Metformin is associated with favorable outcomes in patients with COVID-19 and type 2 diabetes mellitus
Zhiyuan Ma, Nishit Patel, Pranathi Vemparala, Mahesh Krishnamurthy
Scientific Reports, doi:10.1038/s41598-022-09639-2
Coronavirus disease 2019 (COVID-19 ) is a new pandemic the entire world is facing since December of 2019. Several risk factors are identified in developing severe disease and one of which is preexisting type 2 diabetes mellitus. Metformin is known to have host-directed anti-viral and anti-inflammatory properties. However, whether these effects offer lower mortality remains unclear. In this retrospective study, we aim to address whether metformin use prior to admission decreases mortality in patients with COVID-19 and pre-existing type 2 diabetes mellitus. A total of 1356 hospitalized patients with COVID-19 and pre-existing type 2 diabetes mellitus was analyzed by multivariable regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. We found that metformin therapy prior to admission in patients with COVID-19 and type 2 diabetes mellitus was significantly associated with less primary outcome events including in-hospital mortality and hospice care enrollment with an odds ratio (OR) of 0.25 (95% CI 0.06-0.74) and less in-hospital length of stay, compared to the nonmetformin group. Our results provide supporting evidence that metformin may confer increased survival in patients with COVID-19 and type 2 diabetes mellitus treated with metformin prior to hospitalization. Rapid outbreak and spread of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leads to a global health crisis [1] [2] [3] [4] [5] . Risk factors and comorbidities linked to worse outcomes for COVID-19 patients have been identified. These include old age 5 , chronic pulmonary disease and smoking 6 , cardiovascular disease 6 , hypertension 7 , diabetes mellitus and obesity 8 . Patients with pre-existing diabetes mellitus, depending on nations and patient cohorts, have been reported to account for patients with COVID-19 from 5 to 20% in China, 17% in Lombardy in Italy to 33% in the US 1-5 . Diabetic patients hospitalized with COVID-19 are two-to three-fold more likely to be admitted into intensive care units than that of non-diabetics and the mortality rate is at least doubled 6,9-11 , suggesting urgent need for effective treatments in patients with COVID-19 and diabetes mellitus. Metformin is widely used as the first-line therapy for type 2 diabetes mellitus 12 . Metformin is effective, safe, and inexpensive and may reduce the risk for cardiovascular events and death in type 2 diabetes mellitus 13 . Historically, because of its host-directed anti-viral properties, metformin was used during the treatment of influenza outbreak 14 . Likewise, based on the pathogenesis of SARS-CoV-2, several mechanisms have been speculated about the possible beneficial effects of metformin in COVID-19 patients with pre-existing type 2 diabetes mellitus, such as anti-inflammatory effects 15 , reduction in neutrophils 16 , increasing..
Author contributions Z.M. and M.K. designed the study and wrote the manuscript. Z.M., N.P., and P.V. collected the data. Z.M. performed and analyzed data. M.K. reviewed data. All authors reviewed the results and approved the final version of the manuscript.
Competing interests The authors declare no competing interests.
References
Bramante, Metformin and risk of mortality in patients hospitalised with COVID-19: A retrospective cohort analysis, Lancet Healthy Longev,
doi:10.1016/S2666-7568(20)30033-7Bramante, Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity, J. Med. Virol,
doi:10.1002/jmv.26873Cariou, Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: The CORONADO study, Diabetologia,
doi:10.1007/s00125-020-05180-xChen, Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication, Diabetes Care,
doi:10.2337/dc20-0660Cheng, Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes, Cell. Metab,
doi:10.1016/j.cmet.2020.08.013Crouse, Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes, Front Endocrinol,
