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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Wightman, D. P., et al.
(författare)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Tidskriftsartikel (refereegranskat)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 7. |
- Sirivåg, K, et al.
(författare)
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Physical EXercise Augmented COGnitive Behaviour Therapy for Older Adults with Generalised Anxiety Disorder (PEXACOG)
- 2016
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Konferensbidrag (refereegranskat)abstract
- Generalised anxiety disorder (GAD) is the most prevalent severe anxiety disorder among older adults. The disorder has a pervasive influence on the lives of those affected, and is a risk factor for other severe disorders such as depression, dementia and coronary heart disease. Cognitive behaviour therapy (CBT) is the treatment of choice for this disorder, but older adults have shown reduced effect of treatment compared to working age adults. Physical exercise has been suggested as intervention to improve the effects of treatment for GAD, via its demonstrated positive effect on cognitive functioning, increased plasticity in the brain, and increased availability of neurotrophins important for extinction of fear associations. The aim of the current research project is to investigate whether augmenting CBT with physical exercise will lead to improved effects of CBT on GAD in older adults in a randomized controlled trial (RCT). Participants between 60-75 years of age with a primary diagnosis of GAD will be randomised to one of two treatment conditions. The effects of treatment will be assessed on outcome measures, biological, physiological and cognitive measures at pre- interim-, and post-treatment, and follow-up assessments at 6- and 12-months post intervention. Participants in both groups will receive five weeks of pre-treatment intervention consisting of either physical exercise or weekly telephone contact. Participants thereafter receive either ten weeks of manualised CBT for GAD combined with manualised physical exercise or ten weeks of manualised CBT for GAD combined with weekly telephone contact. We expect that the treatment effect of the physical exercise augmented CBT will be greater than that of CBT combined with weekly telephone contact, as measured by a reduction in GAD symptoms on the Penn State Worry Questionnaire and in the proportion of remitted patients. The study also aims to determining the possible beneficial and augmenting properties of physical exercise in combination with CBT, and our understanding of clinical characteristics of GAD and mechanisms involved in treatment effect. Treatment rationale, procedures and protocols will be presented in detail together with preliminary results from the initial feasibility study comprises eight participants.
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| 11. |
- Farioli, A, et al.
(författare)
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Occupational exposure to asbestos and risk of cholangiocarcinoma: a population-based case-control study in four Nordic countries
- 2018
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Ingår i: Occupational and environmental medicine. - : BMJ. - 1470-7926 .- 1351-0711. ; 75:3, s. 191-198
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Tidskriftsartikel (refereegranskat)abstract
- To assess the association between occupational exposure to asbestos and the risk of cholangiocarcinoma (CC).MethodsWe conducted a case–control study nested in the Nordic Occupational Cancer (NOCCA) cohort. We studied 1458 intrahepatic CC (ICC) and 3972 extrahepatic CC (ECC) cases occurring among subjects born in 1920 or later in Finland, Iceland, Norway and Sweden. Each case was individually matched by birth year, gender and country to five population controls. The cumulative exposure to asbestos (measured in fibres (f)/ml × years) was assessed by applying the NOCCA job-exposure matrix to data on occupations collected during national population censuses (conducted in 1960, 1970, 1980/81 and 1990). Odds ratios (OR) and 95% CI were estimated using conditional logistic regression models adjusted by printing industry work.ResultsWe observed an increasing risk of ICC with cumulative exposure to asbestos: never exposed, OR 1.0 (reference category); 0.1–4.9 f/mL × years, OR 1.1 (95% CI 0.9 to 1.3); 5.0–9.9 f/mL × years, OR 1.3 (95% CI 0.9 to 2.1); 10.0–14.9 f/mL × years, OR 1.6 (95% CI 1.0 to 2.5); ≥15.0 f/mL × years, OR 1.7 (95% CI 1.1 to 2.6). We did not observe an association between cumulative asbestos exposure and ECC.ConclusionsOur study provides evidence that exposure to asbestos might be a risk factor for ICC. Our findings also suggest that the association between ECC and asbestos is null or weaker than that observed for ICC. Further studies based on large industrial cohorts of asbestos workers and possibly accounting for personal characteristics and clinical history are needed.
