{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T11:38:06Z","timestamp":1764675486721,"version":"3.46.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA285013","U01CA285013","U01CA285013"],"award-info":[{"award-number":["U01CA285013","U01CA285013","U01CA285013"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017192","name":"USC Norris Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["5P30CA014089-40","5P30CA014089-40"],"award-info":[{"award-number":["5P30CA014089-40","5P30CA014089-40"]}],"id":[{"id":"10.13039\/100017192","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hart Family Research Fund"},{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"publisher","award":["R-202312-00614","R-202312-00614","R-202312-00614"],"award-info":[{"award-number":["R-202312-00614","R-202312-00614","R-202312-00614"]}],"id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USC Michelson Center Convergent Science Institute in Cancer"},{"name":"Vassiliadis Research Fund"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Precis. Onc."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple myeloma (MM) arises from abnormal plasma cells (PCs) progressing from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding this transition and progression to overt MM requires improved non-invasive strategies. We employed a liquid biopsy approach to detect and characterize circulating PCs across disease states in 68 patients (MGUS\u2009=\u200911, SMM\u2009=\u200921, NDMM\u2009=\u200919, RRMM\u2009=\u200917) using multi-channel immunofluorescence staining and machine learning-assisted rare event detection. PCs were identified by CD138 and B-cell maturation antigen (BCMA) expressions, with distinct phenotypic subpopulations stratifying disease states. The D\u2009|\u2009CD138\u2009|\u2009BCMA-Memb phenotype was the most predictive, with incidence increasing from MGUS to SMM and overt MM (p\u2009&lt;\u20090.005). Multivariate modeling distinguished precursors from overt disease with 86% accuracy. Shifts in BCMA and CD45 expression suggested immune cell profile alterations with progression and treatment. These findings underscore PB-based liquid biopsy as a promising tool for MM detection and monitoring, revealing circulating PC heterogeneity.<\/jats:p>","DOI":"10.1038\/s41698-025-01175-2","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T11:33:00Z","timestamp":1764675180000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterizing circulating rare cells in peripheral blood for detecting and monitoring multiple myeloma and precursor states"],"prefix":"10.1038","volume":"9","author":[{"given":"Stephanie N.","family":"Shishido","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Mason","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Kamal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia Maryam","family":"Setayesh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amishi U.","family":"Vora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Berrios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz Yurany Moreno","family":"Rueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krina","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet E.","family":"Manasanch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert Z.","family":"Orlowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"1175_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74, 12\u201349 (2024).","journal-title":"CA Cancer J. Clin."},{"key":"1175_CR2","doi-asserted-by":"publisher","first-page":"S78","DOI":"10.1016\/j.clml.2014.05.004","volume":"14","author":"C Bories","year":"2014","unstructured":"Bories, C. & Jagannath, S. Asymptomatic monoclonal gammopathies. Clin. Lymphoma Myeloma Leuk. 14, S78\u2013S86 (2014).","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"1175_CR3","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/s41375-018-0206-x","volume":"33","author":"AK Dutta","year":"2019","unstructured":"Dutta, A. K. et al. Subclonal evolution in disease progression from MGUS\/SMM to multiple myeloma is characterised by clonal stability. Leukemia 33, 457\u2013468 (2019).","journal-title":"Leukemia"},{"key":"1175_CR4","doi-asserted-by":"publisher","first-page":"6845","DOI":"10.1182\/blood-2024-203100","volume":"144","author":"F Feng","year":"2024","unstructured":"Feng, F. et al. Single-cell multi-omics analysis reveals heterogeneity of malignant plasma cell during progression of multiple myeloma. Blood 144, 6845\u20136845 (2024).","journal-title":"Blood"},{"key":"1175_CR5","unstructured":"Ahmed, A. & Killeen, R. B. Relapsed and Refractory Multiple Myeloma, in StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Robert Killeen declares no relevant financial relationships with ineligible companies. (StatPearls, 2025)."