic hemolytic anemia and thrombocytopenia. Further testing revealed a deficiency of ADAMTS13 protein, or von Willebrand factor-cleaving protease, a finding diagnostic of congenital thrombotic thrombocytopenic purpura, or Upshaw-Schulman syndrome. This rare disease is often misdiagnosed, especially in the newborn period.

OBJECTIVE To correlate intrauterine and postnatal growth with bronchopulmonary dysplasia (BPD) classification at 36 weeks postmenstrual age (PMA). STUDY DESIGN A retrospective cohort design reviewing medical records for infants

We present a case of a late-preterm infant admitted for suspected cyanotic heart disease who was found to have a thrombosed ductus arteriosus. Maternal history was significant for heterozygosity for Factor V Leiden, treated with enoxaparin during her pregnancy, and congenital hearing loss. The neonate did not have a Factor V Leiden mutation detected, but was found to have a heterozygous mutation within the MFTHR gene. He was treated with anticoagulation, with improving hemodynamics measured by echocardiogram. This case presents a rare disease, which is potentially fatal if diagnosis is delayed.