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- Andreassen, BK, et al.
(författare)
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Identification of potential carcinogenic and chemopreventive effects of prescription drugs: a protocol for a Norwegian registry-based study
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:4, s. e028504-
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Tidskriftsartikel (refereegranskat)abstract
- Surveillance of unintended effects of pharmaceuticals (pharmacovigilance or drug safety) is crucial, as knowledge of rare or late side effects is limited at the time of the introduction of new medications into the market. Side effects of drugs may involve increased or decreased risk of cancer, but these typically appear after a long induction period. This fact, together with low incidences of many cancer types, limits the usefulness of traditional pharmacovigilance strategies, primarily based on spontaneous reporting of adverse events, to identify associations between drug use and cancer risk. Postmarketing observational pharmacoepidemiological studies are therefore crucial in the evaluation of drug-cancer associations.Methods and analysisThe main data sources in this project will be the Norwegian Prescription Database and the Cancer Registry of Norway. The underlying statistical model will be based on a multiple nested case–control design including all adult (~200 000) incident cancer cases within the age-range 18–85 years from 2007 through 2015 in Norway as cases. 10 cancer-free population controls will be individually matched to these cases with respect to birth year, sex and index date (date of cancer diagnosis). Drug exposure will be modelled as chronic user/non-user by counting prescriptions, and cumulative use by summarising all dispensions’ daily defined doses over time. Conditional logistic regression models adjusted for comorbidity (National Patient Register), socioeconomic parameters (Statistics Norway), concomitant drug use and, for female cancers, reproduction data (Medical Birth Registry), will be applied to identify drug-use–cancer-risk associations.Ethics and disseminationThe study is approved by the regional ethical committee and the Norwegian data protection authority. Results of the initial screening step and analysis pipeline will be described in a key paper. Subsequent papers will report the evaluation of identified signals in replication studies. Results will be published in peer-reviewed journals, at scientific conferences and through press releases.
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| 20. |
- Bratland-Sanda, S., et al.
(författare)
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Physical activity in treatment units for eating disorders : Clinical practice and attitudes
- 2009
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Ingår i: Eating and Weight Disorders. - 1124-4909 .- 1590-1262. ; 14:2-3, s. E106-E112
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Physical activity (PA) in eating disorders (ED) may be harmful, but in a therapeutic setting also beneficial. The purpose of this survey was to examine these contradictory aspects of PA in ED specialist treatment settings. We examined whether 1) PA is assessed by the unit, 2) the units have guidelines for managing excessive PA, 3) the units have staff with higher education and special competence in PA and exercise science, 4) how units regard PA in ED, 5) whether regular PA is integrated in the treatment programs, and 6) how the units rate the role of PA in the treatment of ED compared with other mental disorders. METHODS: Of the 49 units located in Scandinavia and the United Kingdom, 41 (84%) responded to a questionnaire. RESULTS: In 28 units (68%) PA was assessed regularly. Excessive PA was considered a harmful symptom in ED, and most units reported guidelines to manage excessive PA. Thirty-two units included PA in their treatment programmes. Clinicians found PA most relevant in the treatment of obesity and, except for binge eating, less for ED. CONCLUSION: PA was more commonly integrated in treatment compared to previous studies. Future research should address how to manage excessive PA, and the potential beneficial role of PA in the treatment of ED. (Eating Weight Disord. 14: e106-e112, 2009). (C) 2009, Editrice Kurtis
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| 21. |
- Martinsen, E, et al.
(författare)
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Om depression
- 2018
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Ingår i: Fysisk aktivitet som medicin. - Stockholm : SISU idrottsböcker. - 9789177270355 ; , s. 177-182
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Bokkapitel (populärvet., debatt m.m.)
