{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:42:30Z","timestamp":1790700150213,"version":"4.1.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81974208"],"award-info":[{"award-number":["81974208"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81974181"],"award-info":[{"award-number":["81974181"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81701156"],"award-info":[{"award-number":["81701156"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004829","name":"Science & Technology Department of Sichuan Province","doi-asserted-by":"crossref","award":["2017SZ0007"],"award-info":[{"award-number":["2017SZ0007"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004829","name":"Science & Technology Department of Sichuan Province","doi-asserted-by":"crossref","award":["2021YJ0433"],"award-info":[{"award-number":["2021YJ0433"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the 1\u00b73\u00b75 project for disciplines of excellence, West China Hospital, Sichuan University","award":["ZYGD18009"],"award-info":[{"award-number":["ZYGD18009"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>We aimed to explore the association of serum level of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and its related inflammatory biomarkers (hypoxia inducible factor-1\u03b1, cathepsin B, caspase-1 and matrix metalloproteinase-9) with malignant brain edema (MBE) in patients with acute ischemic stroke.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We prospectively enrolled patients with acute ischemic stroke admitted\u2009&lt;\u200924\u00a0h from onset of symptoms. Brain CT was performed on admission and blood samples were collected. Repeated brain CT\/MRI was performed\u2009&lt;\u20097 days of admission to identify the presence of MBE, defined as neurological deterioration with imaging signs of midline shift or compressed basal cisterns. Logistic regression analysis was performed to assess the association between inflammatory biomarkers and MBE, adjusted for age and National Institutes of Health Stroke Scale (NIHSS).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>200 patients (69.3\u2009\u00b1\u200914.3 years; male 55\u2009%) were included for analysis, of whom 26 patients developed MBE (median time from stroke onset to MBE 32.5\u00a0h). Compared with patients without MBE, those with MBE had higher level of serum concentration of NLRP3 (median time from onset to blood collection 3\u00a0h, 1.85 ng\/ml vs. 1.11 ng\/ml, <jats:italic>P<\/jats:italic>\u2009=\u20090.026). NLRP3 level was positively correlated with NIHSS on admission (Spearman \u03c1\u2009=\u20090.18, <jats:italic>P<\/jats:italic>\u2009=\u20090.01) and the association between NLRP3 and MBE was attenuated (OR 1.47, 95\u2009% CI 0.88\u20132.46, <jats:italic>P<\/jats:italic>\u2009=\u20090.138) after adjusting for age and NIHSS. There was no significant difference in other biomarkers between MBE and non-MBE groups.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>There was a trend of association between a higher level of serum concentration of NLRP3 and an increased risk of MBE after ischemic stroke, possibly confounded by the severity of stroke, which is worth further validation in large cohort studies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12883-021-02369-4","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T04:02:50Z","timestamp":1630987370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Association between serum NLRP3 and malignant brain edema in patients with acute ischemic stroke"],"prefix":"10.1186","volume":"21","author":[{"given":"Yanan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simiao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,7]]},"reference":[{"issue":"5","key":"2369_CR1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/S1474-4422(19)30034-1","volume":"18","author":"CO Johnson","year":"2019","unstructured":"Johnson CO, Nguyen M, Roth GA, Nichols E, Alam T, Abate D, Abd-Allah F, Abdelalim A, Abraha HN, Abu-Rmeileh NM, et al. Global, regional, and national burden of stroke, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2019;18(5):439\u201358.","journal-title":"The Lancet Neurology"},{"issue":"6","key":"2369_CR2","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1161\/01.STR.10.6.743","volume":"10","author":"OB White","year":"1979","unstructured":"White OB, Norris JW, Hachinski VC, Lewis A. Death in early stroke, causes and mechanisms. Stroke. 1979;10(6):743.","journal-title":"Stroke"},{"issue":"10","key":"2369_CR3","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/S1474-4422(09)70224-8","volume":"8","author":"HB Huttner","year":"2009","unstructured":"Huttner HB, Schwab S. Malignant middle cerebral artery infarction: clinical characteristics, treatment strategies, and future perspectives. The Lancet Neurology. 2009;8(10):949\u201358.","journal-title":"The Lancet Neurology"},{"issue":"1\u20132","key":"2369_CR4","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1159\/000113736","volume":"25","author":"J Hofmeijer","year":"2008","unstructured":"Hofmeijer J, Algra A, Kappelle LJ, van der Worp HB. Predictors of life-threatening brain edema in middle cerebral artery infarction. Cerebrovascular diseases (Basel, Switzerland). 