Hydroxychloroquine and tocilizumab therapy in COVID-19 patients—An observational study
Andrew Ip, Donald A Berry, Eric Hansen, Andre H Goy, Andrew L Pecora, Brittany A Sinclaire, Urszula Bednarz, Michael Marafelias, Scott M Berry, Nicholas S Berry, Shivam Mathura, Ihor S Sawczuk, Noa Biran, Ronaldo C Go, Steven Sperber, Julia A Piwoz, Bindu Balani, Cristina Cicogna, Rani Sebti, Jerry Zuckerman, Keith M Rose, Lisa Tank, Laurie G Jacobs, Jason Korcak, Sarah L Timmapuri, Joseph P Underwood, Gregory Sugalski, Carol Barsky, Daniel W Varga, Arif Asif, Joseph C Landolfi, Stuart L Goldberg
PLOS ONE, doi:10.1371/journal.pone.0237693
Hydroxychloroquine has been touted as a potential COVID-19 treatment. Tocilizumab, an inhibitor of IL-6, has also been proposed as a treatment of critically ill patients. In this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized COVID-19 patients. Patients were hospitalized at a 13-hospital network spanning New Jersey USA between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2. Follow up was through May 5, 2020. Among 2512 hospitalized patients with COVID-19 there have been 547 deaths (22%), 1539 (61%) discharges and 426 (17%) remain hospitalized. 1914 (76%) received at least one dose of hydroxychloroquine and 1473 (59%) received hydroxychloroquine with azithromycin. After adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was 25%, 20%, 18%, and 20%, respectively. Among 547 evaluable ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted HR, 0.76 [95% CI, 0.57-1.00]), with 30 day unadjusted mortality with and without tocilizumab of 46% versus 56%. This observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized COVID-19 patients. Tocilizumab demonstrated a trend association towards reduced mortality among ICU patients. Our findings
References
Anderson, Miniño, Hoyert, Rosenberg, Comparability of cause of death between ICD-9 and ICD-10: preliminary estimates, Natl Vital Stat Rep
Austin, An introduction to propensity score methods for reducing the effects of confounding in observational studies, Multivariate Behav Res,
doi:10.1080/00273171.2011.568786Cavalcanti, Zampieri, Rosa, Hydroxychloroquine with or without Azithromycin in Mildto-Moderate Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2019014Channappanavar, Perlman, Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Semin immunopathol,
doi:10.1007/s00281-017-0629-xChen, Liu, Liu, A pilot study of hydroxychlorquine in treatment of patients with common coronavirus disease-19 (COVID-19), Journal of Zhejiang University (Medical Sciences)
Conceptualization, Ip, Hansen, Goy, Pecora et al., Formal analysis: Andrew Ip
Food, Administration, Re: Request for Emergency Use Authorization for Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied from the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease
Garcia-Cremades, Solans, Hughes, Optimizing Hydroxychloroquine Dosing for Patients with COVID-19: An Integrative Modeling Approach for Effective Drug Repurposing, Clin. Pharmacol. Ther,
doi:10.1002/cpt.1856Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, International Journal of Antimicrobial Agents
Geleris, Sun, Platt, Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
Guan, Ni, Hu, Clinical Characteristics of Coronavirus Disease 2019 in China, N Engl J of Med
Harris, Taylor, Minor, The REDCap consortium: Building an international community of software partners, J Biomed Inform,
doi:10.1016/j.jbi.2019.103208Harris, Taylor, Thielke, Payne, Gonzalez et al., Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform,
doi:10.1016/j.jbi.2008.08.010Holshue, Debolt, Lindquist, First Case of 2019 Novel Coronavirus in the United States, N Engl J of Med
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov,
doi:10.1038/s41421-020-0156-0Luo, Liu, Qiu, Liu, Liu et al., Tocilizumab treatment in COVID-19: A single center experience, J Med Virol,
doi:10.1002/jmv.25801Rosenbaum, Db, Reducing bias in observational studies using subclassification on the propensity score, J Am Stat Assoc