doi:10.3389/fendo.2020.600439Cummings, Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: A prospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)31189-2Garcia, Flumamine, a new synthetic analgesic and anti-flu drug, J. Philipp. Med. Assoc
Grasselli, Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, JAMA,
doi:10.1001/jama.2020.5394Holman, Paul, Bethel, Matthews, Neil, 10-year follow-up of intensive glucose control in type 2 diabetes, N. Engl. J. Med,
doi:10.1056/NEJMoa0806470Huang, Lim, Pranata, Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia: A systematic review, meta-analysis, and meta-regression, Diabetes Metab. Syndr,
doi:10.1016/j.dsx.2020.04.018Lighter, Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission, Clin. Infect. Dis,
doi:10.1093/cid/ciaa415Luo, Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis, Am. J. Trop. Med. Hyg,
doi:10.4269/ajtmh.20-0375Roncon, Zuin, Rigatelli, Zuliani, Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome, J. Clin. Virol,
doi:10.1016/j.jcv.2020.104354Siddiqi, Mehra, COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, J. Heart Lung. Transplant,
doi:10.1016/j.healun.2020.03.012Yang, Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A singlecentered, retrospective, observational study, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30079-5Yang, Effect of hypertension on outcomes of adult inpatients with COVID-19 in Wuhan, China: A propensity scorematching analysis, Respir. Res,
doi:10.1186/s12931-020-01435-8Zhou, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)30566-3{ 'indexed': {'date-parts': [[2022, 8, 10]], 'date-time': '2022-08-10T09:05:49Z', 'timestamp': 1660122349922},
'reference-count': 27,
'publisher': 'Springer Science and Business Media LLC',
'issue': '1',
'license': [ { 'start': { 'date-parts': [[2022, 4, 1]],
'date-time': '2022-04-01T00:00:00Z',
'timestamp': 1648771200000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'},
{ 'start': { 'date-parts': [[2022, 4, 1]],
'date-time': '2022-04-01T00:00:00Z',
'timestamp': 1648771200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2022, 12]]},
'abstract': '<jats:title>Abstract</jats:title><jats:p>Coronavirus disease 2019 (COVID-19) is a new '
'pandemic the entire world is facing since December of 2019. Several risk factors are '
'identified in developing severe disease and one of which is preexisting type 2 diabetes '
'mellitus. Metformin is known to have host-directed anti-viral and anti-inflammatory '
'properties. However, whether these effects offer lower mortality remains unclear. In this '
'retrospective study, we aim to address whether metformin use prior to admission decreases '
'mortality in patients with COVID-19 and pre-existing type 2 diabetes mellitus. A total of '
'1356 hospitalized patients with COVID-19 and pre-existing type 2 diabetes mellitus was '
'analyzed by multivariable regression. Covariates that potentially confound the association '
'were further adjusted using propensity score matching or inverse probability of treatment '
'weighting. We found that metformin therapy prior to admission in patients with COVID-19 and '
'type 2 diabetes mellitus was significantly associated with less primary outcome events '
'including in-hospital mortality and hospice care enrollment with an odds ratio (OR) of 0.25 '
'(95% CI 0.06–0.74) and less in-hospital length of stay, compared to the\xa0non-metformin '
'group. Our results provide supporting evidence that metformin may confer increased survival '
'in patients with COVID-19 and type 2 diabetes mellitus treated with metformin prior to '
'hospitalization.</jats:p>',
'DOI': '10.1038/s41598-022-09639-2',
'type': 'journal-article',
'created': {'date-parts': [[2022, 4, 1]], 'date-time': '2022-04-01T14:26:56Z', 'timestamp': 1648823216000},
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 2,
'title': 'Metformin is associated with favorable outcomes in patients with COVID-19 and type 2 diabetes '
'mellitus',
'prefix': '10.1038',
'volume': '12',
'author': [ {'given': 'Zhiyuan', 'family': 'Ma', 'sequence': 'first', 'affiliation': []},
{'given': 'Nishit', 'family': 'Patel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Pranathi', 'family': 'Vemparala', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mahesh', 'family': 'Krishnamurthy', 'sequence': 'additional', 'affiliation': []}],
