{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T11:29:48Z","timestamp":1782991788010,"version":"3.54.5"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007132","name":"Otsuka Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011746","name":"NOVARTIS Foundation (Japan) for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011746","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010793","name":"Pfizer Japan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008664","name":"Ono Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008664","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Asahikasei"},{"name":"Akita University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Clin Oncol"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p><jats:italic>Wilms' tumor gene 1<\/jats:italic> (<jats:italic>WT1<\/jats:italic>) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the <jats:italic>WT1<\/jats:italic> mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether <jats:italic>WT1<\/jats:italic> mRNA dynamics could predict long-term prognosis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>33 patients with untreated or relapsed\/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The median age was 73\u00a0years (range 39\u201387). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334\u00a0days (95% CI 210\u2013482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of <jats:italic>WT1<\/jats:italic> mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482\u00a0days vs. 237\u00a0days, p\u2009=\u20090.049; median EFS 270\u00a0days vs. 125\u00a0days, p\u2009=\u20090.02). The negativity of post-treatment <jats:italic>WT1<\/jats:italic> mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482\u00a0days vs. 256\u00a0days, p\u2009=\u20090.02; median EFS not reached vs. 150\u00a0days, p\u2009=\u20090.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p\u2009=\u20090.024 and HR 0.15, p\u2009=\u20090.013, respectively). The increase in <jats:italic>WT1<\/jats:italic> mRNA values was correlated with relapse.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This study demonstrates that <jats:italic>WT1<\/jats:italic> mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10147-024-02480-9","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T05:02:26Z","timestamp":1707454946000},"page":"481-492","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy"],"prefix":"10.1007","volume":"29","author":[{"given":"Honami","family":"Sato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9914-7517","authenticated-orcid":false,"given":"Takahiro","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kameoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Teshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaya","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Michisita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohito","family":"Fujishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Kuroki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"2480_CR1","doi-asserted-by":"publisher","first-page":"3481","DOI":"10.1182\/blood-2005-09-3724","volume":"107","author":"FR Appelbaum","year":"2006","unstructured":"Appelbaum FR, Gundacker H, Head DR et al (2006) Age and acute myeloid leukemia. Blood 107:3481\u20133485. https:\/\/doi.org\/10.1182\/blood-2005-09-3724","journal-title":"Blood"},{"key":"2480_CR2","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00277-015-2351-x","volume":"94","author":"BC Medeiros","year":"2015","unstructured":"Medeiros BC, Satram-Hoang S, Hurst D et al (2015) Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol 94:1127\u20131138. https:\/\/doi.org\/10.1007\/s00277-015-2351-x","journal-title":"Ann Hematol"},{"key":"2480_CR3","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.blre.2019.04.005","volume":"36","author":"RM Shallis","year":"2019","unstructured":"Shallis RM, Wang R, Davidoff A et al (2019) Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev 36:70\u201387. https:\/\/doi.org\/10.1016\/j.blre.2019.04.005","journal-title":"Blood Rev"},{"key":"2480_CR4","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1056\/nejmoa2012971","volume":"383","author":"CD DiNardo","year":"2020","unstructured":"DiNardo CD, Jonas BA, Pullarkat V et al (2020) Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617\u2013629. https:\/\/doi.org\/10.1056\/nejmoa2012971","journal-title":"N Engl J Med"},{"key":"2480_CR5","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1182\/blood.2020004856","volume":"135","author":"AH Wei","year":"2020","unstructured":"Wei AH, Montesinos P, Ivanov V et al (2020) Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood 135:2137\u20132145. https:\/\/doi.org\/10.1182\/blood.2020004856","journal-title":"Blood"},{"key":"2480_CR6","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1056\/nejmra1406184","volume":"373","author":"H D\u00f6hner","year":"2015","unstructured":"D\u00f6hner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373:1136\u20131152. https:\/\/doi.org\/10.1056\/nejmra1406184","journal-title":"N Engl J Med"},{"key":"2480_CR7","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1182\/bloodadvances.2018016378","volume":"2","author":"F Ravandi","year":"2018","unstructured":"Ravandi F, Walter RB, Freeman SD (2018) Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv 2:1356\u20131366. https:\/\/doi.org\/10.1182\/bloodadvances.2018016378","journal-title":"Blood Adv"},{"key":"2480_CR8","doi-asserted-by":"publisher","first-page":"2753","DOI":"10.1182\/blood.2021013626","volume":"138","author":"M Heuser","year":"2021","unstructured":"Heuser M, Freeman SD, Ossenkoppele GJ et al (2021) 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood 138:2753\u20132767. https:\/\/doi.org\/10.1182\/blood.2021013626","journal-title":"Blood"},{"key":"2480_CR9","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1200\/jco.21.01546","volume":"40","author":"KW Pratz","year":"2022","unstructured":"Pratz KW, Jonas BA, Pullarkat V et al (2022) Measurable residual disease response and prognosis in treatment-na\u00efve acute myeloid leukemia with venetoclax and azacitidine. J Clin Oncol 40:855\u2013865. https:\/\/doi.org\/10.1200\/jco.21.01546","journal-title":"J Clin Oncol"},{"key":"2480_CR10","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/343774a0","volume":"343","author":"M Gessler","year":"1990","unstructured":"Gessler M, Poustka A, Cavenee W et al (1990) Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774\u2013778. https:\/\/doi.org\/10.1038\/343774a0","journal-title":"Nature"},{"key":"2480_CR11","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1038\/sj.leu.2402675","volume":"16","author":"D Cilloni","year":"2002","unstructured":"Cilloni D, Gottardi E, De Micheli D et al (2002) Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 16:2115\u20132121. https:\/\/doi.org\/10.1038\/sj.leu.2402675","journal-title":"Leukemia"},{"key":"2480_CR12","doi-asserted-by":"publisher","first-page":"3306","DOI":"10.3390\/jcm11123306","volume":"11","author":"D Lazzarotto","year":"2022","unstructured":"Lazzarotto D, Candoni A (2022) The role of Wilms\u2019 tumor gene (WT1) expression as a marker of minimal residual disease in acute myeloid leukemia. J Clin Med 11:3306. https:\/\/doi.org\/10.3390\/jcm11123306","journal-title":"J Clin Med"},{"key":"2480_CR13","doi-asserted-by":"publisher","first-page":"833","DOI":"10.3324\/haematol.2009.011908","volume":"95","author":"G Gianfaldoni","year":"2010","unstructured":"Gianfaldoni G, Mannelli F, Ponziani V et al (2010) Early reduction of WT1 transcripts during induction chemotherapy predicts for longer disease free and overall survival in acute myeloid leukemia. Haematologica 95:833\u2013836. https:\/\/doi.org\/10.3324\/haematol.2009.011908","journal-title":"Haematologica"},{"key":"2480_CR14","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.leukres.2011.09.005","volume":"36","author":"JX Gray","year":"2012","unstructured":"Gray JX, McMillen L, Mollee P et al (2012) WT1 expression as a marker of minimal residual disease predicts outcome in acute myeloid leukemia when measured post-consolidation. Leuk Res 36:453\u2013458. https:\/\/doi.org\/10.1016\/j.leukres.2011.09.005","journal-title":"Leuk Res"},{"key":"2480_CR15","doi-asserted-by":"publisher","first-page":"e998","DOI":"10.1016\/j.clml.2020.07.014","volume":"20","author":"C \u0160\u00e1lek","year":"2020","unstructured":"\u0160\u00e1lek C, Vydra J, Cerovsk\u00e1 E et al (2020) WT1 expression in peripheral blood at diagnosis and during the course of early consolidation treatment correlates with survival in patients with intermediate and poor-risk acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 20:e998\u2013e1009. https:\/\/doi.org\/10.1016\/j.clml.2020.07.014","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"2480_CR16","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1200\/jco.2003.04.036","volume":"21","author":"BD Cheson","year":"2003","unstructured":"Cheson BD, Bennett JM, Kopecky KJ et al (2003) Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642\u20134649. https:\/\/doi.org\/10.1200\/jco.2003.04.036","journal-title":"J Clin Oncol"},{"key":"2480_CR17","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","volume":"129","author":"H D\u00f6hner","year":"2017","unstructured":"D\u00f6hner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129:424\u2013447. https:\/\/doi.org\/10.1182\/blood-2016-08-733196","journal-title":"Blood"},{"key":"2480_CR18","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.3109\/10428194.2010.507829","volume":"51","author":"S Miyawaki","year":"2010","unstructured":"Miyawaki S, Hatsumi N, Tamaki T et al (2010) Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. Leuk Lymphoma 51:1855\u20131861. https:\/\/doi.org\/10.3109\/10428194.2010.507829","journal-title":"Leuk Lymphoma"},{"key":"2480_CR19","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/2040620715614529","volume":"7","author":"HB Ommen","year":"2016","unstructured":"Ommen HB (2016) Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies. Ther Adv Hematol 7:3\u201316. https:\/\/doi.org\/10.1177\/2040620715614529","journal-title":"Ther Adv Hematol"},{"key":"2480_CR20","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.cancergen.2012.02.008","volume":"205","author":"JM Alonso-Dominguez","year":"2012","unstructured":"Alonso-Dominguez JM, Tenorio M, Velasco D et al (2012) Correlation of WT1 expression with the burden of total and residual leukemic blasts in bone marrow samples of acute myeloid leukemia patients. Cancer Genet 205:190\u2013191. https:\/\/doi.org\/10.1016\/j.cancergen.2012.02.008","journal-title":"Cancer