{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:21:12Z","timestamp":1789928472798,"version":"4.0.1"},"reference-count":53,"publisher":"American Academy of Pediatrics (AAP)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,9,1]]},"abstract":"<jats:p>CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease.<\/jats:p>\n               <jats:p>OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease.<\/jats:p>\n               <jats:p>METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5\u201318) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies.<\/jats:p>\n               <jats:p>RESULTS. Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics.<\/jats:p>\n               <jats:p>CONCLUSIONS. Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.<\/jats:p>","DOI":"10.1542\/peds.2005-2895","type":"journal-article","created":{"date-parts":[[2006,9,1]],"date-time":"2006-09-01T21:17:38Z","timestamp":1157145458000},"page":"924-932","source":"Crossref","is-referenced-by-count":132,"title":["Enzyme-Replacement Therapy With Agalsidase Alfa in Children With Fabry Disease"],"prefix":"10.1542","volume":"118","author":[{"given":"Markus","family":"Ries","sequence":"first","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe T.R.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina","family":"Whybra","sequence":"additional","affiliation":[{"name":"Center for Lysosomal Storage Diseases, Children's Hospital, University of Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Timmons","sequence":"additional","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chevalia","family":"Robinson","sequence":"additional","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley L.","family":"Schlaggar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Pastores","sequence":"additional","affiliation":[{"name":"Departments of Neurology"},{"name":"Pediatrics, New York University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Howard","family":"Lien","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kampmann","sequence":"additional","affiliation":[{"name":"Center for Lysosomal Storage Diseases, Children's Hospital, University of Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roscoe O.","family":"Brady","sequence":"additional","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Beck","sequence":"additional","affiliation":[{"name":"Center for Lysosomal Storage Diseases, Children's Hospital, University of Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Schiffmann","sequence":"additional","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2006,9,1]]},"reference":[{"key":"2021120822500411400_R1","doi-asserted-by":"crossref","unstructured":"Brady R, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease. N Engl J Med.\u20081967;276:1163\u20131167","DOI":"10.1056\/NEJM196705252762101"},{"key":"2021120822500411400_R2","doi-asserted-by":"crossref","unstructured":"Bernstein HS, Bishop DF, Astrin KH, et al. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J Clin Invest.\u20081989;83:1390\u20131399","DOI":"10.1172\/JCI114027"},{"key":"2021120822500411400_R3","doi-asserted-by":"crossref","unstructured":"Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA.\u20081999;281:249\u2013254","DOI":"10.1001\/jama.281.3.249"},{"key":"2021120822500411400_R4","doi-asserted-by":"crossref","unstructured":"Dobyns WB, Filauro A, Tomson BN, et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A.\u20082004;129:136\u2013143","DOI":"10.1002\/ajmg.a.30123"},{"key":"2021120822500411400_R5","doi-asserted-by":"crossref","unstructured":"MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet.\u20082001;38:750\u2013760","DOI":"10.1136\/jmg.38.11.750"},{"key":"2021120822500411400_R6","doi-asserted-by":"crossref","unstructured":"Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest.\u20082004;34:236\u2013242","DOI":"10.1111\/j.1365-2362.2004.01309.x"},{"key":"2021120822500411400_R7","doi-asserted-by":"crossref","unstructured":"Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr.\u20082003;162:767\u2013772","DOI":"10.1007\/s00431-003-1299-3"},{"key":"2021120822500411400_R8","doi-asserted-by":"crossref","unstructured":"Guffon N. Clinical presentation in female patients with Fabry disease. J Med Genet.\u20082003;40:e38","DOI":"10.1136\/jmg.40.4.e38"},{"key":"2021120822500411400_R9","unstructured":"Sessa A, Toson A, Nebuloni M, et al. Renal ultrastructural findings in Anderson-Fabry disease. J Nephrol.\u20082002;15:109\u2013112"},{"key":"2021120822500411400_R10","unstructured":"Sheth KJ, Werlin SL, Freeman ME, Hodach AE. Gastrointestinal structure and function in Fabry's disease. Am J Gastroenterol.\u20081981;76:246\u2013251"},{"key":"2021120822500411400_R11","doi-asserted-by":"crossref","unstructured":"Ferrans VJ, Hibbs RG, Burda CD. The heart in Fabry's disease. A histochemical and electron microscopic study. Am J Cardiol.\u20081969;24:95\u2013110","DOI":"10.1016\/0002-9149(69)90055-1"},{"key":"2021120822500411400_R12","doi-asserted-by":"crossref","unstructured":"Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA.