{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:38:09Z","timestamp":1787863089579,"version":"build-2784847793"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["CASI"],"award-info":[{"award-number":["CASI"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["K25AI140783"],"award-info":[{"award-number":["K25AI140783"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Deep molecular profiling of biological tissues is an indicator of health and disease. We used imaging mass cytometry (IMC) to acquire spatially resolved 20-plex protein data in tissue sections from normal and chronic tonsillitis cases. We present SpatialViz, a suite of algorithms to explore spatial relationships in multiplexed tissue images by visualizing and quantifying single-cell granularity and anatomical complexity in diverse multiplexed tissue imaging data. Single-cell and spatial maps confirmed that CD68+ cells were correlated with the enhanced Granzyme B expression and CD3+ cells exhibited enrichment of CD4+ phenotype in chronic tonsillitis. SpatialViz revealed morphological distributions of cellular organizations in distinct anatomical areas, spatially resolved single-cell associations across anatomical categories, and distance maps between the markers. Spatial topographic maps showed the unique organization of different tissue layers. The spatial reference framework generated network-based comparisons of multiplex data from healthy and diseased tonsils. SpatialViz is broadly applicable to multiplexed tissue biology.<\/jats:p>","DOI":"10.1038\/s42003-021-02166-2","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T10:16:36Z","timestamp":1622110596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Spatially visualized single-cell pathology of highly multiplexed protein profiles in health and disease"],"prefix":"10.1038","volume":"4","author":[{"given":"Mayar","family":"Allam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyi","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3519-5341","authenticated-orcid":false,"given":"Krishnan","family":"Laxminarayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Hughley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-1524","authenticated-orcid":false,"given":"Ahmet F.","family":"Coskun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"2166_CR1","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.cels.2018.03.010","volume":"6","author":"J Salamon","year":"2018","unstructured":"Salamon, J., Qian, X., Nilsson, M. & Lynn, D. J. Network visualization and analysis of spatially aware gene expression data with InsituNet. Cell Syst. 6, 626\u2013630 (2018).","journal-title":"Cell Syst."},{"key":"2166_CR2","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon, P. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498\u20132504 (2003).","journal-title":"Genome Res."},{"key":"2166_CR3","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1038\/nbt.4260","volume":"36","author":"Q Zhu","year":"2018","unstructured":"Zhu, Q., Shah, S., Dries, R., Cai, L. & Yuan, G.-C. Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data. Nat. Biotechnol. 36, 1183\u20131190 (2018).","journal-title":"Nat. Biotechnol."},{"key":"2166_CR4","doi-asserted-by":"crossref","unstructured":"Dries, R. et al. Giotto, a toolbox for integrative analysis and visualization of spatial expression data. Genome Biology 22, 78 (2021).","DOI":"10.1186\/s13059-021-02286-2"},{"key":"2166_CR5","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/nmeth.4634","volume":"15","author":"D Edsg\u00e4rd","year":"2018","unstructured":"Edsg\u00e4rd, D., Johnsson, P. & Sandberg, R. Identification of spatial expression trends in single-cell gene expression data. Nat. Methods 15, 339\u2013342 (2018).","journal-title":"Nat. Methods"},{"key":"2166_CR6","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41592-019-0701-7","volume":"17","author":"S Sun","year":"2020","unstructured":"Sun, S., Zhu, J. & Zhou, X. Statistical analysis of spatial expression patterns for spatially resolved transcriptomic studies. Nat. Methods 17, 193\u2013200 (2020).","journal-title":"Nat. Methods"},{"key":"2166_CR7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1182\/blood-2020-140258","volume":"136","author":"JA Timms","year":"2020","unstructured":"Timms, J. A. et al. Immunocluster: a computational tool to explore the immune profile and cellular heterogeneity of hematological diseases using liquid and imaging mass, and flow cytometry data. Blood 136, 9\u201310 (2020).","journal-title":"Blood"},{"key":"2166_CR8","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/s41584-019-0338-z","volume":"16","author":"FJ Hartmann","year":"2020","unstructured":"Hartmann, F. J. & Bendall, S. C. Immune monitoring using mass cytometry and related high-dimensional imaging approaches. Nat. Rev. Rheumatol. 