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Gustavsson, I. M., Aarnio, R., Myrnäs, M., Lindberg, J. H., Taku, O., Meiring, T., . . . Gyllensten, U. B. (2019). Clinical validation of the HPVIR high-risk HPV test on cervical samples according to the international guidelines for human papillomavirus DNA test requirements for cervical cancer screening. Virology Journal, 16(1), Article ID 107.
Open this publication in new window or tab >>Clinical validation of the HPVIR high-risk HPV test on cervical samples according to the international guidelines for human papillomavirus DNA test requirements for cervical cancer screening
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2019 (English)In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 16, no 1, article id 107Article in journal (Refereed) Published
Abstract [en]

Background

The indicating FTA card is a dry medium used for collection of cervical samples. HPVIR is a multiplex real-time PCR test that detects 12 high-risk human papillomavirus types (hrHPV) and provides single genotype information for HPV16, − 31, − 35, − 39, − 51, − 56, and − 59 and pooled type information for HPV18/45 and HPV33/52/58. The aim of this study was to evaluate whether a strategy with cervical samples collected on the FTA card and subsequently analysed with the HPVIR test complies with the criteria of the international guidelines for a clinically validated method for cervical screening.

Methods

We performed a non-inferiority test comparing the clinical sensitivity and specificity of the candidate test (FTA card and HPVIR) with a clinically validated reference test (Cobas® HPV test) based on liquid-based cytology (LBC) samples. Two clinical samples (LBC and FTA) were collected from 896 participants in population-based screening. For evaluation of the specificity we used 799 women without ≥ CIN2, and for clinical sensitivity we used 67 women with histologically confirmed ≥ CIN2. The reproducibility was studied by performing inter- and intra-laboratory tests of 558 additional clinical samples.

Results

The clinical sensitivity and specificity for samples collected on the FTA card and analysed using the HPVIR test were non-inferior to samples analysed with the Cobas® HPV test based on LBC samples (non-inferiority test score, p = 1.0 × 10− 2 and p = 1.89 × 10− 9, respectively). Adequate agreement of > 87% was seen in both the intra- and inter-laboratory comparisons.

Conclusions

Samples collected on the indicating FTA card and analysed with HPVIR test fulfil the requirements of the international guidelines and can therefore be used in primary cervical cancer screening.

Keywords
HPV, DNA testing, Primary cervical cancer screening, International guidelines
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-394268 (URN)10.1186/s12985-019-1216-7 (DOI)000483382500001 ()31438976 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Cancer Society
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-10-09Bibliographically approved
Sakornsakolpat, P., Prokopenko, D., Lamontagne, M., Reeve, N. F., Guyatt, A. L., Jackson, V. E., . . . Zeigler-Heitbrock, L. (2019). Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nature Genetics, 51(3), 494-505
Open this publication in new window or tab >>Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 494-505Article in journal (Refereed) Published
Abstract [en]

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

National Category
Respiratory Medicine and Allergy Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379346 (URN)10.1038/s41588-018-0342-2 (DOI)000459947200017 ()30804561 (PubMedID)
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Enroth, S., Berggrund, M., Lycke, M., Broberg, J., Lundberg, M., Assarsson, E., . . . Gyllensten, U. B. (2019). High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer. Communications biology, 2, Article ID 221.
Open this publication in new window or tab >>High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
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2019 (English)In: Communications biology, ISSN 2399-3642, Vol. 2, article id 221Article in journal (Refereed) Published
Abstract [en]

Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
Keywords
Diagnostic markers, Machine learning, Ovarian cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-388611 (URN)10.1038/s42003-019-0464-9 (DOI)000472439200002 ()31240259 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer SocietyVinnova
Note

These authors contributed equally: Stefan Enroth, Malin Berggrund

Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-08-07Bibliographically approved
Berggrund, M., Enroth, S., Lundberg, M., Assarsson, E., Stålberg, K., Lindquist, D., . . . Gyllensten, U. (2019). Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay. Molecular & Cellular Proteomics, 18(4), 735-743
Open this publication in new window or tab >>Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743Article in journal (Refereed) Published
Abstract [en]

Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared with controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared with population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

National Category
Cancer and Oncology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-383873 (URN)10.1074/mcp.RA118.001208 (DOI)000466934700009 ()30692274 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer Society
Available from: 2019-06-14 Created: 2019-06-14 Last updated: 2019-06-14Bibliographically approved
Cui, T., Enroth, S., Ameur, A., Gustavsson, I., Lindquist, D. & Gyllensten, U. (2019). Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology. Carcinogenesis, 40(2), 269-278
Open this publication in new window or tab >>Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology
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2019 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, no 2, p. 269-278Article in journal (Refereed) Published
Abstract [en]

Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-388612 (URN)10.1093/carcin/bgy183 (DOI)000472792800012 ()30596972 (PubMedID)
Funder
Swedish Cancer Society, CF23560Swedish Research Council, 2012-2884Swedish Society for Medical Research (SSMF)Knut and Alice Wallenberg Foundation, KAW2011.0205
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-08-23Bibliographically approved
Shrine, N., Guyatt, A. L., Erzurumluoglu, A. M., Jackson, V. E., Hobbs, B. D., Melbourne, C. A., . . . Wain, L. V. (2019). New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nature Genetics, 51(3), 481-493
Open this publication in new window or tab >>New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 481-493Article in journal (Refereed) Published
Abstract [en]

