MiniMed 780G™ in 2- to 6-Year-Old Children: Safety and Clinical Outcomes After the First 12 Weeks.

Objective: The safety and impact of the advanced hybrid closed-loop (AHCL) system on glycemic outcome in 2- to 6-year-old children with type 1 diabetes and the diabetes distress of caregivers were evaluated. Research Design and Methods: This was an open-label prospective study (n = 35) with historical controls matched by treatment unit, diabetes duration, age, gender, and baseline treatment modality. The inclusion criteria were (1) type 1 diabetes diagnosis >6 months, (2) total daily dose of insulin ≥8 U/day, (3) HbA1c <10% (85 mmol/mol), and (4) capability to use insulin pump and continuous glucose monitoring. The MiniMed 780G™ AHCL in SmartGuard™ Mode was used for 12 weeks. Parental diabetes distress was evaluated with a validated Problem Areas In Diabetes-Parent, revised (PAID-PR) survey. Results: No events of diabetic ketoacidosis or severe hypoglycemia occurred. Between 0 and 12 weeks, HbA1c (mean change = -2.7 mmol/mol [standard deviation 5.7], P = 0.010), mean sensor glucose value (SG) (-0.8 mmol/L [1.0], P < 0.001), and time above range (TAR) (-8.6% [9.5], P < 0.001) decreased and time in range (TIR) (8.3% [9.3], P < 0.001) increased significantly, whereas no significant change in time below range (TBR) was observed. At the same time, PAID-PR score decreased from 37.5 (18.2) to 27.5 (14.8) (P = 0.006). Conclusions: MiniMed 780G™ AHCL is a safe system and 12-week use was associated with improvements in glycemic control in 2- to 6-year-old children with type 1 diabetes. In addition, AHCL is associated with a reduction in parental diabetes distress after 12-week use. ClinicalTrials.gov registration number: NCT04949022.

A role for matrix metalloproteinase 9 in IFNγ-mediated injury in developing lungs: relevance to bronchopulmonary dysplasia.

We noted a marked increase in IFNγ mRNA in newborn (NB) murine lungs after exposure to hyperoxia. We sought to evaluate the role of IFNγ in lung injury in newborns. Using a unique triple-transgenic (TTG), IFNγ-overexpressing, lung-targeted, externally regulatable NB murine model, we describe a lung phenotype of impaired alveolarization, resembling human bronchopulmonary dysplasia (BPD). IFNγ-mediated abnormal lung architecture was associated with increased cell death and the upregulation of cell death pathway mediators caspases 3, 6, 8, and 9, and angiopoietin 2. Moreover, an increase was evident in cathepsins B, H, K, L, and S, and in matrix metalloproteinases (MMPs) 2, 9, 12, and 14. The IFNγ-mediated abnormal lung architecture was found to be MMP9-dependent, as indicated by the rescue of the IFNγ-induced pulmonary phenotype and survival during hyperoxia with a concomitant partial deficiency of MMP9. This result was concomitant with a decrease in caspases 3, 6, 8, and 9 and angiopoietin 2, but an increase in the expression of angiopoietin 1. In addition, NB IFNγ TTG mice exhibited significantly decreased survival during hyperoxia, compared with littermate controls. Furthermore, as evidence of clinical relevance, we show increased concentrations of the downstream targets of IFNγ chemokine (C-X-C motif) ligands (CXCL10 and CXCL11) in baboon and human lungs with BPD. IFNγ and its downstream targets may contribute significantly to the final common pathway of hyperoxia-induced injury in the developing lung and in human BPD.

Endostatin concentration in cord plasma predicts the development of bronchopulmonary dysplasia in very low birth weight infants.

INTRODUCTION: Endostatin is an antiangiogenic growth factor. Together with proangiogenic growth factors it acts to shape the developing vasculature. Dysregulation of angiogenesis is a component in the pathogenesis of bronchopulmonary dysplasia. OBJECTIVE: Our goal was to study whether the concentration of circulating endostatin at birth is associated with the development of bronchopulmonary dysplasia in very low birth weight infants. PATIENTS AND METHODS: Endostatin concentration was measured in cord plasma from 92 very low birth weight infants (gestational age < 32 weeks; birth weight < 1500 g) and 48 healthy term infants (gestational age > 37 weeks; birth weight > 2500 g). RESULTS: Endostatin concentration in very low birth weight infants was lower than in healthy term infants. Within the very low birth weight group no correlation existed between endostatin concentration and gestational age or relative birth weight. Very low birth weight infants who subsequently developed bronchopulmonary dysplasia had higher cord endostatin than those who did not. Higher endostatin concentration was associated with higher odds for bronchopulmonary dysplasia. Adjusted for gestational age, the odds for bronchopulmonary dysplasia were higher. CONCLUSIONS: Circulating endostatin in term infants was higher than in very low birth weight infants, suggesting a temporal pattern for fetal endostatin concentration. In very low birth weight infants a high concentration of circulating endostatin at birth is associated with the subsequent development of bronchopulmonary dysplasia.