'member': '297',
'published-online': {'date-parts': [[2022, 4, 1]]},
'reference': [ { 'key': '9639_CR1',
'doi-asserted-by': 'publisher',
'first-page': '1708',
'DOI': '10.1056/NEJMoa2002032',
'volume': '382',
'author': 'WJ Guan',
'year': '2020',
'unstructured': 'Guan, W. J. et al. Clinical characteristics of coronavirus disease 2019 '
'in China. N. Engl. J. Med. 382, 1708–1720. '
'https://doi.org/10.1056/NEJMoa2002032 (2020).',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': '9639_CR2',
'doi-asserted-by': 'publisher',
'author': 'Z Wu',
'year': '2020',
'unstructured': 'Wu, Z. & McGoogan, J. M. Characteristics of and important lessons from '
'the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a '
'report of 72314 cases from the Chinese center for disease control and '
'prevention. JAMA https://doi.org/10.1001/jama.2020.2648 (2020).',
'journal-title': 'JAMA',
'DOI': '10.1001/jama.2020.2648'},
{ 'key': '9639_CR3',
'doi-asserted-by': 'publisher',
'first-page': '475',
'DOI': '10.1016/S2213-2600(20)30079-5',
'volume': '8',
'author': 'X Yang',
'year': '2020',
'unstructured': 'Yang, X. et al. Clinical course and outcomes of critically ill patients '
'with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, '
'retrospective, observational study. Lancet Respir. Med. 8, 475–481. '
'https://doi.org/10.1016/S2213-2600(20)30079-5 (2020).',
'journal-title': 'Lancet Respir. Med.'},
{ 'key': '9639_CR4',
'doi-asserted-by': 'publisher',
'first-page': '1763',
'DOI': '10.1016/S0140-6736(20)31189-2',
'volume': '395',
'author': 'MJ Cummings',
'year': '2020',
'unstructured': 'Cummings, M. J. et al. Epidemiology, clinical course, and outcomes of '
'critically ill adults with COVID-19 in New York City: A prospective '
'cohort study. Lancet 395, 1763–1770. '
'https://doi.org/10.1016/S0140-6736(20)31189-2 (2020).',
'journal-title': 'Lancet'},
{ 'key': '9639_CR5',
'doi-asserted-by': 'publisher',
'author': 'G Grasselli',
'year': '2020',
'unstructured': 'Grasselli, G. et al. Baseline characteristics and outcomes of 1591 '
'patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy '
'region, Italy. JAMA https://doi.org/10.1001/jama.2020.5394 (2020).',
'journal-title': 'JAMA',
'DOI': '10.1001/jama.2020.5394'},
{ 'key': '9639_CR6',
'doi-asserted-by': 'publisher',
'author': 'WJ Guan',
'year': '2020',
'unstructured': 'Guan, W. J. et al. Comorbidity and its impact on 1590 patients with '
'COVID-19 in China: A nationwide analysis. Eur. Respir. J. '
'https://doi.org/10.1183/13993003.00547-2020 (2020).',
'journal-title': 'Eur. Respir. J.',
'DOI': '10.1183/13993003.00547-2020'},
{ 'key': '9639_CR7',
'doi-asserted-by': 'publisher',
'first-page': '172',
'DOI': '10.1186/s12931-020-01435-8',
'volume': '21',
'author': 'Q Yang',
'year': '2020',
'unstructured': 'Yang, Q. et al. Effect of hypertension on outcomes of adult inpatients '
'with COVID-19 in Wuhan, China: A propensity score-matching analysis. '
'Respir. Res. 21, 172. https://doi.org/10.1186/s12931-020-01435-8 (2020).',
'journal-title': 'Respir. Res.'},
{ 'key': '9639_CR8',
'doi-asserted-by': 'publisher',
'first-page': '896',
'DOI': '10.1093/cid/ciaa415',
'volume': '71',
'author': 'J Lighter',
'year': '2020',
'unstructured': 'Lighter, J. et al. Obesity in patients younger than 60 years is a risk '
'factor for COVID-19 hospital admission. Clin. Infect. Dis. 71, 896–897. '
'https://doi.org/10.1093/cid/ciaa415 (2020).',
'journal-title': 'Clin. Infect. Dis.'},
{ 'key': '9639_CR9',
'doi-asserted-by': 'publisher',
'first-page': '1054',
'DOI': '10.1016/S0140-6736(20)30566-3',
'volume': '395',
'author': 'F Zhou',
'year': '2020',
'unstructured': 'Zhou, F. et al. Clinical course and risk factors for mortality of adult '
'inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. '
'Lancet 395, 1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3 '
'(2020).',
'journal-title': 'Lancet'},
{ 'key': '9639_CR10',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.jcv.2020.104354',
'volume': '127',
'author': 'L Roncon',
'year': '2020',
'unstructured': 'Roncon, L., Zuin, M., Rigatelli, G. & Zuliani, G. Diabetic patients with '
