Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.

Clinical impact of implementing humidified high-flow nasal cannula on interhospital transport among children admitted to a PICU with respiratory distress: a cohort study.

BACKGROUND: There is a limited evidence for humidified high-flow nasal cannula (HHFNC) use on inter-hospital transport. Despite this, its use during transport is increasing in children with respiratory distress worldwide. In 2015 HHFNC was implemented on a specialized pediatric retrieval team serving for Victoria. The aim of this study is to investigate the effect of the HHFNC implementation on the retrieval team on the paediatric intensive care unit (PICU) length of stay and respiratory support use. METHODS: We performed a cohort study using a comparative interrupted time-series approach controlling for patient and temporal covariates, and population-adjusted analysis. We studied 3022 children admitted to a PICU in Victoria with respiratory distress January 2010-December 2019. Patients were divided in pre-intervention era (2010-2014) and post-intervention era (2015-2019). RESULTS: 1006 children following interhospital transport and 2016 non-transport children were included. Median (IQR) age was 1.4 (0.7-4.5) years. Pneumonia (39.1%) and bronchiolitis (34.3%) were common. On retrieval, HHFNC was used in 5.0% (21/420) and 45.9% (269/586) in pre- and post-intervention era. In an unadjusted model, median (IQR) PICU length of stay was 2.2 (1.1-4.2) and 1.7 (0.9-3.2) days in the pre- and post-intervention era in transported children while the figures were 2.4 (1.3-4.9) and 2.1 (1.2-4.5) days in non-transport children. In the multivariable regression model, the intervention was associated with the reduced PICU length of stay (ratio 0.64, 95% confidential interval 0.49-0.83, p = 0.001) with the predicted reduction of PICU length of stay being - 10.6 h (95% confidential interval - 16.9 to - 4.3 h), and decreased respiratory support use (- 25.1 h, 95% confidential interval - 47.9 to - 2.3 h, p = 0.03). Sensitivity analyses including a model excluding less severe children showed similar results. In population-adjusted analyses, respiratory support use decreased from 4837 to 3477 person-hour per year in transported children over the study era, while the reduction was 594 (from 9553 to 8959) person-hour per year in non-transport children. With regard to the safety, there were no escalations of respiratory support mode during interhospital transport. CONCLUSIONS: The implementation of HHFNC on interhospital transport was associated with the reduced PICU length of stay and respiratory support use among PICU admissions with respiratory distress.

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in neonatal sepsis.

BACKGROUND: Efficient and accurate diagnosis of neonatal sepsis is challenging. The potential impact for a reduction in morbidity and mortality as well as antibiotic usage has stimulated the ongoing search for biomarkers of early sepsis. The objective of this pilot study was to quantify the levels of sTREM-1 and correlate with blood cultures and inflammatory markers in neonates evaluated for sepsis. METHODS: Neonates with suspected sepsis were enrolled (n = 83; Preterm n = 35; Term n = 48). Routine bloods for sepsis evaluation were included and plasma sTREM-1 levels were quantified by ELISA. RESULTS: Term and preterm neonates (n = 83; Preterm n = 35; Term n = 48) were enrolled and 16 neonates had positive blood cultures (preterm n = 15; term n = 1). sTREM-1 levels were not significantly different in infants with culture-positive or culture-negative sepsis (356 ± 218 pg/mL and 385 ± 254 pg/mL respectively). The immature-to-total granulocyte (I/T) ratio showed a significant positive correlation with sTREM-1 in the preterm group with positive blood cultures. Additionally, sTREM-1 showed a positive correlation with CRP in the preterm group with negative blood cultures. CONCLUSIONS: sTREM-1 was associated with traditional markers of inflammation (I/T ratio and CRP). However, in this cohort sTREM-1 did not improve the early detection of neonatal culture-positive sepsis.