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  • van Es, Michael A, et al. (författare)
  • ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis : a genome-wide association study.
  • 2007
  • Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:10, s. 869-77
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
  • Vellas, Bruno, et al. (författare)
  • Disease-modifying trials in Alzheimer's disease : a European task force consensus.
  • 2007
  • Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:1, s. 56-62
  • Forskningsöversikt (refereegranskat)abstract
    • After symptomatic treatments, the new target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs. The concept of disease modification in Alzheimer's disease is controversial and the design of these trials raises many questions. Which populations should be studied? For how long? With which principal and secondary endpoints? Are surrogate markers available? Here, we present a European consensus on disease-modifying trials in Alzheimer's disease, agreed under the auspices of the European Alzheimer's Disease Consortium and based on the European perspective of the concept of disease modification, study designs, the role for biomarkers, risk benefit, and pharmacoeconomic issues.
  • Vellas, Bruno, et al. (författare)
  • Endpoints for trials in Alzheimer's disease : a European task force consensus.
  • 2008
  • Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 7:5, s. 436-450
  • Forskningsöversikt (refereegranskat)abstract
    • Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.
  • Wardlaw, Joanna M, et al. (författare)
  • Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3) : secondary analysis of a randomised controlled trial.
  • 2015
  • Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 14:5, s. 485-96
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase.METHODS: IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0-2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518.FINDINGS: 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55-0·81), large lesion (0·51, 0·38-0·68), swelling (0·59, 0·46-0·75), hyperattenuated artery (0·59, 0·47-0·75), atrophy (0·74, 0·59-0·94), and leukoaraiosis (0·72, 0·59-0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18-2·51), tissue hypoattenuation (1·54, 1·04-2·27), and hyperattenuated artery (1·54, 1·03-2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9-20·7; both signs absent, excess 3·2%, 1·4-5·1). However, no imaging findings-individually or combined-modified the effect of alteplase on independence or symptomatic intracranial haemorrhage.INTERPRETATION: Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke.FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.
  • Wiegers, Eveline Janine Anna, et al. (författare)
  • Fluid balance and outcome in critically ill patients with traumatic brain injury (CENTER-TBI and OzENTER-TBI) : a prospective, multicentre, comparative effectiveness study
  • 2021
  • Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:8, s. 627-638
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Fluid therapy-the administration of fluids to maintain adequate organ tissue perfusion and oxygenation-is essential in patients admitted to the intensive care unit (ICU) with traumatic brain injury. We aimed to quantify the variability in fluid management policies in patients with traumatic brain injury and to study the effect of this variability on patients' outcomes.METHODS: We did a prospective, multicentre, comparative effectiveness study of two observational cohorts: CENTER-TBI in Europe and OzENTER-TBI in Australia. Patients from 55 hospitals in 18 countries, aged 16 years or older with traumatic brain injury requiring a head CT, and admitted to the ICU were included in this analysis. We extracted data on demographics, injury, and clinical and treatment characteristics, and calculated the mean daily fluid balance (difference between fluid input and loss) and mean daily fluid input during ICU stay per patient. We analysed the association of fluid balance and input with ICU mortality and functional outcome at 6 months, measured by the Glasgow Outcome Scale Extended (GOSE). Patient-level analyses relied on adjustment for key characteristics per patient, whereas centre-level analyses used the centre as the instrumental variable.FINDINGS: 2125 patients enrolled in CENTER-TBI and OzENTER-TBI between Dec 19, 2014, and Dec 17, 2017, were eligible for inclusion in this analysis. The median age was 50 years (IQR 31 to 66) and 1566 (74%) of patients were male. The median of the mean daily fluid input ranged from 1·48 L (IQR 1·12 to 2·09) to 4·23 L (3·78 to 4·94) across centres. The median of the mean daily fluid balance ranged from -0·85 L (IQR -1·51 to -0·49) to 1·13 L (0·99 to 1·37) across centres. In patient-level analyses, a mean positive daily fluid balance was associated with higher ICU mortality (odds ratio [OR] 1·10 [95% CI 1·07 to 1·12] per 0·1 L increase) and worse functional outcome (1·04 [1·02 to 1·05] per 0·1 L increase); higher mean daily fluid input was also associated with higher ICU mortality (1·05 [1·03 to 1·06] per 0·1 L increase) and worse functional outcome (1·04 [1·03 to 1·04] per 1-point decrease of the GOSE per 0·1 L increase). Centre-level analyses showed similar associations of higher fluid balance with ICU mortality (OR 1·17 [95% CI 1·05 to 1·29]) and worse functional outcome (1·07 [1·02 to 1·13]), but higher fluid input was not associated with ICU mortality (OR 0·95 [0·90 to 1·00]) or worse functional outcome (1·01 [0·98 to 1·03]).INTERPRETATION: In critically ill patients with traumatic brain injury, there is significant variability in fluid management, with more positive fluid balances being associated with worse outcomes. These results, when added to previous evidence, suggest that aiming for neutral fluid balances, indicating a state of normovolaemia, contributes to improved outcome.FUNDING: European Commission 7th Framework program and the Australian Health and Medical Research Council.
  • Wu, Yu-Tzu, et al. (författare)
  • Dementia in western Europe : epidemiological evidence and implications for policy making
  • 2016
  • Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 15:1, s. 116-124
  • Tidskriftsartikel (refereegranskat)abstract
    • Dementia is receiving increasing attention from governments and politicians. Epidemiological research based on western European populations done 20 years ago provided key initial evidence for dementia policy making, but these estimates are now out of date because of changes in life expectancy, living conditions, and health profiles. To assess whether dementia occurrence has changed during the past 20-30 years, investigators of five different studies done in western Europe (Sweden [Stockholm and Gothenburg], the Netherlands [Rotterdam], the UK [England], and Spain [Zaragoza]) have compared dementia occurrence using consistent research methods between two timepoints in well-defined geographical areas. Findings from four of the five studies showed non-significant changes in overall dementia occurrence. The only significant reduction in overall prevalence was found in the study done in the UK, powered and designed explicitly from its outset to detect change across generations (decrease in prevalence of 22%; p=0.003). Findings from the study done in Zaragoza (Spain) showed a significant reduction in dementia prevalence in men (43%; p=0.0002). The studies estimating incidence done in Stockholm and Rotterdam reported non-significant reductions. Such reductions could be the outcomes from earlier population-level investments such as improved education and living conditions, and better prevention and treatment of vascular and chronic conditions. This evidence suggests that attention to optimum health early in life might benefit cognitive health late in life. Policy planning and future research should be balanced across primary (policies reducing risk and increasing cognitive reserve), secondary (early detection and screening), and tertiary (once dementia is present) prevention. Each has their place, but upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.
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