'COVID-19 infection are at higher risk of ICU admission and poor '
'short-term outcome. J. Clin. Virol. 127, 104354. '
'https://doi.org/10.1016/j.jcv.2020.104354 (2020).',
'journal-title': 'J. Clin. Virol.'},
{ 'key': '9639_CR11',
'doi-asserted-by': 'publisher',
'first-page': '395',
'DOI': '10.1016/j.dsx.2020.04.018',
'volume': '14',
'author': 'I Huang',
'year': '2020',
'unstructured': 'Huang, I., Lim, M. A. & Pranata, R. Diabetes mellitus is associated with '
'increased mortality and severity of disease in COVID-19 pneumonia: A '
'systematic review, meta-analysis, and meta-regression. Diabetes Metab. '
'Syndr. 14, 395–403. https://doi.org/10.1016/j.dsx.2020.04.018 (2020).',
'journal-title': 'Diabetes Metab. Syndr.'},
{ 'key': '9639_CR12',
'doi-asserted-by': 'publisher',
'first-page': '6',
'DOI': '10.2337/dc17-S004',
'volume': '40',
'author': 'American Diabetes',
'year': '2017',
'unstructured': 'American Diabetes. Promoting health and reducing disparities in '
'populations. Diabetes Care 40, 6–10. https://doi.org/10.2337/dc17-S004 '
'(2017).',
'journal-title': 'Diabetes Care'},
{ 'key': '9639_CR13',
'doi-asserted-by': 'publisher',
'first-page': '1577',
'DOI': '10.1056/NEJMoa0806470',
'volume': '359',
'author': 'RR Holman',
'year': '2008',
'unstructured': 'Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. '
'10-year follow-up of intensive glucose control in type 2 diabetes. N. '
'Engl. J. Med. 359, 1577–1589. https://doi.org/10.1056/NEJMoa0806470 '
'(2008).',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': '9639_CR14',
'first-page': '287',
'volume': '26',
'author': 'EY Garcia',
'year': '1950',
'unstructured': 'Garcia, E. Y. Flumamine, a new synthetic analgesic and anti-flu drug. J. '
'Philipp. Med. Assoc. 26, 287–293 (1950).',
'journal-title': 'J. Philipp. Med. Assoc.'},
{ 'key': '9639_CR15',
'doi-asserted-by': 'publisher',
'first-page': '652',
'DOI': '10.1161/CIRCRESAHA.116.308445',
'volume': '119',
'author': 'AR Cameron',
'year': '2016',
'unstructured': 'Cameron, A. R. et al. Anti-inflammatory effects of metformin '
'irrespective of diabetes status. Circ. Res. 119, 652–665. '
'https://doi.org/10.1161/CIRCRESAHA.116.308445 (2016).',
'journal-title': 'Circ. Res.'},
{ 'key': '9639_CR16',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.diabres.2020.108230',
'volume': '164',
'author': 'R Dalan',
'year': '2020',
'unstructured': 'Dalan, R. Metformin, neutrophils and COVID-19 infection. Diabetes Res. '
'Clin. Pract. 164, 108230. https://doi.org/10.1016/j.diabres.2020.108230 '
'(2020).',
'journal-title': 'Diabetes Res. Clin. Pract.'},
{ 'key': '9639_CR17',
'doi-asserted-by': 'publisher',
'unstructured': 'Esam, Z. A proposed mechanism for the possible therapeutic potential of '
'Metformin in COVID-19. Diabetes Res. Clin. Pract. 108282. '
'doi:https://doi.org/10.1016/j.diabres.2020.108282 (2020).',
'DOI': '10.1016/j.diabres.2020.108282'},
{ 'key': '9639_CR18',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.diabres.2020.108167',
'volume': '164',
'author': 'F Ursini',
'year': '2020',
'unstructured': 'Ursini, F., Ciaffi, J., Landini, M. P. & Meliconi, R. COVID-19 and '
'diabetes: Is metformin a friend or foe?. Diabetes Res. Clin. Pract. 164, '
'108167. https://doi.org/10.1016/j.diabres.2020.108167 (2020).',
'journal-title': 'Diabetes Res. Clin. Pract.'},
{ 'key': '9639_CR19',
'doi-asserted-by': 'publisher',
'first-page': '1500',
'DOI': '10.1007/s00125-020-05180-x',
'volume': '63',
'author': 'B Cariou',
'year': '2020',
'unstructured': 'Cariou, B. et al. Phenotypic characteristics and prognosis of inpatients '
'with COVID-19 and diabetes: The CORONADO study. Diabetologia 63, '
'1500–1515. https://doi.org/10.1007/s00125-020-05180-x (2020).',
'journal-title': 'Diabetologia'},
{ 'key': '9639_CR20',
'doi-asserted-by': 'publisher',
'first-page': '1399',
'DOI': '10.2337/dc20-0660',
'volume': '43',
'author': 'Y Chen',
'year': '2020',
'unstructured': 'Chen, Y. et al. Clinical characteristics and outcomes of patients with '
'diabetes and COVID-19 in association with glucose-lowering medication. '
'Diabetes Care 43, 1399–1407. https://doi.org/10.2337/dc20-0660 (2020).',
