{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:10:39Z","timestamp":1776319839955,"version":"3.50.1"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T00:00:00Z","timestamp":1627948800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T00:00:00Z","timestamp":1627948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Key elements for viral pathogenesis include viral strains, viral load, co-infection, and host responses. Several studies analyzing these factors in the function of disease severity of have been published; however, no studies have shown how all of these factors interplay within a defined cohort. To address this important question, we sought to understand how these four key components interplay in a cohort of COVID-19 patients. We determined the viral loads and gene expression using high throughput sequencing and various virological methods. We found that viral loads in the upper respiratory tract in COVID-19 patients at an early phase of infection vary widely. While the majority of nasopharyngeal (NP) samples have a viral load lower than the limit of detection of infectious viruses, there are samples with an extraordinary amount of SARS-CoV-2 RNA and a high viral titer. No specific viral factors were identified that are associated with high viral loads. Host gene expression analysis showed that viral loads were strongly correlated with cellular antiviral responses. Interestingly, however, COVID-19 patients who experience mild symptoms have a higher viral load than those with severe complications, indicating that naso-pharyngeal viral load may not be a key factor of the clinical outcomes of COVID-19. The metagenomics analysis revealed that the microflora in the upper respiratory tract of COVID-19 patients with high viral loads were dominated by SARS-CoV-2, with a high degree of dysbiosis. Finally, we found a strong inverse correlation between upregulation of interferon responses and disease severity. Overall our study suggests that a high viral load in the upper respiratory tract may not be a critical factor for severe symptoms; rather, dampened antiviral responses may be a critical factor for a severe outcome from the infection.<\/jats:p>","DOI":"10.1038\/s41598-021-95197-y","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T10:06:43Z","timestamp":1627985203000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Induction of interferon response by high viral loads at early stage infection may protect against severe outcomes in COVID-19 patients"],"prefix":"10.1038","volume":"11","author":[{"given":"Eric C.","family":"Rouchka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia H.","family":"Chariker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Alejandro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Adcock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth E.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda B.","family":"Lasnik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Carrico","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Forest W.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Furmanek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie A.","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Waigel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Zacharias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose","family":"Bordon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-172X","authenticated-orcid":false,"given":"Donghoon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,3]]},"reference":[{"key":"95197_CR1","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1001\/jama.2020.19759","volume":"324","author":"DM Cutler","year":"2020","unstructured":"Cutler, D. M. & Summers, L. H. The COVID-19 pandemic and the $16 trillion virus. JAMA 324, 1495 (2020).","journal-title":"JAMA"},{"key":"95197_CR2","doi-asserted-by":"publisher","first-page":"e238","DOI":"10.1016\/S1473-3099(20)30484-9","volume":"20","author":"E Petersen","year":"2020","unstructured":"Petersen, E. et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect. Dis. 20, e238\u2013e244 (2020).","journal-title":"Lancet Infect. Dis."},{"key":"95197_CR3","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1056\/NEJMoa2026116","volume":"383","author":"DF Gudbjartsson","year":"2020","unstructured":"Gudbjartsson, D. F. et al. Humoral immune response to SARS-CoV-2 in iceland. N. Engl. J. Med. 383, 1724\u20131734 (2020).","journal-title":"N. Engl. J. Med."},{"key":"95197_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00459-7","author":"B Hu","year":"2020","unstructured":"Hu, B., Guo, H., Zhou, P. & Shi, Z.