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Bao, X., Borne, Y., Muhammad, I. F., Nilsson, J., Lind, L., Melander, O., . . . Engström, G. (2019). Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort. Diabetologia, 62(1), 78-86
Open this publication in new window or tab >>Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 1, p. 78-86Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor- superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population.

Methods: Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.45.96years, 38.6% men) who were participants in the Malmo Diet and Cancer-Cardiovascular Cohort. After a follow-up of 19.05.16years (mean +/- SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP).

Results: During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p<0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n=3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged 55, 56-60 (>55 and 60) and >60years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p=0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061).

Conclusions/interpretation: GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are 60years old.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Cohort analysis, Diabetes mellitus, Growth differentiation factor 15, Macrophage inhibitory cytokine-1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-372881 (URN)10.1007/s00125-018-4751-7 (DOI)000452776600010 ()30350239 (PubMedID)
Funder
Swedish Heart Lung Foundation, 2016-0315Swedish Heart Lung Foundation, 2017-0626
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Forsberg, L. A., Halvardson, J., Rychlicka-Buniowska, E., Danielsson, M., Moghadam, B. T., Mattisson, J., . . . Dumanski, J. P. (2019). Mosaic loss of chromosome Y in leukocytes matters [Letter to the editor]. Nature Genetics, 51(1), 4-7
Open this publication in new window or tab >>Mosaic loss of chromosome Y in leukocytes matters
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal, Letter (Other academic) Published
National Category
Medical Genetics Genetics
Identifiers
urn:nbn:se:uu:diva-373366 (URN)10.1038/s41588-018-0267-9 (DOI)000454108800004 ()30374072 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Morris, A. P., Le, T. H., Wu, H., Akbarov, A., van der Most, P. J., Hemani, G., . . . Franceschini, N. (2019). Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies. Nature Communications, 10(1), Article ID 29.
Open this publication in new window or tab >>Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, no 1, article id 29Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-372078 (URN)10.1038/s41467-018-07867-7 (DOI)000454756900006 ()30604766 (PubMedID)
Funder
NIH (National Institute of Health), R01-DK-113632, 5P50-HD-028138-27, R37-NS-029993, U54-TR-002736, R01-MD-012765, R56-DK-104806, R01-DK-117445-01A1Wellcome trust, 208806/Z/17/Z
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2019-01-28Bibliographically approved
Liu, C., Marioni, R. E., Hedman, Å. K., Pfeiffer, L., Tsai, P.-C., Reynolds, L. M., . . . Levy, D. (2018). A DNA methylation biomarker of alcohol consumption.. Molecular Psychiatry, 23, 422-433
Open this publication in new window or tab >>A DNA methylation biomarker of alcohol consumption.
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2018 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, p. 422-433Article in journal (Refereed) Published
Abstract [en]

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-319698 (URN)10.1038/mp.2016.192 (DOI)000423441700028 ()27843151 (PubMedID)
Note

De tio första författarna delar på förstaförfattarskapet. De sex sista författarna delar på sistaförfattarskapet.

Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-03-19Bibliographically approved
Chen, X., Gustafsson, S., Whitington, T., Borne, Y., Lorentzen, E., Sun, J., . . . Magnusson, P. K. E. (2018). A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia. Human Molecular Genetics, 27(10), 1809-1818
Open this publication in new window or tab >>A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 10, p. 1809-1818Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-356866 (URN)10.1093/hmg/ddy094 (DOI)000431886200012 ()29547969 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Heart Lung Foundation, 20070481
Available from: 2018-08-15 Created: 2018-08-15 Last updated: 2018-08-15Bibliographically approved
Jiang, J., Thalamuthu, A., Ho, J. E., Mahajan, A., Ek, W. E., Brown, D. A., . . . Mather, K. A. (2018). A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. Frontiers in Genetics, 9, Article ID 97.
Open this publication in new window or tab >>A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood
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2018 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 9, article id 97Article in journal (Refereed) Published
Abstract [en]

