BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

In Table 2, the mutation for patient no. 11 in the column labeled "cDNA, aa change" is incorrect. The correct mutation is NM_002524.4:c.182A>G; NRAS p.(Q61R). The JCI regrets the error.

Objective:Severe Coronavirus disease 2019 (COVID-19) is associated with an extensive pneumonitis, and frequent coagulopathy. We sought the true incidence of thrombotic complications in critically ill patients with severe COVID-19 on the intensive care unit (ICU), with or without extracorporeal membrane oxygenation (ECMO). Design:We undertook a single-centre, retrospective analysis of 72 critically ill patients with COVID-19 associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen and pelvis were performed on admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers and survival were evaluated..

S evere acute respiratory failure is the dominant cause of death in patients with coronavirus disease 2019 (CO-VID-19) (1). The pathophysiology and imaging features of severe COVID-19 pneumonia have been the focus of considerable interest from the outset of the pandemic. In early disease, widespread ground-glass opacification predominates at thoracic CT (2-6) and is supposedly associated with highly compliant lungs and disrupted vasoregulation (7). Vascular dysregulation is believed to be consequence of exaggerated activation of inflammatory and coagulation cascades (termed immunothrombosis) (1,(8)(9)(10)(11)(12). Later in the course of disease, CT more commonly shows consolidation and fibrosis associated with lower lung compliance (13).There is growing evidence from radiologic and pathologic studies of a significant vasculopathy in COVID-19 pneumonia (14-17); in a recent study of postmortem lungs in COVID-19, there were widespread microthromboses and striking new vessel formation (16). Furthermore, based on qualitative analyses, a number of studies have highlighted the potential role of dual-energy CT pulmonary angiography (DECTPA) (15,(18)(19)(20)(21). Accordingly, in the present study, we aimed to evaluate the relationships between a quantitative measure of perfusion at DECTPA (relative perfused blood volume [PBV], ie, PBV relative to pulmonary artery enhancement [PBV/PAenh]) ( 22) and (a) disease duration, (b) right ventricular dysfunction (RVD) at echocardiography, (c) d-dimer levels, and (d) obstruction score (23) in patients with severe COVID-19 pneumonia. A secondary aim was to compare PBV/PAenh in COVID-19 pneumonia to that of healthy volunteers.

Childhood empyema incidence has increased markedly in South Auckland. Paediatric S. aureus empyema is becoming increasingly common in South Auckland. Pre-hospital antibiotic prescribing may mitigate the need for surgical intervention in our population.