Genet"},{"key":"2480_CR21","doi-asserted-by":"publisher","first-page":"387","DOI":"10.3390\/biomedicines9040387","volume":"9","author":"V Giudice","year":"2021","unstructured":"Giudice V, Gorrese M, Vitolo R et al (2021) WT1 expression levels combined with flow cytometry blast counts for risk stratification of acute myeloid leukemia and myelodysplastic syndromes. Biomedicines 9:387. https:\/\/doi.org\/10.3390\/biomedicines9040387","journal-title":"Biomedicines"},{"key":"2480_CR22","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1182\/blood-2002-02-0532","volume":"101","author":"W Kern","year":"2003","unstructured":"Kern W, Haferlach T, Schoch C et al (2003) Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood 101:64\u201370. https:\/\/doi.org\/10.1182\/blood-2002-02-0532","journal-title":"Blood"},{"key":"2480_CR23","doi-asserted-by":"publisher","first-page":"74","DOI":"10.4149\/neo_2013_011","volume":"60","author":"J Polak","year":"2013","unstructured":"Polak J, Hajkova H, Haskovec C et al (2013) Quantitative monitoring of WT1 expression in peripheral blood before and after allogeneic stem cell transplantation for acute myeloid leukemia - a useful tool for early detection of minimal residual disease. Neoplasma 60:74\u201382. https:\/\/doi.org\/10.4149\/neo_2013_011","journal-title":"Neoplasma"},{"key":"2480_CR24","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/bmt.2016.318","volume":"52","author":"R Dul\u00e9ry","year":"2017","unstructured":"Dul\u00e9ry R, Nibourel O, Gauthier J et al (2017) Impact of Wilms\u2019 tumor 1 expression on outcome of patients undergoing allogeneic stem cell transplantation for AML. Bone Marrow Transplant 52:539\u2013543. https:\/\/doi.org\/10.1038\/bmt.2016.318","journal-title":"Bone Marrow Transplant"},{"key":"2480_CR25","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1038\/sj.leu.2403809","volume":"19","author":"M Weisser","year":"2005","unstructured":"Weisser M, Kern W, Rauhut S et al (2005) Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19:1416\u20131423. https:\/\/doi.org\/10.1038\/sj.leu.2403809","journal-title":"Leukemia"},{"key":"2480_CR26","doi-asserted-by":"publisher","first-page":"5195","DOI":"10.1200\/jco.2009.22.4865","volume":"27","author":"D Cilloni","year":"2009","unstructured":"Cilloni D, Renneville A, Hermitte F et al (2009) Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 27:5195\u20135201. https:\/\/doi.org\/10.1200\/jco.2009.22.4865","journal-title":"J Clin Oncol"},{"key":"2480_CR27","doi-asserted-by":"publisher","first-page":"5258","DOI":"10.1182\/bloodadvances.2021004322","volume":"5","author":"J Lambert","year":"2021","unstructured":"Lambert J, Thomas X, Marceau-Renaut A et al (2021) Early detection of WT1 measurable residual disease identifies high-risk patients, independent of transplantation in AML. Blood Adv 5:5258\u20135268. https:\/\/doi.org\/10.1182\/bloodadvances.2021004322","journal-title":"Blood Adv"},{"key":"2480_CR28","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/ejh.13664","volume":"107","author":"C Rautenberg","year":"2021","unstructured":"Rautenberg C, Lauseker M, Kaivers J et al (2021) Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1-mRNA expression in patients with AML and MDS. Eur J Haematol 107:283\u2013292. https:\/\/doi.org\/10.1111\/ejh.13664","journal-title":"Eur J Haematol"},{"key":"2480_CR29","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.3892\/mmr.2019.10440","volume":"20","author":"H Liu","year":"2019","unstructured":"Liu H, Wang X, Zhang H et al (2019) Dynamic changes in the level of WT1 as an MRD marker to predict the therapeutic outcome of patients with AML with and without allogeneic stem cell transplantation. Mol Med Rep 20:2426\u20132432. https:\/\/doi.org\/10.3892\/mmr.2019.10440","journal-title":"Mol Med Rep"}],"container-title":["International Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-024-02480-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10147-024-02480-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-024-02480-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T08:08:58Z","timestamp":1711354138000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10147-024-02480-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,9]]},"references-count":29,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["2480"],"URL":"https:\/\/doi.org\/10.1007\/s10147-024-02480-9","relation":{},"ISSN":["1341-9625","1437-7772"],"issn-type":[{"value":"1341-9625","type":"print"},{"value":"1437-7772","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,9]]},"assertion":[{"value":"27 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Naoto Takahashi received honoraria from Otsuka, Novartis, and Pfizer. Naoto Takahashi received research funding from Otsuka, Novartis, Pfizer, Astellas, Asahikasei, and Ono.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The multicenter prospective observational study was conducted in Akita prefecture, Japan. This study enrolled patients with AML who were judged ineligible for intensive chemotherapy by the attending physician and treated by VEN combination therapy. It was conducted in accordance with the 1964 Helsinki Declaration and approved by the Ethics Committee of Akita University (August 6, 2021\/No. 2696). Written informed consent was obtained from all participants before enrollment.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Statements and declarations"}}]}}