},{"key":"1175_CR6","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1056\/NEJMra1011442","volume":"364","author":"A Palumbo","year":"2011","unstructured":"Palumbo, A. & Anderson, K. Multiple myeloma. N. Engl. J. Med 364, 1046\u20131060 (2011).","journal-title":"N. Engl. J. Med"},{"key":"1175_CR7","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1182\/hematology.2023000445","volume":"2023","author":"B Razzo","year":"2023","unstructured":"Razzo, B., Garfall, A. L. & Cohen, A. D. Options at the time of relapse after anti-BCMA therapy. Hematology 2023, 450\u2013458 (2023).","journal-title":"Hematology"},{"key":"1175_CR8","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1182\/blood.2022017848","volume":"141","author":"O Van Oekelen","year":"2023","unstructured":"Van Oekelen, O. et al. Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy. Blood 141, 756\u2013765 (2023).","journal-title":"Blood"},{"key":"1175_CR9","doi-asserted-by":"publisher","first-page":"e538","DOI":"10.1016\/S1470-2045(14)70442-5","volume":"15","author":"SV Rajkumar","year":"2014","unstructured":"Rajkumar, S. V. et al. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15, e538\u2013e548 (2014).","journal-title":"Lancet Oncol."},{"key":"1175_CR10","doi-asserted-by":"publisher","first-page":"786451","DOI":"10.3389\/fonc.2022.786451","volume":"12","author":"B Dhakal","year":"2022","unstructured":"Dhakal, B. et al. Assessment of molecular residual disease using circulating tumor DNA to identify multiple myeloma patients at high risk of relapse. Front Oncol. 12, 786451 (2022).","journal-title":"Front Oncol."},{"key":"1175_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-023-00469-6","volume":"11","author":"S Li","year":"2023","unstructured":"Li, S., Zhang, E. & Cai, Z. Liquid biopsy by analysis of circulating myeloma cells and cell-free nucleic acids: a novel noninvasive approach of disease evaluation in multiple myeloma. Biomark. Res 11, 27 (2023).","journal-title":"Biomark. Res"},{"key":"1175_CR12","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1007\/s00277-022-04771-5","volume":"101","author":"EKM Mack","year":"2022","unstructured":"Mack, E. K. M. et al. Monitoring multiple myeloma in the peripheral blood based on cell-free DNA and circulating plasma cells. Ann. Hematol. 101, 811\u2013824 (2022).","journal-title":"Ann. Hematol."},{"key":"1175_CR13","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.neo.2015.11.011","volume":"18","author":"SR Krishnan","year":"2016","unstructured":"Krishnan, S. R. et al. Isolation of human CD138+microparticles from the plasma of patients with multiple myeloma1. Neoplasia 18, 25\u201332 (2016).","journal-title":"Neoplasia"},{"key":"1175_CR14","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/hon.2648","volume":"37","author":"ZY Liu","year":"2019","unstructured":"Liu, Z. Y. et al. The potential diagnostic power of CD138+microparticles from the plasma analysis for multiple myeloma clinical monitoring. Hematol. Oncol. 37, 401\u2013408 (2019).","journal-title":"Hematol. Oncol."},{"key":"1175_CR15","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1182\/blood-2016-09-742296","volume":"129","author":"S Manier","year":"2017","unstructured":"Manier, S. et al. Prognostic role of circulating exosomal miRNAs in multiple myeloma. Blood 129, 2429\u20132436 (2017).","journal-title":"Blood"},{"key":"1175_CR16","doi-asserted-by":"crossref","unstructured":"Wang, X. et al. Recent progress of exosomes in multiple myeloma: pathogenesis, diagnosis, prognosis and therapeutic strategies. Cancers 13, 1635 (2021).","DOI":"10.3390\/cancers13071635"},{"key":"1175_CR17","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/1097-0142(19930701)72:1<108::AID-CNCR2820720121>3.0.CO;2-T","volume":"72","author":"TE Witzig","year":"1993","unstructured":"Witzig, T. E. et al. Quantitation of circulating peripheral blood plasma cells and their relationship to disease activity in patients with multiple myeloma. Cancer 72, 108\u2013113 (1993).","journal-title":"Cancer"},{"key":"1175_CR18","doi-asserted-by":"publisher","first-page":"3120","DOI":"10.1200\/JCO.21.01393","volume":"40","author":"L Bertamini","year":"2022","unstructured":"Bertamini, L. et al. High levels of circulating tumor plasma cells as a key hallmark of aggressive disease in transplant-eligible patients with newly diagnosed multiple myeloma. J. Clin. Oncol. 