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Hellman, U., Mörner, S. & Henein, M. (2019). Genetic variants in cardiac calcification in Northern Sweden. Medicine (Baltimore, Md.), 98(15), Article ID e15065.
Open this publication in new window or tab >>Genetic variants in cardiac calcification in Northern Sweden
2019 (English)In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 98, no 15, article id e15065Article in journal (Refereed) Published
Abstract [en]

Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.

In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).

Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.

We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.

Place, publisher, year, edition, pages
Wolters Kluwer, 2019
Keywords
arterial calcification, coronary artery disease, gene
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-158611 (URN)10.1097/MD.0000000000015065 (DOI)000467331500017 ()30985656 (PubMedID)2-s2.0-85064852879 (Scopus ID)
Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-06-18Bibliographically approved
Hellman, U., Engström-Laurent, A., Larsson, A. & Lindqvist, U. (2019). Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome. Scandinavian Journal of Rheumatology
Open this publication in new window or tab >>Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome
2019 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objective: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab.

Methods: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients’ assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined.

Results: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution.

Conclusion: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2019
National Category
Rheumatology and Autoimmunity
Research subject
rheumatology
Identifiers
urn:nbn:se:umu:diva-158612 (URN)10.1080/03009742.2019.1577490 (DOI)000471466100001 ()31032710 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasTorsten Söderbergs stiftelseRagnar Söderbergs stiftelse
Available from: 2019-05-02 Created: 2019-05-02 Last updated: 2019-07-09
Lorén, C., Dahl, C. P., Do, L., Almaas, V. M., Geiran, O. R., Mörner, S. & Hellman, U. (2019). Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy. Cells, 8(2), Article ID 97.
Open this publication in new window or tab >>Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy
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2019 (English)In: Cells, ISSN 2073-4409, Vol. 8, no 2, article id 97Article in journal (Refereed) Published
Abstract [en]

During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
GEMMA, glucose, hyaluronan, hypertrophic cardiomyopathy, metabolomics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156750 (URN)10.3390/cells8020097 (DOI)000460896000019 ()30699940 (PubMedID)
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-04-04Bibliographically approved
Franklin, O., Billing, O., Öhlund, D., Berglund, A., Herdenberg, C., Wang, W., . . . Sund, M. (2019). Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. Journal of Pathology, 5(2), 130-141
Open this publication in new window or tab >>Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed) Published
Abstract [en]

The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
CD44, biomarkers, hyaluronan, osteopontin, pancreatic cancer, type IV collagen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-154564 (URN)10.1002/cjp2.122 (DOI)000465218700006 ()30456933 (PubMedID)2-s2.0-85064472279 (Scopus ID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-05-20Bibliographically approved
Hellman, U., Lång, K., Ihse, E., Jonasson, J., Olsson, M., Lundgren, H.-E., . . . Anan, I. (2019). Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type. Scandinavian Journal of Clinical and Laboratory Investigation, 1-5
Open this publication in new window or tab >>Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type
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2019 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, p. 1-5Article in journal (Refereed) Epub ahead of print
Abstract [en]

For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Amyloidosis, amyloid fibril, cardiomyopathy, neuropathy, transthyretin
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-160383 (URN)10.1080/00365513.2019.1624977 (DOI)000474016000001 ()31169435 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationVästerbotten County Council
Available from: 2019-06-18 Created: 2019-06-18 Last updated: 2019-07-26
Holm, A., Hellman, U., Laurent, C., Laurell, G., Nylander, K. & Olofsson, K. (2018). Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis. Acta Oto-Laryngologica, 138(11), 1020-1027
Open this publication in new window or tab >>Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis
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2018 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 11, p. 1020-1027Article in journal (Refereed) Published
Abstract [en]

Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.

Abstract [zh]

背景:透明质酸(HA)是一种糖胺聚糖, 具有声带(VF)振动和发声所必需的粘弹性。HA 分子量的变化可能与人乳头瘤病毒相关, 还可能影响复发性呼吸道乳头状瘤病(RRP)的形成或持续。

目的:描述HA的量和定位, HA受体CD44在VF中的定位和假性声带(FVF)在RRP中的定位。

材料和方法:24名RRP患者的VF和FVF的活组织检查。用组织/免疫组织化学方法研究12个样品的上皮、基质和RRP病变中的HA和CD44。用气-相-电泳 - 分子-迁移率-分析仪(GEMMA)分析另12个样品的HA分子量分布。

