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Bergengren, L., Karlsson, M. & Helenius, G. (2020). Prevalence of HPV and pathological changes among women 70 years of age, 10 years after exclusion from the Swedish cervical cancer screening program. Cancer Causes and Control
Open this publication in new window or tab >>Prevalence of HPV and pathological changes among women 70 years of age, 10 years after exclusion from the Swedish cervical cancer screening program
2020 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225Article in journal (Refereed) Epub ahead of print
Abstract [en]

PURPOSE: Örebro County introduced an updated screening program 2016 with primary HPV test for women over 30 years and prolonged screening, increasing the cut-off age from 56-60 to 64-70. The aim of this study was to investigate the prevalence of HPV genotypes and their correlation to histological changes in women, 10 years after exclusion from the screening program, due to an eventual implementation of a catch-up program including all women aged 60-70.

METHODS: All women in Örebro County, born 1,946 (n = 1,968), were invited to a liquid-based cell sample with primary HPV screening. Samples were analyzed for hrHPV mRNA and positive samples were genotyped. hrHPV positive women were offered to do a conization.

RESULTS: Out of 809 participants, 31 (3.8%) were hrHPV positive, of these 22 did a conization. Histologically, 5/22 (23%) had LSIL and 5/22 (23%) had HSIL. Normal histology was found in 12/22 (55%). The most prevalent genotypes were HPV 16, 33, 52, 56, and 68. Of the women with HSIL, one case of cervical cancer was confirmed in a recone biopsy after 4 months.

CONCLUSION: The study showed considerable prevalence of hrHPV and histologically confirmed LSIL/HSIL. These data led to catch-up screening for women between 60 and 70 years when overlapping two screening strategies.

Place, publisher, year, edition, pages
Kluwer Academic/Plenum Publishers, 2020
Keywords
Cervical cancer, HPV genotypes, HPV prevalence, Older women, Screening
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-80175 (URN)10.1007/s10552-020-01278-0 (DOI)32076907 (PubMedID)
Available from: 2020-02-25 Created: 2020-02-25 Last updated: 2020-02-25Bibliographically approved
Bergengren, L., Lillsunde-Larsson, G., Helenius, G. & Karlsson, M. G. (2019). HPV-based screening for cervical cancer among women 55-59 years of age. PLoS ONE, 14(6), Article ID e0217108.
Open this publication in new window or tab >>HPV-based screening for cervical cancer among women 55-59 years of age
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217108Article in journal (Refereed) Published
Abstract [en]

AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.

METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.

RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.

CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

Place, publisher, year, edition, pages
PLOS, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-74701 (URN)10.1371/journal.pone.0217108 (DOI)000471587000007 ()31199811 (PubMedID)2-s2.0-85067434997 (Scopus ID)
Note

Funding Agencies:

Region Örebro County Research Committee  

Örebro University Hospital Research Foundation  

BBMRI.se 

Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-11-14Bibliographically approved
Kaliff, M., Karlsson, M., Sorbe, B., Bohr Mordhorst, L., Helenius, G. & Lillsunde-Larsson, G. (2019). HPV-negative Tumors in a Swedish Cohort of Cervical Cancer. International Journal of Gynecological Pathology
Open this publication in new window or tab >>HPV-negative Tumors in a Swedish Cohort of Cervical Cancer
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2019 (English)In: International Journal of Gynecological Pathology, ISSN 0277-1691, E-ISSN 1538-7151Article in journal (Refereed) Epub ahead of print
Abstract [en]

Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

Place, publisher, year, edition, pages
Wolters Kluwer, 2019
Keywords
Uterine cervical neoplasms, Papillomaviridae, Human papillomavirus DNA tests, Formalin-fixed paraffin-embedded tissues, False-negative reactions
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-79634 (URN)10.1097/PGP.0000000000000612 (DOI)31206367 (PubMedID)
Note

Supported by Örebro country council research committee in Sweden.

