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Background and purposeNuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH.MethodsTen tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools.ResultsOne SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12–1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL = 1.3 × 10−7).ConclusionsThe NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

Aβ, amyloid beta, CAA, cerebral amyloid angiopathy, CT, computed tomographic scanning, IPAD, intramural periarterial drainage, ISF, interstitial fluid, MRI, magnetic resonance imaging, PVS, perivascular spaces, WMH, white matter hyperintensities.Cerebral white matter hyperintensities (WMH) observed on magnetic resonance imaging (MRI), or low attenuation on computed tomographic scanning (CT), are the most frequent brain imaging finding in patients with small vessel disease or dementia. It has been assumed that WMH are due to arteriosclerosis or blood-brain barrier breakdown, though recently it was demonstrated that WMH have distinct molecular signatures in Alzheimer's disease (AD) where markers of Wallerian degeneration are present, compared to normal ageing [1]. This article is protected by copyright. All rights reserved.

We performed a prospective, single-centre study of times to treatment of patients with life-threatening, traumatic, extra- and subdural haematomas requiring surgical evacuation between May 2006 and May 2007. The mean time to surgical decompression was 5.0 h and 32% were performed within 4 h. Patients who initially presented to a district hospital and required transfer for neurosurgery were decompressed in 5.4 h vs 3.7 h for those admitted directly. The current standard of surgical evacuation of all haematomas within 4 h is not being met. Delays were identified in every stage in the management of these patients and no single step was identified as the major cause. Initial treatment in district hospitals led to delays greater than the added driving time. There may be time savings from carrying out treatment steps in parallel instead of in series.