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Erschienen in: European Journal of Clinical Microbiology & Infectious Diseases 11/2011

01.11.2011 | Article

DNA microarray-based characterisation of Panton–Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus from Italy

verfasst von: A. Sanchini, F. Campanile, M. Monaco, V. Cafiso, J.-P. Rasigade, F. Laurent, J. Etienne, S. Stefani, A. Pantosti

Erschienen in: European Journal of Clinical Microbiology & Infectious Diseases | Ausgabe 11/2011

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Abstract

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates are widespread in many countries, with varying distribution and epidemiology. The aim of this study was to collect and characterise the CA-MRSA isolates circulating in Italy, since only some case reports have been published. Eighteen Panton–Valentine-positive CA-MRSA isolates were collected from different Italian hospitals during the period 2005–2009 from severe infections (skin and soft tissue infections, n = 10; necrotising pneumonia, n = 7; and sepsis, n = 1). Accessory gene regulator (agr) typing, staphylococcal cassette chromosome (SCC) mec typing, spa typing, multi-locus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and DNA microarray were applied to categorise isolates into clones and to compare the relevant genetic features of each clone. Six different clones were identified, the most common (7 out of 18 isolates, 38.8%) being agrI/ST8/SCCmecIV, corresponding to the USA300 clone. Six out of the seven USA300 isolates did not harbour the arginine catabolic mobile element (ACME). Four strains (22.2%) were agrIII/ST80/SCCmecIV, corresponding to the European clone. Two of the other clones, namely, agrIII/ST88/SCCmecV and agrIII/ST772/SCCmecV, corresponded to CA-MRSA clones rarely found in other countries and probably originating from Africa or the Indian subcontinent. The results of microarray hybridisations showed that the distribution of resistance genes and other virulence factors was specific to each clone. Some characteristics could be exploited as specific markers for a clone or a group of isolates, e.g. the mer operon, recovered only in ACME-negative USA300 strains. DNA microarray contributed to a more complete description of the variety of different CA-MRSA clones circulating in Italy.
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Literatur
5.
Zurück zum Zitat Shore AC, Rossney AS, Kinnevey PM, Brennan OM, Creamer E, Sherlock O, Dolan A, Cunney R, Sullivan DJ, Goering RV, Humphreys H, Coleman DC (2010) Enhanced discrimination of highly clonal ST22-methicillin-resistant Staphylococcus aureus IV isolates achieved by combining spa, dru, and pulsed-field gel electrophoresis typing data. J Clin Microbiol 48:1839–1852. doi:10.1128/JCM.02155-09 PubMedCrossRef Shore AC, Rossney AS, Kinnevey PM, Brennan OM, Creamer E, Sherlock O, Dolan A, Cunney R, Sullivan DJ, Goering RV, Humphreys H, Coleman DC (2010) Enhanced discrimination of highly clonal ST22-methicillin-resistant Staphylococcus aureus IV isolates achieved by combining spa, dru, and pulsed-field gel electrophoresis typing data. J Clin Microbiol 48:1839–1852. doi:10.​1128/​JCM.​02155-09 PubMedCrossRef
6.
Zurück zum Zitat Dauwalder O, Lina G, Durand G, Bes M, Meugnier H, Jarlier V, Coignard B, Vandenesch F, Etienne J, Laurent F (2008) Epidemiology of invasive methicillin-resistant Staphylococcus aureus clones collected in France in 2006 and 2007. J Clin Microbiol 46:3454–3458. doi:10.1128/JCM.01050-08 PubMedCrossRef Dauwalder O, Lina G, Durand G, Bes M, Meugnier H, Jarlier V, Coignard B, Vandenesch F, Etienne J, Laurent F (2008) Epidemiology of invasive methicillin-resistant Staphylococcus aureus clones collected in France in 2006 and 2007. J Clin Microbiol 46:3454–3458. doi:10.​1128/​JCM.​01050-08 PubMedCrossRef
7.