\u20082000;284:2771\u20132775","DOI":"10.1001\/jama.284.21.2771"},{"key":"2021120822500411400_R13","doi-asserted-by":"crossref","unstructured":"Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore).\u20082002;81:122\u2013138","DOI":"10.1097\/00005792-200203000-00003"},{"key":"2021120822500411400_R14","doi-asserted-by":"crossref","unstructured":"Senechal M, Germain DP. Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients. Clin Genet.\u20082003;63:46\u201352","DOI":"10.1034\/j.1399-0004.2003.630107.x"},{"key":"2021120822500411400_R15","doi-asserted-by":"crossref","unstructured":"MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet.\u20082001;38:769\u2013775","DOI":"10.1136\/jmg.38.11.769"},{"key":"2021120822500411400_R16","doi-asserted-by":"crossref","unstructured":"Moore DF, Altarescu G, Ling GS, et al. Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke.\u20082002;33:525\u2013531","DOI":"10.1161\/hs0202.102601"},{"key":"2021120822500411400_R17","doi-asserted-by":"crossref","unstructured":"Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurol.\u20082002;2:4","DOI":"10.1186\/1471-2377-2-4"},{"key":"2021120822500411400_R18","doi-asserted-by":"crossref","unstructured":"Ries M, Gupta S, Moore DF, et al. Pediatric Fabry disease. Pediatrics.\u20082005;115(3). Available at: www.pediatrics.org\/cgi\/content\/full\/115\/3\/e344","DOI":"10.1542\/peds.2004-1678"},{"key":"2021120822500411400_R19","doi-asserted-by":"crossref","unstructured":"Beck M, Whybra C, Wendrich K, Gal A, Ries M. Anderson-Fabry disease in children and adolescents. Contrib Nephrol.\u20082001;251\u2013255","DOI":"10.1159\/000060197"},{"key":"2021120822500411400_R20","doi-asserted-by":"crossref","unstructured":"Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr.\u20082004;144:S20\u2013S26","DOI":"10.1016\/j.jpeds.2004.01.051"},{"key":"2021120822500411400_R21","doi-asserted-by":"crossref","unstructured":"Ries M, Moore DF, Robinson CJ, et al. Quantitative dysmorphology assessment in Fabry disease. Genet Med.\u20082006; 8: 96\u2013101","DOI":"10.1097\/01.gim.0000200950.25118.dd"},{"key":"2021120822500411400_R22","doi-asserted-by":"crossref","unstructured":"Obrador GT, Ojo A, Thadhani R. End-stage renal disease in patients with Fabry disease. J Am Soc Nephrol.\u20082002; 13: S144\u2013S116","DOI":"10.1097\/01.ASN.0000015237.87719.DC"},{"key":"2021120822500411400_R23","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA.\u20082001; 285: 2743\u20132749","DOI":"10.1001\/jama.285.21.2743"},{"key":"2021120822500411400_R24","doi-asserted-by":"crossref","unstructured":"Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry's disease. N Engl J Med.\u20082001; 345:9\u201316","DOI":"10.1056\/NEJM200107053450102"},{"key":"2021120822500411400_R25","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve.\u20082003;28:703\u2013710","DOI":"10.1002\/mus.10497"},{"key":"2021120822500411400_R26","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant.\u20082006;21: 345\u2013354","DOI":"10.1093\/ndt\/gfi152"},{"key":"2021120822500411400_R27","doi-asserted-by":"crossref","unstructured":"Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation.\u20082003;108: 1299\u20131301","DOI":"10.1161\/01.CIR.0000091253.71282.04"},{"key":"2021120822500411400_R28","doi-asserted-by":"crossref","unstructured":"Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study. J Inherit Metab Dis.\u20082003;26: 617\u2013627","DOI":"10.1023\/B:BOLI.0000005658.14563.77"},{"key":"2021120822500411400_R29","doi-asserted-by":"crossref","unstructured":"Beck M, Ricci R, Widmer U, et al. Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest.\u20082004;34: 838\u2013844","DOI":"10.1111\/j.1365-2362.2004.01424.x"},{"key":"2021120822500411400_R30","doi-asserted-by":"crossref","unstructured":"Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet.\u20082004; 75:65\u201374","DOI":"10.1086\/422366"},{"key":"2021120822500411400_R31","doi-asserted-by":"crossref","unstructured":"Jardim L, Vedolin L, Schwartz IV, et al. CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme replacement therapy. J Inherit Metab Dis.\u20082004;27: 229\u2013240","DOI":"10.1023\/B:BOLI.0000028794.04349.91"},{"key":"2021120822500411400_R32","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Ries M. Fabry Disease: an important risk factor for stroke. Lancet.\u20082005; 366: 1754\u20131756","DOI":"10.1016\/S0140-6736(05)67636-2"},{"key":"2021120822500411400_R33","doi-asserted-by":"crossref","unstructured":"Breunig F, Weidemann F, Strotmann J, Knoll A, Wanner C. Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int.\u20082006; 69: 1216\u20131221","DOI":"10.1038\/sj.ki.5000208"},{"key":"2021120822500411400_R34","doi-asserted-by":"crossref","unstructured":"Hoffmann B, Garcia de Lorenzo A, Mehta A, Beck M, Widmer U, Ricci R. Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet.\u20082005;42:247\u2013252","DOI":"10.1136\/jmg.2004.025791"},{"key":"2021120822500411400_R35","doi-asserted-by":"crossref","unstructured":"Guffon N, Fouilhoux A. Clinical benefit in Fabry patients given enzyme replacement therapy-A case series. J Inherit Metab Dis.