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of similar to 5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 x 10(-35)), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the "COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
genome-wide association study, growth differentiation factor-15, macrophage inhibitory cytokine-1, community-based individuals, chromosome 19
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-354354 (URN)10.3389/fgene.2018.00097 (DOI)000428198300001 ()
Funder
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2012-1397Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Research Council, 80576801Swedish Research Council, 70374401Swedish Foundation for Strategic Research Australian Research Council, DP0774213Australian Research Council, DP0773584Australian Research Council, LP0669645
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Stubleski, J., Kukucka, P., Salihovic, S., Lind, P. M., Lind, L. & Kärrman, A. (2018). A method for analysis of marker persistent organic pollutants in low-volume plasma and serum samples using 96-well plate solid phase extraction. Journal of Chromatography A, 1546, 18-27, Article ID S0021-9673(18)30253-X.
Open this publication in new window or tab >>A method for analysis of marker persistent organic pollutants in low-volume plasma and serum samples using 96-well plate solid phase extraction
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2018 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1546, p. 18-27, article id S0021-9673(18)30253-XArticle in journal (Refereed) Published
Abstract [en]

The objective of this study was to develop and validate a 96-well plate solid phase extraction method for analysis of 23 lipophilic persistent organic pollutants (POPs) in low-volume plasma and serum samples which is applicable for biomonitoring and epidemiological studies. The analysis of selected markers for internal exposure: 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and polybrominated diphenylether 47 (BDE 47) was evaluated by comparing two SPE sorbents and GC-HRMS or GC-MS/MS detection. The final method extracted 23 POPs from 150 μL of serum and plasma using a 96-well extraction plate containing 60 mg Oasis HLB sorbent per well prior to GC-HRMS magnetic sector analysis. The extraction method was applied to 40 plasma samples collected for an epidemiological study. The recovery of selected POPs ranged from 31% to 63% (n = 48), and detection limits ranged from 2.2 to 45 pg/mL for PCBs, 4.2 to 167 pg/mL for OCPs, 7.8 pg/mL for OCDD and 6.1 pg/mL for BDE 47. This method showed good precision with relative standard deviations of selected POP concentrations in quality control samples (n = 48) ranging from 11% to 25%. The trueness was determined with standard reference material serum (n = 48) and the deviation from certified values ranged from 1 to 27%. Of the 23 POPs analyzed, 18 were detected in 43% to 100% of plasma samples collected for the epidemiological study. The method showed good robustness with low inter-well plate variation (11-31%) determined by twelve 96-well plate extractions, and can extract 96 samples, including quality controls and procedural blanks in 2-3 days. Comparison with GC-MS/MS analysis showed that similar concentrations (within 0.5% to 30%) of most POPs could be obtained with GC-APCI-MS/MS. Larger deviations were observed for PCB 194 (60%) and trans-nonachlor (43%). The developed method produces accurate concentrations of low-level marker POPs in plasma and serum, providing a suitable high-throughput sample preparation procedure for biomonitoring and epidemiological studies involving large sample size and limited sample volume. GC-HRMS was chosen over GC-MS/MS, however the latter showed promising results, and could be used as an alternative to GC-HRMS analysis for most POPs.