2008;25(1\u20132):176\u201384.","journal-title":"Cerebrovascular diseases (Basel, Switzerland)"},{"issue":"9","key":"2369_CR5","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1007\/s00415-011-6003-3","volume":"258","author":"M Bar","year":"2011","unstructured":"Bar M, Mikulik R, Skoloudik D, Czerny D, Lipina R, Sames M, Choc M, Novak Z, Stary M, Benes V, et al. Decompressive surgery for malignant supratentorial infarction remains underutilized after guideline publication. Journal of neurology. 2011;258(9):1689\u201394.","journal-title":"Journal of neurology"},{"issue":"4","key":"2369_CR6","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/S1474-4422(18)30500-3","volume":"18","author":"S Wu","year":"2019","unstructured":"Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson CS, Sandercock P, Wang Y, Huang Y, Cui L, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management. The Lancet Neurology. 2019;18(4):394\u2013405.","journal-title":"The Lancet Neurology"},{"issue":"11","key":"2369_CR7","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/S1474-4422(16)30196-X","volume":"15","author":"KN Sheth","year":"2016","unstructured":"Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, Ostwaldt AC, Del Zoppo GJ, Simard JM, Jacobson S, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Neurology. 2016;15(11):1160\u20139.","journal-title":"The Lancet Neurology"},{"issue":"3","key":"2369_CR8","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/S1474-4422(07)70055-8","volume":"6","author":"JM Simard","year":"2007","unstructured":"Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. The Lancet Neurology. 2007;6(3):258\u201368.","journal-title":"The Lancet Neurology"},{"key":"2369_CR9","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1186\/1742-2094-8-164","volume":"8","author":"A D\u00e9nes","year":"2011","unstructured":"D\u00e9nes A, Ferenczi S, Kov\u00e1cs KJ. Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation. 2011;8:164.","journal-title":"J Neuroinflammation"},{"issue":"9","key":"2369_CR10","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1093\/brain\/awx133","volume":"140","author":"MK Mamik","year":"2017","unstructured":"Mamik MK, Power C. Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts. Brain: a journal of neurology. 2017;140(9):2273\u201385.","journal-title":"Brain: a journal of neurology"},{"issue":"2","key":"2369_CR11","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1111\/bpa.12476","volume":"27","author":"J Barrington","year":"2017","unstructured":"Barrington J, Lemarchand E, Allan SM. A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? Brain Pathol. 2017;27(2):205\u201312.","journal-title":"Brain Pathol"},{"issue":"1","key":"2369_CR12","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s12974-019-1498-0","volume":"16","author":"P Hong","year":"2019","unstructured":"Hong P, Gu RN, Li FX, Xiong XX, Liang WB, You ZJ, Zhang HF. NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes. J Neuroinflammation. 2019;16(1):121.","journal-title":"J Neuroinflammation"},{"key":"2369_CR13","doi-asserted-by":"publisher","first-page":"117638","DOI":"10.1016\/j.lfs.2020.117638","volume":"251","author":"H Wang","year":"2020","unstructured":"Wang H, Chen H, Jin J, Liu Q, Zhong D, Li G. Inhibition of the NLRP3 inflammasome reduces brain edema and regulates the distribution of aquaporin-4 after cerebral ischaemia-reperfusion. Life sciences. 2020;251:117638.","journal-title":"Life sciences"},{"key":"2369_CR14","doi-asserted-by":"crossref","unstructured":"Franke M, Bieber M, Kraft P, Weber ANR, Stoll G, Schuhmann MK: The NLRP3 inflammasome drives inflammation in ischemia\/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain, behavior, and immunity 2020.","DOI":"10.1016\/j.bbi.2020.12.009"},{"issue":"8","key":"2369_CR15","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","volume":"19","author":"KV Swanson","year":"2019","unstructured":"Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature reviews Immunology. 2019;19(8):477\u201389.","journal-title":"Nature reviews Immunology"},{"key":"2369_CR16","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.brainres.2018.06.029","volume":"1699","author":"S Rashad","year":"2018","unstructured":"Rashad S, Niizuma K, Sato-Maeda M, Fujimura M, Mansour A, Endo H, Ikawa S, Tominaga T. Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis. Brain research. 2018;1699:54\u201368.","journal-title":"Brain research"},{"issue":"1","key":"2369_CR17","doi-asserted-by":"publisher","first-page":"25","DOI":"10.4103\/1673-5374.264444","volume":"15","author":"H Nakanishi","year":"2020","unstructured":"Nakanishi H. Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging. Neural regeneration research. 2020;15(1):25\u20139.","journal-title":"Neural regeneration research"},{"key":"2369_CR18","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.neuroscience.2020.09.036","volume":"448","author":"Q Jiang","year":"2020","unstructured":"Jiang Q, Geng X, Warren J, Eugene Paul Cosky E, Kaura S, Stone C, Li F, Ding Y. Hypoxia Inducible Factor-1\u03b1 (HIF-1\u03b1) Mediates NLRP3 Inflammasome-Dependent-Pyroptotic and Apoptotic Cell Death Following Ischemic Stroke. Neuroscience. 