'journal-title': 'Diabetes Care'},
{ 'key': '9639_CR21',
'doi-asserted-by': 'publisher',
'first-page': '600439',
'DOI': '10.3389/fendo.2020.600439',
'volume': '11',
'author': 'AB Crouse',
'year': '2020',
'unstructured': 'Crouse, A. B. et al. (2020). Metformin use is associated with reduced '
'mortality in a diverse population with COVID-19 and diabetes. Front '
'Endocrinol 11, 600439, https://doi.org/10.3389/fendo.2020.600439',
'journal-title': 'Front. Endocrinol.'},
{ 'key': '9639_CR22',
'doi-asserted-by': 'publisher',
'first-page': 'e34',
'DOI': '10.1016/S2666-7568(20)30033-7',
'volume': '2',
'author': 'CT Bramante',
'year': '2021',
'unstructured': 'Bramante, C. T. et al. Metformin and risk of mortality in patients '
'hospitalised with COVID-19: A retrospective cohort analysis. Lancet '
'Healthy Longev. 2, e34–e41. '
'https://doi.org/10.1016/S2666-7568(20)30033-7 (2021).',
'journal-title': 'Lancet Healthy Longev.'},
{ 'key': '9639_CR23',
'doi-asserted-by': 'publisher',
'author': 'CT Bramante',
'year': '2021',
'unstructured': 'Bramante, C. T. et al. Outpatient metformin use is associated with '
'reduced severity of COVID-19 disease in adults with overweight or '
'obesity. J. Med. Virol. https://doi.org/10.1002/jmv.26873 (2021).',
'journal-title': 'J. Med. Virol.',
'DOI': '10.1002/jmv.26873'},
{ 'key': '9639_CR24',
'doi-asserted-by': 'publisher',
'first-page': '69',
'DOI': '10.4269/ajtmh.20-0375',
'volume': '103',
'author': 'P Luo',
'year': '2020',
'unstructured': 'Luo, P. et al. Metformin treatment was associated with decreased '
'mortality in COVID-19 patients with diabetes in a retrospective '
'analysis. Am. J. Trop. Med. Hyg. 103, 69–72. '
'https://doi.org/10.4269/ajtmh.20-0375 (2020).',
'journal-title': 'Am. J. Trop. Med. Hyg.'},
{ 'key': '9639_CR25',
'doi-asserted-by': 'publisher',
'first-page': '537',
'DOI': '10.1016/j.cmet.2020.08.013',
'volume': '32',
'author': 'X Cheng',
'year': '2020',
'unstructured': 'Cheng, X. et al. Metformin is associated with higher incidence of '
'acidosis, but not mortality, in individuals with COVID-19 and '
'pre-existing type 2 diabetes. Cell. Metab. 32, 537–547. '
'https://doi.org/10.1016/j.cmet.2020.08.013 (2020).',
'journal-title': 'Cell. Metab.'},
{ 'key': '9639_CR26',
'doi-asserted-by': 'publisher',
'first-page': '405',
'DOI': '10.1016/j.healun.2020.03.012',
'volume': '39',
'author': 'HK Siddiqi',
'year': '2020',
'unstructured': 'Siddiqi, H. K. & Mehra, M. R. COVID-19 illness in native and '
'immunosuppressed states: A clinical-therapeutic staging proposal. J. '
'Heart Lung. Transplant. 39, 405–407. '
'https://doi.org/10.1016/j.healun.2020.03.012 (2020).',
'journal-title': 'J. Heart Lung. Transplant.'},
{ 'key': '9639_CR27',
'doi-asserted-by': 'publisher',
'first-page': '1236',
'DOI': '10.3389/fimmu.2018.01236',
'volume': '9',
'author': 'F Ursini',
'year': '2018',
'unstructured': 'Ursini, F. et al. Metformin and autoimmunity: A “new deal” of an old '
'drug. Front Immunol. 9, 1236. https://doi.org/10.3389/fimmu.2018.01236 '
'(2018).',
'journal-title': 'Front Immunol.'}],
'container-title': 'Scientific Reports',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.nature.com/articles/s41598-022-09639-2.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41598-022-09639-2',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41598-022-09639-2.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 4, 1]],
'date-time': '2022-04-01T14:45:29Z',
'timestamp': 1648824329000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41598-022-09639-2'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 4, 1]]},
'references-count': 27,
'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}},
'alternative-id': ['9639'],
'URL': 'http://dx.doi.org/10.1038/s41598-022-09639-2',
'relation': {},
'ISSN': ['2045-2322'],
'subject': ['Multidisciplinary'],
'container-title-short': 'Sci Rep',
'published': {'date-parts': [[2022, 4, 1]]},
'assertion': [ { 'value': '21 September 2021',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '25 March 2022',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '1 April 2022',
'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': '5553'}
