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Sökning: WFRF:(Engström C) > (2015-2019)

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1.
  • Pulit, SL, et al. (författare)
  • Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
  • 2016
  • Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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4.
  • Di Angelantonio, E., et al. (författare)
  • Association of Cardiometabolic Multimorbidity With Mortality
  • 2015
  • Ingår i: JAMA. - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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5.
  • Lorenz, M. W., et al. (författare)
  • Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration
  • 2018
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
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  • Lestinsky, M., et al. (författare)
  • Physics book: CRYRING@ESR
  • 2016
  • Ingår i: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6401 .- 1951-6355. ; 225:5, s. 797-882
  • Forskningsöversikt (refereegranskat)abstract
    • The exploration of the unique properties of stored and cooled beams of highly-charged ions as provided by heavy-ion storage rings has opened novel and fascinating research opportunities in the realm of atomic and nuclear physics research. Since the late 1980s, pioneering work has been performed at the CRYRING at Stockholm (Abrahamsson et al. 1993) and at the Test Storage Ring (TSR) at Heidelberg (Baumann et al. 1988). For the heaviest ions in the highest charge-states, a real quantum jump was achieved in the early 1990s by the commissioning of the Experimental Storage Ring (ESR) at GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt (Franzke 1987) where challenging experiments on the electron dynamics in the strong field regime as well as nuclear physics studies on exotic nuclei and at the borderline to atomic physics were performed. Meanwhile also at Lanzhou a heavy-ion storage ring has been taken in operation, exploiting the unique research opportunities in particular for medium-heavy ions and exotic nuclei (Xia et al. 2002).
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  • Chami, Nathalie, et al. (författare)
  • Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits
  • 2016
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 8-21
  • Tidskriftsartikel (refereegranskat)abstract
    • Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 x 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 x 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 x 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
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  • Chen, X., et al. (författare)
  • A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
  • 2018
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
  • Tidskriftsartikel (refereegranskat)abstract
    • Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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  • Muller, David C., et al. (författare)
  • Modifiable causes of premature death in middle-age in Western Europe : Results from the EPIC cohort study
  • 2016
  • Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death. Methods: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models. Results: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers. Conclusions: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.
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  • Toren, K., et al. (författare)
  • Measures of bronchodilator response of FEV1, FVC and SVC in a Swedish general population sample aged 50-64 years, the SCAPIS Pilot Study
  • 2017
  • Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - : DOVE MEDICAL PRESS LTD. - 1176-9106 .- 1178-2005. ; 12, s. 973-980
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Data are lacking from general population studies on how to define changes in lung function after bronchodilation. This study aimed to analyze different measures of bronchodilator response of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC). Materials and methods: Data were derived from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) Pilot study. This analysis comprised 1,050 participants aged 50-64 years from the general population. Participants were investigated using a questionnaire, and FEV1, FVC and SVC were recorded before and 15 minutes after inhalation of 400 mu g of salbutamol. A bronchodilator response was defined as the relative change from baseline value expressed as the difference in units of percent predicted normal. Predictors of bronchodilator responses were assessed using multiple linear regression models. Airway obstruction was defined as FEV1/FVC ratio below lower limit of normal (LLN) before bronchodilation, and COPD was defined as an FEV1/FVC ratio below LLN after bronchodilation. Physician-diagnosed asthma was defined as an affirmative answer to " Have you ever had asthma diagnosed by a physician?". Asymptomatic never-smokers were defined as those not reporting physician-diagnosed asthma, physician-diagnosed COPD or emphysema, current wheeze or chronic bronchitis and being a lifelong never-smoker. Results: Among all subjects, the greatest bronchodilator responses (FEV1, FVC and SVC) were found in subjects with asthma or COPD. The upper 95th percentile of bronchodilator responses in asymptomatic never-smokers was 8.7% for FEV1, 4.2% for FVC and 5.0% for SVC. The bronchodilator responses were similar between men and women. In a multiple linear regression model comprising all asymptomatic never-smokers, the bronchodilator response of FEV1 was significantly associated with airway obstruction and height. Conclusion: When the bronchodilator response in asymptomatic never-smokers is reported as the difference in units of predicted normal, significant reversibility of FEV1, FVC and SVC to bronchodilators is 9%, 4% and 5%, respectively.
