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Carlsson, A. C., Ruge, T., Kjøller, E., Hilden, J., Kolmos, H. J., Sajadieh, A., . . . Ärnlöv, J. (2018). 10-Year Associations between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients with Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 7(9), Article ID e008299.
Open this publication in new window or tab >>10-Year Associations between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients with Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.
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2018 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, no 9, article id e008299Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

METHODS AND RESULTS: <0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

CONCLUSIONS: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

Keyword
cohort study, coronary atherosclerosis, tumor necrosis factor‐α
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-349365 (URN)10.1161/JAHA.117.008299 (DOI)29686027 (PubMedID)
Funder
Swedish Research CouncilMarianne and Marcus Wallenberg FoundationSwedish Heart Lung Foundation
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-05-30Bibliographically approved
Hardt, U., Larsson, A., Gunnarsson, I., Clancy, R. M., Petri, M., Buyon, J. P., . . . Grönwall, C. (2018). Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis. Arthritis Research & Therapy, 20, Article ID 36.
Open this publication in new window or tab >>Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis
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2018 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, article id 36Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties.

METHODS: Herein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University.

RESULTS: In two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9-3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.

CONCLUSIONS: Elevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.

Keyword
Autoantibodies, Disease activity, Lupus nephritis, MDA, Malondialdehyde protein modification, Natural antibodies, SLE
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-345090 (URN)10.1186/s13075-018-1530-2 (DOI)000426328200004 ()29482604 (PubMedID)
Funder
Swedish Research CouncilÅke Wiberg FoundationMagnus Bergvall FoundationSwedish Heart Lung FoundationSwedish Rheumatism AssociationKing Gustaf V Jubilee FundNIH (National Institute of Health), R01 AR043727NIH (National Institute of Health), R01 AR069572Stockholm County Council
Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-04-26Bibliographically approved
Nelander, M., Wikström, A.-K., Weis, J., Bergman, L., Larsson, A., Sundström Poromaa, I. & Wikström, J. (2018). Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study. American Journal of Hypertension, 31(7), 847-853
Open this publication in new window or tab >>Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study
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2018 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 31, no 7, p. 847-853Article in journal (Refereed) Published
Abstract [en]

Abstract

Background: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia.

Method: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n=30), normal pregnancy (n=32) and non-pregnant controls (n=16). Cerebral levels organic osmolytes were further correlated to plasma osmolality, and plasma levels of glutamate and sodium.

Results: Compared to non-pregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes myo-inositol, choline and creatine (p=0.001 or less), and all these metabolites correlated with each other (p<0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (p<0.008), and cerebral myo-inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (p<0.05).

Conclusion: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia.

Keyword
Preeclampsia, eclampsia, proton magnetic resonance spectroscopy, cerebral osmolytes, glutamate
National Category
Medical and Health Sciences
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-341642 (URN)10.1093/ajh/hpy019 (DOI)
Funder
Swedish Research Council, 2014-3561
Available from: 2018-02-12 Created: 2018-02-12 Last updated: 2018-06-19Bibliographically approved
Niemelä, V., Burman, J., Blennow, K., Zetterberg, H., Larsson, A. & Sundblom, J. (2018). Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease. PLoS ONE, 13(2), Article ID e0193492.
Open this publication in new window or tab >>Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193492Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification.

METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).

RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.

CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-342996 (URN)10.1371/journal.pone.0193492 (DOI)000426049500119 ()29474427 (PubMedID)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-05-24Bibliographically approved
Alehagen, U., Aaseth, J., Alexander, J., Svensson, E., Johansson, P. & Larsson, A. (2018). Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?. Biofactors, 44(2), 137-147
Open this publication in new window or tab >>Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?
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2018 (English)In: Biofactors, ISSN 0951-6433, E-ISSN 1872-8081, Vol. 44, no 2, p. 137-147Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In an intervention study where 221 healthy elderly persons received selenium and coenzyme Q10 as a dietary supplement, and 222 received placebo for 4 years we observed improved cardiac function and reduced cardiovascular mortality. As fibrosis is central in the aging process, we investigated the effect of the intervention on biomarkers of fibrogenic activity in a subanalysis of this intervention study.

MATERIAL AND METHODS: In the present subanalysis 122 actively treated individuals and 101 controls, the effect of the treatment on eight biomarkers of fibrogenic activity were assessed. These biomarkers were: Cathepsin S, Endostatin, Galectin 3, Growth Differentiation Factor-15 (GDF-15), Matrix Metalloproteinases 1 and 9, Tissue Inhibitor of Metalloproteinases 1 (TIMP 1) and Suppression of Tumorigenicity 2 (ST-2). Blood concentrations of these biomarkers after 6 and 42 months were analyzed by the use of T-tests, repeated measures of variance, and factor analyses.