Rosenberg, Dufort, Udo, Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State, JAMA,
doi:10.1001/jama.2020.8630Schrezenmeier, Dorner, Mechanisms of action of hydroxychloroquine and chloroquine: implicaetions for rheumatology, Nat Rev Rheumatol,
doi:10.1038/s41584-020-0372-xSherman, Anderson, Gray, Real-World Evidence-What is it and What can it tell us?, N Engl J of Med
Somers, Eschenauer, Troost, Tocilizumab for treatment of mechanically ventilated patients with COVID-19, Clinical Infectious Diseases,
doi:10.1093/cid/ciaa954Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J,
doi:10.1186/1743-422X-2-69Wang, Cao, Zhang, Remdesivir and Chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Xu, Han, Li, Sun, Wang et al., Effective treatment of severe COVID-19 patients with tocilizumab, Proc National Acad Sci,
doi:10.1073/pnas.2005615117Yao, Ye, Zhang, In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
doi:10.1093/cid/ciaa237{ 'indexed': {'date-parts': [[2024, 3, 3]], 'date-time': '2024-03-03T01:45:15Z', 'timestamp': 1709430315813},
'reference-count': 35,
'publisher': 'Public Library of Science (PLoS)',
'issue': '8',
'license': [ { 'start': { 'date-parts': [[2020, 8, 13]],
'date-time': '2020-08-13T00:00:00Z',
'timestamp': 1597276800000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': ['www.plosone.org'], 'crossmark-restriction': False},
'DOI': '10.1371/journal.pone.0237693',
'type': 'journal-article',
'created': {'date-parts': [[2020, 8, 13]], 'date-time': '2020-08-13T18:50:40Z', 'timestamp': 1597344640000},
'page': 'e0237693',
'update-policy': 'http://dx.doi.org/10.1371/journal.pone.corrections_policy',
'source': 'Crossref',
'is-referenced-by-count': 81,
'title': 'Hydroxychloroquine and tocilizumab therapy in COVID-19 patients—An observational study',
'prefix': '10.1371',
'volume': '15',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0456-5618',
'authenticated-orcid': True,
'given': 'Andrew',
'family': 'Ip',
'sequence': 'first',
'affiliation': []},
{'given': 'Donald A.', 'family': 'Berry', 'sequence': 'additional', 'affiliation': []},
{'given': 'Eric', 'family': 'Hansen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Andre H.', 'family': 'Goy', 'sequence': 'additional', 'affiliation': []},
{'given': 'Andrew L.', 'family': 'Pecora', 'sequence': 'additional', 'affiliation': []},
{'given': 'Brittany A.', 'family': 'Sinclaire', 'sequence': 'additional', 'affiliation': []},
{'given': 'Urszula', 'family': 'Bednarz', 'sequence': 'additional', 'affiliation': []},
{'given': 'Michael', 'family': 'Marafelias', 'sequence': 'additional', 'affiliation': []},
{'given': 'Scott M.', 'family': 'Berry', 'sequence': 'additional', 'affiliation': []},
{'given': 'Nicholas S.', 'family': 'Berry', 'sequence': 'additional', 'affiliation': []},
{'given': 'Shivam', 'family': 'Mathura', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ihor S.', 'family': 'Sawczuk', 'sequence': 'additional', 'affiliation': []},
{'given': 'Noa', 'family': 'Biran', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6100-7773',
'authenticated-orcid': True,
'given': 'Ronaldo C.',
'family': 'Go',
'sequence': 'additional',
'affiliation': []},
{'given': 'Steven', 'family': 'Sperber', 'sequence': 'additional', 'affiliation': []},
{'given': 'Julia A.', 'family': 'Piwoz', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bindu', 'family': 'Balani', 'sequence': 'additional', 'affiliation': []},
{'given': 'Cristina', 'family': 'Cicogna', 'sequence': 'additional', 'affiliation': []},
{'given': 'Rani', 'family': 'Sebti', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jerry', 'family': 'Zuckerman', 'sequence': 'additional', 'affiliation': []},
{'given': 'Keith M.', 'family': 'Rose', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lisa', 'family': 'Tank', 'sequence': 'additional', 'affiliation': []},
{'given': 'Laurie G.', 'family': 'Jacobs', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jason', 'family': 'Korcak', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sarah L.', 'family': 'Timmapuri', 'sequence': 'additional', 'affiliation': []},