Zurück zum Zitat McDougal LK, Fosheim GE, Nicholson A, Bulens SN, Limbago BM, Shearer JE, Summers AO, Patel J (2010) Emergence of resistance among USA300 methicillin-resistant Staphylococcus aureus isolates causing invasive disease in the United States. Antimicrob Agents Chemother 54:3804–3811. doi:10.1128/AAC.00351-10 PubMedCrossRef McDougal LK, Fosheim GE, Nicholson A, Bulens SN, Limbago BM, Shearer JE, Summers AO, Patel J (2010) Emergence of resistance among USA300 methicillin-resistant Staphylococcus aureus isolates causing invasive disease in the United States. Antimicrob Agents Chemother 54:3804–3811. doi:10.​1128/​AAC.​00351-10 PubMedCrossRef
9.
Zurück zum Zitat Diep BA, Stone GG, Basuino L, Graber CJ, Miller A, des Etages SA, Jones A, Palazzolo-Ballance AM, Perdreau-Remington F, Sensabaugh GF, DeLeo FR, Chambers HF (2008) The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus. J Infect Dis 197:1523–1530. doi:10.1086/587907 PubMedCrossRef Diep BA, Stone GG, Basuino L, Graber CJ, Miller A, des Etages SA, Jones A, Palazzolo-Ballance AM, Perdreau-Remington F, Sensabaugh GF, DeLeo FR, Chambers HF (2008) The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus. J Infect Dis 197:1523–1530. doi:10.​1086/​587907 PubMedCrossRef
11.
Zurück zum Zitat Monaco M, Antonucci R, Palange P, Venditti M, Pantosti A (2005) Methicillin-resistant Staphylococcus aureus necrotizing pneumonia. Emerg Infect Dis 11:1647–1648PubMed Monaco M, Antonucci R, Palange P, Venditti M, Pantosti A (2005) Methicillin-resistant Staphylococcus aureus necrotizing pneumonia. Emerg Infect Dis 11:1647–1648PubMed
12.
Zurück zum Zitat Valentini P, Parisi G, Monaco M, Crea F, Spanu T, Ranno O, Tronci M, Pantosti A (2008) An uncommon presentation for a severe invasive infection due to methicillin-resistant Staphylococcus aureus clone USA300 in Italy: a case report. Ann Clin Microbiol Antimicrob 7:11. doi:10.1186/1476-0711-7-11 PubMedCrossRef Valentini P, Parisi G, Monaco M, Crea F, Spanu T, Ranno O, Tronci M, Pantosti A (2008) An uncommon presentation for a severe invasive infection due to methicillin-resistant Staphylococcus aureus clone USA300 in Italy: a case report. Ann Clin Microbiol Antimicrob 7:11. doi:10.​1186/​1476-0711-7-11 PubMedCrossRef
13.
Zurück zum Zitat Tinelli M, Pantosti A, Lusardi C, Vimercati M, Monaco M (2007) First detected case of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infection in Italy. Euro Surveill 12:E070412.1PubMed Tinelli M, Pantosti A, Lusardi C, Vimercati M, Monaco M (2007) First detected case of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infection in Italy. Euro Surveill 12:E070412.1PubMed
14.
Zurück zum Zitat Marchese A, Gualco L, Maioli E, Debbia E (2009) Molecular analysis and susceptibility patterns of meticillin-resistant Staphylococcus aureus (MRSA) strains circulating in the community in the Ligurian area, a northern region of Italy: emergence of USA300 and EMRSA-15 clones. Int J Antimicrob Agents 34:424–428. doi:10.1016/j.ijantimicag.2009.06.016 PubMedCrossRef Marchese A, Gualco L, Maioli E, Debbia E (2009) Molecular analysis and susceptibility patterns of meticillin-resistant Staphylococcus aureus (MRSA) strains circulating in the community in the Ligurian area, a northern region of Italy: emergence of USA300 and EMRSA-15 clones. Int J Antimicrob Agents 34:424–428. doi:10.​1016/​j.​ijantimicag.​2009.​06.​016 PubMedCrossRef
15.