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  • Vouzouneraki, Konstantina, et al. (författare)
  • Temporal relationship of sleep apnea and acromegaly: a nationwide study
  • 2018
  • Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 62:2, s. 456-463
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposePatients with acromegaly have an increased risk of sleep apnea, but reported prevalence rates vary largely. Here we aimed to evaluate the sleep apnea prevalence in a large national cohort of patients with acromegaly, to examine possible risk factors, and to assess the proportion of patients diagnosed with sleep apnea prior to acromegaly diagnosis.MethodsCross-sectional multicenter study of 259 Swedish patients with acromegaly. At patients' follow-up visits at the endocrine outpatient clinics of all seven university hospitals in Sweden, questionnaires were completed to assess previous sleep apnea diagnosis and treatment, cardiovascular diseases, smoking habits, anthropometric data, and S-IGF-1 levels. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale. Patients suspected to have undiagnosed sleep apnea were referred for sleep apnea investigations.ResultsOf the 259 participants, 75 (29%) were diagnosed with sleep apnea before the study start. In 43 (57%) of these patients, sleep apnea had been diagnosed before the diagnosis of acromegaly. After clinical assessment and sleep studies, sleep apnea was diagnosed in an additional 20 patients, yielding a total sleep apnea prevalence of 37%. Higher sleep apnea risk was associated with higher BMI, waist circumference, and index finger circumference. Sleep apnea was more frequent among patients with S-IGF-1 levels in the highest quartile.ConclusionSleep apnea is common among patients with acromegaly, and is often diagnosed prior to their acromegaly diagnosis. These results support early screening for sleep apnea in patients with acromegaly and awareness for acromegaly in patients with sleep apnea.
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  • Wang, X., et al. (författare)
  • Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study
  • 2017
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
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  • Weng, Lu Chen, et al. (författare)
  • Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation : The AFGen Consortium
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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  • Zhu, Y., et al. (författare)
  • Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis
  • 2017
  • Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 45:5, s. 2629-2643
  • Tidskriftsartikel (refereegranskat)abstract
    • Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene annotation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodialis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating-type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host-microbe interaction studies.
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  • Ashar, Foram N., et al. (författare)
  • A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
  • 2018
  • Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39:44, s. 3961-
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
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  • Dahlström, Christina, et al. (författare)
  • Structural Change of Cellulose Nanofibers in Supercapacitor Electrodes during Galvanostatic Cycling
  • 2015
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Graphene and other carbon-based materials are often used as electrodes in electrochemical double-layer supercapacitors (EDLCs), due to their ability to store electrical energy. Cellulose nanofibers (CNF) have been proven to be suitable as a dispersion agent and binder in graphite based electrodes for supercapacitor applications, especially due to their capability to improve the wet and dry strength of the electrode. At the same time the capacitance is maintained or even increased with addition of CNF. It is reasonable to believe that the addition of CNF manages to stabilize smaller graphite particles in the dispersion which results in larger internal surface area in the dry material. When the amount of CNF is around 20 wt%, (in ratio to the total mass of active material), both scanning electron microscopy and XPS analysis showed that the surface is almost completely covered with the nano-cellulose. Even with this isolating layer of cellulose it is interesting to note that the capacitance is as high as 90 F/g, compared to around 50 F/g for the lowest CNF amount of 5 wt%. However, by applying voltage pulses during the galvanostatic cycling procedure for capacitance measurements, an initial transient behavior is observed during the first cycles. Therefore the capacitance is calculated after 4000 charge and discharge curves, when curves are completely stabilized. We found that the electrode structure changes significantly during this capacitance measurement and already after a short pulse of 10 s and 0.3 V the structural change is noticeable. After cycling for 24 hours, a completely new structure emerges where large fiber-like structures are developed with diameters around 20-30 µm. The galvanostatic cycling procedure has created fiber-like cellulose structures around 1000 times larger than the initial size of the nano-cellulose. Structural properties of the electrode have often been related to the electronic properties in the supercapacitor. Our result shows that due to this change in the CNF structure, the electrode properties after galvanostatic cycling are indeed also of interest to study. This structural change might be critical to device performance and durability.    
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19.
  • Engström, Alexander C, 1985- (författare)
  • Olikhetens praktiker : Adlig begravningskultur i Sverige c:a 1630-1680
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis examines how the nobility created status and disparity through funeral culture in 17th century Sweden. There were significant societal changes throughout the century that made it problematic to reach consensus on status. This makes the funeral culture a fitting lens to study noble practices.By emphasizing the importance of practice this study moves the perspective from a generally applied view where the subject is considered the master of its surroundings, to one where the subject is dependent on a certain set of material cultures, participants, spaces and sounds in order to create status and difference.This study argues that hierarchies like gender, age, noble rank, merit, pedigree and marital status made certain practices available to just some of the nobility. Noble funeral culture was therefore not uniform, meaning that some engaged with prominent funeral practices while some were left with practices that were not dissimilar to those practiced by people lower on the social hierarchy. Men of the higher elite were generally those which received the most spectacular funerals.  Societal changes saw that certain values were changing all across the nobility, where merits for instance rose above noble titles in significance. The increasing need of specific spaces and participants in the funeral culture saw a growing number of urban funerals, particularly in the capital Stockholm. The increasing participants, territorializations and paraphernalia resulted in increasingly articulated social differences, causing discord within the noble community as with the clergy, congregations and urban inhabitants.Through a broad and diverse empirical body and a novel theoretical approach around how status was generated, this thesis argues that noble status was not uniform, static nor self-evident, but rather cumulatively created. Practices and the creation of status and disparity were dependent on several mutually corresponding and sometimes shifting hierarchies, as well as a corresponding relationship between materiality, participants, space and sound.
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20.
