Randomized Trial of Weight-Based Versus Fixed Limit High-Flow Nasal Cannula in Bronchiolitis.

BACKGROUND: High flow nasal cannula (HFNC) is increasingly used to treat bronchiolitis. Although lower HFNC rates (≤8 L per minute) are commonly employed, higher weight-based flows more effectively alleviate dyspnea. The impact of higher flows on the need for care escalation is unclear. METHODS: A randomized clinical trial was performed in a community hospital inpatient pediatric unit. Patients with bronchiolitis on HFNC were randomized to an existing "standard" HFNC protocol (max flow of 8 L per minute), or to a novel weight-based protocol (max flow of 2 L/kg per minute). Weaning of HFNC for the patients in the standard arm was left to provider discretion but was prescribed in the weight-based arm. The primary outcome was interhospital transfer to a PICU. The study was powered to detect a 35% difference in transfer rate. RESULTS: 51 patients were randomized to the weight-based or standard HFNC arms. The interhospital PICU transfer rate did not differ significantly between the standard (41.7%) and weight-based arms (51.9%) P = .47. Hospital length of stay was significantly shorter in the weight-based arm with protocolized weaning (45 h [interquartile range 42.1-63.3] versus 77.6 h [interquartile range 47.3-113.4]); P = .01. There were no significant adverse events in either group. CONCLUSIONS: Weight-based provision of HFNC did not significantly impact the number of patients with bronchiolitis requiring interhospital transfer from a community hospital to a PICU, though we were underpowered for this outcome. Patients who received weight-based flow with protocolized weaning had a shorter length of stay, which may reflect a clinical impact of weight-based flow or the efficacy of the aggressive weaning pathway.

Cellular responses to protein accumulation involve autophagy and lysosomal enzyme activation.

Protein oligomerization and aggregation are key events in age-related neurodegenerative disorders, causing neuronal disturbances including microtubule destabilization, transport failure and loss of synaptic integrity that precede cell death. The abnormal buildup of proteins can overload digestive systems and this, in turn, activates lysosomes in different disease states and stimulates the inducible class of lysosomal protein degradation, macroautophagy. These responses were studied in a hippocampal slice model well known for amyloidogenic species, tau aggregates, and ubiquitinated proteins in response to chloroquine-mediated disruption of degradative processes. Chloroquine was found to cause a pronounced appearance of prelysosomal autophagic vacuoles in pyramidal neurons. The vacuoles and dense bodies were concentrated in the basal pole of neurons and in dystrophic neurites. In hippocampal slice cultures treated with Abeta(142), ultrastructural changes were also induced. Autophagic responses may be an attempt to compensate for protein accumulation, however, they were not sufficient to prevent axonopathy indicated by swellings, transport deficits, and reduced expression of synaptic components. Additional chloroquine effects included activation of cathepsin D and other lysosomal hydrolases. Abeta(142) produced similar lysosomal activation, and the effects of Abeta(142) and chloroquine were not additive, suggesting a common mechanism. Activated levels of cathepsin D were enhanced with the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK). PADK-mediated lysosomal enhancement corresponded with the restoration of synaptic markers, in association with stabilization of microtubules and transport capability. To show that PADK can modulate the lysosomal system in vivo, IP injections were administered over a 5-day period, resulting in a dose-dependent increase in lysosomal hydrolases. The findings indicate that degradative responses can be modulated to promote synaptic maintenance.

A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency.

CONTEXT: Short stature is a common reason for referral to pediatric endocrinology centers. Frequently, the underlying etiology of short stature is unknown, resulting in a diagnosis of idiopathic short stature. Rare genetic defects in the GH/IGF-1 axis have been found to cause short stature. OBJECTIVE: The objective of this study was to identify the genetic etiology of short stature in a patient with Idiopathic Short Stature and to review the clinical presentation of patients with genetic defects in IGF1, and specifically IGF-1 haploinsufficiency. DESIGN/SETTING/PARTICIPANTS: The index patient was evaluated at an academic medical center, and DNA was obtained from the proband and both parents. INTERVENTION: Genome-wide copy number analysis was performed in the proband with confirmatory quantitative PCR in the proband and his parents. MAIN OUTCOME MEASURE: We measured novel copy number variants (CNVs) thought to explain the patient's short stature. RESULTS: CNV analysis revealed that the proband carried a paternally inherited heterozygous IGF1 gene deletion. His phenotypic features are consistent with those found in previous case reports of IGF-1 deficiency. CONCLUSIONS: This study, as the first case of a complete heterozygous 1GF1 deletion, provides insight into the effects of true IGF-1 haploinsufficiency. Given the similarities in phenotype between the present proband and those previously described, it is highly likely that his IGF1 deletion is the cause for his short stature. Broadly, this study emphasizes how CNV analysis and other genetic sequencing techniques are evolving as an important tool to identify genetic causes underlying human disease, allowing for improved diagnosis and targeted treatment.