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- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 3. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 4. |
- Abraham, Louisa J., et al.
(författare)
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Morale, stress and coping strategies of staff working in the emergency department: A comparison of two different-sized departments
- 2018
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Ingår i: EMA - Emergency Medicine Australasia. - : Wiley. - 1742-6731 .- 1742-6723. ; 30:3, s. 375-381
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Tidskriftsartikel (refereegranskat)abstract
- Objective : Clinical staff in EDs are subject to a range of stressors. The objective of this study was to describe and compare clinical staff perceptions of their ED's working environment across two different Australian EDs. Methods : This was a cross-sectional, descriptive, research design that included distribution of three survey tools to clinical staff in two Australian EDs in 2016. Descriptive statistics were reported to characterise workplace stressors, coping styles and the ED environment. These data were compared by hospital and the employee's clinical role (nurse or physician). Results : In total, 146 ED nurses and doctors completed the survey (response rate: 67%). Despite geographical variation, the staff at the two locations had similar demographic profiles in terms of age, sex and years of experience. Staff reported moderate levels of workload and self-realisation but low levels of conflict or nervousness in the workplace. Nurses and physicians reported similar perceptions of the work environment, although nurses reported slightly higher median levels of workload. Staff rated the death or sexual abuse of a child as most stressful, followed by workplace violence and heavy workload. Staff used a large range of coping strategies, and these were similar across both sites. Conclusion : These findings are the first multi-site and multidisciplinary examinations of Australian ED staff perceptions, improving our understanding of staff stressors and coping strategies and highlighting similarities across different EDs. These data support the development and implementation of strategies to improve ED working environments to help ensure professional longevity of ED staff.
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| 5. |
- Greenslade, Jaimi H., et al.
(författare)
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Key occupational stressors in the ED: an international comparison
- 2020
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Ingår i: Emergency Medicine Journal. - : BMJ PUBLISHING GROUP. - 1472-0205 .- 1472-0213. ; 37:2, s. 106-
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Tidskriftsartikel (refereegranskat)abstract
- Background The ED Stressor Scale outlines 15 stressors that are of importance for ED staff. Limited research has identified how commonly such stressors occur, or whether such factors are perceived with similar importance across different hospitals. This study sought to examine the frequency or perceived severity of these 15 stressors using a multicentre cohort of emergency clinicians (nurses and physicians) in EDs in two countries (Australia and Sweden). Method This was a cross-sectional survey of staff working in eight hospitals in Australia and Sweden. Data were collected between July 2016 and June 2017 (depending on local site approvals) via a printed survey incorporating the 15-item ED stressor scale. The median stress score for each item and the frequency of experiencing each event was reported. Results Events causing most distress include heavy workload, death or sexual abuse of a child, inability to provide optimum care and workplace violence. Stressors reported most frequently include dealing with high acuity patients, heavy workload and crowding. Violence, workload, inability to provide optimal care, poor professional relations, poor professional development and dealing with high-acuity patients were reported more commonly by Australian staff. Swedish respondents reported more frequent exposure to mass casualty incidents, crisis management and administrative concerns. Conclusions Workload, inability to provide optimal care, workplace violence and death or sexual abuse of a child were consistently reported as the most distressing events across sites. The frequency with which these occurred differed in Australia and Sweden, likely due to differences in the healthcare systems.
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