{'given': 'Joseph P.', 'family': 'Underwood', 'sequence': 'additional', 'affiliation': []},
{'given': 'Gregory', 'family': 'Sugalski', 'sequence': 'additional', 'affiliation': []},
{'given': 'Carol', 'family': 'Barsky', 'sequence': 'additional', 'affiliation': []},
{'given': 'Daniel W.', 'family': 'Varga', 'sequence': 'additional', 'affiliation': []},
{'given': 'Arif', 'family': 'Asif', 'sequence': 'additional', 'affiliation': []},
{'given': 'Joseph C.', 'family': 'Landolfi', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-2175-4082',
'authenticated-orcid': True,
'given': 'Stuart L.',
'family': 'Goldberg',
'sequence': 'additional',
'affiliation': []}],
'member': '340',
'published-online': {'date-parts': [[2020, 8, 13]]},
'reference': [ { 'issue': '5',
'key': 'pone.0237693.ref001',
'doi-asserted-by': 'crossref',
'first-page': '533',
'DOI': '10.1016/S1473-3099(20)30120-1',
'article-title': 'An interactive web-based dashboard to track COVID-19 in real time',
'volume': '20',
'author': 'E Dong',
'year': '2020',
'journal-title': 'Lancet Infect Dis'},
{ 'key': 'pone.0237693.ref002',
'doi-asserted-by': 'crossref',
'first-page': '929',
'DOI': '10.1056/NEJMoa2001191',
'article-title': 'First Case of 2019 Novel Coronavirus in the United States',
'volume': '382',
'author': 'M Holshue',
'year': '2020',
'journal-title': 'N Engl J of Med'},
{ 'key': 'pone.0237693.ref003',
'doi-asserted-by': 'crossref',
'first-page': '1708',
'DOI': '10.1056/NEJMoa2002032',
'article-title': 'Clinical Characteristics of Coronavirus Disease 2019 in China',
'volume': '382',
'author': 'W Guan',
'year': '2020',
'journal-title': 'N Engl J of Med'},
{ 'key': 'pone.0237693.ref004',
'unstructured': 'COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) '
'Treatment Guidelines. National Institutes of Health. '
'https://www.covid19treatmentguidelines.nih.gov/. Accessed [May 12, '
'2020].'},
{ 'key': 'pone.0237693.ref005',
'first-page': 'ciaa237',
'article-title': 'In Vitro Antiviral Activity and Projection of Optimized Dosing Design '
'of Hydroxychloroquine for the Treatment of Severe Acute Respiratory '
'Syndrome Coronavirus 2 (SARS-CoV-2)',
'author': 'X Yao',
'year': '2020',
'journal-title': 'Clin Infect Dis'},
{ 'key': 'pone.0237693.ref006',
'first-page': '1',
'article-title': 'Hydroxychloroquine, a less toxic derivative of chloroquine, is '
'effective in inhibiting SARS-CoV-2 infection in vitro',
'volume': '16',
'author': 'J Liu',
'year': '2020',
'journal-title': 'Cell Discov'},
{ 'key': 'pone.0237693.ref007',
'doi-asserted-by': 'crossref',
'first-page': '269',
'DOI': '10.1038/s41422-020-0282-0',
'article-title': 'Remdesivir and Chloroquine effectively inhibit the recently emerged '
'novel coronavirus (2019-nCoV) in vitro',
'volume': '30',
'author': 'M Wang',
'journal-title': 'Cell Res'},
{ 'key': 'pone.0237693.ref008',
'doi-asserted-by': 'crossref',
'first-page': '69',
'DOI': '10.1186/1743-422X-2-69',
'article-title': 'Chloroquine is a potent inhibitor of SARS coronavirus infection and '
'spread',
'volume': '2',
'author': 'M Vincent',
'year': '2005',
'journal-title': 'Virol J'},
{ 'issue': '11',
'key': 'pone.0237693.ref009',
'doi-asserted-by': 'crossref',
'first-page': '722',
'DOI': '10.1016/S1473-3099(03)00806-5',
'article-title': 'Effects of chloroquine on viral infections: an old drug against today’s '
'diseases?',
'volume': '3',
'author': 'A Savarino',
'year': '2003',
'journal-title': 'Lancet Infect Dis'},
{ 'issue': '8',
'key': 'pone.0237693.ref010',
'doi-asserted-by': 'crossref',
'first-page': '1435',
'DOI': '10.1080/15548627.2018.1474314',
'article-title': 'Chloroquine inhibits autophagic flux by decreasing '
'autophagosome-lysosome fusion',
'volume': '14',
'author': 'M Mauthe',
'year': '2018',
'journal-title': 'Autophagy'},
{ 'issue': '3',
'key': 'pone.0237693.ref011',
'doi-asserted-by': 'crossref',
'first-page': '155',
'DOI': '10.1038/s41584-020-0372-x',
'article-title': 'Mechanisms of action of hydroxychloroquine and chloroquine: '