Zurück zum Zitat Stefani S, Bongiorno D, Cafiso V, Campanile F, Crapis M, Cristini F, Sartor A, Scarparo C, Spina D, Viale P (2009) Pathotype and susceptibility profile of a community-acquired methicillin-resistant Staphylococcus aureus strain responsible for a case of severe pneumonia. Diagn Microbiol Infect Dis 63:100–104. doi:10.1016/j.diagmicrobio.2008.09.012 PubMedCrossRef Stefani S, Bongiorno D, Cafiso V, Campanile F, Crapis M, Cristini F, Sartor A, Scarparo C, Spina D, Viale P (2009) Pathotype and susceptibility profile of a community-acquired methicillin-resistant Staphylococcus aureus strain responsible for a case of severe pneumonia. Diagn Microbiol Infect Dis 63:100–104. doi:10.​1016/​j.​diagmicrobio.​2008.​09.​012 PubMedCrossRef
17.
Zurück zum Zitat Clinical and Laboratory Standards Institute (CLSI) (2008) Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement. M100-S18. Vol. 28; No. 1. CLSI, Wayne, PA Clinical and Laboratory Standards Institute (CLSI) (2008) Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement. M100-S18. Vol. 28; No. 1. CLSI, Wayne, PA
19.
Zurück zum Zitat Monaco M, Sanchini A, Grundmann H, Pantosti A, EARSS-Italy S. aureus typing Group (2010) Vancomycin-heteroresistant phenotype in invasive methicillin-resistant Staphylococcus aureus isolates belonging to spa type 041. Eur J Clin Microbiol Infect Dis 29:771–777. doi:10.1007/s10096-010-0922-2 PubMedCrossRef Monaco M, Sanchini A, Grundmann H, Pantosti A, EARSS-Italy S. aureus typing Group (2010) Vancomycin-heteroresistant phenotype in invasive methicillin-resistant Staphylococcus aureus isolates belonging to spa type 041. Eur J Clin Microbiol Infect Dis 29:771–777. doi:10.​1007/​s10096-010-0922-2 PubMedCrossRef
20.
Zurück zum Zitat Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, Davidson MG, Lin F, Lin J, Carleton HA, Mongodin EF, Sensabaugh GF, Perdreau-Remington F (2006) Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367:731–739. doi:10.1016/S0140-6736(06)68231-7 PubMedCrossRef Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, Davidson MG, Lin F, Lin J, Carleton HA, Mongodin EF, Sensabaugh GF, Perdreau-Remington F (2006) Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367:731–739. doi:10.​1016/​S0140-6736(06)68231-7 PubMedCrossRef
21.
Zurück zum Zitat McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC (2003) Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 41:5113–5120PubMedCrossRef McDougal LK, Steward CD, Killgore GE, Chaitram JM, McAllister SK, Tenover FC (2003) Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 41:5113–5120PubMedCrossRef
22.
Zurück zum Zitat van Belkum A, Tassios PT, Dijkshoorn L, Haeggman S, Cookson B, Fry NK, Fussing V, Green J, Feil E, Gerner-Smidt P, Brisse S, Struelens M, European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Epidemiological Markers (ESGEM) (2007) Guidelines for the validation and application of typing methods for use in bacterial epidemiology. Clin Microbiol Infect 13(Suppl 3):S1–S46. doi:10.1111/j.1469-0691.2007.01786.x CrossRef van Belkum A, Tassios PT, Dijkshoorn L, Haeggman S, Cookson B, Fry NK, Fussing V, Green J, Feil E, Gerner-Smidt P, Brisse S, Struelens M, European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Epidemiological Markers (ESGEM) (2007) Guidelines for the validation and application of typing methods for use in bacterial epidemiology. Clin Microbiol Infect 13(Suppl 3):S1–S46. doi:10.​1111/​j.​1469-0691.​2007.​01786.​x CrossRef
24.