  • Engström, Olof, 1943, et al. (författare)
  • Properties of Metal/High-k Oxide/Graphene Structures
  • 2017
  • Ingår i: ECS Transactions. - : The Electrochemical Society. - 1938-5862 .- 1938-6737. ; 80:1, s. 157-176
  • Konferensbidrag (refereegranskat)abstract
    • The challenge of interpreting experimental data from capacitance versus voltage (C-V) measurements on metal/high-k oxide/graphene (MOG) structures is discussed. Theoretical expressions for the influence of interface states, bulk oxide traps, measurement frequency, temperature and puddles are derived and compared with experiments. The nature of oxide traps and their impact on C-V data is treated especially from the view of electron-lattice interaction at electron emission and capture and possible performance as border traps, resembling interface states. We find that characterization on detailed physical origins leading to effects on C-V data is a more complicated issue than the corresponding analysis of metal/oxide/semiconductor (MOS) structures.
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21.
  • Engström, Patrik, et al. (författare)
  • Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication
  • 2015
  • Ingår i: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221 .- 1618-0607. ; 305:3, s. 378-382
  • Tidskriftsartikel (refereegranskat)abstract
    • Chlamydia trachomatis replication takes place inside of a host cell, exclusively within a vacuole known as the inclusion. During an infection, the inclusion expands to accommodate the increasing numbers of C. trachomatis. However, whether inclusion expansion requires bacterial replication and/or de novo protein synthesis has not been previously investigated in detail. Therefore, using a chemical biology approach, we herein investigated C. trachomatis inclusion expansion under varying conditions in vitro. Under normal cell culture conditions, inclusion expansion correlated with C trachomatis replication. When bacterial replication was inhibited using KSK120: an inhibitor that targets C. trachomatis glucose metabolism, inclusions expanded even in the absence of bacterial replication. In contrast, when bacterial protein synthesis was inhibited using chloramphenicol, expansion of inclusions was blocked. Together, these data suggest that de novo protein synthesis is necessary, whereas bacterial replication is dispensable for C trachomatis inclusion expansion. (C) 2015 The Authors. Published by Elsevier GmbH.
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22.
  • Fernandez, C., et al. (författare)
  • Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality
  • 2018
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820. ; 284:4, s. 377-387
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality. Objectives: To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality. Methods: Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3–21.7 years follow-up. Results: An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14–1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all-cause mortality (1229 events; HR = 1.12, CI = 1.05–1.19, P = 0.001) after full multivariable adjustment. Conclusion: Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.
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23.
  • Georgakis, Marios K., et al. (författare)
  • Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke : Meta-Analysis of Population-Based Studies Involving 17 180 Individuals
  • 2019
  • Ingår i: Circulation Research. - 0009-7330. ; 125:8, s. 773-782
  • Tidskriftsartikel (refereegranskat)abstract
    • Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.
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24.
  • Gijsberts, Crystel M, et al. (författare)
  • Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
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25.
  • Gorda, O., et al. (författare)
  • Ion-optical design of CRYRING@ESR
  • 2015
  • Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T166
  • Tidskriftsartikel (refereegranskat)abstract
    • In 2012 the CRYRING storage ring was delivered from Stockholm to Darmstadt as a part of the Swedish in-kind contribution to the FAIR project. The ring lattice has been slightly changed for optimal injection and to provide additional space for experiment equipment. For the injection from the experimental storage ring (ESR), a new transfer line has been designed. The local injector line has been significantly modified compared to the previous one in Stockholm taking into account the geometry of the existing GSI building. In this paper we present the ion-optical properties of CRYRING@ESR after the described modifications. Single-turn injection from the ESR and multi-turn injection from the local injector are discussed. Ion-optical calculations of fast and slow extraction from CRYRING are also presented. The closed orbit correction scheme is considered taking into account the future arrangement of the beam position monitors and correction magnets. Based on the results of the calculations the requirements for the magnet alignment are finally discussed.
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26.
  • Henry, R. C., et al. (författare)
  • Food supply and bioenergy production within the global cropland planetary boundary
  • 2018
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Supplying food for the anticipated global population of over 9 billion in 2050 under changing climate conditions is one of the major challenges of the 21st century. Agricultural expansion and intensification contributes to global environmental change and risks the long-term sustainability of the planet. It has been proposed that no more than 15% of the global ice-free land surface should be converted to cropland. Bioenergy production for land-based climate mitigation places additional pressure on limited land resources. Here we test normative targets of food supply and bioenergy production within the cropland planetary boundary using a global land-use model. The results suggest supplying the global population with adequate food is possible without cropland expansion exceeding the planetary boundary. Yet this requires an increase in food production, especially in developing countries, as well as a decrease in global crop yield gaps. However, under current assumptions of future food requirements, it was not possible to also produce significant amounts of first generation bioenergy without cropland expansion. These results suggest that meeting food and bioenergy demands within the planetary boundaries would need a shift away from current trends, for example, requiring major change in the demand-side of the food system or advancing biotechnologies.
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27.
  • Hindy, George, et al. (författare)
  • Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes : A Mendelian Randomization Study
  • 2018
  • Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 49:4, s. 820-827
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR).METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias.RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes.CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.
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28.