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| 22. |
- Martinsen, V., et al.
(författare)
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pH effects of the addition of three biochars to acidic Indonesian mineral soils
- 2015
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Ingår i: Soil science and plant nutrition (Tokyo). - : Informa UK Limited. - 0038-0768 .- 1747-0765. ; 61:5, s. 821-834
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Tidskriftsartikel (refereegranskat)abstract
- Soil acidity may severely reduce crop production. Biochar (BC) may increase soil pH and cation exchange capacity (CEC) but reported effects differ substantially. In a systematic approach, using a standardized protocol on a uniquely large number set of 31 acidic soils, we quantified the effect of increasing amounts (0-30%; weight:weight) of three types of field-produced BCs (from cacao (Theobroma cacao. L.) shell, oil palm (Elaeis guineensis. Jacq.) shell and rice (Oryza sativa. L.) husk) on soil pH and CEC. Soils were sampled from croplands at Java, Sumatra and Kalimantan, Indonesia. All BCs caused a significant increase in mean soil pH with a stronger response and a greater maximum increase for the cacao shell BC addition, due to a greater acid neutralizing capacity (ANC) and larger amounts of extractable base cations. At 1% BC addition, corresponding to about 30tonsha(-1), the estimated increase in soil pH from the initial mean pH of 4.7 was about 0.5 units for the cacao shell BC, whereas this was only 0.05 and 0.04 units for the oil palm shell and rice husk BC, respectively. Besides depending on BC type, the increase in soil pH upon the addition of each of the three BCs was mainly dependent on soil CEC (low CEC resulting in stronger pH increase), and to a lesser extent on initial soil pH (higher initial pH resulting in stronger pH increase). Addition of BC also increased the amount of exchangeable base cations (cacao shell >> oil palm and rice husk) and CEC. Through this systematic screening of the effect of BC on pH and CEC of acidic soils, we show that a small addition of BC, in particular if made of cacao shell, to acidic agricultural soils increases soil pH and CEC. However, the response is highly dependent on the type, quality and amount of the added BC as well as on intrinsic soil properties, mainly CEC.
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| 24. |
- Sandström, A, et al.
(författare)
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Altered cerebral pain processing of noxious stimuli from inflamed joints in rheumatoid arthritis : An event-related fMRI study.
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 81, s. 272-279
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To our knowledge, this is the first study assessing brain activation in response to painful stimulation over disease-relevant (finger joint) vs. neutral area (thumb nail) in patients suffering from rheumatoid arthritis (RA) compared to healthy controls (HC).METHOD: Thirty-one RA patients and 23 HC underwent functional magnetic resonance imaging (fMRI) while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100 mm VAS scale (P50) at disease-affected finger joint and thumbnail (left hand), and corresponding sites in HC.RESULTS: Compared to controls, RA patients had significantly increased pain sensitivity (lower P50) at the inflamed joints but not at the thumbnail. RA patients exhibited significantly less activation in regions related to pain- and somatosensory processing (S1, M1, anterior insula, S2, SMG and MCC) during painful joint stimulation, compared to HC. No group difference in cerebral pain processing was found for the non-affected thumbnail. Within RA patients, significantly less brain activation was found in response to painful stimulation over disease-affected joint compared to non-affected thumbnail in bilateral S1, bilateral S2, and anterior insula. Further, RA patients exhibited a right-sided dlPFC deactivation, psycho-physiologically interacting (PPI) with the left dlPFC in response to painful stimulation at disease-affected joints.CONCLUSION: The results indicate normal pain sensitivity and cerebral pain processing in RA for non-affected sites, while the increased sensitivity at inflamed joints indicate peripheral/spinal sensitization. Brain imaging data suggest that disease-relevant pain processing in RA is marked by aberrations and a failed initiation of cortical top-down regulation.
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