A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations.

Congenital disorders of glycosylation (CDGs) affect multiple systems and present a broad spectrum of clinical features, often including skeletal dysplasia. Exome sequencing has led to the identification of new CDG genes. Immune and skeletal phenotypes associated with mutations in PGM3, encoding a protein that converts N-acetyl-glucosamine-6-phosphate into N-acetyl-glucosamine-1-phosphate, were recently reported. Through exome sequencing, we identified a novel homozygous mutation (c.1135T>C; p.Phe379Leu) in PGM3 in two siblings with bone marrow failure, severe combined immunodeficiency, renal and intestinal malformations, and a skeletal dysplasia resembling Desbuquois dysplasia. Severe respiratory compromise secondary to lung hypoplasia and pulmonary hypertension, and intestinal obstruction led to their demise. We thus report the most severe phenotype described so far associated with PGM3 mutations. This CDG should be considered in the presence of skeletal dysplasia associated with severe immunodeficiency. © 2017 American Society for Bone and Mineral Research.

Learning Neonatal Intubation Using the Videolaryngoscope: A Randomized Trial on Mannequins.

INTRODUCTION: The use of the videolaryngoscope (VL) facilitates intubation in adults and children, but experience in neonates is scarce. The objective of this study was to compare the VL with the classic laryngoscope (CL) in acquiring the skill of neonatal endotracheal intubation (ETI) and evaluate transferability of skill from VL to CL. We hypothesize that, on a neonatal mannequin, the VL will be superior to the CL with regard to success rate and that the skill will be transferred from VL to CL. METHODS: A randomized controlled trial was held at Sainte-Justine Hospital's simulation center. Third- and fourth-year medical students were randomized into group A, which used VL for the first phase and CL for the second phase, and group B, which used CL for both phases. Each subject performed 9 ETI on 3 simulated neonatal airways in each phase. RESULTS: Thirty-four students performed 612 intubations. Success in group A was higher than in group B in the first phase of the study (96.5% vs. 84.6%, P < 0.001). During phase 2, group A's success did not change significantly (91.7% vs. 96.5%, P = 0.07). Time to successful intubation was longer using the VL (27.6 vs. 15.6 seconds, P < 0.001), but there was no difference in phase 2 (12.5 vs. 10.2 seconds, P = 0.24). There were no esophageal intubations using the VL. CONCLUSIONS: Success rate of ETI on mannequins was improved, and esophageal intubations decreased while learning ETI using the VL compared with the CL. Once ETI is learned on mannequins using the VL, this skill is transferrable to the CL.

Videolaryngoscope for Teaching Neonatal Endotracheal Intubation: A Randomized Controlled Trial.

OBJECTIVE: To assess whether the videolaryngoscope (VL) is superior to the classic laryngoscope (CL) in acquiring skill in neonatal endotracheal intubation (ETI) and, once acquired with the VL, whether the skill is transferable to the CL. METHODS: This randomized controlled trial, in a level 3 Canadian hospital, recruited junior pediatric residents who performed ETI in the NICU. The primary outcome was success rate of ETI. Secondary outcomes were time to successful intubation, number of bradycardia episodes andlowest oxygen saturation during procedure, occurrence of mucosal trauma, reason for ETI failure, and recognition of problems related to ETI bysupervisor andresident. RESULTS: In phase 1, 34 pediatric residents performed 213 ETIs by using either VL or CL. Intervention groups were comparable at baseline. The success rate was higher (75.2% vs 63.4%, P = .03), and time to successful intubation was longer, inVL group (57 vs 47 seconds, P = .008). In phase 2, 23 residents performed 55 ETIs using CL. The success rate of residents inVL group performing ETI by using the CL was 63% (compared with 75% in phase 1, P = .16). CONCLUSIONS: When learning ETI, the success rate is improved with the VL. Time to successful intubation is longer, but the difference is not clinically significant. When switched to the CL, residents' success rate slightly decreased, but not significantly. This suggests that residents retain a certain level of ETI skill when switched to the CL. The VL is a promising tool for teaching neonatal ETI.

Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial.

CONTEXT: Even though red blood cells (RBCs) are lifesaving in neonatal intensive care, transfusing older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and length of hospital stay. OBJECTIVE: To determine if RBCs stored for 7 days or less compared with usual standards decreased rates of major nosocomial infection and organ dysfunction in neonatal intensive care unit patients requiring at least 1 RBC transfusion. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized controlled trial in 377 premature infants with birth weights less than 1250 g admitted to 6 Canadian tertiary neonatal intensive care units between May 2006 and June 2011. INTERVENTION: Patients were randomly assigned to receive transfusion of RBCs stored 7 days or less (n = 188) vs standard-issue RBCs in accordance with standard blood bank practice (n = 189). MAIN OUTCOME MEASURES: The primary outcome was a composite measure of major neonatal morbidities, including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular hemorrhage, as well as death. The primary outcome was measured within the entire period of neonatal intensive care unit stay up to 90 days after randomization. The rate of nosocomial infection was a secondary outcome. RESULTS: The mean age of transfused blood was 5.1 (SD, 2.0) days in the fresh RBC group and 14.6 (SD, 8.3) days in the standard group. Among neonates in the fresh RBC group, 99 (52.7%) had the primary outcome compared with 100 (52.9%) in the standard RBC group (relative risk, 1.00; 95% CI, 0.82-1.21). The rate of clinically suspected infection in the fresh RBC group was 77.7% (n = 146) compared with 77.2% (n = 146) in the standard RBC group (relative risk, 1.01; 95% CI, 0.90-1.12), and the rate of positive cultures was 67.5% (n = 127) in the fresh RBC group compared with 64.0% (n = 121) in the standard RBC group (relative risk, 1.06; 95% CI, 0.91-1.22). CONCLUSION: In this trial, the use of fresh RBCs compared with standard blood bank practice did not improve outcomes in premature, very low-birth-weight infants requiring a transfusion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00326924; Current Controlled Trials Identifier: ISRCTN65939658.

Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia.

OBJECTIVE: This randomized, controlled trial was designed to determine the efficacy of inhaled fluticasone propionate on oxygen therapy weaning in a population of preterm infants who were born at <32 weeks of gestation and experienced moderate bronchopulmonary dysplasia (BPD). METHODS: Thirty-two infants who were < or =32 weeks of gestation, had moderate BPD that required supplemental oxygen (fraction of inspired oxygen > or =0.25), and were aged between 28 and 60 days were randomized. Fluticasone propionate 125 microg twice daily for 3 weeks and once daily for a fourth week was delivered to infants who weighed between 500 and 1200 g. The dosage was doubled for infants who weighed > or =1200 g. RESULTS: Compared with placebo, treatment had no effect on either duration of supplemental O2 therapy or ventilatory support as assessed by survival analysis. At 28 days, a trend toward a lower cortisol/creatinine ratio in the treatment group was noted compared with placebo (25.1 +/- 18.9 vs 43 +/- 14.4). In the fluticasone group at 28 days, the systolic arterial pressure (78 +/- 3 vs 68 +/- 3 mm Hg) and diastolic arterial pressure (43 +/- 3.4 mm Hg vs 38 +/- 2.0 mm Hg) were higher compared with baseline fluticasone values. The chest radiograph score was lower than baseline (2.8 +/- 1.4 vs 3.7 +/- 2.2) in the fluticasone group at 28 days. This study has a statistical power of 1.0 to detect a significant difference in the duration of oxygen supplementation of >21 days between the study groups. CONCLUSION: We conclude that fluticasone propionate reduces neither supplemental O2 use nor the need for ventilatory support in this patient population. However, fluticasone does have a positive radiologic effect in lowering chest radiograph scores. In addition, our data point to a possible association among inhaled fluticasone treatment and higher arterial blood pressure. Thus, the results of this investigation do not support the use of inhaled corticosteroids in the treatment of oxygen-dependent infants who have established moderate BPD.

The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.

The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.