40, 3120\u20133131 (2022).","journal-title":"J. Clin. Oncol."},{"key":"1175_CR19","doi-asserted-by":"publisher","first-page":"2929","DOI":"10.3390\/cancers16172929","volume":"16","author":"I Vigliotta","year":"2024","unstructured":"Vigliotta, I. et al. Circulating multiple myeloma cells (CMMCs) as prognostic and predictive markers in multiple myeloma and smouldering MM patients. Cancers 16, 2929 (2024).","journal-title":"Cancers"},{"key":"1175_CR20","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1182\/blood.V88.1.289.289","volume":"88","author":"DD Billadeau","year":"1996","unstructured":"Billadeau, D. D. et al. Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. Blood 88, 289\u2013296 (1996).","journal-title":"Blood"},{"key":"1175_CR21","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/j.bbmt.2013.04.025","volume":"19","author":"M Korthals","year":"2013","unstructured":"Korthals, M. et al. Molecular monitoring of minimal residual disease in the peripheral blood of patients with multiple myeloma. Biol. Blood Marrow Transpl. 19, 1109\u20131115 (2013).","journal-title":"Biol. Blood Marrow Transpl."},{"key":"1175_CR22","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/leu.2012.237","volume":"27","author":"G Bianchi","year":"2013","unstructured":"Bianchi, G. et al. High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma. Leukemia 27, 680\u2013685 (2013).","journal-title":"Leukemia"},{"key":"1175_CR23","doi-asserted-by":"publisher","first-page":"5668","DOI":"10.1200\/JCO.2005.03.159","volume":"23","author":"S Kumar","year":"2005","unstructured":"Kumar, S. et al. Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J. Clin. Oncol. 23, 5668\u20135674 (2005).","journal-title":"J. Clin. Oncol."},{"key":"1175_CR24","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1182\/blood.V88.5.1780.1780","volume":"88","author":"TE Witzig","year":"1996","unstructured":"Witzig, T. E. et al. Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma. Blood 88, 1780\u20131787 (1996).","journal-title":"Blood"},{"key":"1175_CR25","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1111\/j.1365-2141.1994.tb04908.x","volume":"87","author":"TE Witzig","year":"1994","unstructured":"Witzig, T. E. et al. Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma. Br. J. Haematol. 87, 266\u2013272 (1994).","journal-title":"Br. J. Haematol."},{"key":"1175_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22140-0","volume":"12","author":"B Oben","year":"2021","unstructured":"Oben, B. et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. Nat. Commun. 12, 1861 (2021).","journal-title":"Nat. Commun."},{"key":"1175_CR27","doi-asserted-by":"crossref","unstructured":"Bowcock, S. et al. Presenting symptoms in newly diagnosed myeloma, relation to organ damage, and implications for symptom-directed screening: a secondary analysis from the tackling early morbidity and mortality in myeloma (TEAMM) Trial. Cancers 15, 3337 (2023).","DOI":"10.3390\/cancers15133337"},{"key":"1175_CR28","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1111\/ijlh.12504","volume":"38","author":"NW van de Donk","year":"2016","unstructured":"van de Donk, N. W. et al. Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Int J. Lab Hematol. 38, 110\u2013122 (2016).","journal-title":"Int J. Lab Hematol."},{"key":"1175_CR29","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nrclinonc.2016.122","volume":"14","author":"S Manier","year":"2017","unstructured":"Manier, S. et al. Genomic complexity of multiple myeloma and its clinical implications. Nat. Rev. Clin. Oncol. 14, 100\u2013113 (2017).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"1175_CR30","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nrc3257","volume":"12","author":"GJ Morgan","year":"2012","unstructured":"Morgan, G. J., Walker, B. A. & Davies, F. E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer 12, 335\u2013348 (2012).","journal-title":"Nat. Rev. Cancer"},{"key":"1175_CR31","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1080\/16078454.2021.1948208","volume":"26","author":"W Han","year":"2021","unstructured":"Han, W. et al. Prognostic value of circulating clonal plasma cells in newly diagnosed multiple myeloma. Hematology 26, 510\u2013517 (2021).","journal-title":"Hematology"},{"key":"1175_CR32","doi-asserted-by":"publisher","first-page":"2218","DOI":"10.1182\/blood.2019002610","volume":"134","author":"L Sanoja-Flores","year":"2019","unstructured":"Sanoja-Flores, L. et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood 134, 2218\u20132222 (2019).","journal-title":"Blood"},{"key":"1175_CR33","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1007\/s00277-019-03833-5","volume":"98","author":"N Wang","year":"2019","unstructured":"Wang, N. et al. Enrichment of circulating myeloma cells by immunomagnetic beads combined with flow cytometry for monitoring minimal residual disease and relapse in patients with multiple myeloma. Ann. Hematol. 