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Björkqvist, O., Repsilber, D., Seifert, M., Brislawn, C., Jansson, J., Engstrand, L., . . . Halfvarson, J. (2019). Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn's disease: a longitudinal study. Scandinavian Journal of Gastroenterology, 54(4), 577-585
Open this publication in new window or tab >>Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn's disease: a longitudinal study
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2019 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 4, p. 577-585Article in journal (Refereed) Published
Abstract [en]

Objectives: Crohn's disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity.

Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn's disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin.

Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = -0.39; p = .009). Changes in C. leptum (R = -0.18, p = .23) and number of copies of the BCoAT gene (R = -0.12; p = .42) did not correlate with f-calprotectin.

Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn's disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Faecalibacterium prausnitzii, Crohn's disease, calprotectin, butyrate, dysbiosis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-74541 (URN)10.1080/00365521.2019.1599417 (DOI)000468702300001 ()31104514 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RB13-0160
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2019-11-22Bibliographically approved
Engelsöy, U., Rangel, I. & Demirel, I. (2019). Impact of Proinflammatory Cytokines on the Virulence of Uropathogenic Escherichia coli. Frontiers in Microbiology, 10, Article ID 1051.
Open this publication in new window or tab >>Impact of Proinflammatory Cytokines on the Virulence of Uropathogenic Escherichia coli
2019 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 1051Article in journal (Refereed) Published
Abstract [en]

The effect of a urinary tract infection on the host is a well-studied research field. However, how the host immune response affects uropathogenic Escherichia coli (CFT073) virulence is less studied. The aim of the present study was to investigate the impact of proinflammatory cytokine exposure on the virulence of uropathogenic Escherichia coli. We found that all tested proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, IL-8 and IFN-gamma) induced an increased CFT073 growth. We also found that biofilm formation and hemolytic activity was reduced in the presence of all proinflammatory cytokines. However, a reduction in siderophore release was only observed in the presence of IL-1 beta, IL-6 and IL-8. Real time-qPCR showed that all proinflammatory cytokines except TNF-alpha significantly increased genes associated with the iron acquisition system in CFT073. We also found that the proinflammatory cytokines induced significant changes in type-1 fimbriae, P-fimbriae and gluconeogenetic genes. Furthermore, we also showed, using a Caenorhabditis elegans (C. elegans) killing assay that all cytokines decreased the survival of C. elegans worms significantly. Taken together, our findings show that proinflammatory cytokines have the ability to alter the virulence traits of UPEC.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
uropathogenic Escherichia coli, proinflammatory cytokines, cross kingdom interaction, virulence, bacterial growth
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:oru:diva-74408 (URN)10.3389/fmicb.2019.01051 (DOI)000467422200001 ()
Note

Funding Agency:

Faculty of Medicine and Health at Örebro University

Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-05-28Bibliographically approved
Gorreja, F., Rangel, I., Rush, S., Wall, R., De Vos, W. M. & Brummer, R. J. (2018). Double-blind cross-over trial reveals human mucosal transcriptome responses to variants of LGG administration in vivo. In: Peter Konturek (Ed.), Targeting microbiota: 6th World congress on targeting microbiota towards clinical revolution. Paper presented at 6th World Congress on Targeting Microbiota, Porto, Portugal, October 28-30, 2018. Porto, Portugal: ISM, 5, Article ID 978-2-35609-010-2.
Open this publication in new window or tab >>Double-blind cross-over trial reveals human mucosal transcriptome responses to variants of LGG administration in vivo
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2018 (English)In: Targeting microbiota: 6th World congress on targeting microbiota towards clinical revolution / [ed] Peter Konturek, Porto, Portugal: ISM , 2018, Vol. 5, article id 978-2-35609-010-2Conference paper, Poster (with or without abstract) (Other academic)
Place, publisher, year, edition, pages
Porto, Portugal: ISM, 2018
Series
Archives of international society of microbiota, ISSN 978-2-35609-010-2
National Category
Medical and Health Sciences Genetics
Identifiers
urn:nbn:se:oru:diva-69884 (URN)
Conference
6th World Congress on Targeting Microbiota, Porto, Portugal, October 28-30, 2018
Available from: 2018-10-28 Created: 2018-10-28 Last updated: 2018-11-12Bibliographically approved
Björkqvist, O., Repsilber, D., Seifert, M., Engstrand, L., Rangel, I. & Halfvarson, J. (2018). Increasing abundance of faecalibacterium prausnitzii is associated with decreased intestinal inflammation in Crohn's disease: A longitudinal study. Journal of Crohn's & Colitis, 12(Suppl. 1), S468-S469
Open this publication in new window or tab >>Increasing abundance of faecalibacterium prausnitzii is associated with decreased intestinal inflammation in Crohn's disease: A longitudinal study
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2018 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no Suppl. 1, p. S468-S469Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-66747 (URN)000427318902090 ()
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-08-31Bibliographically approved
Neumann, G., Wall, R., Rangel, I., Marques, T. M. & Repsilber, D. (2018). Qualitative modelling of the interplay of inflammatory status and butyrate in the human gut: a hypotheses about robust bi-stability. BMC Systems Biology, 12(1), Article ID 144.
Open this publication in new window or tab >>Qualitative modelling of the interplay of inflammatory status and butyrate in the human gut: a hypotheses about robust bi-stability
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2018 (English)In: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 12, no 1, article id 144Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Gut microbiota interacts with the human gut in multiple ways. Microbiota composition is altered in inflamed gut conditions. Likewise, certain microbial fermentation products as well as the lipopolysaccharides of the outer membrane are examples of microbial products with opposing influences on gut epithelium inflammation status. This system of intricate interactions is known to play a core role in human gut inflammatory diseases. Here, we present and analyse a simplified model of bidirectional interaction between the microbiota and the host: in focus is butyrate as an example for a bacterial fermentation product with anti-inflammatory properties.

RESULTS: We build a dynamical model based on an existing model of inflammatory regulation in gut epithelial cells. Our model introduces both butyrate as a bacterial product which counteracts inflammation, as well as bacterial LPS as a pro-inflammatory bacterial product. Moreover, we propose an extension of this model that also includes a feedback interaction towards bacterial composition. The analysis of these dynamical models shows robust bi-stability driven by butyrate concentrations in the gut. The extended model hints towards a further possible enforcement of the observed bi-stability via alteration of gut bacterial composition. A theoretical perspective on the stability of the described switch-like character is discussed.

CONCLUSIONS: Interpreting the results of this qualitative model allows formulating hypotheses about the switch-like character of inflammatory regulation in the gut epithelium, involving bacterial products as constitutive parts of the system. We also speculate about possible explanations for observed bimodal distributions in bacterial compositions in the human gut. The switch-like behaviour of the system proved to be mostly independent of parameter choices. Further implications of the qualitative character of our modeling approach for the robustness of the proposed hypotheses are discussed, as well as the pronounced role of butyrate compared to other inflammatory regulators, especially LPS, NF- κB and cytokines.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Bi-stability, Butyrate, Dynamical model, Dysbiosis, Gut microbiome, Inflammation, Short chain fatty acids
National Category
Gastroenterology and Hepatology Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:oru:diva-70827 (URN)10.1186/s12918-018-0667-6 (DOI)000453547300001 ()30558589 (PubMedID)2-s2.0-85058628095 (Scopus ID)
Funder
Knowledge Foundation, 20110225
Available from: 2018-12-21 Created: 2018-12-21 Last updated: 2019-04-24Bibliographically approved
Wall, R., Marques, T., Edebol-Carlman, H., Sundin, J., Vumma, R., Rangel, I. & Brummer, R. J. (2017). Altered expression of membrane transporters in colonic mucosa of patients with Irritable Bowel Syndrome (IBS) and Post-infectious (PI)-IBS compared to healthy subjects. Neurogastroenterology and Motility, 29(Suppl. 2), 107-108
Open this publication in new window or tab >>Altered expression of membrane transporters in colonic mucosa of patients with Irritable Bowel Syndrome (IBS) and Post-infectious (PI)-IBS compared to healthy subjects
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2017 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no Suppl. 2, p. 107-108Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Irritable bowel syndrome (IBS) affects 5%- 15% of adults in the general population, and is characterized by chronic recurrent abdominal pain and discomfort and associated with altered bowel habits. The pathophysiology of IBS is complex and not fully under-stood. Hence, treatment is often based on symptomatology rather than underlying physiological aberrancies.

