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Nilsson Ekdahl, KristinaORCID iD iconorcid.org/0000-0001-7888-1571
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Publications (10 of 128) Show all publications
N.Ekdahl, K., Fromell, K., Mohlin, C., Teramura, Y. & Nilsson, B. (2019). A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity. Science and Technology of Advanced Materials, 20(1), 688-698
Open this publication in new window or tab >>A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
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2019 (English)In: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 20, no 1, p. 688-698Article, review/survey (Refereed) Published
Abstract [en]

In this review article, we focus on activation of the soluble components of the innate immune system triggered by nonbiological compounds and stress variances in activation due to the difference in size between nanoparticles (NPs) and larger particles or bulk material of the same chemical and physical composition. We then discuss the impact of the so-called protein corona which is formed on the surface of NPs when they come in contact with blood or other body fluids. For example, NPs which bind inert proteins, proteins which are prone to activate the contact system (e.g., factor XII), which may lead to clotting and fibrin formation or the complement system (e.g., IgG or C3), which may result in inflammation and vascular damage. Furthermore, we describe a whole blood model which we have developed to monitor activation and interaction between different components of innate immunity: blood protein cascade systems, platelets, leukocytes, cytokine generation, which are induced by NPs. Finally, we describe our own studies on innate immunity system activation induced by three fundamentally different species of NPs (two types of engineered NPs and diesel NPs) as demonstrator of the utility of an initial determination of the composition of the protein corona formed on NPs exposed to ethylenediaminetetraacetic acid (EDTA) plasma and subsequent analysis in our whole blood model. [GRAPHICS] .

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Coagulation system, complement system, contact, kallikrein system, inflammation, innate immunity, nanoparticles, protein corona, screening, toxicity, whole blood model
National Category
Pharmacology and Toxicology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390411 (URN)10.1080/14686996.2019.1625721 (DOI)000472611100001 ()31275460 (PubMedID)
Funder
Swedish Research Council, 2016-20755-1Swedish Research Council, 2016-04519Swedish Research Council, 2018-04199
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-12-14Bibliographically approved
Tjernberg, A. R., Woksepp, H., Sandholm, K., Johansson, M., Dahle, C., Ludvigsson, J. F., . . . Nilsson Ekdahl, K. (2019). Celiac disease and complement activation in response to Streptococcus pneumoniae. European Journal of Pediatrics
Open this publication in new window or tab >>Celiac disease and complement activation in response to Streptococcus pneumoniae
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2019 (English)In: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076Article in journal (Refereed) Published
Abstract [en]

Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999–2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively).

Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.

Keywords
Coeliac, Pneumococcal, Infection, Innate immunity, MBL
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-397648 (URN)10.1007/s00431-019-03490-w (DOI)000494392200001 ()31691001 (PubMedID)
Funder
Swedish Research Council, 522-2A09-195Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2018-04087The Research Council of Norway, 274332
Note

Early access: Article that have been peer-reviewed and accepted for publication. The article content has been finalized, but it has not been assigned to an issue yet.

Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-12-14Bibliographically approved
Mohebnasab, M., Eriksson, O., Persson, B., Sandholm, K., Mohlin, C., Huber-Lang, M., . . . Nilsson, B. (2019). Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics. Frontiers in Immunology, 10, Article ID 2539.
Open this publication in new window or tab >>Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2539Article, review/survey (Refereed) Published
Abstract [en]

Aberrations in complement system functions have been identified as either direct or indirect pathophysiological mechanisms in many diseases and pathological conditions, such as infections, autoimmune diseases, inflammation, malignancies, and allogeneic transplantation. Currently available techniques to study complement include quantification of (a) individual complement components, (b) complement activation products, and (c) molecular mechanisms/function. An emerging area of major interest in translational studies aims to study and monitor patients on complement regulatory drugs for efficacy as well as adverse events. This area is progressing rapidly with several anti-complement therapeutics under development, in clinical trials, or already in clinical use. In this review, we summarized the appropriate indications, techniques, and interpretations of basic complement analyses, exemplified by a number of clinical disorders.

Keywords
clinical trial, laboratory investigation, immunoassays, functional assays, CV%
National Category
Immunology in the medical area Immunology
Identifiers
urn:nbn:se:uu:diva-398795 (URN)10.3389/fimmu.2019.02539 (DOI)000498927000001 ()31787968 (PubMedID)
Funder
Swedish Research Council, 2015-06429Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Note

Maedeh Mohebnasab and Oskar Eriksson are joint first authors.

Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2020-01-08Bibliographically approved
Sandholm, K., Persson, B., Skattum, L., Eggertsen, G., Nyman, D., Gunnarsson, I., . . . Nilsson Ekdahl, K. (2019). Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use. Frontiers in Immunology, 10, Article ID 7.
Open this publication in new window or tab >>Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 7Article in journal (Refereed) Published
Abstract [en]

Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The "gold standard" assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
C1q, immunoassays, plasma, CSF, SLE, nephritis
National Category
Rheumatology and Autoimmunity Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-376814 (URN)10.3389/fimmu.2019.00007 (DOI)000456846400001 ()
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-02-19 Created: 2019-02-19 Last updated: 2019-12-14Bibliographically approved
Nilsson Ekdahl, K., Mohlin, C., Adler, A., Åman, A., Manivel, V. A., Sandholm, K., . . . Nilsson, B. (2019). Is generation of C3(H2O) necessary for activation of the alternative pathway in real life?. Paper presented at 17th European Meeting on Complement in Human Disease (EMCHD), 14-17 September 2019, Madrid, SPAIN. Molecular Immunology, 114, 353-361
Open this publication in new window or tab >>Is generation of C3(H2O) necessary for activation of the alternative pathway in real life?
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2019 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 353-361Article in journal (Refereed) Published
Abstract [en]

In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the “C3b-like” C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces.

During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by the classical/lectin pathway (CP/LP) convertases. After the discovery of LP's recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules.

Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases. Therefore, C3(H2O) generation in vivo may be less important for AP activation during specific attack or dysregulated homeostasis, but may be an important ligand for C3 receptors in cell-cell interactions and a source of C3 for the intracellular complement reservoir.

Keywords
Complement system, C3(H2O), Conformation, Analysis, Proteases, Alternative pathway
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-396739 (URN)10.1016/j.molimm.2019.07.032 (DOI)000490625600041 ()31446306 (PubMedID)
Conference
17th European Meeting on Complement in Human Disease (EMCHD), 14-17 September 2019, Madrid, SPAIN
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519German Research Foundation (DFG), CRC1149A01
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-12-14Bibliographically approved
Noiri, M., Asawa, K., Okada, N., Kodama, T., Murayama, Y., Inoue, Y., . . . Teramura, Y. (2019). Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium. Journal of Biomedical Materials Research. Part A, 107(8), 1779-1792
Open this publication in new window or tab >>Modification of human MSC surface with oligopeptide-PEG-lipids for selective binding to activated endothelium
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2019 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 107, no 8, p. 1779-1792Article in journal (Refereed) Published
Abstract [en]

Promising cell therapies using mesenchymal stem cells (MSCs) is proposed for stroke patients. Therefore, we aimed to efficiently accumulate human MSC (hMSC) to damaged brain area to improve the therapeutic effect using poly(ethylene glycol) (PEG)-conjugated phospholipid (PEG-lipid) carrying an oligopeptide as a ligand, specific for E-selectin which is upregulated on activated endothelial cells under hypoxia-like stroke. Here we synthesized E-selectin-binding oligopeptide (ES-bp) conjugated with PEG spacer having different molecular weights from 1 to 40 kDa. We found that ES-bp can be immobilized onto the hMSC surface through PEG-lipid without influence on cell growth and differentiation into adipocytes and osteocytes, respectively. It is also possible to control the immobilization of ES-bp on hMSC surface (<10(8) ES-bp per cell). Immobilized ES-bp can be continuously immobilized at the outside of cell membrane when PEG-lipids with PEG 5 and 40 kDa were used. In addition, the modified hMSC can specifically attach onto E-selectin-immobilized surface as a model surface of activated endothelium in human blood, indicating the sufficient number of immobilized ES-bp onto hMSC. Thus, this technique is one of the candidates for hMSC accumulation to cerebral infarction area.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
cell surface modification, E-selectin, mesenchymal stem cell (MSC), poly(ethylene glycol)-conjugated phospholipid (PEG-lipid), stroke
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-390077 (URN)10.1002/jbm.a.36697 (DOI)000471813900020 ()30983125 (PubMedID)
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-12-14Bibliographically approved
Toda, S., Fattah, A., Asawa, K., Nakamura, N., Nilsson Ekdahl, K., Nilsson, B. & Teramura, Y. (2019). Optimization of Islet Microencapsulation with Thin Polymer Membranes for Long-Term Stability. Micromachines, 10(11), Article ID 755.
Open this publication in new window or tab >>Optimization of Islet Microencapsulation with Thin Polymer Membranes for Long-Term Stability
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2019 (English)In: Micromachines, ISSN 2072-666X, E-ISSN 2072-666X, Vol. 10, no 11, article id 755Article in journal (Refereed) Published
Abstract [en]

Microencapsulation of islets can protect against immune reactions from the host immune system after transplantation. However, sufficient numbers of islets cannot be transplanted due to the increase of the size and total volume. Therefore, thin and stable polymer membranes are required for the microencapsulation. Here, we undertook the cell microencapsulation using poly(ethylene glycol)-conjugated phospholipid (PEG-lipid) and layer-by-layer membrane of multiple-arm PEG. In order to examine the membrane stability, we used different molecular weights of 4-arm PEG (10k, 20k and 40k)-Mal to examine the influence on the polymer membrane stability. We found that the polymer membrane made of 4-arm PEG(40k)-Mal showed the highest stability on the cell surface. Also, the polymer membrane did not disturb the insulin secretion from beta cells.