-L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. https:\/\/doi.org\/10.1038\/s41579-020-00459-7 (2020).","journal-title":"Nat. Rev. Microbiol."},{"key":"95197_CR5","first-page":"72","volume":"4","author":"J Ramirez","year":"2020","unstructured":"Ramirez, J., Bordon, J., Cavallazzi, R. & Arnold, F. Characteristics and outcomes of adults hospitalized with SARS-CoV-2 community-acquired pneumonia in Louisville Kentucky. J. Respir. Infect. 4, 72 (2020).","journal-title":"J. Respir. Infect."},{"key":"95197_CR6","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.07.982264","author":"KG Lokugamage","year":"2020","unstructured":"Lokugamage, K. G. et al. Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. biorxiv https:\/\/doi.org\/10.1101\/2020.03.07.982264 (2020).","journal-title":"biorxiv"},{"key":"95197_CR7","first-page":"2","volume":"370","author":"Q Zhang","year":"2020","unstructured":"Zhang, Q. et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, 2 (2020).","journal-title":"Science"},{"key":"95197_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-020-03070-1","author":"E Meffre","year":"2020","unstructured":"Meffre, E. & Iwasaki, A. Interferon deficiency can lead to severe COVID. Nature https:\/\/doi.org\/10.1038\/d41586-020-03070-1 (2020).","journal-title":"Nature"},{"key":"95197_CR9","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/j.chom.2020.04.004","volume":"27","author":"X Xie","year":"2020","unstructured":"Xie, X. et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 27, 841-848.e3 (2020).","journal-title":"Cell Host Microbe"},{"key":"95197_CR10","doi-asserted-by":"publisher","first-page":"e3000849","DOI":"10.1371\/journal.pbio.3000849","volume":"18","author":"NAP Lieberman","year":"2020","unstructured":"Lieberman, N. A. P. et al. In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age. PLOS Biol. 18, e3000849 (2020).","journal-title":"PLOS Biol."},{"key":"95197_CR11","doi-asserted-by":"publisher","first-page":"e70","DOI":"10.1016\/S2213-2600(20)30354-4","volume":"8","author":"E Pujadas","year":"2020","unstructured":"Pujadas, E. et al. SARS-CoV-2 viral load predicts COVID-19 mortality. Lancet Respir. Med. 8, e70 (2020).","journal-title":"Lancet Respir. Med."},{"key":"95197_CR12","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.ccell.2020.09.007","volume":"38","author":"LF Westblade","year":"2020","unstructured":"Westblade, L. F. et al. SARS-CoV-2 viral load predicts mortality in patients with and without cancer who are hospitalized with COVID-19. Cancer Cell 38, 661-671.e2 (2020).","journal-title":"Cancer Cell"},{"key":"95197_CR13","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1016\/j.ajpath.2020.07.001","volume":"190","author":"KV Argyropoulos","year":"2020","unstructured":"Argyropoulos, K. V. et al. Association of initial viral load in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients with outcome and symptoms. Am. J. Pathol. 190, 1881\u20131887 (2020).","journal-title":"Am. J. Pathol."},{"key":"95197_CR14","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.30.20048108","author":"CBF Vogels","year":"2020","unstructured":"Vogels, C. B. F. et al. Analytical sensitivity and efficiency comparisons of SARS-COV-2 qRT-PCR primer-probe sets. medRxiv https:\/\/doi.org\/10.1101\/2020.03.30.20048108 (2020).","journal-title":"medRxiv"},{"key":"95197_CR15","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.3389\/fmicb.2020.01800","volume":"11","author":"D Mercatelli","year":"2020","unstructured":"Mercatelli, D. & Giorgi, F. M. Geographic and genomic distribution of SARS-CoV-2 mutations. Front. Microbiol. 11, 1800 (2020).","journal-title":"Front. Microbiol."},{"key":"95197_CR16","unstructured":"Hou, Y. J. et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell (2020)."},{"key":"95197_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe8499","author":"YJ Hou","year":"2020","unstructured":"Hou, Y. J. et al. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science https:\/\/doi.org\/10.1126\/science.abe8499 (2020).","journal-title":"Science"},{"key":"95197_CR18","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/s41594-020-0385-9","volume":"27","author":"V K\u00f6nigs","year":"2020","unstructured":"K\u00f6nigs, V. et al. SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly. Nat. Struct. Mol. Biol. 27, 260\u2013273 (2020).