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Mörth, C., Valachis, A., Sabaa, A. A., Marshall, K., Hedström, G., Flogegård, M., . . . Enblad, G. (2019). Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome. Acta Oncologica, 58(8), 1170-1177
Open this publication in new window or tab >>Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome
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2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 8, p. 1170-1177Article in journal (Refereed) Published
Abstract [en]

Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever.

Patients and methods: All adult patients treated 2000–2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records.

Results: The number of patients with AID was 106 (17.3%). Thyroid disease dominated (n = 33, 31.1%) followed by rheumatoid arthritis (RA) (n = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) (p = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS (p = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%, p = .034) and those with neutropenic fever had a worse OS (p = .026) in Kaplan-Meier analyses.

Conclusion: There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren’s syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-384705 (URN)10.1080/0284186X.2019.1619936 (DOI)000469744800001 ()31131659 (PubMedID)
Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-11-20Bibliographically approved
Tessier-Cloutier, B., Twa, D. D. W., Baecklund, E., Gascoyne, R., Johnson, N. A., Backlin, C., . . . Bernatsky, S. (2019). Cell of origin in diffuse large B-cell lymphoma in systemic lupus erythematosus: molecular and clinical factors associated with survival. Lupus Science and Medicine, 6(1), Article ID e000324.
Open this publication in new window or tab >>Cell of origin in diffuse large B-cell lymphoma in systemic lupus erythematosus: molecular and clinical factors associated with survival
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2019 (English)In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 6, no 1, article id e000324Article in journal (Refereed) Published
Abstract [en]

Background SLE is associated with increased risk of diffuse large B-cell lymphoma (DLBCL). DLBCL is routinely classified by cell of origin (COO), with germinal centre B-cell (GCB) being more common and indicating better prognosis in the general population. We studied COO subtyping in patients with SLE diagnosed with DLBCL and their survival. Patients and methods We evaluated 20 cases of SLE with DLBCL. Immunohistochemistry analysis was performed (BCL2, MYC, BCL6, CD10, CD20, FOXP1, GCET1, MUM1) in tissue microarrays. We examined associations between molecular and clinical features, including overall survival. Results Of the 20 DLBCL SLE cases, 12/20 cases (60%) were classified as non-GCB using Hans or Choi algorithms. MYC and BCL2 protein expression was positive in 6/20 (30%) and 8/20 (40%) SLE cases, respectively, with 2/20 (10%) co-expressing both markers. Seven (7/20) had only extranodal involvement at DLBCL diagnosis. As expected, non-GCB cases had worse survival. Cases presenting exclusively with extranodal disease were associated with shorter SLE duration and better survival despite higher BCL2 protein expression. Conclusions We present novel data characterising DLBCL in SLE. Sixty per cent of the DLBCL in patients with SLE were non-GCB. The nodal and extranodal distribution in SLE was similar to what is known in the general population, but extranodal disease occurred more often with short SLE duration and was associated with longer overall survival. More research on cancer in SLE is the key to further understanding the complex interplay between cancer and the immune system.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2019
National Category
Cancer and Oncology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-389985 (URN)10.1136/lupus-2019-000324 (DOI)000471929000011 ()31205728 (PubMedID)
Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically approved
Vasaitis, L., Nordmark, G., Theander, E., Backlin, C., Smedby, K. E., Askling, J., . . . Baecklund, E. (2019). Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome. Scandinavian Journal of Rheumatology, 48(3), 207-212
Open this publication in new window or tab >>Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome
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2019 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 3, p. 207-212Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

National Category
Rheumatology and Autoimmunity Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-366237 (URN)10.1080/03009742.2018.1523456 (DOI)000467940900005 ()30422723 (PubMedID)
Funder
Swedish Cancer SocietySwedish Rheumatism AssociationSwedish Society of MedicineThe King Gustaf V's Jubilee Foundation
Available from: 2018-11-18 Created: 2018-11-18 Last updated: 2020-01-08Bibliographically approved
Kinch, A., Sundström, C., Baecklund, E., Backlin, C., Molin, D. & Enblad, G. (2019). Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation. Leukemia and Lymphoma, 60(2), 376-384
Open this publication in new window or tab >>Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation
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2019 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 60, no 2, p. 376-384Article in journal (Refereed) Published
Abstract [en]