98, 2769\u20132780 (2019).","journal-title":"Ann. Hematol."},{"key":"1175_CR34","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.3390\/curroncol29050242","volume":"29","author":"LJ Ndacayisaba","year":"2022","unstructured":"Ndacayisaba, L. J. et al. Enrichment-free single-cell detection and morphogenomic profiling of myeloma patient samples to delineate circulating rare plasma cell clones. Curr. Oncol. 29, 2954\u20132972 (2022).","journal-title":"Curr. Oncol."},{"key":"1175_CR35","doi-asserted-by":"crossref","unstructured":"Ndacayisaba, L. J. et al. Characterization of BCMA expression in circulating rare single cells of patients with plasma cell neoplasms. Int. J. Mol. Sci. 23, 13427 (2022).","DOI":"10.3390\/ijms232113427"},{"key":"1175_CR36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41698-023-00446-0","volume":"7","author":"SM Setayesh","year":"2023","unstructured":"Setayesh, S. M. et al. Targeted single-cell proteomic analysis identifies new liquid biopsy biomarkers associated with multiple myeloma. NPJ Precis Oncol. 7, 95 (2023).","journal-title":"NPJ Precis Oncol."},{"key":"1175_CR37","doi-asserted-by":"publisher","first-page":"016003","DOI":"10.1088\/1478-3975\/9\/1\/016003","volume":"9","author":"D Marrinucci","year":"2012","unstructured":"Marrinucci, D. et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys. Biol. 9, 016003 (2012).","journal-title":"Phys. Biol."},{"key":"1175_CR38","doi-asserted-by":"publisher","first-page":"198","DOI":"10.5858\/arpa.2016-0483-OA","volume":"142","author":"M Rodriguez-Lee","year":"2018","unstructured":"Rodriguez-Lee, M. et al. Effect of Blood Collection Tube Type and Time to Processing on the Enumeration and High-Content Characterization of Circulating Tumor Cells Using the High-Definition Single-Cell Assay. Arch. Pathol. Lab Med 142, 198\u2013207 (2018).","journal-title":"Arch. Pathol. Lab Med"},{"key":"1175_CR39","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.jmoldx.2019.11.006","volume":"22","author":"SN Shishido","year":"2020","unstructured":"Shishido, S. N. et al. Preanalytical Variables for the Genomic Assessment of the Cellular and Acellular Fractions of the Liquid Biopsy in a Cohort of Breast Cancer Patients. J. Mol. Diagn. 22, 319\u2013337 (2020).","journal-title":"J. Mol. Diagn."},{"key":"1175_CR40","doi-asserted-by":"crossref","unstructured":"Chai, S. et al. Platelet-coated circulating tumor cells are a predictive biomarker in patients with metastatic castrate resistant prostate cancer. Mol. Cancer Res. 19, 2036\u20132045 (2021).","DOI":"10.1158\/1541-7786.MCR-21-0383"},{"key":"1175_CR41","doi-asserted-by":"crossref","unstructured":"Narayan, S. et al. Defining a liquid biopsy profile of circulating tumor cells and oncosomes in metastatic colorectal cancer for clinical utility. Cancers 14, 4891 (2022).","DOI":"10.3390\/cancers14194891"},{"key":"1175_CR42","doi-asserted-by":"crossref","unstructured":"Shishido, S. N. et al. Characterization of cellular and acellular analytes from pre-cystectomy liquid biopsies in patients newly diagnosed with primary bladder cancer. Cancers 14, 758 (2022).","DOI":"10.3390\/cancers14030758"}],"container-title":["npj Precision Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41698-025-01175-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41698-025-01175-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41698-025-01175-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T11:33:04Z","timestamp":1764675184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41698-025-01175-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1175"],"URL":"https:\/\/doi.org\/10.1038\/s41698-025-01175-2","relation":{},"ISSN":["2397-768X"],"issn-type":[{"type":"electronic","value":"2397-768X"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"assertion":[{"value":"27 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The HDSCA technology described here is licensed to Epic Sciences. P.K. has ownership in Epic Sciences. E.E.M. is an employee at GSK. All other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"388"}}