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"95197_CR19","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.molcel.2010.04.013","volume":"38","author":"N He","year":"2010","unstructured":"He, N. et al. HIV-1 tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol. Cell 38, 428\u2013438 (2010).","journal-title":"Mol. Cell"},{"key":"95197_CR20","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/1742-2094-10-80","volume":"10","author":"Y-J Li","year":"2013","unstructured":"Li, Y.-J. et al. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels. J. Neuroinflamm. 10, 80 (2013).","journal-title":"J. Neuroinflamm."},{"key":"95197_CR21","doi-asserted-by":"publisher","first-page":"e29870","DOI":"10.1371\/journal.pone.0029870","volume":"7","author":"D Oudshoorn","year":"2012","unstructured":"Oudshoorn, D. et al. HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. PLoS ONE 7, e29870 (2012).","journal-title":"PLoS ONE"},{"key":"95197_CR22","doi-asserted-by":"publisher","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","volume":"11","author":"S Anders","year":"2010","unstructured":"Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).","journal-title":"Genome Biol."},{"key":"95197_CR23","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s12915-019-0703-z","volume":"17","author":"C Kumpitsch","year":"2019","unstructured":"Kumpitsch, C., Koskinen, K., Sch\u00f6pf, V. & Moissl-Eichinger, C. The microbiome of the upper respiratory tract in health and disease. BMC Biol. 17, 87 (2019).","journal-title":"BMC Biol."},{"key":"95197_CR24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/2049-2618-2-27","volume":"2","author":"CM Bassis","year":"2014","unstructured":"Bassis, C. M., Tang, A. L., Young, V. B. & Pynnonen, M. A. The nasal cavity microbiota of healthy adults. Microbiome 2, 27 (2014).","journal-title":"Microbiome"},{"key":"95197_CR25","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/s41591-020-0869-5","volume":"26","author":"X He","year":"2020","unstructured":"He, X. et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat. Med. 26, 672\u2013675 (2020).","journal-title":"Nat. Med."},{"key":"95197_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.043","author":"B Korber","year":"2020","unstructured":"Korber, B. et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell https:\/\/doi.org\/10.1016\/j.cell.2020.06.043 (2020).","journal-title":"Cell"},{"key":"95197_CR27","doi-asserted-by":"publisher","DOI":"10.1101\/2020.05.19.20107144","author":"R Lorenzo-Redondo","year":"2020","unstructured":"Lorenzo-Redondo, R. et al. A unique clade of SARS-CoV-2 viruses is associated with lower viral loads in patient upper airways. medRxiv https:\/\/doi.org\/10.1101\/2020.05.19.20107144 (2020).","journal-title":"medRxiv"},{"key":"95197_CR28","doi-asserted-by":"publisher","first-page":"16602","DOI":"10.1038\/s41598-020-73554-7","volume":"10","author":"J Puenpa","year":"2020","unstructured":"Puenpa, J. et al. Molecular epidemiology of the first wave of severe acute respiratory syndrome coronavirus 2 infection in Thailand in 2020. Sci. Rep. 10, 16602 (2020).","journal-title":"Sci. Rep."},{"key":"95197_CR29","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1186\/s12879-020-05374-z","volume":"20","author":"E Sharifipour","year":"2020","unstructured":"Sharifipour, E. et al. Evaluation of bacterial co-infections of the respiratory tract in COVID-19 patients admitted to ICU. BMC Infect. Dis. 20, 646 (2020).","journal-title":"BMC Infect. Dis."},{"key":"95197_CR30","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/s41392-021-00614-3","volume":"6","author":"S Ma","year":"2021","unstructured":"Ma, S. et al. Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19. Signal Transduct. Target. Ther. 6, 191 (2021).","journal-title":"Signal Transduct. Target. Ther."},{"key":"95197_CR31","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.synbio.2021.06.002","volume":"6","author":"J Liu","year":"2021","unstructured":"Liu, J. et al. Association between the nasopharyngeal microbiome and metabolome in patients with COVID-19. Synth. Syst. Biotechnol. 6, 135\u2013143 (2021).","journal-title":"Synth. Syst. Biotechnol."},{"key":"95197_CR32","doi-asserted-by":"publisher","first-page":"101200","DOI":"10.1016\/j.genrep.2021.101200","volume":"23","author":"MN Hoque","year":"2021","unstructured":"Hoque, M. N. et al. Diversity and genomic determinants of the microbiomes associated with COVID-19 and non-COVID respiratory diseases. Gene Rep. 23, 101200 (2021).","journal-title":"Gene Rep."},{"key":"95197_CR33","doi-asserted-by":"publisher","DOI":"10.1101\/2021.02.23.21252221","author":"I Sulaiman","year":"2021","unstructured":"Sulaiman, I. et al. Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome. MedRxiv Prepr. Serv. Health Sci. https:\/\/doi.org\/10.1101\/2021.02.23.21252221 (2021).","journal-title":"MedRxiv Prepr. Serv. Health Sci."},{"key":"95197_CR34","doi-asserted-by":"publisher","first-page":"653399","DOI":"10.3389\/fmicb.2021.653399","volume":"12","author":"P Mehta","year":"2021","unstructured":"Mehta, P. et al. Respiratory co-infections: Modulators of SARS-CoV-2 patients\u2019 clinical sub-phenotype. Front. Microbiol. 12, 653399 (2021).","journal-title":"Front. Microbiol."},{"key":"95197_CR35","doi-asserted-by":"publisher","first-page":"e01969","DOI":"10.1128\/mBio.01969-20","volume":"11","author":"HH Mostafa","year":"2020","unstructured":"Mostafa, H. H. et al. Metagenomic next-generation sequencing of nasopharyngeal specimens collected from confirmed and suspect COVID-19 patients. MBio 11, e01969-e2020 (2020).","journal-title":"MBio"},{"key":"95197_CR36","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1053\/j.gastro.2020.05.048","volume":"159","author":"T Zuo","year":"2020","unstructured":"Zuo, T. et al. Alterations in gut microbiota of patients With COVID-19 during time of hospitalization. Gastroenterology 159, 944-955.e8 (2020).","journal-title":"Gastroenterology"},{"key":"95197_CR37","first-page":"276","volume":"70","author":"T Zuo","year":"2021","unstructured":"Zuo, T. et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70, 276\u2013284 (2021).","journal-title":"Gut"},{"key":"95197_CR38","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/j.chom.2016.05.016","volume":"19","author":"GM Boxx","year":"2016","unstructured":"Boxx, G. M. & Cheng, G. The roles of type I interferon in bacterial infection. Cell Host Microbe 19, 760\u2013769 (2016).","journal-title":"Cell Host Microbe"},{"key":"95197_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2312-y","author":"L Bao","year":"2020","unstructured":"Bao, L. et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature https:\/\/doi.org\/10.1038\/s41586-020-2312-y (2020).","journal-title":"Nature"},{"key":"95197_CR40","unstructured":"Real-Time RT-PCR Panel for Detection 2019-Novel Coronavirus. 12 (2020)."},{"key":"95197_CR41","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","volume":"27","author":"LJ Reed","year":"1938","unstructured":"Reed, L. J. & Muench, H. A simple method of estimating fifty per cent endpoints12. Am. J. Epidemiol. 27, 493\u2013497 (1938).","journal-title":"Am. J. Epidemiol."},{"key":"95197_CR42","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1093\/bioinformatics\/btv033","volume":"31","author":"D Li","year":"2015","unstructured":"Li, D., Liu, C.-M., Luo, R., Sadakane, K. & Lam, T.-W. MEGAHIT: An ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics 31, 1674\u20131676 (2015).","journal-title":"Bioinformatics"},{"key":"95197_CR43","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: Ultrafast universal RNA-seq aligner. Bioinforma. Oxf. Engl. 29, 15\u201321 (2013).","journal-title":"Bioinforma. Oxf. Engl."},{"key":"95197_CR44","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The sequence alignment\/map format and SAMtools. Bioinformatics 25, 2078\u20132079 (2009).","journal-title":"Bioinformatics"},{"key":"95197_CR45","unstructured":"Harris, R. IMPROVED PAIRWISE ALIGNMENT OF GENOMIC DNA. (2007)."},{"key":"95197_CR46","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/nmeth.2066","volume":"9","author":"N Segata","year":"2012","unstructured":"Segata, N. et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat. Methods 9, 811\u2013814 (2012).","journal-title":"Nat. Methods"},{"key":"95197_CR47","doi-asserted-by":"publisher","first-page":"R60","DOI":"10.1186\/gb-2011-12-6-r60","volume":"12","author":"N Segata","year":"2011","unstructured":"Segata, N. et al. Metagenomic biomarker discovery and explanation. Genome Biol. 12, R60 (2011).","journal-title":"Genome Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95197-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95197-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95197-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T11:54:45Z","timestamp":1670068485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-95197-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,3]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["95197"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-95197-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,3]]},"assertion":[{"value":"2 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 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":"15715"}}