16, 87\u201399 (2020).","journal-title":"Nat. Rev. Rheumatol."},{"key":"2166_CR9","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1080\/00016480260046472","volume":"122","author":"K Ohtsuka","year":"2002","unstructured":"Ohtsuka, K., Tomita, H. & Murakami, G. Anatomy of the tonsillar bed: topographical relationship between the palatine tonsil and the lingual branch of the glossopharyngeal nerve. Acta Otolaryngol. 122, 99\u2013109 (2002).","journal-title":"Acta Otolaryngol."},{"key":"2166_CR10","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1177\/014107689008300216","volume":"83","author":"GK Scadding","year":"1990","unstructured":"Scadding, G. K. Immunology of the tonsil: a review. J. R. Soc. Med. 83, 104\u2013107 (1990).","journal-title":"J. R. Soc. Med."},{"key":"2166_CR11","doi-asserted-by":"publisher","first-page":"e0220721","DOI":"10.1371\/journal.pone.0220721","volume":"14","author":"W-C Chao","year":"2019","unstructured":"Chao, W.-C., Lin, C.-H., Chen, Y.-M., Jiang, R.-S. & Chen, H.-H. Association between tonsillitis and newly diagnosed ankylosing spondylitis: a nationwide, population-based, case-control study. PLoS ONE 14, e0220721 (2019).","journal-title":"PLoS ONE"},{"key":"2166_CR12","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s12288-015-0629-8","volume":"32","author":"R Duggal","year":"2016","unstructured":"Duggal, R., Rana, A., Vaid, A., Sood, N. & Handa, K. K. Bilateral tonsillar enlargement as a first manifestation of chronic lymphocytic leukemia\/small lymphocytic lymphoma with an unusual interfollicular pattern of infiltration. J. Indian Hematol. Blood Transfus. 32, 152\u2013155 (2016).","journal-title":"J. Indian Hematol. Blood Transfus."},{"key":"2166_CR13","doi-asserted-by":"publisher","first-page":"e42136","DOI":"10.1371\/journal.pone.0042136","volume":"7","author":"JL Proenca-Modena","year":"2012","unstructured":"Proenca-Modena, J. L. et al. High rates of detection of respiratory viruses in tonsillar tissues from children with chronic adenotonsillar disease. PLoS ONE 7, e42136 (2012).","journal-title":"PLoS ONE"},{"key":"2166_CR14","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.3389\/fimmu.2019.02657","volume":"10","author":"H Baharlou","year":"2019","unstructured":"Baharlou, H., Canete, N. P., Cunningham, A. L., Harman, A. N. & Patrick, E. Mass cytometry imaging for the study of human diseases\u2014applications and data analysis strategies. Front. Immunol. 10, 2657 (2019).","journal-title":"Front. Immunol."},{"key":"2166_CR15","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1002\/cyto.a.24211","volume":"97","author":"P Niewold","year":"2020","unstructured":"Niewold, P., Ashhurst, T. M., Smith, A. L. & King, N. J. C. Evaluating spectral cytometry for immune profiling in viral disease. Cytom. Part J. Int. Soc. Anal. Cytol. 97, 1165\u20131179 (2020).","journal-title":"Cytom. Part J. Int. Soc. Anal. Cytol."},{"key":"2166_CR16","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3389\/fonc.2019.00415","volume":"9","author":"R Gadalla","year":"2019","unstructured":"Gadalla, R. et al. Validation of CyTOF against flow cytometry for immunological studies and monitoring of human cancer clinical trials. Front. Oncol. 9, 415 (2019).","journal-title":"Front. Oncol."},{"key":"2166_CR17","doi-asserted-by":"publisher","first-page":"e31657","DOI":"10.7554\/eLife.31657","volume":"7","author":"J-R Lin","year":"2018","unstructured":"Lin, J.-R. et al. Highly multiplexed immunofluorescence imaging of human tissues and tumors using t-CyCIF and conventional optical microscopes. eLife 7, e31657 (2018).","journal-title":"eLife"},{"key":"2166_CR18","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.2869","volume":"11","author":"C Giesen","year":"2014","unstructured":"Giesen, C. et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11, 417\u2013422 (2014).","journal-title":"Nat. Methods"},{"key":"2166_CR19","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/s41586-019-1876-x","volume":"578","author":"HW Jackson","year":"2020","unstructured":"Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615\u2013620 (2020).","journal-title":"Nature"},{"key":"2166_CR20","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.cels.2016.03.008","volume":"2","author":"B Bodenmiller","year":"2016","unstructured":"Bodenmiller, B. Multiplexed epitope-based tissue imaging for discovery and healthcare applications. Cell Syst. 2, 225\u2013238 (2016).","journal-title":"Cell Syst."