With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations.
We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment.
A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making.
The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children.
Electronic supplementary material
The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.
BackgroundStudies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation.MethodsWe performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case.ResultsWe identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements.ConclusionsOur results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0606-6) contains supplementary material, which is available to authorized users.
There is insufficient evidence to determine whether inhaled nitric oxide is beneficial or harmful for acute hypoxemic respiratory failure in children and adults. While awaiting further studies to prove its benefit, inhaled nitric oxide should not either be recommended as a standard management or excluded for the treatment of acute hypoxemic respiratory failure.
Cardiopulmonary resuscitation is offered more frequently than is observed in northern countries. In contrast, life support limitation is offered through do-not-resuscitate orders. These findings and the low participation of the families in the decision-making process reflect the difficulties to be overcome by those professionals who are responsible for handling critically ill children in southern Brazil.
The present paper studies the flexural behaviour of hand manufactured hybrid laminated composites with a hemp natural fibre/polypropylene core and two glass fibres/polypropylene surface layers at each side of the specimen. When compared with full glass fibres reinforced polypropylene laminates, the hybrid composites have economical, ecological and recycling advantages and also specific fatigue strength benefits. Static and fatigue tests were performed in three point bending for both laminates to evaluate flexural strength properties and fatigue behaviour. Fatigue damage was measured in terms of the stiffness loss. Failure sites and mechanisms were evaluated through microscopy studies and a 3D numerical analysis using finite element method.
This paper concerns fatigue studies of polypropylene/glass-®bre thermoplastic composites produced from a bi-directional woven cloth of co-mingled E-glass ®bres and polypropylene ®bres with a ®bre volume fraction V f of 0.338. The eect of lay-up design and load conditions on fatigue performance were investigated. The S-N curves, the rise in the temperature of the specimens, and the loss of stiness during the tests, are discussed. Fatigue tests were performed in controlled displacement mode and in an imposed stress range. Similar results were obtained for both load conditions. The loss of stiness was used as a damage parameter and related to the rise of temperature. The results show that the damage parameter E present a nearly linear relationship with the rise in temperature. A small deviation was probably caused by the stress release observed in the ®rst period of fatigue life. #
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