2020;448:126\u201339.","journal-title":"Neuroscience"},{"issue":"7872","key":"2369_CR19","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S0140-6736(74)91639-0","volume":"2","author":"G Teasdale","year":"1974","unstructured":"Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81\u20134.","journal-title":"Lancet"},{"issue":"7","key":"2369_CR20","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1161\/01.STR.20.7.864","volume":"20","author":"T Brott","year":"1989","unstructured":"Brott T, Adams HP Jr., Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864\u201370.","journal-title":"Stroke"},{"issue":"1","key":"2369_CR21","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1161\/01.STR.24.1.35","volume":"24","author":"HP Adams Jr.","year":"1993","unstructured":"Adams HP Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE. 3rd: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35\u201341.","journal-title":"Stroke"},{"issue":"12","key":"2369_CR22","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1161\/STROKEAHA.118.022001","volume":"49","author":"S Wu","year":"2018","unstructured":"Wu S, Yuan R, Wang Y, Wei C, Zhang S, Yang X, Wu B, Liu M. Early Prediction of Malignant Brain Edema After Ischemic Stroke. Stroke. 2018;49(12):2918\u201327.","journal-title":"Stroke"},{"issue":"9136","key":"2369_CR23","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/S0140-6736(98)08020-9","volume":"352","author":"W Hacke","year":"1998","unstructured":"Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245\u201351.","journal-title":"Lancet"},{"issue":"4","key":"2369_CR24","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/jcbfm.2013.242","volume":"34","author":"F Yang","year":"2014","unstructured":"Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q, et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. 2014;34(4):660\u20137.","journal-title":"Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism"},{"issue":"3","key":"2369_CR25","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0966-842X(00)01936-3","volume":"9","author":"BT Cookson","year":"2001","unstructured":"Cookson BT, Brennan MA. Pro-inflammatory programmed cell death. Trends in microbiology. 2001;9(3):113\u20134.","journal-title":"Trends in microbiology"},{"issue":"3","key":"2369_CR26","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/glia.10108","volume":"39","author":"GA Rosenberg","year":"2002","unstructured":"Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39(3):279\u201391.","journal-title":"Glia"},{"issue":"1","key":"2369_CR27","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.yexcr.2017.11.015","volume":"362","author":"H Bai","year":"2018","unstructured":"Bai H, Yang B, Yu W, Xiao Y, Yu D, Zhang Q. Cathepsin B links oxidative stress to the activation of NLRP3 inflammasome. Experimental cell research. 2018;362(1):180\u20137.","journal-title":"Experimental cell research"},{"issue":"4","key":"2369_CR28","doi-asserted-by":"publisher","first-page":"191","DOI":"10.4103\/bc.bc_35_18","volume":"4","author":"Q Jiang","year":"2018","unstructured":"Jiang Q, Stone CR, Geng X, Ding Y. Hypoxia-inducible factor-1 \u03b1 and RIP3 triggers NLRP3 inflammasome in ischemic stroke. Brain circulation. 2018;4(4):191\u20132.","journal-title":"Brain circulation"},{"key":"2369_CR29","doi-asserted-by":"crossref","unstructured":"Ke XJ, Zhang JJ: Changes in HIF-1\u03b1, VEGF, NGF and BDNF levels in cerebrospinal fluid and their relationship with cognitive impairment in patients with cerebral infarction. Journal of Huazhong University of Science and Technology Medical sciences = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban 2013, 33(3):433\u2013437.","DOI":"10.1007\/s11596-013-1137-4"},{"key":"2369_CR30","doi-asserted-by":"crossref","unstructured":"Wu S, Mair G, Cohen G, Morris Z, von Heijne A, Bradey N, Cala L, Peeters A, Farrall AJ, Adami A et al: Hyperdense artery sign, symptomatic infarct swelling and effect of alteplase in acute ischaemic stroke. Stroke Vasc Neurol 2020.","DOI":"10.1136\/svn-2020-000569"},{"issue":"4","key":"2369_CR31","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1001\/jamaneurol.2017.5162","volume":"75","author":"WT Kimberly","year":"2018","unstructured":"Kimberly WT, Dutra BG, Boers AMM, Alves H, Berkhemer OA, van den Berg L, Sheth KN, Roos Y, van der Lugt A, Beenen LFM, et al. Association of Reperfusion With Brain Edema in Patients With Acute Ischemic Stroke: A Secondary Analysis of the MR CLEAN Trial. JAMA Neurol. 2018;75(4):453\u201361.","journal-title":"JAMA Neurol"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-021-02369-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12883-021-02369-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-021-02369-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T04:03:06Z","timestamp":1630987386000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-021-02369-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,7]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2369"],"URL":"https:\/\/doi.org\/10.1186\/s12883-021-02369-4","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,7]]},"assertion":[{"value":"15 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was\u00a0performed according to the Helsinki Declaration and approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University (No. 2017[130]), and conformed to local and international ethical criteria. Written informed consent was obtained from all patients or their next of kin.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Participants consent for publication: Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"341"}}