Zurück zum Zitat Monecke S, Berger-Bächi B, Coombs G, Holmes A, Kay I, Kearns A, Linde HJ, O’Brien F, Slickers P, Ehricht R (2007) Comparative genomics and DNA array-based genotyping of pandemic Staphylococcus aureus strains encoding Panton–Valentine leukocidin. Clin Microbiol Infect 13:236–249. doi:10.1111/j.1469-0691.2006.01635.x PubMedCrossRef Monecke S, Berger-Bächi B, Coombs G, Holmes A, Kay I, Kearns A, Linde HJ, O’Brien F, Slickers P, Ehricht R (2007) Comparative genomics and DNA array-based genotyping of pandemic Staphylococcus aureus strains encoding Panton–Valentine leukocidin. Clin Microbiol Infect 13:236–249. doi:10.​1111/​j.​1469-0691.​2006.​01635.​x PubMedCrossRef
25.
Zurück zum Zitat Montgomery CP, Boyle-Vavra S, Daum RS (2009) The arginine catabolic mobile element is not associated with enhanced virulence in experimental invasive disease caused by the community-associated methicillin-resistant Staphylococcus aureus USA300 genetic background. Infect Immun 77:2650–2656. doi:10.1128/IAI.00256-09 PubMedCrossRef Montgomery CP, Boyle-Vavra S, Daum RS (2009) The arginine catabolic mobile element is not associated with enhanced virulence in experimental invasive disease caused by the community-associated methicillin-resistant Staphylococcus aureus USA300 genetic background. Infect Immun 77:2650–2656. doi:10.​1128/​IAI.​00256-09 PubMedCrossRef
26.
Zurück zum Zitat Larsen AR, Goering R, Stegger M, Lindsay JA, Gould KA, Hinds J, Sørum M, Westh H, Boye K, Skov R (2009) Two distinct clones of methicillin-resistant Staphylococcus aureus (MRSA) with the same USA300 pulsed-field gel electrophoresis profile: a potential pitfall for identification of USA300 community-associated MRSA. J Clin Microbiol 47:3765–3768. doi:10.1128/JCM.00934-09 PubMedCrossRef Larsen AR, Goering R, Stegger M, Lindsay JA, Gould KA, Hinds J, Sørum M, Westh H, Boye K, Skov R (2009) Two distinct clones of methicillin-resistant Staphylococcus aureus (MRSA) with the same USA300 pulsed-field gel electrophoresis profile: a potential pitfall for identification of USA300 community-associated MRSA. J Clin Microbiol 47:3765–3768. doi:10.​1128/​JCM.​00934-09 PubMedCrossRef
27.
Zurück zum Zitat Ito T, Katayama Y, Asada K, Mori N, Tsutsumimoto K, Tiensasitorn C, Hiramatsu K (2001) Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 45:1323–1336. doi:10.1128/AAC.45.5.1323-1336.2001 PubMedCrossRef Ito T, Katayama Y, Asada K, Mori N, Tsutsumimoto K, Tiensasitorn C, Hiramatsu K (2001) Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 45:1323–1336. doi:10.​1128/​AAC.​45.​5.​1323-1336.​2001 PubMedCrossRef
28.
Zurück zum Zitat Monecke S, Ehricht R, Slickers P, Tan HL, Coombs G (2009) The molecular epidemiology and evolution of the Panton–Valentine leukocidin-positive, methicillin-resistant Staphylococcus aureus strain USA300 in Western Australia. Clin Microbiol Infect 15:770–776. doi:10.1111/j.1469-0691.2009.02792.x PubMedCrossRef Monecke S, Ehricht R, Slickers P, Tan HL, Coombs G (2009) The molecular epidemiology and evolution of the Panton–Valentine leukocidin-positive, methicillin-resistant Staphylococcus aureus strain USA300 in Western Australia. Clin Microbiol Infect 15:770–776. doi:10.​1111/​j.​1469-0691.​2009.​02792.​x PubMedCrossRef
29.