We studied the expression of programed death 1 (PD-1) receptor and its ligands (PD-L1/-L2) by immunohistochemistry and its association with clinicopathological features in 81 posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation. Overall, 67% (54/81) of the PTLDs were positive in any of the three immunostainings. PD-1 was detected on tumor-infiltrating cells in 41% (33/81) of the PTLDs. PD-L1 was expressed on ≥5% of the tumor cells in 50% (40/80) and PD-L2 in 32% (23/72) of the PTLDs. All Burkitt lymphomas were PD-L1 negative. Expression of PD-L1 tended to be associated with non-germinal center-type of diffuse large B-cell lymphoma (63% vs. 33% in GC-type, p = .14) and latent membrane protein-1+ PTLD (76% vs. 44% in LPM1-, p = .09). Heart recipients had more frequent PTLDs with PD-1+ microenvironment (p = .01). The frequent expression of PD-1 or -L1/-L2 in PTLD warrants further clinical evaluation of the efficacy and safety of PD-(L)1 inhibitors for refractory PTLD.

Keywords
LMP1, PTLD, lymphoma, programed death protein 1, solid organ transplantation, tumor microenvironment
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-365801 (URN)10.1080/10428194.2018.1480767 (DOI)000463555600014 ()30033844 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2020-01-08Bibliographically approved
Hellbacher, E., Hjorton, K., Backlin, C., Enblad, G., Sundström, C., Baecklund, E. & Knight, A. (2019). Malignant lymphoma in granulomatosis with polyangiitis: subtypes, clinical characteristics and prognosis [Letter to the editor]. Acta Oncologica, 58(11), 1655-1659
Open this publication in new window or tab >>Malignant lymphoma in granulomatosis with polyangiitis: subtypes, clinical characteristics and prognosis
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2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 11, p. 1655-1659Article in journal, Letter (Other academic) Published
Abstract [en]

Several autoimmune and inflammatory conditions, such as rheumatoid arthritis (RA) and primary Sjögrens’s syndrome (pSS), have repeatedly been linked to an increased risk of malignant lymphoma [1,2]. Certain inflammatory conditions are also associated with the development of specific lymphoma subtypes such as mucosa-associated lymphoid tissue (MALT) lymphoma in pSS and diffuse large B-cell lymphoma (DLBCL) in RA. The underlying mechanisms behind this association remain unclear. The highly increased risk of developing MALT lymphoma of the parotid gland in pSS indicates that local inflammatory processes can promote lymphoma development at the site of chronic inflammation [3]. In RA, an association between disease severity and risk of lymphoma has been shown.

Granulomatosis with polyangiitis (GPA), formerly Wegener’s granulomatosis, is a systemic small vessel vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and characterized by granulomatous inflammation and necrotizing vasculitis of the airways and kidneys but possibly affecting any organ system. An increased risk of lymphoma in patients with GPA has been reported in several epidemiological studies [4,5]. However, very little is known about risk factors for lymphoma development in this group, possible relation to disease severity, treatment and lymphoma subtypes or the prognosis for the lymphomas. This is the first published study on GPA and lymphoma, giving detailed information on the GPA characteristics and possible risk factors for lymphoma and also lymphoma subtypes treatment and survival.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-398532 (URN)10.1080/0284186X.2019.1634833 (DOI)000481027700001 ()31407922 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2020-01-08Bibliographically approved
Karlsson Sundbaum, J., Eriksson, N., Hallberg, P., Lehto, N., Wadelius, M. & Baecklund, E. (2019). Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice. INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, 22(7), 1226-1232
Open this publication in new window or tab >>Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice
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2019 (English)In: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, no 7, p. 1226-1232Article in journal (Refereed) Published
Abstract [en]

Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis.

Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
liver toxicity, liver transaminases, methotrexate, non-alcoholic fatty liver disease, rheumatoid arthritis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-391959 (URN)10.1111/1756-185X.13576 (DOI)000476560400008 ()31012257 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved
Gron, K. L., Arkema, E. V., Glintborg, B., Mehnert, F., Ostergaard, M., Dreyer, L., . . . Hetland, M. L. (2019). Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden. Annals of the Rheumatic Diseases, 78(3), 320-327
Open this publication in new window or tab >>Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 3, p. 320-327Article in journal (Refereed) Published
Abstract [en]

