{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:27:38Z","timestamp":1783434458007,"version":"3.54.6"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"James and Esther King Biomedical Research Program","award":["9JK08"],"award-info":[{"award-number":["9JK08"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg\/kg b.w. per day) or vehicle (saline) treatment (2\u20133 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.<\/jats:p>","DOI":"10.3390\/biom12050621","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:07:22Z","timestamp":1650604042000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Chronic Nicotine Exposure Increases Hematoma Expansion following Collagenase-Induced Intracerebral Hemorrhage in Rats"],"prefix":"10.3390","volume":"12","author":[{"given":"Ashish K.","family":"Rehni","sequence":"first","affiliation":[{"name":"Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Neurology Research Building, 1420 NW 9th Avenue, Room # 203, Miami, FL 33136, USA"},{"name":"Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunjoo","family":"Cho","sequence":"additional","affiliation":[{"name":"Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Neurology Research Building, 1420 NW 9th Avenue, Room # 203, Miami, FL 33136, USA"},{"name":"Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Miami, Coral Gables, FL 33146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Miami, Coral Gables, FL 33146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1757-9947","authenticated-orcid":false,"given":"Ami P.","family":"Raval","sequence":"additional","affiliation":[{"name":"Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Neurology Research Building, 1420 NW 9th Avenue, Room # 203, Miami, FL 33136, USA"},{"name":"Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Perez-Pinzon","sequence":"additional","affiliation":[{"name":"Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Neurology Research Building, 1420 NW 9th Avenue, Room # 203, Miami, FL 33136, USA"},{"name":"Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunjan R.","family":"Dave","sequence":"additional","affiliation":[{"name":"Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Neurology Research Building, 1420 NW 9th Avenue, Room # 203, Miami, FL 33136, USA"},{"name":"Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1161\/STR.0b013e318296aeca","article-title":"An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association\/American Stroke Association","volume":"44","author":"Sacco","year":"2013","journal-title":"Stroke"},{"key":"ref_2","unstructured":"GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795\u2013820."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1161\/01.STR.24.6.796","article-title":"Long-term survival after first-ever stroke: The Oxfordshire Community Stroke Project","volume":"24","author":"Dennis","year":"1993","journal-title":"Stroke"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1474-4422(03)00266-7","article-title":"Stroke epidemiology: A review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century","volume":"2","author":"Feigin","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1161\/STROKEAHA.109.575043","article-title":"Stroke incidence is decreasing in whites but not in blacks: A population-based estimate of temporal trends in stroke incidence from the Greater Cincinnati\/Northern Kentucky Stroke Study","volume":"41","author":"Kleindorfer","year":"2010","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S1474-4422(09)70340-0","article-title":"Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: A systematic review and meta-analysis","volume":"9","author":"Luitse","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1212\/01.wnl.0000208408.98482.99","article-title":"Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage","volume":"66","author":"Davis","year":"2006","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0140-6736(10)60834-3","article-title":"Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): A case-control study","volume":"376","author":"Xavier","year":"2010","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.5853\/jos.2016.00864","article-title":"Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: An Update","volume":"19","author":"An","year":"2017","journal-title":"J. Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1161\/01.STR.0000080678.09344.8D","article-title":"Risk factors for intracerebral hemorrhage in the general population: A systematic review","volume":"34","author":"Ariesen","year":"2003","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.5853\/jos.2020.04770","article-title":"Tobacco Use: A Major Risk Factor of Intracerebral Hemorrhage","volume":"23","author":"Cho","year":"2021","journal-title":"J. Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e005090","DOI":"10.1161\/JAHA.116.005090","article-title":"Age-Specific Vascular Risk Factor Profiles According to Stroke Subtype","volume":"6","author":"Hauer","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1212\/01.wnl.0000228277.84760.a2","article-title":"Intracerebral hemorrhage in pregnancy: Frequency, risk factors, and outcome","volume":"67","author":"Bateman","year":"2006","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1161\/STROKEAHA.107.496752","article-title":"Cigarette smoking, systolic blood pressure, and cardiovascular diseases in the Asia-Pacific region","volume":"39","author":"Nakamura","year":"2008","journal-title":"Stroke"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e003540","DOI":"10.1161\/JAHA.116.003540","article-title":"Race-Specific Predictors of Mortality in Intracerebral Hemorrhage: Differential Impacts of Intraventricular Hemorrhage and Age Among Blacks and Whites","volume":"5","author":"Faigle","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"214","DOI":"10.7461\/jcen.2013.15.3.214","article-title":"The outcomes of spontaneous intracerebral hemorrhage in young adults\u2014A clinical study","volume":"15","author":"Go","year":"2013","journal-title":"J. Cereb. Endovasc. Neurosurg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.tcm.2016.03.001","article-title":"Cardiovascular toxicity of nicotine: Implications for electronic cigarette use","volume":"26","author":"Benowitz","year":"2016","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/0024-3205(87)90020-8","article-title":"Nicotine administration to rats: Methodological considerations","volume":"40","author":"Murrin","year":"1987","journal-title":"Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.neuroscience.2011.02.036","article-title":"Nicotine and estrogen synergistically exacerbate cerebral ischemic injury","volume":"181","author":"Raval","year":"2011","journal-title":"Neuroscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/00004647-199702000-00002","article-title":"Chronic nicotine treatment enhances focal ischemic brain injury and depletes free pool of brain microvascular tissue plasminogen activator in rats","volume":"17","author":"Wang","year":"1997","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1177\/0271678X20925164","article-title":"Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats","volume":"41","author":"Diaz","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jns.2017.05.057","article-title":"Sex differences in intracerebral hemorrhage expansion and mortality","volume":"379","author":"Marini","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ane.12359","article-title":"Lower hazard ratio for death in women with cerebral hemorrhage","volume":"132","author":"Shigematsu","year":"2015","journal-title":"Acta Neurol. Scand"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.neuroscience.2009.02.065","article-title":"Pretreatment with a single estradiol-17beta bolus activates cyclic-AMP response element binding protein and protects CA1 neurons against global cerebral ischemia","volume":"160","author":"Raval","year":"2009","journal-title":"Neuroscience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/sj.jcbfm.9600548","article-title":"Intracerebral hemorrhage models in rat: Comparing collagenase to blood infusion","volume":"28","author":"MacLellan","year":"2008","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s12975-019-00754-3","article-title":"Automated Assessment of Hematoma Volume of Rodents Subjected to Experimental Intracerebral Hemorrhagic Stroke by Bayes Segmentation Approach","volume":"11","author":"Zhang","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1161\/01.STR.27.9.1616","article-title":"Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model","volume":"27","author":"Belayev","year":"1996","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1161\/01.STR.20.10.1383","article-title":"Photochemical stroke model: Flunarizine prevents sensorimotor deficits after neocortical infarcts in rats","volume":"20","author":"Borgers","year":"1989","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jneumeth.2010.05.004","article-title":"Digitally quantifying cerebral hemorrhage using Photoshop and Image J","volume":"190","author":"Tang","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/0003-2697(81)90089-0","article-title":"A continuous spectrophotometric assay for Clostridium histolyticum collagenase","volume":"113","author":"Steinbrink","year":"1981","journal-title":"Anal. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jpba.2008.10.003","article-title":"Nicotine exposure can be detected in cerebrospinal fluid of active and passive smokers","volume":"49","author":"Malkawi","year":"2009","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Koob, G.F., and Le Moal, M. (2006). Nicotine. Neurobiology of Addiction, Elsevier Academic.","DOI":"10.1016\/B978-012419239-3\/50043-6"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMsa1211128","article-title":"21st-century hazards of smoking and benefits of cessation in the United States","volume":"368","author":"Jha","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_35","unstructured":"Villarroel, M.A., Cha, A.E., and Vahratian, A. (2021, July 10). Electronic Cigarette Use Among U.S. Adults, Available online: https:\/\/www.cdc.gov\/nchs\/products\/databriefs\/db365.htm."