'implicaetions for rheumatology',
'volume': '16',
'author': 'E Schrezenmeier',
'year': '2020',
'journal-title': 'Nat Rev Rheumatol'},
{ 'issue': '1',
'key': 'pone.0237693.ref012',
'first-page': '1',
'article-title': 'A pilot study of hydroxychlorquine in treatment of patients with common '
'coronavirus disease-19 (COVID-19)',
'volume': '49',
'author': 'J Chen',
'year': '2020',
'journal-title': 'Journal of Zhejiang University (Medical Sciences)'},
{ 'key': 'pone.0237693.ref013',
'unstructured': 'Gautret P., Lagier JC, Parola P., et al. “Hydroxychloroquine and '
'azithromycin as a treatment of COVID-19: results of an open-label '
'non-randomized clinical trial.” International Journal of Antimicrobial '
'Agents (2020), https://doi.org/10.1016.j.ijantimicag.2020.105949'},
{ 'key': 'pone.0237693.ref014',
'article-title': 'Observational Study of Hydroxychloroquine in Hospitalized Patients with '
'Covid-19',
'author': 'J Geleris',
'year': '2020',
'journal-title': 'N Engl J Med'},
{ 'key': 'pone.0237693.ref015',
'article-title': 'Association of Treatment With Hydroxychloroquine or Azithromycin With '
'In-Hospital Mortality in Patients With COVID-19 in New York State',
'author': 'ES Rosenberg',
'journal-title': 'JAMA'},
{ 'key': 'pone.0237693.ref016',
'article-title': 'Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate '
'Covid-19',
'volume': '23',
'author': 'AB Cavalcanti',
'year': '2020',
'journal-title': 'N Engl J Med'},
{ 'key': 'pone.0237693.ref017',
'doi-asserted-by': 'crossref',
'first-page': '529',
'DOI': '10.1007/s00281-017-0629-x',
'article-title': 'Pathogenic human coronavirus infections: causes and consequences of '
'cytokine storm and immunopathology',
'volume': '39',
'author': 'R Channappanavar',
'year': '2017',
'journal-title': 'Semin immunopathol'},
{ 'key': 'pone.0237693.ref018',
'doi-asserted-by': 'crossref',
'first-page': '497',
'DOI': '10.1016/S0140-6736(20)30183-5',
'article-title': 'Clinical features of patients infected with 2019 novel coronavirus in '
'Wuhan, China',
'volume': '395',
'author': 'C Huang',
'year': '2020',
'journal-title': 'Lancet'},
{ 'key': 'pone.0237693.ref019',
'doi-asserted-by': 'crossref',
'first-page': '420',
'DOI': '10.1016/S2213-2600(20)30076-X',
'article-title': 'Pathological findings of COVID-19 associated with acute respiratory '
'distress syndrome',
'volume': '8',
'author': 'Z Xu',
'year': '2020',
'journal-title': 'The Lancet Respir med'},
{ 'key': 'pone.0237693.ref020',
'first-page': '202005615',
'article-title': 'Effective treatment of severe COVID-19 patients with tocilizumab',
'author': 'X Xu',
'year': '2020',
'journal-title': 'Proc National Acad Sci'},
{ 'key': 'pone.0237693.ref021',
'first-page': '1',
'article-title': 'Tocilizumab treatment in COVID‐19: A single center experience',
'author': 'P Luo',
'year': '2020',
'journal-title': 'J Med Virol'},
{ 'key': 'pone.0237693.ref022',
'unstructured': 'Tocilizumab improves significantly clinical outcomes of patients with '
'moderate or severe COVID-19 pneumonia [press release]. April 2020. '
'[Online]. '
'https://www.aphp.fr/contenu/tocilizumab-improves-significantly-clinical-outcomes-patients-moderate-or-severe-covid-19. '
'[Accessed May 12, 2020].'},
{ 'key': 'pone.0237693.ref023',
'article-title': 'Tocilizumab in patients with severe COVID-19: a retrospective cohort '
'study',
'author': 'G Guaraldi',
'year': '2020',
'journal-title': 'Lancet Rheumatol'},
{ 'key': 'pone.0237693.ref024',
'first-page': 'ciaa954',
'article-title': 'Tocilizumab for treatment of mechanically ventilated patients with '
'COVID-19',
'author': 'EC Somers',
'journal-title': 'Clinical Infectious Diseases'},
{ 'key': 'pone.0237693.ref025',
'doi-asserted-by': 'crossref',
'first-page': '2293',
'DOI': '10.1056/NEJMsb1609216',
'article-title': 'Real-World Evidence—What is it and What can it tell us?',
'volume': '375',
'author': 'R Sherman',
'year': '2016',
'journal-title': 'N Engl J of Med'},
{ 'key': 'pone.0237693.ref026',
'unstructured': 'Food and Drug Administration, "Use of Electronic Health Record Data in '