Objective: To compare the expression of membrane transporters in mucosal biopsies of healthy subjects, IBS patients and post- infectious (PI)- IBS patients.

Methods: Mucosal biopsies were obtained from the unprepared sigmoid colon in 18 IBS patients, 9 PI- IBS patients and 10 healthy subjects. Total RNA was isolated and prepared for gene expression analyses using quantitative reverse- transcription polymerase chain reaction (qRT- PCR). We compared the expression of genes encoding membrane- spanning transporters, using GAPDH as a reference gene, and by using the comparative 2- ΔΔCt method.

Results: Colonic expression of SCL7A5 and SLC3A2 (together com-prising the amino acid transporter LAT1+4F2hc) was significantly lower in IBS patients, but not in PI- IBS patients, compared to healthy controls (P<.001). The expression of SLC7A8 (LAT2) tended to be lower in IBS patients compared to controls (P=.06). Mucosal gene ex-pression of the short chain fatty acid transporter SMCT1 (SLC5A8) was lower in both IBS- patients and PI- IBS patients compared to healthy subjects (P<.01).

Conclusions: The amino acid transporters LAT1 and LAT2 appeared to be affected in IBS patients, but not in PI- IBS patients, compared to healthy subjects, suggesting a possible alteration in amino acids transport in this patient group. Furthermore, our results suggest a lower uptake of short chain fatty acids in both IBS- and PI- IBS pa-tients. Altered expression of these transporters may be involved in the pathophysiology of IBS as well as being a potential biomarker of this aberration, and therefore deserves further study in IBS.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Gastroenterology and Hepatology Neurology
Identifiers
urn:nbn:se:oru:diva-60601 (URN)10.1111/nmo.13180 (DOI)000407643600220 ()
Available from: 2017-09-05 Created: 2017-09-05 Last updated: 2019-04-24Bibliographically approved
Demirel, I., Rangel, I., Petersson, U., Persson, K. & Kruse, R. (2017). Transcriptional Alterations of Virulence-Associated Genes in Extended Spectrum Beta-Lactamase (ESBL)-Producing Uropathogenic Escherichia coli during Morphologic Transitions Induced by Ineffective Antibiotics. Frontiers in Microbiology, 8, Article ID 1058.
Open this publication in new window or tab >>Transcriptional Alterations of Virulence-Associated Genes in Extended Spectrum Beta-Lactamase (ESBL)-Producing Uropathogenic Escherichia coli during Morphologic Transitions Induced by Ineffective Antibiotics
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2017 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 8, article id 1058Article in journal (Refereed) Published
Abstract [en]

It is known that an ineffective antibiotic treatment can induce morphological shifts in uropathogenic Escherichia coli (UPEC) but the virulence properties during these shifts remain to be studied. The present study examines changes in global gene expression patterns and in virulence factor-associated genes in an extended spectrum beta-lactamase (ESBL)-producing UPEC (ESBL019) during the morphologic transitions induced by an ineffective antibiotic and in the presence of human primary bladder epithelial cells. Microarray results showed that the different morphological states of ESBL019 had significant transcriptional alterations of a large number of genes (Transition; 7%, Filamentation; 32%, and Reverted 19% of the entities on the array). All three morphological states of ESBL019 were associated with a decreased energy metabolism, altered iron acquisition systems and altered adhesion expression. In addition, genes associated with LPS synthesis and bacterial motility was also altered in all the morphological states. Furthermore, the transition state induced a significantly higher release of TNF-alpha from bladder epithelial cells compared to all other morphologies, while the reverted state was unable to induce INF-alpha release. Our findings show that the morphological shifts induced by ineffective antibiotics are associated with significant transcriptional virulence alterations in ESBL-producing UPEC, which may affect survival and persistence in the urinary tract.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2017
Keywords
filamentation, extended-spectrum beta-lactamase, uropathogenic Escherichia coli, ineffective antibiotics, morphological plasticity
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:oru:diva-58778 (URN)10.3389/fmicb.2017.01058 (DOI)000403139300001 ()28659883 (PubMedID)2-s2.0-85020493714 (Scopus ID)
Funder
Swedish Society of Medicine
Note