Zurück zum Zitat Blanco R, Tristan A, Ezpeleta G, Larsen AR, Bes M, Etienne J, Cisterna R, Laurent F (2011) Molecular epidemiology of Panton–Valentine leukocidin-positive Staphylococcus aureus in Spain: emergence of the USA300 clone in an autochthonous population. J Clin Microbiol 49:433–436. doi:10.1128/JCM.02201-10 PubMedCrossRef Blanco R, Tristan A, Ezpeleta G, Larsen AR, Bes M, Etienne J, Cisterna R, Laurent F (2011) Molecular epidemiology of Panton–Valentine leukocidin-positive Staphylococcus aureus in Spain: emergence of the USA300 clone in an autochthonous population. J Clin Microbiol 49:433–436. doi:10.​1128/​JCM.​02201-10 PubMedCrossRef
30.
Zurück zum Zitat Wilson GG (1991) Organization of restriction-modification systems. Nucleic Acids Res 19:2539–2566PubMedCrossRef Wilson GG (1991) Organization of restriction-modification systems. Nucleic Acids Res 19:2539–2566PubMedCrossRef
31.
Zurück zum Zitat Breurec S, Zriouil SB, Fall C, Boisier P, Brisse S, Djibo S, Etienne J, Fonkoua MC, Perrier-Gros-Claude JD, Pouillot R, Ramarokoto CE, Randrianirina F, Tall A, Thiberge JM; Working Group on Staphylococcus aureus infections, Laurent F, Garin B (2011) Epidemiology of methicillin-resistant Staphylococcus aureus lineages in five major African towns: emergence and spread of atypical clones. Clin Microbiol Infect 17:160–165. doi:10.1111/j.1469-0691.2010.03219.x Breurec S, Zriouil SB, Fall C, Boisier P, Brisse S, Djibo S, Etienne J, Fonkoua MC, Perrier-Gros-Claude JD, Pouillot R, Ramarokoto CE, Randrianirina F, Tall A, Thiberge JM; Working Group on Staphylococcus aureus infections, Laurent F, Garin B (2011) Epidemiology of methicillin-resistant Staphylococcus aureus lineages in five major African towns: emergence and spread of atypical clones. Clin Microbiol Infect 17:160–165. doi:10.​1111/​j.​1469-0691.​2010.​03219.​x
32.
Zurück zum Zitat Yao D, Yu FY, Qin ZQ, Chen C, He SS, Chen ZQ, Zhang XQ, Wang LX (2010) Molecular characterization of Staphylococcus aureus isolates causing skin and soft tissue infections (SSTIs). BMC Infect Dis 10:133. doi:10.1186/1471-2334-10-133 PubMedCrossRef Yao D, Yu FY, Qin ZQ, Chen C, He SS, Chen ZQ, Zhang XQ, Wang LX (2010) Molecular characterization of Staphylococcus aureus isolates causing skin and soft tissue infections (SSTIs). BMC Infect Dis 10:133. doi:10.​1186/​1471-2334-10-133 PubMedCrossRef
33.
Zurück zum Zitat de Bentzmann S, Tristan A, Etienne J, Brousse N, Vandenesch F, Lina G (2004) Staphylococcus aureus isolates associated with necrotizing pneumonia bind to basement membrane type I and IV collagens and laminin. J Infect Dis 190:1506–1515. doi:10.1086/424521 PubMedCrossRef de Bentzmann S, Tristan A, Etienne J, Brousse N, Vandenesch F, Lina G (2004) Staphylococcus aureus isolates associated with necrotizing pneumonia bind to basement membrane type I and IV collagens and laminin. J Infect Dis 190:1506–1515. doi:10.​1086/​424521 PubMedCrossRef
34.