'Clinical Investigations Guidance for Industry," July 2018. [Online]. '
'https://www.fda.gov/media/97567/download. [Accessed 8 April 2020].'},
{ 'key': 'pone.0237693.ref027',
'unstructured': 'Food and Drug Administration, "Use of real-world evidence to support '
'regulatory decision-making for medical devices: draft guidance for '
'industry and Food and Drug Administration staff," 31 August 2017. '
'[Online]. https://www.fda.gov/media/120060/download. [Accessed 8 April '
'2020].'},
{ 'key': 'pone.0237693.ref028',
'unstructured': 'Food and Drug Administration, "Framework for FDA’s Real-World Evidence '
'Program," December 2018. [Online]. '
'https://www.fda.gov/media/120060/download. [Accessed 8 April 2020].'},
{ 'issue': '2',
'key': 'pone.0237693.ref029',
'doi-asserted-by': 'crossref',
'first-page': '377',
'DOI': '10.1016/j.jbi.2008.08.010',
'article-title': 'Research electronic data capture (REDCap)–A metadata-driven methodology '
'and workflow process for providing translational research informatics '
'support',
'volume': '42',
'author': 'PA Harris',
'year': '2009',
'journal-title': 'J Biomed Inform'},
{ 'key': 'pone.0237693.ref030',
'article-title': 'The REDCap consortium: Building an international community of software '
'partners',
'author': 'PA Harris',
'year': '2019',
'journal-title': 'J Biomed Inform'},
{ 'issue': '2',
'key': 'pone.0237693.ref031',
'first-page': '1',
'article-title': 'Comparability of cause of death between ICD-9 and ICD-10: preliminary '
'estimates',
'volume': '49',
'author': 'RN Anderson',
'year': '2001',
'journal-title': 'Natl Vital Stat Rep'},
{ 'key': 'pone.0237693.ref032',
'doi-asserted-by': 'crossref',
'first-page': '516',
'DOI': '10.1080/01621459.1984.10478078',
'article-title': 'Reducing bias in observational studies using subclassification on the '
'propensity score',
'volume': '79',
'author': 'PR Rosenbaum',
'year': '1984',
'journal-title': 'J Am Stat Assoc'},
{ 'key': 'pone.0237693.ref033',
'doi-asserted-by': 'crossref',
'first-page': '399',
'DOI': '10.1080/00273171.2011.568786',
'article-title': 'An introduction to propensity score methods for reducing the effects of '
'confounding in observational studies',
'volume': '46',
'author': 'PC Austin',
'year': '2011',
'journal-title': 'Multivariate Behav Res'},
{ 'key': 'pone.0237693.ref034',
'unstructured': 'Food and Drug Administration, “Re: Request for Emergency Use '
'Authorization for Use of Chloroquine Phosphate or Hydroxychloroquine '
'Sulfate Supplied from the Strategic National Stockpile for Treatment of '
'2019 Coronavirus Disease.” March 2020. [Online]. '
'https://fda.gov/media/136534/download. [Accessed 8 April 2020]'},
{ 'issue': '2',
'key': 'pone.0237693.ref035',
'doi-asserted-by': 'crossref',
'first-page': '253',
'DOI': '10.1002/cpt.1856',
'article-title': 'Optimizing Hydroxychloroquine Dosing for Patients with COVID-19: An '
'Integrative Modeling Approach for Effective Drug Repurposing',
'volume': '108',
'author': 'M Garcia-Cremades',
'year': '2020',
'journal-title': 'Clin. Pharmacol. Ther'}],
'container-title': 'PLOS ONE',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://dx.plos.org/10.1371/journal.pone.0237693',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2020, 8, 13]],
'date-time': '2020-08-13T18:51:07Z',
'timestamp': 1597344667000},
'score': 1,
'resource': {'primary': {'URL': 'https://dx.plos.org/10.1371/journal.pone.0237693'}},
'subtitle': [],
'editor': [{'given': 'Chiara', 'family': 'Lazzeri', 'sequence': 'first', 'affiliation': []}],
'short-title': [],
'issued': {'date-parts': [[2020, 8, 13]]},
'references-count': 35,
'journal-issue': {'issue': '8', 'published-online': {'date-parts': [[2020, 8, 13]]}},
'URL': 'http://dx.doi.org/10.1371/journal.pone.0237693',
'relation': { 'has-preprint': [ { 'id-type': 'doi',
'id': '10.1101/2020.05.21.20109207',
'asserted-by': 'object'}]},
'ISSN': ['1932-6203'],
'subject': ['Multidisciplinary'],
'container-title-short': 'PLoS ONE',
'published': {'date-parts': [[2020, 8, 13]]}}