Keywords
APCI-MS/MS, GC-HRMS, High-throughput SPE, Persistent organic pollutants
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-348564 (URN)10.1016/j.chroma.2018.02.057 (DOI)000430766800003 ()29510870 (PubMedID)
Funder
Swedish Research Council Formas, 216-2013-478
Available from: 2018-04-16 Created: 2018-04-16 Last updated: 2018-06-26Bibliographically approved
Beijer, K., Sundström, J., Arnlöv, J., Fall, T., Ingelsson, E. & Lind, L. (2018). A targeted proteomic profile of prevalent diabetes in a population-based sample. Paper presented at 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY. Diabetologia, 61, S252-S252
Open this publication in new window or tab >>A targeted proteomic profile of prevalent diabetes in a population-based sample
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S252-S252Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-367122 (URN)000443556003105 ()
Conference
54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2018-11-30Bibliographically approved
Li, Y., Thijs, L., Asayama, K., Hansen, T. W., Boggia, J., Björklund-Bodegård, K., . . . Staessen, J. A. (2018). Age- sex- and ethnicity-specific prediction of cardiovascular outcomes by in-office and out-of-the-office blood pressure: a subject-level meta-analysis of 17,383 adults enrolled in 17 population studies. Paper presented at 27th Scientific Meeting of the International-Society-of-Hypertension, SEP 20-23, 2018, Beijing, PEOPLES R CHINA. Journal of Hypertension, 36, E310-E311
Open this publication in new window or tab >>Age- sex- and ethnicity-specific prediction of cardiovascular outcomes by in-office and out-of-the-office blood pressure: a subject-level meta-analysis of 17,383 adults enrolled in 17 population studies
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2018 (English)In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, p. E310-E311Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
Keywords
ambulatory blood pressure monitoring, cardiovascular disease, home blood pressure, hypertension, mortality, population science
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-376316 (URN)10.1097/01.hjh.0000549267.21310.56 (DOI)000455594806048 ()
Conference
27th Scientific Meeting of the International-Society-of-Hypertension, SEP 20-23, 2018, Beijing, PEOPLES R CHINA
Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-02-04Bibliographically approved
Titova, O. E., Lindberg, E., Elmstahl, S., Lind, L., Schiöth, H. B. & Benedict, C. (2018). Associations Between the Prevalence of Metabolic Syndrome and Sleep Parameters Vary by Age. Frontiers in Endocrinology, 9, Article ID 234.
Open this publication in new window or tab >>Associations Between the Prevalence of Metabolic Syndrome and Sleep Parameters Vary by Age
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2018 (English)In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 234Article in journal (Refereed) Published
Abstract [en]

Objective: To examine whether the relationship between the metabolic syndrome (MetS) and various sleep parameters [sleep duration, symptoms of sleep-disordered breathing (SDB), and sleep disturbances] varies by age. Methods: Waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose were used to determine MetS status in a cohort (N = 19,691) of middle-aged (aged 45-64 years) and older (aged >= 65 years) subjects. Habitual sleep duration (short, <= 6 h/day; normal, 7-8 h/day; and long >= 9 h/day), sleep disturbances (such as problems with falling and staying asleep), and symptoms of sleep-disordered breathing (SDB, such as snoring and sleep apneas) were measured by questionnaires. Results: Among the participants, 4,941 subjects (25.1%) fulfilled the criteria for MetS. In the entire sample, both short and long sleep durations were associated with higher prevalence of MetS as compared to normal sleep duration. When stratified by age, a similar pattern was observed for middle-aged subjects (<65 years old; prevalence ratio (PR) [95% CI], 1.13 [1.06-1.22] for short sleep and 1.26 [1.06-1.50] for long sleep duration). In contrast, in older individuals (>= 65 years old), only long sleep duration was linked to a higher prevalence of MetS (1.26 [1.12-1.42]; P < 0.01 for sleep duration x age). In the entire cohort, having at least one SDB symptom >= 4 times per week was linked to an increased prevalence of MetS; however, the PR was higher in middle-aged subjects compared with older subjects (1.50 [1.38-1.63] vs. 1.36 [1.26-1.47], respectively; P < 0.001 for SDB x age). Finally, independent of subjects' age, reports of sleep disturbances (i.e., at least one symptom >= 4 times per week) were associated with a higher likelihood of having MetS (1.12 [1.06-1.18]; P > 0.05 for sleep disturbance x age). Conclusion: Our results suggest that age may modify the associations between some sleep parameters and the prevalence of MetS.

Keywords
sleep duration, sleep disturbance, sleep-disordered breathing, metabolic syndrome, age
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-356873 (URN)10.3389/fendo.2018.00234 (DOI)000431867800001 ()29867766 (PubMedID)
Funder
Swedish Research Council, 2015-03100The Swedish Brain FoundationNovo Nordisk, NNF14OC0009349
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2019-01-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2335-8542

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