结果:23个染色中的3个(VF和FVF组合)在上皮细胞中显示出微弱的HA染色;基质中有更强的染色。 CD44存在于FVF和VF的所有区域, 它与HA不同时存在。 GEMMA分析显示非常高量的HA(vHMHA), 它在VF中的量多变。

结论/意义:HA主要分布在基质中。 CD44不与HA接合可能解释所描述的RRP中的非炎症反应。在VF和FVF中观察到可能交合的vHMHA, 而在VF样品中具有更多的变量。抗HA交合可能成为RRP的治疗选择。

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Vocal folds, hyaluronan, CD44, human papilloma virus, recurrent respiratory papillomatosis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156749 (URN)10.1080/00016489.2018.1500712 (DOI)000459000600012 ()30776265 (PubMedID)2-s2.0-85061778147 (Scopus ID)
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-04-29Bibliographically approved
Kumar, A., Do, L., Hellman, U. & Forsblad-d'Elia, H. (2018). OVEREXPRESSION OF MACROPHAGE MIGRATION INHIBITORY FACTOR IN PATIENTS WITH ANKYLOSING SPONDYLITIS AND ITS RELATION TO SEX, INFLAMMATION AND TREATMENT. Clinical and Experimental Rheumatology, 36(4), 716-716
Open this publication in new window or tab >>OVEREXPRESSION OF MACROPHAGE MIGRATION INHIBITORY FACTOR IN PATIENTS WITH ANKYLOSING SPONDYLITIS AND ITS RELATION TO SEX, INFLAMMATION AND TREATMENT
2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 4, p. 716-716Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CLINICAL & EXPER RHEUMATOLOGY, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-151065 (URN)000440741300103 ()
Available from: 2018-09-04 Created: 2018-09-04 Last updated: 2018-09-04Bibliographically approved
Svennerholm, K., Rodsand, P., Hellman, U., Waldenström, A., Lundholm, M., Ahrén, D., . . . Haney, M. (2016). DNA content in extracellular vesicles isolated from porcine coronary venous blood directly after myocardial ischemic preconditioning. PLoS ONE, 11(7), Article ID e0159105.
Open this publication in new window or tab >>DNA content in extracellular vesicles isolated from porcine coronary venous blood directly after myocardial ischemic preconditioning
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159105Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Extracellular vesicles (EV) are nano-sized membranous structures released from most cells. They have the capacity to carry bioactive molecules and gene expression signals between cells, thus mediating intercellular communication. It is believed that EV confer protection after ischemic preconditioning (IPC). We hypothesize that myocardial ischemic preconditioning will lead to rapid alteration of EV DNA content in EV collected from coronary venous effluent.

MATERIALS AND METHODS: In a porcine myocardial ischemic preconditioning model, EV were isolated from coronary venous blood before and after IPC by differential centrifugation steps culminating in preparative ultracentrifugation combined with density gradient ultracentrifugation. The EV preparation was validated, the DNA was extracted and further characterized by DNA sequencing followed by bioinformatics analysis.

RESULTS: Porcine genomic DNA fragments representing each chromosome, including mitochondrial DNA sequences, were detected in EV isolated before and after IPC. There was no difference detected in the number of sequenced gene fragments (reads) or in the genomic coverage of the sequenced DNA fragments in EV isolated before and after IPC. Gene ontology analysis showed an enrichment of genes coding for ion channels, enzymes and proteins for basal metabolism and vesicle biogenesis and specific cardiac proteins.

CONCLUSIONS: This study demonstrates that porcine EV isolated from coronary venous blood plasma contain fragments of DNA from the entire genome, including the mitochondria. In this model we did not find specific qualitative or quantitative changes of the DNA content in EV collected immediately after an in vivo myocardial IPC provocation. This does not rule out the possibility that EV DNA content changes in response to myocardial IPC which could occur in a later time frame.

Place, publisher, year, edition, pages
Public Libray Science, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-124283 (URN)10.1371/journal.pone.0159105 (DOI)000380169600033 ()27434143 (PubMedID)
Available from: 2016-08-01 Created: 2016-08-01 Last updated: 2019-05-23Bibliographically approved
Opheim, L. R., Hellman, U., Engström-Laurent, A. & Laurent, C. (2016). Hyaluronan in Human Vocal Folds in Smokers and Nonsmokers: A Histochemical Study. Journal of Voice, 30(3), 255-262
Open this publication in new window or tab >>Hyaluronan in Human Vocal Folds in Smokers and Nonsmokers: A Histochemical Study
2016 (English)In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588, Vol. 30, no 3, p. 255-262Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES/HYPOTHESIS: To study the hyaluronan occurrence in human vocal folds, with special regards to gender and smoking and to discuss the implications of findings.