},{"key":"2166_CR21","doi-asserted-by":"publisher","first-page":"3054","DOI":"10.1158\/1078-0432.CCR-18-2599","volume":"25","author":"DE Carvajal-Hausdorf","year":"2019","unstructured":"Carvajal-Hausdorf, D. E. et al. Multiplexed (18-Plex) measurement of signaling targets and cytotoxic T cells in trastuzumab-treated patients using imaging mass cytometry. Clin. Cancer Res. 25, 3054\u20133062 (2019).","journal-title":"Clin. Cancer Res."},{"key":"2166_CR22","doi-asserted-by":"publisher","first-page":"e48051","DOI":"10.7554\/eLife.48051","volume":"8","author":"V Ramaglia","year":"2019","unstructured":"Ramaglia, V. et al. Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry. eLife 8, e48051 (2019).","journal-title":"eLife"},{"key":"2166_CR23","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.cels.2017.12.001","volume":"6","author":"D Schulz","year":"2018","unstructured":"Schulz, D. et al. Simultaneous multiplexed imaging of mRNA and proteins with subcellular resolution in breast cancer tissue samples by mass cytometry. Cell Syst. 6, 25\u201336 (2018).","journal-title":"Cell Syst."},{"key":"2166_CR24","doi-asserted-by":"publisher","first-page":"e2005970","DOI":"10.1371\/journal.pbio.2005970","volume":"16","author":"C McQuin","year":"2018","unstructured":"McQuin, C. et al. CellProfiler 3.0: next-generation image processing for biology. PLoS Biol. 16, e2005970 (2018).","journal-title":"PLoS Biol."},{"key":"2166_CR25","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1038\/nmeth.4391","volume":"14","author":"D Schapiro","year":"2017","unstructured":"Schapiro, D. et al. histoCAT: analysis of cell phenotypes and interactions in multiplex image cytometry data. Nat. Methods 14, 873\u2013876 (2017).","journal-title":"Nat. Methods"},{"key":"2166_CR26","doi-asserted-by":"publisher","first-page":"12244","DOI":"10.1073\/pnas.1510227113","volume":"113","author":"WM Abdelmoula","year":"2016","unstructured":"Abdelmoula, W. M. et al. Data-driven identification of prognostic tumor subpopulations using spatially mapped t-SNE of mass spectrometry imaging data. Proc. Natl Acad. Sci. USA 113, 12244\u201312249 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2166_CR27","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1038\/labinvest.2009.91","volume":"89","author":"WA Boivin","year":"2009","unstructured":"Boivin, W. A., Cooper, D. M., Hiebert, P. R. & Granville, D. J. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab. Invest. 89, 1195\u20131220 (2009).","journal-title":"Lab. Invest."},{"key":"2166_CR28","doi-asserted-by":"publisher","first-page":"627","DOI":"10.2478\/v10042-009-0117-9","volume":"47","author":"J Paw\u0142owska","year":"2010","unstructured":"Paw\u0142owska, J. et al. Different distribution of CD4 and CD8 T cells in synovial membrane and peripheral blood of rheumatoid arthritis and osteoarthritis patients. Folia Histochem. Cytobiol. 47, 627\u2013632 (2010).","journal-title":"Folia Histochem. Cytobiol."},{"key":"2166_CR29","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.4049\/jimmunol.1402316","volume":"194","author":"S Elavazhagan","year":"2015","unstructured":"Elavazhagan, S. et al. Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity. J. Immunol. 194, 2786\u20132795 (2015).","journal-title":"J. Immunol."},{"key":"2166_CR30","doi-asserted-by":"publisher","first-page":"e11762","DOI":"10.1371\/journal.pone.0011762","volume":"5","author":"MS Suchard","year":"2010","unstructured":"Suchard, M. S. et al. FOXP3 expression is upregulated in CD4+ T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS ONE 5, e11762 (2010).","journal-title":"PLoS ONE"},{"key":"2166_CR31","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1182\/blood-2005-06-2277","volume":"107","author":"M Firan","year":"2006","unstructured":"Firan, M., Dhillon, S., Estess, P. & Siegelman, M. H. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood 107, 619\u2013627 (2006).","journal-title":"Blood"},{"key":"2166_CR32","doi-asserted-by":"publisher","first-page":"4407","DOI":"10.4049\/jimmunol.174.7.4407","volume":"174","author":"MP Eggena","year":"2005","unstructured":"Eggena, M. P. et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J. Immunol. 174, 4407\u20134414 (2005).","journal-title":"J. Immunol."