Placental growth factor and vascular endothelial growth factor receptor-2 in human lung development.

OBJECTIVE: We examined the pulmonary expression of 2 proangiogenic factors, namely, placental growth factor and vascular endothelial growth factor receptor-2, during lung development and acute and chronic lung injury in newborn infants. METHODS: Six groups were included in an immunohistochemical study of placental growth factor and vascular endothelial growth factor receptor-2, that is, 9 fetuses, 4 preterm and 8 term infants without lung injury who died soon after birth, 5 preterm infants with respiratory distress syndrome of <2 days and 7 with respiratory distress syndrome of >10 days, and 6 with bronchopulmonary dysplasia. Placental growth factor concentrations in tracheal aspirate fluid were measured in 70 samples from 20 preterm infants during the first postnatal week. RESULTS: In immunohistochemical analyses, placental growth factor staining was seen in bronchial epithelium and macrophages in all groups. Distal airway epithelium positivity was observed mostly in fetuses and in preterm infants who died soon after birth. Vascular endothelial growth factor receptor-2 staining was seen in vascular endothelium in all groups and also in lymphatic endothelium in fetuses. Vascular endothelial growth factor receptor-2 staining in arterial endothelium was associated with higher and staining in venous endothelium with lower gestational age. In capillaries, less vascular endothelial growth factor receptor-2 staining was seen in bronchopulmonary dysplasia. The mean placental growth factor protein concentration in tracheal aspirate fluid during the first postnatal week was 0.64 +/- 0.42 pg/mL per IgA-secretory component unit. Concentrations during the first postnatal week were stable. Lower placental growth factor concentrations correlated with chorioamnionitis and lactosyl ceramide positivity. CONCLUSIONS: The vascular endothelial growth factor receptor-2 staining pattern seems to reflect ongoing differentiation and activity of different endothelia. Lower vascular endothelial growth factor receptor-2 expression in capillary endothelium in bronchopulmonary dysplasia might be a reflection of the dysregulation of vascular development that is characteristic of bronchopulmonary dysplasia.

Pulmonary endostatin perinatally and in lung injury of the newborn infant.

OBJECTIVE: Endostatin is a potent angiogenesis inhibitor. Angiogenesis is central for the development of the human lung. The role of endostatin in the development of the human lung and its connection to chronic lung disease remain unclear. We set out to study the role of endostatin in the developing human lung and in acute and chronic lung injury in the preterm infant. METHODS: Nine fetuses, 14 control neonates without primary lung disease, 14 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia were included in the immunohistochemistry study. Tracheal aspirate-fluid samples of intubated very low birth weight infants during postnatal weeks 1 through 5 were analyzed with enzyme-linked immunosorbent assay. RESULTS: Endothelial cell staining was positive for endostatin in all 45 samples. Staining of epithelial cells (cuboidal, bronchiolar, and alveolar) was seen mostly in fetuses, as well as in infants with late respiratory distress syndrome and bronchopulmonary dysplasia. Staining in alveolar macrophages was most abundant in infants with late respiratory distress syndrome and bronchopulmonary dysplasia. Endostatin was expressed consistently in tracheal aspirate fluid, being highest during the first postnatal day. Higher endostatin concentrations correlated with parameters reflecting lower lung maturity. CONCLUSIONS: The pattern of pulmonary endostatin protein expression in immunohistochemistry and consistent endostatin protein appearance in tracheal aspirate fluid in human preterm infants indicate a role in the physiologic development of the lung. Preterm birth influences pulmonary endostatin protein expression, which may alter normal lung development and response to lung injury.

Up-regulation of trypsin and mesenchymal MMP-8 during development of hyperoxic lung injury in the rat.

Acute lung injury is marked by damage to alveolar-capillary barrier. High pulmonary levels of matrix-degrading serine proteinase trypsin and matrix metalloproteinases (MMP)-2, -8, and -9 have been shown in preterm infants with respiratory distress syndrome (RDS). We studied expression of trypsin and MMP-2, -8, and -9 in rats exposed to >95% oxygen for 24, 48, or 60 h. As demonstrated by zymography and Western immunoblotting, levels of trypsin and MMP-2, -8, and -9 in bronchoalveolar lavage fluid (BALF) sharply increased after 48 h of hyperoxia relative to normoxia controls. This coincided with increase in alveolar-capillary permeability, as indicated by increased protein concentration in BALF. Both neutrophil-derived 80-kD and mesenchymal cell-derived 60-kD MMP-8 isoforms were detected in BALF. Of them, mesenchymal-type MMP-8 predominated. In immunohistochemistry, alveolar epithelium showed strong trypsin expression at 48 and 60 h of hyperoxia, whereas it was predominantly negative in controls. MMP-8 was mostly expressed in macrophages. Marked up-regulation of trypsin and MMP-8 early during hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury and may therefore be potential targets for therapy of lung injury.

Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants.

RATIONALE: In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear. OBJECTIVES: We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants. METHODS: Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1-5 were analyzed with ELISA. RESULTS: Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid. CONCLUSIONS: The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.