  • Johnson, Charisse M., et al. (författare)
  • The role of social capital in explaining mental health inequalities between immigrants and Swedish-born : a population-based cross-sectional study
  • 2017
  • Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Social capital may theoretically explain health inequalities between social groups, but empirical evidence is lacking. Some studies indicate that social capital may be particularly important for immigrant health. Nearly 16% of Sweden's population are foreign-born immigrants and research has shown them to be susceptible to psychological distress, though significant variation has been found between groups. In this study, we investigate the following hypotheses: 1) if non-refugees have better mental health than Swedish-born, and refugees experience worse mental health than Swedish-born; 2) if mental health status converges with that of Swedish-born with longer duration of residence; and 3) if social capital mediates the effect of immigrant status on psychological distress for different immigrant groups as compared to Swedish-born.Methods: This cross-sectional study uses baseline data from the Stockholm Public Health Cohort and includes 50,498 randomly-selected individuals from Stockholm County in 2002, 2006, and 2010. Mental health was measured as psychological distress, using the 12-item General Health Questionnaire. Social capital was measured using indicators of bonding, bridging, and linking social capital. Both cognitive and structural aspects were measured for the latter two indicators. Mediation was tested using logistic regression and the Sobel test.Results: The results show that refugees generally had greater odds of psychological distress than non-refugees compared to their respective Swedish-born counterparts. Among immigrant men, both refugees and non-refugees had significantly greater odds of psychological distress than Swedish-born men. Only refugee women in Sweden 10 years or more had significantly greater odds of psychological distress compared to Swedish-born women. The mediation analysis demonstrated that indicators of social capital mediated the association for all immigrant men (except non-refugees in Sweden 3-9 years) and for refugee women in Sweden 10 years or more. While bonding social capital showed the greatest mediatory role among the three social capital types, adding them together had the strongest explanatory effect.Conclusions: Social capital explains differences in mental health for some immigrant groups, highlighting its role as a potentially important post-migration factor. Increased investment from policy-makers regarding how social capital can be promoted among new arrivals may be important for preventing psychological distress.
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29.
  • Kraen, M., et al. (författare)
  • Matrix Metalloproteinases in COPD and atherosclerosis with emphasis on the effects of smoking
  • 2019
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Matrix metalloproteinases (MMP´s) are known biomarkers of atherosclerosis. MMP´s are also involved in the pathophysiological processes underlying chronic obstructive pulmonary disease (COPD). Cigarette smoking plays an important role in both disease states and is also known to affect the concentration and activity of MMP´s systemically. Unfortunately, the epidemiological data concerning the value of MMP´s as biomarkers of COPD and atherosclerosis with special regards to smoking habits are limited. Methods 450 middle-aged subjects with records of smoking habits and tobacco consumption were examined with comprehensive spirometry, carotid ultrasound examination and biomarker analysis of MMP-1, -3, -7, -10 and -12. Due to missing data 33 subjects were excluded. Results The remaining 417 participants were divided into 4 different groups. Group I (n = 157, no plaque and no COPD), group II (n = 136, plaque but no COPD), group III (n = 43, COPD but no plaque) and group IV (n = 81, plaque and COPD). Serum levels of MMP-1,-7,-10-12 were significantly influenced by smoking, and MMP-1, -3, -7 and-12 were elevated in subjects with COPD and carotid plaque. This remained statistically significant for MMP-1 and-12 after adjusting for traditional risk factors. Conclusion COPD and concomitant plaque in the carotid artery were associated with elevated levels of MMP-1 and -MMP-12 even when adjusting for risk factors. Further studies are needed to elucidate if these two MMP´s could be useful as biomarkers in a clinical setting. Smoking was associated with increased serum levels of MMP´s (except for MMP-3) and should be taken into account when interpreting serum MMP results.
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30.
  • Liu, Ning-Ning, et al. (författare)
  • Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence
  • 2018
  • Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 14:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells' oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress.
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31.
  • Moberg, L., et al. (författare)
  • Increased blood cadmium levels were not associated with increased fracture risk but with increased total mortality in women: the Malmo Diet and Cancer Study
  • 2017
  • Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 28:8, s. 2401-2408
  • Tidskriftsartikel (refereegranskat)abstract
    • This study aimed to investigate if high levels of blood cadmium at baseline were associated with increased fracture risk during follow-up in middle-aged women. No increased fracture risk was observed during follow-up, but women with higher levels of cadmium had an increased overall mortality. Introduction Exposure to high levels of cadmium has been associated with an increased fracture risk. The aim was to investigate a perceived association between low levels of blood cadmium (B-Cd) at baseline and risk of first incident fracture. Methods From the population-based Malm Diet and Cancer Study Cardiovascular cohort, 2920 middle-aged women with available background questionnaire and B-Cd measurements were included. Women were divided into quartiles (Q) according to their cadmium levels (Cd-Q1 < 0.18 mu g/L, Cd-Q2 0.180.28 mu g/L, Cd-Q3 0.28-0.51 ae g/ L, and Cd-Q4 > 0.51 mu g/L). National registries were analysed for prospective risk of fractures or death. Associations between B-Cd and fracture risk were assessed by survival analysis (Cox regression analysis). Results In total, 998 first incident fractures occurred in women during a follow-up lasting 20.2 years (median) (12.5-21.2 years) (25th-75th percentile). Women in Cd-Q4 were more often current smokers than in Cd-Q1 78.4 vs. 3.3% (p < 0.001) and the number of cigarettes smoked per day correlated with B-Cd (r = 0.49; p < 0.001). The risk of fracture was not associated with baseline B-Cd in adjusted models. The hazard ratio (HR) Cd-Q4 vs. Cd-Q1 was 1.06 (95% confidence interval (CI) 0.89-1.27). In the multivariate Cox regression, independent variables for increased fracture risk were history of gastric ulcer and increasing age, whereas increasing body mass index (BMI) lowered fracture risk. Overall mortality was significantly higher for women with high B-Cd, HR 2.06 (95% CI 1.57-2.69). Conclusions Higher blood levels of cadmium did not increase fracture risk in middle-aged women but reduced overall survival.