\u20082004;27:221\u2013227","DOI":"10.1023\/B:BOLI.0000028726.11177.8b"},{"key":"2021120822500411400_R36","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Murray GJ, Treco D, et al. Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci USA.\u20082000;97:365\u2013370","DOI":"10.1073\/pnas.97.1.365"},{"key":"2021120822500411400_R37","doi-asserted-by":"crossref","unstructured":"Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM. Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child.\u20081976;51:875\u2013878","DOI":"10.1136\/adc.51.11.875"},{"key":"2021120822500411400_R38","unstructured":"Kidney Disease Outcome Quality Initiative. K\/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.\u20082002;39(2 suppl 2):S1\u2013S246"},{"key":"2021120822500411400_R39","doi-asserted-by":"crossref","unstructured":"Daniels SR. Hypertension-induced cardiac damage in children and adolescents. Blood Press Monit.\u20081999;4:165\u2013170","DOI":"10.1097\/00126097-199906000-00011"},{"key":"2021120822500411400_R40","doi-asserted-by":"crossref","unstructured":"de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol.\u20081995;25:1056\u20131062","DOI":"10.1016\/0735-1097(94)00540-7"},{"key":"2021120822500411400_R41","unstructured":"Morgan SH, Rudge P, Smith SJ, et al. The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency): investigation of symptomatic and presymptomatic patients. Q J Med.\u20081990;75:491\u2013507"},{"key":"2021120822500411400_R42","doi-asserted-by":"crossref","unstructured":"Schiffmann R, Scott LJ. Pathophysiology and assessment of neuropathic pain in Fabry disease. Acta Paediatr.\u20082002;91(suppl):48\u201352","DOI":"10.1111\/j.1651-2227.2002.tb03110.x"},{"key":"2021120822500411400_R43","doi-asserted-by":"crossref","unstructured":"Cable WJ, Kolodny EH, Adams RD. Fabry disease: impaired autonomic function. Neurology.\u20081982;32:498\u2013502","DOI":"10.1212\/WNL.32.5.498"},{"key":"2021120822500411400_R44","doi-asserted-by":"crossref","unstructured":"Massin M, von Bernuth G. Normal ranges of heart rate variability during infancy and childhood. Pediatr Cardiol.\u20081997;18:297\u2013302","DOI":"10.1007\/s002469900178"},{"key":"2021120822500411400_R45","unstructured":"Hilz MJ, Marthol H, Brys M, et al. Enzyme replacement therapy improves cardiovascular control in Fabry patients during orthostatic stress. Am J Hum Genet.\u20082002;71(suppl):581"},{"key":"2021120822500411400_R46","doi-asserted-by":"crossref","unstructured":"Massin MM, Derkenne B, Tallsund M, et al. Cardiac autonomic dysfunction in diabetic children. Diabetes Care.\u20081999;22:1845\u20131850","DOI":"10.2337\/diacare.22.11.1845"},{"key":"2021120822500411400_R47","doi-asserted-by":"crossref","unstructured":"Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care.\u20082003;26:1553\u20131579","DOI":"10.2337\/diacare.26.5.1553"},{"key":"2021120822500411400_R48","doi-asserted-by":"crossref","unstructured":"Altarescu G, Moore DF, Pursley R, et al. Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke.\u20082001;32:1559\u20131562","DOI":"10.1161\/01.STR.32.7.1559"},{"key":"2021120822500411400_R49","doi-asserted-by":"crossref","unstructured":"Linhart A, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease. J Inherit Metab Dis.\u20082001;24(suppl 2):75\u201383","DOI":"10.1023\/A:1012428009627"},{"key":"2021120822500411400_R50","doi-asserted-by":"crossref","unstructured":"Kampmann C, Baehner F, Whybra C, et al. Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol.\u20082002;40:166816\u2013166874","DOI":"10.1016\/S0735-1097(02)02380-X"},{"key":"2021120822500411400_R51","doi-asserted-by":"crossref","unstructured":"Grubb A, Nyman U, Bjork J, et al. Simple cystatin C-based prediction equations for glomerular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the Schwartz and the Counahan-Barratt prediction equations for children. Clin Chem.\u20082005;51:142014\u201331","DOI":"10.1373\/clinchem.2005.051557"},{"key":"2021120822500411400_R52","doi-asserted-by":"crossref","unstructured":"Altarescu G, Moore DF, Schiffmann R. Effect of genetic modifiers on cerebral lesions in Fabry disease. Neurology.\u20082005;64:2148\u20132150","DOI":"10.1212\/01.WNL.0000166000.24321.4F"},{"key":"2021120822500411400_R53","doi-asserted-by":"crossref","unstructured":"Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int.\u20082004;66:1589\u20131595","DOI":"10.1111\/j.1523-1755.2004.00924.x"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/118\/3\/924\/1072989\/zpe00906000924.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/118\/3\/924\/1072989\/zpe00906000924.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T02:42:30Z","timestamp":1639017750000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/118\/3\/924\/69218\/Enzyme-Replacement-Therapy-With-Agalsidase-Alfa-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,9,1]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2006,9,1]]},"published-print":{"date-parts":[[2006,9,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2005-2895","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,9,1]]}}}