RESULTS: Compared with placebo, in those receiving supplementation with selenium and coenzyme Q10, all biomarkers except ST2 showed significant decreased concentrations in blood. The changes in concentrations, that is, effects sizes as given by partial eta2 caused by the intervention were considered small to medium.

CONCLUSION: The significantly decreased biomarker concentrations in those on active treatment with selenium and coenzyme Q10 compared with those on placebo after 36 months of intervention presumably reflect less fibrogenic activity as a result of the intervention. These observations might indicate that reduced fibrosis precedes the reported improvement in cardiac function, thereby explaining some of the positive clinical effects caused by the intervention. © 2017 BioFactors, 2017.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keyword
coenzyme Q10, fibrosis, intervention, selenium
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-335915 (URN)10.1002/biof.1404 (DOI)000430002200004 ()29220105 (PubMedID)
Available from: 2017-12-10 Created: 2017-12-10 Last updated: 2018-06-11Bibliographically approved
Carlsson, A. C., Jansson, J.-H., Söderberg, S., Ruge, T., Larsson, A. & Ärnlöv, J. (2018). Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden. Atherosclerosis, 272, 41-46
Open this publication in new window or tab >>Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden
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2018 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, p. 41-46Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS:

Soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) have been associated with cardiovascular diseases, and some evidence points towards a difference in associated risk between men and women. We aimed to study the association between sTNFR1 and sTNFR2 and incident myocardial infarctions (MI) and to explore the influence of established cardiovascular risk factors in men and women.

METHODS:

We conducted a nested case control study in three large Swedish cohorts, including 533 myocardial infarction cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.

RESULTS:

An association between circulating sTNFR1 and sTNFR2 and an increased risk for MI was found when comparing cases and controls. The odds ratios were significant after adjustment for established cardiovascular risk factors and C-reactive protein in women (OR 1.44, 95% CI 1.08-1.93 for TNFR1, and 1.61, 95% CI 1.11-2.34 for TNFR2), but was abolished in men. Women with a combination of elevated CRP and values in the upper quartile of TNFR1 or TNFR2 had a 5-fold higher risk of myocardial infarction versus those with normal CRP and values in the lower three quartiles of TNFR1 or TNFR2.

CONCLUSIONS:

As the risk estimates for TNFR1 and TNFR2 were higher and remained significant after adjustments for established cardiovascular risk factors in women but not in men, a potential role for TNFR1 and TNFR2 in identifying women with a higher MI risk is possible. The future clinical role of TNFR1 and TNFR2 in combination with CRP to identify high risk patients for coronary heart disease has yet to be determined.

Keyword
All-cause mortality, CRP, Community based cohort, Cytokines, Inflammation, Oxidative stress, Tumor necrosis factor
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-349227 (URN)10.1016/j.atherosclerosis.2018.03.020 (DOI)000430383800007 ()29547707 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationMarianne and Marcus Wallenberg Foundation
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-06-19Bibliographically approved
Peura, S., Fall, T., Almqvist, C., Andolf, E., Hedman, A., Pershagen, G., . . . Larsson, A. (2018). Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study. Scandinavian Journal of Clinical and Laboratory Investigation, 78(1-2), 120-124
Open this publication in new window or tab >>Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study
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2018 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, no 1-2, p. 120-124Article in journal (Refereed) Published
Abstract [en]

Faecal calprotectin is a protein used as a diagnostic marker for inflammatory bowel diseases. We determined upper limits for normal calprotectin values for neonatal, 6, 12 and 24 months old children using a turbidimetric immunoassay in a cohort of Swedish children. The advantage of the method is that opposite to previously used enzyme-linked immunosorbent assay (ELISA) method, it enables measuring single samples, and thus, shortens the analysis time significantly. There were 72 samples (41.7% female) collected neonatally, 63 samples (34.9% female) at 6 months, 60 samples (40.0% female) at 12 months and 51 samples (43.1% female) at 24 months. The upper limits for normal values were 233, 615, 136 and 57 µg mg-1 for infants aged 0, 6, 12 and 24 months, respectively.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2018
Keyword
Calprotectin, abdominal pain, inflammatory bowel disease, normal values, turbidimetric immunoassay
National Category
Gastroenterology and Hepatology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-337523 (URN)10.1080/00365513.2017.1420216 (DOI)000424952600019 ()29283308 (PubMedID)
Funder
Swedish Research Council, 2015-03477 2010-15062-79050-11 2015-02434Stockholm County CouncilSwedish Heart Lung Foundation
Available from: 2017-12-30 Created: 2017-12-30 Last updated: 2018-04-10Bibliographically approved
Larsson, A. & Ridefelt, P. (2018). Pediatric reference intervals for liver markers derived from healthy community-based subjects will improve diagnostic interpretation in children and adolescents. Journal of Laboratory and Precision Medicine, 3, 2
Open this publication in new window or tab >>Pediatric reference intervals for liver markers derived from healthy community-based subjects will improve diagnostic interpretation in children and adolescents
2018 (English)In: Journal of Laboratory and Precision Medicine, ISSN 2519-9005, Vol. 3, p. 2-Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Uppsala: , 2018
National Category
Clinical Laboratory Medicine
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:uu:diva-343000 (URN)10.21037/jlpm.2018.01.01 (DOI)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-03-15Bibliographically approved
Roth, G. A., Johnson, C. O., Abate, K. H., Abd-Allah, F., Ahmed, M., Alam, K., . . . Murray, C. J. (2018). The Burden of Cardiovascular Diseases Among US States, 1990-2016.. JAMA cardiology
Open this publication in new window or tab >>The Burden of Cardiovascular Diseases Among US States, 1990-2016.
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2018 (English)In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591Article in journal (Refereed) Epub ahead of print
Abstract [en]

