{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T19:04:52Z","timestamp":1724785492249},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01 HL137880","U24 HL141762"],"award-info":[{"award-number":["U01 HL137880","U24 HL141762"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells\/mm basement membrane. GCD was divided into tertiles based on log<jats:sub>10<\/jats:sub> transformed values. Log<jats:sub>10<\/jats:sub>GCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log<jats:sub>10<\/jats:sub> GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high log<jats:sub>10<\/jats:sub>GCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.<\/jats:p>","DOI":"10.1038\/s41598-020-77229-1","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T11:05:54Z","timestamp":1605697554000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Current smoking with or without chronic bronchitis is independently associated with goblet cell hyperplasia in healthy smokers and COPD subjects"],"prefix":"10.1038","volume":"10","author":[{"given":"Victor","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huaqing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehmet","family":"Kesimer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard C.","family":"Boucher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Michael","family":"Wells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Christenson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MeiLan K.","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Dransfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"Robert","family":"Paine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher B.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Barjaktarevic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell","family":"Bowler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey L.","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Kaner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah L.","family":"O\u2019Beirne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanda K.","family":"O\u2019Neal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen I.","family":"Rennard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando J.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prescott G.","family":"Woodruff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"77229_CR1","doi-asserted-by":"publisher","unstructured":"Collaborators, U. S. B. o. D. et al. The State of US Health, 1990\u20132016: burden of diseases, injuries, and risk factors among US states. JAMA 319, 1444. doi:https:\/\/doi.org\/10.1001\/jama.2018.0158 (2018).","DOI":"10.1001\/jama.2018.0158"},{"key":"77229_CR2","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/MCP.0000000000000145","volume":"21","author":"V Kim","year":"2015","unstructured":"Kim, V. & Criner, G. J. The chronic bronchitis phenotype in COPD: features and implications. Curr. Opin. Pulm. Med. 21, 133 (2015).","journal-title":"Curr. Opin. Pulm. Med."},{"key":"77229_CR3","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201512-800OC","author":"V Kim","year":"2016","unstructured":"Kim, V. et al. Persistent and newly developed chronic bronchitis are associated with worse outcomes in chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc. https:\/\/doi.org\/10.1513\/AnnalsATS.201512-800OC (2016).","journal-title":"Ann. Am. Thorac. Soc."},{"key":"77229_CR4","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1164\/rccm.201511-2210OC","volume":"193","author":"JP Allinson","year":"2016","unstructured":"Allinson, J. P. et al. The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am. J. Respir. Crit. Care Med. 193, 662. https:\/\/doi.org\/10.1164\/rccm.201511-2210OC (2016).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR5","doi-asserted-by":"publisher","first-page":"2645","DOI":"10.1056\/NEJMoa032158","volume":"350","author":"JC Hogg","year":"2004","unstructured":"Hogg, J. C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645. https:\/\/doi.org\/10.1056\/NEJMoa032158 (2004).","journal-title":"N. Engl. J. Med."},{"key":"77229_CR6","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1164\/ajrccm.161.3.9907080","volume":"161","author":"M Saetta","year":"2000","unstructured":"Saetta, M. et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am. J. Respir. Crit. Care Med. 161, 1016 (2000).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR7","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1378\/chest.130.4.1102","volume":"130","author":"AL Innes","year":"2006","unstructured":"Innes, A. L. et al. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 130, 1102. https:\/\/doi.org\/10.1378\/chest.130.4.1102 (2006).","journal-title":"Chest"},{"key":"77229_CR8","doi-asserted-by":"publisher","first-page":"e0116108","DOI":"10.1371\/journal.pone.0116108","volume":"10","author":"V Kim","year":"2015","unstructured":"Kim, V. et al. Chronic bronchitis and current smoking are associated with more goblet cells in moderate to severe COPD and smokers without airflow obstruction. PLoS ONE 10, e0116108. https:\/\/doi.org\/10.1371\/journal.pone.0116108 (2015).","journal-title":"PLoS ONE"},{"key":"77229_CR9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1164\/rccm.200405-659OC","volume":"171","author":"V Kim","year":"2005","unstructured":"Kim, V. et al. Small airway morphometry and improvement in pulmonary function after lung volume reduction surgery. Am. J. Respir. Crit. Care Med. 171, 40. https:\/\/doi.org\/10.1164\/rccm.200405-659OC (2005).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR10","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1164\/rccm.200612-1772OC","volume":"176","author":"JC Hogg","year":"2007","unstructured":"Hogg, J. C. et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am. J. Respir. Crit. Care Med. 176, 454. https:\/\/doi.org\/10.1164\/rccm.200612-1772OC (2007).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR11","unstructured":"11Sciurba, F. et al. The Effect of Small Airway Pathology on Survival Following Lung Volume Reduction Surgery (LVRS). Abstract. Proc. Am. Thorac. Soc. 3, A712 (2006)."},{"key":"77229_CR12","doi-asserted-by":"crossref","unstructured":"12Mullen, J. B., Wright, J. L., Wiggs, B. R., Pare, P. D. & Hogg, J. C. Reassessment of inflammation of airways in chronic bronchitis. Br. Med. J. (Clinical research ed.) 291, 1235 (1985).","DOI":"10.1136\/bmj.291.6504.1235"},{"key":"77229_CR13","doi-asserted-by":"publisher","unstructured":"13Wells, J. M. et al. Safety and tolerability of comprehensive research bronchoscopy in chronic obstructive pulmonary disease. results from the SPIROMICS bronchoscopy substudy. Ann. Am. Thorac. Soc. 16, 439\u2013446. https:\/\/doi.org\/10.1513\/AnnalsATS.201807-441OC (2019).","DOI":"10.1513\/AnnalsATS.201807-441OC"},{"key":"77229_CR14","unstructured":"Rasband, W. S. Image J. https:\/\/rsb.info.nih.gov\/ij\/ (2006)."},{"key":"77229_CR15","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1056\/NEJMoa1701632","volume":"377","author":"M Kesimer","year":"2017","unstructured":"Kesimer, M. et al. Airway mucin concentration as a marker of chronic bronchitis. N. Engl. J. Med. 377, 911. https:\/\/doi.org\/10.1056\/NEJMoa1701632 (2017).","journal-title":"N. Engl. J. Med."},{"key":"77229_CR16","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1136\/thoraxjnl-2013-203897","volume":"69","author":"D Couper","year":"2014","unstructured":"Couper, D. et al. Design of the subpopulations and intermediate outcomes in COPD study (SPIROMICS). Thorax 69, 491. https:\/\/doi.org\/10.1136\/thoraxjnl-2013-203897 (2014).","journal-title":"Thorax"},{"key":"77229_CR17","first-page":"1","volume":"118","author":"BG Ferris","year":"1978","unstructured":"Ferris, B. G. Epidemiology standardization project (American thoracic society). Am. Rev. Respir. Dis. 118, 1 (1978).","journal-title":"Am. Rev. Respir. Dis."},{"key":"77229_CR18","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1378\/chest.112.2.319","volume":"112","author":"SE Fligiel","year":"1997","unstructured":"Fligiel, S. E. et al. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and\/or tobacco. Chest 112, 319\u2013326. https:\/\/doi.org\/10.1378\/chest.112.2.319 (1997).","journal-title":"Chest"},{"key":"77229_CR19","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1164\/rccm.201806-1016LE","volume":"198","author":"M Kesimer","year":"2018","unstructured":"Kesimer, M. et al. Mucin concentrations and peripheral airway obstruction in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 198, 1453\u20131456. https:\/\/doi.org\/10.1164\/rccm.201806-1016LE (2018).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR20","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.rmed.2013.11.003","volume":"108","author":"CH Martinez","year":"2014","unstructured":"Martinez, C. H. et al. The clinical impact of non-obstructive chronic bronchitis in current and former smokers. Respir. Med. 108, 491. https:\/\/doi.org\/10.1016\/j.rmed.2013.11.003 (2014).","journal-title":"Respir. Med."