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Seminars in Fetal & Neonatal Medicine Oct 2023Safe and effective management of the neonatal airway requires knowledge, teamwork, preparation and experience. At baseline, the neonatal airway can present significant... (Review)
Review
Safe and effective management of the neonatal airway requires knowledge, teamwork, preparation and experience. At baseline, the neonatal airway can present significant challenges to experienced neonatologists and paediatric anaesthesiologists, and increased difficulty can be due to anatomical abnormalities, physiological instability or increased situational stress. Neonatal airway obstruction is under recognised, and should be considered an emergency until the diagnosis and physiological implications are understood. When multiple types of difficulties are present or there are multiple levels of anatomical obstruction, the challenge increases exponentially. In these situations, preparation, multi-disciplinary teamwork and a consistent hospital-wide approach will help to reduce errors and morbidity.
Topics: Humans; Infant, Newborn; Airway Obstruction; Neonatology
PubMed: 38030433
DOI: 10.1016/j.siny.2023.101483 -
Journal of Hepatology Dec 2023Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most...
BACKGROUND & AIMS
Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.
METHODS
We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.
RESULTS
A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA.
CONCLUSIONS
BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes.
IMPACT AND IMPLICATIONS
Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.
Topics: Child; Animals; Mice; Humans; Biliary Atresia; Genome-Wide Association Study; Genetic Predisposition to Disease; Zebrafish; Canada
PubMed: 37572794
DOI: 10.1016/j.jhep.2023.07.039