Importance: Cardiovascular disease (CVD) is the leading cause of death in the United States, but regional variation within the United States is large. Comparable and consistent state-level measures of total CVD burden and risk factors have not been produced previously.

Objective: To quantify and describe levels and trends of lost health due to CVD within the United States from 1990 to 2016 as well as risk factors driving these changes.

Design, Setting, and Participants: Using the Global Burden of Disease methodology, cardiovascular disease mortality, nonfatal health outcomes, and associated risk factors were analyzed by age group, sex, and year from 1990 to 2016 for all residents in the United States using standardized approaches for data processing and statistical modeling. Burden of disease was estimated for 10 groupings of CVD, and comparative risk analysis was performed. Data were analyzed from August 2016 to July 2017.

Exposures: Residing in the United States.

Main Outcomes and Measures: Cardiovascular disease disability-adjusted life-years (DALYs).

Results: Between 1990 and 2016, age-standardized CVD DALYs for all states decreased. Several states had large rises in their relative rank ordering for total CVD DALYs among states, including Arkansas, Oklahoma, Alabama, Kentucky, Missouri, Indiana, Kansas, Alaska, and Iowa. The rate of decline varied widely across states, and CVD burden increased for a small number of states in the most recent years. Cardiovascular disease DALYs remained twice as large among men compared with women. Ischemic heart disease was the leading cause of CVD DALYs in all states, but the second most common varied by state. Trends were driven by 12 groups of risk factors, with the largest attributable CVD burden due to dietary risk exposures followed by high systolic blood pressure, high body mass index, high total cholesterol level, high fasting plasma glucose level, tobacco smoking, and low levels of physical activity. Increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors.

Conclusions and Relevance: Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden. Differences in CVD burden are largely attributable to modifiable risk exposures.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-349224 (URN)10.1001/jamacardio.2018.0385 (DOI)29641820 (PubMedID)
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-05-03Bibliographically approved
Nilsen, T., Sunde, K., Hansson, L.-O., Mandic Havelka, A. & Larsson, A. (2017). A novel turbidimetric immunoassay for fecal calprotectin optimized for routine chemistry analyzers. Journal of clinical laboratory analysis (Print), 31(4), Article ID e22061.
Open this publication in new window or tab >>A novel turbidimetric immunoassay for fecal calprotectin optimized for routine chemistry analyzers
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2017 (English)In: Journal of clinical laboratory analysis (Print), ISSN 0887-8013, E-ISSN 1098-2825, Vol. 31, no 4, article id e22061Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Fecal calprotectin assays are widely used to exclude inflammatory bowel disease (IBD) in patients with suspected IBD. A problem with the fecal calprotectin assays is the rather long test-turnaround times. A particle enhanced turbidimetric immunoassays (PETIA) for fecal calprotectin would reduce test-turnaround times and would permit more laboratories to perform the measurements. The aim of this study was to evaluate a new feces calprotectin PETIA.

METHOD: Using routine fecal samples the feces calprotectin PETIA was validated on two chemistry analyzers, Mindray BS-380 and Cobas 501.

RESULTS: The assay is linear in the range 11-2000 μg/g, with a limit of quantitation of approximately 10 μg/g. No antigen excess hook effect was observed up to 10 000-15 000 μg/g depending on the instrument used. The turbidimetric method showed a good agreement with the Bühlmann ELISA. The total coefficient of variation was 3%-8% in the 50-100 μg/g range.

CONCLUSION: The fecal calprotectin PETIA, fCal Turbo, is well suited for rapid analysis of fecal calprotectin on Mindray BS-380 or Cobas 501 clinical chemistry analyzers. The test results are commutable with Bühlmann fecal MRP8/14 ELISA.

Keyword
biological markers, calprotectin, feces, humans, inflammatory bowel diseases, method validation
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-303897 (URN)10.1002/jcla.22061 (DOI)000406107900001 ()27629827 (PubMedID)
Funder
EU, Horizon 2020, Eurostar project E!7991
Available from: 2016-09-26 Created: 2016-09-26 Last updated: 2017-11-02Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3161-0402

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