},{"key":"ref_36","first-page":"e9618","article-title":"Cardiovascular Outcomes Associated with Adult Electronic Cigarette Use","volume":"12","author":"Vindhyal","year":"2020","journal-title":"Cureus"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.redox.2017.06.006","article-title":"Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: Is Metformin a viable countermeasure?","volume":"13","author":"Kaisar","year":"2017","journal-title":"Redox Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrcardio.2017.36","article-title":"Cardiovascular effects of electronic cigarettes","volume":"14","author":"Benowitz","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1161\/01.STR.0000100165.36466.95","article-title":"Smoking and risk of hemorrhagic stroke in women","volume":"34","author":"Kurth","year":"2003","journal-title":"Stroke"},{"key":"ref_40","first-page":"295","article-title":"Influence of hypertension, lipometabolism disorders, obesity and other lifestyles on spontaneous intracerebral hemorrhage","volume":"16","author":"Zhou","year":"2003","journal-title":"Biomed. Environ. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1212\/WNL.0b013e318260cbba","article-title":"Hematoma growth and outcomes in intracerebral hemorrhage: The INTERACT1 study","volume":"79","author":"Delcourt","year":"2012","journal-title":"Neurology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1161\/01.STR.27.10.1783","article-title":"Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course","volume":"27","author":"Kazui","year":"1996","journal-title":"Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/S0140-6736(09)60371-8","article-title":"Intracerebral haemorrhage","volume":"373","author":"Qureshi","year":"2009","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrcardio.2013.8","article-title":"The biology behind the atherothrombotic effects of cigarette smoke","volume":"10","author":"Csordas","year":"2013","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.04.038","article-title":"Hematoma Expansion Predictors: Laboratory and Radiological Risk Factors in Patients with Acute Intracerebral Hemorrhage: A Prospective Observational Study","volume":"28","author":"Elkhatib","year":"2019","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1161\/01.STR.24.7.987","article-title":"Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality","volume":"24","author":"Broderick","year":"1993","journal-title":"Stroke"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s12028-015-0147-4","article-title":"The HEP Score: A Nomogram-Derived Hematoma Expansion Prediction Scale","volume":"23","author":"Yao","year":"2015","journal-title":"Neurocrit. Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1161\/01.STR.0000128794.30660.e8","article-title":"Cigarette smoking and risk of stroke and its subtypes among middle-aged Japanese men and women: The JPHC Study Cohort I","volume":"35","author":"Mannami","year":"2004","journal-title":"Stroke"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1136\/tc.2009.029751","article-title":"The effects of smoking and smoking cessation on mortality from cardiovascular disease among Japanese: Pooled analysis of three large-scale cohort studies in Japan","volume":"19","author":"Honjo","year":"2010","journal-title":"Tob. Control"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1161\/STROKEAHA.108.540781","article-title":"Sex differences in stroke espidemiology: A systematic review","volume":"40","author":"Appelros","year":"2009","journal-title":"Stroke"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1001\/archinte.1989.00390090099020","article-title":"Cigarette smoking. A risk factor for hemorrhagic and nonhemorrhagic stroke","volume":"149","author":"Gill","year":"1989","journal-title":"Arch. Intern. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1002\/jnr.24016","article-title":"Cortical hemorrhage-associated neurological deficits and tissue damage in mice are ameliorated by therapeutic treatment with nicotine","volume":"95","author":"Anan","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1124\/jpet.111.182519","article-title":"Therapeutic effect of nicotine in a mouse model of intracerebral hemorrhage","volume":"338","author":"Hijioka","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00213-010-1848-1","article-title":"Meta-analysis of the acute effects of nicotine and smoking on human performance","volume":"210","author":"Heishman","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuroscience.2012.07.024","article-title":"\u03b17 Nicotinic acetylcholine receptor agonist attenuates neuropathological changes associated with intracerebral hemorrhage in mice","volume":"222","author":"Hijioka","year":"2012","journal-title":"Neuroscience"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1161\/STROKEAHA.111.639989","article-title":"\u03b17 nicotinic acetylcholine receptor agonism confers neuroprotection through GSK-3beta inhibition in a mouse model of intracerebral hemorrhage","volume":"43","author":"Krafft","year":"2012","journal-title":"Stroke"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/5\/621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:58:23Z","timestamp":1760137103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/5\/621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["biom12050621"],"URL":"https:\/\/doi.org\/10.3390\/biom12050621","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]}}}