Available from: 2020-01-31 Created: 2020-01-31 Last updated: 2020-02-17Bibliographically approved
Helenius, G., Lillsunde-Larsson, G., Bergengren, L., Kaliff, M. & Karlsson, M. (2019). Preliminary data from a Swedish self-sampling study in postmenopausal women. In: : . Paper presented at EUROGIN 2019 – International Multidisciplinary HPV Congress, Monte Carlo, Monaco, December 4-7, 2019.
Open this publication in new window or tab >>Preliminary data from a Swedish self-sampling study in postmenopausal women
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Background: An updated screening algorithm was introduced in Sweden 2015. Primary HPV test for women >30 years old and a prolonged screening with the last test after 64 years of age were some of the changes. In the region of Örebro County, the previous cut-off age was 60 years and with a screening interval of 5 years, women left their last sample when they were 55-59 years old. In the shift between two screening programs, a group of women, 60-64 years old, that left the program 5-10 years ago were now included in the new screening. For re-inclusion, a two year long program was formed to catch-up this group of women and screen them according to the new screening algorithm. At the same time a research project investigating self-sampling was launched. At the same time as the women were invited for a last screening sample they were also asked to participate in a study where they should take a vaginal self-test up to one week after their ordinary screening sample was taken by a midwife.

Method: Postmenopausal women between 64-70 years was included in the study. HPV status in samples from midwife sampling (MS) was compared to self-sampling (SS) samples. HPV was analyzed using HPV Aptima and all HPV positive samples, independent of sampling method, was triaged with cytology and followed-up according to national guidelines.

Results: So far, 585 women with paired samples have been included in the study. In the MS, 4% of the women are positive for hrHPV compared to 11% in the SS group. In 486/585 women, the results of the two samples are concordant. Among the non-concordant samples (13%), 62% were positive in SS and negative in MS. The opposite, negative in SS and positive in MS were seen in 4% of the samples. Among the MS negative samples, 32% were invalid in SS. Cytology was used as a triage test for HPV positive women, both for MS and SS. Of 23 hrHPV positive, 18 had normal cytology, 2 ASCUS, 1 LSIL and 1 HSIL. In the samples with abnormal cytology, 4/5 were hrHPV positive in both SS and MS. One sample was positive in SS but negative in MS.

Discussion: In this age group, more women are hrHPV positive in SS compared to MS. This is in line with what other have seen. Among the very few hrHPV positive samples with abnormal cytology, the majority was hrHPV positive in both MS and SS. But since cytology is a poor triage marker in this age group clinical follow-up is needed before the effectiveness of the both sampling methods can be concluded.

National Category
Medical and Health Sciences Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-77781 (URN)
Conference
EUROGIN 2019 – International Multidisciplinary HPV Congress, Monte Carlo, Monaco, December 4-7, 2019
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2020-02-03Bibliographically approved
Hadgu, E., Seifu, D., Tigneh, W., Bokretsion, Y., Bekele, A., Abebe, M., . . . Karlsson, M. (2018). Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa. BMC Women's Health, 18(1), Article ID 40.
Open this publication in new window or tab >>Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa
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2018 (English)In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 18, no 1, article id 40Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa.

METHODS: In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases.

RESULTS: The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer.

CONCLUSION: The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Breast cancer; Molecular subtypes; Ethiopia; Africa
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-65200 (URN)10.1186/s12905-018-0531-2 (DOI)000425159000001 ()29444670 (PubMedID)2-s2.0-85042084690 (Scopus ID)
Note

Funding Agencies:

Addis Ababa University, School of Graduate Studies  

Addis Ababa University, thematic research group "clinico-epidemiological characterization of breast cancer in Ethiopia"  

Armauer Hansen Research Institute (AHRI)  

Swedish International Developmental Agency (SIDA) 

Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-08-20Bibliographically approved
Bergengren, L., Kaliff, M., Lillsunde-Larsson, G., Karlsson, M. & Helenius, G. (2018). Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women. International Journal of Gynecology & Obstetrics, 142(3), 359-364
Open this publication in new window or tab >>Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women
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2018 (English)In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, no 3, p. 359-364Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women.

METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared.

RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827).

CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2018
Keywords
Cervical cancer, HPV, Postmenopausal women, Professional sampling, Screening, Self-sample
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-67134 (URN)10.1002/ijgo.12538 (DOI)000440652000017 ()29856071 (PubMedID)2-s2.0-85051073715 (Scopus ID)
Note

Funding Agencies:

Region Örebro County Research Committee  

Örebro University Hospital Research Foundation  

BBMRI.se

Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-08-30Bibliographically approved
Åström, M., Tajeddinn, W., Karlsson, M. G., Linder, O., Palmblad, J. & Lindblad, P. (2018). Cytokine Measurements for Diagnosing and Characterizing Leukemoid Reactions and Immunohistochemical Validation of a Granulocyte Colony-Stimulating Factor and CXCL8-Producing Renal Cell Carcinoma. Biomarker Insights, 13, Article ID UNSP 1177271918792246.
Open this publication in new window or tab >>Cytokine Measurements for Diagnosing and Characterizing Leukemoid Reactions and Immunohistochemical Validation of a Granulocyte Colony-Stimulating Factor and CXCL8-Producing Renal Cell Carcinoma
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2018 (English)In: Biomarker Insights, ISSN 1177-2719, E-ISSN 1177-2719, Vol. 13, article id UNSP 1177271918792246Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Various paraneoplastic syndromes are encountered in renal cell carcinomas. This case report illustrates that a paraneoplastic leukemoid reaction may precede the diagnosis of renal cell carcinoma and be explained by cytokine production from the cancer cells.

CASE PRESENTATIONS: A 64-year-old man was referred for hematology workup due to pronounced leukocytosis. While being evaluated for a possible hematologic malignancy as the cause, he was found to have a metastasized renal cell carcinoma, and hyperleukocytosis was classified as a leukemoid reaction. A multiplex panel for measurement of 25 serum cytokines/chemokines showed highly elevated levels of granulocyte colony-stimulating factor (G-CSF) and CXCL8 (C-X-C-motif chemokine ligand 8, previously known as interleukin [IL]-8). By immunohistochemistry it was shown that the renal carcinoma cells expressed both these cytokines. Two additional, consecutive patients with renal cell carcinoma with paraneoplastic leukocytosis also showed elevated serum levels of CXCL8, but not of G-CSF. Nonparametric statistical evaluation showed significantly higher serum concentrations of CXCL8, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor, but lower interferon gamma (IFN-gamma) and IL-1 alpha, for the 3 renal cell carcinoma cases compared with healthy blood donors.

CONCLUSIONS: In suspected paraneoplastic leukocytosis, multiplex serum cytokine analyses may facilitate diagnosis and provide an understanding of the mechanisms for the reaction. In the index patient, combined G-CSF and CXCL8 protein expression by renal carcinoma cells was uniquely documented. A rapidly fatal course was detected in all 3 cases, congruent with the concept that autocrine/paracrine growth signaling in renal carcinoma cells may induce an aggressive tumor phenotype. Immune profiling studies could improve our understanding for possible targets when choosing therapies for patients with metastatic renal cell carcinoma.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
chemokine, IL-6, IL-10, monocytosis, paraneoplastic leukocytosis, autocrine signaling, multiplex, inflammatory response, precision medicine, biomarker
National Category
Immunology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:oru:diva-68648 (URN)10.1177/1177271918792246 (DOI)000441829800001 ()30147294 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved
Helenius, G., Ottestig, E., Kaliff, M., Lillsunde-Larsson, G., Karlsson, M. & Bergengren, L. (2018). Distribution of HPV-genotypes in a Swedish screening population. In: : . Paper presented at Eurogin 2018 International multidisciplinary HPV Congress, Lisabon Portugal, December 2-5, 2018.
Open this publication in new window or tab >>Distribution of HPV-genotypes in a Swedish screening population
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2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-69348 (URN)
Conference
Eurogin 2018 International multidisciplinary HPV Congress, Lisabon Portugal, December 2-5, 2018
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Kaliff, M., Sorbe, B., Mordhorst, L. B., Helenius, G., Karlsson, M. G. & Lillsunde-Larsson, G. (2018). Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy. OncoTarget, 9(27), 18786-18796
Open this publication in new window or tab >>Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18786-18796Article in journal (Refereed) Published
Abstract [en]

Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

Place, publisher, year, edition, pages
Impact Journals LLC, 2018
Keywords
HPV, cervical cancer, recurrences, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-71672 (URN)10.18632/oncotarget.24666 (DOI)29721161 (PubMedID)2-s2.0-85045206587 (Scopus ID)
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-01-24Bibliographically approved
Lillsunde-Larsson, G., Kaliff, M., Sorbe, B., Helenius, G. & Karlsson, M. (2018). HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA. In: : . Paper presented at 32nd International Papillomavirus Conference IPVC 2018, Sydney, Australia, 2-6 October, 2018.
Open this publication in new window or tab >>HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA
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2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-73753 (URN)
Conference
32nd International Papillomavirus Conference IPVC 2018, Sydney, Australia, 2-6 October, 2018
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-16Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6881-237X

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