Funding Agencies:

Research Committee of Örebro County Council, Nyckelfonden

Faculty of Medicine and Health at Örebro University

Available from: 2017-07-26 Created: 2017-07-26 Last updated: 2018-02-05Bibliographically approved
Rangel, I., Ganda Mall, J. P., Roger, W., Sjöberg, F. & Hultgren-Hörnquist, E. (2016). Degree of colitis correlates with microbial composition and cytokine responses in colon and caecum of Gαi2-deficient mice. FEMS Microbiology Ecology, 92(7), Article ID fiw098.
Open this publication in new window or tab >>Degree of colitis correlates with microbial composition and cytokine responses in colon and caecum of Gαi2-deficient mice
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2016 (English)In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 92, no 7, article id fiw098Article in journal (Refereed) Published
Abstract [en]

An altered immune response and gut microbiota have been associated with the pathology of Inflammatory Bowel Diseases (IBD). However, there is limited knowledge of how inflammation is associated with changes in the microbiota. We studied the microbiota in the intestine and faeces as well as the cytokine gene expressions in caecum and colon of a mouse model (Gαi2(-/-)) of colitis, and analysed them in relation to the degrees of inflammation in the colon. The degree of colitis was associated with general changes in the complexity of the microbiota and was corroborated by quantitative analyses of the Bacteroides and Lactobacillus High gene expression levels of IL-17 and IFN-γ in colon and caecum were detected in Gαi2(-/-) mice with moderate and severe colitis. High IL-27 gene expression in the colon of mice with moderate and severe colitis and in the caecum of mice with moderate colitis was also detected. Negative correlations between IL-27 and Bacteroides and Lactobacillus and between IFN-γ and Lactobacillus were detected in caecum. This research indicates that the degree of colitis in IBD correlates with the gene expression of cytokines and with disturbances in the gut microbiota. Furthermore, the caecum could have an important role in the pathology of IBD.

Place, publisher, year, edition, pages
Oxford, United Kingdom: Oxford University Press, 2016
Keywords
Microbiota, gut, IBD, cytokines, colon, caecum
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:oru:diva-50318 (URN)10.1093/femsec/fiw098 (DOI)000379693700009 ()27162181 (PubMedID)2-s2.0-84978438318 (Scopus ID)
Available from: 2016-05-27 Created: 2016-05-16 Last updated: 2018-07-10Bibliographically approved
Sundin, J., Rangel, I., Fuentes, S., Jong, H.-d., Hultgren-Hörnquist, E., de Vos, W. M. & Brummer, R.-J. (2015). Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress. Alimentary Pharmacology and Therapeutics, 41(4), 342-351
Open this publication in new window or tab >>Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress
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2015 (English)In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 41, no 4, p. 342-351Article in journal (Refereed) Published
Abstract [en]

Background: A subset of irritable bowel syndrome (IBS) patients, denoted post-infectious IBS (PI-IBS), develop symptoms after an enteric infection. Bacterial dysbiosis and mucosal inflammation have been proposed to be involved in the pathophysiology of this entity.

Aim: To characterise the mucosal and faecal microbiota in PI-IBS, general IBS and healthy controls, and to investigate associations between the microbiota and the mucosal immune system.

Methods: Mucosal biopsies and faeces were collected from 13 PI-IBS patients, 19 general IBS patients and 16 healthy controls. Global bacterial composition was determined by generating 16S rRNA amplicons that were examined by phylogenetic microarray hybridisation, principal component and redundancy analysis. We correlated previously reported lymphocyte proportions with the microbiota.