STUDY DESIGN: This is a descriptive/morphologic study.

METHODS: Sixteen cadaveric vocal folds from eight individuals between 58 and 90 years old (six women and two men) were removed and studied morphologically. Three of the individuals had been cigarette smokers. A direct method for hyaluronan histochemistry using a hyaluronan-binding protein probe (HABP) was used to visualize the polysaccharide. Five examiners performed an analysis of the intensities of hyaluronan staining, independently.

RESULTS: We observed intense hyaluronan staining of the vocal folds of which those from women stained considerably stronger than those from men. Stratified squamous epithelium stained for hyaluronan in all sections, whereas respiratory epithelium only stained weakly or not at all. The highest accumulation of hyaluronan occurred subepithelially in the lamina propria, corresponding to Reinke's space. It was observed that vocal folds from smokers were more intensively stained than those from nonsmokers.

CONCLUSIONS: Hyaluronan is found in all layers of the human vocal fold. Contradictory to earlier studies, hyaluronan was visualized in squamous epithelium, where it may function as an impact protector. The occurrence of hyaluronan in smokers may have implications in the development of vocal fold inflammation and tumor initiation as hyaluronan is an important molecule in these processes.

Keywords
Vocal folds, Hyaluronan, Smoking, Cigarette, Histochemistry
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-111028 (URN)10.1016/j.jvoice.2015.05.007 (DOI)000376232400002 ()26471808 (PubMedID)
Available from: 2015-11-02 Created: 2015-11-02 Last updated: 2018-06-07Bibliographically approved
Kerje, S., Hellman, U., Do, L., Larsson, G., Kämpe, O., Engström-Laurent, A. & Lindqvist, U. (2016). Is low molecular hyaluronan an early indicator of disease in avian systemic sclerosis?. Connective Tissue Research, 57(5), 337-346
Open this publication in new window or tab >>Is low molecular hyaluronan an early indicator of disease in avian systemic sclerosis?
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2016 (English)In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 57, no 5, p. 337-346Article in journal (Refereed) Published
Abstract [en]

AIM OF THE STUDY: To further elucidate the pathogenesis of systemic sclerosis (SSc) an experimental avian model was used. University of California at Davies line 200-chicken (UCD-200) spontaneously develops a SSc like disease that has most features of human SSc with vascular effects, inflammation, autoimmunity and fibrosis. The first signs of disease in UCD-200 are swelling and ischemic lesions of the comb, a tissue containing high amounts of the glycosaminoglycan hyaluronan. The aim was to evaluate inflammatory and fibrotic processes of the disease with regard to the molecular weight of hyaluronan.

MATERIAL AND METHODS: Comb biopsies from UCD-200 and healthy White Leghorn (WL) chickens as controls at different ages were studied with histochemical localization of hyaluronan, hyaluronidase 1, CD3, IgY and collagen I and III. Hyaluronan molecular weight distribution was estimated with gas phase electrophoretic analysis.

RESULTS: At 2 days of age hyaluronan was visualized in UCD-200 at the dermal part of the comb with no simultaneous staining of Hyal-1. In adult UCD-200 the comb skin was almost totally devoid of hyaluronan compared to WL of the same age. An increase of low molecular weight (LMW) hyaluronan was detected in comb tissue from UCD-200 at 1 day, 1, 2, 4 weeks in contrast to adult animals.

CONCLUSIONS: An early inflammatory process involving LMW hyaluronan was confirmed as a possible profibrotic process. This indicates that hyaluronan might be an important participant in early inflammatory events of SSc in UCD-200 chicken and that disappearance of hyaluronan in skin predisposes to fibrosis.

Place, publisher, year, edition, pages
Taylor & Francis, 2016
Keywords
Avian model, hyaluronan, inflammation, systemic sclerosis, UCD-200 chicken
National Category
Other Basic Medicine Orthopaedics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-121000 (URN)10.1080/03008207.2016.1182997 (DOI)000383444600002 ()27135250 (PubMedID)
Available from: 2016-05-24 Created: 2016-05-24 Last updated: 2018-06-07Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3822-0725

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