},{"key":"2166_CR33","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.it.2005.10.001","volume":"26","author":"J Huehn","year":"2005","unstructured":"Huehn, J. & Hamann, A. Homing to suppress: address codes for Treg migration. Trends Immunol. 26, 632\u2013636 (2005).","journal-title":"Trends Immunol."},{"key":"2166_CR34","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/s11904-008-0004-6","volume":"5","author":"N Seddiki","year":"2008","unstructured":"Seddiki, N. & Kelleher, A. D. Regulatory T cells in HIV infection: who\u2019s suppressing what? Curr. HIV\/AIDS Rep. 5, 20\u201326 (2008).","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"2166_CR35","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.4049\/jimmunol.1302783","volume":"192","author":"C Giesecke","year":"2014","unstructured":"Giesecke, C. et al. Tissue distribution and dependence of responsiveness of human antigen-specific memory B cells. J. Immunol. 192, 3091\u20133100 (2014).","journal-title":"J. Immunol."},{"key":"2166_CR36","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1097\/01.pas.0000209855.28282.ce","volume":"30","author":"DM Dorfman","year":"2006","unstructured":"Dorfman, D. M., Brown, J. A., Shahsafaei, A. & Freeman, G. J. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30, 802\u2013810 (2006).","journal-title":"Am. J. Surg. Pathol."},{"key":"2166_CR37","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1128\/JVI.01579-09","volume":"84","author":"SD Blackburn","year":"2010","unstructured":"Blackburn, S. D. et al. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J. Virol. 84, 2078\u20132089 (2010).","journal-title":"J. Virol."},{"key":"2166_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09689-x","volume":"7","author":"L Sarmiento Varon","year":"2017","unstructured":"Sarmiento Varon, L. et al. Characterization of tonsillar IL10 secreting B cells and their role in the pathophysiology of tonsillar hypertrophy. Sci. Rep. 7, 11077 (2017).","journal-title":"Sci. Rep."},{"key":"2166_CR39","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1016\/j.stemcr.2015.09.020","volume":"5","author":"SYC Kang","year":"2015","unstructured":"Kang, S. Y. C. et al. Characterization of epithelial progenitors in normal human palatine tonsils and their HPV16 E6\/E7-induced perturbation. Stem Cell Rep. 5, 1210\u20131225 (2015).","journal-title":"Stem Cell Rep."},{"key":"2166_CR40","doi-asserted-by":"publisher","first-page":"1259425","DOI":"10.1126\/science.1259425","volume":"349","author":"MH Spitzer","year":"2015","unstructured":"Spitzer, M. H. et al. An interactive reference framework for modeling a dynamic immune system. Science 349, 1259425\u20131259425 (2015).","journal-title":"Science"},{"key":"2166_CR41","doi-asserted-by":"publisher","first-page":"e98679","DOI":"10.1371\/journal.pone.0098679","volume":"9","author":"M Jacomy","year":"2014","unstructured":"Jacomy, M., Venturini, T., Heymann, S. & Bastian, M. ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software. PLoS ONE 9, e98679 (2014).","journal-title":"PLoS ONE"},{"key":"2166_CR42","doi-asserted-by":"crossref","unstructured":"Hagberg, A. A., Schult, D. A. & Swart, P. J. Exploring network structure, dynamics, and function using NetworkX. In Proceedings of the 7th Python in Science Conference (eds. Varoquaux, G., Vaught, T. & Millman, J.) 11\u201315 (2008).","DOI":"10.25080\/TCWV9851"},{"key":"2166_CR43","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1109\/MCSE.2007.55","volume":"9","author":"JD Hunter","year":"2007","unstructured":"Hunter, J. D. Matplotlib: a 2D graphics environment. Comput. Sci. Eng. 9, 90\u201395 (2007).","journal-title":"Comput. Sci. Eng."},{"key":"2166_CR44","doi-asserted-by":"publisher","unstructured":"Allam, M., Hu, T. & Coskun, A. Spatially visualized single-cell pathology of highly multiplexed protein profiles in health and disease (Version v1.0). Zenodo https:\/\/doi.org\/10.5281\/zenodo.4662854 (2021).","DOI":"10.5281\/zenodo.4662854"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02166-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02166-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02166-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T17:15:00Z","timestamp":1725124500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02166-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,27]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2166"],"URL":"https:\/\/doi.org\/10.1038\/s42003-021-02166-2","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,27]]},"assertion":[{"value":"6 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"632"}}