Results: Faecal microbiota composition of PI-IBS patients differed significantly from both general IBS patients and healthy controls (P < 0.02). Both mucosal (P < 0.01) and faecal (P = 0.05) microbial diversity were reduced in PI-IBS compared to healthy controls. In the intraepithelial lymphocytes the previously published proportion of CD8+ CD45RA+ was negatively correlated with mucosal microbial diversity (P < 0.005). The previously published number of lamina propria lymphocytes was negatively correlated with mucosal microbial diversity (P < 0.05). Faecal microbial diversity was significantly negatively correlated with the Hospital Anxiety and Depression scale (P < 0.05).

Conclusions: We present data that distinguishes the intestinal microbiota of PI-IBS patients from that of both general IBS patients and HC. The microbial composition is significantly associated with the HADs score and alterations in lymphocyte subsets proportions.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell, 2015
National Category
Cell and Molecular Biology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-39955 (URN)10.1111/apt.13055 (DOI)000348731200002 ()25521822 (PubMedID)2-s2.0-84921438829 (Scopus ID)
Note

Funding Agencies:

Medical Faculty, Orebro University

Spinoza award of the Netherlands Organization for Scientific Research

Gravity grant (SIAM) of the Netherlands Organization for Scientific Research

Available from: 2014-12-22 Created: 2014-12-22 Last updated: 2018-01-11Bibliographically approved
Sundin, J., Rangel, I., Repsilber, D. & Brummer, R.-J. (2015). Cytokine Response after Stimulation with Key Commensal Bacteria Differ in Post-Infectious Irritable Bowel Syndrome (PI-IBS) Patients Compared to Healthy Controls. PLoS ONE, 10(9), Article ID e0134836.
Open this publication in new window or tab >>Cytokine Response after Stimulation with Key Commensal Bacteria Differ in Post-Infectious Irritable Bowel Syndrome (PI-IBS) Patients Compared to Healthy Controls
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0134836Article in journal (Refereed) Published
Abstract [en]

Background: Microbial dysbiosis and prolonged immune activation resulting in low-grade inflammation and intestinal barrier dysfunction have been suggested to be underlying causes of post-infectious irritable bowel syndrome (PI-IBS). The aim of this study was to evaluate the difference in cytokine response between mucosal specimens of PI-IBS patients and healthy controls (HC) after ex vivo stimulation with key anaerobic bacteria.

Methods: Colonic biopsies from 11 PI-IBS patients and 10 HC were stimulated ex vivo with the commensal bacteria Bacteroides ovatus, Ruminococcus gnavus, Akkermansia muciniphila, Subdoligranulum variabile and Eubacterium limosum, respectively. The cytokine release (IL-1 beta, IL-2, IL-8, IL-10, IL-13, IL-17, TNF-alpha and IFN-gamma) in stimulation supernatants was analyzed using the LUMINEX assay. Comparison of cytokine release between PI-IBS patients and healthy controls was performed taking both unstimulated and bacterially stimulated mucosal specimens into account.

Key Results: IL-13 release from mucosal specimens without bacterial stimulation was significantly lower in PI-IBS patients compared to HC (p < 0.05). After stimulation with Subdoligranulum variabile, IL-1 beta release from PI-IBS patients was significantly increased compared to HC (p < 0.05). Stimulation with Eubacterium limosum resulted in a significantly decreased IL-10 release in HC compared to PI-IBS patients (p < 0.05) and a tendency to decreased IL-13 release in HC compared to PI-IBS patients (p = 0.07).

Conclusions & Inferences: PI-IBS patients differ from HC with regard to cytokine release ex vivo after stimulation with selected commensal bacteria. Hence, our results support that the pathogenesis of PI-IBS comprises an altered immune response against commensal gut microbes.

National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-46171 (URN)10.1371/journal.pone.0134836 (DOI)000361601100007 ()26366730 (PubMedID)
Note

Funding Agency:

Medical Faculty, Örebro University

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2017-12-01Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-3383-9219

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