},{"key":"77229_CR21","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1378\/chest.08-2062","volume":"135","author":"PR Burgel","year":"2009","unstructured":"Burgel, P. R. et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 135, 975. https:\/\/doi.org\/10.1378\/chest.08-2062 (2009).","journal-title":"Chest"},{"key":"77229_CR22","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/1465-9921-15-52","volume":"15","author":"V Kim","year":"2014","unstructured":"Kim, V. et al. Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir. Res. 15, 52 (2014).","journal-title":"Respir. Res."},{"key":"77229_CR23","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/MCP.0000000000000145","volume":"21","author":"V Kim","year":"2015","unstructured":"Kim, V. & Criner, G. J. The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Curr. Opin. Pulm. Med. 21, 133. https:\/\/doi.org\/10.1097\/MCP.0000000000000145 (2015).","journal-title":"Curr. Opin. Pulm. Med."},{"key":"77229_CR24","doi-asserted-by":"crossref","unstructured":"Vestbo, J., Prescott, E. & Lange, P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am. J. Respir. Crit. Care Med. 153, 1530 (1996).","DOI":"10.1164\/ajrccm.153.5.8630597"},{"key":"77229_CR25","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.rmed.2016.12.018","volume":"123","author":"MK Pelkonen","year":"2017","unstructured":"Pelkonen, M. K., Notkola, I. K., Laatikainen, T. K. & Jousilahti, P. Chronic bronchitis in relation to hospitalization and mortality over three decades. Respir. Med. 123, 87 (2017).","journal-title":"Respir. Med."},{"key":"77229_CR26","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1056\/NEJMoa1505971","volume":"374","author":"PG Woodruff","year":"2016","unstructured":"Woodruff, P. G. et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N. Engl. J. Med. 374, 1811. https:\/\/doi.org\/10.1056\/NEJMoa1505971 (2016).","journal-title":"N. Engl. J. Med."},{"key":"77229_CR27","unstructured":"Kim, V. et al. The St. George's respiratory questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition. Chest 156, 685 (2019)."},{"key":"77229_CR28","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1136\/thx.2008.110619","volume":"64","author":"S Guerra","year":"2009","unstructured":"Guerra, S. et al. Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax 64, 894\u2013900. https:\/\/doi.org\/10.1136\/thx.2008.110619 (2009).","journal-title":"Thorax"},{"key":"77229_CR29","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1378\/chest.130.4.1129","volume":"130","author":"M Pelkonen","year":"2006","unstructured":"Pelkonen, M., Notkola, I. L., Nissinen, A., Tukiainen, H. & Koskela, H. Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men. Chest 130, 1129. https:\/\/doi.org\/10.1378\/chest.130.4.1129 (2006).","journal-title":"Chest"},{"key":"77229_CR30","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1471-2466-11-36;10.1186\/1471-2466-11-36","volume":"11","author":"BA Forey","year":"2011","unstructured":"Forey, B. A., Thornton, A. J. & Lee, P. N. Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. BMC Pulm. Med. 11, 36. https:\/\/doi.org\/10.1186\/1471-2466-11-36;10.1186\/1471-2466-11-36 (2011).","journal-title":"BMC Pulm. Med."},{"key":"77229_CR31","first-page":"A2854","volume":"191","author":"V Kim","year":"2015","unstructured":"Kim, V. et al. Persistent and newly developed chronic bronchitis is associated with worse outcomes and increased respiratory symptoms in smokers with and without chronic obstructive pulmonary disease. 191, A2854 (2015).","journal-title":"Persistent and newly developed chronic bronchitis is associated with worse outcomes and increased respiratory symptoms in smokers with and without chronic obstructive pulmonary disease."},{"key":"77229_CR32","unstructured":"Ebert, R. V. & Terracio, M. J. The bronchiolar epithelium in cigarette smokers. Observations with the scanning electron microscope. Am. Rev. Respir. Dis. 111, 4 (1975)."},{"key":"77229_CR33","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1164\/rccm.200408-1003OC","volume":"171","author":"HS Deshmukh","year":"2005","unstructured":"Deshmukh, H. S. et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am. J. Respir. Crit. Care Med. 171, 305. https:\/\/doi.org\/10.1164\/rccm.200408-1003OC (2005).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR34","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1513\/pats.200502-015AW","volume":"2","author":"MJ Holtzman","year":"2005","unstructured":"Holtzman, M. J. et al. Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2, 132. https:\/\/doi.org\/10.1513\/pats.200502-015AW (2005).","journal-title":"Proc. Am. Thorac. Soc."