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

National Category
Medical Genetics Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-379345 (URN)10.1038/s41588-018-0321-7 (DOI)000459947200016 ()30804560 (PubMedID)
Funder
Wellcome trust, WT202849/Z/16/Z
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Gustavsson, I. M., Aarnio, R., Berggrund, M., Lindberg, J. H., Sanner, K., Wikström, I., . . . Gyllensten, U. B. (2019). Randomised study of HPV prevalence and detection of CIN2+ in vaginal self-sampling compared to cervical specimens collected by medical personnel.. International Journal of Cancer, 144(1), 89-97
Open this publication in new window or tab >>Randomised study of HPV prevalence and detection of CIN2+ in vaginal self-sampling compared to cervical specimens collected by medical personnel.
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 1, p. 89-97Article in journal (Refereed) Published
Abstract [en]

We conducted a randomised study to compare vaginal self-sampling with assisted sampling by medical personnel on the cervix for HPV testing in primary screening. The first aim was to determine if the HPV prevalence is independent of sampling location (vagina versus cervix) and the person performing the sampling. The second aim was to evaluate if the two sampling strategies differed in the detection rate of CIN2+. In total, 19,523 women were randomised into two groups, with 9926 invited to perform self-sampling (SS arm) using the Rover VIBA-brush and 9597 offered assisted sampling using the cytobrush (AS arm). All samples were applied to the indicating FTA elute card and analysed for high-risk HPV using the hpVIR real-time PCR assay. The outcome for the first aim was HPV prevalence and for the second aim the number of CIN2+ based on histology. In the SS arm, 52.7% of invited women participated in the study, as compared to 34.2% in the AS arm. All samples contained sufficient amount of nuclear DNA for a valid HPV result, with vaginal samples having a higher DNA amount than cervical samples (p < 4.62 × 10-11 ). HPV prevalence was 4.6% in the SS arm and 4.1% in the AS arm (p = 5.5 × 10-2 ), and the distribution of HPV types similar between arms. There was no difference in the prevalence of CIN2+ per 1000 women screened between arms (p = 0.86). The results show that vaginal self-sampling is an equivalent alternative to sampling by medical personnel for HPV typing and identification of CIN2+.

Keywords
HPV test, cervical cancer, randomised study, screening, self-sampling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-367086 (URN)10.1002/ijc.31637 (DOI)000451479900009 ()29943822 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Cancer Society
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2019-01-28Bibliographically approved
Jiang, J., Thalamuthu, A., Ho, J. E., Mahajan, A., Ek, W. E., Brown, D. A., . . . Mather, K. A. (2018). A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. Frontiers in Genetics, 9, Article ID 97.
Open this publication in new window or tab >>A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood
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2018 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 9, article id 97Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
genome-wide association study, growth differentiation factor-15, macrophage inhibitory cytokine-1, community-based individuals, chromosome 19
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-354354 (URN)10.3389/fgene.2018.00097 (DOI)000428198300001 ()
Funder
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2012-1397Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Research Council, 80576801Swedish Research Council, 70374401Swedish Foundation for Strategic Research Australian Research Council, DP0774213Australian Research Council, DP0773584Australian Research Council, LP0669645
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Enroth, S., Berggrund, M., Lycke, M., Lundberg, M., Assarsson, E., Olovsson, M., . . . Gyllensten, U. B. (2018). A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer. Clinical Proteomics, 15, Article ID 38.
Open this publication in new window or tab >>A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer
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2018 (English)In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 15, article id 38Article in journal (Refereed) Published
Abstract [en]

Background: Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening.

Methods: In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n=106), endometrial cancer (n=74), benign ovarian tumors (n=150) and healthy population controls (n=399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n=280), endometrial cancer (n=228), women with benign ovarian tumors (n=76) and healthy controls (n=57).

Results: In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC=0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p=9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC=0.89).

Conclusion: The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination.

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Ovarian cancer, Endometrial cancer, Proximity extension assay (PEA), Sensitivity, Specificity, Diagnostics
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-372376 (URN)10.1186/s12014-018-9216-y (DOI)000451777900001 ()30519148 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilVINNOVASwedish Cancer Society
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Lindström, A., Sanchez Hermansson, R., Gustavsson, I. M., Lindberg, J. H., Gyllensten, U. B. & Olovsson, M. (2018). Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing. PLoS ONE, 13(12), Article ID e0207714.
Open this publication in new window or tab >>Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0207714Article in journal (Refereed) Published
Abstract [en]

Background About 30% of the cervical cancer cases in Sweden occur in women older than 60. The primary aim was to evaluate the acceptability of repeated self-sampling at home for HPV-testing in elderly women. The prevalence of HPV and HPV related dysplasia as well as the sensitivity of cytology was evaluated. Methods Repeated self-sampling at home for HPV testing was offered 375 women in each of the four age groups 60, 65, 70 and 75 years. Women with two consecutive positive HPV tests were examined with sampling for histology and cytology. Findings A self-sample was provided by 59.5% (893/1500) of the invited women. The overall prevalence of HPV was 4.4% (95% CI 3.2-6.0, n = 39) in the first test, and 2.5% were persistent positive in the second test (95% C 1.6-3.8, n = 22) collected on average 5.5 months later. Dysplasia, was found in 1.8% (16/893) (95% CI 1.1-3.0) and CIN 2+ in 1.0% (9/893) (95% CI 0.5-2.0) of the women. Of the 16 women with dysplasia in histology, 13 (81.2%) had a normal cytology. Interpretation Repeated self-sampling at home combined with HPV testing was well accepted among elderly women. A high prevalence of CIN was diagnosed by histology. Cytology showed extremely low sensitivity and should not be recommended for this age group.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-372761 (URN)10.1371/journal.pone.0207714 (DOI)000452212400061 ()30517176 (PubMedID)
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6316-3355

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