Zurück zum Zitat D’Souza N, Rodrigues C, Mehta A (2010) Molecular characterization of methicillin-resistant Staphylococcus aureus with emergence of epidemic clones of sequence type (ST) 22 and ST 772 in Mumbai, India. J Clin Microbiol 48:1806–1811. doi:10.1128/JCM.01867-09 PubMedCrossRef D’Souza N, Rodrigues C, Mehta A (2010) Molecular characterization of methicillin-resistant Staphylococcus aureus with emergence of epidemic clones of sequence type (ST) 22 and ST 772 in Mumbai, India. J Clin Microbiol 48:1806–1811. doi:10.​1128/​JCM.​01867-09 PubMedCrossRef
35.
Zurück zum Zitat Ellington MJ, Ganner M, Warner M, Cookson BD, Kearns AM (2010) Polyclonal multiply antibiotic-resistant methicillin-resistant Staphylococcus aureus with Panton–Valentine leucocidin in England. J Antimicrob Chemother 65:46–50. doi:10.1093/jac/dkp386 PubMedCrossRef Ellington MJ, Ganner M, Warner M, Cookson BD, Kearns AM (2010) Polyclonal multiply antibiotic-resistant methicillin-resistant Staphylococcus aureus with Panton–Valentine leucocidin in England. J Antimicrob Chemother 65:46–50. doi:10.​1093/​jac/​dkp386 PubMedCrossRef
36.
Zurück zum Zitat Reyes J, Rincón S, Díaz L, Panesso D, Contreras GA, Zurita J, Carrillo C, Rizzi A, Guzmán M, Adachi J, Chowdhury S, Murray BE, Arias CA (2009) Dissemination of methicillin-resistant Staphylococcus aureus USA300 sequence type 8 lineage in Latin America. Clin Infect Dis 49:1861–1867. doi:10.1086/648426 PubMedCrossRef Reyes J, Rincón S, Díaz L, Panesso D, Contreras GA, Zurita J, Carrillo C, Rizzi A, Guzmán M, Adachi J, Chowdhury S, Murray BE, Arias CA (2009) Dissemination of methicillin-resistant Staphylococcus aureus USA300 sequence type 8 lineage in Latin America. Clin Infect Dis 49:1861–1867. doi:10.​1086/​648426 PubMedCrossRef
37.
Zurück zum Zitat Baldan R, Tassan Din C, Semeraro G, Costa C, Cichero P, Scarpellini P, Moro M, Cirillo DM (2009) Severe community-onset infections in healthy individuals caused by community-acquired MRSA in an Italian teaching hospital, 2006–2008. J Hosp Infect 72:271–273. doi:10.1016/j.jhin.2009.04.007 PubMedCrossRef Baldan R, Tassan Din C, Semeraro G, Costa C, Cichero P, Scarpellini P, Moro M, Cirillo DM (2009) Severe community-onset infections in healthy individuals caused by community-acquired MRSA in an Italian teaching hospital, 2006–2008. J Hosp Infect 72:271–273. doi:10.​1016/​j.​jhin.​2009.​04.​007 PubMedCrossRef
Metadaten
Titel
DNA microarray-based characterisation of Panton–Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus from Italy
verfasst von
A. Sanchini
F. Campanile
M. Monaco
V. Cafiso
J.-P. Rasigade
F. Laurent
J. Etienne
S. Stefani
A. Pantosti
Publikationsdatum
01.11.2011
Verlag
Springer-Verlag
Erschienen in
European Journal of Clinical Microbiology & Infectious Diseases / Ausgabe 11/2011
Print ISSN: 0934-9723
Elektronische ISSN: 1435-4373
DOI
https://doi.org/10.1007/s10096-011-1234-x

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