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32.
  • Mojica, Sergio A., et al. (författare)
  • N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF
  • 2017
  • Ingår i: Antimicrobial Agents and Chemotherapy. - : American society for microbiology. - 0066-4804 .- 1098-6596. ; 61:10
  • Tidskriftsartikel (refereegranskat)abstract
    • The type II fatty acid synthesis (FASII) pathway is essential for bacterial lipid biosynthesis and continues to be a promising target for novel antibacterial compounds. Recently, it has been demonstrated that Chlamydia is capable of FASII and this pathway is indispensable for Chlamydia growth. Previously, a high-content screen with Chlamydia trachomatis-infected cells was performed, and acylated sulfonamides were identified to be potent growth inhibitors of the bacteria. C. trachomatis strains resistant to acylated sulfonamides were isolated by serial passage of a wild-type strain in the presence of low compound concentrations. Results from whole-genome sequencing of 10 isolates from two independent drug-resistant populations revealed that mutations that accumulated in fabF were predominant. Studies of the interaction between the FabF protein and small molecules showed that acylated sulfonamides directly bind to recombinant FabF in vitro and treatment of C. trachomatis-infected HeLa cells with the compounds leads to a decrease in the synthesis of Chlamydia fatty acids. This work demonstrates the importance of FASII for Chlamydia development and may lead to the development of new antimicrobials.
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33.
  • Muller, David C., et al. (författare)
  • Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium
  • 2019
  • Ingår i: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 364
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.Design Nested case-control study.Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States.Participants 5299 patients with incident lung cancer, with individually incidence density matched controls.Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples.Main outcome measure Incident lung cancer diagnosis.Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.
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34.
  • Möller, Marika C, et al. (författare)
  • Fatigue and Cognitive Fatigability in Mild Traumatic Brain Injury are Correlated with Altered Neural Activity during Vigilance Test Performance.
  • 2017
  • Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Fatigue is the most frequently reported persistent symptom following a mild traumatic brain injury (mTBI), but the explanations for the persisting fatigue symptoms in mTBI remain controversial. In this study, we investigated the change of cerebral blood flow during the performance of a psychomotor vigilance task (PVT) by using pseudo-continuous arterial spin labeling (PCASL) MRI technique to better understand the relationship between fatigability and brain activity in mTBI.MATERIAL AND METHODS: Ten patients (mean age: 37.5 ± 11.2 years) with persistent complaints of fatigue after mTBI and 10 healthy controls (mean age 36.9 ± 11.0 years) were studied. Both groups completed a 20-min long PVT inside a clinical MRI scanner during simultaneous measurements of reaction time and regional cerebral blood flow (rCBF) with PCASL technique. Cognitive fatigability and neural activity during PVT were analyzed by dividing the performance and rCBF data into quintiles in addition to the assessment of self-rated fatigue before and after the PVT.RESULTS: The patients showed significant fatigability during the PVT while the controls had a stable performance. The variability in performance was also significantly higher among the patients, indicating monitoring difficulty. A three-way ANOVA, modeling of the rCBF data demonstrated that there was a significant interaction effect between the subject group and performance time during PVT in a mainly frontal/thalamic network, indicating that the pattern of rCBF change for the mTBI patients differed significantly from that of healthy controls. In the mTBI patients, fatigability at the end of the PVT was related to increased rCBF in the right middle frontal gyrus, while self-rated fatigue was related to increased rCBF in left medial frontal and anterior cingulate gyri and decreases of rCBF in a frontal/thalamic network during this period.DISCUSSION: This study demonstrates that PCASL is a useful technique to investigate neural correlates of fatigability and fatigue in mTBI patients. Patients suffering from fatigue after mTBI used different brain networks compared to healthy controls during a vigilance task and in mTBI, there was a distinction between rCBF changes related to fatigability vs. perceived fatigue. Whether networks for fatigability and self-rated fatigue are different, needs to be investigated in future studies.
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35.
  • Norby, Faye L, et al. (författare)
  • Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation : The AFGen Consortium
  • 2016
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts.METHODS: We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score.RESULTS: During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.98-1.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04).CONCLUSIONS: In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF.
