| 1. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 2. |
- Johansson, Kristina, et al.
(författare)
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Phosphatidylethanol Levels, As a Marker of Alcohol Consumption, Are Associated With Risk of Intracerebral Hemorrhage
- 2020
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Ingår i: Stroke. - : Lippincott Williams & Wilkins. - 0039-2499 .- 1524-4628. ; 51:7, s. 2148-2152
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Previous observational studies have shown a moderately increased risk of intracerebral hemorrhage (ICH) with high self-reported alcohol consumption. However, self-reported data tend to underestimate alcohol consumption. Phosphatidylethanol is a specific biomarker reflecting alcohol intake during the last month and correlates with the amount of alcohol consumed. The present study aimed to investigate the association between phosphatidylethanol levels and the risk of future ICH.Methods: This population-based nested case-referent study was conducted within the Northern Sweden Health and Disease Cohort. At baseline, all participants underwent a health examination, including a questionnaire with questions about alcohol consumption. A blood sample was collected and stored at −80°C, and phosphatidylethanol 16:0/18:1 levels were measured in packed erythrocytes. Cases (n=97) were diagnosed with a first-ever ICH between 1985 and 2007. Two referents (n=180) were matched to each case.Results: The mean age at baseline was 55 years, 39% of participants were women, and the mean time from blood sampling to ICH was 7.3 years. Only phosphatidylethanol and hypertension remained independently associated with ICH in a multivariable model. Participants with phosphatidylethanol >0.30 μmol/L had an increased risk of ICH compared with those with phosphatidylethanol <0.01 μmol/L (odds ratio, 4.64 [95% CI, 1.49–14.40]).Conclusions: High blood concentrations of phosphatidylethanol were associated with an increased risk of future ICH. This association was independent of hypertension and other risk factors for ICH. Our findings suggest that phosphatidylethanol, as a marker of alcohol consumption, may be used as a risk marker of future ICH.
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| 3. |
- Nordanstig, Joakim, et al.
(författare)
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Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.
- 2020
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Ingår i: The New England journal of medicine. - : Massachusetts Medical Society. - 1533-4406 .- 0028-4793. ; 383, s. 2538-46
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Tidskriftsartikel (refereegranskat)abstract
- The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).
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| 4. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 5. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 6. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 7. |
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| 8. |
- Bjureland, William, 1987-, et al.
(författare)
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Dimensionering av sprutbetongförstärkning för lösa block med sannolikhetsbaserade metoder
- 2020
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Användning av sannolikhetsbaserade metoder för dimensionering av bergförstärkning är ett tillvägagångssätt som är accepterat i Eurokoderna. Vid dimensionering med dessa metoder beaktas osäkerheter stringent genom att ansätta sannolikhetsfördelningar för relevanta parametrar. Konstruktionens säkerhet säkerställs genom att verifiera att sannolikheten att överskrida bärförmågan är lägre än den i Eurokoderna kravställda brottsannolikheten. För tillämpning av sannolikhetsbaserade metoder för dimensionering av sprutbetongförstärkning för lösa block har ett problem varit att data saknats för att kunna beskriva relevanta parametrar med representativa sannolikhetsfördelningar. Dessutom samverkar de olika brottmoderna och måste därför betraktas ur ett systemperspektiv, vilket inte beaktats i tidigare studier. I denna artikel presenteras resultatet av ett doktorandprojekt med finansiering av SBUF, BeFo, SVC och SKB. Baserat på ovanstående aspekter presenteras en metodik för dimensionering av sprutbetongförstärkning för lösa block med sannolikhetsbaserade metoder. Inledningsvis presenteras sannolikhetsfördelningar för sprutbetongens parametrar baserat på en stor mängd analyserade data från Citybanan. Därefter presenteras den utvecklade dimensioneringsmetodiken, vilken bygger på att en initial dimensionering av sprutbetongen utförs innan tunneldrivningen påbörjas och att den applicerade sprutbetongens bärförmåga därefter verifieras med hjälp av kontrollmätningar från fält och Bayesiansk statistik.
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| 9. |
- Bjureland, William, 1987-, et al.
(författare)
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Influence of spatially varying thickness on load-bearing capacity of shotcrete
- 2020
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Ingår i: Tunnelling and Underground Space Technology. - : Elsevier. - 0886-7798 .- 1878-4364. ; 98
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Tidskriftsartikel (refereegranskat)abstract
- A common approach to verify a shotcrete layer's ability to secure blocks that can exist between rockbolts in a tunnel is to use analytical calculations. For this situation, an attractive approach to account for variability in the shotcrete parameters is to use reliability-based methods. Variability can then be accounted for by assigning suitable probability distributions to all relevant input parameters. Structural safety can be ensured by verifying that the probability of limit exceedance is smaller than an acceptable target probability of failure. However, even though analytical calculations and reliability-based methods can be used to design shotcrete support, one of the commonly made basic assumptions is that the load-bearing capacity of the shotcrete is governed by the spatial average of the input parameters. Thus, the spatial variability of the parameters are neglected. As a result, if the capacity is governed by the lowest value of a certain parameter, this assumption is non-conservative. In this paper, we present a novel approach in which the minimum of either the spatial average of a shotcrete slab of varying thickness, or the spatial average along the periphery of a loose block of that same slab, is used to estimate the load-bearing capacity of the shotcrete in a tunnel. The approach is based on results from numerical simulations of a shotcrete slab that we perform to investigate the effect that a spatially varying thickness has on the flexural load-bearing capacity of the slab. The results from the simulations show that the shotcrete's flexural load-bearing capacity might be overestimated when using the spatial average of shotcrete thickness between four rockbolts in design. Using the presented approach, the spatial variability of shotcrete thickness can be accounted for in practical design of tunnels without complex and time-consuming numerical simulations.
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| 10. |
- Bjureland, William
(författare)
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Reliability-based design of rock tunnel support
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since 2009, design of rock tunnels can be performed in accordance with the Eurocodes, which allows that different design methodologies are applied, such as design by calculation or design using the observational method. To account for uncertainties in design, the Eurocode states that design by calculation should primarily be performed using the partial factor method or reliability-based methods. The basic principle of both of these methods is that it shall be assured that a structure’s resisting capacity is larger than the load acting on the structure, with sufficiently high probability. Even if this might seem straightforward, the practical application of limit state design to rock tunnel support has only been studied to a limited extent.The overall aim of this project has been to develop reliability-based methods for environmental and economic optimization of rock tunnel support, with a special focus on shotcrete support. To achieve this, this thesis aims to: (1) assess the applicability of the partial factor method and reliability-based methods for design of shotcrete support, exclusively or in combination with the observational method, (2) quantify the magnitude and uncertainty of the shotcrete’s input parameters, and (3) assess the influence from spatial variability on shotcrete’s load-bearing capacity and judge the correctness of the assumption that the load-bearing capacity of the support is governed by the mean values of its input parameters.The thesis shows that the partial factor method is not suitable, and in some cases not applicable, to use in design of rock tunnel support. Instead, the thesis presents a reliability-based design methodology for shotcrete in rock tunnels with respect to loose blocks between rockbolts and a design methodology for shotcrete lining based on a combination of the observational method and reliability-based methods. The presented design methodologies enable optimization of the shotcrete support and shotcrete lining by stringently accounting for uncertainties related to input data throughout the design process. The thesis also discusses the limited knowledge that we as an industry sometimes have in our calculation models and the clarifications that should be made in future revisions of the Eurocode related to target reliability and the definition of failure.
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