| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 3. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 4. |
- Jones, Benedict C, et al.
(author)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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In: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Journal article (peer-reviewed)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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| 9. |
- Bjarnadottir, M, et al.
(author)
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Intracellular accumulation of the amyloidogenic L68Q variant of cystatin C in NIH/3T3 cells
- 1998
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In: Molecular Pathology. - 1366-8714. ; 51:6, s. 317-326
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Journal article (peer-reviewed)abstract
- AIM: To study the cellular transport of L68Q cystatin C, the cystatin variant causing amyloidosis and brain haemorrhage in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA). METHODS: Expression vectors for wild-type and L68Q cystatin C were constructed and used to transfect mouse NIH/3T3 cells. Stable cell clones were isolated after cotransfection with pSV2neo. Clones expressing human wild-type and L68Q cystatin C were compared with respect to secreted cystatin C by enzyme linked immunosorbent assay (ELISA), and for intracellular cystatin C by western blotting and immunofluorescence cytochemistry. Colocalisation studies in cells were performed by double staining with antibodies against human cystatin C and marker proteins for lysosomes, the Golgi apparatus, or the endoplasmic reticulum, and evaluated by confocal microscopy. RESULTS: Concentrations of human cystatin C secreted from transfected NIH/3T3 cells were similar to those secreted from human cells in culture. In general, clones expressing the gene encoding L68Q cystatin C secreted slightly lower amounts of the protein than clones expressing wild-type human cystatin C. Both immunofluorescence cytochemistry and western blotting experiments showed an increased accumulation of cystatin C in cells expressing the gene encoding L68Q cystatin C compared with cells expressing the gene for the wild-type protein. The intracellularly accumulating L68Q cystatin C was insoluble and located mainly in the endoplasmic reticulum. CONCLUSIONS: The cellular transport of human cystatin C is impeded by the pathogenic amino acid substitution Leu68-- >Gln. The resulting intracellular accumulation and increased localised concentration of L68Q cystatin C might be an important event in the molecular pathophysiology of amyloid formation and brain haemorrhage in patients with HCCAA.
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| 10. |
- Bjarnadottir, M, et al.
(author)
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Intracellular accumulation of the amyloidogenic L68Q variant of human cystatin C in NIH/3T3 cells
- 1998
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In: Molecular Pathology. - : BMJ. - 1366-8714. ; 51, s. 317-326
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Journal article (peer-reviewed)abstract
- AIM: To study the cellular transport of L68Q cystatin C, the cystatin variant causing amyloidosis and brain haemorrhage in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA).METHODS: Expression vectors for wild-type and L68Q cystatin C were constructed and used to transfect mouse NIH/3T3 cells. Stable cell clones were isolated after cotransfection with pSV2neo. Clones expressing human wild-type and L68Q cystatin C were compared with respect to secreted cystatin C by enzyme linked immunosorbent assay (ELISA), and for intracellular cystatin C by western blotting and immunofluorescence cytochemistry. Colocalisation studies in cells were performed by double staining with antibodies against human cystatin C and marker proteins for lysosomes, the Golgi apparatus, or the endoplasmic reticulum, and evaluated by confocal microscopy.RESULTS: Concentrations of human cystatin C secreted from transfected NIH/3T3 cells were similar to those secreted from human cells in culture. In general, clones expressing the gene encoding L68Q cystatin C secreted slightly lower amounts of the protein than clones expressing wild-type human cystatin C. Both immunofluorescence cytochemistry and western blotting experiments showed an increased accumulation of cystatin C in cells expressing the gene encoding L68Q cystatin C compared with cells expressing the gene for the wild-type protein. The intracellularly accumulating L68Q cystatin C was insoluble and located mainly in the endoplasmic reticulum.CONCLUSIONS: The cellular transport of human cystatin C is impeded by the pathogenic amino acid substitution Leu68-->Gln. The resulting intracellular accumulation and increased localised concentration of L68Q cystatin C might be an important event in the molecular pathophysiology of amyloid formation and brain haemorrhage in patients with HCCAA.
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| 11. |
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| 12. |
- Sermeus, W, et al.
(author)
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A workplace organisational intervention to improve hospital nurses' and physicians' mental health: study protocol for the Magnet4Europe wait list cluster randomised controlled trial
- 2022
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In: BMJ open. - : BMJ. - 2044-6055. ; 12:7, s. e059159-
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Journal article (peer-reviewed)abstract
- The increasing burden of mental distress reported by healthcare professionals is a matter of serious concern and there is a growing recognition of the role of the workplace in creating this problem. Magnet hospitals, a model shown to attract and retain staff in US research, creates positive work environments that aim to support the well-being of healthcare professionals.Methods and analysisMagnet4Europe is a cluster randomised controlled trial, with wait list controls, designed to evaluate the effects of organisational redesign, based on the Magnet model, on nurses’ and physicians’ well-being in general acute care hospitals, using a multicomponent implementation strategy. The study will be conducted in more than 60 general acute care hospitals in Belgium, England, Germany, Ireland, Norway and Sweden. The primary outcome is burnout among nurses and physicians, assessed in longitudinal surveys of nurses and physicians at participating hospitals. Additional data will be collected from them on perceived work environments, patient safety and patient quality of care and will be triangulated with data from medical records, including case mix-adjusted in-hospital mortality. The process of implementation will be evaluated using qualitative data from focus group and key informant interviews.Ethics and disseminationThis study was approved by the Ethics Committee Research UZ/KU Leuven, Belgium; additionally, ethics approval is obtained in all other participating countries either through a central or decentral authority. Findings will be disseminated at conferences, through peer-reviewed manuscripts and via social media.Trial registration numberISRCTN10196901.
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| 13. |
- van Buul, Laura W, et al.
(author)
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The Development of a Decision Tool for the Empiric Treatment of Suspected Urinary Tract Infection in Frail Older Adults: A Delphi Consensus Procedure.
- 2018
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In: Journal of the American Medical Directors Association. - : Elsevier BV. - 1538-9375 .- 1525-8610. ; 19:9, s. 757-764
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Journal article (peer-reviewed)abstract
- Nonspecific signs and symptoms combined with positive urinalysis results frequently trigger antibiotic therapy in frail older adults. However, there is limited evidence about which signs and symptoms indicate urinary tract infection (UTI) in this population. We aimed to find consensus among an international expert panel on which signs and symptoms, commonly attributed to UTI, should and should not lead to antibiotic prescribing in frail older adults, and to integrate these findings into a decision tool for the empiric treatment of suspected UTI in this population.A Delphi consensus procedure.An international panel of practitioners recognized as experts in the field of UTI in frail older patients.In 4 questionnaire rounds, the panel (1) evaluated the likelihood that individual signs and symptoms are caused by UTI, (2) indicated whether they would prescribe antibiotics empirically for combinations of signs and symptoms, and (3) provided feedback on a draft decision tool.Experts agreed that the majority of nonspecific signs and symptoms should be evaluated for other causes instead of being attributed to UTI and that urinalysis should not influence treatment decisions unless both nitrite and leukocyte esterase are negative. These and other findings were incorporated into a decision tool for the empiric treatment for suspected UTI in frail older adults with and without an indwelling urinary catheter.A decision tool for suspected UTI in frail older adults was developed based on consensus among an international expert panel. Studies are needed to evaluate whether this decision tool is effective in reaching its aim: the improvement of diagnostic evaluation and treatment for suspected UTI in frail older adults.
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