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36.
  • Noresson, A. L., et al. (författare)
  • Designing interactions by control of protein-ligand complex conformation : Tuning arginine-arene interaction geometry for enhanced electrostatic protein-ligand interactions
  • 2018
  • Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 9:4, s. 1014-1021
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated galectin-3 binding to 3-benzamido-2-O-sulfo-galactoside and -thiodigalactoside ligands using a combination of site-specific mutagenesis, X-ray crystallography, computational approaches, and binding thermodynamics measurements. The results reveal a conformational variability in a surface-exposed arginine (R144) side chain in response to different aromatic C3-substituents of bound galactoside-based ligands. Fluorinated C3-benzamido substituents induced a shift in the side-chain conformation of R144 to allow for an entropically favored electrostatic interaction between its guanidine group and the 2-O-sulfate of the ligand. By contrast, binding of ligands with non-fluorinated substituents did not trigger a conformational change of R144. Hence, a sulfate-arginine electrostatic interaction can be tuned by the choice of ligand C3-benzamido structures to favor specific interaction modes and geometries. These results have important general implications for ligand design, as the proper choice of arginine-aromatic interacting partners opens up for ligand-controlled protein conformation that in turn may be systematically exploited in ligand design.
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37.
  • Pallavicini, Nicola, et al. (författare)
  • Ranges of B, Cd, Cr, Cu, Fe, Pb, Sr, Tl, and Zn Concentrations and Isotope Ratios in Environmental Matrices from an Urban Area
  • 2018
  • Ingår i: Journal of Spectroscopy. - : Hindawi Publishing Corporation. - 2314-4920 .- 2314-4939. ; , s. 1-17
  • Tidskriftsartikel (refereegranskat)abstract
    • Isotopic information may provide powerful insight into the elemental cycling processes which occur in natural compartments. Further implementation of isotopic techniques in natural sciences requires a better understanding of the range of elemental and isotopic compositional variability in environmental matrices. This study assesses the local-scale concentration and isotopic composition variability of nine elements: boron (B), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), strontium (Sr), thallium (Tl), and zinc (Zn) in lysimetric waters, mushrooms, litter, needles, leaves, and lichens. Sequential extractions were also performed on soil samples from 6 depth profiles providing more detailed information on the variability of elemental concentrations and isotope ratios between the elemental pools present in soil. For most of the sample types studied the range of isotopic variability between samples spans almost the entire ranges reported in the literature for natural samples. These results represent a starting point for discussing the role of natural variability in isotopic studies (for example, as a limiting factor in the use of isotopic mixing models) and a baseline for future in-depth studies examining the controls on isotope fraction in natural systems
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38.
  • Parwal, Arvind, et al. (författare)
  • Wave Energy Research at Uppsala University and The Lysekil Research Site, Sweden : A Status Update
  • 2015
  • Konferensbidrag (refereegranskat)abstract
    • This paper provides a summarized status update ofthe Lysekil wave power project. The Lysekil project is coordinatedby the Div. of Electricity, Uppsala University since 2002, with theobjective to develop full-scale wave power converters (WEC). Theconcept is based on a linear synchronous generator (anchored tothe seabed) driven by a heaving point absorber. This WEC has nogearbox or other mechanical or hydraulic conversion systems,resulting in a simpler and robust power plant. Since 2006, 12 suchWECs have been build and tested at the research site located atthe west coast of Sweden. The last update includes a new andextended project permit, deployment of a new marine substation,tests of several concepts of heaving buoys, grid connection,improved measuring station, improved modelling of wave powerfarms, implementation of remote operated vehicles forunderwater cable connection, and comprehensive environmentalmonitoring studies.
  •  
39.
  • Pontér, Simon, et al. (författare)
  • Chromium isotope ratio measurements in environmental matrices by MC-ICP-MS
  • 2016
  • Ingår i: Journal of Analytical Atomic Spectrometry. - : Royal Society of Chemistry (RSC). - 0267-9477 .- 1364-5544. ; 31:7, s. 1464-1471
  • Tidskriftsartikel (refereegranskat)abstract
    • An analytical procedure consisting of high pressure/temperature acid digestion using an UltraCLAVE system and a one pass, single column matrix separation using DOWEX AG 1X8 anion exchange resin was applied to the determination of Cr concentrations and delta Cr-53 in chromites, soils, and biological matrices (epiphytic lichens and mosses) using a combination of ICP-SFMS and MC-ICP-MS. The overall reproducibility of the method was assessed by replicate preparation and Cr isotope ratio measurements performed by different operators in multiple analytical sessions over a few months and was found to be 0.11 parts per thousand (2 sigma). The accuracy was evaluated using commercially available reference materials for which measured data were compared with certified values (for Cr concentrations) and previously published results (for isotope data). The results demonstrate a uniform Cr isotope composition in soil depth profiles sampled in different urban environments. A strong negative correlation between delta Cr-53 and Cr concentrations in lichens and mosses indicates that airborne Cr from local anthropogenic source(s) is depleted in heavy isotopes.
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40.