Objective To estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with abatacept, rituximab or tocilizumab in routine care. Methods This is an observational cohort study conducted in parallel in Denmark and Sweden including patients with RA in Denmark (DANBIO) and Sweden (Anti-Rheumatic Treatment in Sweden Register/Swedish Rheumatology Quality Register) who started abatacept/rituximab/tocilizumab in 2010-2015. Patients could contribute to more than one treatment course. Incident SI (hospitalisations listing infection) and potential confounders were identified through linkage to national registries. Age-and gender-adjusted IRs of SI per 100 person years and additionally adjusted RRs of SI during 0-12 and 0-24 months since start of treatment were assessed (Poisson regression). Country-specific RRs were pooled using inverse variance weighting. Results We identified 8987 treatment courses (abatacept: 2725; rituximab: 3363; tocilizumab: 2899). At treatment start, rituximab-treated patients were older, had longer disease duration and more previous malignancies; tocilizumab-treated patients had higher C reactive protein. During 0-12 and 0-24 months of follow-up, 456 and 639 SI events were identified, respectively. The following were the age-and gender-adjusted 12-month IRs for abatacept/rituximab/tocilizumab: 7.1/8.1/6.1 for Denmark and 6.0/6.4/4.7 for Sweden. The 24-month IRs were 6.1/7.5/5.2 for Denmark and 5.6/5.8/4.3 for Sweden. Adjusted 12-month RRs for tocilizumab versus rituximab were 0.82 (0.50 to 1.36) for Denmark and 0.76 (0.57 to 1.02) for Sweden, pooled 0.78 (0.61 to 1.01); for abatacept versus rituximab 0.94 (0.55 to 1.60) for Denmark and 0.86 (0.66 to 1.13) for Sweden, pooled 0.88 (0.69 to 1.12); and for abatacept versus tocilizumab 1.15 (0.69 to 1.90) for Denmark and 1.14 (0.83 to 1.55) for Sweden, pooled 1.13 (0.91 to 1.42). The adjusted RRs for 0-24 months were similar. Conclusion For patients starting abatacept, rituximab or tocilizumab, differences in baseline characteristics were seen. Numerical differences in IR of SI between drugs were observed. RRs seemed to vary with drug (tocilizumab < abatacept < rituximab) but should be interpreted with caution due to few events and risk of residual confounding.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-389881 (URN)10.1136/annrheumdis-2018-214326 (DOI)000471061000009 ()30612115 (PubMedID)
Funder
NordForsk
Note

Eva Baecklund ingår i gruppen The ARTIS Study Group.

Available from: 2019-07-31 Created: 2019-07-31 Last updated: 2019-07-31Bibliographically approved
Tessier-Cloutier, B., Twa, D., Baecklund, E., Gascoyne, R., Johnson, N. A., Backlin, C., . . . Bernatsky, S. (2018). An Analysis of Cell-of-Origin in Diffuse Large B-Cell Lymphoma in Systemic Lupus Erythematosus, Including Molecular and Clinical Factors Associated with Survival. Arthritis & Rheumatology, 70
Open this publication in new window or tab >>An Analysis of Cell-of-Origin in Diffuse Large B-Cell Lymphoma in Systemic Lupus Erythematosus, Including Molecular and Clinical Factors Associated with Survival
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2018 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-369630 (URN)000447268901243 ()
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved
Baecklund, E., Backlin, C., Rönnelid, J., Toes, R., Huizinga, T., Åhlin, E., . . . Smedby, K. E. (2018). Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis. Scandinavian Journal of Rheumatology, 47(4), 270-275
Open this publication in new window or tab >>Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis
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2018 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, no 4, p. 270-275Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA.

METHOD: subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression.

RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA.

CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1–4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342980 (URN)10.1080/03009742.2017.1376108 (DOI)000438147400002 ()29336646 (PubMedID)
Funder
Swedish Cancer SocietyThe King Gustaf V's Jubilee Foundation
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-09-14Bibliographically approved
Thorlacius, G. E., Hultin-Rosenberg, L., Sandling, J. K., Imgenberg-Kreuz, J., Theander, E., Kvarnstrom, M., . . . Nordmark, G. (2018). Genetic basis and clinical evidence for two variants of primary Sjögren's syndrome with distinct outcomes. Clinical and Experimental Rheumatology, 36(3), S246-S247
Open this publication in new window or tab >>Genetic basis and clinical evidence for two variants of primary Sjögren's syndrome with distinct outcomes
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2018 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 3, p. S246-S247Article 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:uu:diva-369087 (URN)000446486100047 ()
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5033-0188

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