},{"key":"77229_CR35","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1136\/thx.2003.018879","volume":"59","author":"PR Burgel","year":"2004","unstructured":"Burgel, P. R. & Nadel, J. A. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992. https:\/\/doi.org\/10.1136\/thx.2003.018879 (2004).","journal-title":"Thorax"},{"key":"77229_CR36","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1164\/ajrccm\/151.3_Pt_1.630","volume":"151","author":"F Verra","year":"1995","unstructured":"Verra, F. et al. Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers. Am. J. Respir. Crit. Care Med. 151, 630 (1995).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"77229_CR37","doi-asserted-by":"publisher","first-page":"12501","DOI":"10.1073\/pnas.1811787115","volume":"115","author":"B Button","year":"2018","unstructured":"Button, B. et al. Roles of mucus adhesion and cohesion in cough clearance. Proc. Natl. Acad. Sci. U S A 115, 12501\u201312506. https:\/\/doi.org\/10.1073\/pnas.1811787115 (2018).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"77229_CR38","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1136\/thx.2004.028043","volume":"59","author":"RA O'Donnell","year":"2004","unstructured":"O\u2019Donnell, R. A. et al. Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 59, 1032. https:\/\/doi.org\/10.1136\/thx.2004.028043 (2004).","journal-title":"Thorax"},{"key":"77229_CR39","first-page":"274","volume":"266","author":"LM Reid","year":"1954","unstructured":"Reid, L. M. Pathology of chronic bronchitis. Lancet 266, 274 (1954).","journal-title":"Lancet"},{"key":"77229_CR40","first-page":"A396","volume":"2","author":"V Kim","year":"2005","unstructured":"Kim, V. et al. Small airway inflammation and morphometry in patients with advanced emphysema abstract. Proc. Am. Thorac. Soc. 2, A396 (2005).","journal-title":"Proc. Am. Thorac. Soc."},{"key":"77229_CR41","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1378\/chest.06-2194","volume":"131","author":"WD Kim","year":"2007","unstructured":"Kim, W. D. et al. The association between small airway obstruction and emphysema phenotypes in COPD. Chest 131, 1372. https:\/\/doi.org\/10.1378\/chest.06-2194 (2007).","journal-title":"Chest"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-77229-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-77229-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-77229-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T23:47:49Z","timestamp":1670370469000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-77229-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,18]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["77229"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-77229-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,18]]},"assertion":[{"value":"5 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"In the past three years, Victor Kim has received personal fees from Gala Therapeutics, AstraZeneca, and Boehringer Ingelheim outside of the submitted work. Jeffrey L. Curtis reports a grant from NIH\/NHLBI during the conduct of this study; grants from NIH\/NHBLI, NIH\/NIAID, the Department of Veterans Affairs, and the Department of Defense outside the submitted work; and personal fees from AstraZeneca outside the submitted work. Stephanie Jeong, Huaqing Zhao, Mehmet Kesimer, Richard C. Boucher, Stephanie A. Christenson, Meilan K. Han, Mark Dransfield, Robert Paine III, Christopher B. Cooper, Igor Barjaktarevic, Russell Bowler, Robert J. Kaner, Sara L. O\u2019Beirne, Wanda K. O\u2019Neal, and Fernando J. Martinez report no conflicts of interest. J. Michael Wells reports grants from NIH\/NHLBI, during the conduct of the study; grants from NIH\/NCATS, grants from Bayer, grants and other from GSK, other from Boehringer Ingelheim, grants and other from Mereo BioPharma, other from ICON, other from PRA, other from Vertex Pharmaceuticals, outside the submitted work. Stephen I. Rennard was employed by AstraZeneca until November, 2019 and has consulted for GSK and BerGenBio. Prescott G Woodruff reports personal fees from Glaxosmithkline, personal fees from NGM biopharmaceuticals, personal fees from Amgen, personal fees from Glenmark Pharmaceuticals, personal fees from Theravance, personal fees from Clarus Ventures, personal fees from Astra Zeneca, personal fees from 23andMe, personal fees from Sanofi, personal fees from Regeneron, personal fees from Genentech, outside the submitted work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20133"}}