Keywords
microencapsulation, bioartificial pancreas, islet transplantation, polyethylene glycol-lipid (PEG-lipid), cell surface modification
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-400755 (URN)10.3390/mi10110755 (DOI)000502255300041 ()31698737 (PubMedID)
Funder
Swedish Research Council, 2018-04199Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-01-03Bibliographically approved
Eriksson, O., Mohlin, C., Nilsson, B. & N. Ekdahl, K. (2019). The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System. Frontiers in Immunology, 10, Article ID 1590.
Open this publication in new window or tab >>The Human Platelet as an Innate Immune Cell: Interactions Between Activated Platelets and the Complement System
2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1590Article, review/survey (Refereed) Published
Abstract [en]

Platelets play an essential role in maintaining homeostasis in the circulatory system after an injury by forming a platelet thrombus, but they also occupy a central node in the intravascular innate immune system. This concept is supported by their extensive interactions with immune cells and the cascade systems of the blood. In this review we discuss the close relationship between platelets and the complement system and the role of these interactions during thromboinflammation. Platelets are protected from complement-mediated damage by soluble and membrane-expressed complement regulators, but they bind several complement components on their surfaces and trigger complement activation in the fluid phase. Furthermore, localized complement activation may enhance the procoagulant responses of platelets through the generation of procoagulant microparticles by insertion of sublytic amounts of C5b9 into the platelet membrane. We also highlight the role of post-translational protein modifications in regulating the complement system and the critical role of platelets in driving these reactions. In particular, modification of disulfide bonds by thiol isomerases and protein phosphorylation by extracellular kinases have emerged as important mechanisms to fine-tune complement activity in the platelet microenvironment. Lastly, we describe disorders with perturbed complement activation where part of the clinical presentation includes uncontrolled platelet activation that results in thrombocytopenia, and illustrate how complement-targeting drugs are alleviating the prothrombotic phenotype in these patients. Based on these clinical observations, we discuss the role of limited complement activation in enhancing platelet activation and consider how these drugs may provide opportunities for further dissecting the complex interactions between complement and platelets.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
complement, platelets, lectin pathway, disulfides, phosphorylation, thiol isomerases, innate immunity
National Category
Immunology in the medical area Immunology
Identifiers
urn:nbn:se:uu:diva-390426 (URN)10.3389/fimmu.2019.01590 (DOI)000474774200001 ()31354729 (PubMedID)
Funder
Swedish Research Council, 2015-06429Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-12-14Bibliographically approved
Asif, S., Asawa, K., Yuuki, I., Ishihara, K., Lindell, B., Holmgren, R., . . . Nilsson Ekdahl, K. (2019). Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models. Macromolecular Bioscience, 19(5), Article ID 1800485.
Open this publication in new window or tab >>Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
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2019 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed) Published
Abstract [en]

Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2019
Keywords
blood compatibility, blood model systems, coagulation system, complement system, heparin coat, MPC polymer coat
National Category
Clinical Laboratory Medicine Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-374785 (URN)10.1002/mabi.201800485 (DOI)000471340300015 ()30786149 (PubMedID)
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Note

Kazuhiko Ishihara har tillkommit som författare sedan posten lades in som manuskript.

Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-12-14Bibliographically approved
Mohlin, C., Sandholm, K., Kvanta, A., Nilsson Ekdahl, K. & Johansson, K. (2018). A model to study complement involvement in experimental retinal degeneration. Upsala Journal of Medical Sciences, 123(1), 28-42
Open this publication in new window or tab >>A model to study complement involvement in experimental retinal degeneration
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 28-42Article in journal (Refereed) Published
Abstract [en]

Background: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

Method and materials: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

Results: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

Discussion: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
AMD, complement system, ocular diseases, retina, RPE
National Category
Ophthalmology
Identifiers
urn:nbn:se:uu:diva-354542 (URN)10.1080/03009734.2018.1431744 (DOI)000428060300004 ()29436895 (PubMedID)
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareMedical Research Council of Southeast Sweden (FORSS)
Available from: 2018-06-21 Created: 2018-06-21 Last updated: 2019-12-14Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7888-1571

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