  • Ricci, Cristian, et al. (författare)
  • Alcohol intake in relation to non-fatal and fatal coronary heart disease and stroke : EPIC-CVD case-cohort study
  • 2018
  • Ingår i: The BMJ. - : BMJ PUBLISHING GROUP. - 1756-1833 .- 0959-8138. ; 361
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. DESIGN Multicentre case-cohort study. SETTING A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. PARTICIPANTS 32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. MAIN OUTCOME MEASURES Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). RESULTS There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/ day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. CONCLUSIONS Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.
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41.
  • Rodushkin, Ilia, et al. (författare)
  • Application of double-focusing sector field ICP-MS for determination of ultratrace constituents in samples characterized by complex composition of the matrix
  • 2018
  • Ingår i: Science of the Total Environment. - : ELSEVIER SCIENCE BV. - 0048-9697 .- 1879-1026. ; 622-623, s. 203-213
  • Tidskriftsartikel (refereegranskat)abstract
    • The performance of double focusing, sector fieldmass spectrometry (ICP-SFMS) for determination of analytes, including technology critical elements (TCE), at ultra-trace levels in environmental and clinical matrices was critically evaluated. Different configurations of the ICP-SFMS introduction system as well as various sample preparations, pre-concentration andmatrix separation methods were employed and compared. Factors affecting detection capabilities and accuracy of data produced (instrumental sensitivity, contamination risks, purity of reagents, spectral interferences, matrix effects, analyte recovery and losses) were discussed. Optimized matrixspecific methods were applied to a range of reference and control materials (riverine, brackish and seawaters; whole blood, serumand urine) as well as tap water and snow samples collected in the area of Lulea city, northern Sweden; brackish and seawater from the Laptev Sea; venous blood samples with a special emphasis on determination of Au, Ag, Ir, Os, Pd, Pt, Re, Rh, Ru, Sb and Te. Even though these low abundant elements are relatively under-documented, the results produced were compared with published data, where available.
  •  
42.
  • Rodushkin, Ilia, et al. (författare)
  • Assessment of the natural variability of B, Cd, Cu, Fe, Pb, Sr, Tl and Zn concentrations and isotopic compositions in leaves, needles and mushrooms using single sample digestion and two-column matrix separation
  • 2016
  • Ingår i: Journal of Analytical Atomic Spectrometry. - 0267-9477 .- 1364-5544. ; 31:1, s. 220-233
  • Tidskriftsartikel (refereegranskat)abstract
    • An analytical procedure allowing multi-elemental analyses and isotope ratio measurements of eight of these (B, Cd, Cu, Fe, Pb, Sr, Tl and Zn) in matrices relevant for bio-monitoring using a single highpressure acid digestion was developed. Method blanks, separation efficiency of matrix elements, repeatability and reproducibility were evaluated using sets of preparation blanks, certified reference materials and duplicate samples prepared and analyzed over a period of several months. The method was used to assess the natural variability of concentrations and isotopic compositions in bio-indicators (tree leaves, needles and mushrooms, over 240 samples) collected mainly from a confined area in North-East Sweden. Ranges found from leaves and needles were compared with data obtained for limited numbers of samples collected in Spain, Italy, France, United Kingdom and Iceland.
  •  
43.
  • Samudyata, Samudyata, et al. (författare)
  • Interaction of Sox2 with RNA binding proteins in mouse embryonic stem cells
  • 2019
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 381:1, s. 129-138
  • Tidskriftsartikel (refereegranskat)abstract
    • Sox2 is a master transcriptional regulator of embryonic development. In this study, we determined the protein interactome of Sox2 in the chromatin and nucleoplasm of mouse embryonic stem (mES) cells. Apart from canonical interactions with pluripotency-regulating transcription factors, we identified interactions with several chromatin modulators, including members of the heterochromatin protein 1 (HP1) family, suggesting a role for Sox2 in chromatin-mediated transcriptional repression. Sox2 was also found to interact with RNA binding proteins (RBPs), including proteins involved in RNA processing. RNA immunoprecipitation followed by sequencing revealed that Sox2 associates with different messenger RNAs, as well as small nucleolar RNA Snord34 and the non-coding RNA 7SK. 7SK has been shown to regulate transcription at gene regulatory regions, which could suggest a functional interaction with Sox2 for chromatin recruitment. Nevertheless, we found no evidence of Sox2 modulating recruitment of 7SK to chromatin when examining 7SK chromatin occupancy by Chromatin Isolation by RNA Purification (ChIRP) in Sox2 depleted mES cells. In addition, knockdown of 7SK in mES cells did not lead to any change in Sox2 occupancy at 7SK-regulated genes. Thus, our results show that Sox2 extensively interacts with RBPs, and suggest that Sox2 and 7SK co-exist in a ribonucleoprotein complex whose function is not to regulate chromatin recruitment, but could rather regulate other processes in the nucleoplasm.
  •  
44.
  • Schmitz, G. J., et al. (författare)
  • Software Solutions for ICME
  • 2016
  • Ingår i: JOM. - : Springer. - 1047-4838 .- 1543-1851. ; 68:1, s. 70-76
  • Tidskriftsartikel (refereegranskat)abstract
    • The Integrated Computational Materials Engineering expert group (ICMEg), a coordination activity of the European Commission, aims at developing a global and open standard for information exchange between the heterogeneous varieties of numerous simulation tools. The ICMEg consortium coordinates respective developments by a strategy of networking stakeholders in the first International Workshop on Software Solutions for ICME, compiling identified and relevant software tools into the Handbook of Software Solutions for ICME, discussing strategies for interoperability between different software tools during a second (planned) international workshop, and eventually proposing a scheme for standardized information exchange in a future book or document. The present article summarizes these respective actions to provide the ICME community with some additional insights and resources from which to help move this field forward.
  •  
45.
  • Schnabel, Renate B., et al. (författare)
  • Searching for Atrial Fibrillation Poststroke : A White Paper of the AF-SCREEN International Collaboration
  • 2019
  • Ingår i: Circulation. - 1524-4539. ; 140:22, s. 1834-1850
  • Tidskriftsartikel (refereegranskat)abstract
    • Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.
  •  
46.
  • Sterner, Thomas, 1952, et al. (författare)
  • Policy design for the Anthropocene
  • 2019
  • Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 2, s. 14-21
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2019, Springer Nature Limited. Today, more than ever, ‘Spaceship Earth’ is an apt metaphor as we chart the boundaries for a safe planet1. Social scientists both analyse why society courts disaster by approaching or even overstepping these boundaries and try to design suitable policies to avoid these perils. Because the threats of transgressing planetary boundaries are global, long-run, uncertain and interconnected, they must be analysed together to avoid conflicts and take advantage of synergies. To obtain policies that are effective at both international and local levels requires careful analysis of the underlying mechanisms across scientific disciplines and approaches, and must take politics into account. In this Perspective, we examine the complexities of designing policies that can keep Earth within the biophysical limits favourable to human life.
  •  
47.
  • Sundström, Johan, Professor, 1971-, et al. (författare)
  • Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
  • 2019
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
  •  
48.
  • Tagetti, A., et al. (författare)
  • A genetic risk score for hypertension is associated with risk of thoracic aortic aneurysm
  • 2019
  • Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 33:9, s. 658-663
  • Tidskriftsartikel (refereegranskat)abstract
    • A genetic risk score (GRS) based on 29 single nucleotide polymorpysms (SNPs) associated with high blood pressure (BP) was prospectively associated with development of hypertension, stroke and cardiovascular events. The aim of the present study was to evaluate the impact of this GRS on the incidence of aortic disease, including aortic dissection (AD), rupture or surgery of a thoracic (TAA) or abdominal (AAA) aortic aneurysm. More than 25,000 people from the Swedish Malmo Diet and Cancer Study had information on at least 24 SNPs and were followed up for a median ≥ 18 years. The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS. In Cox regression models, adjusted for traditional cardiovascular risk factors including hypertension, we found significant associations of the BP-GRS, prospectively, with incident TAA (hazard ratio (HR) 1.64 (95% confidence interval (CI) 1.081–2.475 comparing the third vs. the first tertile; p = 0.020) but not with either AAA or aortic dissection. Calibration, discrimination and reclassification analyses show modest improvement in prediction using the BP-GRS in addition to the model which used only traditional risk factors. A GRS for hypertension associates with TAA suggesting a link between genetic determinants of BP and aortic disease. The effect size is small but the addition of more SNPs to the GRS might improve its discriminatory capability.
  •  
49.
  • Zimmermann, Frederik M., et al. (författare)
  • Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions : meta-analysis of individual patient data
  • 2019
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 40:2, s. 180-186
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To assess the effect of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) with contemporary drug-eluting stents on the composite of cardiac death or myocardial infarction (MI) vs. medical therapy in patients with stable coronary lesions. Methods and results: We performed a systematic review and meta-analysis of individual patient data (IPD) of the three available randomized trials of contemporary FFR-guided PCI vs. medical therapy for patients with stable coronary lesions: FAME 2 (NCT01132495), DANAMI-3-PRIMULTI (NCT01960933), and Compare-Acute (NCT01399736). FAME 2 enrolled patients with stable coronary artery disease (CAD), while the other two focused on non-culprit lesions in stabilized patients after acute coronary syndrome. A total of 2400 subjects were recruited from 54 sites world-wide with 1056 randomly assigned to FFR-guided PCI and 1344 to medical therapy. The pre-specified primary outcome was a composite of cardiac death or MI. We included data from extended follow-ups for FAME 2 (up to 5.5 years follow-up) and DANAMI-3-PRIMULTI (up to 4.7 years follow-up). After a median follow-up of 35 months (interquartile range 12-60 months), a reduction in the composite of cardiac death or MI was observed with FFR-guided PCI as compared with medical therapy (hazard ratio 0.72, 95% confidence interval 0.54-0.96; P = 0.02). The difference between groups was driven by MI. Conclusion: In this IPD meta-analysis of the three available randomized controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or MI compared with medical therapy, which was driven by a decreased risk of MI.
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